[Federal Register: October 26, 1999 (Volume 64, Number 206)]
[Rules and Regulations]
[Page 57699-57733]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26oc99-21]

[[Page 57699]]

_______________________________________________________________________

Part II

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

_______________________________________________________________________

21 CFR Part 101

Food Labeling: Health Claims; Soy Protein and Coronary Heart Disease;
Final Rule

[[Page 57700]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 98P-0683]

Food Labeling: Health Claims; Soy Protein and Coronary Heart
Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is authorizing the use,
on food labels and in food labeling, of health claims on the
association between soy protein and reduced risk of coronary heart
disease (CHD). Based on its review of evidence submitted with comments
to the proposed rule, as well as evidence described in the proposed
rule, the agency has concluded that soy protein included in a diet low
in saturated fat and cholesterol may reduce the risk of CHD by lowering
blood cholesterol levels.

DATES: This regulation is effective October 26, 1999, except for
Sec. 101.82(c)(2)(ii)(B), which contains information collection
requirements that have not been approved by the Office of Management
and Budget (OMB). Upon approval, the FDA will publish a document in the
Federal Register announcing the effective date of those requirements.

FOR FURTHER INFORMATION CONTACT: Susan M. Pilch, Center for Food Safety
and Applied Nutrition (HFS-465), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-205-4500.

SUPPLEMENTARY INFORMATION:

I. Background Information

    On November 8, 1990, the President signed into law the Nutrition
Labeling and Education Act of 1990 (the 1990 amendments) (Public Law
101-535). This new law amended the Federal Food, Drug, and Cosmetic Act
(the act) in a number of important ways. One notable aspect of the 1990
amendments was that they provided procedures whereby FDA is to regulate
health claims on food labels and in food labeling.
    In the Federal Register of January 6, 1993 (58 FR 2478), FDA issued
a final rule that implemented the health claim provisions of the act
(hereinafter referred to as the 1993 health claims final rule). In that
final rule, FDA adopted Sec. 101.14 (21 CFR 101.14), which sets out
rules for the authorization and use of health claims by regulation.
Additionally, Sec. 101.70 (21 CFR 101.70) establishes a process for
petitioning the agency to authorize by regulation the use of health
claims about a substance-disease relationship (Sec. 101.70(a)) and sets
out the types of information that any such petition must include
(Sec. 101.70(f)).
    In response to the 1990 amendments, FDA also conducted an extensive
review of the evidence on 10 substance-disease relationships. As a
result of its review, FDA has authorized claims for 8 of these 10
relationships, one of which focused on the relationship between dietary
saturated fat and cholesterol and reduced risk of CHD. CHD is the most
common, most frequently reported, and most serious form of
cardiovascular disease (CVD) (58 FR 2739, January 6, 1993). Further,
although the agency denied the use on food labeling of health claims
relating dietary fiber to reduced risk of CVD (58 FR 2552), it
authorized a health claim relating diets low in saturated fat and
cholesterol and high in fruits, vegetables, and grain products that
contain dietary fiber (particularly soluble fiber) to a reduced risk of
CHD.
    In the proposed rule entitled ``Health Claims and Label Statements;
Lipids and Cardiovascular Disease'' (56 FR 60727, November 27, 1991)
(hereinafter referred to as the saturated fat/cholesterol proposed
rule), FDA set out criteria for evaluating evidence on diet and CVD
relationships. The agency focused on those aspects of the dietary lipid
and CVD relationship for which the strongest scientific evidence
andagreement existed. FDA noted that, because of the public health
importance of CHD, identification of ``modifiable'' risk factors for
CHD had been the subject of considerable research and public policy
attention. The agency also noted that there is general agreement that
elevated blood cholesterol levels are one of the major ``modifiable''
risk factors in the development of CHD. FDA cited Federal Government
and other reviews that concluded that there is substantial
epidemiologic and clinical evidence that high blood levels of total and
low density lipoprotein (LDL)-cholesterol are a cause of
atherosclerosis and represent major contributors to CHD. Further,
factors that decrease total blood cholesterol and LDL-cholesterol will
also decrease the risk of CHD. FDA concluded that it is generally
accepted that blood total and LDL-cholesterol levels are major risk
factors for CHD, and that dietary factors affecting blood cholesterol
levels affect the risk of CHD. High intakes of dietary saturated fat
and, to a lesser degree, of dietary cholesterol are consistently
associated with elevated blood cholesterol levels. FDA tentatively
concluded that the publicly available data supported an association
between diets low in saturated fat and cholesterol and reduced risk of
CHD (56 FR 60727 at 60737), and it confirmed that conclusion in the
saturated fat/cholesterol final rule (58 FR 2739 at 2751).
    Based on its review using the stated criteria, and on its
consideration of comments received in response to the proposed rule
entitled ``Health Claims; Dietary Fiber and Cardiovascular Disease''
(56 FR 60582), FDA concluded that the publicly available scientific
information supported an association between diets low in saturated fat
and cholesterol and high in fruits, vegetables, and grain products
(i.e., foods that are low in saturated fat and cholesterol and that are
good sources of dietary fiber) and reduced risk of heart disease (58 FR
2552 at 2572). In the 1993 dietary fiber and CVD final rule, in
response to a comment regarding the apparent hypocholesterolemic
properties of specific food fibers, FDA again articulated its criteria
for evaluating diet and CHD relationships (58 FR 2552 at 2567). FDA
agreed that the effectiveness of naturally occurring fibers in foods in
reducing the risk of CHD may be documented for specific food products.
Further, the agency indicated that if manufacturers could document,
through appropriate studies, that dietary consumption of the soluble
fiber in a particular food has a beneficial effect on blood lipids
predictive of CHD risk, they should petition for a health claim for
that particular product. In response to two petitions that documented
such evidence, FDA has authorized health claims for soluble fiber from
certain foods and reduced risk of CHD in Sec. 101.81 (21 CFR 101.81)
(62 FR 3600, January 23, 1997, and amended at 62 FR 15344, March 31,
1997, and 62 FR 8119, February 18, 1998).
    In the Federal Register of November 10, 1998 (63 FR 62977), and in
response to a petition from Protein Technologies International, Inc.
(Ref. 1 and Ref. 2), the agency proposed Sec. 101.82 to provide for
health claims on the relationship of soy protein and reduced risk of
CHD (hereinafter referred to as the soy protein proposed rule). In the
soy protein proposed rule, FDA considered the relevant scientific
studies and data presented in the petition as part of its review of the
scientific literature on soy protein and CHD. The agency summarized
this evidence in the soy protein proposed rule and presented the
rationale for a health claim on this food-disease relationship as
provided for under the significant scientific

[[Page 57701]]

agreement standard in section 403(r)(3)(B)(i) of the act and
Sec. 101.14(c) of FDA's regulations.
    Proposed Sec. 101.82(c)(2)(ii)(A) identified the substance that is
the subject of the proposed claim as soy protein from the legume seed
Glycine max. The soy protein proposed rule included qualifying criteria
for the purpose of identifying soy protein-containing foods eligible to
bear the proposed health claim. The proposal also specified mandatory
content for health claim statements; identified additional, optional
information for such statements; and provided model health claims.
    In its evaluation of the scientific evidence for a relationship
between consumption of soy protein and blood total and LDL-cholesterol
levels, the agency found the data suggestive but not sufficient to
establish a dose-response for this relationship. However, the agency
did find consistent, clinically significant reductions of total and
LDL-cholesterol levels in controlled trials that used at least 25 grams
(g) of soy protein per day. Thus, the agency proposed to base the
qualifying level of soy protein on a total daily intake of 25 g, as
suggested by the petitioner. Therefore, in Sec. 101.82(c)(2)(iii)(A),
FDA proposed the qualifying criterion for a food to bear the claim as
6.25 g of soy protein per reference amount customarily consumed (RACC)
(i.e., 25 g divided by 4 eating occasions per day).
    In the soy protein proposed rule, FDA had tentatively indicated its
intention to use a specific analytical method to measure soy protein
for assessing compliance with the qualifying criterion. Comments
persuaded the agency that the method would be inadequate for many
products. Therefore, in the Federal Register of August 23, 1999 (64 FR
45932), FDA issued a proposed rule to provide for an alternative
procedure for assessing compliance (hereinafter referred to as the soy
protein reproposal). In the soy protein reproposal, in
Sec. 101.82(c)(2)(ii)(B) FDA proposed that it would rely on measurement
of total protein and require manufacturers, when soy is not the sole
source of protein in foods, to maintain records that document the
amount of soy protein in products and to make these records available
to appropriate regulatory officials for inspection and copying upon
request.

II. Summary of Comments and the Agency's Responses

    In response to the soy protein proposed rule, the agency received
approximately 130 submissions, each containing one or more comments,
from consumers, consumer organizations, professional organizations,
government agencies, industry, trade associations, health care
professionals, and research scientists.
    About half of these submissions supported the proposed rule without
providing grounds for this support other than those provided by FDA in
the preamble to the soy protein proposed rule. The majority of the
remaining comments were generally supportive, but requested
modification of one or more provisions of the proposed rule. Some
comments provided additional data on the relationship between soy
protein and CHD, including one submission, originally submitted as a
health claim petition and converted to a comment on the soy protein
proposed rule (Ref. 3), that included a comprehensive review of
available scientific evidence about the relationship. Some of the
comments that disagreed with the soy protein proposed rule provided
specific support for their positions. Some of the comments were
received after the date for submitting comments had passed. Although
the agency is not obligated to respond to late comments, in the
interest of assessing the totality of the available data, it has
considered each of these comments to the extent that it provided
complete information for review or references accessible to the agency
and addressed issues not raised in earlier comments. The agency has
summarized and addressed the relevant issues raised in the comments in
the sections of this document that follow.
    In response to the soy protein reproposal, the Agency received
approximately 10 submissions, each containing one or more comments. The
agency has summarized and addressed these comments in section II.C.2 of
this document.

A. Eligibility of Soy Protein as the Subject of a Health Claim

    In the soy protein proposed rule, the agency assessed whether soy
protein satisfied the preliminary requirement that a substance that is
the subject of a health claim is associated with a disease for which
the U.S. population is at risk (63 FR 62977 at 62978). Based on
analyses presented in earlier rulemakings and its review of data on the
mortality, morbidity, and costs of CHD and prevalence of ``high risk''
and ``borderline high'' total and LDL-cholesterol levels in the United
States (Refs. 4 through 8), the agency tentatively concluded that, as
required in Sec. 101.14(b)(1), CHD is a disease for which the U.S.
population is at risk. One comment reviewed additional sources of
information and reached the same conclusion.
    In the soy protein proposed rule, FDA also tentatively concluded
that soy protein from Glycine max satisfied the preliminary requirement
of Sec. 101.14(b)(3)(i) that the substance be a food that contributes
taste, aroma, or nutritive value (63 FR 62977 at 62978). Sources of soy
protein identified in the soy protein proposed rule included foods
composed of or derived from whole soybeans and foods that contain
processed soy protein ingredients: Isolated soy protein (ISP), soy
protein concentrate (SPC), soy flour (SF), texturized soy protein, or
texturized vegetable protein (TVP). In addition to protein, these foods
and ingredients contain other naturally occurring soy constituents,
such as isoflavones, fiber, and saponins. The specific processing steps
employed determine the extent of retention of such naturally occurring
constituents in the final product.
    In assessing whether the petitioner had demonstrated that soy
protein is safe and lawful at the level necessary to justify the claim,
FDA noted that the petitioner stated that soy protein ingredients were
in common use in food before January 1, 1958, and that they are
generally recognized as safe (GRAS) by self-determination (63 FR 62977
at 62978). Because the fractionation procedures used to convert
vegetable flours to vegetable protein isolates and concentrates were
commonplace prior to 1958, the petitioner also asserted that ISP and
SPC can be defined as soy flour ``subject only to conventional
processing as practiced prior to January 1, 1958.'' In addition, FDA
reviewed information submitted by the petitioner about potential risks
of consuming soy products: allergenicity (Refs. 9 and 10), exposure to
trypsin inhibitors (Refs. 11 through 16), reduced bioavailability of
minerals (Refs. 13, 17, 18, 19, and 20), and hormonal disturbances due
to soy isoflavones (Refs. 21 through 26). Based on the totality of the
evidence and, in particular, its common use in food, the agency did not
take issue with the petitioner's view that the use of soy protein is
safe and lawful as required in Sec. 101.14(b)(3)(ii). Thus, FDA
tentatively concluded that the petitioner provided evidence that
satisfied the requirement in Sec. 101.14(b)(3)(ii) that use of soy
protein at the levels necessary to justify a claim is safe and lawful
under the applicable food safety provisions of the act (63 FR 62977 at
62979).
    Several comments agreed with the agency's conclusion and some
provided the rationale for their support. A number of comments disputed
the

[[Page 57702]]

petitioner's assertion of GRAS status for soy protein and raised
questions about the safety of soy protein-containing foods. The
specific aspects of disagreement are summarized and discussed in the
following sections of this document.
1. Concerns About the Safety of Soy Protein-Based Infant Formulas
    (Comment 1). Many of the comments that raised concerns about the
safety of consuming soy protein-containing foods addressed the safety
of soy protein-based infant formulas. The observed or hypothesized
detrimental effects of such formulas discussed in these comments
included: hormonal disturbances due to estrogenic effects of soy
isoflavones; thyroid abnormalities; altered mineral balance, especially
for zinc; and diabetogenic effects in infants.
    FDA is aware of concerns raised about the safety of soy infant
formulas, but notes that these are speculative at this time, pending
the results of definitive research. FDA also notes that the American
Academy of Pediatrics (Ref. 73) and the New Zealand Ministry of Health
(Ref. 74) have recently issued guidelines for the safe and suitable use
of soy-based infant formulas. Some issues regarding effects of infant
formula are unique because infants may be entirely dependent on formula
as a sole source of nutrition and the relevance of such issues for soy
protein consumed as part of a mixed diet by the general U.S. population
is not clear.
    In any case, concerns about effects of soy protein specific to
infant formulas are beyond the scope of the current rule, which
authorizes a health claim about the relationship of soy protein and CHD
for foods intended for use by the general population. Health claims are
not permitted on foods represented or purported for use by infants and
toddlers less than 2 years of age unless specifically provided for in
the authorizing regulation (21 CFR 101.14(e)(5)). Diets restricted in
fat, saturated fat, and cholesterol are not recommended for infants and
young children, and the current rule (Sec. 101.82) contains no
provisions for use of the health claim about the relationship between
soy protein and CHD on foods for infants and toddlers.
2. Comments on Petitioner's Self-Determination of GRAS Status for Soy
Protein
    (Comment 2). One comment specifically agreed with the petitioner's
assertion that soy protein-containing food ingredients are generally
recognized as safe (GRAS) by self-determination and based on common use
in food before January 1, 1958, in conformance with Sec. 201(s) of the
act. The comment also noted that, although soy protein is not listed as
GRAS or prior sanctioned in Title 21 of the CFR, FDA has noted that
these lists ``do not include all substances generally recognized as
safe for their intended use'' and, as stated at 21 CFR 182.1, ``[i]t is
impracticable [for FDA] to list all substances that are GRAS for their
intended use.'' This comment also agreed with the petitioner's
conclusion that fractionation procedures used to convert vegetable
flours to vegetable protein concentrates and isolates were commonplace
in various sectors of the grain industry, such as corn processing, well
before 1958. Therefore, SPC and ISP can be defined as soy flour
``subject only to conventional processing as practiced prior to January
1, 1958.'' The comment concluded that SF (including steam-treated SF),
SPC, and ISP all fall within the category of ingredients that are GRAS
through experience based on their common use. Several comments objected
to the petitioner's self-determination of GRAS status, citing a variety
of reasons. As stated previously, FDA does not take issue with the
petitioner's self-determination of GRAS status, and the comments,
discussed below, have not convinced the agency to change that
conclusion.
    (Comment 3). Some comments raised objections on the basis that FDA
has not approved the GRAS status of soy protein.
    Although FDA has not ruled formally on the GRAS status of soy
protein ingredients, it has not challenged determinations that soy's
use as dietary protein is GRAS. Food ingredients whose use is generally
recognized as safe by qualified experts are not required by law to
receive FDA approval. Under the health claim petition process, FDA
evaluates whether the substance is ``safe and lawful'' under the
applicable food safety provisions of the act (Sec. 101.14(b)(3)(ii)).
As discussed in greater detail below, FDA did not receive sufficient
evidence from comments to challenge the petitioner's assertion that soy
protein ingredients are GRAS by self-determination. The petitioner met
the showing required by Sec. 101.14(b)(3)(ii) that the substance be
``safe and lawful.''
    (Comment 4). One comment claimed that the Center for Food Safety
and Applied Nutrition recently returned a petition requesting GRAS
recognition for soy protein.
    The document referred to by the comment was a notification by
Archer Daniels Midland Company (GRN 000001), rather than a petition for
FDA action, and the subject of the notification was soy isoflavone
extract, rather than soy protein. At the company's request, FDA ceased
evaluation of the GRAS Notification pending the company's updating of
the file (Ref. 75). Thus, this comment was incorrect.
    (Comment 5). A comment asserted that petitioner's basis for GRAS
self-determination of the use of soy protein as a dietary protein
ingredient (i.e., common use in food before January 1, 1958) was
incorrect. Because the 1979 Select Committee on GRAS Substances (SCOGS)
report (Ref. 76) determined that, at the time of the report, likely
average dietary exposure to soy protein isolate was only about 150
milligrams (mg) from food items, the comment asserted that soy protein
isolates could not have been in common use before 1958.
    FDA finds that this comment is groundless and inaccurately
characterizes the findings of the SCOGS. The 1979 SCOGS report includes
the background statement ``Edible soy protein isolates for food uses
appeared about 1957 as a major article of commerce.'' The 1979 SCOGS
Report also cited a 1972 National Research Council survey of GRAS
ingredients that listed 14 food categories in which soy protein
isolates were used and calculated an average daily intake of several
grams. Soy protein isolates represent only one of several possible
sources of soy protein in foods. In addition, for purposes of
determining if a substance is GRAS, common use is not restricted to
common use in the United States.
    (Comment 6). A comment supporting the petitioner's self-
determination of GRAS status noted that use of soy as a food dates to
about the 11th century BC in the eastern half of north China. From
about the first century AD to the 15th-16th century, soybeans were
introduced in Korea, Japan, Indonesia, the Philippines, Vietnam,
Thailand, Malaysia, Burma, Nepal, and northern India. Soybeans first
grew in the United States in 1765 and were used then to manufacture soy
sauce and vermicelli (soybean paste) (Ref. 77). A comment that disputed
the petitioner's self-determination of GRAS status speculated that the
species of soybean grown early in its history in Asia may have differed
significantly in its content of nutrients and other active components
from the modern species that is cultivated in this country.
    FDA does not find this comment compelling. Although the composition
of soybeans has likely changed over time, modern soybean species and

