[Federal Register Volume 61, Number 20 (Tuesday, January 30, 1996)]
[Rules and Regulations]
[Pages 3118-3173]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1584]




[[Page 3117]]

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Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 172



Food Additives Permitted for Direct Addition to Food for Human 
Consumption: Olestra; Final Rule

Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / 
Rules and Regulations 

[[Page 3118]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 87F-0179]


Food Additives Permitted for Direct Addition to Food for Human 
Consumption; Olestra

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the food 
additive regulations to provide for the safe use of sucrose esterified 
with medium and long chain fatty acids (olestra) as a replacement for 
fats and oils. This action is in response to a petition filed by the 
Procter & Gamble Co.

DATES: The regulation is effective January 30, 1996. Submit written 
objections and requests for a hearing by February 29, 1996. Submit 
written comments on the labeling requirement (Sec. 172.867(c)) by April 
1, 1996. The Director of the Office of the Federal Register approves 
the incorporations by reference in accordance with 5 U.S.C. 552(a) and 
1 CFR part 51 of certain publications at 21 CFR 172.867, effective 
January 30, 1996.
ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Helen R. Thorsheim, Center for Food 
Safety and Applied Nutrition (HFS-216), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3092.

SUPPLEMENTARY INFORMATION: 
Table of Contents
I. Introduction
    A. Safety Testing--Background
1. Legal Context of the Safety Evaluation
2. Dietary Context of the Safety Evaluation
    B. Toxicological Studies--Overview
    C. Nutritional Impact Studies--Overview
    D. GI Effects--Overview
    E. FDA's Decision Process
II. Identity and Use
    A. Manufacturing Processes
    B. Constituents
    C. Specifications
    D. Stability
    E. Use and Intended Technical Effect
    F. Estimated Daily Intake for Olestra (EDI)
III. Toxicity Data--Discussion and Evaluation
    A. Absorption, Distribution, Metabolism, and Elimination.
 1. Rat Studies
 2. Guinea Pig Studies
 3. Mini-Pig Studies
    B. Genetic Toxicity Studies
    C. Animal Toxicity Studies
1. Teratogenicity studies
2. Subchronic and chronic feeding studies
a. Ninety-day subchronic olestra feeding study in rats
b. Two-year carcinogenicity studies in rats
c. Two-year chronic toxicity and carcinogenicity studies in mice
d. Dog feeding studies
    D. Toxicology summary
IV. Effect of Olestra on Absorption of Drugs
    A. Effect of Olestra on the Absorption of Selected Lipophilic Drugs 
(EC-40)
    B. Effect of Olestra on the Absorption of Selected Lipophilic Drugs 
(EC-41)
    C. Effect of Olestra on Drug Bioavailability (EC-42)
    D. Effect of Olestra on the Systemic Levels of Steroidal Hormones 
in Women Taking Oral Contraceptives (EC-51)
    E. Summary
V. Nutritional Studies
    A. Issues Associated with Olestra
    B. Effects of Olestra on Fat-Soluble Vitamins
1. Primary Human Studies
a. Eight-week DR study design
b. Eight-week VR study design
c. Results and conclusions from primary human studies
i. Vitamin A
ii. Vitamin E
iii. Vitamin D
iv. Vitamin K
v. Carotenoids
2. Other Human Studies
a. Six-week vitamin D/K study
b. Sixteen-week vitamin E study
c. Vitamin A/Fat Study
    3. Pig Studies
    a. Study design of the 12-, 26-, and 39-week studies
    i. Twelve-week DR Study
    ii. Twelve-week VR Study
    iii. Twenty-six week DR/VR Study
    iv. Thirty-nine week VR Study
    b. Study design of the 4-week DC study
    c. Results and conclusions from pig studies
    i. Vitamin A
    ii. Vitamin E
    iii. Vitamin D
    a. Petitioner conclusions
    b. FDA Conclusions
    iv. Vitamin K
    4. Overall Conclusions Regarding Olestra's Effects on Fat-Soluble 
Vitamins
    a. Consumption scenarios
    b. Vitamin A
    c. Vitamin E
    d. Vitamin D
    e. Vitamin K
    i. Petitioner conclusions
    ii. FDA conclusions
    f. Carotenoids
    i. Data and information regarding carotenoids
    ii. FDA's evaluation of olestra's effects on carotenoids
    C. Effects of Olestra on Water-Soluble Nutrients that are Hard-to-
Absorb or Limited in Diet
    1. Results and Conclusions from Human Studies
    a. Vitamin B<INF>12
    b. Iron
    c. Folate
    d. Zinc
    2. Results and Conclusions from Pig Studies
    a. Vitamin B<INF>12
    b. Iron
    c. Folate
    d. Zinc-
    e. Calcium
    3. Overall Conclusions Regarding Olestra's Effects on Water-Soluble 
Nutrients
    a. Vitamin B<INF>12
    b. Folate and Iron
    c. Zinc
    d. Calcium
VI. Effect of Olestra on the Gastrointestinal (GI) Tract
    A. Introduction
    B. Effect of Olestra on GI Symptoms
    1. Study of GI Symptoms in 8-week Studies in Normal Subjects
    a. Petitioner's evaluation of GI symptoms
    b. FDA's evaluation of the GI symptoms
    2. GI Symptoms in the Oil Loss Study
    a. Effect of olestra stiffness on passive oil loss
    b. Effect of olestra stiffness on OIT
    c. Effect of olestra stiffness on GI symptoms
    3. Study of Selected Fecal Parameters in Subjects Consuming Olestra
    a. Study design
    b. Petitioner conclusions
    C. FDA Conclusions
    4. Study in Patients with Inflammatory Bowel Disease
    5. GI Symptoms in Young Children
    C. Effect of Olestra on Intestinal Microflora Metabolism
    1. Effect of Olestra on Breath Gas and Microflora-Associated 
Characteristics
    2. Potential for Intestinal Microflora to Metabolize Olestra
    D. Effect of Olestra on Bile Acid Metabolism
    E. Overall Conclusions on Effects on the GI Tract
    
[[Page 3119]]

VII. Labeling of Foods Containing Olestra
    A. Labeling Authority
    B. Labeling with Respect to GI Effects
    C. Labeling with Respect to Effects on Nutrients
    D. FAC Discussions Regarding Labeling
    1. GI Effects
    2. Fat-Soluble Vitamins and Carotenoids
    E. Agency Conclusions Regarding Labeling of Foods Containing 
Olestra
VIII. Response to Comments
    A. Comments on Procedures
    B. Substantive Comments
IX. Environmental Impact Considerations
X. FDA's Overall Conclusions
XI. Administrative Record and Inspection of Documents
XII. Objections
XIII. References

I. Introduction

    Olestra, also called sucrose polyester, is the common name for a 
mixture of substances formed by chemical combination of sucrose with 
six, seven, or eight fatty acids. The fatty acids, bound to sucrose by 
ester bonds, are of the type commonly found in edible oils and fats. 
Olestra has physical properties similar to those of natural fats. 
Olestra's particular physical properties depend on the specific fatty 
acids used and the degree of esterification.
    The Procter & Gamble Co., 6071 Center Hill Rd., Cincinnati, OH 
45224-1703 (the petitioner), submitted a petition to FDA on April 15, 
1987, for the use of olestra in shortenings and oils as a calorie-free 
replacement for fats and oils. The petition (FAP 7A3997) was filed on 
May 7, 1987. In a notice in the Federal Register of June 23, 1987 (52 
FR 23606), FDA announced that the food additive petition had been filed 
by Procter & Gamble, proposing the issuance of a food additive 
regulation providing for the safe use of sucrose esterified with medium 
and long chain fatty acids as a replacement for fats and oils. On July 
6, 1990, the petitioner amended the petition to limit the intended use 
of olestra to a 100 percent replacement for conventional fats in the 
preparation of savory snacks (i.e., snacks that are salty or piquant 
but not sweet, such as potato chips, cheese puffs and crackers). During 
the course of the petition evaluation, the petitioner also amended the 
proposed specifications that describe the additive.
    In the Federal Register of October 17, 1995 (60 FR 53740), FDA 
announced that a public meeting of the agency's Food Advisory Committee 
(the FAC) and a working group of the FAC would be held on November 14 
through 17, 1995. The working group was asked to discuss and comment on 
whether all relevant issues associated with olestra had been addressed 
(Ref. 1). The discussion covered all aspects of the safety review of 
olestra, including nutrient effects and compensation, gastrointestinal 
effects, and labeling (Ref. 2\1\).

    \1\The transcript of the Olestra Working Group and full Food 
Advisory Committee meetings are provided as reference. Throughout 
the preamble to this final rue, reference is made to comments of 
Committee members and presenters to the Committee; footnotes 
indicate the transcript volum and page numbers of these. The 
affiliation and credentials of the commenter are also described.
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    In the Federal Register of November 16, 1995 (60 FR 57586), FDA 
announced that it would consider public comments on the petition, 
including comments on the proceedings before the FAC, only if filed on 
or before December 1, 1995. This action allowed the agency to identify 
precisely which data and information to consider in making its decision 
on the petition. This measure was necessary to facilitate the agency's 
decision making process and to come to closure on the petition. By 
letter dated December 8, 1995, FDA extended to December 21, 1995, the 
time by which such comments could be submitted. This extension was in 
response to a request of the Center for Science in the Public Interest 
(CSPI).\2\

    \2\On October 25, 1995, CSPI submitted a comment to the olestra 
petition entitiled ``White Paper on Olestra'' (the White Paper). 
(CSPI subsequently submitted revised versions of the White Paper on 
November 2 and 3, 1995.) The November 3, 1995, White Paper was 
provided to the Olestra Working Group and FAc members for 
consideration at the meetins of November 14-17, 1995 (Ref.3). In 
addition, the authors of the White Paper, Drs. Myra Karstadt and 
Michael Jacobson, presented data from the White Paper on all of the 
issues covered in the White Papers, namely, (1) consumption 
estimates, (2) effect of olestra on carotenoids, (3) effect of 
supplementation of olestra with vitamin K on coumadin therpay, (4) 
effect of olestra on GI symptoms, and (5) animal carcinogenicity 
studies.
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A. Safety Testing-Background

1. Legal Context of the Safety Evaluation
    Section 409 of the act (21 U.S.C. 348), sets forth the statutory 
requirements for approval of a food additive (21 U.S.C. 321(s)). With 
the enactment of the Food Additives Amendment of 1958 (the Amendment), 
Congress established a premarket approval system whereby the company 
seeking to market a food additive must first obtain approval from FDA. 
Through this mechanism, Congress sought to shield the public from 
unsafe or potentially unsafe products.
    Under section 409(c)(3) of the act, 21 U.S.C. 348(c)(3), FDA is not 
to approve a food additive petition ``* * * if a fair evaluation of the 
data before the Secretary\3\ * * * fails to establish that the proposed 
use of the food additive, under the conditions of use to be specified 
in the regulation, will be safe * * *. This provision is commonly 
referred to as the ``general safety clause.''

    \3\This decision has been delegated to the Commissioner of Food 
and Drugs, 21 CFR 5.10(a)(1).
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    By requiring that the data concerning a food additive ``establish'' 
safety, Congress squarely placed the burden of proving safety on the 
sponsor of a food additive petition, in this case Procter & Gamble. FDA 
need not prove that the additive is unsafe in order to deny approval.
    The term ``safe'' is not defined in the act itself. The legislative 
history of the Amendment makes clear, however, that a demonstration of 
absolute harmlessness is not required to sustain the approval of a food 
additive:
    Safety requires proof of a reasonable certainty that no harm 
will result from the proposed use of an additive. It does not-- and 
cannot--require proof beyond any possible doubt that no harm will 
result under any conceivable circumstance. This was emphasized 
particularly by the scientific panel which testified before the 
subcommittee. The scientists pointed out that it is impossible in 
the present state of scientific knowledge to establish with complete 
certainty the absolute harmlessness of any chemical substance.
H. Rept. No. 2284, 85th Cong., 2d sess. 4-5 (1958). Accord: S. Rept. 
No. 2422, 85th Cong., 2d sess. 2 (1958). FDA regulations incorporate 
the concept of safety articulated in the Amendment's legislative 
history. 21 CFR 170.3(i). (``Safe'' means that ``* * * there is a 
reasonable certainty in the minds of competent scientists that the 
substance is not harmful under the intended conditions of use.'')
    Although the concept of ``harm'' is central to the act's safety 
standard, neither the statute, nor regulations implementing the food 
additive provisions, define harm. Once again, however, congressional 
intent is clear from the legislative history of the amendment. 
Specifically, ``harm'' means the capacity to injure or otherwise damage 
the health of individuals consuming the additive.+
    The concept of safety used in this legislation involves the 
question of whether a substance is hazardous to the health of man or 
animal.
H. Rept. No. 2284, 85th Cong., 2d sess. 4 (1958). See also Letter from 
Assistant Secretary of Health, Education, and Welfare Elliot L. 
Richardson to Congressman Lister Hill, Chairman, 

[[Page 3120]]
Senate Committee on Labor and Human Resources, dated July 29, 1958. 
(``* * * in our opinion the bill is aimed at preventing the addition to 
the food our people eat of any substances the ingestion of which would 
expect to produce not just cancer but any disease or disability.'')
    The concept of harm was discussed during the Olestra Working Group 
and FAC meetings. One FAC member expressed the opinion that he would 
consider an effect that is undesirable as harmful or adverse\4\. 
However, the legislative history reflects that an effect is harmful if 
it affects health, not if it is simply an undesirable or unexpected 
effect that has no adverse health consequences.

    \4\Statement of Dr. Dennis Hsieh. Dr. Hsieh is a professor of 
environmental toxicology at the University of California at Davis. 
Transcript of the November 14 to 17, 1995, meeting of FAC 
(hereinafter Transcript), vol. 3, p. 40.
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    The statute leaves the methods and criteria for interpreting data 
up to the discretion and expertise of the agency. Congress did, 
however, direct FDA to consider the following three factors:
    (A) The probable consumption of the additive and of any substance 
formed in or on food because of the use of the additive;
    (B) The cumulative effect of such additive in the diet of man or 
animals, taking into account any chemically or pharmacologically 
related substance or substances in such diet; and
    (C) Safety factors which in the opinion of experts qualified by 
scientific training and experience to evaluate the safety of food 
additives are generally recognized as appropriate for the use of animal 
experimentation data. (21 U.S.C. 348(c)(5).)
    In the case of olestra, the product's broad marketing potential and 
expected consumption by persons of all ages, including children, are 
aspects that have been considered in the safety evaluation.
    Importantly, Procter & Gamble is not required to show, nor is FDA 
permitted to consider, that olestra has benefits, health or otherwise, 
for consumers of the additive. Again, the legislative history of the 
Amendment is clear on this point.
    The question of whether an additive produces such [a technical] 
effect (or how much of an additive is required for such an effect) 
is a factual one, and does not involve any judgement on the part of 
the Secretary of whether such effect results in any added 'value' to 
the consumer of such food or enhances the marketability from a 
merchandising point of view.
S. Rept. No. 2422, 85th Cong., 2d sess. 7 (1958). Accord: H. Rept. No. 
2284, 85th Cong., 2d sess. 6 (1958).
    In summary, the general safety clause places on Procter & Gamble 
the burden of proving that a fair evaluation of the data in the 
administrative record establishes that there is a reasonable certainty 
that olestra will not be harmful under the prescribed conditions of 
use. Only if Procter & Gamble meets this burden can the food additive 
be approved.
2. Dietary Context of Safety Evaluation
    Olestra presents a different set of safety issues compared to most 
food additives. For example, most substances can induce toxic effects 
provided that the dose administered is sufficiently high. The primary 
purpose of most safety testing is to determine the toxic dose and to 
evaluate whether there is a sufficient margin of safety between the 
highest dose that is not toxic and the expected human exposure.
    Because olestra is intended to substitute for fat, a substantial 
component of the diet, it is difficult, if not impossible, to feed 
olestra to laboratory animals in amounts sufficiently high to allow use 
of the 100-fold safety factor that is commonly used to ensure safety 
(21 CFR 170.22), when evaluating animal studies. The use of a safety 
factor is intended to account for the uncertainty of extrapolating from 
toxicity data from animals to humans. (See 21 U.S.C. 348(c)(5)(c).) FDA 
concludes that in the case of the olestra petition, the agency is 
justified in not using the 100-fold safety factor for the following 
reasons. First, no toxic effects from olestra consumption were observed 
when olestra was fed atpara.levels up to 10 percent of the diet of 
laboratory animals (as discussed in section III. of this document). 
Second, olestra is not appreciably absorbed by the body and the 
minuscule amount of material that is absorbed is metabolized to 
substances (sucrose and fatty acids) that are further metabolized 
normally in the body. Thus, no major component of olestra is available 
to produce a toxic effect. Finally, a significant number of human 
studies have been performed to assess the safety of olestra, which 
assessment may be performed without the need for a safety factor.
    The fact that olestra is not absorbed also means, however, that as 
food components are absorbed from the intestine, the amounts of olestra 
present in the intestine will become an increasingly larger fraction of 
the total intestinal contents. Thus, the safety issues for olestra are 
focused on effects in the intestine, including potential interference 
with absorption of nutrients.
    The petitioner completed the standard toxicological testing program 
to demonstrate safety for a direct food additive, as outlined in FDA's 
guidance on such testing (Ref. 4). However, to account for the possible 
variations in composition, effects on composition due to heating, and 
inherent difficulties in extrapolating from laboratory animals to 
humans, the initial animal tests have been supplemented with a variety 
of human and additional animal studies taking into account the 
properties of olestra. In fact, since the original petition was 
submitted inpara.1987, Procter & Gamble has submitted more than 50 
additional safety studies for review. In 1992 and 1993, the pivotal 
safety studies with regard to nutritional effects from the petitioned 
use of olestra were submitted.

B. Toxicological Studies--Overview

    The petition submitted to FDA consists of data and information from 
toxicity studies in several animal species, including the rat, mouse, 
dog, and rabbit. The toxicity data base includes a battery of three 
mutagenicity/genotoxicity tests; subchronic feeding studies in mice, 
rats, hamsters, and dogs; and reproduction/teratology testing in the 
rat and rabbit. To determine whether olestra affects the structure and 
function of the gastrointestinal (GI) tract, a series of absorption, 
distribution, metabolism, and elimination (ADME) studies were conducted 
in rats, mini-pigs, and guinea pigs.

C. Nutritional Impact Studies--Overview

    The limited digestibility of olestra poses a number of nutrition 
issues, including olestra's effect on fat-soluble vitamins and whether 
these effects could be compensated for by the addition of an 
appropriate amount of the affected vitamins. As a result, the 
petitioner conducted several studies, including those listed below, in 
both pigs and humans. Procter & Gamble conducted studies in swine 
because they have a digestive system similar to humans and can be 
evaluated for nutrient stores in the liver and bone. Five of the 
studies that were carried out in swine are: (1) a 12-week dose-response 
study (the 12-week DR study) of olestra on the status of 
vitaminspara.A, D, E, and K, and on hard-to-absorb and limited-in-diet 
nutrients; (2) a 12-week vitamin restoration study (the 12-week VR 
study) to determine levels of vitamins A, D, and E needed to offset 
olestra effects; (3) a 26-week dose-response and vitamin restoration 
study (the 26-week DR/VR study) to extend 

[[Page 3121]]
the findings of the 12-week DR and 12-week VR studies to longer times 
and lower olestra intake levels; (4) a 39-week study (the 39-week VR 
study) to confirm the effects of 0.25 percent olestra and added vitamin 
A and E measured in the 26-week DR/VR study over a longer exposure 
time; and (5) a 4-week dietary context study (the 4-week DC study) to 
compare olestra's effects on vitamins A and E when olestra is consumed 
either with the diet or between meals.
     Procter & Gamble conducted studies of olestra in humans to 
eliminate any uncertainty related to extrapolating from pigs and to 
obtain subject reports on gastrointestinal effects. Those objectives 
were pursued in several human studies including: Two clinical studies, 
two studies in free-living subjects,\5\ and one short-term study 
designed to assess olestra's effect on vitamin A and fat absorption 
(the vitamin A/fat study). The two human clinical studies were an 8-
week study to determine the dose response of olestra on the status of 
vitamins A, D, E, and K, and on hard-to-absorb and limited-in-diet 
nutrients (the 8-week DR study) and an 8-week study to confirm the 
compensation levels for vitamins A and E (the 8-week VR study). The 
free-living studies were a 16-week study to assess the status of 
vitamin E in subjects consuming 18 grams/day (g/d) olestra (the 16-week 
vitamin E study) and a 6-week study to determine the effect of 20 g/d 
olestra on vitamins D and K (the 6-week vitamin D/K study).

