[Federal Register Volume 64, Number 206 (Tuesday, October 26, 1999)]
[Rules and Regulations]
[Pages 57700-57733]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-27693]



[[Page 57699]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 101



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

  Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / 
Rules and Regulations  

[[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 1
----------------------------------------------------------------------------------------------------------------
                                                            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 
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October, 1997.
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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