[[Page 57703]]

cultivars are, in any case, encompassed within the period of common use
of soy and soy protein in food.
    (Comment 7). One comment questioned whether the Asian experience
could provide assurance that soy is safe. Drawing parallels with herbal
medicine in terms of attitudes, monitoring deficiencies, and the
general difficulty in detecting toxicities with long latency, this
comment concluded that the long history of apparent safe use of soy
products cannot assure they are without risk (Ref. 78).
    The comment did not provide evidence to document that soy products,
consumed at levels necessary to justify the claim, are not generally
recognized as safe. Moreover, considerable research is underway at this
time because of the hypothesized benefits of the historical use of soy
products by certain population groups. FDA supports the ongoing
research to clarify the effects, both potentially beneficial and
potentially adverse, of soy and agrees that any effects due to changes
in the conditions of use should be monitored. However, the information
currently available does not lead FDA to object to the petitioner's
self-determination of GRAS status of soy protein.
    (Comment 8). Several other comments asserted that the proposal did
not adequately establish the GRAS status of soy protein food
ingredients in that the proposal did not include a thorough evaluation
of the safety of potentially harmful components, e.g., lysinoalanine,
nitrites and nitrosamines, trypsin inhibitors, phytate, and
isoflavones.
    FDA notes that the 1979 SCOGS report (Ref. 76) discussed several of
these components extensively and recommended that it would be prudent
to develop food grade specifications for soy protein isolates that
would set acceptable limits on the levels of lysinoalanine, nitrites,
and nitrosamines. But, the possible presence of these components in soy
protein isolates did not lead the SCOGS panel to recommend against GRAS
status of soy protein isolates.
    As noted above, the agency finds the petitioner met the showing
required by Sec. 101.14(b)(3)(ii) that soy protein is ``safe and
lawful.'' The agency lacks documented evidence of adverse effects in
humans and has received no information about actual levels of
potentially harmful components or about threshold levels for adverse
effects in humans. Accordingly, the agency has no basis to conclude
that soy protein is not safe and lawful. The specific comments about
potentially harmful components of soy are discussed below.
3. Lysinoalanine: Potential Toxic Effects
    (Comment 9). A few comments noted concerns about the presence of
lysinoalanine in soy protein isolates and cited the SCOGS report (Ref.
76), which indicated that lysinoalanine was implicated as a renal toxic
factor in rats.
    FDA finds that the comments inaccurately reflected the findings of
the SCOGS report. The SCOGS report noted that the relatively severe
alkali treatment used to modify viscosity and adhesive properties of
soy protein isolates used as sizing and coating adhesives in the
production of paper and paperboard products can cause formation of
lysinoalanine. The report evaluated the risk of lysinoalanine exposure
from soy protein adhesives and binders used in paper and paperboard
food packaging. The 1979 SCOGS report noted that, ``For edible isolated
protein production, extraction is usually carried out at a pH below 9
to avoid hydrolytic or rheological changes'' and concluded that, while
relatively low levels of lysinoalanine had been reported in some
samples of food grade soy protein isolate, available information
indicated that the levels of lysinoalanine in food grade soy protein
isolates pose no hazard to the consumer (Ref. 76).
    FDA notes that the comments that expressed concern about
lysinoalanine in soy protein ingredients did not provide any
information about lysinoalanine levels in food grade soy protein
ingredients nor about use of alkali-processed soy protein as a food
ingredient. FDA finds that the potential presence of lysinoalanine in
soy protein isolates used for sizing and coating adhesives in paper and
paperboard products is not relevant to the safe and lawful use of soy
protein in food. FDA also notes that the production of small amounts of
lysinoalanine during alkali processing has also been documented with
casein and lactalbumin, so it is not unique to soy. Good manufacturing
practices are and should be employed to minimize the production of
lysinoalanine because of its deleterious effects on protein quality.
4. Nitrites and Nitrosamines: Potential Carcinogenic Effects
    (Comment 10). Some comments expressed concerns about the potential
presence of nitrites in soy protein and the potential their presence
poses for the in vivo formation of nitrosamines, which have been shown
to be carcinogenic in experimental animals.
    FDA notes that many natural and processed foods contribute to the
total human intake of nitrite. In an appendix titled ``Health Aspects
of Nitrites in Soy Protein Isolates,'' the SCOGS report (Ref. 76)
presented an estimate of the consumer exposure to nitrite contributed
by soy protein in perspective to nitrite from other dietary sources and
that formed in the gastrointestinal tract by reduction of salivary and
dietary nitrate. The SCOGS report estimated the maximum daily nitrite
consumption for a vegetarian eating meat alternatives prepared from soy
protein to be 0.04 mg/kilogram (kg) body weight (or 2.8 mg for a 70-kg
person). The report estimated daily per capita intake of nitrite from
other foods of plant origin and cured meats to be about 2.4 mg and
daily exposure to nitrite from saliva to be 15 mg. The report estimated
that nitrite formed in the intestine from reduction of ammonia or
organic nitrogen compounds contributed about 90 mg/day. Given the
relatively minor potential contribution of soy protein to total nitrite
exposure, and the fact that no data were submitted to document the
current levels of nitrites or nitrosamines in soy protein isolates, FDA
is not persuaded of the necessity for establishing specifications for
acceptable levels of these compounds.
5. Trypsin Inhibitors: Potential Effects on Pancreatic Function
    (Comment 11). A number of comments presented evidence that modern
heat treatment and other processing do not entirely eliminate the
activity of trypsin inhibitors in soy protein-containing products.
Additional references provided in comments (Refs. 79, 80, 81, and 82)
suggested that the mechanism of feedback regulation of pancreatic
enzyme secretion may be responsible for deleterious effects on the
pancreas--hyperplasia and formation of nodules--seen in animal studies.
Further, Leiner (Ref. 80) demonstrated that infusion of high levels of
isolated trypsin inhibitor in humans can evoke this mechanism but noted
that further research was needed to assess whether frequent exposures
to low levels of trypsin inhibitors consumed in the diet could have the
same effect. Other comments cited evidence for potential
anticarcinogenic effects of these and other protease inhibitors (Ref.
83). Leiner (Ref. 82) hypothesized that any anticarcinogenic effect of
protease inhibitors would likely be manifested at levels too low to
evoke their adverse effects on the pancreas.
    FDA notes that the observed adverse effects have been limited to
animal

[[Page 57704]]

studies. To date, deleterious effects of consumption of low levels of
soybean trypsin inhibitors have not been documented in humans. For
example, Mills et al. (Ref. 84) conducted a prospective study of fatal
pancreas cancer among 34,000 California Seventh-day Adventists, a group
with high soy consumption. Compared to all U.S. whites, Adventists
experienced decreased risk from pancreas cancer death, which was not
statistically significant. Although there was a suggestive relationship
between increasing meat, egg, and coffee consumption and increased
pancreatic cancer risk, these variables were not significantly related
to risk after controlling for cigarette smoking. However, increasing
consumption of vegetarian protein products, beans, lentils, and peas as
well as dried fruit was associated with highly significant protective
relationships to pancreas cancer risk.
    Therefore, FDA finds that the information presented in these
comments has not documented deleterious effects of dietary intake of
trypsin inhibitors from soy in humans and, thus, does not lead the
agency to take issue with the petitioner's conclusion that the use of
soy protein is safe and lawful as required by Sec. 101.14(b)(3)(iii).
6. Phytate: Effects on Mineral Balance
    Comments raised concerns about the potential deleterious effect of
soy protein and its phytate content on mineral status. Phytate, the
salt of phytic acid or inositol hexaphosphate, is a natural plant
constituent containing six negatively charged phosphate groups that can
form strong complexes with divalent cations such as calcium, magnesium,
iron, zinc, and copper. Concerns relative to soy have concentrated
mainly on iron and zinc, based primarily on studies of the absorption
and bioavailability of these minerals.
    (Comment 12). One comment cited a study in which a soy protein-
based purified diet induced iron deficiency in monkeys (Ref. 85). The
same comment also noted two studies in humans--one that found
inhibition of the absorption of nonheme iron from both semisynthetic
meals and meals comprising conventional foods by various soy protein-
containing ingredients (Ref. 86), and one that found increasing
inhibition of nonheme iron absorption with increasing amounts of
phytate in liquid formula meals that contained soy protein isolates
(Ref. 87). In a study cited in another comment, the substitution of
some meat in a mixed meal by soy protein caused a decrease in the
absorption of nonheme iron and an increase in the absorption of heme
iron (Ref. 88), so that overall iron absorption was not compromised.
Another comment reported that human feeding studies with soy protein
that have examined measures of iron status have not shown detrimental
effects (Ref. 89).
    A comment raised concerns about the effect of soy protein on zinc
status based on studies of absorption of zinc from soy infant formula
(Ref. 90) and a study that showed decreased serum thymulin in subjects
fed a low-zinc, soy protein-based experimental diet designed to produce
mild zinc deficiency (Ref. 91). As noted earlier, issues specific to
infant formula are outside the scope of this rulemaking and the
experimental diet in the latter study (Ref. 91) is of limited relevance
to the likely conditions of consumption of soy protein in the
population that is the target of the health claim. Another comment
cited two studies (Refs. 92 and 93) showing no adverse effects of soy
protein on absorption of zinc from meals in subjects with adequate zinc
status.
    One comment provided additional information on the mechanism of
phytate interference with zinc homeostasis (Ref. 94) and characterized
the problem as more than a matter of decreased bioavailability of the
zinc consumed in a meal. The comment noted that phytate can remove from
the duodenum zinc that is mainly derived from pancreatic secretions,
that is, zinc that may have been consumed 1-2 weeks earlier. Although
these data are derived from animal studies, the comment indicated that
the physiology of zinc homeostasis is not qualitatively different
across species.
    This comment expressed concern that high consumption of soy protein
might exacerbate marginal zinc deficiency, which is difficult to
diagnose, and suggested that labeling should include the content of
both zinc and phytate so consumers can be educated that a molar ratio
of phytate:zinc of less than 10 is needed to avoid detrimental effects
on zinc status, as suggested by research in animals (including Ref.
95). The comment acknowledged that education would be needed for the
public to utilize such labeling. The agency recognizes that adequacy of
iron and zinc status in largely plant-based diets is a legitimate
concern.
    FDA finds that the evidence of potential adverse effects of soy
protein on iron and zinc status is equivocal. Interpretation of the
evidence is difficult because findings in human studies are often
inconsistent with results of animal studies. Moreover, many factors
affect the absorption of these minerals, including the amount consumed
in a meal, the enhancing and inhibiting effects of other components of
the meal, and the nutritional status of the subject. Animal studies
suggest that zinc status is a strong determinant of effects of phytate/
soy on zinc absorption: zinc absorption is more impaired with zinc
deficiency, in contrast to the effect of low iron status, which
enhances iron absorption. However, given the lack of documented
evidence for impaired iron and zinc status in humans consuming soy
protein as part of a mixed diet, FDA is not persuaded of the necessity
for the suggested labeling with respect to the phytate: zinc molar
ratio. Nor is it persuaded that many consumers would find the suggested
information, which is highly technical, useful at this time.
7. Soy Isoflavones: Estrogenic Effects
    Many comments addressed concerns about the possible deleterious
consequences of phytoestrogen effects of the soy isoflavones, genistein
and daidzein. Most of these addressed proliferative (and potentially
carcinogenic) effects on estrogen-sensitive tissues, effects on
circulating hormone levels and potential deleterious effects on
fertility, and potentially adverse effects on sexual development.
    a. Proliferative effects. (Comment 13). Several comments cited a
number of studies of in vitro effects of individual isoflavones on
proliferation of estrogen-sensitive cells. For example, Dees et al.
(Ref. 96) found that genistein increased a number of indices for
proliferative activity in MCF-7 human breast cancer cells. As the
authors noted, these findings are consistent with the conclusion that
dietary estrogens at low concentrations do not act as antiestrogens,
but act like estradiol to stimulate human breast cancer cells to enter
the cell cycle. However, many other studies (reviewed in Refs. 97 and
98) have found that the phytoestrogens present in soybeans inhibit
breast cancer cell proliferation in vitro (at lower concentrations,
closer to physiological levels) and inhibit mammary cancer development
in various animal models. FDA concludes that studies in transformed
cells cannot predict with certainty whether effects will be beneficial
or detrimental in humans consuming soy protein.
    (Comment 14). Comments argued that two reports showed effects of
dietary intake of soy isoflavones on breast tissue in women. Petrakis
et al. (Ref. 99) studied 24 normal pre- and postmenopausal white women,
ages 30

[[Page 57705]]

to 58 years, who underwent monthly nipple aspiration of breast fluid
and gave blood and 24-hour urine samples for biochemical studies. The
women consumed no soy in months 1-3 and 10-12. During months 4-9 the
women ingested daily 38 grams (g) of soy protein isolate containing 38
mg of genistein (daidzein content was not reported). This study's
findings indicated that prolonged consumption of soy protein isolate
had a stimulatory effect on the breast of premenopausal women,
characterized by increased secretion of breast fluid and elevated
levels of plasma estradiol. The study also detected evidence of
epithelial proliferation (hyperplasia) in 7 of the 24 subjects during
consumption of soy. McMichael-Phillips et al. (Ref. 100) examined the
effects of dietary soy supplementation on the proliferation rate of
premenopausal, histologically normal breast epithelium and the
expression of progesterone receptor. Women (n = 48) with benign or
malignant breast disease were randomly assigned to receive their normal
diet either alone or with a 60-g soy supplement (containing 45 mg
isoflavones) taken daily for 14 days. Serum concentrations of the
isoflavones genistein and daidzein increased in the soy group at 14
days. The proliferation rate of breast lobular epithelium significantly
increased after soy supplementation when both the day of menstrual
cycle and the age of patient were accounted for. Progesterone receptor
expression increased significantly in the soy group. The authors
concluded that further studies are required to determine whether the
short-term stimulation of breast proliferation is due to estrogen
agonist activity and to examine the long-term effects of soy on both
the pituitary gland and breast.
    FDA finds that the detection of proliferative effects in these two
studies suggests the need for additional research. The findings do not,
however, establish that the observed effects are detrimental and are
not supported by the findings of epidemiologic studies of soy intake
and risk of premenopausal breast cancer (Ref. 101).
    b. Fertility and Hormone Levels. (Comment 15). Some comments
referenced a number of studies that reported reduced fertility in
animals exposed to phytoestrogens (including Refs. 102, 103, and 104).
Some of these studies involved phytoestrogens other than those found in
soy or consumption of soy under extreme or unusual conditions. FDA is
not convinced of the relevance of these studies to human consumption of
soy protein.
    (Comment 16). Comments cited the study of Cassidy et al. 1994 (Ref.
105) as suggesting the potential for deleterious effects on human
fertility. These investigators examined the influence of a diet
containing soy protein on the hormonal status and regulation of the
menstrual cycle in six premenopausal women. Soy protein (60 g
containing 45 mg isoflavones) given daily for 1 month significantly
(p<0.01) increased follicular phase length and/or delayed menstruation.
Midcycle surges of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) were significantly suppressed during dietary intervention
with soy protein. Plasma estradiol concentrations increased in the
follicular phase and cholesterol concentrations decreased 9.6 percent.
The authors concluded that responses to soy protein are potentially
beneficial with respect to risk factors for breast cancer and may in
part explain the low incidence of breast cancer and its correlation
with a high soy intake in Japanese and Chinese women. One of the
comments that cited this study acknowledged that it is unclear whether
these soy effects are beneficial or adverse. FDA notes that the study
found that soy did not interfere with ovulation and the study did not
assess effects on fertility.
    In a similar study with a longer duration, Duncan et al. (Ref. 106)
studied effects of isoflavone consumption in 14 premenopausal women.
The women consumed isoflavones in soy protein powders (control diet,
10; low isoflavone diet, 64; high isoflavone diet, 128 mg/day) for
three menstrual cycles plus 9 days in a randomized cross-over design.
The low isoflavone diet decreased LH and FSH levels during the
periovulatory phase. The high isoflavone diet decreased free T3 and
dehydroepiandrosterone sulfate levels during the early follicular phase
and estrone levels during the midfollicular phase. No other significant
changes were observed in hormone concentrations or in the length of the
menstrual cycle, follicular phase, or luteal phase. Endometrial
biopsies performed in the luteal phase of cycle 3 of each diet period
revealed no effect of isoflavone consumption on histological dating.
FDA notes that although this study's findings varied somewhat from
those of Cassidy et al. (Ref. 105), it also did not directly address
the effect of soy on human fertility. FDA finds that these two studies
do not provide sufficient evidence to address the effect of soy protein
on human fertility.
    c. Developmental Effects. (Comment 17). One comment cited the study
of Faber and Hughes, 1993 (Ref. 107) as showing alterations in LH
regulation following developmental treatment with genistein, suggesting
that during pregnancy in humans, isoflavones could be a risk factor for
abnormal brain and reproductive tract development. This study involved
injection of 0, 1, 10, 100, 200, 400, 500, or 1,000 micrograms of
genistein into neonatal rats on days 1-10. Because of the differences
in developmental stages between rodents and humans, this type of
experiment is used as a model for prenatal (third trimester) effects of
diethylstilbestrol (DES). Increased exposure to genistein led to
decreased LH secretion; the volume of the sexually dimorphic nucleus of
the preoptic area increased compared to controls only in animals that
received the two highest doses of genistein. An earlier paper by Faber
and Hughes 1991 (Ref. 108) showed that effects elicited by neonatal
injections of 1000 micrograms of genistein were similar to those of 0.1
micrograms of DES. The comment also cited studies using a similar
experimental model by Medlock et al. (Refs. 109 and 110) as
demonstrating that equol (a metabolite of daidzein in some individuals)
acts as an endocrine disruptor during development. FDA finds that the
relevance of these studies to an assessment of potential prenatal
effects of dietary soy protein during pregnancy is uncertain.
    (Comment 18). One comment cited the study of Harrison et al. (Ref.
111) that showed pregnant Rhesus monkeys fed genistein had serum
estradiol levels 50 to 100 percent higher than the controls in three
different areas of the maternal circulation. The comment also noted the
finding that the fetuses of genistein fed monkeys had a 70 percent
higher serum estradiol level than did the controls. In this study, five
monkeys were fed genistein (amount not specified) during pregnancy and
compared to five controls. No differences were reported in maternal
weight gain, fetal weights at delivery, or placental weights.
Significant differences in estradiol levels (but not progesterone) were
noted at delivery in maternal peripheral blood, uterine veins, ovarian
veins, and the fetus, and in maternal blood during pregnancy, but
values were not reported. FDA received only an abstract describing this
study. Without more complete documentation, the merits or weaknesses of
this study cannot be evaluated. Therefore, FDA has not used this study
to evaluate the concerns raised in this comment.
    FDA notes that, in another study that examined dietary effects,
Fritz et al. (Ref. 112) fed female rats genistein from

[[Page 57706]]

conception to day 21 postpartum in the diet at concentrations of 0, 25
and 250 mg genistein/kg diet. They found that genistein in the diet at
``physiological levels'' (equivalent to those in Asians consuming a
traditional high soy diet) enhances cell differentiation, resulting in
programming of mammary gland cells for reduced susceptibility to
chemically induced mammary cancer, with no observed toxicity to the
fertility of dams or the reproductive tract of female offspring. FDA
finds that these dietary studies in animals do not provide evidence for
detrimental developmental effects in humans.
    (Comment 19). Another comment raised the possibility that soy
phytoestrogens could be responsible for inducing premature puberty and
cited the case-control study of estrogenic exposures by Freni-Titulaer
et al. (Ref. 113) of patients with premature thelarche seen in Puerto
Rico between 1978 and 1981. In subjects 2 years of age or older at the
onset of thelarche, the study found no statistically significant
associations. In subjects with onset before 2 years of age,
statistically significant positive associations were found with a
maternal history of ovarian cysts, consumption of soy-based formula,
and consumption of various meat products. A statistically significant
negative association was found with consumption of corn products. The
authors concluded that these statistical associations were not
sufficient to explain the reported increase in premature thelarche
because in over 50 percent of the case subjects there was no exposure
to any of the risk factors for which statistical associations were
found.
    Thus, FDA concludes that this study provides no convincing evidence
that soy was responsible for premature thelarche. Moreover, FDA notes
that the study documents no deleterious effects of consuming soy
protein at the levels necessary to justify the health claim in
population groups that are the target of the claim.
    d. Other. (Comment 20). One comment cited a study associating
intake of tofu in mid-life by Japanese-American men in Hawaii with
vascular dementia and brain atrophy in old age (Ref. 114). This comment
hypothesized that isoflavone inhibition of aromatase, which catalyzes
the conversion of testosterone to estradiol, may provide a mechanistic
explanation for this finding. The report cited (Ref. 116) is an
abstract that indicates the researchers found an association of high
tofu intake with low cognitive test scores and with Alzheimer's
disease, rather than vascular dementia.
    FDA finds that this abstract does not provide a sufficient basis to
evaluate the merits and weaknesses of this study. As such, it is not
useful in evaluating the safety concerns at issue. Moreover, the report
does not provide information on total soy intake or what variables were
controlled in the analysis. If tofu or soy were implicated in
Alzheimer's disease, its prevalence would be expected to be higher in
Japan than in Hawaii, but White et al. (Ref. 115) found the prevalence
of Alzheimer's disease was higher in Hawaii than in Japan. Therefore,
FDA is not persuaded by the comment raising concerns about potential
adverse effects of soy protein in dementia and brain atrophy in older
persons.
    (Comment 21). One comment addressed the general issue of threshold
effects for estrogenic compounds, citing a study (Ref. 116) that showed
no threshold dose for estradiol-induced sex reversal of turtle embryos.
It also cited a study (Ref. 117), available in abstract form, that
reviewed 31 dose-response curves for hormone-mimicking chemicals that
also failed to show a threshold. The report of this study did not
include mention of soy isoflavones and did not specify the estrogenic
effects examined. FDA does not find this evidence particularly useful.
The relevance of the turtle model to humans is uncertain and the other
cited evidence was available only in abstract form.
    e. Conclusion. Soy isoflavones and other dietary phytoestrogens are
known to exert hormonal effects--both estrogenic and antiestrogenic--
depending on the amount and type consumed and endogenous hormonal
status of the organism studied; they are much less potent than
endogenous estrogen or synthetic estrogens such as DES. There is
considerable variability from person to person in the absorption,
metabolism, and disposition of the soy isoflavones, genistein and
daidzein (Ref. 118), and researchers have found that their metabolism
and excretion depend on the duration of ingestion and the subject's sex
(Ref. 119).
    Overall, the evidence for proliferative effects, effects on
fertility and hormone levels, and developmental and other effects in
humans due to the estrogenic effects of soy isoflavones is very
limited. Both possible beneficial effects and possible detrimental
effects are still hypothetical. FDA finds that the information
presented in the comments has not adequately documented deleterious
effects of dietary intake of soy isoflavones in humans.
8. Soy Isoflavones: Goitrogenic Effects
    (Comment 22). Comments noted that isoflavones are inhibitors of the
enzyme thyroid peroxidase (TPO), which produces the thyroid hormones T3
and T4, and indicated that its inhibition can be expected to generate
thyroid abnormalities. Other comments, however, noted the lack of
evidence for consequential effects of TPO inhibition (i.e., high
prevalence of goiter) in populations with high soy consumption.
    One comment noted that there exists a body of animal data that
demonstrates goitrogenic and even carcinogenic effects of soy products
and cited the study by Kimura et al. (Ref. 120). These researchers
developed malignant goiter in rats by feeding diets containing 40
percent defatted soybean and no iodine. No deleterious effects were
seen in controls fed the same diet with iodine added.
    Comments noted the existence of a number of case reports in the
older literature of soy inducing goiter in infants (Refs. 121 through
125). Van Wyk et al. (Ref. 121) studied one infant who developed goiter
on a soybean formula and tested the same product in 12 adults. In
adults, the product did not interfere with iodine absorption, impair
iodine uptake, interfere with oxidation of iodine in the thyroid, or
(in most subjects) interfere with the release of protein-bound iodine
into the blood. Hydovitz (Ref. 12) provided a single case report;
Shepard et al. (Ref. 123) described three cases and presented evidence
that soybean goiter was caused by iodine deficiency. Pinchera et al.
(Ref. 124) reported on a case of a congenitally hypothyroid infant and
found high fecal losses of thyroxine. Addition of adequate iodine to
soy-based infant formulas in the 1960's generally resolved or prevented
goiter. However, Chorazy et al. (Ref. 125) more recently reported on a
hypothyroid infant who was semi-refractory to thyroid hormone therapy
while consuming soy formula.
    Several comments cited the study of Ishizuki et al. (Ref. 126) as
evidence for goitrogenic effects of soy in adults. This study is
published in Japanese and the available English abstract is poorly
translated. As described in that abstract, the design and findings are
unclear: goiters were said to occur in half the subjects eating 30 g
soybeans daily for 3 months, though ``various parameters of serum
thyroid hormones remained unchanged by taking soybeans.'' The soybean
preparation used (reported in some comments to be roasted, pickled
soybeans), iodine intake, and other dietary changes were not reported.