    \5\Free-living subjects maintain their normal diets and eating 
patterns except for consumption of the test article as instructed.
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D. GI Effects--Overview

    The petitioner performed several studies to evaluate olestra's 
effects on the gastrointestinal (GI) tract including the following. The 
two clinical studies (the 8-week DR and 8-week VR studies) were used to 
evaluate adverse gastrointestinal effects as reported by the test 
subjects. In addition, the effect of olestra on intestinal microflora 
was measured by conducting a breath gas expiration study. Several 
studies were also conducted to evaluate olestra's effects on bile acid 
metabolism and absorption. In order to determine olestra's effects, if 
any, in an at-risk population, studies were conducted in inflammatory 
bowel disease patients. Because some drugs are lipophilic (fat-soluble) 
and may partition into (i.e., be partially absorbed by) olestra, 
olestra's potential to affect absorption of drugs was also 
investigated. In addition, because nonabsorbable liquid oil can 
separate from other fecal material in the colon and leak through the 
anal sphincter, a human clinical study was performed to determine the 
relationship between olestra's stiffness and passive oil loss.

E. FDA's Decision Process

    In light of the novel issues raised by the review of the olestra 
data, FDA's Center for Food Safety and Applied Nutrition (CFSAN) 
determined that it would be valuable to obtain additional expertise in 
resolving certain issues that had been raised. A Regulatory Decision 
Team (RDT) composed of senior FDA managers was established for the 
purpose of recommending, to the Director of CFSAN, a decision on the 
olestra food additive petition. In addition, FDA retained the services 
of several scientific consultants from outside the agency to facilitate 
the agency's deliberations.
    As is the case with all food additive petitions, the olestra data 
were reviewed by staff scientists. Because of the large number of 
studies and the diverse nature of the information, each of these 
scientists reviewed a portion of the total body of data on the 
additive, focusing on his particular area of expertise. These staff-
level reviews, including any questions or issues raised by such 
reviews, were subsequently considered by the RDT, assisted by the 
outside consultants. In the RDT deliberations, an overall Center 
position on olestra's safety was synthesized; in the process, issues 
raised by individual reviewers were resolved, were determined to be not 
significant, or were incorporated into the synthesized position. During 
this deliberative process, the members of the RDT weighed the various 
pieces of scientific information and applied their scientific judgement 
as they developed an overall Center position.
    After the conclusion of the RDT deliberations and the meetings with 
consultants from outside the agency, FDA convened a public meeting of 
its FAC and a special Olestra Working Group of the FAC on November 14 
through 17, 1995, to undertake a scientific discussion of the agency's 
evaluation of the safety data in the petition. The membership of the 
standing Committee was supplemented with temporary members and 
consultants to the Committee, representing scientific disciplines 
appropriate to the evaluation of a macro-ingredient fat substitute.
    At the Olestra Working Group meeting, Procter & Gamble presented a 
summary of the data it considered adequate to establish the safety of 
olestra, the experts with whom the agency had consulted presented their 
views on the sufficiency of the information to assess the safety of 
olestra, interested members of the public presented their opinions and 
evaluations of the data, and FDA presented its evaluation of the data. 
The Committee was asked to assess, in light of the state of the science 
relative to macro food ingredients, whether all critical safety issues 
with respect to the use of olestra in savory snack foods had been 
addressed.
    As set out in detail below, having completed its evaluation of the 
data in the petition and having considered the deliberations of the 
Olestra Working Group and the FAC, including all presentations to the 
Committee, and the comments received on the petition, the agency is 
amending the food additive regulations to permit the use of olestra in 
place of fats and oils in prepackaged ready-to-eat savory snacks.

II. Identity and Use

    Olestra is the common name for the mixture of sucrose esters formed 
from the addition of six, seven, or eight fatty acids to the available 
eight free hydroxyl moieties of sucrose. Saturated and unsaturated 
fatty acids of chain length C12 to C20 and higher can be used to 
manufacture olestra. The final product is defined by specifications 
which include the fatty acid composition.-
    The identity of sucrose octaester as the principal component of 
olestra has been verified by infrared, mass, and nuclear magnetic 
(proton and 13carbon) spectrometry (Ref. 5). The generalized structure 
for olestra is set forth below.

BILLING CODE 4160-01-F

[[Page 3122]]
[GRAPHIC][TIFF OMITTED]TR30JA96.000



BILLING CODE 4160-01-C

[[Page 3123]]


A. Manufacturing Processes

    Olestra is prepared by the addition of medium- and long-chain fatty 
acid methyl esters to sucrose in the presence of catalysts. The 
postsynthesis purification steps are the same as those generally 
practiced in the edible oils industry. These purification steps depend 
upon physical separations and do not involve chemical bond 
rearrangement or the use of solvents or catalysts.
    The methyl esters used to prepare olestra can be obtained by 
procedures common in the food industry such as the reaction of refined 
triglyceride oils with methanol in the presence of sodium methoxide or 
from esterification of their fatty acids. The resulting esters are 
washed with water to remove residual methanol, dried under vacuum, and 
distilled. The fats and oils can be derived from a variety of edible 
sources such as, but not limited to, soybean, palm, coconut, fully 
hydrogenated rapeseed, and cottonseed.
    Sucrose and the methyl esters are mixed with an alkali metal soap 
of a long-chain fatty acid. A small amount of transesterification 
catalyst such as an alkali metal (sodium or potassium) carbonate, 
bicarbonate, hydride, or alkoxide is added and the mixture heated under 
vacuum to withdraw the volatile methanol byproduct. Following the 
reaction, excess methyl esters and free methanol are removed by 
evaporation under vacuum. Standard steam deodorization removes free 
fatty acids and odors. Different lots of olestra may be mixed to 
achieve desired properties or to meet product specifications.
    The manufacture of olestra can be well controlled, based upon the 
petitioner's analysis of representative lots (Ref. 5).

B. Constituents

    The principal trace constituents of olestra are collectively 
identified as the unsaponifiable fraction, ranging in concentration 
from 0.08 percent to 0.3 percent. These constituents are primarily 
aliphatic hydrocarbons and plant sterols that naturally arise from the 
edible triglyceride sources of fatty acids used in the synthesis of 
olestra. In this respect, these trace constituents of olestra do not 
differ from those found in typical edible oils. Additionally, difatty 
ketones (DFK's), formed during its manufacture, are found as trace 
constituents in olestra as consumed.
    DFK's form in olestra during the alkaline rearrangement 
manufacturing process. The DFK's that are present in olestra are a 
family of compounds with a common general structure consisting of two 
fatty acid chains with a central keto group. They are formed from 
naturally occurring vegetable oil-derived fatty acids used to make 
olestra. The length and degree of unsaturation of the fatty acid chains 
are determined by the source oil used to make olestra.
    Quantitative analysis of olestra by gas chromatography and mass 
spectrometry of 15 typical lots of olestra determined that olestra 
contains 36 to 416 parts per million (ppm) DFK's. The potential DFK 
range of olestra was altered to 100 to 300 ppm when the method of 
manufacture was updated. Qualitative analysis of soybean oil-based 
olestra showed that the DFK's ranged from 31 to 35 carbons in length, 
consistent with the predominance of C<INF>16 and C<INF>18 fatty acids 
in soybean oil.
    Identical analytical techniques showed that similar types 
(C<INF>29-C<INF>35 fatty acid chain length), but lower levels, of DFK 
are found in vegetables (5 to 86 ppm), cooked meat fat (0.15 to 2.73 
ppm), and food-approved emulsifiers (10 to 55 ppm). Historically, the 
once-common commercial practice of rearranging fats and oils by base-
catalyzed methods produced levels of DFK that exceeded 300 ppm. These 
results show that olestra is an additional dietary source of those 
DFK's that are now, and have been, commonly consumed in the food supply 
(Ref. 6).

C. Specifications

    Olestra comprises a range of possible compositions that can be 
identified by a three-dimensional matrix defined by: (1) Fatty acid 
chain length; (2) the degree of fatty acid unsaturation; and (3) the 
distribution of full and partial esters of olestra. The petitioner has 
proposed specifications that include ranges for fatty acid chain length 
and degree of unsaturation to ensure functional products for use in 
savory snacks. The specified range of esterification ensures the 
nonabsorbable and noncaloric nature of the product.
    Traditional edible oil specifications that ensure purity and safety 
also are incorporated into the olestra specifications. These values 
include specifications for free fatty acid content, total methanol 
residues, water, residue on ignition, peroxide value, total heavy metal 
content, and lead.

D. Stability

    Olestra is stable under ambient and high-temperature storage 
conditions. In all cases, olestra is at least as stable as 
triglycerides with similar fatty acid composition.
    Polymers form in both olestra and triglycerides during cooking, 
purification, or storage, when olestra or triglycerides are exposed to 
heat, moisture, and air. The polymers, comprised almost entirely of 
dimers and trimers, form by cross-linking at points of unsaturation on 
the fatty acid chains. This mechanism of cross-linking in olestra is 
the same as that which occurs in triglycerides. The amount of polymer 
found in olestra is less than that found in a conventional edible oil 
stored under identical, controlled conditions.
    Typical bulk lots of olestra were demonstrated to be as stable as 
triglycerides of similar fatty acid composition when stored at room and 
elevated temperatures (120 F) for up to 1 month. These olestra batches 
were found to be stable based upon the lack of significant change in 
fatty acid composition, ester distribution, free fatty acid levels, 
polymer levels, and oxidative stability (Ref. 7).
    Heating food fats in the presence of moisture and air results in 
the production of decomposition byproducts. Such byproducts are removed 
regularly from commercial cookers to maintain an effective frying 
system under good manufacturing practice. Use of olestra for frying 
savory snacks will similarly lead to production of byproducts. The 
petitioner conducted research to determine the extent of byproduct 
production from olestra compared to conventional frying fats, and to 
determine whether unique byproducts would be formed.
    A variety of analytical techniques were employed to characterize 
the profile of byproducts formed during the heating of olestra and 
conventional frying fats. The gross identity of the heated products was 
determined by standard methods such as fatty acid composition, carbon 
number profile, and peroxide value. In addition, comprehensive analyses 
of changes to the fatty acid side chains were undertaken. Fatty acids 
were methylated by transesterification, isolated by silica gel column 
chromatography or solid phase extraction, and analyzed by a variety of 
techniques including gas chromatography (GC), GC/mass spectrometry 
(MS), two-dimensional GC/MS, and high performance liquid chromatography 
(HPLC). This battery of tests provided an analytical sensitivity to 
detect a component present in the heated oil at a level of 17 ppm 
(equivalent to 0.05 ppm in the diet of 90th percentile consumers of 
olestra) (Ref. 8).
    For both olestra and conventional frying fats (triglycerides), the 
predominant chemical changes that occur under frying conditions are 

[[Page 3124]]
oxidation reactions on the fatty acid side chains (Ref. 8). The 
principal byproducts of frying are polymers (dimers and trimers) which 
are joined primarily by bonds between unsaturated fatty acid 
components. Both olestra and conventional fats of similar fatty acid 
composition undergo a similar number of polymerization reactions under 
common heating conditions. For example, the amount of polymer increased 
0.003 mole/100 g for olestra and 0.004 mole/100 g for a triglyceride of 
similar fatty acid composition.
    Levels of olestra and triglyceride polymers absorbed into the 
cooked foods under worst-case conditions are similar and show that 
there is no selective concentration in food. For example, polymer 
levels in food fried in either olestra or triglyceride ranged from 4 to 
6 percent of total lipid weight. These values correspond to the 
concentration of olestra and triglyceride polymer in the bulk heated 
oil phases (Ref. 8).
    Baking conditions do not degrade olestra or triglyceride as readily 
as frying conditions, even though soda crackers commercially prepared 
with olestra may experience temperatures ranging from 250 to 350 
deg.F. This is because crackers are exposed to such temperatures for 
only a few minutes (not hours), and the temperature within the body of 
the cracker can be expected to be substantially lower than the oven 
temperature.
    This stability in baking assessment was confirmed when both olestra 
and a triglyceride of similar fatty acid composition were used to 
prepare soda crackers, and the crackers were baked for 6 minutes at the 
more common commercial temperature of about 250  deg.F. The neat (i.e., 
prior to baking) olestra and triglyceride were analytically 
characterized, and the profiles compared to those obtained from the 
fats extracted after the soda crackers were baked.
    Unlike during frying, neither olestra nor the triglyceride formed 
any measurable polymer during the 250 F baking (Ref. 9.). Consistent 
with a lack of change in polymer content, results demonstrate that 
neither olestra nor the triglyceride experienced any significant change 
in primary structural composition (i.e., ester distribution for 
olestra; or the tri-, di-, or monoglyceride profile for the 
triglyceride).
    The only notable change in both olestra and the triglyceride was a 
slight increase in free fatty acid content. This latter effect is 
expected because free fatty acids may be present in the cracker raw 
ingredients, and the alkaline chemical leavening agents used in soda 
cracker production can promote ester hydrolysis. The similarity of 
changes in olestra and triglycerides during soda cracker baking is 
consistent with the fact that the chemical changes in both products 
take place on the fatty acids, and yield the same decomposition 
products.
    To test stability during storage after baking, both olestra and a 
triglyceride of similar fatty acid composition were used to make soda 
crackers, unflavored plain crackers, and unflavored snack crackers. All 
products were packed in air to reflect current market practice, aged 
under controlled temperatures and time to reflect common and worst-case 
storage conditions, and analyzed for parent, polymer, and decomposition 
products. The results demonstrate that the stability of olestra and 
triglyceride were comparable under the conditions studied (Ref. 9).
    FDA concludes that use of olestra in frying media for savory snacks 
results in neither more nor different byproducts of the frying process 
than currently experienced with conventional oils. Also, olestra is as 
stable as triglyceride in crackers during baking and in baked crackers 
stored under expected and worst-case conditions.

E. Use and Intended Technical Effect

    Olestra is proposed for use as a calorie-free replacement for up to 
100 percent of the conventional fats and oils used in the preparation 
of savory snacks such as flavored and unflavored chips and crisps, 
flavored and unflavored extruded snacks, and crackers. These uses 
include substitution for fat for frying as well as sources of fat in 
dough conditioners, oil sprays, and flavors. Olestra will function in 
savory snacks as a texturizer and as a formulation aid (21 CFR 
170.3(o)) at levels not in excess of that reasonably required to 
produce its intended effect.

F. Estimated Daily Intake for Olestra (EDI)

    When conducting a food additive safety evaluation, FDA typically 
uses estimated 90th percentile chronic intakes. The petitioner has 
provided a study of probable intake for olestra, completed by the 
Market Research Corporation of America (MRCA), that contains sufficient 
information to estimate both chronic and acute exposures to olestra.
    The MRCA methodology estimates the daily consumption of olestra 
from savory snacks for individuals by combining: (1) The individual's 
frequency of consumption of savory snacks; (2) the average amount eaten 
per eating occasion of that savory snack; and (3) the amount of olestra 
in that savory snack. Eating occasion frequencies were determined from 
14-day dietary diaries that were kept by heads of household. The amount 
of food eaten per eating occasion was derived from the USDA's 
Nationwide Food Consumption Surveys. The amount of olestra in snacks 
was determined in the petitioner's laboratories.
    The MRCA survey data show that at the 90th percentile, the probable 
lifetime-averaged intake of olestra is 6.4 g/p/d. FDA believes however, 
that it is appropriate to consider energy needs in estimating the daily 
intake of olestra. Based on the assumption that consumers of olestra 
will compensate for calories ``lost'' due to consumption of olestra by 
increasing their intake of food (including olestra-containing snacks), 
the agency has concluded that the lifetime-averaged EDI for olestra 
should be increased by 10 percent to 7.0 g/p/d (Ref. 10).
    Any effects of olestra on nutrients or nutrient absorption could be 
exhibited during less than chronic exposure conditions. To evaluate 
sub-chronic conditions, FDA has estimated that a ``high'' acute 
consumer of olestra (every day for 12 weeks) would consume 20 g/p/d, 
equivalent to eating a 2-ounce (oz) bag of potato chips every day (Ref. 
11). The MRCA survey information submitted by the petitioner shows that 
the 99th-percentile, 14-day average intake for olestra would be 14.8 g/
p/d (corrected to 16.3 g/p/d for caloric compensation) in the 18 to 44 
year old male group. The 99th-percentile single-day intake of olestra 
for the group consuming the highest level of savory snacks (13 to 17 
year old male group) is 40.4 g/p/d (corrected to 45 g/p/d). It is not 
likely that this high single day intake would be repeated every day in 
the 12-week time frame previously mentioned.
    In terms of consumption patterns, the MRCA data also show that 
approximately 9 percent of lunch and dinner meals include a snack food 
that could potentially contain olestra. The data also show that 63 
percent of snack food eating occasions occur with a meal.
    Consumption estimates of olestra-containing savory snacks were 
discussed at the Olestra Working Group and FAC meetings. In particular, 
CSPI raised three concerns about these estimates. First, CSPI presented 
several consumption scenarios to the Olestra Working Group\6\ that the 
organization 

[[Page 3125]]
asserted better represented expected olestra consumption. These 
consumption estimates ranged from 4.2 g/p/d to 37.5 g/p/d. CSPI's 
higher consumption estimates included an increase in consumption of 
olestra-containing snacks over full-fat snacks; this increase was based 
on the results of a telephone survey, which survey indicated that 
people think they would eat 25 percent more snacks if the snacks 
contained lower fat. Based on these scenarios, CSPI asserted that there 
would likely be a substantial number of snack eaters consuming olestra 
in quantities similar to those fed in the 8-week human studies (8, 20, 
and 32 g/d).

    \6\These CSPI comments were presented by Dr. Myra Karstadt, 
Ph.D. Transcript, vol. 2, p. 49. This information is also discussed 
in CSPI's White Paper (Ref. 3).
---------------------------------------------------------------------------

    Second, CSPI asserted that consumers usually eat an entire bag of 
chips at one sitting, and that bags marked ``single-serving'' typically 
contain from three-quarters of an ounce to 2 ounces. Therefore, CSPI 
claimed that in many cases, people would eat several ounces of chips at 
one sitting, and that, in evaluating olestra's for GI effects, it is 
important to consider single-sitting consumption levels.
    Third, CSPI expressed concern that the MRCA survey population may 
not represent the most vulnerable high-volume consumers of snack 
products, such as minority teenagers resident in low socioeconomic 
areas, who may both consume large quantities of savory snacks and have 
poor nutritional status.
    Dr. Gail Harrison, consultant to the petitioner,\7\ presented her 
analysis of the MRCA survey demographics to the Olestra Working Group, 
which responded to CSPI's third concern. Dr. Harrison stated that the 
MRCA survey population is very representative of the U.S. population in 
terms of regional census areas, census regions, and urbanization. 
Further, in terms of different population groups, she said that 
children of all ages are appropriately represented, while young 
homemakers are slightly underrepresented. In addition, there is a 
slight, though not statistically significant underrepresentation of 
minority households, and the income distribution slightly 
underrepresents highest-income and lowest-income households by about 
three to four percent. Also, information was provided to the Olestra 
Working Group by the petitioner from an analysis of USDA's 1990-1991 
Continuing Survey of Food Intake that the average intake of salty 
snacks (crackers, popcorn, pretzels, and corn chips) by food-stamp 
recipients was about 4 g/p/d while nonrecipients consumed about 7 g/p/
d.\8\

    \7\Dr. Gail Harrison, Professor, School of Public Health, 
University of California-Los Angeles. Dr. Harrison presented at the 
petitioner's request. Transcript, vol. 2, p. 73.
    \8\Information from testimony by Mr. Thomas Breaker from the 
Mathematica Policy Research Group before the Committee on 
Agriculture's Subcommittee on Department Operations and Nutrition 
(Transcript, vol. 2, p. 163).
---------------------------------------------------------------------------

    After presentations by the petitioner, CSPI, FDA, and others, the 
members of the Olestra Working Group generally agreed that all issues 
with regard to the chemistry and consumption of olestra had been 
adequately addressed.
    FDA agrees that it is appropriate to use conservative assumptions 
in the safety evaluation of olestra, the effect of which is likely to 
over-estimate consumption patterns. For this reason, FDA has assumed 
that 100 percent of all savory snacks will be replaced by olestra-
containing snacks. That is, once olestra is approved, some consumers 
will eat only savory snacks containing olestra. FDA further believes 
that it is appropriate to rely on the MRCA survey data to estimate 
consumption because the survey is well designed, includes a large base 
of people, and a sound methodology in that the survey relies on food-
intake diaries kept by participants rather than relying on 
participants' recall of what they ate sometime in the past. In light of 
the discussion before the Olestra Working Group, FDA further concludes 
that the MRCA survey data are sufficiently representative of the eating 
habits of the U.S. population and, in particular, that the eating 
patterns of low-income individuals are captured by the MRCA data and 
thus, such individuals are included in the agency's consumption 
estimates. In addition, FDA finds that a scenario-driven estimate of 20 
g/p/d, based on consumption of 2 oz of chips per day, which is greater 
than the 99th percentile, 14-day average intake in the highest 
consuming group of snack eaters (18 to 44 year old makes), is a 
reasonable estimate of a ``short-term'' high consumer. FDA has not used 
the largest amount reported to have been eaten in one sitting during 
the MRCA survey period because that amount represents an extreme that 
is unlikely to be repeated for more than a few days. FDA further 
concludes that there are no scientific data to justify increasing the 
estimated olestra exposure derived from the MRCA survey in order to 
account for the potential consumers' increase in consumption of snacks 
because the snacks are low-fat.
    FDA has also evaluated the potential chronic exposure to DFK's 
formed from the manufacture of olestra. Mean DFK intake from olestra-
prepared snacks is 0.4 mg/p/d (DFK level of 125 ppm). The 90th 
percentile for DFK's, based on an olestra intake of 7 g/p/d, is 0.87 
mg/p/d. For perspective, the mean level of DFK in foods (primarily 
beef, chicken, pork, and the brassica vegetables) is 9 mg/p/d and the 
90<SUP>th percentile background exposure (typically approximately twice 
the mean for commonly consumed foods such as meat and vegetables) would 
be 18 mg/p/d (Refs. 12 and 13).
    Thus, FDA has determined that the available data and information 
support the use of 7 g/p/d olestra as an estimate of chronic 
consumption by the 90th percentile snack eater and 20 g/p/d olestra as 
an estimate of shorter term consumption.

III. Toxicity Data--Discussion and Evaluation

A. Absorption, Distribution, Metabolism, and Elimination

    The petitioner conducted a series of preliminary studies to assess 
the absorption of olestra in rats. In order to identify which organs 
might accumulate intact olestra or metabolize olestra if absorbed, rats 
were intravenously (IV) injected with olestra radiolabelled with 14C on 
the sucrose portion of the molecule. The radiolabelled olestra 
initially deposited in the liver and, to a lesser extent, in the 
spleen. The data in these early studies show that, olestra was taken up 
rapidly by the reticuloendothelial system and deposited in the liver 
and spleen within 3 days following intravenous injection. There was a 
minor accumulation in the fatty tissues with only a trace amount 
detected in expired air. At 21 days, the concentration of olestra in 
the liver dropped to about 50 percent of the 3-day level. Olestra was 
excreted unchanged via the biliary and fecal routes.
    These results demonstrate that the olestra that accumulated in the 
liver following intravenous injection was not metabolized because 
radiolabel was not accumulated in other tissues, which would have 
occurred if olestra had been hydrolyzed by hepatic enzymes. The absence 
of olestra's metabolization was confirmed by thin-layer chromatography, 
which showed intact olestra in the bile and feces. The half-life of 
olestra in the liver was about 5 days.
    Examination by electron microscopy of liver tissue from rats 
injected intravenously with olestra showed that, at 56 days after 
dosing, lipid accumulation was greatest in the Kupffer cells. By 84 
days post-dosing, the greatest accumulation was in the parenchymal 
cells, indicating that both kinds of cells handle olestra following 

[[Page 3126]]
iv administration. Tissue deposition studies were also conducted in 
rats fed one percent olestra for 30 days. Based on the data submitted, 
there was no significant radioactivity detected in the liver, spleen, 
lung, thymus, or adipose tissue from animals fed olestra.
     Procter & Gamble conducted a series of studies in male and female 
rats to determine the fate of penta-, hexa-, hepta- and octa-ester 
preparations of olestra administered by gavage. The livers were removed 
and lipid extracts were analyzed for the various esters. No esters were 
detected by thin layer chromatography. However, the overall sensitivity 
of the method was only approximately 2 to 3 percent of the administered 
dose. Therefore, any olestra in rat liver extracts containing less than 
3 percent of the administered olestra ester preparations could not be 
detected. Additional fat balance studies conducted in the rat 
demonstrated that enzymatic hydrolysis can convert mono- through penta-
ester formulations of olestra to sucrose and fatty acids while hexa- 
through octa-ester formulations are not absorbed (Ref. 14).
    To assess further the potential for olestra to be absorbed from the 
GI tract, the petitioner conducted a series of absorption studies in 
rats, guinea pigs, and mini-pigs. These studies used uniformly-labeled 
olestra with high specific activity and sensitive analytical methods to 
analyze tissues, especially liver, for intact olestra and urine for 
<SUP>14C-sucrose, a metabolic product that would result from the 
metabolism of any absorbed olestra.
1. Rat Studies
    In the rat studies, in order to detect the absorption of a very 
small amount of the administered dose, olestra of high chemical and 
radiochemical purity and high specific activity (1 millicurie/g) was 
dosed at high levels (0.1 millicurie/rat). Tissues were collected, 
combusted, and analyzed for radiolabelled CO<INF>2, or the lipid 
fraction was extracted and analyzed for intact olestra by HPLC. Urine, 
feces, expired CO<INF>2, and the carcass were analyzed for <SUP>14C. 
The urine was analyzed for <SUP>14C-sucrose to assess whether olestra 
had been absorbed and metabolized (Refs. 15 through 19).
    Five samples which represented the extremes, and beyond, of the 
olestra specification range, as well as a typical mid-range 
composition, were tested. This set of samples included the following: 
(1) a sample in which the fatty acid chains were 100 percent saturated; 
(2) a sample in which the fatty acid chains were highly (85 percent) 
unsaturated; (3) a sample rich in short-chain length fatty acids (59 
percent) and penta- and hexa-esters (84 percent); (4) a sample which 
represented the unheated mid-range of the olestra specification; and 
(5) a mid-range olestra sample which was subjected to conditions of 
repeated thermal stress as would occur in the commercial preparation of 
savory snacks. Although the short-chain length fatty acids (59 percent) 
and penta- and hexaesters (84 percent) sample falls outside the olestra 
specifications proposed in the petition, the sample was tested to 
determine the absorption of these components that might occur in 
olestra in trace amounts.
    The mean recovery of unabsorbed radiolabel from the rat feces, GI 
tract and contents, animal wipes and animal rinse solutions, and cage 
wipes and cage rinse solutions was greater than 98.5 percent of the 
administered dose regardless of the radiolabeled olestra formulation 
studied (Ref. 19). This recovered amount represents olestra that is not 
absorbed. The recovery of absorbed radiolabel carbon from olestra 
ranged from 0.02 percent of the administered dose of the high saturated 
olestra formulation to 1.5 percent of the administered dose of the 
short chain length and low ester formulation. The majority of the 
absorbed radioactivity was found in the expired CO2 and urine. Analysis 
of liver lipids for intact olestra and urine for 14C-sucrose did not 
show any radiolabelled carbon. These data demonstrate that most of the 
ingested olestra remains intact and is not absorbed, but is excreted 
intact in the feces. The percent absorption of these olestra 
formulations are shown in Table 1 below.

                                     TABLE 1.--PERCENT ABSORPTION OF OLESTRA FORMULATIONS IN RAT ABSORPTION STUDIES                                     
--------------------------------------------------------------------------------------------------------------------------------------------------------
               Olestra Composition                                                            Percent Absorbed                                          
--------------------------------------------------------------------------------------------------------------------------------------------------------
Low Chain/Low Ester..............................                                                                                                   1.50
Mid-Range........................................                                                                                                   0.16
Heated Mid-Range.................................                                                                                                   0.14
High Unsaturates.................................                                                                                                   0.05
High Saturates...................................                                                                                                   0.02
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The absorption measured for the sample rich in short-chain fatty 
acids and penta and lower esters was 1.5 percent of the administered 
dose. This higher value, compared to the other olestra formulations 
tested, resulted from the hydrolysis of the penta and lower esters to 
sucrose and free fatty acids in the GI tract. Sucrose molecules 
released by hydrolysis of the lower esters in the GI tract were further 
hydrolyzed by intracellular mucosal sucrase and passed into the portal 
system as the monosaccharides glucose and fructose. These molecules 
were metabolized normally and the radiolabel was excreted rapidly in 
expired air and urine. The only variable that significantly affected 
absorption was the lower chain length and lower degree of 
esterification. Restriction of these lower chain length and lower 
esters in olestra through specifications for the additive limits the 
absorption to less than 0.16 percent of the administered dose. Of the 
five radiolabelled olestra formulations studied in the rat, the heated 
mid-range formulation with 0.14 percent recovery of absorbed radiolabel 
represents the olestra formulation proposed to be marketed for human 
consumption. FDA concludes that the low level (0.14 percent) of 
absorbed radiolabelled carbon from penta- and lower esters contained in 
the heated olestra is biologically insignificant because the only 
components shown to be absorbed are metabolized to sucrose and fatty 
acids which are metabolized normally (Ref. 19).
2. Guinea Pig Studies
    The petitioner conducted studies in male and female poligeenan-fed 
guinea pigs to assess the potential for increased absorption of olestra 
across a damaged intestinal mucosa. (Poligeenan is known to cause 
intestinal damage.) Male and female guinea pigs were given 3 percent 
poligeenan in tap water, or tap water alone (controls), for 5 weeks 
until GI lesions similar to those seen in acute and chronic human GI 
diseases (such as ulcerative colitis and Crohn's disease) were induced. 
The guinea pigs were then dosed with 200 microcuries of a heated 
olestra and the absorption of 

[[Page 3127]]
olestra was compared between animals with normal GI tracts and those 
with compromised GI tracts.
    The total recovery of radiolabelled olestra was greater than 97 
percent of the administered dose for female guinea pigs in both the 
normal and compromised groups.\9\ The majority of radiolabel, 87 
percent to 95 percent, was found in feces and GI contents. Guinea pigs 
in the compromised group had comparable amounts of radiolabel in the GI 
tract and contents compared to the normal group. In addition, there 
were no consistent differences between the normal and compromised 
groups in the distribution of the absorbed radiolabel among various 
tissues, blood, urine, or expired CO<INF>2. These findings show that 
the absorption of intact olestra is no greater in guinea pigs with 
compromised GI tracts than in guinea pigs with normal GI tracts (Refs. 
20 and 21).

    \9\Incomplete collection of fecal material from support screens, 
sides and bottoms of cages, and fur of animals for male guinea pigs 
resulted in lower radiolabel recovery (88.1 percent) and greater 
variability in results than for female guinea pigs.
---------------------------------------------------------------------------

3. Mini-Pig Studies
    The absorption of a typical, mid-range heated olestra was 
determined in weanling mini-pigs. The weanling mini-pig was chosen 
because its GI tract is physiologically and anatomically similar to 
humans and, like man, the mini-pig can tolerate a high fat diet. The 
design for the mini-pig study was similar to the design in the rat 
absorption studies except that expired CO2 was not collected from the 
mini-pigs because metabolic cages large enough to house mini-pigs were 
not available at the contract laboratory. In addition, the dose of 
radiolabelled olestra was increased to 0.35 millicuries per mini-pig so 
that the detection limit was comparable to that in the rat studies.
    For both male and female mini-pigs, 98.9 percent of the recovered 
radiolabel was found unabsorbed in the feces, GI tract plus contents, 
and animal rinse solutions. No radiolabelled olestra was found in the 
lipid fraction that would have contained olestra, if present, in the 
lipids extracted from livers of the mini-pigs (Ref. 22).
    Overall, the results from these studies in rats, guinea pigs, and 
mini-pigs demonstrate that while a small percentage of the olestra 
formulation consisting of penta- and lower esters is absorbed and 
metabolized to fatty acids and sucrose, nearly all of the ingested 
olestra remains intact and is not absorbed (Refs. 19, 21, and 22). 
Heating does not significantly increase olestra absorption and 
absorption is no greater when the GI tract is compromised than when it 
is intact.

B. Genetic Toxicity Studies

    The petitioner conducted a battery of genetic toxicity studies with 
the unheated mid-range olestra formulation. Olestra was not genotoxic 
in any of the following test systems: An Ames Salmonella test with or 
without metabolic activation, a mouse lymphoma cell mutagenicity assay 
with or without activation, an unscheduled DNA synthesis test, and a 
Chinese hamster ovary cell in vitro cytogenetics test with or without 
activation.
    Because of solubility problems with olestra in these early genetic 
toxicity studies, the petitioner conducted an additional battery of in 
vitro assays and in vivo cytogenetic studies on heated mid-range 
olestra with Pluronic F-68, a nontoxic, nonionic surfactant to ensure 
cell contact with olestra. No evidence of mutagenicity or genetic 
toxicity from heated olestra was observed in the following test 
systems: The Salmonella/mammalian microsome mutagenesis assay; the 
L5178Y TK +/- mouse lymphoma assay; the test for chemical induction of 
unscheduled DNA synthesis in rat hepatocytes; and the cytogenicity 
study in Chinese hamster ovary (CHO) cells. These tests were conducted 
in the presence and absence of liver enzyme (S-9) activation at 
concentrations of up to 5 mg/mL. In addition, there was no evidence of 
chromosomal aberrations from heated mid-range olestra observed 
following examination of the bone marrow in the in vivo cytogenicity 
assays (using both acute and chronic dosing protocols) conducted on 
Sprague-Dawley rats (Ref. 23). Based upon the foregoing result, FDA 
concludes that olestra is not genotoxic.

C. Animal Toxicity Studies

1. Teratogenicity Studies
    The teratogenic potential of olestra was evaluated in studies 
conducted in the rat and rabbit. These studies establish that olestra 
was not teratogenic when fed during organogenesis in either species. 
Olestra was also not teratogenic nor did it affect reproduction in a 
multi-generation rat reproduction/teratology study.
    Olestra was fed to rats (10/group) at 3.2 percent, 6.4 percent, or 
12 percent of the diet beginning on the 6th day of pregnancy. Dams were 
sacrificed on days 13 and 20 of pregnancy, and the fetuses examined for 
abnormalities. The uterine contents of rats killed on day 13 of 
pregnancy were evaluated for implantation, resorption sites, and the 
number of corpora lutea. The fetuses of the dams sacrificed on day 20 
were removed and corpora lutea counted; the pups were sacrificed and 
evaluated for anomalies. One-third of the fetuses were cleared and 
stained for study of the skeleton, and two-thirds were sectioned for 
study of the soft tissues. This study provided no evidence that olestra 
is teratogenic or embryotoxic (Ref. 24).
    In a rabbit teratology study, heated olestra was administered via 
gavage at doses representing 1 percent, 5 percent, and 10 percent of 
the diet during the critical stages of gestation (days 6 to 19); 
control animals were dosed with distilled water. Dams were sacrificed 
on day 30 of pregnancy and the fetuses examined for abnormalities. This 
study provided no evidence that olestra was teratogenic (Ref. 25).
    For the multi-generation study, weanling rats were maintained on 
diets containing 0 percent, 1 percent, 5 percent, or 10 percent olestra 
for a 91-day growth period. The mid- and high-dose diets were 
supplemented with vitamin A (2.5 times the National Research Council 
(NRC) requirements\10\) and vitamin E (five times the NRC 
requirements), in order to compensate for the reduced absorption of 
these nutrients in the presence of olestra. At the end of 91 days, 
F<INF>0 dams were mated for a reproduction (F<INF>1A) phase and then 
were mated again for a teratology (F<INF>1B ) phase. After the growth 
period, the F<INF>1A offspring were mated for the F<INF>2A and F<INF>2B 
generations. Olestra had no effect on mating, conception, embryonic 
development, fetal and postnatal viability, or postnatal growth in 
either generation (Ref. 24).