[[Page 57707]]

    In one comment, researchers indicated that they had identified
genistein and daidzein as the goitrogenic isoflavonoid components of
soy and defined the mechanisms for inhibition of TPO-catalyzed thyroid
hormone synthesis using in vitro studies of the pure isoflavones (Refs.
127 and 128). The comment noted that the observed irreversible
inactivation of TPO by isoflavones, through covalent binding to TPO,
raises the possibility of neoantigen formation. The comment also noted
that anti-TPO is the principal autoantibody present in autoimmune
thyroid disease and proposed that this hypothetical mechanism is
consistent with the reports of Fort et al. (Refs. 129 and 130) of a
doubling of risk for autoimmune thyroiditis in children who had
received soy formulas as infants compared to infants receiving other
forms of milk. However, the studies of Fort et al. were retrospective
case-control analyses of early feeding practices in children with
diabetes (Ref. 129) or autoimmune thyroid disease (Ref. 130). The
studies did not establish a cause-and-effect relationship or assess
medical indications for use of soy formula in these children.
    FDA notes that no data or other information presented in the
comments documents deleterious effects on thyroid function of consuming
soy protein at the levels necessary to justify the health claim in
population groups that are the target of the claim.
9. Allergenicity of Soy Protein
    (Comment 23). One comment disputed the statement in the soy protein
proposed rule that soy allergies are often outgrown. FDA finds that the
comment cited data that did not directly address this issue but
documented the following with respect to soy: a case report of an
anaphylactic reaction to soy in an adult (131); severe reactions to soy
in several Swedish children and adolescents, who had known severe
reactions to peanuts and asthma but had not reacted previously to soy
(Refs. 132 and 133); cross reactivity of some soy and peanut allergens
(Ref. 134); and an outbreak of gastrointestinal illness associated with
consumption of an improperly processed soy protein tuna salad extender
in which only a few individuals exhibited signs of true
hypersensitivity reactions (Ref. 135).
    (Comment 24). One comment noted that use of soy protein health
claims will highlight the presence of soy protein in foods. Another
comment noted that any food protein can stimulate a food allergy and
that such allergies are commonly due to milk, egg, and nut proteins.
This comment noted that infants who develop cow's milk allergies or
intolerance are frequently prescribed soy substitutes and a small
subset of these high-risk children also develop soy protein allergy.
    FDA finds that the comments that noted concerns about the
allergenicity of soy protein cited these concerns as evidence that
consumption of soy is unsafe, but did not propose that any particular
action be taken by the agency as a consequence to protect consumers
with soy allergies. FDA does not believe that, because some persons may
have allergic reactions to a food, it is unsafe. FDA has previously
stated that the declaration of an allergenic substance in the
ingredient statement on the food label provides adequate information
for consumers regarding the presence of the allergenic ingredient in
the product (63 FR 8103 at 8113), and sees no reason to change this
view with respect to soy. FDA notes, in agreement with one of the
comments received, that authorization of a health claim for soy protein
and CHD will highlight the presence of soy protein in those food
products that bear the claim. The agency, therefore, anticipates that
persons with known soy allergies will be able more easily to avoid soy
protein based products.

B. Updated Review of Scientific Evidence and Issues Related to the
Evidence

    In the soy protein proposed rule, FDA conducted a comprehensive
review of the human studies submitted in the petition (Refs. 27 through
66) (63 FR 62977 at 62980). Of these, the agency gave particular weight
to 14 clinical trials (Refs. 27, 28, 30 (1 trial), 31, 36, 37 (1
trial), 40 (2 trials), 44, 49, 51, 54, 58, and 59). These 14 trials met
the criteria for selection set out by the agency (63 FR 62977 at
62980): they included subjects representative of the general U.S.
population; were well controlled; reported information on intakes of
saturated fat and cholesterol; and avoided problems associated with
small sample size, lack of a placebo, and other design problems. The
agency summarized these studies in Table 1 of the soy protein proposed
rule (63 FR 62977 at 62998). The agency also summarized seven clinical
trials in adults (Refs. 33, 35, 46, 55, 56, 60, and 64) and three
trials in children (Refs. 34, 42/45, and 63) with type II or familial
hypercholesterolemia in Table 2 of the soy protein proposed rule (63 FR
62977 at 63011). In addition, FDA reviewed the results of one
epidemiological study (Ref. 65 and 63 FR 62977 at 62986) and a meta-
analysis (Ref. 66 and 63 FR 62977 at 62987) that included a number of
the soy protein studies submitted in the petition.
    Based on these studies, FDA concluded there was scientific evidence
for a consistent, clinically significant effect of soy protein on blood
total and LDL-cholesterol levels (63 FR 62977 at 62989). The
hypocholesterolemic effect of soy protein was seen in addition to the
effects of a low saturated fat and low cholesterol diet. The degree of
lowering of blood total and LDL-cholesterol was consistently and highly
dependent on initial levels, within and across studies of subjects with
normal, moderately elevated, and severely elevated blood lipid levels,
with persons having higher blood lipid levels showing greater effects.
Soy protein consistently caused only statistically nonsignificant
effects or slight elevations in high density lipoprotein (HDL)-
cholesterol levels. The intervention studies indicated that a minimum
level of approximately 25 g of soy protein was needed to have a
clinically significant effect on total and LDL-cholesterol levels.
1. Additional Data Submitted With Comments and New Studies
    (Comment 25). Several comments included submissions of additional
studies of the effects of soy protein on total and LDL-cholesterol or
directed FDA to studies published since it issued the soy protein
proposed rule. FDA reviewed these studies and found that two (Refs. 136
and 137) meet its criteria for consideration.
    One comment included an unpublished paper by Teixeira et al., 1999
(Ref. 136) that examined the effects of feeding four graded levels of
soy protein in moderately hypercholesterolemic men. After a three-week
lead-in on a National Cholesterol Education Program (NCEP) Step 1 diet,
subjects were randomly assigned to one of five experimental groups.
Each group received 50 g protein daily, provided in a variety of baked
goods and ready-to-mix beverages, from ISP or casein in different
proportions for 6 weeks. The proportions of protein were 50, 40, 30,
20, and 0 g (for control) as ISP and 0, 10, 20, 30, and 50 g as casein,
respectively. At 3 weeks, statistically significant (p<0.05) reductions
in total and non-HDL-cholesterol were seen only in the groups consuming
40 and 50 g of soy protein. At 6 weeks, statistically significant
reductions (p<0.05) from baseline were found for non-HDL cholesterol
levels in all soy protein-consuming groups and, in all except the 40 g
soy protein group, for total cholesterol level. Although a reduction in
total cholesterol was noted in this

[[Page 57708]]

latter group, it was non-significant (p=0.07). The authors noted that
neither non-compliance with the diet nor alterations in blood
isoflavone content could account for this result. The study also showed
that levels of HDL-cholesterol were not affected by dietary treatment
at any soy consumption level investigated.
    FDA also noted the recently published study by Wong et al., 1998
(Ref. 137), who conducted a well designed and controlled trial using
NCEP Step 1 diets with most protein provided by soy (50 g/day of soy
protein) or animal protein. Subjects were 13 normocholesterolemic and
13 hypercholesterolemic men aged 20-50 years and the trial was a
randomized, 2-part, crossover study. Subjects were fed either an NCEP
Step I soy protein-containing diet or an NCEP Step I animal protein
diet for 5 weeks. After a washout period of 10-15 weeks, the subjects
were fed the alternate diet for 5 weeks. The study found the
hypocholesterolemic effect of soy protein to be independent of age,
body weight, pretreatment plasma lipid concentrations, and sequence of
dietary treatment. Regardless of plasma lipid status, the soy protein
diet was associated with a statistically significant decrease in the
plasma concentrations of LDL cholesterol (p=0.029). FDA finds these two
studies supportive of the relationship of soy protein to reduced risk
of CHD.
    (Comment 26). One comment cited two metabolic ward studies by
Fumagalli et al. 1982 (Ref. 138), designed to examine fecal steroid
excretion in adults with familial type II hypercholesterolemia, that
had not been reviewed by FDA in the soy protein proposed rule, as
supportive of the ability of soy protein to lower total cholesterol
levels. However, FDA finds these studies had a very small number of
subjects, short duration of treatment, and reported insufficient
information to determine the amounts of soy protein in the diets
consumed. These studies failed to meet FDA's selection criteria for
review and, so, FDA has not considered them further.
    (Comment 27). Comments included information on two studies by
Jenkins et al. 1999 (Refs. 139 and 140) that assessed the effects of
inclusion of soy protein and soluble dietary fiber in an NCEP Step II
diet in hypercholesterolemic subjects in a randomized crossover design.
Dietary saturated fat (less than 7 percent of energy) and cholesterol
(less that 80 mg/day) did not differ in the test and control metabolic
diets (Ref. 139). Compared with the control diet, the test diet (which
provided 33 grams of soy protein from a variety of commercially
available foods) resulted in a 6 percent decrease in total cholesterol
and a 7 percent decrease in LDL-cholesterol levels. The second study
(Ref. 140) used a similar design but was only available as an abstract
that contained too little detail for the agency to evaluate it.
    FDA finds that neither of these studies can provide support for a
hypocholesterolemic effect of soy protein per se because both soy
protein and soluble fiber were varied concurrently. However, these
studies do suggest that inclusion of these specific components can
further enhance the lipid-lowering effect of a low saturated fat, low
cholesterol diet.
    (Comment 28). A comment also submitted the recent study by Washburn
et al., 1999 (Ref. 141) for consideration. In this randomized, double-
blind crossover trial, 51 normocholesterolemic, perimenopausal women
consumed supplements for 6-week periods of 20 g of complex
carbohydrate, 20 g of soy protein containing 34 mg of phytoestrogens
given in a single dose, and 20 g of soy protein containing 34 mg of
phytoestrogens split into two doses. Significant declines in total
cholesterol level (6 percent lower) and LDL- cholesterol level (7
percent lower) were observed with both soy treatments compared to the
carbohydrate placebo control. However, no dietary assessments were
performed; thus, FDA cannot determine whether the women may have
modified their usual dietary intake in response to the supplements and
whether and how intake of dietary constituents may have differed among
the treatment groups.
    FDA identified two additional recently published studies for
consideration. Nilausen and Meinertz, 1998 (Ref. 142) employed liquid
formula diets containing a very high level of protein (150 g/day) with
soy or casein as the sole protein source to examine individual
variability in lipemic response in a small metabolic study of
normocholesterolemic men. In most subjects effects of soy protein on
both LDL- and HDL-cholesterol levels were favorable, but considerable
variability in response was observed. Duane, 1999 (Ref. 143) also
conducted a small metabolic ward study in normocholesterolemic men that
compared effects of (1) a control diet with ``standard'' amounts of
dietary cholesterol, (2) a diet with essentially no dietary cholesterol
and all animal sources of protein substituted by TVP, and (3) a diet
similar to the second one with eggs isocalorically substituted for
protein and fat to bring dietary cholesterol levels to the moderate
range. Diets containing soy protein decreased LDL-cholesterol but the
effect was of borderline statistical significance. FDA notes that the
small number of subjects and the unusual dietary conditions employed in
these two studies limit their usefulness in adding to the body of
evidence about the effects of soy protein on circulating lipid levels.
    In summary, although most of the new studies considered had flawed
or unusual designs that compromised their evaluation, the two better
designed and controlled studies (Ref. 136 and Ref. 137) provide
additional support for the cholesterol lowering effects of inclusion of
reasonable amounts of soy protein in diets low in saturated fat and
cholesterol.
2. Interpretation of the Clinical Trial Data for Soy Protein
    (Comment 29). One comment raised concerns about the apparent
inconsistency in FDA's application of its review selection criteria,
especially with respect to giving the greatest weight in evaluation of
the health claim to those studies that reported information about the
dietary intake of constituents known to have the greatest influence on
total and LDL-cholesterol levels. The comment noted that values for
dietary saturated fat and cholesterol were not reported for some
studies and that an outmoded description of polyunsaturated fatty acid
to saturated fatty acid ratio was reported for some studies.
    FDA agrees that values for these dietary constituents were not
reported explicitly in all of the studies selected for review. In such
cases, FDA relied upon other documentation contained in the study
publications regarding the contents of the test and control diets, such
as sample menus and reported manipulations of sources of saturated fat
and cholesterol, for assurance that dietary saturated fat and
cholesterol did not differ significantly in the test conditions.
    (Comment 30). One comment questioned the appropriateness of
including studies in which only total cholesterol levels were measured.
    As noted above, in earlier rulemakings on diet and CHD
relationships, FDA concluded that it is generally accepted that blood
total and LDL-cholesterol levels are major risk factors for CHD, and
that dietary factors affecting blood cholesterol levels affect the risk
of CHD. FDA notes that a few of the older studies that it considered
and reviewed in the soy protein proposed rule, and in previous

[[Page 57709]]

rulemakings, measured only total cholesterol levels. FDA concluded that
inclusion of these studies for review was desirable in order to assess
the totality of the publicly available scientific evidence on the
relationship of soy protein and risk of CHD, even though LDL-
cholesterol levels are now considered to be a more powerful risk factor
than total cholesterol levels.
    (Comment 31). A few comments disagreed with FDA's tentative
decision to authorize a health claim for the relationship between soy
protein and CHD because not all of the studies reviewed in the soy
protein proposed rule showed significant reductions of total and plasma
cholesterol levels.
    A recent review and meta-analysis of the effectiveness of NCEP Step
1 and Step 2 dietary interventions in free-living subjects by Yu-Poth
et al. (Ref. 144) noted an appreciable range of response to the dietary
interventions with the maximal effect being more than twice the average
response reported in controlled feeding studies with Step 1 diets. The
interventions reviewed were designed to achieve reduction of dietary
saturated fat and cholesterol and weight reduction, factors known to
have a major impact on circulating cholesterol levels. (The
hypocholesterolemic effects of soy protein, like those of soluble fiber
from whole oats and psyllium seed, are of a lesser magnitude than those
of reduced dietary saturated fat and cholesterol.) Denke (Ref. 145), in
an editorial comment on the study by Yu-Poth et al., notes that
cholesterol-lowering dietary therapy is subject to profound individual
variation in response. In metabolic ward studies of subjects with
unselected cholesterol levels, 5 percent of individuals had no
cholesterol-lowering response to dietary modification and the
percentage of nonresponders increased to 10-25 percent in outpatient
studies (Denke, 1995, Ref. 146). Such nonresponse can result in a
significant underestimation of the effectiveness of dietary
intervention when only the mean response is considered. The small
metabolic ward study of Nilausen and Meinertz (Ref. 142), described
above, documented evidence for considerable inter-individual
variability in the response of cholesterol levels to diets containing
soy protein.
    Based on the studies reviewed in the soy protein proposed rule and
the new studies reviewed in this document, FDA concludes that the
totality of the available scientific evidence supports a consistent, if
not universal, hypocholesterolemic effect of soy protein included in a
low saturated fat and low cholesterol diet. The degree of consistency
is notable in light of the different experimental designs and diets
studied, the different forms and amounts of soy protein tested, and the
variability in initial cholesterol levels of the subjects. The modest
lowering of total and LDL-cholesterol levels generally observed in
these studies can effect a significant reduction in CHD risk.
    (Comment 32). Other comments reviewed various possible mechanisms
for the cholesterol-lowering effects of soy protein and some argued
that until the mechanism of action of soy protein is clearly
established, no health claim should be authorized. FDA notes, however,
that such knowledge is not necessarily required for authorization of a
health claim.
3. Role of Soy Isoflavones in and Effect of Processing on the
Hypocholesterolemic Effect of Soy Protein
    In the soy protein proposed rule, FDA examined the limited evidence
that addressed whether the hypocholesterolemic effects of soy protein
intake were dependent, as suggested by the petitioner, on concomitant
intake of a specified level of naturally occurring soy isoflavones,
i.e., 2 mg isoflavones per g of soy protein (Refs. 22, 28, 31, 70, and
71). FDA also took note of a letter to the editor from Sirtori et al.
(Ref. 72), who conducted a number of trials in which soy protein
exhibited hypocholesterolemic effects and asserted that the products
used in those trials were essentially devoid of isoflavones. Given the
limited number of studies and the contradictory outcomes, FDA was not
persuaded that the isoflavone component of soy protein was a relevant
factor to the diet-disease relationship. Rather, FDA tentatively
concluded that the evidence from a wide range of studies using
differently processed soy protein was supportive of a relationship
between soy protein per se and reduced risk of CHD.
    (Comment 33). Several comments reviewed and discussed the animal
and human studies that examined effects of isoflavones directly or that
compared the effects of ISP processed with and without alcohol
extraction that can remove essentially all isoflavones. Some of these
studies examined effects on parameters in addition to cholesterol
levels, such as measures of lipid-related gene expression,
atherosclerosis, and vascular reactivity. Because the health claim for
soy protein and CHD is based on the hypocholesterolemic effect of soy
protein, only that aspect of the studies is summarized below.
    In one study, Balmir et al. (Ref. 147) fed male rats diets
containing protein from ethanol-acetone extracted ISP, nonextracted
ISP, casein, or casein to which the ethanol-acetone extract was added.
Rats fed either ISP diet had lower serum total cholesterol
concentrations compared with those fed either casein diet. Lower serum
LDL-cholesterol concentrations were found in rats fed either ISP diet
and in rats fed casein plus extract compared with those fed casein.
Sugano and Koba (Ref. 148) found that a methanol-extracted soy fraction
was not as effective as the unextracted fraction in maintaining low
plasma cholesterol levels in rats. Kirk et al. (Ref. 149) showed that a
soy protein-based isoflavone-containing diet resulted in a reduction in
cholesterol levels in C57BL/6 mice compared to a diet containing
alcohol-washed soy protein, although it had no effect on cholesterol
levels in transgenic mice that lacked the LDL receptor. In another
study, Balmir et al. (Ref. 147) fed male Golden Syrian hamsters diets
containing protein from ISP, ISP with added ethanol-acetone extract,
casein, or casein with added extract. Lower serum total cholesterol and
LDL cholesterol concentrations were observed in hamsters fed ISP, ISP
with extract, or casein with extract compared with those fed casein.
Addition of the extract to casein at higher levels did not lower serum
lipids relative to casein. Tovar-Palacio et al. (Ref. 150) fed gerbils
one of five experimental diets containing either casein or alcohol-
washed ISP provided alone, or ISP supplemented with one of three
different levels of an alcohol extract of isolated soy protein
contributing either 2.1, 3.6 or 6.2 mg isoflavones/g protein. Gerbils
fed all of the soy-based diets had significantly lower total and LDL +
very low density lipoprotein (VLDL)-cholesterol levels than those fed
casein. The additions of the alcohol extract to ISP did not reduce
serum cholesterol levels any further. This study suggests that, in
gerbils, consumption of an isoflavone-containing extract does not
contribute to the hypocholesterolemic effect of alcohol-extracted soy
protein. These reports did not characterize the nature of the extracts
used in the studies. Overall, FDA finds that studies in these animal
models do not clarify the role of isoflavones in the
hypocholesterolemic effect of soy protein.
    Comments noted a series of studies conducted in monkeys that
examined the effect of removal of isoflavones and other alcohol-
extractable compounds from soy protein on its cholesterol-lowering
activity. Anthony et al. (Ref.