    \10\NRC requirements are actually recommendations set at levels 
close to the amount required for good health in the subject animals.
---------------------------------------------------------------------------

2. Subchronic and Chronic Feeding Studies
    Early feeding studies in rats with unheated olestra at levels of 4 
percent, 8 percent, or 15 percent of the diet for 28 or 91 days 
resulted in no deaths, no decrease in the absorption of triglycerides 
or protein, no differences in urine or blood chemistry, hematology, or 
gross or microscopic histopathology. These studies are not addressed 
further.
    a.  Ninety-Day subchronic feeding study in rats. The petitioner 
conducted two subchronic toxicity studies in rats. The first subchronic 
olestra feeding study in rats showed no adverse effects but used 
unheated olestra. Therefore, the petitioner, conducted a second 90-day 
toxicity study in rats using olestra 

[[Page 3128]]
that had been heat abused to a degree exceeding that likely to occur 
during the preparation of savory snacks. Specifically, olestra that had 
been heated for 7 days at 190  deg.C (representing an extreme heating 
condition) was fed to 6 groups of 40 rats each (20 rats per sex) at 0 
percent, 0 percent, 1 percent, 5 percent, 10 percent, and 0 percent in 
rodent chow ad libitum for 90 days. Groups I and II were chow controls 
while Group VI control rats were maintained on a diet that contained 10 
percent previously heated triglyceride. Diets for groups II-V were 
supplemented with vitamins A, D, and K (five times the NRC 
requirement); vitamin E was added to these four diets at 8.0 times, 0.8 
times, 4.0 times, and 8.0 times the NRC recommended levels, 
respectively.
    The study included twice-daily observations and weekly physical 
examinations. Body weight, body weight changes, food consumption, and 
olestra intake were determined weekly. Ophthalmoscopic examinations 
were performed pretest and at study termination. Clinical chemistry, 
hematology, and urinalysis parameters were measured at study 
termination on 10 animals/sex/group.
    Complete gross postmortem examinations were performed on all 
animals at study termination. The brain, adrenals, ovaries, testes 
(with epididymides), kidneys, and liver were removed, weighed, and 
organ-to-body-weight and organ-to-brain-weight ratios were calculated. 
A full complement of tissues was examined histopathologically from all 
animals in Groups I, II, V, and VI surviving to study termination, and 
any animals in Groups III and IV dying unscheduled deaths. Lungs, 
liver, kidneys, and gross lesions were evaluated from Group III and IV 
animals surviving to study termination.
    Survival, physical condition, body weight, food consumption, feed 
efficiency, organ weight, organ-to-body weight ratios, hematologic 
parameters, and histomorphology were evaluated. Olestra fed rats 
compensated for the decrease in caloric intake due to olestra having 
zero calories by consuming more food than control rats. No adverse 
treatment-related effects were observed. These results establish that 
heated olestra is not-toxic when fed to rats at levels as high as 10 
percent of their diet for a period of 90 days (Ref. 26).
    b. Two-year carcinogenicity studies in rats. Two 2-year 
carcinogenicity studies of olestra were conducted in rats. In the first 
study, Fischer 344 rats, 70 per sex per group, were fed olestra at 
levels of 0 percent, 1 percent, 5 percent, or 9 percent of the diet for 
2 years with interim sacrifices at 12 and 18 months. In the second 
study, Fischer 344 rats, 50 males and 73 females per group, were fed 
olestra at 0 percent or 9 percent of the diet for 2 years with an 
interim sacrifice at 12 months. In both studies, diets were 
supplemented with five times the NRC recommended levels of vitamins A, 
D, E, and K, to offset the reduced absorption of fat-soluble vitamins 
in the presence of olestra. The diets in both studies also contained 2 
percent fully hydrogenated palm oil to control passive oil loss (anal 
leakage). The studies included twice-daily observations, and weekly 
physical examinations. Body weight, body weight changes, food 
consumption, and olestra intake were determined weekly for the first 12 
weeks and monthly thereafter. Feed efficiency was determined during the 
first 12 weeks. Ophthalmoscopic examinations were conducted pretest, 
and at scheduled sacrifice. Clinical chemistry, hematology, and 
urinalysis parameters were measured at 12 and 24 months. Complete gross 
postmortem examinations were performed on all animals. Selected organs 
were removed, weighed, and organ-to-body-weight and organ-to-brain-
weight ratios were calculated for all rats surviving to scheduled 
sacrifice periods. Liver samples were taken from rats in the 9 percent 
olestra groups from both studies for analysis of olestra.
    Histopathological evaluations were conducted on a full complement 
of tissues from animals in the control and 9 percent olestra groups 
from both studies. Liver, pituitary gland, gross lesions, and tissue 
masses were evaluated for all animals on study. The duodenum, jejunum, 
ileum, cecum, and colon were examined for all animals sacrificed at 12, 
18, and 24 months.
    Rats compensated for the caloric dilution of olestra by consuming 
more food than was consumed by the controls. Olestra had no effect on 
ophthalmology, organ weight, organ-to-body- and organ-to-brain-weight 
ratios, clinical chemistry, hematology, or urinalysis parameters. There 
was no evidence that intact olestra accumulated in the liver tissue of 
rats fed 9 percent olestra for 2 years.
    There were no treatment-related adverse effects on growth, 
longevity, or general health, and there were no treatment-related 
neoplastic responses or evidence of chronic toxicity in either study. 
In the first study, there were four instances in which differences 
between treated groups and controls required FDA pathologists to assess 
whether the effect was treatment-related: male survival, incidence of 
pituitary adenoma (males and females), mononuclear cell leukemia 
(males), and basophilic liver foci (females). FDA pathologists also 
evaluated the following differences in incidence in the second chronic 
rat study: Incidence of pituitary cysts (males), mineralization of the 
renal cortex and bile duct hyperplasia, and basophilic liver foci in 
females. The differences observed between treated groups and controls 
in both chronic studies are marginal.
    Pituitary adenomas are very common spontaneous tumors in Fischer-
344 rats with a tendency for highly variable background incidences 
(Ref. 27). The increased incidence of pituitary adenoma in both sexes 
in the first chronic rat study represent expected variations in 
spontaneous background incidences. Thus, FDA concluded that there was 
no association of the pituitary adenomas with olestra treatment.
    Likewise, FDA concludes that there was no association between the 
incidence of leukemia in male rats and treatment with olestra for 
several reasons. First, the possible association is not supported by 
the results of the second study in which there was no comparable 
development of leukemia. Second, the incidences in the first study, 
particularly the control group, are unusually low compared to 
historical data from the National Toxicology Program (NTP) data base 
and compared to the results of the second study (Ref. 27). Third, 
mononuclear cell leukemia in Fischer-344 rats is a common spontaneous 
disease in old age with considerable tendency for background variation 
(Ref. 27). Therefore, such differences in incidence are not unusual but 
rather are expected from the normal variation of spontaneous tumor 
incidences.
    In the first rat study, there was an increase in the number of 
olestra-treated female rats with basophilic liver foci at the 1 year 
interim sacrifice without any clear increase in the severity of this 
lesion at the end of 2 years. However, female groups including the 
terminal sacrificed animals as well as the unscheduled deaths, 
demonstrated no clear increase in the incidence of basophilic liver 
foci with olestra treatment. The same phenomenon of early occurrence of 
basophilic liver foci in olestra-fed female rats was observed in the 
second study. In both studies, the basophilic foci in the control and 
treated rats were similar morphologically.
    In presentations to the Olestra Working Group and the FAC, and in 
its White Paper, CSPI expressed concern about the significantly higher 
incidence of basophilic liver foci at the end of 12 months, although 
CSPI acknowledged 

[[Page 3129]]
that the difference between control and treatment groups disappeared by 
24 months. CSPI asserted that, although 24 months is the majority of a 
rat's lifetime, the study should have been carried out for the rats' 
entire lifetime because it is possible that the foci might have 
progressed to cancer. CSPI also recommended that an expert Committee 
(such as NTP review) the findings.\11\

    \11\Transcript, vol. 2, p. 135.
---------------------------------------------------------------------------

    Based upon an examination of all of the data in both studies, FDA 
pathologists concluded that these findings represented normal 
biological variability in 24-month-old rats and were not related to 
olestra ingestion for the following reasons. First, the findings lacked 
a dose-response effect and were not observed in both male and female 
rats in both chronic studies (Refs. 28 and 29). Second, the spontaneous 
occurrence of basophilic liver foci is frequent and variable in aging 
Fischer-344 rats (Refs. 30 and 31) and the incidence can reach 100 
percent at 2 years (Refs. 32 and 33). Further, the majority of foci do 
not become neoplasms. Third, the most recent studies indicate that 
hepatocarcinogens induce more morphologically variable foci than those 
observed spontaneously (Refs. 30, 34, and 35). Thus, the early 
occurrence and morphological similarity of the basophilic liver foci in 
the control and the olestra-treated female rats are not indicative of 
hepatocarcinogenic potential for olestra in the rat.
    Dr. John Doull, a clinical toxicologist and temporary member of the 
FAC, agreed with the FDA evaluation that the basophilic liver foci 
findings are not significant and that basophilic liver foci are not 
predictors of carcinogenicity.\12\ Dr. Eugene McConnell,\13\ a 
presenter to the Olestra Working Group, agreed with Dr. Doull, and 
noted that the control groups in both chronic rat studies exhibited 
abnormally low incidences of foci compared to the foci rate 
historically observed in rats at these ages; he postulated that the 
addition of vitamins to the feed in both chronic rat studies may have 
caused this low foci occurrence rate in the control groups. The rate of 
foci in the treatment groups was compared to historical control rates 
and was slightly lower than historical controls.

    \12\Dr. John Doull, Kansas University Medical Center Transcript 
vol. 2, p. 113.
    \13\Dr. Eugene McConnell, D.V.M, D.V.B.T was chief of the 
Pathology Branch and Director of the Division of Toxicology Research 
and Testing for the NTP. Dr. McConnell is a diplomate of the 
American College of Veterinary Pathologists and the American Board 
of Toxicology. Dr. McConnell consulted for the petitioner and 
presented at its request. Transcript, vol. 2, p. 147.
---------------------------------------------------------------------------

    Dr. McConnell also noted that the slides were reviewed by (1) 
Board-certified pathologists in the contractor lab performing the study 
(2) board-certified pathologists employed by the petitioner, (3) an 
independent pathology laboratory,(4) a group of internationally known 
pathologists, and (5) FDA pathologists. All of the reviewers came to 
the same conclusion that none of the data suggests evidence of 
carcinogenic activity in either species.
    Therefore, in light of the discussion of the Olestra Working Group 
and the presentations of CSPI and Dr. McConnell, FDA confirms its 
conclusion that there was no olestra-related toxicity or 
carcinogenicity in these studies.
    c. Two-year chronic toxicity and carcinogenicity studies in mice. 
Two 2-year mouse studies were conducted to evaluate the chronic 
toxicity and carcinogenicity potential of olestra. The first mouse 
study compared three levels of olestra (2.5 percent, 5.0 percent, and 
10.0 percent of the daily diet) to two control groups. Olestra was 
supplemented with vitamins A, D, E, and K to account for amounts which 
potentially would be lost due to the high levels of olestra fed. One of 
the two control groups provided basal levels of fat-soluble vitamins; 
the second control group was fed supplemental vitamins A, D, E, and K. 
To confirm the findings, a second mouse study was conducted with a 
chow-fed control group and a 10 percent olestra group supplemented with 
vitamins A, D, E, and K.
    One hundred mice of each sex were placed in a total of seven groups 
in the two studies. (The first mouse study had five groups and the 
second mouse study had two groups.) Fifty animals/sex/group were 
allocated to the carcinogenicity portions of each study, and all 
survivors sacrificed at 24 months. Fifteen animals/sex/group were 
allocated to the toxicity portion of each study, and all were 
sacrificed at 12 months. Finally, sentinel animals (35/sex/group) were 
included, and seven/sex/group were sacrificed at one, two, three, six, 
and nine months for assessment of hepatic vitamin A and E status.
    The studies included daily observations and weekly examinations. 
Body weights and food consumption were determined weekly. 
Ophthalmoscopic examinations were conducted pretest, and at scheduled 
sacrifice. Clinical chemistry and hematology data, gross necropsy 
observations, and organ weights were collected on animals sacrificed at 
12 and 24 months in both studies. Complete gross postmortem 
examinations were performed on all animals. Selected organs were 
removed, weighed, and organ-to-body-weight and organ-to-brain-weight 
ratios were calculated for all mice surviving to scheduled necropsy. 
Histopathological evaluations were conducted on a full complement of 
tissues from all control and treated animals assigned to the 
carcinogenicity portion of both chronic studies.
    At the end of 24 months, there were no treatment-related effects in 
either study as determined by mortality, body weights, clinical 
pathology, gross necropsy findings, organ weights, hematology, clinical 
chemistries, or histopathology of a comprehensive collection of 
tissues.
    In the first study, there was an increase in the incidence of lung 
carcinomas and combined lung carcinomas and adenomas in mid-dose 
olestra-fed male mice but not in any other group. This association of 
olestra consumption with lung tumors in male mice in the first mouse 
study was not confirmed by the results of the second mouse study. Lung 
adenomas and carcinomas are common lesions in Swiss CD-1 mice and tend 
to have a high and variable background rate (Refs. 36 and 37). The 
increased combined incidence of lung adenomas or carcinomas in male 
mice in the first mouse study (Ref. 38) cannot credibly be associated 
with olestra consumption, and represents expected variation in 
spontaneous incidence of lung tumors in Swiss CD-1 mice (Ref. 37). 
Thus, upon review, FDA pathologists concluded that this was not an 
olestra-related effect because there was no other lung pathology, there 
was no relation between olestra exposure and time-to-onset of the 
tumors, the incidence of the tumors was typical for mice of this age 
and sex based on historical data, and there was no association between 
olestra exposure and lung tumors in other chronic rodent studies (Ref. 
39).
    At the Olestra Working Group meeting, CSPI expressed concern about 
the increase in the incidence of combined lung carcinomas and adenomas 
in the mid-dose male mice.\14\ Dr. Doull noted that an analysis of the 
data for CSPI by Dr. Renata Kimbrough (Ref. 3) essentially agreed with 
FDA's conclusions. Specifically, although the mid-dose male mice in the 
first chronic study had an increased incidence in lung tumors, there 
was no dose response, the increased incidence of 

[[Page 3130]]
lung tumors was not repeated in the second study, and the lung tumor 
incidence rate was within the range of that observed in the NTP program 
in lung tumors.\15\ Dr. Doull further stated his view that this data 
leads to the conclusion that olestra is not carcinogenic.\16\

    \14\Transcript, vol. 2, p. 136. Discussion of this concern also 
appears in the White Paper (Ref. 3)
    \15\Transcript, vol. 2, p. 111.
    \16\Transcript, vol. 4, p. 113.
---------------------------------------------------------------------------

    Therefore, in light of the discussion before the Olestra Working 
Group, FDA confirms its conclusion that the lung tumors in this study 
were not an olestra-related effect.
    d. Dog feeding studies. The petitioner conducted two short-term 
feeding studies of olestra in beagle dogs. Olestra was fed at a level 
of 4 percent of the diet for 28 days or 15 percent of the diet for 30 
days. Histological examination of several tissues, including the liver, 
revealed no abnormalities. The olestra-fed animals consumed more food 
because of the caloric dilution of the diet by olestra, but there was 
no difference in body weight gain. In a third study, olestra was fed to 
dogs at 10 percent of the diet for 91 days. No adverse effects were 
noted among the treated animals in terms of histopathology, hematology, 
or blood chemistries.
    The petitioner also conducted a 20 month chronic feeding study in 
five male and five female beagle dogs. The animals were fed a chow diet 
with 0 percent, 5 percent, or 10 percent olestra. Olestra diets were 
supplemented by adding 1.5 times the NRC recommended dietary level of 
vitamin A and 2.5 times the NRC recommended dietary level of vitamin E 
to the low-dose (5 percent) diet. The high-dose (10 percent) diet 
received 3.0 times the NRC recommended dietary level of vitamin A and 
5.0 times the NRC recommended dietary level of vitamin E. The study 
included twice-daily observations, as well as weekly physical 
examinations, and determination of growth and food intake. Hematology, 
clinical chemistry, serum vitamin A and E concentrations, and 
ophthalmoscopic status were evaluated after 12 and 20 months of 
treatment.
    At the end of the study, all dogs were sacrificed and their tissues 
subjected to complete gross and microscopic examination. Organ weights 
and organ-to-body-weight ratios were determined for brain, adrenals, 
kidney, liver, ovary, testes, and thyroid/parathyroid. A complete set 
of tissues from all animals was examined by light microscopy.
    No evidence of toxicity was observed, and all animals survived the 
entire length of the study. Growth, as measured by body weight gain, 
was not affected by olestra ingestion. Food consumption was increased 
to offset the caloric dilution of the diet by olestra. No biologically 
significant changes were seen in any of the hematological or 
biochemical parameters measured. Histopathology revealed no olestra-
related effects (Ref. 40).

D. Toxicology Summary

    In summary, the results of the toxicological tests submitted by the 
petitioner support the conclusion that olestra is not toxic or 
carcinogenic, not genotoxic, and not teratogenic. Heating olestra, as 
would occur in the commercial preparation of savory snacks made using 
olestra, does not increase the absorption of the additive or affect its 
toxicity.

IV. Effect of Olestra on Absorption of Drugs

    Because olestra is a fat-like material that has been shown to alter 
the absorption of some lipophilic nutrients, FDA considered whether the 
bioavailability of lipophilic drugs might also be affected by 
consumption of olestra. To address this question, the petitioner 
carried out a series of studies in both animals and humans.
The petitioner established the following criteria to use in deciding 
which drugs to study:
(1)-The drugs should have wide spread use by the general population.
(2)-The absorption, metabolism and elimination of the drugs should be 
similar in rats and humans.
(3)-The drugs should cover a wide range of solubilities, from water-
soluble to fat-soluble.
(4)-The drugs should include representatives of those used to prevent 
life-threatening situations.
(5)-Most of the drugs should have partition coefficient data already 
available.
(6)-The drugs must be commercially available in radiolabeled form.
    Using these criteria, the petitioner selected the following drugs 
for use in two rat studies: aspirin, diazepam, propranolol, and the 
oral contraceptives ethinyl estradiol and norethindrone. Because 
results of studies in rats are not definitive predictors of human 
conditions (Ref. 41), the petitioner also sponsored two human clinical 
trials to study the olestra/drug issue. In the first of these clinical 
trials, propranolol, diazepam, norethindrone, and ethinyl estradiol 
were included; in the second clinical study, the oral contraceptive Lo/
Ovral-28, containing norgestrel and ethinyl estradiol, was evaluated.

A. Effect of Olestra on the Absorption of Selected Lipophilic Drugs 
(EC-40)

    The primary objective of this study was to determine whether 
olestra affects absorption of drugs relative to corn oil.This study was 
conducted in Sprague-Dawley derived male and female rats and had three 
separate experimental components. The olestra used was prepared from 
safflower oil, while corn oil served as the triglyceride control. 
Hydrogenated palm oil was added to both the olestra and control diets, 
to mimic the earlier proposed use of olestra in combination with 
convention oils.
    In the first experiment, 20 male rats were fed either a control 
diet with 6 percent added corn oil or a similar diet but with 6 percent 
added olestra for 13 days; the test animals were then fasted, weighed, 
subdivided into four groups (five rats per group), and gavaged with 
slurries of either the control or olestra diets to which tritiated 
diazepam or tritiated propranolol had been added. In the second and 
third experiments, no initial acclimation period was used. In the 
second experiment, 20 female rats were fasted, weighed, divided into 
four groups (five rats per group), and gavaged with slurries of either 
control or olestra diets to which tritiated ethinyl estradiol or 
tritiated norethindrone had been added. In the third experiment, 10 
male rats were fasted, weighed, divided into 2 groups (5 rats per 
group), and gavaged with slurries of either control or olestra diets to 
which C14-labeled acetylsalicylic acid (aspirin) had been added.
    In all three experiments, serial blood and urine samples were taken 
over a 48-hour period after dosing. Fecal samples were also collected 
at 24-hour intervals. All samples collected were assayed for drug 
associated radioactivity, and the results evaluated for treatment 
related effects on drug absorption.
    The five drugs studied in these experiments cover a range of 
lipophilicity, from nonlipophilic (aspirin) to strongly lipophilic 
(ethinyl estradiol and norethindrone). The petitioner concluded that 
co-administration of the drugs with olestra did not affect the 
absorption of any of the drugs tested when compared with corn oil.
    FDA concludes that the petitioner's choice of drugs, which were 
selected based on physico-chemical properties, was reasonable. Further, 
the study correctly focused on rate and extent of absorption, both of 
which are important factors in the overall evaluation of human drug 
absorption. Although the use of total radioactivity measurements, 

[[Page 3131]]
as was done in this study, is not a comprehensive evaluation taken 
alone, the study design is adequate as a first exploration of olestra/
drug interactions (Ref. 41).

B. Effect of Olestra on the Absorption of Selected Lipophilic Drugs 
(EC-41)

    The objective of this study was to determine whether a single dose 
of olestra caused an alteration of the absorption or excretion profiles 
of lipophilic drugs that were orally administered prior to the olestra. 
This study was conducted with Sprague-Dawley derived male rats. After a 
4 day acclimation period all rats were fasted, weighed, divided into 
treatment groups (four/group), and gavaged with either tritiated 
diazepam, tritiated propranolol, or C<SUP>14-labeled aspirin 
(acetylsalicylic acid). Following each drug dosing, rats were gavaged 
with one ml of either water, corn oil, or olestra. Additional rats 
dosed with propranolol and aspirin received an olestra emulsion (one of 
the projected final forms for initial marketing of olestra).
    Serial blood and urine samples were collected over a 48-hour 
period, postdosing, while fecal samples were obtained at 24-hour 
intervals. Forty-eight hours after dosing all rats were sacrificed, 
their gastrointestinal tracts removed and the contents collected, 
selected organs excised, and carcasses frozen in liquid nitrogen and 
ground. All samples were assayed for drug-associated radioactivity. 
Results of the radioactivity assays were evaluated for treatment-
related effects.
    The petitioner concluded that there were no differences in rate or 
extent of absorption of diazepam, propranolol, or acetylsalicylic acid 
when administered before olestra consumption compared with 
administration prior to water consumption. Drug excretion profiles were 
also not affected by olestra. Corn oil (a control substance) reduced 
the rate of absorption of all drugs studied. The petitioner concludes 
that these results demonstrate that olestra would not be expected to 
affect the acute absorption of drugs such as diazepam, propranolol or 
aspirin, and thus are consistent with EC-40. FDA concludes that, as 
with EC-40, the design and conduct of this investigation are adequate 
as a further exploratory study of the potential for olestra/drug 
interactions (Ref. 41).