[[Page 57710]]

22) fed peripubertal male and female rhesus monkeys moderately
atherogenic diets in which the source of dietary protein was a soy
protein isolate, either containing isoflavones or with the isoflavones
removed by alcohol extraction, in a crossover design with each period
lasting for 6 months. The intact soy protein (compared with the
extracted soy protein) significantly reduced LDL+VLDL-cholesterol
levels in both males and females and significantly increased HDL-
cholesterol levels for females. Honore et al. (Ref. 23) fed young adult
rhesus monkeys with pre-existing diet-induced atherosclerosis one of
two soy-based diets, which were identical in composition except that
the isoflavones were extracted from one and intact in the other, for 6
months. Total and LDL-cholesterol levels were significantly lower in
females fed the intact soy protein than in those fed the extracted soy
protein. The same trend was seen in males, but the difference was not
statistically significant for total cholesterol. Anthony et al. (Ref.
70) studied young male cynomolgus macaques fed one of three moderately
atherogenic diets for 14 months. The groups differed only in the source
of dietary protein, which was either casein/lactalbumin, soy protein
with the isoflavones intact, or soy protein with the isoflavones mostly
extracted. Animals fed intact soy protein had significantly lower total
and LDL+VLDL-cholesterol levels compared with the other two groups. The
animals fed intact soy protein had the highest HDL-cholesterol level,
the casein group had the lowest level, and the group fed the extracted
soy protein was intermediate. Anthony et al. (Ref. 151) randomized male
and female macaques to groups fed a casein-containing diet or diets
with soy protein with the isoflavones intact or extracted. Fat and
cholesterol were identical in all diets. The LDL+VLDL-cholesterol
levels were highest in the casein group, slightly lower in the group
fed extracted soy protein, and significantly lower in the group fed
intact soy protein. The HDL-cholesterol levels were significantly
higher in both soy protein groups than in the casein group. FDA notes
that the alcohol extraction procedure used by these researchers, which
was not characterized in the study reports, appeared to diminish the
hypocholesterolemic effect of ISP.
    Comments submitted three human studies of isolated isoflavones that
examined their role in cholesterol lowering. In a study published only
as an abstract, Colquhoun et al. (Ref. 152) administered daidzein and
genistein to 23 male and female subjects with an average cholesterol
level of 243 mg/deciliter (dL) in a blinded crossover design. Nestel et
al. (Ref. 52) studied 21 women in a randomized cross-over design with
two active treatment periods (80 mg of isolated soy isoflavones) and
one 5-week placebo period, while they consumed a soy-free diet. Hodgson
et al. (Ref. 153) conducted a randomized, blinded, placebo-controlled
trial of 8 weeks duration and a two-way parallel design that tested the
administration of 55 mg of soy isoflavones to 46 men and 13
postmenopausal women. Plasma lipid levels were not affected by soy
isoflavones in any of these studies. FDA notes that these studies do
not support a role for isolated isoflavones in cholesterol lowering.
    Three studies submitted in comments examined the effects of
variation of isoflavone content in soy protein-containing diets in
human subjects. Cassidy et al. (Ref. 154) conducted metabolic ward
studies of the effects of various soy products with and without
isoflavones in small numbers of healthy, nonvegetarian, premenopausal
women. During one (control) menstrual cycle, the women ate a constant
diet containing no soy products. Then, over a second complete cycle six
subjects consumed a similar diet into which 60 g TVP/day, containing 45
mg conjugated isoflavones, was incorporated. Three participants had 50
g miso, containing 25 mg unconjugated isoflavones, added daily to their
diet over a menstrual cycle, and six others consumed 28 g TVP/day,
containing 23 mg conjugated isoflavones. Five participants completed a
third diet period in which they were randomly assigned to consume
either the control diet over a cycle, or a similar diet incorporating
60 g of a ISP from which the isoflavones had been chemically extracted.
A significant reduction in total cholesterol was found with 45 mg
conjugated isoflavones, but not with 23 mg conjugated isoflavones or
isoflavone-free ISP.
    As previously reviewed in the soy protein proposed rule (63 FR
62977 at 62988), the study of Baum et al. (Ref. 28) investigated the
impact of soy protein as ISP containing different levels of isoflavones
in hypercholesterolemic, postmenopausal women. Adjusted mean
differences in the change from baseline for total serum cholesterol
level did not differ in the two soy groups and the control group.
However, there was a statistically significant reduction of 8-9 percent
in non-HDL (LDL+VLDL)-cholesterol in both of the ISP treatment groups
(p<0.05) compared to the control group. HDL-cholesterol was also
significantly increased (p<0.05) in both soy groups compared to the
control. The level of isoflavones did not affect any of the blood lipid
levels measured.
    FDA also previously reviewed the unpublished study by Crouse et
al., which was subsequently accepted and published (Ref. 31), in the
soy protein proposed rule (63 FR 62977 at 62987). This study examined
the effect of soy protein containing different levels of isoflavones in
hypercholesterolemic men and women. Subjects with qualifying serum
lipid levels (LDL-cholesterol greater than 140 mg/dL) after one month
and who were compliant with the study regimen were randomized into one
of five treatment groups. The treatment groups received 25 g protein
from ISP prepared from soy with different levels of isoflavones (either
1.0, 1.6, or 2.5 mg total aglycone isoflavones/g protein), or 25 g
protein from alcohol-washed ISP that contained essentially no
isoflavones (0.2 mg total aglycone isoflavones/g protein) or 25 g
protein from casein (no isoflavones) in beverages for 9 weeks. Results
indicated that compared to casein the ISP containing the highest level
of isoflavones significantly lowered total (p<0.05) and LDL-cholesterol
(p<0.05), by 4 percent and 6 percent, respectively, while HDL-
cholesterol was not altered. In subjects with LDL-cholesterol in the
top half of the study population, serum total and LDL-cholesterol were
reduced by 9 percent (p<0.03) and 12 percent (p<0.03), respectively, by
the ISP with the highest isoflavone content, and by 8 percent (p<0.03)
and 9 percent (p<0.03), respectively by the ISP with the second highest
isoflavone content, while HDL-cholesterol concentrations were
maintained. The authors reported a dose-response effect of increasing
amounts of isoflavones on total and LDL cholesterol level. One comment
included a reanalysis of the dose-response data that did not include
data for the casein diet, in order to control for an independent effect
from soy protein itself, and found no significant effect based on
isoflavone content. A comment from the petitioner disagreed with this
analysis. It also indicated that the study did not eliminate the
possibility that isolated soy protein per se has cholesterol-lowering
properties, but rather suggested that soy protein with higher levels of
isoflavones might have even greater effects. FDA finds that the
disparity in these comments does not clarify the equivocal nature of
the available evidence. FDA finds that these studies do not provide
sufficiently consistent results to cause the agency to

[[Page 57711]]

change the conclusion reached in the soy protein proposed rule.
    (Comment 34). One comment objected to FDA's consideration of the
letter to the editor by Sirtori et al. (Ref. 72) because the reference
substantiating the technique for processing the soy protein product was
missing from the letter, the products were not tested for isoflavone
content at the time of the studies, different soy products (isolate and
flour) were used to manufacture the textured soy protein used in the
studies, and the references for studies cited in the letter did not
match the ones cited by FDA in the soy protein proposed rule. FDA
agrees that the reference for the patented procedure for the production
of the TVP, described as making use of rapid heating under high
pressure, was omitted in the letter by Sirtori et al. (Ref. 72) and
that the isoflavone content of the products reported (Cholsoy and
Croksoy) was not measured at the time the studies in which they were
used were conducted.
    The letter by Sirtori et al. (Ref. 72) cites two older studies--
Sirtori et al., 1979 (Ref. 55) and Sirtori et al., 1979 (Ref. 155)--as
well more recent studies--Sirtori et al., 1995 (Ref. 156)--conducted by
their group. The five studies of Sirtori's group that FDA reviewed and
cited in the soy protein proposed rule as using products that contained
essentially no isoflavones (Refs. 33, 34, 35, 46, and 56) are included
in the reference list of Sirtori et al., 1995 (Ref. 156), which is a
review article. The agency did not review Sirtori et al., 1979 (Ref.
155) in the soy protein proposed rule, and it did not cite Sirtori et
al., 1977 (Ref. 55) because it specifically indicated use of a soy
protein product different from those tested for isoflavone content. FDA
gives some credence to the knowledge of the investigator about the
products used in his studies, but agrees that the letter to the editor
does not provide sufficient documentation to permit an unequivocal
conclusion that the products found to be devoid of isoflavones were
identical to those used in the clinical studies.
    (Comment 35). One comment asserted that most of the studies
reported by Sirtori's group were performed using a textured soy protein
based on steam-treated soy flour; this treatment would be expected to
remove isoflavones. The comment also included a letter from Sirtori
(Ref. 157) stating that essentially all of his group's studies
beginning in 1980 were with products without isoflavones. However, the
patent referenced in this letter was not included with this submission.
Thus, FDA cannot verify that the process used to produce the products
used in Sirtori's studies over time was the same used to produce the
products analyzed recently for isoflavone content.
    (Comment 36). The interpretation of the data available on the role
of soy isoflavones in and the effects of processing on the
hypocholesterolemic effect of soy protein varied widely in the
comments. Several comments agreed with FDA's conclusion that the
evidence did not support a significant role for soy isoflavones in
cholesterol-lowering effects of soy protein. One comment supported the
petitioner's original conclusion that a level of 2 mg aglycone
isoflavones per g soy protein was necessary for cholesterol lowering.
In a comment, the petitioner agreed with FDA ``that a relationship
exists between soy protein per se and reduced risk of CHD.''
    The additional evidence about the role of isoflavones is
contradictory and inconclusive and has not persuaded FDA to alter its
original conclusion about the inability to identify a specific
contribution of soy isoflavones to the cholesterol-lowering effects of
soy protein. At the same time, the evidence shows a clear relationship
between soy protein and reduced risk of CHD despite lack of a clearly
defined mechanism for its effect.
    (Comment 37). Several comments interpreted the evidence as showing
that alcohol extraction used in the processing of certain soy protein
ingredients (to the extent that they are rendered essentially devoid of
isoflavones) impairs or eliminates the hypocholesterolemic effects of
soy protein and recommended that the health claim not be allowed for
alcohol-washed products. Comments also raised some questions about the
extent to which extensively alcohol-washed products, such as those used
in the animal studies, are available commercially. One comment asserted
that some of ISP products used in the primate studies were subjected to
additional alcohol extraction by the investigators, but the agency
could not independently verify this assertion. This comment also stated
that all commercial sources of soy protein contain some isoflavones.
    FDA examined the recently compiled USDA-Iowa State University
Isoflavone Database (Ref. 158), which documents the following ranges of
total isoflavone content for various soy protein-containing
ingredients, and found that most, but not all, contained levels of
isoflavones higher than those that would result from harsh alcohol
extraction procedures:

                                 Table 1
------------------------------------------------------------------------
                                                    Aglycone isoflavones
                      Product                         (mg/100 g edivle
                                                           portion
------------------------------------------------------------------------
Soy flour, textured...............................           4.40-295.55
Soy flour, defatted...............................          73.72-168.09
Soy flour, full-fat, raw..........................          59.80-264.84
Soy flour, full-fat, roasted......................         131.70-260.50
Soy protein concentrate, aqueous washed...........          61.23-167.00
Soy protein concentrate produced by alcohol                   2.08-31.82
 extraction.......................................
Soy protein isolate...............................          46.50-199.25
Instant beverage, soy powder......................         100.10-125.00
------------------------------------------------------------------------

    FDA agrees that the data from the animal studies reviewed suggest
that alcohol washing of soy protein can reduce its hypocholesterolemic
effects. With respect to human studies, FDA finds the available
evidence is insufficient to permit any conclusions about the impact of
processing by alcohol extraction on the hypocholesterolemic effect of
soy protein. Thus, FDA concludes it would be premature to exclude
alcohol-washed products from eligibility to bear the health claim.
    (Comment 38). One comment noted that several clinical trials
designed to resolve questions about the impact of processing and
isoflavone content are

[[Page 57712]]

currently in progress. Many of the comments on these issues urged that
FDA proceed with the health claim regulation as proposed, but monitor
research developments and make changes in the regulation as warranted
by the results.
    As noted above, FDA finds that, in light of the evidence that soy
protein processed in various ways, containing unknown amounts of
isoflavones, has hypocholesterolemic effects, FDA is not applying any
criteria for inclusion of naturally occurring isoflavones or excluding
alcohol-washed products from eligibility to bear the health claim on
soy protein and CHD.
    (Comment 39). A few comments suggested that, regardless of the
conclusions about the significance of soy isoflavones to the reduction
of CHD risk, food products that bear the soy protein health claim be
allowed or required to state the isoflavone content of the product on
the label. The comments did not provide any evidence that persuaded the
agency that consumers would find this information helpful in making
healthful dietary choices. Accordingly, the agency is not adopting this
suggestion.
4. Amount of Soy Protein Required for Significant Effect on Cholesterol
Levels
    Based on the limited data reviewed that supported a dose-response
and the data that showed clinically significant reductions in total and
LDL-cholesterol with soy protein ingestion in the range of 17-31 g/day,
and recognizing that the hypocholesterolemic effects of soy protein
were dependent on initial blood lipid levels, the agency tentatively
concluded that 25 g/day represented a reasonable, effective amount of
soy protein (63 FR 62977 at 62992). In addition, the agency noted that
an amount of 25 g/day of soy protein represents half of the Reference
Daily Intake (RDI) of 50 g for protein and is a reasonable level of
consumption in the context of the total daily diet. Thus, FDA
tentatively concluded that the amount of soy protein associated with
reduction in total and LDL-cholesterol levels and, thus, with reduced
risk of CHD was 25 g or more of soy protein per day (63 FR 62977 at
62992).
    (Comment 40). Many comments agreed with the agency's conclusion
that 25 g or more of soy protein per day was associated with reduction
in total and LDL-cholesterol levels. Several comments raised concerns
about the adequacy of the available data to support an assessment of
dose-response. One comment expressed concern that higher levels of soy
protein are needed to modify cholesterol levels in normocholesterolemic
individuals and that this should be indicated as part of the claim.
    FDA agrees that the available data on the hypocholesterolemic
effects of soy protein do not permit a dose-response assessment.
However, FDA notes that dose-response data are not required to
establish the qualifying criteria for a substance that is the subject
of a health claim. Under Sec. 101.70, which describes the requirements
for health claim petitions, the petition must address whether there is
an optimum level of the particular substance to be consumed beyond
which no benefit would be expected (Sec. 101.70(f)(B)(1)). This
information may or may not be based on dose-response data. For example,
in its evaluation of the scientific evidence for a relationship between
consumption of soluble fiber from psyllium seed husk and blood total
and LDL-cholesterol levels, the agency found no reliable data to
establish a dose-response for this relationship (62 FR 28234 at 28240).
However, the agency did find that, in placebo-controlled studies that
tested an intake of 10.2 g of psyllium seed husk per day as a part of a
diet low in saturated fat and cholesterol, there were consistently
significant effects of psyllium husk on blood total and LDL-cholesterol
levels. Therefore, the agency based the qualifying level of soluble
fiber from psyllium seed husk on a total daily intake of 10.2 g husk or
about 7 g of soluble fiber.
    The qualifying level of 25 g/day has been demonstrated to have a
consistent, clinically significant effect on total and LDL-cholesterol
levels. This 25 g/day level of intake for cholesterol lowering is
confirmed by the new study of Teixeira et al. (Ref. 136), which showed
significant hypocholesterolemic effects of 20 g/day of soy protein.
Therefore, the agency disagrees with the comments suggesting that dose-
response data are needed before the agency can authorize a health
claim. The totality of scientific data, which establish a clinically
significant reduction in blood cholesterol based on an intake of at
least 25 g/day of soy protein, provides an adequate basis for
establishing a qualifying level for soy protein-containing products.
    The agency agrees that the available data indicate that the
hypocholesterolemic effect of soy protein may be dependent on initial
cholesterol levels, but notes that moderately hypercholesterolemic
individuals are generally more responsive to dietary interventions than
normocholesterolemic individuals. As the leading cause of death in this
country, CHD is a disease for which the general U.S. population is at
risk. The risk of dying from CHD is related to serum cholesterol levels
in a continuous and positive manner, increasing slowly for levels
between 150 mg/dL and 200 mg/dL and more rapidly when the cholesterol
level exceeds 200 mg/dL (Ref. 37). The public health policy articulated
by the NCEP, National Heart, Lung, and Blood Institute, is to extend
the benefits of cholesterol lowering to the population as a whole by
promoting adoption of eating patterns that can help lower the blood
cholesterol levels of most Americans (Ref. 67). A dietary intervention
that lowers blood cholesterol levels only in persons with high levels
would, like an intervention that lowers cholesterol levels across the
entire population range, cause a shift in the population distribution
of blood cholesterol levels resulting in a decrease in the mean value
for the blood cholesterol level in the general population (Ref. 67).
The anticipated effect of such a shift would be to reduce the morbidity
from CHD and to produce a continued or accelerated decline in the CHD
mortality rate in the United States. The agency is persuaded by the
evidence it has reviewed in this rulemaking that the consumption of soy
protein, as part of a low saturated fat and cholesterol diet, can be a
useful public health measure to assist in the national policy of
promoting eating patterns that will help in achieving or maintaining
desirable blood cholesterol levels in the general population.
Therefore, it concludes that the health claim need not indicate that
hypercholesterolemic individuals may be more responsive to consumption
of soy protein than normocholesterolemic individuals. In addition,
consistent with the agency's conclusions in rulemaking on the dietary
saturated fat and cholesterol/CHD claim (58 FR 2739 at 2745, January 6,
1993), the wording of the health claim as `` `may' or `might' reduce
the risk of heart disease'' adequately represents the fact that not all
persons will realize the same magnitude of benefit from adopting the
dietary change.
5. Summary of the Scientific Evidence
    FDA reviewed human studies submitted by the petitioner and in
comments that evaluated the effects on serum cholesterol and LDL-
cholesterol levels of dietary interventions with soy protein in
subjects with normal to elevated serum cholesterol levels and that met
the agency's criteria for selection.
    Most intervention trials in subjects with total cholesterol levels
less than 300 mg/dL found that soy protein

[[Page 57713]]

reduced total and/or LDL-cholesterol levels to a clinically significant
degree (Refs. 31, 28, 27, 51, 44, 37, 49, 30, 58, 29, 43, 136, and
137.). Moreover, HDL-cholesterol levels were unchanged (Refs. 31, 27,
51, 40, 37, 49, 36, 53, 136, and 137) or slightly increased (Refs. 28,
44, 58, and 59). In some cases (Refs. 27, 44, and 49), decreases in
total and LDL-cholesterol were statistically significant only in
subsets of subjects with the higher initial blood lipid levels. Results
in normocholesterolemic subjects (Refs. 30, 36, 58, 59, and 53) were
more variable than those in hypercholesterolemic subjects (Refs. 31,
28, 27, 51, 44, 40, 37, 49, 54, 29, 43, and 136) except in the study of
Wong et al. (Ref. 137), in which normocholesterolemic and moderately
hypercholesterolemic subjects were equally responsive. The outcome of
an epidemiologic study (Ref. 65) also supported a relationship between
higher levels of soy protein intake and lower blood lipid levels.
    Most of the studies in subjects with total cholesterol levels less
than 300 mg/dL used low saturated fat and low cholesterol diets (Refs.
31, 28, 27, 51, 44, 30, 36, 53, 29, 43, 136, and 137), but some used
``usual'' diets (Refs. 37, 49, 54, 36, 58, and 59). Although soy
protein was found to lower blood lipid levels in some of the studies
using ``usual'' diets, hypocholesterolemic effects of soy protein were
more consistently observed with diets low in saturated fat and
cholesterol. Given the variability of amounts and forms in which soy
protein was provided in the diets, the response of blood lipid levels
appears robust and notably consistent, particularly in subjects with
moderate hypercholesterolemia.
    Data from studies of adults with type II and familial forms of
hypercholesterolemia (and total cholesterol levels in excess of 300 mg/
dL) (Refs. 55, 33, 64, 56, 64, 46, and 35) were also consistent in
showing large and statistically significant decreases in total and LDL-
cholesterol, accompanied by no changes or slight increases in HDL-
cholesterol levels. Nearly all of the subjects in these trials consumed
low saturated fat and low cholesterol diets during the studies and had
consumed such diets prior to studies with soy protein. Soy protein was
tested in a variety of foods but produced fairly consistent results
regardless of the food form fed and apparent differences in processing
techniques.
    The FDA concludes, based on the evidence submitted and reviewed,
that soy protein, included in a diet low in saturated fat and
cholesterol, can lower blood total and LDL-cholesterol levels, without
adversely affecting HDL-cholesterol levels. The agency also concludes
that the effect is due to soy protein per se and is not consistently
related to the presence or absence of isoflavones. The evidence
currently available, as reviewed in section II.B.3 of this document,
does not permit a conclusion regarding how significantly alcohol
processing may affect the hypocholesterolemic effects of soy protein.
The intervention studies reviewed indicate that a minimum level of
approximately 25 g of soy protein per day results in a clinically
significant effect on total and LDL-cholesterol levels.
    With respect to the scientific data and information about the
relationship of soy protein and CHD, the relevant data are provided by
well controlled and well designed studies. Soy protein, the food
substance that is the subject of the claim, is measured in those
studies. The relationship of the biomarkers evaluated--total and LDL-
cholesterol--to the risk of CHD is validated and the studies measured
the biomarkers appropriately. Finally, a consistent body of evidence
from a variety of studies is available. Accordingly, the agency is able
to conclude, based on the totality of the publicly available scientific
evidence, that there is significant scientific agreement that soy
protein, included at a level of 25 g/day in a diet low in saturated fat
and cholesterol, can help reduce total and LDL-cholesterol levels, and
that such reductions may reduce the risk of CHD.

C. Nature of the Food Eligible to Bear the Claim

1. The Qualifying Amount of Soy Protein
    Using 25 g of soy protein as the qualifying amount for a CHD claim,
the petitioner suggested that a single serving of a soy protein-
containing product (i.e., one RACC) should provide \1/4\ of this amount
(based on four servings a day). Thus, a soy protein-containing product
would have to contain at least 6.25 g soy protein (\1/4\  x  25 g) per
RACC. The petitioner stated that this approach was reasonable because
it would permit a wide variety of low fat, soy protein-containing
products to bear the health claim. The petitioner provided a list of
products on the market that currently meet the proposed requirements
and a list of products that could be modified to meet them (Ref. 1,
Appendix V). The agency has generally made the assumption that a daily
food consumption pattern includes three meals and a snack (see 58 FR
2302 at 2379, January 6, 1993). The agency tentatively concluded in the
soy protein proposed rule that the assumption of four servings per day
of soy protein-containing foods was reasonable. Therefore, the agency
found that use of the qualifying criterion set forth in the petition
would be appropriate (63 FR 62977 at 62992).
    Most comments agreed that the qualifying level of 6.25 g soy
protein per RACC was appropriate. Many of these comments also indicated
that a sufficient number and variety of soy protein-containing foods
are available to enable consumers to select suitable products to
consume a total of 25 g soy protein per day.
    (Comment 41). Several comments suggested rounding the qualifying
level to 6 or 7 g of soy protein per RACC, in keeping with the
requirements for the labeling of protein in the Nutrition Facts panel.
    FDA, however, notes that the Nutrition Facts panel contains the
amount of total protein per serving of the product, regardless of the
source ingredient. For many products that may bear the claim, soy
protein may not be the sole contributor to total protein. Therefore,
FDA finds that the amount of soy protein in a serving of a food that
may bear the health claim will neither be required nor permitted to
appear in the Nutrition Facts panel. The qualifying level need not
conform to requirements specific to the Nutrition Facts Panel.
    (Comment 42). One comment received in response to the soy protein
reproposal indicated that food processors will be required to declare
the corrected amount of protein and the percent Daily Value of protein
on the Nutrition Facts panel, in accordance with 21 CFR 101.9(c)(7)(i).
This comment noted that, in nearly all cases, the amount of protein
declared will be lower than the quantity of protein present in the
product and may, in some instances, be lower than the qualifying amount
of soy protein.
    FDA notes that compliance with the requirements of this regulation
will be based on the actual amount of soy protein present in the food
and not on the amount of protein declared on the nutrition label.
    (Comment 43). One comment suggested that the qualifying level
should be increased to 12.5 g soy protein per RACC because of concerns
that consumers would not choose soy protein-containing foods frequently
enough during a day to reach a total of 25 g and might believe that the
health benefit may be attained by eating a single serving of a food
that provided no more than 6.25 g soy protein. Several

[[Page 57714]]

other comments also raised concerns that consuming soy protein-
containing foods up to four times daily would represent a significant
change from the typical American diet that might not be selected by
many consumers.
    FDA cannot assess how many consumers would be interested in making
such a change, but it is persuaded that it will be feasible for
motivated consumers to do so. Doubling the qualifying level of soy
protein per RACC would greatly and unnecessarily restrict the number of
foods potentially eligible to bear the health claim. Because
Sec. 101.82(c)(2)(i)(G) requires that the claim specify both the daily
dietary intake of soy protein that is necessary to reduce the risk of
coronary heart disease and the contribution that one serving of the
product makes to the specified daily dietary intake, consumers will not
be misled about the amount of soy protein needed for the health effect.
    (Comment 44). A number of comments suggested that greater
flexibility in meeting the recommended total daily intake of 25 g soy
protein per day could be achieved by permitting a lower qualifying
level on the basis of increasing the number of servings or eating
occasions per day from four to five or six or more. Several of these
comments proposed that the qualifying level of soy protein should be
reduced to 4 g per RACC; one suggested lowering the qualifying level to
2.5 g per RACC. Most of these comments indicated that 4 g soy protein
per RACC is the maximum amount of soy protein from soy flour that can
be incorporated in baked products that consumers find palatable and
acceptable. These comments suggested that lowering the qualifying level
would stimulate manufacturers to develop a wider range of products and
indicated that use of ISP in baked products would be prohibitively
expensive. One comment challenged FDA's assertion that consumers would
be able to consume an effective amount of soy protein from a variety of
products, including baked goods. FDA based the assertion on its
observation that baked products had been used to provide soy protein in
some studies the agency relied upon to justify authorization of the
health claim (Refs. 27, 28, and 51); in one study (Ref. 27), the
authors indicated that 25 g soy protein daily was provided in four
muffins. ISP was the source of soy protein in the baked products used
in these studies. Some comments stated that FDA need not base the
qualifying level on four eating occasions per day as the agency had
done for other health claims for substances (beta-glucan soluble fiber
from whole oats and soluble fiber from psyllium seed husks).
    FDA finds that these comments did not provide a compelling
rationale for selecting an appropriate number of eating occasions on
any other basis. The agency has not limited its previous determinations
of an appropriate qualifying level of a substance that does not have a
Daily Value in a food to be eligible to bear a health claim to
consideration of the number of individual foods or classes of food
products then available that might bear the claim. Rather, in
determining what constitutes a level of the substance sufficiently high
to justify the claim, FDA considers factors such as the number of
servings likely to be consumed and the feasibility of developing a
variety of foods that contain a significant proportion of the total
daily intake needed for the claimed benefit. For example, when the
psyllium claim was authorized, FDA was aware of only one conventional
food product that would have been eligible to bear the claim and
concluded that, if various psyllium-containing foods were available,
consumption of four servings daily could be achieved. Based on
experience with that claim and other health claims, FDA believes that
manufacturers will be encouraged by the availability of a health claim
for soy protein and CHD to develop new products that will be eligible
to bear the claim. The agency is not persuaded by the comments received
that it should abandon its assumption that a daily food consumption
pattern includes three meals and a snack (see 58 FR 2302 at 2379,
January 6, 1993) and that one serving of a soy protein-containing
product could reasonably be consumed at each eating occasion. As noted
in the discussion above of the comments that expressed concerns about
the willingness of consumers to select soy protein-containing foods as
many as four times a day, such an eating pattern represents a
considerable change from a typical American diet. Although one of the
comments included detailed menus that illustrated the possibility of
consuming more than one soy protein-containing product per eating
occasion, FDA has concluded that it should not lower the amount of soy
protein required for a food to be eligible to bear the health claim.
    (Comment 45). One comment suggested that the amount of soy protein
required for eligibility to bear the health claim be permitted to be
determined on the basis of serving size as well as RACC.
    This comment is outside the scope of this rulemaking. Current
regulations (21 CFR 101.12(g)) require that, ``The reference amount
[i.e., the reference amount customarily consumed] * * * shall be used
in determining whether a product meets the criteria * * * for health
claims.'' In a previous rulemaking, FDA had considered permitting this
option, but comments persuaded the agency that the most reasonable
approach was to base claim evaluations on the reference amount (58 FR
2229 at 2287). FDA agreed with the comments that claims should reflect
the true characteristics of a product, and that those characteristics
do not change if the product is packaged in a different size container.
The comment received in response to the soy protein proposed rule did
not provide a convincing rationale to justify a change in this
decision.
2. Method for Determining Qualifying Amount of Soy Protein in Foods
    In the soy protein proposed rule (63 FR 62977 at 62992), FDA
proposed use of the Association of Official Analytical Chemists (AOAC)
official method of analysis No. 988.10 to measure soy protein in foods.
As described in the soy protein reproposal (64 FR 45932 at 45933), each
of the comments on this proposed analytical method disagreed with its
use and concluded that the method was unlikely to produce a reliable
measure of the soy protein content in every food. The comments noted a
variety of problems with the assay. These comments persuaded the agency
that AOAC official method of analysis No. 988.10 was not an appropriate
method for the quantitation of soy protein in many of the products that
may be eligible to bear the health claim.
    In the soy protein reproposal, FDA discussed the alternative
approaches suggested in comments for assessing compliance with the
qualifying level of soy protein in products that bear the health claim.
Based on this information, the agency provided its tentative rationale
for a procedure employing measurement of total protein and, for
products containing sources of protein other than soy, calculation of
the soy protein content based on information contained in
manufacturers' records (64 FR 45932 at 45934). Thus, in the soy protein
reproposal, FDA modified previously proposed Sec. 101.82(c)(2)(ii)(B)
to provide for this alternative approach for compliance assessment that
relied, in some cases, on records that the agency could inspect.
    The agency received approximately 10 comments in response to the
soy protein reproposal. One of the comments did not address the
proposed

[[Page 57715]]

procedure for compliance assessment but, rather, reiterated concerns
raised in comments on the soy protein proposed rule about the safety of
soy isoflavones. Among the materials it referenced were two documents
authored by FDA staff that the comment characterized as ``reports.''
FDA could not identify one of these documents from the citation given
and the other was a letter submitted as a comment to Docket 98P-0683 in
response to the soy protein proposed rule. Another comment raised
concerns about the GRAS status of soy protein. FDA has addressed the
issues raised in the earlier comments regarding GRAS status and safety
in Section II.A of this document. In addition to commenting about the
reproposal, one comment raised a technical issue about the nutrition
labeling declaration of protein that is addressed in Section II.C.1.
    (Comment 46). Two comments objected to the 30-day comment period
allowed for the soy protein reproposal. FDA stated its rationale and
authority for selecting this period in the soy protein reproposal (64
FR 45932 at 45936 and 45937) and notes that these comments were
submitted and received in timely fashion. One of these comments
asserted that after the comment period for the soy protein proposed
rule had passed, no new submissions or evidence after that date other
than that of FDA origin (or from published scientific documents
accessed by FDA) was acceptable. As noted in the introduction of
Section II of this document, FDA disagrees with this assertion. FDA
considered comments received after the initial comment period,
regardless of source, to the extent that each provided complete
information for review or references accessible to the agency and
addressed issues not raised in earlier comments.
    (Comment 47). A comment asserted that the issue of the method FDA
will use to verify that foods contain the qualifying amount of soy
protein is irrelevant because FDA was required to consider and evaluate
only the claims made for the substance identified in the petition, soy
protein with naturally occurring isoflavones.
    This comment misunderstands FDA's responsibility to review and
evaluate the available scientific evidence and reach appropriately
supported conclusions about the substance-disease relationship based on
information provided in the petition, accessed in the public scientific
literature, and received in comments. FDA notes, for example, that in
response to a petition for oat bran and oatmeal, it proposed to
authorize a health claim on the relationship of those foods and CHD (61
FR 296). Comments received in response to that proposal persuaded FDA
to change the substance of its final rule to beta-glucan soluble fiber
from whole oats (62 FR 3584). The agency has addressed the earlier
comments on the role of isoflavones in the hypocholesterolemic effect
of soy protein in Section II.B.3 of this document.
    (Comment 48). Two comments objected to any use of recordkeeping for
compliance assessment, questioning whether it could be an appropriate
substitute for analytical methods to assess the truthfulness of health
claims. One of these comments also reiterated objections to
authorization of the health claim, because of concerns about incomplete
scientific understanding of the biological activity of soy components,
in terms of both safety and contribution to the protective effect of
soy protein in CHD. The agency has addressed these concerns, which were
raised in comments on the soy protein proposed rule, in Sections II.A
and II.B.3, respectively, of this document.
    The other comment asserted that an approved, scientifically
accurate methodology is needed for any health claim. However, it also
indicated that FDA should finalize its regulation as originally
proposed, but did not propose an alternative for compliance
verification other than suggesting that a manufacturer might
voluntarily share analytical data with the agency if questions about
compliance were raised.
    FDA does not agree with the contention that an analytical method is
an absolute requirement for a health claim, even though it is the
preferred means for verifying compliance with the requirements of a
health claim regulation and substantiating the truthfulness of all
label statements.
    (Comment 49). Many other comments supported continued work to
develop appropriate analytical methodology for measuring the content of
soy protein in foods, and urged FDA, in collaboration with other
government agencies, industry, and scientific organizations, to pursue
this effort. As noted in the soy protein reproposal, FDA intends to do
so, to the extent that resources permit. Also, as noted in the soy
protein reproposal, and as urged in a number of comments, FDA would
propose to amend its regulation to provide for compliance verification
based on one or more analytical methodologies when such methods have
been validated.
    (Comment 50). Several of the comments specifically addressed the
method for assessing compliance set out in the soy protein reproposal.
None of these comments objected to use of an analytical method for
measuring total protein as a measure of soy protein in foods that
contain soy as the only source of protein. Absent an appropriate
analytical methodology, each of these comments supported the need for
manufacturers to have and keep records to substantiate the amount of
soy protein in a food that bears the health claim and contains sources
of protein other than soy, and to make such records available to
appropriate regulatory officials upon request. These comments noted
that in cases where records are needed to substantiate label claims,
food manufacturers have historically provided such records voluntarily
upon request to the FDA and could be expected to continue to do so in
the future. They argued that FDA need not assert broad records
inspection authority in order to obtain the information needed for
compliance assessment. They noted 21 CFR 101.13(j)(ii)(A), which
requires firms to have substantiation for the basis of nutrient
reference values in comparative nutrient content claims and to make
such substantiation available to appropriate regulatory officials upon
request, as a model for requests of records.
    FDA agrees that a manufacturer must have substantiation that a
qualifying amount of soy protein is present in a product that bears the
health claim and that such records can serve as the basis for
substantiation of use of the health claim. FDA noted in the Federal
Register of February 2, 1996 (61 FR 3885 at 3886) several examples of
regulations that implemented the 1990 amendments in which the agency
could not independently, using analytical methodology, verify the basis
for statements on the food label, but instead would rely on access to a
manufacturers' information supporting its labeling claims. These
include access to:
    (1) A detailed protocol and records of all data used to derive a
density-adjusted reference amount for aerated foods (58 FR 2229 at 2272
and Sec. 101.12(e));
    (2) Information that provides the basis for deriving reference
nutrient values for comparative nutrient content claims such as
``light'' (58 FR 2302 at 2365 and Sec. 101.13(j)(1)(ii)(A));
    (3) Specific information with respect to the caloric content of new
products with reduced digestibility (58 FR 2079 at 2087 and 2111 and
Sec. 101.9(c)(1)(i)(D)); and
    (4) Information supporting nutrient content claims for restaurant
foods (58 FR 2302 at 2388 and Sec. 101.13(q)(5)(ii)).

[[Page 57716]]

    In each of these cases, verification of the truthfulness of a label
claim can be assessed by FDA only with access to information known only
by the manufacturer. The same is true, in the absence of a validated
analytical method to measure the amount of soy protein in the presence
of other proteins, for verifying that the qualifying amount of soy
protein to bear the health claim is present in a food that contains
sources of protein in addition to soy. Thus, the agency concludes, in
agreement with these comments, that it is appropriate to require access
to manufacturers' records substantiating the ratio of soy protein to
total protein for foods that contain sources of protein in addition to
soy to assess their compliance with this regulation. Also, in agreement
with these comments, the agency concludes that it need not assert broad
records inspection authority to have access to appropriate records. The
agency disagrees, however, with comments that indicate that reliance on
the voluntary provision of records by manufacturers is sufficient to
meet the agency's need to verify compliance. Rather, the agency is
taking the approach of codifying a requirement for the manufacturer to
provide appropriate records, on request, as the agency has done
previously.
    Although most of the comments supported the use of records, in
principle, for compliance assessment, they also raised concerns about
the types of records that FDA might request, the circumstances under
which FDA would request records, and the legal authority of the FDA to
require records and records inspection.
    (Comment 51). Several comments indicated that FDA had used overly
broad and imprecise language in the soy protein reproprosal to describe
the types of records that FDA would request. They indicated that a
manufacturer is best able to determine the nature of the records that
would be needed to substantiate the amount of soy protein in its own
products and urged that manufacturers be allowed the flexibility to
determine how to document substantiation. One comment argued that a
recipe-based system would be too complex and burdensome for baked goods
in particular. Other comments expressed concern that FDA would, in all
cases, require inspection of a wide variety of records, including
nutrient data bases or analyses, recipes or formulations, purchase
orders for ingredients, and others.
    FDA agrees that the manufacturer will be in the best position to
know which of its records provide documentation of the amount of soy
protein in its products, and specifically the ratio of soy protein to
total protein. By listing the types of records that could provide such
documentation in the soy protein reproposal, FDA did not intend to
indicate that it would request all of these records and subject them to
inspection, or even that it would specify any particular records when
it requests them. Instead, FDA intended to suggest the types of records
a manufacturer might use to substantiate the levels of soy protein in
its foods. Accordingly, FDA has modified Sec. 182(c)(2)(ii)(B) to
clarify that the manufacturer is to identify these materials.
    (Comment 52). One comment questioned whether FDA might request
records for products in which soy is the only source of protein and
urged FDA to specify that it would not request records for such
products.
    FDA agrees that, because measurement of total protein provides
adequate assessment of compliance for products in which soy is the sole
source of protein, that it would not, under the regulation, request
records for substantiation of the amount of soy protein in such
products. The agency believes that the proposed language adequately
communicates this point and has made no changes to the regulatory
language in response to this comment.
    (Comment 53). One comment requested that FDA identify what
circumstances would precipitate a request for records. Although FDA
cannot specify all such circumstances, it notes, as did another of the
comments, that a substantial proportion of its enforcement actions are
undertaken in response to trade complaints.
    (Comment 54). One comment asked that the agency specify that any
records requested could be provided on site without the need for
reproduction or duplication by the investigator. Another comment,
however, objected to FDA making requests for information on site,
arguing that most companies would have the necessary information at
headquarters rather than at production facilities. This comment urged
that FDA make any such requests in writing and allow the manufacturers
to provide appropriate substantiation within a reasonable period of
time. As FDA will not require inspection of records on site, the
concern about reproduction or duplication is moot. FDA agrees that
making a request for records in writing is appropriate and has modified
the regulation accordingly.
    (Comment 55). Some comments objected to the alternative offered in
the soy protein reproposal that FDA would authorize the claim only for
products that contain soy as the sole source of protein, if it could
not proceed with a regulation to provide access to records for
compliance verification. These comments noted that such an action would
give unfair advantage to certain products, unfairly penalize products
that were equally beneficial, and dilute the potential benefit of the
health claim to consumers. Because the agency has authorized the claim
for any food that contains adequate amounts of soy protein, without
regard to other sources of protein, these comments are moot.
    (Comment 56). One comment noted that, in addition to providing FDA,
upon request, information regarding substantiation of the claim, food
processors may, on a voluntary basis, present information on the food
label or in labeling that may support the eligibility of the product to
bear the claim and facilitate an FDA compliance review. Such
information might take the form of statements about the percentage
composition of soy protein in a serving of food. The agency agrees that
manufacturers may voluntarily provide such truthful and not misleading
information and that the provision of such information may aid consumer
understanding of the claim.
    (Comment 57). Several of the comments strongly objected to the
proposal for records inspection on the basis that FDA lacks the
statutory authority to require access to records for foods. Another
comment argued that, once the agency determined that a substance-
disease relationship meets the standard of significant scientific
agreement, the act requires the agency to authorize a claim, and the
agency may not require that manufacturers maintain records or that FDA
be able to request or inspect them. This comment also asserted that,
were FDA to require recordkeeping, record production, or records
inspection, it would violate the First Amendment by conditioning the
exercise of speech rights on the recordkeeping, record production, or
records inspection requirement.
    FDA disagrees with these comments. Other comments have convinced
the agency that, in this instance, it need not assert its rulemaking
authority to provide for inspection of records. This issue is therefore
moot. The agency maintains, however, that it has the legal authority,
using section 701(a) of the act, to promulgate record inspection
requirements for the efficient enforcement of the act. The requirements
that records be maintained and submitted to the agency upon request
pass the test in National Confectioners Association v. Califano, 569
F.2d 690, 693 & n.9 (D.C. Cir. 1979). First, these requirements are
limited to those records that the manufacturer

[[Page 57717]]

reasonably determines substantiate the level of soy protein in its
food, and only with respect to foods that contain a source of protein
in addition to soy. Second, the requirements assist in the efficient
enforcement of the act. They focus only on those foods for which an
adequate analytical method is not available. They allow FDA to verify
that the authorized soy health claim is truthful and not misleading
when it is used on such foods. The requirements, therefore, assist in
the effective and efficient enforcement of the act. Third, these
requirements are not unduly burdensome. They require maintenance of
records that manufacturers should already have to validate that their
food product may lawfully bear the claim, and they permit them to
identify the records that substantiate their claim. FDA requests copies
of the records in writing without inspection. These burdens are not
unreasonably onerous.
    With respect to significant scientific agreement, the comment
misreads the statute. Under section 403(r)(3)(B)(i) of the act, FDA
authorizes a claim about a substance-disease relationship only if the
standard of significant scientific agreement is met. Under that
section, significant scientific agreement is a necessary condition, but
not a sufficient one, for FDA to authorize a health claim. FDA may
impose other requirements in accordance with section 403(r) of the act.
    The agency also disagrees that the recordkeeping and record access
provisions violate the First Amendment. Under section 201(g)(1) of the
act, a food is not a drug solely because its labeling contains a health
claim authorized and made in accordance with the requirements of
section 403(r) of the act. Section 201(g)(1) provides no such provision
for a food whose labeling contains a health claim that is not
authorized and made in accordance with the requirements of section
403(r) of the act. Congress provided for the use on foods of health
claims authorized under and made in accordance with the requirements of
section 403(r) of the act to promote the public health by, in part,
helping consumers maintain balanced and healthful diets (58 FR at
2514). FDA has required that foods whose labels contain an authorized
health claim must contain a sufficiently high level of the substance
that is the subject of the claim in question (see 21 CFR
101.14(d)(2)(vii)). This provision assures that a food bearing the
claim in fact contributes to the claimed effect (56 FR at 60553) and so
may help consumers to maintain a balanced and healthful diet. Absent
the recordkeeping and access provisions, FDA could not assure that,
when the soy protein health claim appears on foods, they will, in fact,
contain sufficiently high levels of soy protein. These provisions,
therefore, directly advance Congress' substantial interest in
permitting the use of health claims on foods and they are narrowly
tailored to do so. In addition, when used on a food, the authorized soy
protein health claim must identify the amount of soy protein in a
serving of food. Accordingly, the provisions also permit FDA to assure
that the claim as it appears on a food is not false and misleading.
3. Requirement that Food Meets the Criterion for Low Fat
    In Sec. 101.82(c)(2)(iii)(B), the agency proposed, consistent with
other authorized heart disease health claims, that foods bearing the
health claim meet the requirements for ``low saturated fat,'' ``low
cholesterol,'' and ``low fat.'' In the preamble to the final rule
authorizing the fruits, vegetables, and grain products and heart
disease claim (Sec. 101.77, 58 FR 2552 at 2572), the agency stated that
populations with diets rich in these low saturated fat and low
cholesterol foods experience many health advantages, including lower
rates of heart disease. In the preamble to the saturated fat/
cholesterol proposed rule (56 FR 60727 at 60739), the agency stated
that while total fat is not directly linked to increased risk of CHD,
it may have significant indirect effects. Foods that are low in total
fat facilitate reductions in intakes of saturated fat and cholesterol
to recommended levels. Therefore, the agency tentatively concluded that
proposed Sec. 101.82(c)(2)(iii)(B) set forth appropriate requirements
for foods to be eligible to bear the soy protein and CHD claim.
    (Comment 58). No comments objected to the requirements that a food
meet the criteria for ``low saturated fat'' and ``low cholesterol'' in
order to bear a health claim about the relationship of soy protein and
CHD. However, many comments objected to the requirement that a food
meet the criterion for ``low fat,'' mainly on the basis that all foods
made from whole soybeans would be disqualified by virtue of the
inherent ratio of protein to fat (approximately 2 to 1) in soybeans.
Several of these comments noted that makers of such foods would have to
use soy protein isolates to develop qualifying products. The comments
that provided additional rationale argued that saturated fat and
cholesterol were properly restricted for a CHD claim, but that total
fat need not be restricted to the same degree because it is not
directly related to risk of CHD. These comments noted that products
derived from whole soybeans that contain 6.25 g of protein per RACC
would just exceed the criterion for ``low fat'' of 3 g fat per RACC.
However, these products would not lead to an increase in the intake of
saturated fat or cholesterol and, thus, negate the health benefits of
soy protein. In addition, they would serve as sources of the essential
fatty acids, linoleic acid and linolenic acid.
    As noted above, the FDA has required that foods bearing any of the
previously authorized CHD health claims meet the requirements for ``low
saturated fat,'' ``low cholesterol,'' and ``low fat.'' In the saturated
fat/cholesterol proposed rule, FDA proposed that in order for a food to
bear the health claim, the food must also meet the requirements for a
``low'' claim relative to total fat content (56 FR 60727 at 60739). The
agency noted that, while total fat is not directly related to increased
risk for CHD, it may have significant indirect effects. Low fat diets
facilitate reductions in the intake of saturated fat and cholesterol to
recommended levels. Furthermore, the agency noted that obesity is a
major risk factor for CHD, and dietary fats, which have more than twice
as many calories per gram as proteins and carbohydrates, are major
contributors to total calorie intakes. For many adults, maintenance of
desirable body weight is more readily achieved with moderation of
intake of total fat. The agency also concluded that this approach would
be most consistent with the U.S. Dietary Guidelines and other dietary
guidance that recommends diets low in saturated fat, total fat, and
cholesterol. In the saturated fat/cholesterol final rule (58 FR 2739 at
2742), FDA reiterated the requirement for ``low fat,'' but allowed for
the exception that fish and game meats could meet the requirement for
``extra lean,'' because these foods are appropriately included in a
diet low in fat, saturated fat, and cholesterol. FDA also noted that
the ``low fat'' requirement for foods to make the saturated fat/
cholesterol and heart disease health claim would limit a manufacturer's
ability to increase trans-fatty acid levels in foods, since any
substitution of trans-fatty acids for saturated fatty acids would have
to be accomplished within the 3 g per RACC or per 50 g limit for total
fat. The agency considered this approach unlikely to result in
significantly increased levels of trans-fatty acids in foods bearing
the health claim (58 FR 2739 at 2744).
    The latter consideration is not applicable to the case of foods
made from whole soybeans. No substitution of one type of fatty acid for
another is

[[Page 57718]]

contemplated for these products. The amount by which foods made from
whole soybeans that are otherwise eligible to bear the soy protein
health claim would exceed the ``low fat'' criterion due to the inherent
fat content of soybeans is small and well below the disqualifying level
for total fat that a food bearing any health claim must meet
(Sec. 101.14 (a)(4)). FDA is persuaded that products derived from whole
soybeans are useful sources of soy protein that they, like fish and
game meats that are ``extra lean,'' can be appropriately incorporated
in a diet that is low in fat, saturated fat, and cholesterol. Thus, FDA
is modifying Sec. 101.82(c)(2)(iii)(B) to require that all products
meet the criteria for ``low saturated fat'' and ``low cholesterol'' and
adding Sec. 101.82(c)(2)(iii)(C) to require that a food meet the
criterion for ``low fat'' in order to bear the soy protein health
claim, except for products consisting of or derived from whole soybeans
without additional fat.