C. Effect of Olestra on Drug Bioavailability (EC-42)

    The objective of this clinical trial, consisting of 3 experiments, 
was to determine whether olestra consumption alters drug 
bioavailability in humans when used as a substitute for absorbable 
dietary fat. Subjects were assigned to test one drug in a crossover 
design so that bioavailability of the drug was evaluated with single 
doses of olestra, water, or a triglyceride (partially hydrogenated 
soybean oil) placebo treatment. Table 2 provides basic information on 
subject and treatment assignment.

                               TABLE 2.--SUBJECT AND TREATMENT ASSIGNMENT IN EC-42                              
----------------------------------------------------------------------------------------------------------------
                                                                                            Drug and treatment  
               Exp. No.                Subject No. male/female     Age Range (years)              amount        
----------------------------------------------------------------------------------------------------------------
1....................................  5/3....................  27 to 47...............  Propranolol, 20 mg     
2....................................  4/4....................  20 to 40...............  Diazepam, 5 mg         
3....................................  0/10...................  not available..........  Norethindrone, 1 mg and
                                                                                          Ethinyl estradiol,    
                                                                                          0.07 mg               
----------------------------------------------------------------------------------------------------------------

    In each experiment, 18 g of olestra, 18 g of triglyceride, or six 
ounces of water were consumed following ingestion of the respective 
drug under study. Serial blood samples collected from all subjects were 
processed and the resulting serums frozen for subsequent drug analyses. 
The data on peak serum concentrations, times to peak, and areas under 
the concentration curves (AUC) were analyzed statistically for 
treatment effects.
    Based on its analyses of the results from the three experiments, 
the petitioner concluded that there were no statistically significant 
differences in the absorption of the drugs administered with olestra, 
triglyceride placebo, or water as assessed by total area under the 
curve (AUC) and time to peak concentration data. The time to peak 
concentration values for diazepam were slightly longer with the 
triglyceride placebo than with olestra. There was wide, although not 
unexpected, between-patient variability. The petitioner concluded that 
a single dose of 18 g of olestra did not alter the 
bioavailabilitypara.characteristics of orally administered propranolol, 
diazepam, or norethindrone/ethinyl estradiol when compared to water or 
a triglyceride such as partially hydrogenated soybean oil.
    FDA concludes that the design of this clinical study was excellent, 
and that the study may be used by itself, without any reliance on the 
two studies in rats, to assess olestra's potential for affecting 
absorption of lipophilic drugs. The results from EC-42 demonstrate that 
olestra does not interfere with the absorption of drugs when 
administered at the 18 g dose (Ref. 41).

D. Effect of Olestra on the Systemic Levels of Steroidal Hormones in 
Women Taking Oral Contraceptives (EC-51)

    The objective of this clinical trial was to determine the effect, 
if any, of chronic olestra consumption (targeted at 20 g/d) on the 
absorption and efficacy of a low-dose oral contraceptive in normal 
women.
    Thirty healthy, menstruating female subjects aged 20 to 38 years 
were assigned to two groups. A double-blind, placebo-controlled, 
crossover study design was used which covered two complete ovarian 
cycles. Subjects were instructed to begin taking the oral contraceptive 
Lo/Ovral-28 (0.30 mg norgestrel and 0.03 mg ethinyl estradiol), 5 days 
before the onset of menstruation. One group of subjects received food 
items with triglyceride placebo, while the other group received similar 
food items containing a ``mid-range'' olestra formulation.
    Daily intake of olestra was set at 18 g with one-third (6 g) of the 
daily dose being consumed at each meal. At the conclusion of the first 
28-day cycle, the treatments were crossed over (placebo to olestra, 
olestra to placebo). All subjects were asked to take their oral 
contraceptive only in the morning and before the morning meal. Serum 
progesterone levels were determined at a baseline visit, 5 to 7 days 
after menstruation and twice weekly for the remainder of the ovarian 
cycles.
    Serial blood samples were collected during each of the two ovarian 
cycles. These samples were then processed and the serums frozen for 
subsequent drug analysis. Results were evaluated for treatment effects 
by comparing AUC, maximum drug concentration, and time to maximum 
concentration data.
    The petitioner concluded that there were no significant effects of 
consuming 18 g of olestra on the absorption of either norgestrel or 
ethinyl estradiol, the 

[[Page 3132]]
two steroid components of Lo/Ovral-28. Serum progesterone levels in 
subjects in both the olestra and triglyceride placebo groups were found 
to remain in a range that would prevent ovulation, thereby providing 
evidence that oral contraceptive efficacy was not affected by olestra. 
The petitioner also stated that because the oral contraceptive used in 
this study contains the lowest amounts of two of the most lipophilic 
steroid hormones (norgestrel and ethinyl estradiol), the results from 
this study should prove valid for ``all high-dose oral contraceptives 
having less lipophilic constituents.'' In addition, the petitioner 
believes that the data from EC-51 provide further support generally for 
the conclusion from other studies in animals and humans that olestra 
consumption does not alter the absorption of lipophilic drugs, and 
therefore, will not affect the efficacy of orally administered drugs.
    FDA believes that this study is an excellent extension from single-
dose olestra to chronic dosing, at least for the once-a-day situation. 
Further, in this study, there was no evidence that olestra would affect 
the efficacy of orally administered drugs (Ref. 41).

E. Summary

    The petitioner has submitted two animal studies and two clinical 
studies assessing olestra's potential to alter drug absorption. Procter 
& Gamble believes that these studies demonstrate that olestra does not 
alter the absorption nor affect the efficacy of orally administered 
drugs.
    Members of the Olestra Working Group were unanimous that, with 
respect to drugs, all the issues had been identified and there were 
sufficient data to address each issue.\17\ There was also nearly 
unanimous agreement that, with respect to drug interactions, there was 
no obstacle to approval and reasonable certainty of no harm from 
olestra consumption.\18\

    \17\Transcript, vol. 4, p. 50.
    \18\Transcript, vol. 4, p. 50.
---------------------------------------------------------------------------

    During the Olestra Working Group and FAC meetings and in numerous 
comments to FDA, individuals have expressed concern about the effects 
of olestra on coumarin drugs (e.g., Coumadin or warfarin, Dicumarol, 
etc.) as well as other drugs. Dr. Ian Greaves, a specialist in 
environmental and occupational medicine,\19\ expressed concern about 
persons taking anticoagulants such as coumarin drugs that antagonize 
Vitamin K. He asked how olestra would bind to coumarin and whether 
there would be difficulty in maintaining an anticoagulant status in 
people receiving coumarin who intermittently eat olestra-containing 
products. He stated that his experience with managing patients on 
anticoagulants is that some of them are very variable for no good 
reason, and he could easily foresee a patient becoming either overly 
anticoagulated or under-anticoagulated, depending on whether Vitamin K 
was being bound or whether the coumarin was being bound. Also, if a 
person taking coumarin happened to have an intra-cerebral bleed or 
bleed from his gastrointestinal tract and was also consuming olestra, 
he felt it would be difficult to know whether olestra had a role in the 
bleeding. Finally, he stated he was concerned about other fat-soluble 
drugs, particularly those that cross the blood-brain barrier such as 
anticonvulsants, psychotropic drugs, and antidepressants. Dr. Greaves's 
questions covered the concerns that were raised by other individuals.

    \19\Dr. Ian Greaves is an Associate Professor and Deputy 
Director, Minnesota Center for Environmental and Health Policy, 
University of Minnesota School of Public Health. Dr. Greaves 
presented at the request of CSPI. Transcript, vol. 2, p. 265.
---------------------------------------------------------------------------

    FDA notes that the results concerning the hormonal preparations are 
extremely useful because these drugs represent extremely lipophilic 
substances and are substances that have a narrow therapeutic index in 
which a lowering of the absorbed concentration would be a concern. In 
addition, the drug, propranolol, is a compound that has very similar 
physical/chemical properties to Coumadin or sodium warfarin,\20\ a drug 
about which FDA has received comments concerning olestra's effects. In 
response to a question by an FAC member, FDA noted that in the previous 
5 years, there has been only one drug that FDA has reviewed that is 
more lipophilic than the hormone drugs tested in the human drug-
interaction studies. That drug is a very specialized drug (Atovaquone), 
which is an anti-pneumocystis drug used in AIDS patients.\21\ 
Therefore, FDA expects that the results observed in the reviewed 
studies would be representative of nearly any drug on the market.

    \20\Transcript, vol. p. 124.
    \21\Transcript, vol. p. 124.
---------------------------------------------------------------------------

    Regarding coumarin drugs specifically, FDA notes that the effects 
of a variety of meals (e.g., high-protein, high-carbohydrate, and high-
fat) on absorption of sodium warfarin (Coumadin), the most commonly 
prescribed form of coumarin, were studied and no effect was seen in the 
total amount of sodium warfarin absorbed. Also, there was no effect on 
absorption when Coumadin was consumed with high-fat or high-protein 
meals. When consumed with a high-carbohydrate meal, Coumadin was more 
slowly absorbed, but only for the first hour after ingestion of the 
drug\22\ (Ref. 42). Therefore, FDA would not expect significant effects 
on Coumadin absorption from olestra consumption.

    \22\Transcript, vol. p. 119.
---------------------------------------------------------------------------

    Olestra's effects on vitamin K are discussed in the Nutritional 
Studies section below.
    FDA concludes that the test compounds studied adequately represent 
the range of physical properties of drugs marketed for human use, and 
that the magnitude of olestra's effects on drug absorption were 
minimal, when compared to the effects normally encountered in drug-food 
interaction studies. FDA further concludes, considering the results of 
all four studies, the discussions during the Olestra Working Group and 
FAC meetings, comments received, and information in the literature, 
that there is no evidence that consumption of olestra would 
significantly influence the rate or extent of absorption of drugs 
(including Coumadin drugs).

V. Nutritional Studies

A. Issues Associated with Olestra

    The petitioner has hypothesized that olestra interferes with the 
absorption of fat-soluble nutrients when the nutrients partition into 
olestra in the GI tract. When this happens, the portion of the 
nutrients that is present in the olestra phase is unavailable to the 
micelle-mediated transport system and, rather than being absorbed by 
the body, is excreted in the feces along with the olestra.
    Neither existing olestra data nor the partitioning mechanism 
suggest that water-soluble nutrients would be affected by olestra. 
However, certain water-soluble nutrients such as folate and vitamin B12 
(hard-to-absorb nutrients) are absorbed in multi-step processes. The 
multi-step nature of the processes might allow the opportunity for 
olestra to interfere with key steps in the processes, such as binding 
or cleavage reactions. Calcium, zinc, and iron are limited in the U.S. 
diet; thus, any effect on their absorption might increase the risk of 
nutritional inadequacy. In addition, the nutrients would be present in 
the diet at levels that are small, on a mass basis, relative to the 
amount of olestra. Thus, if olestra has an effect on water-soluble 
nutrients, these five nutrients (folate, vitamin B<INF>12, calcium, 
zinc, and iron) would be the most important water-soluble nutrients 

[[Page 3133]]
to monitor and the most likely to reflect adverse nutritional effects. 
Therefore, folate, vitamin B<INF>12, calcium, zinc, and iron were 
chosen as representative markers for olestra's effects on the 
nutritional status of water-soluble nutrients.
    The potential nutritional effects of olestra consumption were 
studied in both humans and animals. The pig was chosen as the 
appropriate animal model because it has a gastrointestinal tract 
similar to that of man; it is able to ingest, tolerate, and metabolize 
fat at a level comparable to that found in the human diet; and its 
vitamin stores and nutritional indices are responsive to dietary 
changes. Where possible, FDA has relied upon the results of human 
consumption studies as the primary determinants of olestra's safety, 
thereby avoiding the uncertainties raised by extrapolating from the pig 
to humans. Thus, FDA is relying primarily on the human studies to 
assess olestra's effects on vitamins E, D, K, and B<INF>12, and on 
folate and iron. There are certain nutrients, such as vitamin A, for 
which no noninvasive procedure can be used to assess status in humans. 
Therefore, FDA has relied upon the results of the pig studies for 
determining olestra's effects on vitamin A. In addition, there are 
certain advantages to studying olestra's nutritional status in pigs. 
The studies can be conducted over the major developmental and growth 
periods of the pig's life, dose levels higher than those in man can be 
studied, and invasive techniques can be used to measure nutrient stores 
in tissues (such as bone and liver). Therefore, results from the pig 
studies are valuable supportive information that expand upon the 
knowledge gained in the human studies.
    To apply the results of the pig studies to humans, it is necessary 
to correlate the percent olestra fed in the pig diet to g/p/d olestra. 
Olestra's effects on nutrients are caused by its physical presence in 
the gut. If nutrients dissolve into olestra, they will be carried out 
of the body with the olestra rather than being absorbed. The amount of 
olestra's effect depends on the amount of olestra present in the GI 
tract compared to other fats (as well as on the solubility of the 
vitamins in olestra). Thus, FDA has concluded that the most appropriate 
means for correlating olestra's effects in animals to humans is the 
percentage by weight of olestra in the diet. For a person eating about 
2,000 calories/d, 10 g of olestra would be about 2.4 percent of the 
diet (Ref. 43).

B. Effects of Olestra on Fat-Soluble Vitamins-

    The effect of olestra on fat-soluble vitamins was assessed in five 
nutritional studies with humans and five studies with pigs, as 
summarized in Table 3.

           TABLE 3.--SUMMARY OF STUDIES DESIGNED TO ASSESS NUTRITIONAL EFFECTS OF OLESTRA CONSUMPTION           
----------------------------------------------------------------------------------------------------------------
                     Human Studies                                             Pig Studies                      
----------------------------------------------------------------------------------------------------------------
8-week clinical dose response (8-week DR)                26-week dose response and vitamin restoration (26-week 
                                                          DR/VR)                                                
8-week clinical vitamin restoration (8-week VR)          39-week vitamin restoration (39-week VR)               
6-week vitamin D/K status in free-living subjects (6-    12-week dose response (12-week DR)                     
 week vitamin D/K)                                                                                              
16-week vitamin E status in free-living subjects (16-    12-week vitamin restoration (12-week VR)               
 week vitamin E)                                                                                                
14-day vitamin A/fat absorption (14-day vitamin A/fat)   4-week dietary context (4-week DC)                     
----------------------------------------------------------------------------------------------------------------

    In evaluating olestra's nutritional effects, FDA believes that it 
is appropriate to rely primarily on the two 8-week clinical studies 
because in these studies, there was complete control of nutrient 
intake, they were well designed, and most nutritional parameters were 
monitored. Also, these two studies were performed recently using state-
of-the-art analytical techniques and were designed taking into 
consideration findings from previous studies.
    FDA believes that the 16-week vitamin E study, the 6-week vitamin 
D/K study, and the 14-day vitamin A/fat study are appropriately used to 
support the findings in the two 8-week studies. The results of these 
latter three studies do not weigh as heavily in the safety evaluation 
because of their limitations: the 16-week vitamin E and 6-week vitamin 
D/K studies were conducted in free-living subjects so that it was not 
possible to control completely or have more than imprecise knowledge of 
nutrient intake; the vitamin A/fat study investigated only olestra's 
effects on preformed vitamin A absorption and provides less information 
than the pig studies for assessing olestra's long-term effects on 
vitamin A stores (which are derived from both preformed vitamin A and 
carotenoids).
    Of the studies performed in the pig, FDA believes that it is 
appropriate to rely primarily on the results of the 26-week DR/VR and 
39-week VR studies to assess olestra's nutritional effects because 
these studies were the longest term and were designed to confirm the 
results of the 12-week DR and 12-week VR studies. The 4-week DC study 
was more limited in scope and duration, and was intended to demonstrate 
how olestra's effects are modified by changes in dietary patterns.
1. Primary Human Studies-
    The petitioner performed two 8-week human studies, in both of which 
the entire diet of the subjects was controlled during the study. The 
first study was the 8-week DR study which was intended to determine the 
dose-response effect of olestra on the status of folate, zinc, iron, 
and vitamins A, E, D, K; on the absorption of vitamin B<INF>12; and on 
the bioavailability of <greek-b>-carotene and total carotenoids. The 8-
week VR study was intended to determine the efficacy and safety of 
compensation with vitamins A, E, and D, and to confirm the conclusions 
drawn in the 8-week DR study about the effects of olestra on vitamin K, 
zinc, and iron status, serum 25-hydroxyvitamin D<INF>2 (25-OHD<INF>2) 
concentration, carotenoid bioavailability, and vitamin B<INF>12 
absorption. These two studies are of similar design and the results are 
complementary.
    a. Eight-week DR study design. The 8-week DR study was a parallel, 
double-blind, placebo-controlled study with controlled diets fed for 8 
weeks. Subjects were normal, healthy, 18 to 44 year-old males and 
females. The study had four groups of 21 to 24 subjects per group (88 
subjects total). Subjects were randomly assigned to treatment groups 
that were balanced with respect to age, sex, body mass index (BMI), 
serum <greek-a>-tocopherol, and total serum carotenoid concentrations. 
Subjects were provided with all meals for 56 days.-
    The diets were formulated to provide about 15 percent of calories 
from protein, about 55 percent of calories from carbohydrate, and about 
30 percent of calories from fat. The total digestible fat content was 
kept the same across the four treatment groups by adding 

[[Page 3134]]
triglyceride, in the form of butter, margarine, or vegetable oil, into 
the diets to compensate for the amount of fat replaced by olestra in 
the olestra-containing foods. Therefore, the total amount of lipid 
(digestible fat plus olestra) increased with increasing olestra dose.
    Olestra was added to food items (potato chips, muffins, biscuits, 
and cookies) by substituting olestra for triglyceride in recipes or in 
cooking oils. Because each meal contained olestra, or the corresponding 
placebo (triglyceride), this study design provided maximum opportunity 
for olestra to interfere with nutrient absorption.
    The diets provided each subject with 80 percent to 120 percent of 
the RDA of folate, zinc, and vitamins A, D, E, and K. Calcium and iron 
intakes were not targeted to be within the 80 percent -120 percent RDA 
range, although they were controlled and kept consistent among the 
diets. Vitamin B<INF>12 levels were allowed to exceed the 80 to 120 
percent RDA range in order to maintain zinc and protein consumption at 
the target levels. In addition to the vitamin D in the diet, subjects 
were given 20 <greek-m>g/day (two RDA) of vitamin D<INF>2 as a 
supplement, one third of which was consumed with each meal.-
    The dosages of olestra were 0 (placebo), 8, 20, and 32 g/d. Body 
weights were measured every week and the subjects were questioned daily 
about changes in their health, including GI symptoms. If a GI symptom 
was experienced, the subject completed a detailed questionnaire that 
asked about the type, severity, and duration of symptoms they 
experienced. (The monitoring and reporting methods for adverse 
experiences is discussed in section VI.B. of this document.) Table 4 
summarizes the measurements that were made to assess the status of the 
various nutrients. Most parameters were measured at baseline (week 0) 
and at 2-week intervals throughout the 56-day study period.

                    TABLE 4.--MEASUREMENTS OF MICRONUTRIENT STATUS IN THE EIGHT WEEK DR STUDY                   
----------------------------------------------------------------------------------------------------------------
                        Nutrient                                               Measurements                     
----------------------------------------------------------------------------------------------------------------
Vitamin A                                                Serum retinol concentration\23\, serum carotenoid      
                                                          concentration                                         
Vitamin E                                                Serum <greek-a>-tocopherol concentration               
Vitamin D                                                Serum concentration of 25-OHD<INF>2, 25-hydroxyvitamin D<INF>3   
                                                          (25-OHD<INF>3), and 1,25-dihydroxyvitamin D (1,25-(OH)<INF>2D)  
Vitamin K                                                Serum phylloquinone concentration, urinary excretion of
                                                          <greek-g>-carboxy glutamic acid, plasma concentration 
                                                          of des-carboxy prothrombin (PIVKA-II), plasma         
                                                          prothrombin concentration, and prothrombin time, and  
                                                          partial thromboplastin time                           
Folate                                                   Serum and red blood cell folate concentration          
Vitamin B<INF>12                                              Schilling test, serum vitamin B<INF>12, serum vitamin B<INF>12   
                                                          metabolites                                           
Zinc                                                     Serum and urinary zinc concentrations                  
----------------------------------------------------------------------------------------------------------------
\23\Serum retinol concentration is the only practical measure of preformed vitamin A status that can be made in 
  humans who have adequate liver stores. (Other measures require invasive tissue sampling, such as measurements 
  of liver stores.)                                                                                             

b. Eight-week VR study design. The study design for the 8-week VR study 
was the same as that of the 8-week DR study, except for the following 
elements. The 8-week VR study had 6 groups, each containing 16 or 17 
subjects (100 subjects total). The measurements of micronutrient status 
in the 8-week VR study differed from those in Table 4 in that folate 
and zinc were not monitored while iron status was monitored by 
measuring serum ferritin and iron concentrations and total iron binding 
capacity. Unlike the 8-week DR study, no vitamin D<INF>2 supplement was 
consumed by the test subjects. Finally, in addition to the vitamins 
provided in the diet, graded levels of vitamins A, E, and D were 
provided, as described in Table 5.