D. Required Elements for the Claim

1. Context of the Total Daily Diet
    In the soy protein proposed rule (63 FR 62977 at 62991), the agency
tentatively found that, for the public to understand fully, in the
context of the total daily diet, the significance of consumption of soy
protein on the risk of CHD (see section 403(r)(3)(B)(iii) of the act),
information about the total diet must be included as part of the claim.
Therefore, in Sec. 101.82(c)(2)(i)(D), the agency proposed to require
that the claim include the fact that the effect of dietary consumption
of soy protein on the risk of CHD is evident when it is consumed as
part of a healthy diet and that, consistent with other authorized
health claims related to CHD, the fat component of the diet be
specified as ``saturated fat'' and ``cholesterol.''
    (Comment 59). One comment objected to this requirement on several
grounds: that FDA has been inconsistent in requiring specification of
the need to consume diets low in saturated fat and cholesterol in
previously authorized CHD health claims; that the effect of soy protein
on blood cholesterol levels is independent of a low fat, low saturated
fat, and low cholesterol diet; that the statutory requirement to place
the claim in the context of the total daily diet need only relate the
labeled product to the rest of the day's diet; and that consumers will
conclude that soy protein will be of no benefit to them if they cannot
reduce saturated fat and cholesterol in their diets. Other comments
raised similar objections to the requirement. This comment and others
proposed that FDA allow a variety of shortened claims that would
effectively render this requirement an optional element of the claim or
that FDA permit the information in this requirement to be presented in
a split claim.
    FDA disagrees with some of the characterizations of FDA's
requirements for currently authorized heart disease claims. The comment
notes that the agency requires a statement of the role of low saturated
fat and cholesterol diets in the reduction of risk of heart disease in
three of the authorized claims'the dietary lipids claim (21 CFR
101.75), the claim for fruits, vegetables, and grain products that
contain dietary fiber, particularly soluble fiber (21 CFR 101.77), and
the claim for soluble fiber from psyllium seed husks (21 CFR 101.81)--
because the effect of the subject food substances had been established
only in the context of such a diet. However, the comment maintained
that evidence for the hypocholesterolemic effect of soluble fiber from
whole oats showed it to be independent of other dietary changes. Thus,
in requiring that the claim for this substance be stated in the context
of a diet low in saturated fat and cholesterol (21 CFR 101.81), the
comment asserted that FDA had failed to provide a claim that accurately
and truthfully reflected the underlying science.
    FDA disagrees with this characterization. The petition for a health
claim for oat products stated that there was significant scientific
evidence to show that the effect of oats on lowering serum lipids is
independent of a diet low in saturated fat and cholesterol. In light of
this evidence, the petitioner argued that any health claim that is
authorized need not refer to such a diet. In the proposed rule for a
health claim for oat products, the agency acknowledged that there were
a number of studies that showed that high intakes of oat bran and
oatmeal lowered blood total and LDL-cholesterol in subjects that
otherwise consumed a typical American diet (61 FR 296 at 305). However,
the agency also recognized that CHD is a major public health concern in
the United States, and that the totality of the scientific evidence
provides strong and consistent support that diets high in saturated fat
and cholesterol are associated with elevated levels of blood total and
LDL-cholesterol, and thus CHD (56 FR 60727 at 60737). Dietary
guidelines from both government and private scientific bodies conclude
that the majority of the American population would benefit from
decreased consumption of dietary saturated fat and cholesterol.
Although the results of several studies showed that daily consumption
of oat bran or oatmeal lowered total cholesterol and LDL-cholesterol
levels, the agency noted that the effects of dietary intake of oat bran
or oatmeal were particularly evident when the diets were low in
saturated fat and cholesterol (61 FR 296 at 306). Thus, the agency
tentatively found it would be more helpful to Americans' efforts to
maintain healthy dietary practices if the effect of oats on serum
lipids were described in the context of a healthy diet (61 FR 296 at
306).
    This tentative conclusion was supported by many of the comments
received in response to the proposed rule and described in the final
rule authorizing a health claim for soluble fiber from whole oats (62
FR 3584 at 3594). In the final rule, the agency noted that diets low in
saturated fat and cholesterol are considered by expert groups to be the
most effective dietary means of reducing heart disease risk, and that
while soluble fiber from whole oats can contribute to this effect, its
role is generally recognized as being of smaller magnitude (Ref. 5).
Further, expert groups saw selection of foods with soluble fiber from
whole oats as a useful adjunct to selection of diets low in saturated
fat and cholesterol (Ref. 5). The agency concluded that it would not be
in the best interest of public health or consistent with the scientific
evidence to imply that selecting diets with soluble fiber from whole
oats is a substitute for consuming diets low in saturated fat and
cholesterol (62 FR 3584 at 3594). Therefore, FDA emphasized the
importance of the dietary component of the health claim, i.e., the
necessity for soluble fiber from whole oats to be consumed as part of a
low saturated fat, low cholesterol diet, for a complete understanding
of the claim (62 FR 3584 at 3594).
    The comment also characterized the claim for sodium/salt and
hypertension (21 CFR 101.74) as a claim about risk of heart disease and
indicated that FDA was not consistent because this claim is not
required to be stated in the context of a diet low in saturated fat and
cholesterol. FDA disagrees with this characterization of the claim and
the conclusion that follows from it. This claim does not address the
risk of heart disease, but rather is a claim specific for hypertension.
The scientific evidence does not suggest that dietary saturated fat and
cholesterol have a significant effect on blood pressure; thus, no
mention of that dietary context is required. In addition, FDA has
stated (58 FR 2739 at 2746) that it has not been presented with data
that sodium intake

[[Page 57719]]

is a risk factor for heart disease and that a claim characterizing the
relationship between sodium and heart disease would misbrand a food
under section 403(r)(1)(B) of the act unless it were specifically
authorized by the agency. The agency does agree with the comment that
it has not found that all the risk factors for CHD must be stated in
order to ensure that a heart disease health claim is truthful and not
misleading. In fact, for CHD claims authorized more recently (21 CFR
101.81), FDA has not required that CHD be characterized in the claim as
a disease caused by many factors, in contrast to the claims that FDA
authorized earlier as part of the initial NLEA reviews (21 CFR 101.75
and 21 CFR 101.77).
    In addition, FDA disagrees with the assertion that the cholesterol
lowering effect of soy protein is independent of other dietary changes;
the agency interprets the data differently. As noted in the discussion
above, most of the scientific evidence for an effect of soy protein on
blood lipid levels is provided by studies that used diets low in
saturated fat and cholesterol. Although soy protein was found to lower
blood lipid levels in some of the studies using ``usual'' diets,
hypocholesterolemic effects of soy protein were more consistently
observed with diets low in saturated fat and cholesterol. The agency
concludes that the data supporting an independent effect for soy
protein are more limited than those supporting an independent effect of
soluble fiber from whole oats in reducing cholesterol levels. Moreover,
because the hypocholesterolemic effects of soy protein are seen in
addition to the effects of a low saturated fat, low cholesterol diet,
combining the two practices will provide enhanced benefits.
    Nor does FDA agree with the comment's assertion that the statutory
requirement to place the claim in the context of the total daily diet
need only relate the labeled product to the rest of the day's diet. In
the 1993 health claims final rule (58 FR 2478 at 2513), the agency
disagreed with comments that proposed that the requirement to enable
the public to understand the significance of the claim in the context
of the total daily diet would be fulfilled if a health claim merely
characterized the level of a substance vis-a-vis a disease, provided
that there was significant scientific agreement that that level of
intake of the substance was beneficial in reducing the risk of disease.
Rather, FDA found that section 403(r)(3)(B)(iii) of the act requires
that a regulation that authorizes a health claim provide that the claim
be stated in a manner that enables the public to comprehend the
information in the claim and to understand the relationship of the
substance to the disease, the significance of the substance in
affecting the disease, and the significance of the information in the
context of the total daily diet. Thus, a claim may need to address a
wide variety of factors to fulfill these requirements, and the agency
is not limited to requiring only that information that is necessary to
prevent a claim from being misleading.
    Finally, the agency is not persuaded that requiring the soy protein
claim to be stated in the context of a total daily diet low in
saturated fat and cholesterol will deter consumers who are interested
in dietary control of cholesterol levels, and who have made
unsuccessful attempts to lower dietary intake of saturated fat and
cholesterol, from incorporating soy protein into their diets. Consumers
now have had experience with the claims for soluble fiber from whole
oats and psyllium seed husks. These claims, like the soy protein claim,
accurately draw the consumer's attention to the dietary pattern
associated most strongly with reduction of risk from heart disease--a
diet low in saturated fat and cholesterol--and offer choices of
specific foods that can be incorporated into this dietary pattern to
enhance its beneficial effects. Thus, FDA is not modifying the
requirement that the health claim for soy protein be stated in the
context of a diet low in saturated fat and cholesterol.
2. Daily Dietary Intake of Soy Protein and Contribution of One Serving
    In the soy protein proposed rule (63 FR 62977 at 62991), the agency
proposed that Sec. 101.82(c)(2)(i)(G) require that the claim specify
the daily dietary intake of soy protein needed to reduce the risk of
CHD and the contribution one serving of the product makes to achieving
the specified daily dietary intake. The agency noted this requirement
was consistent with requirements set forth in Sec. 101.81 for claims
about soluble fiber from whole oats and psyllium seed husks, food
substances that (like soy protein) do not have Daily Values that can
serve as a guide to consumers for appropriate levels of intake. It is
also required by Sec. 101.14(d)(2)(vii).
    (Comment 60). Almost all of the comments that addressed these
requirements supported the need for the claim to contain this
information. Some comments expressed concern that even with this
information some consumers might be misled into believing that a single
serving of a soy protein-containing food would contribute the full
daily amount needed for the claimed health benefit. FDA notes that
these comments did not suggest what additional information might be
helpful to consumers in understanding the claim.
    (Comment 61). Several comments suggested that the daily dietary
intake of soy protein needed to reduce the risk of CHD be required to
be described as ``at least 25 g/day of soy protein'' or ``a minimum of
25 g/day of soy protein.''
    FDA is not persuaded to require that such statements be used
because it is concerned about the need to balance informing consumers
about the effective level of soy protein intake needed to provide the
claimed health benefit against encouraging excessive consumption of a
single food substance. If consumers were to interpret the claim
erroneously as supporting consumption of soy as the sole source of
dietary protein or supplementing a diet already adequate in protein
from various sources with additional soy protein, then the two most
important tenets of a healthful diet--variety and moderation--would be
violated.
    (Comment 62). One comment noted that, in the second model claim,
the characterization of the total dietary intake of soy protein
appeared to have omitted indication that the amount is ``per day.'' FDA
agrees. This omission was inadvertent and the agency has corrected
Sec. 101.82 (e)(1).
    Although comments generally viewed as desirable providing
information on both the total daily dietary intake of soy protein and
the contribution of a single serving of a food to the total intake,
some comments urged that it need not be provided in one place on the
label with all of the other required information. Many of these
comments encouraged FDA to make provisions for the use of abbreviated
claims that would include a referral statement directing the consumer
elsewhere on the package for the full claim. Issues associated with
abbreviated and split claims are addressed below.
3. Abbreviated/Split Claims
    (Comment 63). Although there were not substantive objections
regarding most of the required elements FDA specified, a large number
of comments objected to the model claims proposed in Sec. 101.82 (e),
asserting that they are excessively long, complicated, and cumbersome,
and requested that FDA devise shorter claim statements. Many of these
comments expressed concerns that manufacturers would be reluctant to
use and consumers unlikely to read

[[Page 57720]]

such long, complex messages. They frequently suggested that FDA provide
for split claims in this rule. These would comprise a short or
abbreviated claim (that need not contain all of the required elements
identified in the rule) appearing on the principle display panel of the
label together with a referral statement for the full claim elsewhere
on the package. As support for these suggestions, many of the comments
cited the Keystone Dialog's (Ref. 159) endorsement of shorter claims
and FDA's own health claim consumer research (Ref. 160), which the
comments characterized as showing that short claims were more effective
than long claims and that splitting claims between the front and back
panels made little difference.
    FDA notes, however, that the results of its consumer research were
more complicated than indicated by that brief summary. The short and
long claims studied differed in the inclusion of information about non-
dietary risk factors and special populations at risk for the subject
disease. The soy protein health claim already lacks these requirements.
The study also found that, for some products with an abbreviated claim
and a referral statement on the principal display panel, subjects were
less likely to look at the back of the package for the full claim.
    Concerns about health claims being too wordy and too lengthy have
been raised to the agency in various ways, including by a petition
submitted by the National Food Processors Association (NFPA) (Docket
No. 94P-0390). In response to the NFPA petition, the agency proposed
several changes to the requirements for health claims in the Federal
Register of December 21, 1995 (60 FR at 66206) (the 1995 proposal). At
that time, FDA stated that it had no desire for its regulations to
stand in the way unnecessarily of the use of health claims and the
presentation of the important information contained in them. The agency
stated that, while health claims are being used on the label and in
labeling, they could be used more extensively. The agency, therefore,
proposed to provide for shorter health claims by making optional some
of the elements that are presently required. FDA also proposed to
authorize the use of abbreviated claims.
    FDA has reviewed the comments received in response to the 1995
proposal on changing the requirements for health claims, including
permitting the use of abbreviated claims, but it has not completed work
on the final rule. Given that this rule is pending, and given its
relevance to the issue of abbreviated claims, FDA has decided to defer
a decision on allowing for abbreviated or split claims on soy protein
and the risk of CHD. The agency intends to resolve this matter in the
context of the rulemaking based on the NFPA petition. Thus, at this
time, the agency is making provision only for a full claim.

E. Other Issues

1. Consideration of Health Claims for Benefits of Soy Protein in
Addition to Effects on Cholesterol Levels and Risk of Coronary Heart
Disease
    (Comment 64). A few comments urged that FDA consider authorizing
claims about other putative beneficial effects of soy protein or soy
products on cardiovascular disease in addition to cholesterol lowering
as well as putative beneficial effects on other diseases or health
conditions such as cancer, osteoporosis, and menopausal symptoms. One
comment suggested that statements derived from preliminary research on
the putative beneficial effects of soy isoflavones be allowed on food
labels and in labeling.
    These suggestions are beyond the scope of the present rulemaking.
The present rulemaking is based on FDA's review of information
submitted in a petition about the relationship of soy protein and
reduced risk of CHD based exclusively on studies of the cholesterol
lowering effects of soy protein. The agency has neither received nor
reviewed relevant data for any other possible effects of soy protein
relevant to risk of heart disease or of other diseases or health-
related conditions. Any interested person who has such data may submit
a petition to the agency detailing the information for FDA's review and
evaluation of whether such information meets the requirements for
authorization of a health claim.
    (Comment 65). At the same time, one comment expressed concern that
the authorization of a health claim on the relationship of soy protein
and risk of CHD might be read by some consumers as an implied claim for
other putative benefits of soy foods.
    FDA concludes, however, that the requirements it has set forth for
the health claim already narrow the focus of the claim sufficiently to
the relationship that FDA evaluated. Accordingly, consumers should not
be so misled by the claim.
2. Drug Claims vs. Health Claims for Foods
    (Comment 66). One comment objected to FDA's provision of a health
claim for foods containing soy protein and reduced risk of CHD when FDA
had not approved estrogen as a drug to have an indication for
prevention of cardiovascular disease despite a large body of supportive
evidence. The comment asserted that FDA must evaluate all products with
the same ground rules.
    This assertion is incorrect. As the agency explained in the 1993
health claims final rule (58 FR at 2506), the scientific standard for
authorization of a health claims is less stringent than the
requirements for approval of a new drug under section 505 of the act
(21 U.S.C. 355).
3. Claims for Other Vegetable Proteins
    (Comment 67). One comment reviewed data on the possible mechanisms
for soy protein's hypocholesterolemic effects and concluded that they
may be due in part to its amino acid composition, specifically its high
arginine and low methionine content. The comment noted that other
vegetable proteins, such as pea proteins, have a similar amino acid
profile and would likely have the same effect on risk of CHD as soy
protein. The comment proposed that qualifying levels of both arginine
and isoflavones be required for the health claim and that the claim not
be limited to soy protein. FDA finds that this suggestion is outside
the scope of the current rulemaking. FDA has not reviewed any data on
the hypocholesterolemic effects of specific vegetable proteins other
than soy.
    (Comment 68). Another comment that also discussed the possible
importance of the amino acid composition of soy protein to its
cholesterol-lowering ability suggested that the title of the new claim
should be ``Protein from Certain Foods and Reduced Risk of CHD'' in
anticipation that data will be generated showing hypocholesterolemic
effects of other vegetable proteins with amino acid compositions
similar to soy protein. Having reviewed data only on soy protein and
being aware of no similar body of evidence about any other vegetable
protein, FDA finds this suggestion premature.
4. Regulatory Issues Regarding Soy Protein Claims in Other Countries
    (Comment 69). One comment provided extensive information about a
complaint brought against a company regarding a particular television
advertising campaign for a non-dairy soy beverage product in New
Zealand that was alleged to be deceptive. This information included an
unpublished report of a study comparing the effects of the non-dairy
soy beverage to milk that was inadequate for assessing a

[[Page 57721]]

hypocholesterolemic effect for soy protein or the soy product itself
because dietary saturated fat and cholesterol varied substantially in
the two dietary treatments. Another comment raised concerns about the
importation of foods from the United States that may bear health claims
in violation of Mexican law.
    The FDA advises that violations of laws or regulations of other
countries with respect to claims made on food labels or labeling or
claims made in advertising are outside the scope of the present
rulemaking. Companies doing business in other countries are responsible
for complying with the relevant statutory and regulatory requirements
of those countries.
5. Genetically Modified Soybeans
    (Comment 70). Two comments noted that much of the current soybean
crop in the United States consists of genetically modified varieties of
soybeans. One comment requested that products bearing the health claim
be required to indicate on the label whether genetically modified
soybeans were used. The other comment noted that genetic modification
may alter the content of isoflavones and other biologically active
components of soy and suggested that research was needed to determine
if such genetic modifications raise additional safety concerns. The
comments provided no data or other information to justify labeling or
substantiate any safety concerns.
    FDA has considered these comments and disagrees with both, for the
following reasons. FDA has stated its expectation that companies
consult with the agency early in the process of developing a
bioengineered food and that they provide the agency with a summary of
safety data and a nutritional assessment for its review (Ref. 161). To
date, three companies have consulted with the agency about
bioengineered soybeans. Two companies developed soybeans that are
resistant to the herbicides glyphosate and glufosinate, respectively. A
third company modified the oil composition of the soybean to increase
its levels of oleic acid, and it must be labeled as high oleic acid
soybean. One company stopped further development of a genetically
modified soybean that involved the addition of a brazil nut protein
when it discovered that the protein would cause allergic reactions.
    The safety and nutritional assessments of the three bioengineered
soybeans show that there are no unintended effects of the genetic
modification (Refs. 162 through 167). In particular, these soybeans
possess the same nutritional profile as their parent or other
commercially available soybeans, except that the high oleic acid
soybean has a modified fat profile, as intended. In addition, levels of
isoflavones, trypsin inhibitors, and endogenous allergens are
unchanged. The agency therefore concludes that there is no basis to the
comment's assertion that currently available bioengineered soybeans may
raise additional safety concerns. Nor is there any basis to require
that bioengineered soybeans be identified in food labeling as such.