 TABLE 5.--VITAMIN DOSES EXPRESSED AS PER GRAM OF OLESTRA (/G) AND -PER DAY (/D) FOR THE SIX TREATMENT GROUPS IN
                                                 8-WEEK VR STUDY                                                
----------------------------------------------------------------------------------------------------------------
                                            Vitamin A                 Vitamin E                Vitamin D<INF>2       
                                   -----------------------------------------------------------------------------
   Treatment Group Olestra (g/d)    <greek-m>g/  <greek-m>g/                            <greek-m>g/  <greek-m>g/
                                         g            d           mg/g         mg/d          g            d     
----------------------------------------------------------------------------------------------------------------
0 (placebo).......................            0            0            0            0            0            0
8.................................           83          664          2.5           20            0            0
20................................           33          660          1.5           30         0.20            4
20................................           83         1660          2.5           50            0            0
20................................          132         2640          3.5           70         0.80           16
32................................           83         2656          2.5           80            0            0
----------------------------------------------------------------------------------------------------------------

    c. Results and conclusions from primary human studies.--i. Vitamin 
A. In the human diet, there are two sources of dietary vitamin A, 
preformed vitamin A (retinyl esters) and carotenoids such as <greek-b>-
carotene that are converted in the body into vitamin A (provitamin A 
carotenoids). Partitioning of either of these sources of vitamin A into 
olestra could affect vitamin A levels in the body.
    The petitioner concluded that there was no effect of olestra in 
either of the two 8-week studies on the serum concentration of retinol. 
This result was not unexpected because serum retinol concentrations are 
relatively stable and not subject to significant change except under 
conditions of prolonged and inadequate vitamin A intake. Only under 
such extreme conditions would changes in liver vitamin A storage be 
reflected by changes in serum retinol. Thus, the petitioner concluded, 
and FDA agrees, that to establish the effect of olestra on vitamin A 
status in humans, data on vitamin A liver stores collected in the pig 
studies and data on the postprandial absorption of vitamin 

[[Page 3135]]
A in man must be considered. Those data are discussed in sections 
V.B.3.c.i. and V.B.2.c. of this document.
    ii. Vitamin E. The petitioner evaluated the effect of olestra on 
vitamin E status and found that there was a highly significant trend in 
decreased serum levels of vitamin E with increasing olestra dose in the 
8-week DR study, an effect evident by day 14 of the study. Serum 
vitamin E was reduced by 6 percent, 17 percent, and 20 percent compared 
to control levels when olestra was consumed at 8, 20, and 32 g/d 
respectively in every meal. The maximum effect was obtained between 2 
and 4 weeks.
    The petitioner calculated, based on the results of the 8-week VR 
study, that the effects on tissue concentrations of vitamin E were 
offset by the addition of 2.07 mg of vitamin E (d-<greek-a>-tocopheryl 
acetate) per g olestra. This level is equivalent to 1.9 mg <greek-a>-
tocopherol equivalents/g olestra and 0.94 RDA of vitamin E per 1 oz 
serving of savory snacks containing 10 g of olestra.
    FDA agrees that 1.9 mg of <greek-a>-tocopherol equivalents/g 
olestra adequately restored serum vitamin E levels in this study, as 
indicated in the data adjusted for baseline serum vitamin E levels\24\ 
(Ref. 44). FDA finds that this study adequately controlled vitamin E 
consumption, analyzed appropriately for vitamin E levels, and was of 
sufficient duration to observe olestra's effect, because the effect had 
reached a plateau after a few weeks into the study (Ref. 43). 
Therefore, FDA agrees that compensation for olestra's effects on 
vitamin E can be calculated from the results of this study, and further 
agrees that 1.9 mg of <greek-a>-tocopherol equivalents per g of olestra 
is the appropriate compensation level.

    \24\In controlled diet studies such as this, the controlled diet 
is often better in many respects than the free-living diet of the 
subjects, thus it is not unusual that the basline vitamin E levels 
were lower than controlled-diet levels. Therefore, adjustment for 
baseline levels is appropriate.
---------------------------------------------------------------------------

    iii. Vitamin D. In the human diet, there are two sources of vitamin 
D, dietary (vitamin D<INF>2) and endogenous (vitamin D<INF>3) produced 
in the body via sunlight-catalyzed dermal synthesis. The nature of the 
dose-response effect of olestra on dietary vitamin D<INF>2 was 
determined by measuring serum levels of 25-OHD<INF>2, which is derived 
only from dietary vitamin D. Serum levels of 25-OHD<INF>3 (from 
dermally synthesized vitamin D<INF>3), 1,25-(OH)<INF>2D, and 25-OHD 
were also measured to assess olestra's effects on total vitamin D 
status. The serum concentration of 25-OHD reflects total vitamin D 
status.
    The petitioner found that there was an olestra treatment effect in 
the 8-week DR study on the serum concentration of 25-OHD<INF>2. At the 
end of the study, the reductions in 25-OHD<INF>2 were 23 percent, 13 
percent, and 27 percent for 8, 20, and 32 g olestra/d, respectively, 
relative to control. The effect had levelled off within 4 weeks. There 
was no effect on serum 25-OHD<INF>3 or 1,25-(OH)D. In this study, the 
diet contributed 55 to 68 percent to total vitamin D status (the 
remainder coming from sunlight). The amount supplied by the diet was 
relatively high because of excess vitamin D<INF>2 supplied by the 
dietary supplement.
    Although the subjects in the 8-week VR study did not receive 
supplements (the diet contributed 12 to 20 percent of total vitamin D), 
the reductions in 25-OHD<INF>2 in the 8-week VR study were similar to 
those observed in the 8-week DR study: 22 percent, 29 percent, and 22 
percent for 8, 20, and 32 g olestra/day, respectively, relative to 
control. The reductions in serum total 25-OHD were less compared to the 
reductions in the 8-week DR study because a larger fraction of the 
total vitamin D was endogenous. The petitioner concluded that olestra's 
effect on serum vitamin D<INF>2 in the 8-week VR study could be offset 
by adding 0.07 times the RDA of vitamin D<INF>2 per 1 oz serving of 
savory snack containing 10 g olestra (equivalent to .07 <greek-m>g/g 
olestra or 2.7 IU). The petitioner further concluded that olestra's 
effect on vitamin D status is not nutritionally significant because the 
effect is relatively small (on the order of a few percent in the 18-
week VR study) and sunlight synthesis is a more important contributor 
to total vitamin D levels.
    FDA agrees with the petitioner that olestra reduced serum vitamin D 
in both studies. Because the effect of olestra on serum vitamin D<INF>2 
levels had levelled off within the first 4 weeks of the study, FDA 
considers the studies of sufficient length to assess olestra's effects 
(Ref. 43). However, it is difficult to quantify olestra's effect 
because of confounding factors, such as the lack of a strong 
relationship between dose and reductions in 25-OHD<INF>2 in both 
studies. In addition, the effect of olestra on serum total 25-OHD 
levels is difficult to quantify in the 8-week VR study because total 
serum 25-OHD levels were falling in the control group as well as the 
treated group during the study. (For example, total serum 25-OHD levels 
in the group not consuming olestra decreased 30 percent over the course 
of the study.) Compensation of two of the 20 g/d olestra groups with 
0.2 and 0.8 <greek-m>g vitamin D<INF>2/g olestra reduced the decrease 
in total serum 25-OHD (which was due to both olestra and test diet 
effects). At the 0.2 <greek-m>g/g olestra supplementation level, the 
decrease in total 25-OHD was slightly less than in the group not 
consuming olestra (26.8 percent vs. 30 percent respectively). With the 
higher level of compensation (0.8 <greek-m>g/g olestra) the decrease in 
25-OHD was about one-half that of the group not consuming olestra (15.6 
vs. 30) (Ref. 45).
    Although FDA believes that the variability of the data and the ``on 
diet'' effects on vitamin D status make quantitation of the magnitude 
of olestra's effects difficult, the agency concludes that the 8-week VR 
study can be used to estimate olestra's effects on vitamin D because 
dietary vitamin D<INF>2 consumption was not excessive and the effect of 
olestra had levelled off within 4 weeks. FDA concludes that these 
results show that 0.2 <greek-m>g vitamin D<INF>2/g olestra adequately 
compensated for olestra's effects on vitamin D status in the 8-week VR 
study (Ref. 45).
    iv. Vitamin K. The petitioner found that in the 8-week DR study, 
olestra caused a dose-response decrease in serum phylloquinone (vitamin 
K<INF>1) concentration that levelled out within 2 weeks. Eight, 20, and 
32 g/d olestra reduced serum phylloquinone by 36 percent, 40 percent, 
and 47 percent, respectively. There was no effect of olestra on the 
status of vitamin K as measured by the plasma concentration of des-
carboxylated prothrombin (PIVKA-II), urinary excretion of <greek-g>-
carboxyglutamic acid (urinary Gla), and plasma prothrombin 
concentration, which are all measures of functional activity of vitamin 
K. Prothrombin time (PT) and partial thromboplastin time (PTT), the 
normal measures of clinical vitamin K status, were also not affected by 
olestra intake. The 8-week VR study showed similar results. FDA agrees 
with the petitioner's findings in both studies.
    The petitioner concluded that the lack of any change in vitamin K 
functional activity indicates that the decrease in para.serum 
phylloquinone concentration does not represent a significant reduction 
in vitamin K status. FDA notes that, although olestra did not 
demonstrate any effect on the vitamin K-related functional parameters 
(i.e., urinary excretion of <greek-g>-carboxy glutamic acid, plasma 
concentration of des-carboxy prothrombin (PIVKA-II), plasma prothrombin 
concentration, and clotting times), the length of the study was 
insufficient to rule out possible effects on these vitamin K-related 
functional parameters after longer term consumption of olestra. Also, 
while serum levels in the studies after 56 days 

[[Page 3136]]
can be considered to be only marginally reduced, when compared to true 
deficiency levels, the potential remains for continued decrease with 
long-term olestra consumption.
    To calculate the level of vitamin K that would compensate for the 
reduction of serum vitamin K levels caused by olestra consumption, the 
petitioner relied upon the fact that serum vitamin K levels closely 
reflect the most recent (within 24 hours) intake of vitamin K. (Vitamin 
K has a half-life in serum of approximately 2 hours.) In the 8-week DR 
study, a 6 day rotating menu provided different vitamin K intakes for 
each day. As a result, the level of vitamin K on the days before each 
biweekly blood draw varied.\25\ The serum level of vitamin K that would 
result from consumption of 1 RDA (80 <greek-m>g) of vitamin K in the 
absence of olestra was obtained from the control group measurements. 
The compensation level was calculated as the amount of vitamin K needed 
in the presence of olestra to maintain the serum vitamin K 
concentration at the control level. This calculation yields 
compensation levels of 31 <greek-m>g vitamin K in the 8 g/d group (4 
<greek-m>g/g olestra), 68 <greek-m>g vitamin K in the 20 g/d group (3.2 
<greek-m>g/g olestra), and 82 <greek-m>g vitamin K in the 32 g/d group 
(2.6 <greek-m>g/g olestra). The petitioner averaged these three results 
to yield an estimated compensation level of 3.3 <greek-m>g/g olestra.

    \25\In the 8-week VR study a 7-day rotating menu was used to 
ensure that the subjects received equivalent levels of phylloquinone 
on the days prior to blood draws.
---------------------------------------------------------------------------

    FDA concludes that the response of serum vitamin K to the previous 
day's dietary intake is a reasonable, though imprecise, indicator of 
olestra's effects on serum vitamin K levels. Thus, FDA concludes that 
the petitioner's calculation provides only an estimate of appropriate 
compensation levels. FDA's conclusion regarding the appropriate 
compensation level for vitamin K is addressed in section V.B.4.e. of 
this document.
    v. Carotenoids. In the 8-week DR study, the petitioner found that 
carotenoid bioavailability as measured by serum <greek-b>-carotene and 
total carotenoid concentrations fell markedly with eight g/d olestra 
consumption although higher levels of olestra consumption did not cause 
a much larger decrease. At an olestra intake of 8 or 20 g/d, there was 
about a 60 percent reduction in serum <greek-b>-carotene within the 
first 4 weeks and there was essentially no further decline for the 
remainder of the study. Olestra's effect on total serum carotenoids was 
of a similar magnitude. These results were confirmed in the 8-week VR 
study. FDA's conclusions regarding olestra's effects on carotenoids are 
addressed in section V.B.4.f. of this document.
2. Other Human Studies
    a. Six-week vitamin D/K study. The 6-week vitamin D/K study was a 
double-blind, placebo-controlled, parallel design using 221 normal, 
healthy, free-living subjects. The objective of this study was to 
assess the status of vitamins D and K in subjects consuming 20 g/d 
olestra. Subjects were randomly assigned to treatment groups and 
balanced with respect to age, sex, and body mass index (BMI). Subjects 
consumed a total of 20 g olestra or the corresponding triglyceride 
placebo per day in cookies eaten at each meal. Subjects consumed self-
selected diets with an upper limit of 7 glasses of milk per day. Daily 
food frequency records were used to estimate phylloquinone intake. The 
diet was supplemented with 20 <greek-m>g (800 IU) ergocalciferol 
(vitamin D<INF>2), taken in capsule form with the morning meal. The 
study was conducted from February through April to lessen sunlight 
effects on vitamin D status. Vitamin K status was assessed by 
monitoring serum phylloquinone (vitamin K<INF>1), serum 
Simplastin<Register>/Ecarin<Register> assay (S/E) (a measure of 
functional prothrombin in blood), and prothrombin (PT) and partial 
thromboplastin times (PTT). Vitamin D status was assessed by monitoring 
serum concentrations of 25-OHD<INF>2, 25-OHD<INF>3, and 1,25-
(OH)<INF>2D. All serum parameters were measured every 2 weeks, while PT 
and PTT were measured only at the beginning and end of the study.
    The petitioner found that mean serum concentrations of 25-OHD<INF>2 
rose in both placebo and olestra-fed groups, although serum 
concentrations rose more slowly in the olestra-fed group. At week two 
and beyond, the olestra group showed serum vitamin 25-OHD<INF>2 levels 
that were about 19 percent below placebo, which persisted to the end of 
the study. No statistically significant changes in the measurements 
used to assess vitamin K status (S/E, clotting times, and serum 
phylloquinone concentration) were observed in the study, except that at 
week two, serum phylloquinone levels were lower in the olestra-fed 
subjects. The petitioner concludes from these results that 20 g/d 
olestra does not affect vitamin K status or vitamin D nutritional 
status.
    FDA disagrees with the petitioner's conclusions regarding olestra's 
effects on vitamins D and K. First, the 19 percent decrease in serum 
25-OHD<INF>2 is indicative of an olestra effect on nutritional status 
and specifically, on vitamin D status. Second, the study is of limited 
usefulness in assessing vitamin K status because the sensitivity of the 
tests used to evaluate the impact of low serum vitamin K1 on vitamin K-
dependent clotting protein function is either poor (PT and PTT) or not 
fully validated (S/E). Furthermore, the quantitative precision of the 
study is diminished because the subjects were eating diets that were 
not controlled. Thus, FDA disagrees with the petitioner's conclusion 
that olestra does not affect vitamin D nutritional status and further 
concludes that this study does not provide sufficient information for a 
conclusion regarding olestra's impact on vitamin K<INF>1 nutritional 
status (Ref. 46).
    b. Sixteen-week vitamin E study. The 16-week vitamin E study was 
also a double-blind, placebo-controlled, parallel design with 194 
subjects. The purpose of the study was to assess the adequacy of 1.1 mg 
of d-<greek-a> tocopherol acetate/g olestra in maintaining vitamin E 
status in persons chronically consuming olestra and to determine the 
potential effects of 18 g/d olestra on the status of vitamins K and D, 
absorption of carotenoids, and concentrations of serum retinol. Test 
subjects were normal, healthy, male and female free-living persons 
between the ages of 18 to 65 who consumed 18 g/d olestra, with or 
without 1.1 mg tocopheryl acetate/g olestra, or triglyceride placebo 
for 16 weeks. The daily dose of olestra (contained in cookies and ice 
cream) was to be consumed with meals; meal content was not controlled 
and they were permitted to eat between meals foods of their own 
choosing. Subjects were not specifically requested to evenly divide the 
daily allocation of cookies and ice cream among the meals. Serum 
concentrations of cholesterol, <greek-a>-tocopherol, <greek-b>-
carotene, and total carotenoids were measured biweekly. Serum 25-OHD 
concentration, clotting times (PT and PTT), and serum levels of 
functional prothrombin (S/E) were measured at weeks 0, 8, and 16.
    The petitioner found that serum <greek-a>-tocopherol concentration 
was reduced by 6 percent, relative to control, in the olestra group and 
by 4 percent in olestra with added <greek-a>-tocopheryl acetate group. 
Serum concentrations of <greek-b>-carotene and total carotenoids were 
reduced by 21 to 29 percent in both olestra groups. Serum 25-OHD, 
retinol concentrations, and vitamin K status were unaffected by olestra 
consumption.
    The petitioner concludes that 1.1 mg <greek-a>-tocopheryl acetate/g 
olestra was not sufficient to compensate for olestra's effect in this 
study and that olestra did 

[[Page 3137]]
not affect vitamin D or K status. FDA agrees that compensation for 
olestra's reduction of vitamin E status was not adequate and that there 
was no evidence of an olestra effect on vitamin D and K status in this 
study. However, the value of this study is limited because the subjects 
were free-living, which limits the quantitative precision of the study 
in predicting olestra's nutritional effects (Ref. 47).
    c. Vitamin A/fat study. The vitamin A/fat absorption study was a 
parallel, double-blind, placebo-controlled study of 70 healthy males. 
The subjects consumed 0 or 10 g/d olestra in potato chips for a 30-day, 
free-living adaptation period. The adaptation period was followed by a 
14-day in-house period in which the subjects received 0, 8, 20, or 32 
g/d olestra in potato chips and cookies. One-third of this daily dose 
was eaten with each meal except on the days when vitamin A and fat 
absorption was measured; on those days, the entire dose of olestra was 
consumed in potato chips at breakfast along with the radiolabeled 
marker. The dose response of olestra on the absorption of preformed 
vitamin A was measured using radiolabeled retinyl palmitate.
    The petitioner evaluated the results of the vitamin A aspects of 
this study and concluded that neither 8 nor 20 g of olestra in a single 
meal had any effect on the absorption of 3H-labeled retinyl palmitate 
contained in the meal, and further that 32 g of olestra in the test 
meal reduced vitamin A absorption from that meal by 19 percent relative 
to controls. The petitioner also calculated that when high responders 
(the group of subjects showing high triglyceride levels after fat 
ingestion) were removed from the calculation, olestra's effect on 
vitamin A absorption was reduced to 13 percent.
    FDA finds no justification for removing a part of the subject 
population from the calculation and thus believes that the 13 percent 
reduction figure is of no value in assessing olestra's effects on 
vitamin A. FDA agrees, however, that the study supports the conclusion 
that olestra induced a 19 percent reduction, and considers this amount 
to be the most accurate measurement of olestra's effect on preformed 
vitamin A absorption in this study (Ref. 48).
    The petitioner concluded that the lack of an effect at the lower 
olestra doses (8 and 20 g) indicates that chronic consumption of 
olestra at the 90th percentile estimated intake by the total population 
(7 g/d) or the 90th percentile estimated acute intake for the heaviest 
consumers of savory snacks (18 to 44 year old males, 20 g/d\26\) will 
have no effect on preformed vitamin A absorption. While this 
interpretation of the data appears to be reasonable, FDA notes that 
this study only addresses olestra's effects on preformed vitamin A 
absorption. The study cannot, by design, address the decrease in 
vitamin A stores that would be caused by olestra's effects on 
carotenoid absorption.

    \26\A dose of 20 g is equivalent to the consumption of two 1-oz 
servings of savory snacks at a single meal.
---------------------------------------------------------------------------

3. Pig Studies
    The petitioner conducted five nutritional studies of varying 
lengths (12, 12, 26, 39, and 4 weeks) in pigs. The objective of the 12-
week DR study was to confirm the hypothesized dose-response effect of 
olestra on fat-soluble vitamins A, D, E, and K, and to determine 
whether there were any effects on specific marker nutrients that are 
difficult to absorb or are limited in the American diet (folate, 
vitamin B<INF>12, calcium, iron, and zinc). The purpose of the 12-week 
VR study was to determine whether the effects of olestra on the status 
of vitamins A and E that were observed in the 12-week DR study could 
adequately be compensated for by the addition of vitamins to the diet.
    The 26-week DR/VR and the 39-week VR studies were undertaken after 
the 12-week studies to evaluate olestra's effects on nutrient status in 
the period beyond the maximum growth phase. The purpose of the 26-week 
DR/VR study was three-fold: (1) To confirm the dose-response effect of 
olestra observed in the 12-week DR study; (2) to evaluate the effect of 
olestra on fat-soluble vitamins, folate, vitamin B<INF>12, calcium, 
zinc, and iron, with longer exposure times and lower olestra levels 
than had been tested in the 12-week DR study; and (3) to determine the 
amounts of fat-soluble vitamins that would need to be added to the diet 
to compensate for olestra's effects. The 39-week VR study was designed 
to evaluate over a longer exposure period the effects of 0.25 percent 
olestra and added vitamins A and E that were measured in the 26-week 
DR/VR study. The 4-week DC study was designed to determine whether 
olestra's effects on vitamins A and E were dependent on the timing of 
olestra consumption (with meals or temporally separated from meals) or 
the means by which olestra enters the diet (as chips or admixed with 
feed).
    a. Study design of 12-, 26-, and 39-week studies. The 12-week DR, 
12-week VR, 26-week DR/VR, and 39-week VR pig studies used similar 
materials and methods. The 12-week DR study is described in depth. For 
the three other pig studies, only the differences from the 12-week DR 
study are described.
    i. Twelve-week DR study. The test animals were a domestic, cross-
bred strain of pigs, and were 5 to 7 weeks of age when received. All 
treatment groups contained equal proportions of females and castrated 
males. The pigs were acclimated for 14 to 16 days before being placed 
on experimental diets: During the first 7 to 9 days of the acclimation 
period, the animals were fed a 20 percent protein swine chow 
(University of Wisconsin-Madison) ad libitum; during the last 7 days 
they were fed the purified basal diet that was fed throughout the 
remainder of the study.
    The basal diet was a purified diet consisting of about 25 percent 
casein, 24 percent starch, 24 percent sucrose, 5 percent Alphacel, 14 
percent lard, and 8 percent of a vitamin/mineral premix. The diet 
delivered about 30 percent of calories from fat, a level equivalent to 
the target fat consumption level recommended for the U. S. population, 
but lower than current actual fat consumption. The ratio of calories 
from saturated:monounsaturated:polyunsaturated fats was targeted at 
1:1:1.
    The basal diet provided the National Research Council (NRC) 
requirements of micronutrients for 5 to 10 kilogram (kg) pigs. The NRC 
requirements, as a percentage of the feed, decline for many nutrients 
as a function of increasing body weight. Therefore, as the pigs grew, 
most nutrients were actually fed in excess of the body-weight-specific 
NRC requirements.
    In the basal diet, vitamin A was provided as a 3:1 ratio of retinol 
equivalents from retinyl palmitate and <greek-b>-carotene, 
respectively. This targeted ratio simulated the average dietary sources 
of vitamin A for the U. S. population. Vitamin E was provided in the 
form of d,l-<greek-a>-tocopheryl acetate. Dietary vitamin D was 
supplied as ergocalciferol (vitamin D<INF>2). In addition to dietary 
vitamin D, pigs in this study were exposed to 2 minutes of ultraviolet 
(UV) light each day. Vitamin K was provided as phylloquinone, the major 
source of vitamin K in the human diet, rather than as menadione, the 
form typically added to swine chow.\27\ Folate was provided as folic 
acid, vitamin B<INF>12 was provided as cyanocobalamin, calcium as a 
mixture of CaHPO<INF>4<bullet>2H<INF>2O 

[[Page 3138]]
and CaCO<INF>3, iron as FeSO<INF>4<bullet>7H<INF>2O, and zinc as 
ZnSO4<bullet>7H2O. The micronutrients were added directly to the diet, 
separate from the olestra, during diet preparation.

    \27\The swine NRC nutrient requirement table gives the vitamin K 
requirement as menadione; there is no value listed for 
phylloquinone. Therefore, the petitioner calculated the added amount 
of phylloquinone based on the assumption that phylloquinone is 
equivalent to menadione on a weight basis.
---------------------------------------------------------------------------

    The 12-week DR study consisted of 7 groups of pigs, containing 12 
pigs each (except the control group of 20 pigs). Olestra was added to 
the diets at levels of 0 percent (control), 1.1 percent, 2.2 percent, 
3.3 percent, 4.4 percent, 5.5 percent, and 7.7 percent (by weight). The 
olestra was heated before incorporating into the diet by frying potato 
chips.
    Growth, feed intake, hematology, and clinical chemistry measures 
and the status of vitamins A, B12, D, E, and K, and folate, calcium, 
zinc, and iron were measured at regular intervals. Stores of vitamins 
A, E, B12, calcium, phosphorus, zinc, and iron were measured in the 
liver or bone at the termination of the study. The measurements used to 
assess the status of the various nutrients are summarized in Table 6.

                      TABLE 6.--MEASUREMENTS OF NUTRIENT STATUS IN THE 12-WEEK DR PIG STUDY                     
----------------------------------------------------------------------------------------------------------------
                        Nutrient                                               Measurements                     
----------------------------------------------------------------------------------------------------------------
Vitamin A                                                Liver and serum concentration                          
Vitamin E                                                Liver, serum, and adipose tissue concentration         
Vitamin D                                                Serum concentration of 25-OHD<INF>2, 25-OHD<INF>3, and 1,25-     
                                                          (OH)<INF>2D                                                
Vitamin K                                                Prothrombin time                                       
Folate                                                   Plasma concentration                                   
Vitamin B<INF>12                                              Liver concentration                                    
Calcium                                                  Bone, serum calcium, and bone ash concentration        
Phosphorus                                               Bone and serum concentration                           
Iron                                                     Liver iron concentration and serum concentrations of   
                                                          hemoglobin, hematocrit, mean corpuscular volume (MCV),
                                                          mean corpuscular hemoglobin (MCH), and mean           
                                                          corpuscular hemoglobin concentration (MCHC)           
Zinc                                                     Liver, bone, and serum concentration                   
----------------------------------------------------------------------------------------------------------------

    ii. Twelve-week VR study. The 12-week VR study consisted of 11 
groups of pigs (one baseline, one control, and nine treatment groups), 
each containing 10 pigs (5 castrated males and 5 females). Pigs were 
exposed to 2 minutes of UV light each day. The amount of olestra and 
total amounts of vitamins A, D, and E targeted to be in the diet for 
the nine treatment groups is summarized in Table 7.

[[Page 3139]]


                                                                         TABLE 7.--STUDY DESIGN FOR 12-WEEK VR PIG STUDY                                                                        
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
          Percent Olestra                                Vitamin A (x NRC)\1\                                     Vitamin D (x NRC)<SUP>1                             Vitamin E (x NRC)<SUP>1             
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0 (control).......................                                                         1.00                                           1.00                                           1.00   
1.1...............................                                                         1.05                                           1.20                                           1.20   
1.1...............................                                                         1.35                                           1.80                                           1.90   
1.1...............................                                                         1.65                                           2.40                                           2.60   
4.4...............................                                                         1.65                                           2.40                                           2.60   
4.4...............................                                                         2.40                                           4.20                                           4.60   
4.4...............................                                                         3.15                                           6.00                                           6.60   
7.7...............................                                                         2.05                                           3.80                                           4.15   
7.7...............................                                                         3.45                                           6.60                                           7.30   
7.7...............................                                                         4.85                                           9.40                                          10.45   
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Expressed as multiples of the NRC requirements of pigs.                                                                                                                                      


[[Page 3140]]

    A premix was prepared to provide additional amounts of vitamin A as 
well as vitamin D for each level of olestra fed. Vitamin D was added as 
vitamin D<INF>2 (ergocalciferol), while vitamin A was in the form of 
retinyl palmitate. Above-basal levels of vitamin E, in the form of d-
<greek-a>-tocopheryl acetate, were combined with the olestra instead of 
adding it directly to the diet because this procedure mimics that which 
would be used to add vitamin E to olestra for savory snack use, i.e., 
the vitamin would be added directly to the frying oil.-
    iii. Twenty-six week DR/VR study. The 26-week DR/VR study had 11 
groups, each containing 10 pigs (5 castrated males and 5 females). 
Olestra was fed at five levels (0.25, 0.5, 1.1, 3.3, and 5.5 percent). 
Seven of the groups (baseline, control, 0.25, 0.5, 1.1, 3.3, and 5.5 
percent olestra) did not have any additional vitamins above those 
present in the basal diet. The other four groups consumed added 
vitamins as described in Table 8.

TABLE 8.--VITAMIN DOSES FOR THE FOUR TREATMENT GROUPS IN THE 26-WEEK DR/
               VR PIG STUDY THAT HAD VITAMIN COMPENSATION               
------------------------------------------------------------------------
                                             Vitamin E (mg d-<greek-a>- 
   Percent       Vitamin A (IU/kg diet)         tocopherol acetate/g    
   olestra                                            olestra)          
------------------------------------------------------------------------
5.5           3,300                         1.71                        
0.25          150                           1.71                        
0.25          300                           3.42                        
0.25          600                           5.13                        
------------------------------------------------------------------------

    Additional vitamins were added in the same manner as described for 
the 12-week VR study. The pigs in the vitamin-compensated 5.5 percent 
olestra group were exposed to 2 minutes of UV light each day. UV 
exposure was eliminated in the remainder of the groups in order to 
eliminate the possibility that the UV light might affect the magnitude 
of olestra's effect on dietary vitamin D<INF>2. Instead, the diet was 
modified by increasing the vitamin D level to two times the NRC 
requirement to produce more readily measurable levels of vitamin 
D<INF>2 in the serum.
    In addition to the measurements of nutrient status listed in Table 
6, serum parathyroid hormone (PTH) was monitored.
    iv. Thirty-nine week VR study. The 39-week VR study consisted of 
the following four groups of 10 pigs each (5 castrated males and 5 
females): baseline, control, 0.25 percent olestra, and 0.25 percent 
olestra with 150 IU vitamin A/kg diet (60 IU/g olestra) and 1.71 mg d-
<greek-a>-tocopherol acetate/g olestra. There was no UV exposure in 
this study and the diet was modified by increasing the vitamin D level 
to two times the NRC requirement to produce more readily measurable 
levels of vitamin D<INF>2 in the serum. In addition, vitamin K level in 
the basal diet was lowered to one-fifth the level that was fed in the 
other three studies.
    In addition to the measurements of nutrient status listed in Table 
6, serum parathyroid hormone (PTH) was monitored.
    b. Study design of the 4-week DC study. Young pigs, 7 to 9 weeks of 
age at the start of the study were fed a casein-based diet formulated 
to contain at least one times the NRC requirements of micronutrients. 
Five groups of 10 pigs each were fed 0 percent or 2.2 percent olestra 
for 4 weeks. A sixth group of 10 pigs provided baseline data for 
vitamin A, D, and E tissue concentrations. The olestra was fed either 
admixed in the diet, as chips prior to each meal, as chips prior to the 
noon meal only, or as chips fed between the noon and evening meal.
    The petitioner evaluated the change in status of vitamins A, D, and 
E at the end of the 4-week study through serum measurements of the 
concentrations of vitamin A (retinol), vitamin E (<greek-a>-
tocopherol), and vitamin D (25-hydroxyvitamin D<INF>2 and 25-
hydroxyvitamin D<INF>3) and liver measurements of vitamin A (total 
retinol and retinyl esters) and vitamin E (<greek-a>-tocopherol).
    c. Results and conclusions from pig studies. The results of the 4-
week DC study will be discussed in section V.B.4.a. of this document.
    i. Vitamin A. Data on the dose-response effect of olestra on liver 
vitamin A stores were collected in the 12-week DR study and the 26-week 
DR/VR study. The petitioner observed that olestra caused a nonlinear 
dose-response reduction in hepatic vitamin A stores, in which lower 
amounts of olestra had a greater proportional effect on stores, in both 
the 12-week DR and 26-week DR/VR studies. In the 26-week DR/VR study, 
the decreases in liver vitamin A (relative to controls) were 45 percent 
(0.25 percent olestra), 57 percent (0.5 percent olestra), 65 percent 
(1.1 percent olestra), and 88 percent (3.3 percent and 5.5 percent 
olestra). The reductions observed in the 12-week DR study were very 
similar, with the highest olestra intake (7.7 percent) causing a 
greater than 90 percent decrease. Serum vitamin A levels also decreased 
in a dose-response manner with increasing olestra intake in both 
studies.\28\

    \28\Unlike adult pigs, weanling pigs do not have large stores of 
vitamin A so liver stores are not able to compensate for olestra's 
interference with absorption of vitamin A; thus the effect on 
vitamin A status is also manifest in the serum levels.
---------------------------------------------------------------------------

    In both the 12-week VR and the 26-week DR/VR studies, the addition 
of varying levels of vitamin A to the diet resulted in a linear 
increase in liver vitamin A stores. For the 12-week VR study, the 
petitioner calculated that the effect of olestra on liver vitamin A 
stores could be offset by adding 58.1 IU of vitamin A/g olestra in the 
diet. FDA calculates the appropriate compensation level separately for 
each level of olestra in the diet, because the required compensation 
level in IU/g changed as a function of dietary olestra level, and 
determined that the compensation level ranged from 130.8 IU vitamin A/g 
olestra at 0.1 percent olestra to 45.8 IU vitamin A/g olestra at 7.7 
percent olestra (Ref. 49).
    For the 26-week DR/VR study, the petitioner calculated that 170 IU 
vitamin A/g of olestra compensates for olestra's effects on vitamin A 
liver status, which is equivalent to 93 <greek-m>g retinyl palmitate/g 
olestra, or 0.34 RDA of vitamin A per 1-oz serving of snacks containing 
10 g olestra. FDA agrees that this calculation is appropriate and that 
when olestra is present at 0.25 percent of the pig diet, approximately 
170 IU of retinol/g olestra maintains the liver vitamin A levels at 
control values\29\ (Ref. 49). One hundred and seventy IU of retinol/g 
olestra is equivalent to 51 retinol equivalents/g olestra.

    \29\The estimates from the 12-week study are somewhat smaller 
than estimates obtained from the 26-week pig study; in the 12-week 
study, the required supplementation level for 0.25 percent olestra 
was 128 IU/g olestra.
---------------------------------------------------------------------------

    The petitioner concluded and FDA agrees that the results of the 39-
week VR 

[[Page 3141]]
study confirm olestra's effect on vitamin A liver stores, although FDA 
notes that the amount of vitamin A added to the diet in the 39-week 
study (60 IU vitamin A/g olestra) was not sufficient to compensate for 
olestra's effect on vitamin A.
    ii. Vitamin E. In the 26-week DR/VR study, the decreases in liver 
vitamin E (relative to controls) were 24 percent for 0.25 percent 
olestra, 31 percent for 0.5 percent olestra, 53 percent for 1.1 percent 
olestra, 71 percent for 3.3 percent olestra, and 75 percent for 5.5 
percent olestra. In the 12-week DR study, the reductions were slightly 
larger (e.g., 60 percent for 1.1 percent olestra, 69 percent for 2.2 
percent olestra, 75 percent for 3.3 percent olestra, 78 percent for 4.4 
percent olestra, 80 percent for 5.5 percent olestra, and 81 percent for 
7.7 percent olestra). Vitamin E concentration in adipose tissue showed 
a slightly smaller decrease in both studies; for example, with 5.5 
percent olestra, adipose vitamin E concentration had fallen by about 73 
percent in both the 12-week DR and 26-week DR/VR studies.
    The results of the 12-week DR and 26-week DR/VR studies showed that 
effects of olestra on vitamin E status were similar in the serum and 
liver, although the percent decrease in vitamin E was slightly larger 
for liver than for serum. The petitioner concluded, and FDA concurs, 
that this relationship confirms that serum vitamin E concentration is a 
reliable measure of vitamin E status. The concentration of vitamin E in 
adipose tissue also changed in a similar fashion to the changes in 
serum and liver concentrations although the magnitude and rate of 
change were not as great.
    The petitioner concludes that 2.09 IU of vitamin E/g olestra offset 
olestra's effects in the 12-week VR study; in the 26-week DR/VR study 
(where olestra was fed at a lower level), 2.79 IU of vitamin E/g 
olestra (which translates to 2.06 mg d-<greek-a>-tocopheryl acetate/g 
olestra) offset olestra's effects. FDA concurs with the petitioner's 
general conclusions and with the calculated level of 2.79 IU vitamin E/
g olestra from liver measurements in the 26-week VR/DR study. FDA's 
calculated compensation levels for the other studies, as shown in Table 
9, differ slightly because of small differences in the choices of 
variables to fit the curves in the statistical analyses (Refs. 50 and 
51).