III. Environmental Impact

    The agency has previously considered the environmental effects of
this rule as announced in the soy protein proposed rule (63 FR 62977 at
62993) and the soy protein reproposal (64 FR 45932 at 45935). The
agency determined that this action is of a type that does not
individually or cumulatively have a significant effect on the human
environment, and that neither an environmental assessment nor an
environmental impact statement is required, but provided incorrect
citations for categorical exclusion in the proposed rules. The correct
citation is 21 CFR 25.32(p). No new information or comments have been
received that would affect the agency's previous determination.

IV. Analysis of Economic Impacts

A. Cost-Benefit Analysis

    FDA has examined the impacts of this final rule under Executive
Order 12866. Executive Order 12866 directs federal agencies to assess
the 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 effects; distributive impacts; and equity). According
to Executive Order 12866, a regulatory action is ``economically
significant'' if it meets any one of a number of specified conditions,
including having an annual effect on the economy of $100 million or
adversely affecting in a material way a sector of the economy,
competition, or jobs. A regulation is considered ``significant'' under
Executive Order 12866 if it raises novel legal or policy issues. FDA
finds that this final rule is neither an economically significant nor a
significant regulatory action as defined by Executive Order 12866.
    In addition, FDA has determined that this rule does not constitute
a significant rule under the Unfunded Mandates Reform Act of 1995
requiring cost benefit and other analyses. A significant rule is
defined in 2 U.S.C. 1532 (a) as ``a 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 (adjusted annually
for inflation) in any 1 year.''
    Finally, in accordance with the Small Business Regulatory
Enforcement Fairness Act, 5 U.S.C. 801(a)(1)(A)(ii), the Administrator
of the Office of Information and Regulatory Affairs of the Office and
Management and Budget has determined that this final rule is not a
major rule for the purpose of Congressional review. A major rule for
this purpose is defined in 5 U.S.C. 804 as one that the Administrator
has determined has resulted or is likely to result in: (A) an annual
effect on the economy of $100,000,000 or more; or (B) a major increase
in costs or prices for consumers, individual industries, Federal,
State, or local government agencies, or geographic regions; or (C)
significant adverse effects on competition, employment, investment,
productivity, innovation, or on the ability of United States-based
enterprises to compete with foreign-based enterprises in domestic or
export markets.

B. Regulatory Options

    FDA did not discuss regulatory options in the analysis of the
proposed rule, because no costs were identified in that analysis.
Public comments on the proposed rule raised a number of potential costs
and a number of issues that may affect the benefits of this rule. The
comments also suggested a large number of regulatory options. The
primary options suggested in the comments were as follows:
    (1) Take no new regulatory action.
    (2) Take no action, but generate or wait for additional information
on which to base a future action.
    (3) Take proposed action.
    (4) Take proposed action, but specify a different minimum level of
soy protein for products bearing the claim.
    (5) Take proposed action, but specify a minimum level of soy
isoflavones in addition to a minimum level of soy protein for products
bearing the claim.
    (6) Take proposed action, but revise the wording of the claim or
require that warnings or other statements accompany the claim.
    (7) Take proposed action, but specify a different maximum total fat
content or grant an exemption from the maximum total fat requirement
for foods made with natural soy beans that have no added fat.

[[Page 57722]]

    (8) Take proposed action, but use a different procedure for
determining level of soy protein in particular products.
1. Option One: Take No New Regulatory Action
    By convention, the option of taking no new regulatory action is the
baseline in comparison with which the costs and benefits of the other
options are determined. Therefore, neither costs nor benefits are
associated with taking no new regulatory action.
2. Option Two: Take No Action, But Generate or Wait for Additional
Information on Which To Base a Future Action
    A number of comments suggested delaying action until further
research is carried out on: (1) The mechanism by which soy protein
reduces the risk of coronary heart disease (CHD), including the role of
soy isoflavones; (2) the effect of particular methods of manufacturing
soy protein isolates and products containing soy protein; (3) the
effect of other characteristics of the diet such as fiber or mineral
content; (4) potential health risks associated with increased intake of
soy protein, soy isoflavones, other components of soybeans, and
artifacts of particular methods of manufacturing soy protein isolates
and products containing soy protein; (5) consumption patterns of foods
containing soy protein and the percentage of such foods that meet the
proposed requirements for the health claim; and (6) methods of
measuring the level of soy protein in foods.
    The cost of delay is the elimination of the benefits that would
have been realized between the effective date of the non-delayed rule
and the effective date of the delayed rule. The potential benefits of
delay are: (1) The reduction of potential health risks, if any,
associated with increased intake of soy protein and other relevant
substances; (2) the reduced likelihood of the potential reduction in
the perceived reliability of FDA-approved claims that might occur if
future research were to require the soy protein health claim be
revised; (3) the increase in the health benefits generated by a delayed
health claim that, potentially, would be more accurate or complete.
    As discussed below, the comments did not provide information
establishing that the benefits of delaying the rule outweigh the costs.
3. Option Three: Take Proposed Action Costs
    A number of comments suggested that this rule might lead to adverse
health effects. According to these comments, potential health risks are
associated with an increased intake of: (1) Soy protein; (2) other
components of soybeans including soybean trypsin inhibitors and
isoflavones such as genistein; (3) artifacts of particular methods of
manufacturing soy protein isolates or products containing soy protein,
such as nitrates, nitrosamines, and lysinolanine; and (4) artifacts of
genetically engineered soy protein. Among the potential health concerns
related to these substances mentioned in the comments were the
following: (1) Allergenicity; (2) reduced bioavailability of vitamins
and minerals including zinc and iron; (3) hormonal alterations,
including changes in fertility and functioning of sex glands; (4)
toxicity in estrogen sensitive tissues and an increase in estrogen-
related diseases; (5) vascular dementia; (6) adverse effects on the
central nervous system and behavioral changes; (7) thyroid
abnormalities, including goiter; (8) cancer; (9) diabetes; (10) liver
disease; (11) adverse effects on the immune and endocrine systems; and
(12) adverse effects on metabolism. Other comments argued that no
health concerns would be associated with the intake levels of soy
protein and the other substances that can be associated with soy
protein, such as soy isoflavones or various by-products of
manufacturing soy protein isolates, that are likely to result from the
proposed health claim.
    As discussed previously in the preamble to this rule, FDA finds
that there is no evidence that any increase in the intake of soy
protein or the other substances discussed in the comments presents a
risk of adverse health effects.
    The availability of the health claim may increase the number of
products containing soy protein. Increased availability of products
containing soy protein may increase the likelihood that those who are
allergic to soy protein may consume such products. The net effect of
this rule on the incidence of allergic reactions to soy protein is
unclear. As discussed earlier in the preamble, the presence of the
health claim will serve to notify consumers of the presence of soy
protein in products that bear the claim. However, some consumers who
are allergic to soy protein may not already know they are allergic to
soy protein and some consumers who do know they are allergic may
inadvertently consume such products despite the presence of the health
claim. FDA has insufficient information to estimate the net effect on
the incidence of allergic reactions to soy protein. In addition, the
addition of soy protein to products that do not currently contain soy
protein may reduce, to some degree, the number of soy-free products
that are available to those who are allergic to soy protein. This
reduction in product choice may lead to utility losses for those
consumers. However, a large number of products will continue to not
contain soy protein, so this utility loss will probably be modest. This
rule may also increase the incidence of the adverse health effects
associated with zinc deficiency, which is typically related to largely
plant-based diets, to some degree. However, FDA has insufficient
information to estimate this effect.
    Some comments suggested that this rule might indirectly increase
the incidence of CHD. According to these comments, the proposed health
claim could lead some consumers to overestimate the role of soy protein
in preventing CHD and to neglect other actions that have an equal or
greater effect on the risk of CHD. Other comments argued that this rule
might lead to the adverse health effects caused by poor nutrition
because the proposed health claim might lead some consumers to
concentrate unduly on foods containing soy protein and to neglect the
other components of a balanced diet. Another comment argued the
proposed health claim could lead to miscellaneous adverse health
effects because it might be interpreted by some consumers as an
endorsement of the miscellaneous benefits that are sometimes claimed
for soy products, such as the prevention of cancer or osteoporosis.
This comment argued that this interpretation would lead some consumers
to neglect the actions that reduce the risk of these other conditions.
    Some consumers may misinterpret the proposed health claim (or any
other health claim). However, the fact that the proposed health claim
states that the risk of CHD may be reduced by an unspecified degree by
consuming a specified level of soy protein per day, as part of a low
saturated fat and low cholesterol diet, makes it unlikely that many
consumers will neglect other activities that reduce the risk of CHD or
neglect other types of foods. Similarly, the fact that the health claim
specifies CHD makes it unlikely that many consumers will interpret the
claim as an endorsement of other benefits that are sometimes claimed
for soy products. The comments did not provide sufficient information
to allow FDA to estimate the likelihood of these effects. Furthermore,
these potential effects are no more likely to be associated with the
proposed claim than with any other claim.

[[Page 57723]]

    Some comments suggested that this rule might indirectly increase
the incidence of miscellaneous adverse health effects by decreasing the
perceived reliability of FDA-approved health claims in general. Some
comments noted the presence of a certain degree of uncertainty
concerning the mechanism by which soy protein reduces the risk of CHD.
One comment argued that if further research on this mechanism were to
find that isoflavones or other components of soybeans are involved, and
the health claim were subsequently revised to reflect those findings,
then FDA's scientific reputation and the perceived value of FDA-
approved health claims could be adversely affected. Other comments
implied that uncertainty over the mechanism means that future research
might show that soy protein does not affect the risk of CHD. Other
comments argued that the proposed claim would reduce FDA's scientific
credibility because it would mean that FDA is treating soy protein in a
manner that is inconsistent with how FDA treats certain other
substances that may reduce the risk of CHD, including estrogens and
linseed oil.
    Future research could lead to results that would lead FDA to revise
the soy health claim. However, the comments did not provide sufficient
information to allow FDA to estimate the likelihood of revisions or to
assess the impact of these revisions on the perceived reliability of
FDA-approved health claims in general. The latter relationship is
highly speculative, because it depends on consumers not knowing that
scientific knowledge is in a constant state of development. In
addition, although some revisions may be necessary, it is unlikely that
future research will indicate that soy protein has no effect on CHD. As
stated earlier in the preamble, FDA has concluded that the scientific
evidence establishes that increased intake of soy protein reduces the
risk of CHD and that this effect is not simply an artifact of the
substitution of lower fat and cholesterol products for higher fat and
cholesterol products. The comment that suggested otherwise ignores the
many studies in which fat, saturated fat, and cholesterol were the same
in treatment and control groups and soy protein still exerted an effect
on the risk of CHD. Also, FDA disagrees that the only mechanism
discussed in the petition was the soy isoflavone mechanism. Finally,
the comments did not provide sufficient information to estimate the
effect of the purported inconsistencies on the perceived value of FDA-
approved health claims. However, in general, it is unclear that the
failure to authorize a health claim for one substance would reduce the
effectiveness of a health claim for another substance.
    A number of comments addressed the method FDA proposed to use to
determine the level of soy protein. Many of the comments recommended
revising the proposed rule. These comments are discussed under Option 8
below.

C. Benefits

    The analysis of the proposed rule discussed the benefit of this
rule in terms of the value to consumers of the information communicated
in the proposed health claim. The comments did not provide information
directly relevant to estimating this value. However, a number of
comments addressed the health and other benefits that might be
generated by changes in consumer behavior that might follow from this
rule. As discussed in the analysis of the proposed rule, the value of
these other benefits may be considered a lower bound on the value to
consumers of the information communicated in the health claim. This
value is a lower bound because some consumers might want that
information, but nevertheless choose not to modify their behavior. In
addition, the value of these other benefits may be considered an
appropriate independent metric for valuing the benefits of this rule
because consumers may value the information in the claim based on the
usefulness of that information for reducing the risk of CHD but may
underestimate or overestimate the usefulness of that information.
    Many comments argued that this rule would lead to a reduction in
the incidence of CHD and provided information relevant to estimating
that reduction. A few comments argued that this rule would not lead to
a reduction in the incidence of CHD because soy protein does not affect
the risk of CHD. One comment argued that this rule would generate
benefits by obviating, in some cases, the need for riskier and more
expensive pharmacological treatments for reducing the risk of CHD.
Thus, according to this comment, this rule might generate benefits even
if no reduction in the incidence of CHD were to take place.
    Quantifying the effect of the proposed health claim on the
incidence of CHD would involve a number of uncertainties and any
ensuing estimate would be imprecise. In addition, there would be little
value to generating such an estimate because, as discussed above, the
comments did not provide sufficient information to estimate the
purported costs of this rule. Therefore, although FDA believes this
final rule will generate benefits, this analysis will not attempt to
quantify the effect of this rule on the incidence of CHD.
    Some comments argued that increasing soy intake would generate
benefits other than a reduction in the risk of CHD, including reduction
in the incidence of cancer, osteoporosis, and menopausal symptoms.
These types of effects would be relevant to the estimation of the
benefits of this rule. However, FDA has reviewed no scientific evidence
to assess whether such benefits exist or to estimate the size of such
benefits.
4. Option Four: Take Proposed Action, but Specify a Different Minimum
Level of Soy Protein for Products Bearing the Claim
    Many comments suggested revising the minimum level of soy protein
that is required for a product to be able to bear the proposed health
claim. Some comments addressed the significance of the 25 g per day of
soy protein on which the proposed 6.25 g per RACC requirement was
based. One comment noted that studies have found that soy protein
affects the risk of CHD at intake levels of between 17 g and 31 g per
day. Another comment argued that between 30 g to 50 g of soy protein
per day is necessary to produce clinically significant results on the
incidence of CHD.
    Specifying the particular daily intake of soy protein that will
have a significant effect on the risk of CHD involves some uncertainty.
However, FDA does not have sufficient information to estimate the
effect of specifying different levels and the comments did not provide
sufficient information to allow FDA to do so. As discussed earlier in
the preamble, FDA believes the 25 g soy protein per day level is
supported by the scientific literature and disagrees that intake levels
of 30 g to 50 g per day is necessary to produce clinically significant
results on the incidence of CHD.
    Other comments did not address the 25 g soy protein per day target
level but did address the 6.25 g per RACC requirement derived from the
daily target level. Some comments argued that the per RACC requirement
was overly restrictive and that few products would qualify for the
health claim under this requirement. One comment analyzed the list of
products that was presented in the petition as qualifying for the
health claim and found that only 61 products would qualify if multiple
flavors of the same product were omitted, and that 88 products would

[[Page 57724]]

qualify if multiple flavors were not omitted. This comment also noted
that many of the products on the list that would qualify are products
that are meant to be added to other products rather than consumed on
their own, that it was unclear whether the final products would
themselves meet the requirements for the proposed claim. Another
comment noted that many of the qualifying products listed in the
petition were varieties of non-dairy soy beverages or tofu, which this
comment argued have not been well accepted by American consumers. Other
comments noted that most of the soy products that are available on the
market that would meet the proposed per RACC requirement are entree-
type products that consumers would probably not consume four times per
day. Some comments suggested that only vegetarian or soy burgers,
shakes, tofu, and non-dairy soy beverages would meet the proposed per
RACC requirement. One comment noted that many of the products that meet
the RACC requirements are specialty items that are only available at
health food stores.
    In contrast, other comments argued that many existing soy products
meet the proposed per RACC requirement or could easily be reformulated
to meet that requirement. One comment suggested that the vast majority
of products containing soy protein that are currently available on the
market meet the proposed RACC level. These comments argued that the
assumption of four eating occasions per day that was used to derive the
6.25 g per RACC requirement from the 25 g per day level was reasonable.
Among the products listed in these comments were the following: tofu,
soy-based beverages, soy burgers and other meat alternatives, frozen
deserts, protein bars, cheese and yogurt alternatives, soybeans, soynut
butter, soynuts, tempeh, miso, and soy flour or soy protein powder.
Another comment implied that any product in which protein is normally
consumed could easily be modified to meet the per RACC requirements,
including snack foods, breakfast cereals, burger patties, and more
formal entrees.
    Some comments argued that the 6.25 g per RACC restrictions would
effectively prevent baked products from bearing the claim. One comment
noted that achieving a level of 6.25 g per RACC in these products would
require incorporating soy flour at 15 percent inclusion or greater and
that would yield a product that would be unacceptable to consumers and
would also be too costly to compete effectively with other products.
Many comments argued that the benefits of this rule would be greater if
commonly consumed products such as baked products were able to bear the
proposed health claim. One comment argued that a per RACC requirement
that allowed baked goods containing soy protein to bear the health
claim might lead to additional benefits in terms of encouraging the
consumption of products from grain group of the USDA/DHHS Food Guide
Pyramid, which this comment claims are currently underconsumed.
    Other comments argued that the proposed per RACC requirement would
effectively prevent other types of products from bearing the health
claim. One comment argued that it is difficult to incorporate 6.25 g
soy protein into a single RACC of most such foods in a way that it
would be palatable to most American consumers, given current and
reasonably anticipated technology.
    Some of the comments that argued that few products would be able to
meet the 6.25 g per RACC requirement recommended lowering the minimum
per RACC level to allow a wider variety of foods to qualify for the
health claim and to make it easier for consumers to achieve an intake
of 25 g soy protein per day. Some comments argued that a level of 4 g
per RACC would allow baked goods, allow soy pasta, low-fat extended
meat products, and vegetarian burgers made with soy flour and textured
soy protein to bear the claim. These comments noted that assuming
intake levels of 5 to 6 servings per day of these types of products
would be reasonable and that 4 g per RACC would, therefore, be
consistent with a daily intake of 25 g per day. Another comment
suggested that FDA has legal precedent for setting the per RACC
requirement as low as 2.5 g per RACC.
    In contrast, some of the comments that argued that few products
would meet the 6.25 g per RACC requirement recommended raising the per
RACC level to reduce the number of servings that would be necessary to
obtain 25 g soy protein per day. Some comments argued that if the
primary source of soy protein were from meals in which high protein
meat dishes are currently eaten, then the per RACC requirement should
be based on two or three servings per day, rather than the proposed
assumption of four servings per day. Thus, these comments suggested
that FDA revise the per RACC requirement from 6.25 g to either 8.3 g or
12.5 g.
    FDA has insufficient information on the characteristics of the soy
products that are currently on the market to determine the proportion
of such products that would qualify for the health claim, the ease with
which existing products can be reformulated to meet the requirements
for making the health claims, or the ease with which new products can
be developed that would meet the requirements for making the health
claim. In addition, FDA has insufficient information on the consumption
patterns of the relevant products to determine whether lowering the per
RACC level would lead more or fewer consumers to consume 25 g soy
protein per day.
    Some comments noted that the proposed health claim contains
information on (1) the daily intake level of soy protein that is
associated with reduced risk of CHD and (2) the level of soy protein in
a serving of the product bearing the claim. According to these
comments, the provision of this information obviates the need to
restrict the claim to products having 6.25 g or more soy protein per
RACC, because consumers can easily determine the relative significance
of particular products as a source of soy protein. These comments
implied that specifying a much lower minimum level of soy protein would
increase benefits because a wider variety of products would then be
able to bear the claim and consumers would more easily be able to
achieve an intake of 25 g soy protein per day.
    Allowing the claim to appear on products containing very low levels
of soy protein might increase the usefulness of the claim for consumers
and might lead to a greater reduction in CHD than would be produced by
taking the proposed action. The agency is unable to determine the
likelihood of this effect.
    Other comments suggested revising the per RACC requirement for
other reasons. One comment argued that the per RACC requirement should
be changed to a requirement based on serving size. This comment argued,
for example, that a single veggie burger that contains 6.25 g of soy
protein should qualify for the health claim, even if the product does
not meet the per RACC requirement because the burger pattie is larger
than the applicable RACC.
    Changing the per RACC requirement to a per serving requirement
would probably increase the number of products that would be able to
bear the proposed health claim and might, therefore, increase the
health benefits generated by the claims. However, the comments did not
provide sufficient information to estimate this effect. In addition,
this revision would require revision of the regulations at 21 CFR
101.12(g), and is, therefore, beyond the scope of this rulemaking.

[[Page 57725]]

    One comment noted that the correct declaration of 6.25 g soy
protein is 6 g because current law mandates that the amount of protein
be rounded to the nearest whole number. According to this comment, this
rounding might confuse consumers. If consumers were confused about the
level of soy protein in the RACC of a particular product and the
significance of that product for meeting the specified daily intake
level, then the benefits of the health claim might be lower than they
would be otherwise. This comment suggested that the per RACC
requirement be revised from 6.25 g to either 6 g or 7 g. As discussed
previously, the rounding requirement applies only to the Nutrition
Facts Panel and soy protein content is not allowed to appear on the
Nutrition Facts Panel.
5. Option Five: Take Proposed action, but Specify a Minimum Level of
Soy Isoflavones in Addition to the Proposed Minimum Level of Soy
Protein for Products Bearing the Claim
    Some comments argued that the effect of soy protein on the risk of
CHD may depend on the presence of soy isoflavones. These comments
recommended that the health claim be restricted to products that
contain a minimum level of total soy isoflavones, of particular
isoflavones, of both total isoflavones and particular isoflavones, or
of amino acids such as arginine and methionine. Some of the comments
that argued that the beneficial effects of soy protein may depend on
the presence of soy isoflavones also noted that particular
manufacturing or processing methods can affect the level of soy
isoflavones. These comments recommended that the health claim be
restricted to products that have been manufactured or processed in
particular ways. For example, many comments noted that alcohol washing
reduces isoflavone content and suggested that products containing
alcohol washed or extracted soy protein isolate should not be
authorized to bear the health claim. Some comments added that there is
no evidence that adding purified soy isoflavone extract back into such
products is effective and argued that any isoflavone requirement should
be based on naturally occurring isoflavones.
    As discussed earlier in this preamble, FDA finds that the
scientific evidence does not indicate that the effect of soy protein on
the risk of CHD varies with the presence of soy isoflavones or amino
acids. Therefore, no additional benefit would result from restricting
the claim to products having particular levels of isoflavones, or
produced using particular methods of manufacture.
6. Option Six: Take Proposed Action, but Revise Wording of the Claim or
Require That Warnings or Other Statements Accompany the Claim
    Some comments suggested that FDA require additional information be
put on the labels of product bearing the proposed claim that explains
the conditions under which soy protein reduces the risk of CHD. For
example, some comments suggested that product labels should make it
clear that no benefits should be expected for daily soy protein intake
levels of less than 25 g. Some comments argued that the beneficial
effects of soy protein accrue only to consumers who have high
cholesterol levels and suggested that the proposed health claim be
revised to communicate this fact.
    Although requiring a label statement clarifying that benefits
should not be expected for daily soy protein intake levels of less than
25 g might generate benefits, the marginal benefits of such a statement
are unclear given that the proposed health claim relates health effects
to an intake of 25 g per day and not to the intake of any particular
product. The comment did not provide sufficient information to estimate
the marginal benefit of an additional statement concerning the
significance of the 25 g per day intake level. Finally, as discussed
previously in this preamble, FDA has determined that the effect of soy
protein on the risk of CHD may depend, in part, on initial cholesterol
levels, but does not accrue only to those with high initial cholesterol
levels. Therefore, restricting the health claim to apply to only those
with high initial cholesterol levels would not generate marginal
benefits.
    Some of the comments that argued that the increased consumption of
products containing soy protein could lead to health risks suggested
that FDA require warning labels on those products to alert consumers of
the risks. Other comments suggested that various types of information
relevant to the purported health risks be reported on product labels.
For example, one comment that argued that increased intake of soy
protein could lead to zinc deficiency suggested that the labels of
products bearing the health claim indicate the phytate and zinc content
per serving for those products. One comment suggested that labels
indicate a recommended maximum daily intake of soy protein to prevent
the health risks associated with overconsumption of products containing
soy protein. This comment argued that daily consumption of between 25 g
and 100 g of isolated soy protein could result in nitrosamine exposures
that exceeds established No Significant Risk Levels. One comment argued
that manufacturers should voluntary provide information on product
labels on various issues such as manufacturing methods and the use of
pesticides, because consumers have a right to such information.
    FDA has determined that there is no evidence that health risks are
associated with increased intake of soy protein or the other substances
discussed in the comments. Label statements warning of possible
allergic reactions to soy protein would provide some potentially
valuable information to consumers who do not realize they are allergic
to soy protein or that such allergies are possible. However, such
labeling would not provide useful information to those consumers who
are already aware of the fact that allergies to common foods are
possible, and might discourage the consumption of soy protein by those
who are not allergic to soy protein. FDA has insufficient information
to estimate the costs or benefits of such a warning statement or to
determine if such a warning statement would provide a net benefit to
consumers. Associating warning statements with the proposed health
claim would generate no marginal benefits for consumers who know they
are allergic to soy protein because the health claim would already
indicate the presence of soy protein.
    Label statements addressed to the potential effect of increased
consumption of products containing soy protein on zinc deficiency, such
as a warning statement, indications of the zinc and phytate content of
products containing soy protein, or recommended maximum daily intakes,
might reduce the likelihood that increased consumption of these
products will lead to zinc deficiency. Earlier in the preamble to this
rule, FDA determined that consumers would not find information relating
to the zinc and phytate content of products containing soy protein
useful. The other suggested labeling approaches for addressing the
effect of increased consumption of these products on zinc deficiency
may be useful for some consumers. However, again, the benefit of such
labeling must be compared to the possible costs in terms of
discouraging the use of such products among those who are not at risk
of zinc deficiency. FDA has insufficient information to estimate the
costs or benefits of the other suggested labeling approaches or
determining whether such approaches would generate net benefits.
    One comment suggested eliminating the language relating the effect
of soy protein to diets low in saturated fat and

[[Page 57726]]

cholesterol because the effect of soy protein on the risk of CHD is
independent of these other factors. The benefit of eliminating this
language is that consumers who are not currently eating a diet low in
saturated fat and cholesterol may be more likely to react to the health
claim if the effect of soy protein is not presented as applying only to
those eating diets low in saturated fat and cholesterol. An increase in
the number of consumers likely to react to the health claim may
increase the benefits of the health claim. However, the size of this
marginal benefit is unclear because, as discussed earlier, the
available data on the effects of soy protein show that soy protein has
a more consistent effect on CHD for those consuming a low fat and
cholesterol diet than for others. The cost of eliminating this language
is that some consumers might believe that achieving a certain intake of
soy protein can substitute for eating a diet low in saturated fat and
cholesterol and might, therefore, indirectly increase the intake of
saturated fat and cholesterol. FDA has insufficient information to
determine if eliminating the language relating the effect of soy
protein to diets low in saturated fat and cholesterol would generate
net benefits or costs.
    Some comments suggested that the proposed health claim was either
too long or too complicated to be effective. Many comments argued that
the health claim would be more effective if it were shortened or
replaced by a ``split claim.'' Many comments suggested wording for a
shorter health claim. Increasing the effectiveness of the health claim
would increase the benefits associated with the health claim and would
not affect costs. However, FDA has insufficient information to analyze
the effect of different labeling formats or wording. Although FDA has
studied the effectiveness of split claims for other types of claims,
the relevance of that information for a health claim on soy protein is
unclear.
7. Option Seven: Take Proposed Action, but Specify a Different Maximum
Total Fat Content or Grant an Exemption from the Maximum Total Fat
Requirement for Foods Made With Natural Soybeans That Have No Added Fat
    Many comments noted that the low fat requirement for products
bearing the proposed health claim would prevent soybeans and
traditional soybean products from bearing the health claim. This rule
has been revised so that foods made from whole soybeans with no added
fat are exempted from the low fat requirement. The benefit of this
revision is that more products will be able to bear the proposed health
claim and the benefits generated by the health claim may be increased.
The cost of this revision is that the total fat content of some
products bearing the claim may be slightly higher than under the
proposed rule. As explained earlier in the preamble, a reduction of
total fat facilitates maintenance of normal body weight and, therefore,
reduces the risk of obesity. The reduction of this effect would cause
an increase in the risk of obesity and, therefore, produce a
countervailing increase in the risk of CHD. In this case, the benefit
of increasing the number of products probably outweighs the slight
increase in the total fat content of qualifying products.
8. Option Eight: Take Proposed Action, but Use a Different Procedure
for Determining Level of Soy Protein in Particular Products.
    Many comments on the proposal addressed the analytical method that
FDA proposed to use to confirm the level of soy protein in products
bearing the proposed health claim. These comments were discussed in the
reproposal. The reproposal specified various types of records that
might allow FDA to calculate the level of soy protein in particular
products. FDA received a number of comments on the reproposal. Most of
these comments addressed the issue of which records FDA will use to
determine the soy protein content of foods. Many comments argued that
the reproposal appeared to allow FDA wide discretion in determining
which records to inspect and duplicate. These comments also expressed
the concern that FDA might inspect and duplicate records of each of the
various types that were specified as potentially relevant in the
reproposal, and might also inspect and duplicate as yet unspecified
records that FDA later determines are relevant. According to these
comments, some of the resulting record inspection and duplication might
be unwarranted. Many comments suggested that the rule be revised to
require manufacturers to provide FDA with records that provide a
reasonable basis for concluding that a particular product has
sufficient soy protein content to bear the health claim. According to
these comments, this revision would eliminate the possibility that FDA
will use the records inspections clause to inspect and duplicate
records in situations in which such actions are not strictly necessary.
One comment argued that the records inspection provision would give an
unfair market advantage to firms that manufacture products whose sole
source of protein is soy and which, therefore, need not provide FDA
access to records to establish the level of soy protein in their
products.
    If FDA were to require the inspection and duplication of records
that firms attempting to use the soy protein health claim considered
unnecessary to establish compliance with the requirements for making
that claim, then those firms would have less incentive to use the claim
and the benefits associated with allowing that claim would be reduced.
However, FDA has modified its proposal to inspect records to provide,
instead, that manufacturers must identify and supply to FDA, on written
request, records that substantiate the amount of soy protein in a food
that bears the soy protein health claim if soy is not the sole source
of protein in the food. Therefore, this rule will not require record
inspection or unnecessary duplication of records. This rule may
generate some distributive effects because it may put firms that are
required to provide such records at a competitive disadvantage relative
to firms that produce products in which soy is the only source of
protein. However, these effects will probably be small because
manufacturers probably already maintain the necessary records.

D. Small Entity Analysis

    FDA has examined the impacts of this proposed rule under the
Regulatory Flexibility Act. The Regulatory Flexibility Act (5 U.S.C.
601-612) requires federal agencies to consider alternatives that would
minimize the economic impact of their regulations on small businesses
and other small entities. No compliance costs are generated by this
rule because this rule does not require any labels to be changed, or
any product to be reformulated. Therefore, small businesses will only
relabel or reformulate products if the benefits to those small
businesses outweigh the costs. FDA did not receive any comments that
challenged this conclusion. Accordingly, pursuant to the Regulatory
Flexibility Act, 5 U.S.C. 605(b), FDA certifies that this rule will not
have a significant economic impact on a substantial number of small
entities.

V. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520).
The title, description, and respondent description

[[Page 57727]]

are shown below with an estimate of the annual recordkeeping and
reporting burden. Included in the estimate is the time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
    Title: Record Retention Requirements for the Soy Protein/CHD Health
Claim
    Description: The regulation set forth in this rule authorizes the
use in food labeling of a health claim about the relationship between
soy protein and CHD. Section 403(r) of the act requires that food
bearing a health claim authorized by regulation on a petition to the
agency be labeled in compliance with the regulation issued by FDA. In
response to comments received on the soy protein proposed rule (63 FR
62977), the agency proposed an alternative procedure for assessing
compliance with the requirement that a food contain a qualifying amount
of soy protein in the soy protein reproposal (64 FR 45932). This
procedure would have required that a manufacturer of a product bearing
the proposed soy protein health claim whose product contains a source
or sources of protein in addition to soy retain the records that permit
the calculation of the ratio of soy protein to other sources of protein
in the food. The manufacturer of such a food product would have been
required to make those records available for review and copying by
appropriate regulatory officials upon request and during site visits.
Comments received on the soy protein reproposal have been addressed by
the agency in section II.C.2 of this document, and this rule reflects
modifications made in response to those comments. This final rule
requires a manufacturer of a product bearing the soy protein health
claim whose product contains a source or sources of protein in addition
to soy to identify and retain records that reasonably substantiate the
ratio of soy protein to total protein. The rule also requires the
manufacturer of such a food product to provide those records upon
written request to appropriate regulatory officials.
    FDA had submitted the information collection requirements to OMB
for review under the PRA at the time the August 1999 soy protein
reproposal was published. In response, OMB requested that FDA respond
to the need for the collection and the burden hours that will be
imposed as a result of this collection.
    To bear the soy protein and CHD health claim, foods must contain
6.25 g soy protein per RACC. For foods that contain soy as the sole
source of protein, analytical methods for total protein can be used to
quantify the amount of soy protein. At the present time, there is no
validated analytical methodology available to quantify the amount of
soy protein in foods that contain other proteins. For these latter
foods, FDA must rely on information known only to the manufacturer to
assess compliance with the qualifying amount of soy protein. Thus, FDA
is requiring manufacturers to have and keep records to substantiate the
amount of soy protein in a food that bears the health claim and
contains sources of protein other than soy, and to make such records
available to appropriate regulatory officials upon written request.
    Although no comments on the soy protein reproposal specifically
addressed the estimated burden of the information collection
requirements, several indicated that recordkeeping and record
inspection would be burdensome. These comments expressed concern about
FDA's record inspection authority. In response to this concern, FDA has
determined that, in this case, it need not assert record inspection
authority in order to obtain the information needed for compliance
assessment. The comments also expressed concern about the potentially
broad array of records that FDA might demand. In response to this
concern, FDA clarified that it did not intend to specify the records to
be supplied. Rather, the final rule indicates that records will be
requested in writing and that manufacturers will be responsible for
identifying the records that they have used to substantiate the
proportion of soy protein in their products.
    FDA estimates the burden of this collection of information as
follows:
    Description of Respondents: Businesses or others for-profit.

                                Table 2.--Estimated Annual Recordkeeping Burden <SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
                                                            Annual          Total
               21 CFR                      No. of       frequency per      annual       Hours per    Total Hours
                                        respondents        response       responses     response
----------------------------------------------------------------------------------------------------------------
101.82(c)(2)(ii)(B).................               25                1            25             1           25
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.

                                 Table 3.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                            No. of          Total
           21 CFR Section                  No. of       responses per      annual       Hours per    Total hours
                                        respondents       respondent      responses     response
----------------------------------------------------------------------------------------------------------------
101.82(c)(2)(ii)(B).................                5                1             5             1            5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.

    Manufacturers must determine that their products are qualified to
bear any claim used on foods labels or in labeling, including meeting
the requirement for a qualifying amount of soy protein to bear the
health claim authorized for use by this regulation. In the absence of a
validated analytical methodology for soy protein in foods that contain
other proteins, manufacturers will need to use records, e.g., the
food's formulation or recipe, to determine if such a food contains 6.25
g per RACC. In this rule, FDA is requiring that firms maintain the
records they use to determine that a food is qualified to bear the
claim, and that those records be submitted to FDA upon written request.
Based upon its experience with the use of health claims, FDA estimated
that 25 firms would market products bearing a soy protein and CHD
health claim and that one of each firm's products would contain a
source or sources of protein in addition to soy. FDA received no
comments that challenged this estimate. FDA estimates that, annually,
it would request records to assess compliance from 20 percent of firms
subject to the

[[Page 57728]]

recordkeeping requirement. The records that would be required to be
retained by Sec. 101.82(c)(ii)(B)(2) are records that, as described
above, FDA believes a prudent and responsible manufacturer uses and
retains as a normal part of doing business. Thus, the burden to the
food manufacturer would be that involved in assembling and providing
the records to appropriate regulatory officials upon written request.
The requirements contained in this rule would require only a minimal
burden, no more than one hour per response, from respondents.
    The information collection provisions of this final rule have been
submitted to OMB for review. FDA will publish a notice in the Federal
Register announcing OMB's decision to approve, modify, or disapprove
the information collection provisions in this final rule. An agency may
not conduct or sponsor, and a person is not required to respond to, a
collection of information unless it displays a currently valid OMB
control number.

VI. 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. Protein Technologies International, Inc., ``Health Claim
Petition,'' May 4, 1998 [CP1, vol. 1-3].
    2. Protein Technologies International, Inc., ``Addendum to
Health Claim Petition,'' August 10, 1998 [CP1, vol. 4].
    3. American Soybean Association, ``Health Claim Petition for Soy
Protein,'' October 29, 1998 [C1, vol. 8-12].
    4. DHHS, Public Health Service (PHS), ``The Surgeon General's
Report on Nutrition and Health,'' U.S. Government Printing Office,
Washington, DC, pp. 83-137, 1988.
    5. Food and Nutrition Board, National Academy of Sciences,
``Diet and Health: Implications for Reducing Chronic Disease Risk,''
National Academy Press, Washington, DC, pp. 291-309 and 529-547,
1989.
    6. DHHS, Public Health Service (PHS) and National Institutes of
Health, ``National Cholesterol Education Program: Population Panel
Report,'' Bethesda, MD, pp. 1-40, 1990.
    7. Sempos, C. T., J. I. Cleeman, M. D. Carroll, C. L. Johnson,
P.S. Bachorik, D. J. Gordon, V. L. Burt, R. R. Briefel, C. D. Brown,
K. Lippel, and B. M. Rifkind, ``Prevalence of High Blood Cholesterol
Among U.S. Adults. An Update Based on Guidelines From the Second
Report of the National Cholesterol Education Program Adult Treatment
Panel,'' Journal of the American Medical Association, 269:3009-3014,
1993.
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Participants: DuPont and FDA, December 5, 1996.

List of Subjects in 21 CFR Part 101

    Food labeling, 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, 21 CFR part
101 is amended as follows:

PART 101--FOOD LABELING

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

    1. Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331,
342, 343, 348, 371.

    2. Add Sec. 101.82 to subpart E to read as follows:

Sec. 101.82  Health claims: Soy protein and risk of coronary heart
disease (CHD).

    (a) Relationship between diets that are low in saturated fat and
cholesterol and that include soy protein and the risk of CHD. (1)
Cardiovascular disease means diseases of the heart and circulatory
system. CHD is one of the most common and serious forms of
cardiovascular disease and 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. 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 and LDL-cholesterol levels of
160 mg/dL (4.13 mmol/L) or above. Borderline high risk total
cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18 mmol/L)
and 130 to 159 mg/dL (3.36 to 4.11 mmol/L) of LDL-cholesterol. 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.
    (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) Scientific evidence demonstrates that diets low in saturated
fat and cholesterol may reduce the risk of CHD. Other evidence
demonstrates that the addition of soy protein to a diet that is low in
saturated fat and cholesterol may also help to reduce the risk of CHD.
    (b) Significance of the relationship between diets that are low in
saturated fat and cholesterol and that include soy protein 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) 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 an average of 30 percent or less of
total calories from all fat. 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. Soy protein, when included in a low
saturated fat and cholesterol diet, also helps to lower blood total and
LDL-cholesterol levels.
    (c) Requirements. (1) All requirements set forth in Sec. 101.14
shall be met.
    (2) Specific requirements--(i) Nature of the claim. A health claim
associating diets that are low in saturated fat and cholesterol and
that include soy protein 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 diets that are low in saturated fat and
cholesterol and that include soy protein ``may'' or ``might'' reduce
the risk of heart disease;
    (B) In specifying the disease, the claim uses the following terms:
``heart disease'' or ``coronary heart disease'';
    (C) In specifying the substance, the claim uses the term ``soy
protein'';
    (D) In specifying the fat component, the claim uses the terms
``saturated fat'' and ``cholesterol'';
    (E) The claim does not attribute any degree of risk reduction for
CHD to diets that are low in saturated fat and cholesterol and that
include soy protein;
    (F) The claim does not imply that consumption of diets that are low
in saturated fat and cholesterol and that include soy protein is the
only recognized means of achieving a reduced risk of CHD; and
    (G) The claim specifies the daily dietary intake of soy protein
that is necessary to reduce the risk of coronary heart disease and the
contribution one serving of the product makes to the specified daily
dietary intake level. The daily dietary intake level of soy protein
that has been associated with reduced risk of coronary heart disease is
25 grams (g) or more per day of soy protein.
    (ii) Nature of the substance. (A) Soy protein from the legume seed
Glycine max.
    (B) FDA will assess qualifying levels of soy protein in the
following fashion: FDA will measure total protein content by the
appropriate method of analysis given in the ``Official Methods of
Analysis of the AOAC International,'' as

[[Page 57733]]

described at Sec. 101.9(c)(7). For products that contain no sources of
protein other than soy, FDA will consider the amount of soy protein as
equivalent to the total protein content. For products that contain a
source or sources of protein in addition to soy, FDA will, using the
measurement of total protein content, calculate the soy protein content
based on the ratio of soy protein ingredients to total protein
ingredients in the product. FDA will base its calculation on
information identified and supplied by manufacturers, such as nutrient
data bases or analyses, recipes or formulations, purchase orders for
ingredients, or any other information that reasonably substantiates the
ratio of soy protein to total protein. Manufacturers must maintain
records sufficient to substantiate the claim for as long as the
products are marketed and provide these records, on written request, to
appropriate regulatory officials.
    (iii) Nature of the food eligible to bear the claim. (A) The food
product shall contain at least 6.25 g of soy protein per reference
amount customarily consumed of the food product;
    (B) The food shall meet the nutrient content requirements in
Sec. 101.62 for a ``low saturated fat'' and ``low cholesterol'' food;
and
    (C) The food shall meet the nutrient content requirement in
Sec. 101.62 for a ``low fat'' food, unless it consists of or is derived
from whole soybeans and contains no fat in addition to the fat
inherently present in the whole soybeans it contains or from which it
is derived.
    (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 are low in saturated fat and cholesterol and that include
soy protein 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
are low in saturated fat and cholesterol and that include soy protein
and CHD and the significance of the relationship;
    (4) The claim may state that a diet low in saturated fat and
cholesterol that includes soy protein is consistent with ``Nutrition
and Your Health: Dietary Guidelines for Americans,'' U.S. Department of
Agriculture (USDA) and Department of Health and Human Services (DHHS),
Government Printing Office (GPO);
    (5) 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;
    (6) 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
of Health, or ``Nutrition and Your Health: Dietary Guidelines for
Americans,'' USDA and DHHS, GPO;
    (e) Model health claim. The following model health claims may be
used in food labeling to describe the relationship between diets that
are low in saturated fat and cholesterol and that include soy protein
and reduced risk of heart disease:
    (1) 25 grams of soy protein a day, as part of a diet low in
saturated fat and cholesterol, may reduce the risk of heart disease. A
serving of [name of food] supplies ____ grams of soy protein.
    (2) Diets low in saturated fat and cholesterol that include 25
grams of soy protein a day may reduce the risk of heart disease. One
serving of [name of food] provides ____ grams of soy protein.

    Dated: October 19, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-27693 Filed 10-20-99; 10:35 a.m.]
BILLING CODE 4160-01-P