[[Page 3142]]


                            TABLE 9.--FDA-CALCULATED COMPENSATION LEVELS OF VITAMIN E TO RESTORE LIVER AND SERUM LEVELS BASED ON 12-WEEK VR AND 26-WEEK DR/VR STUDIES                           
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                     Vitamin E compensation (IU/g olestra)                                      
                     Study                            Olestra level (%)      -------------------------------------------------------------------------------------------------------------------
                                                                                              Liver compensation level                                  Serum compensation level                
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
26-week DR/VR                                                           0.25                                                      2.79                                                      2.98
12-week VR                                                               1.1                                                      2.66                                                      2.76
12-week VR                                                               4.4                                                      2.27                                                      2.34
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


[[Page 3143]]

    iii. Vitamin D.--a. Petitioner conclusions. The petitioner 
concluded that the 12-week DR study established a dose-response effect 
for olestra on dietary vitamin D at olestra levels up to 4.4 percent of 
the diet, as measured by serum concentration of 25-OHD<INF>2; the serum 
concentration of 25-OHD<INF>2 was about 10 percent less than control in 
the 1.1 percent olestra group and about 35 percent less than control in 
the 2.2 percent, 3.3 percent, and 4.4 percent groups. At higher olestra 
levels, changes in the dietary contribution to total circulating 25-OHD 
were confounded by changes in the contribution from vitamin D<INF>3 
synthesized in the skin.
    The petitioner also concluded that in the 12-week VR study, serum 
concentration of 25-OHD<INF>2 increased in a dose-response manner as 
the amount of vitamin D<INF>2 added to the basal diet was increased, at 
all levels of olestra. However, interpretation of the serum 25-
OHD<INF>2 data at the mid- and high-olestra levels (4.4 and 7.7 
percent) was confounded because the proportion of 25-OHD<INF>3 in the 
serum decreased with increasing levels of olestra at these treatment 
levels. The petitioner has suggested, that this decrease in serum 25-
OHD<INF>3 may have resulted from the effect of the high levels of 
olestra on the reabsorption of biliary vitamin D<INF>3. Reduced 
reabsorption of biliary vitamin D<INF>3 would tend to increase the 
serum concentration of 25-OHD<INF>2 because of diminished vitamin 
D<INF>3 competition for the liver 25-<greek-a> hydroxylase.
    Using the serum 25-OHD<INF>2 concentrations from the groups fed 1.1 
percent olestra in the 12-week VR study, the petitioner calculated that 
the amount of vitamin D required to restore serum 25-OHD<INF>2 to the 
control level was 13.0 IU vitamin D/g olestra, which is equivalent to 
0.33 RDA/1 oz serving of chips containing 10 g olestra. The petitioner 
considers that the confounding effect of vitamin D<INF>3 was absent or 
minimal when olestra was fed at 1.1 percent of the diet.
    The petitioner concluded that in the 26-week DR/VR study, 5.5 
percent olestra (no extra vitamins) reduced plasma 25-OHD<INF>2 by 20 
percent at week 26. At week 16, serum 25-OHD<INF>2 levels in the 3.3 
percent and 5.5 percent olestra groups were significantly lower than 
controls by 23 percent and 35 percent, respectively.
    The petitioner concluded that in the 39-week VR study, olestra 
decreased serum levels of 25-OHD<INF>2 by the same magnitude as in the 
26-week DR/VR study, while serum 25-OHD<INF>3, total serum 25-OHD, and 
serum 1,25-(OH)<INF>2D were not affected. Serum 25-OHD<INF>2 levels 
were 13 to 15 percent lower than week 12 and week 26. At week 39, the 
values were 6 to 11 percent lower than controls, but this difference 
was not statistically significant.
    b. FDA conclusions. FDA concludes that the results of the pig 
studies are of limited utility for quantifying olestra's effects on 
vitamin D, for several reasons. First, FDA notes that vitamin D levels 
were never measured in the diet as fed in any of the pig studies. This 
lack of measurement leaves open the possibility that addition or mixing 
errors might have occurred, affecting the vitamin D levels in the feed. 
Second, the confounding effect of UV exposure in several of the studies 
makes interpretation of the results difficult.
    The 26-week DR/VR study was designed to prevent UV light exposure 
to any group except the 5.5 percent olestra/low vitamin group where 2 
minutes of exposure were to be provided per day. However, an accidental 
UV light exposure (not more than 13 hours) to this group on day 23 of 
the study likely caused the very high 25-OHD<INF>3 levels and very low 
25-OHD<INF>2 levels observed at week 4. In addition to the accidental 
exposure of the 5.5 percent olestra/low vitamin group to UV light, it 
appears that at least 10 other animals may have been exposed to UV 
light in at least the 12th week of the study, as evidenced by their 
elevated serum 25-OHD<INF>3 levels. Because a definitive cause for 
these elevated serum 25-OHD<INF>3 values could not be determined, FDA 
considers the vitamin D data from the 26-week DR/VR study to be 
confounded (Ref. 52).
    Although pigs in the 39-week study were not exposed to UV light, 
pigs consumed only one level of olestra, therefore no dose-response 
information was obtained.
    FDA agrees with the petitioner that in the 12-week VR study, serum 
concentration of 25-OHD<INF>2 increased in a dose-response manner as 
the amount of vitamin D<INF>2 added to the basal diet was increased, at 
all levels of olestra. FDA further agrees with the petitioner that the 
decrease in serum 25-OHD<INF>3 observed in the mid- and high-level 
groups may have resulted from olestra's effects on the reabsorption of 
biliary vitamin D<INF>3. However, FDA also believes that the serum 25-
OHD<INF>2 levels may have been confounded by the daily 2-minute 
exposure to UV light, which caused an increase in serum levels of 25-
OHD<INF>3 in both 12-week studies. Therefore, FDA concludes that the 
results from the mid- and high-dose groups in the 12-week VR study 
cannot be used to determine a quantitative compensation value for 
vitamin D<INF>2 because of the apparent interaction between serum 25-
OHD<INF>3 and 25-OHD<INF>2 levels.
    FDA believes that the most useful data from the pig studies comes 
from a comparison of the control and 1.1 percent olestra groups in the 
12-week VR study. Accordingly, FDA believes that the petitioner's 
calculation based on the 12-week VR study that 13 IU vitamin D/g 
olestra will compensate for olestra's effects in pigs exposed to daily 
UV light may be an approximation of appropriate supplementation level 
for vitamin D. However, the agency believes that it cannot rely on the 
12-week VR data by themselves to establish a compensation value for 
vitamin D<INF>2, because of the possible confounding effects of UV 
exposure and the lack of measurements of vitamin D levels in the diets 
as fed (Refs. 53 and 54).
    iv. Vitamin K. There were no statistically significant effects of 
olestra on prothrombin time in any of the pig studies. The petitioner 
concluded, therefore, that olestra does not affect vitamin K status. 
Although FDA agrees that prothrombin time was not affected by olestra 
consumption, the agency does not believe that these results are 
adequate to determine the potential effects of olestra on vitamin K 
status, because, as discussed below, prothrombin time is not a 
sufficiently sensitive analytical method and the diets of the test 
animals appear to have been overfortified with vitamin K.
    Prothrombin time is an insensitive indicator of vitamin K status. 
The petitioner agrees that there are more sensitive indicators of 
vitamin K status such as direct measurements of clotting factors in 
blood, urinary excretion of <greek-g>-carboxyglutamic acid, and plasma 
levels of des-carboxylated or under-carboxylated vitamin K-dependent 
proteins (the PIVKA-II assay). The petitioner states however, that 
these methods were not used because they had not been used previously 
or validated in the pig and no body of historical data exists. 
Nevertheless, FDA believes that use of an insensitive indicator limits 
the conclusions that can be drawn from these pig studies regarding 
vitamin K status.
    FDA believes that the usefulness of the data from the 12-week and 
26-week DR/VR studies is further limited because test animal diets were 
oversupplemented with vitamin K. Because vitamin K is a highly 
lipophilic fat-soluble vitamin, FDA considers it reasonable to assume 
that it will partition into the olestra in the GI tract, in the same 
manner as the other fat-soluble vitamins. Thus, oversupplementation is 
significant 

[[Page 3144]]
because it could mask any effect of olestra on vitamin K status.
    FDA believes the pig diets were oversupplemented with vitamin K in 
the 12-week and 26-week DR/VR studies for two reasons. First, the NRC 
requirement for vitamin K in swine is in terms of amounts of menadione, 
not phylloquinone (the form of vitamin K fed to the pigs). The NRC 
requirement for menadione, 500 <greek-m>g/kg, is in a corn-soybean meal 
base and this likely exceeds the requirements needed for a casein-based 
semisynthetic diet that should not contain any substance that might 
inhibit vitamin K metabolism. Second, FDA disagrees with the 
petitioner's assumption that phylloquinone is necessarily of equal 
potency on a weight basis as menadione. Unlike phylloquinone, menadione 
is biologically inactive and must be alkylated in the liver to 
menaquinone to become biologically active. Phylloquinone, following 
intracardiac administration, was 10 times more active than menadione on 
a weight basis at restoring the prothrombin response in rats that were 
partially depleted of vitamin K (Ref. 55). Therefore, FDA cannot rule 
out the possibility that phylloquinone is a more potent source of 
vitamin K on a weight basis than menadione in swine following oral 
administration, which would lead to further oversupplementation (Ref. 
56).
4. Overall Conclusions Regarding Olestra's Effects on Fat-Soluble 
Vitamins-
    a. Consumption scenarios. The petitioner has asserted that in the 
8-week human studies and in all of the pig studies (except the 4-week 
DC study), olestra's effects on fat-soluble nutrients are exaggerated 
because the additive was always consumed with meals. In addition, in 
the pig studies, olestra was admixed with all the feed, rather than 
being present in only select dietary ingredients (such as chips). The 
petitioner hypothesizes that if olestra is eaten in a snack between 
meals (instead of being eaten with a meal), there will be fewer 
nutrients available with which it can interact, and that olestra's 
effects on nutrients would be expected to be greatest when olestra and 
the nutrients are intimately intermixed in the GI tract at the same 
time.
    The petitioner has provided results of consumption surveys showing 
that in the United States, at the estimated 90th percentile consumption 
level, savory snacks are eaten only four times per week, and one-third 
of those occasions are between meals. With this consumption pattern, 
olestra savory snacks will be eaten 32 times in an 8-week period (as 
compared to 168 meals during that time), and 20 of those times will be 
with meals. (In other words, during the 8-week period, 148 meals (or 88 
percent) will be consumed without a savory snack.) These data mean 
that, although a majority of snacks are eaten with meals, because of 
the infrequency of snack consumption, a majority of nutrient intake 
will occur in the absence of olestra savory snacks. In contrast, in 
both 8-week studies, olestra was eaten 165 times in 8 weeks with every 
meal, which means that essentially all of the nutrient intake occurred 
with olestra consumption.
    The petitioner presented the following examples of the consequences 
of consumption patterns on olestra's effects on nutrients. First, the 
petitioner calculated the expected effect of olestra on <greek-b>-
carotene in consumers eating snacks with the eating patterns reported 
in the MRCA survey data.\30\ In the first scenario, the petitioner 
assumed that absorption of <greek-b>-carotene eaten with olestra would 
be decreased by 60 percent and absorption of <greek-b>-carotene eaten 
at all other times would not be affected. In a second scenario, 
presented at the Olestra Working Group and FAC meetings,\31\ the 
petitioner assumed that absorption of <greek-b>-carotene eaten with 
olestra would be decreased by 60 percent, absorption of <greek-b>-
carotene eaten at eating occasions either before or after the olestra 
eating occasion would be decreased by 30 percent, and absorption of 
<greek-b>-carotene eaten at all remaining times would not be affected. 
Using these assumptions the petitioner calculated that an average snack 
consumer would have a decrease in serum <greek-b>-carotene levels of 
5.6 percent in the first scenario and about 6.8 percent in the second 
scenario. For the heaviest consumers (top 10 percent), the first 
scenario would result in a decrease in serum levels of about 10 
percent, while the second scenario would result in decreases of 13 to 
14 percent.

    \30\ Transcript, vol. 1, p. 84 and vol. 3, p. 234.
    \31\Transcript, vol. 3, p. 234.
---------------------------------------------------------------------------

    The petitioner further asserts that the 4-week DC study in pigs and 
16-week vitamin E study provide evidence that olestra's effects on fat-
soluble nutrients measured in the pig studies and in the 8-week human 
studies exaggerate the effects expected with a normal savory snack 
consumption pattern. This effect is confirmed by a comparison of the 8-
week DR study (where olestra and the vitamins were always consumed 
concurrently) with results of the 16-week vitamin E study (in which 
free-living subjects consumed olestra throughout the day but not 
necessarily concurrently with the consumption of all vitamin E or 
carotenoids). In the 8-week DR study, the effects on vitamin E status 
and serum <greek-b>-carotene concentration measured in the 20 g/d 
olestra group are about three-fold greater than those measured in the 
free-living subjects in the 16-week vitamin E study consuming 18 g/d 
olestra.
    In the 4-week DC study in pigs, the reduction of vitamin A liver 
stores in pigs fed 2.2 percent olestra was about 44 percent compared to 
controls when olestra was fed admixed in the diet and about 14 percent 
when olestra was fed in potato chips with all meals. Similarly, the 
reduction of liver and serum vitamin E concentrations in pigs fed 2.2 
percent olestra admixed in the diet was about twice as large (60 
percent for liver and 52 percent for serum compared to controls) when 
olestra was fed admixed as when olestra was fed in potato chips with 
all meals (30 percent and 20 percent for liver and serum, 
respectively). Therefore, the petitioner has concluded that the effects 
of olestra that were measured in the 12-week DR, 12-week VR, 26-week 
DR/VR, and 39-week VR pig studies were exaggerated by about 3-fold for 
vitamin A and about 2-fold for vitamin E over what would have been 
observed if the olestra were fed in chips with meals.
    FDA agrees that when savory snacks containing olestra are eaten 
without other foods, olestra's effects on fat-soluble vitamins will be 
less than the effects measured in the 8-week human studies or in the 
12-, 26-, and 39-week pig studies. However, FDA concludes that, given 
the wide variety of possible dietary patterns, the most protective 
approach is to ensure that compensation levels that accommodate most, 
if not all of those dietary patterns. Slight overcompensation with 
vitamins A, E, D, and K that might occur if an individual were to eat 
all olestra-containing snacks separate from other foods would not raise 
any health concerns, as discussed below. In contrast, the potential for 
developing vitamin deficiencies in some of the population that 
preferentially eat olestra-containing snacks with meals is of 
sufficient concern to merit this approach. Further, calculating 
compensation levels using the with-meal study results provides an 
additional measure of safety, because based on the MRCA data, it is 
probable that not all olestra consumed in savory snacks will be eaten 
with meals. Therefore, FDA is not relying on the results of the 
contextual studies or calculations based on eating patterns in 

[[Page 3145]]
evaluating the safety of olestra with regard to nutrient effects.
    b. Vitamin A. FDA and the petitioner agree that olestra's effects 
on vitamin A present significant health concerns and, therefore, 
compensation for olestra's interference with this vitamin's absorption 
should be made. The pig studies show that olestra consumption has a 
dose-response effect on vitamin A that is nonlinear, having the 
greatest effect (on a per-gram-of-olestra basis) at low olestra 
consumption levels. The level of vitamin A compensation was calculated 
using data from the pig studies in which the effect of olestra and 
olestra with added retinyl palmitate on vitamin status were determined. 
Thus, the pig studies provide the most direct measure of vitamin A 
status. Calculations were based on the effect at the lower olestra 
doses to ensure that compensation is sufficient for all consumers.
    Both the petitioner and FDA have calculated that 170 IU of vitamin 
A/g olestra (51 retinol equivalents/g) compensates for olestra's 
effects on vitamin A (from both preformed vitamin A and the provitamin 
A carotenoids). This amount is equivalent to 0.34 times the RDA in a 1-
oz serving of savory snacks containing 10 g of olestra.
    The results of the vitamin A/fat study in humans showed that only 
the highest dose of olestra (32 g/d) had a measurable effect on 
preformed vitamin A absorption. This direct measurement of olestra's 
effect on absorption of preformed vitamin A in humans shows less of an 
effect than the observed effect on vitamin A stores in the pig studies, 
a difference likely due to the decreased absorption of carotenoids in 
the pig studies, which are therefore less available as provitamin A 
sources. Vitamin A added to olestra in the 12-week DR, 26-week DR/VR 
and 39-week VR pig studies compensated for both the loss of preformed 
vitamin A and carotenoids as provitamin A sources, as it would when 
olestra is compensated in savory snacks. Therefore, FDA concludes that 
relying on the pig data to calculate the compensation level will 
account for olestra's effects on absorption of both preformed vitamin A 
and carotenoids as contributors to the vitamin A body stores.
    During the Olestra Working Group meeting, the members of the 
Olestra Working Group unanimously agreed that FDA had appropriately 
evaluated the amount of vitamin A with which olestra should be 
compensated.\32\

    \32\Transcript, vol. 3, pp. 220-225.
---------------------------------------------------------------------------

    At the FAC meeting, Dr. Rodier, an embryologist and member of the 
FAC, expressed concern about the potential toxicity, especially 
teratogenicity, of the vitamin A that would be added to olestra.\33\ 
She pointed out that since 1986, the Teratology Society has recommended 
that vitamin supplements not contain preformed vitamin A, but that they 
contain carotenoids instead. FDA is aware of a recent study 
investigating the teratogenicity of vitamin A intake (Ref. 57), in 
which an association was found between the prevalence of defects 
associated with cranial-neural-crest tissue in babies and consumption 
by their mothers of preformed vitamin A supplements during pregnancy. 
The researchers found an apparent threshold for the effect of about 
10,000 IU of supplemental preformed vitamin A (i.e., in addition to 
vitamin A consumed in the diet). Consumers eating large amounts of 
olestra might obtain a small amount of bioavailable vitamin A from 
olestra because the compensation level was calculated from low olestra 
doses where the effect/g olestra is the highest. However, because the 
teratogenic effects seen by Rothman et. al., occur with vitamin A 
intakes more than 10,000 IU above that which is consumed in the daily 
diet, and because most of the vitamin A in olestra will remain in the 
olestra as it passes through the body, FDA concludes that there is no 
reasonable scenario of olestra consumption from savory snacks that 
would lead to vitamin A leaching out of the olestra at levels anywhere 
near 10,000 IU. Therefore, the agency is requiring vitamin A 
compensation at 170 IU/g olestra (51 retinol equivalents/g).

    \33\Dr. Patricia Rodier, is a senior scientist in the Department 
of Obstetrics and Gynecology, University of Rochester. Transcript, 
vol. 4, p. 99.
---------------------------------------------------------------------------

    c. Vitamin E. FDA and the petitioner agree that olestra's effects 
on vitamin E present significant health concerns and, therefore, 
compensation for this vitamin should be made. Serum data from the human 
studies provide the basis for calculating the appropriate compensation 
level for vitamin E, and the calculations are supported by the results 
of the pig studies. The petitioner has calculated that 1.9 mg 
<greek-a>-tocopherol equivalents (2.8 IU vitamin E) should be added per 
g of olestra to compensate for olestra's effect on vitamin E levels. 
This amount is equal to 0.94 times the RDA in a 1-oz serving of snack 
containing 10 g of olestra. The compensation level calculated from the 
pig studies for the lowest olestra consumption level (which shows the 
largest effect when calculated per g of olestra) is 2.79 IU vitamin E/g 
olestra, which is essentially the same as the compensation level 
calculated from the 8-week human studies.
    During the Olestra Working Group meeting, the members of the 
Olestra Working Group unanimously agreed that FDA had appropriately 
evaluated the amount of vitamin E with which olestra should be 
compensated. Therefore, FDA is requiring vitamin E compensation at 2.8 
IU/g olestra (1.9 mg <greek-a>-tocopherol equivalents/g olestra), which 
will adequately compensate for olestra's effects in all realistic 
consumption scenarios.
    d. Vitamin D. The petitioner concluded that the effects of olestra 
on vitamin D<INF>2 concentration do not warrant compensation with 
vitamin D. As support, the petitioner cites the absence of changes in 
serum 1,25-OH<INF>2D concentration in the pig studies as evidence that 
olestra has no significant effect on overall vitamin D status despite 
the decrease in dietary vitamin D<INF>2 status. Typically, the 
contribution of dietary vitamin D to total vitamin D status in the 
general population is from 10 to 20 percent (the rest from sunlight-
induced synthesis in the body). Therefore, the petitioner reasons that 
a 23 percent decrease in dietary vitamin D status would result in only 
a 2.3 to 4.6 percent reduction in overall vitamin D status in a normal 
healthy human under the exaggerated conditions of olestra consumption 
used in the studies. In worst-case situations, where dietary vitamin D 
can contribute up to 50 percent of total vitamin D, the petitioner 
calculates that the reduction in overall vitamin D status would be 11.5 
percent when olestra was consumed with every meal.
    FDA disagrees with the petitioner's position that the effect of 
olestra on vitamin D is not sufficient to warrant compensation. 
Although most individuals can produce vitamin D through exposure to 
sunlight, there are some people who may not synthesize sufficient 
vitamin D to compensate for potential decreases due to olestra effects, 
either because they are not exposed to sufficient sunlight or because 
they utilize sunlight poorly to synthesize vitamin D. Therefore, FDA 
concludes that compensation for vitamin D should also be required for 
olestra-containing foods.
    From the 8-week human studies, the petitioner calculated that 0.07 
<greek-m>g vitamin D<INF>2/g olestra (0.07 times the RDA per 10 g of 
olestra) would be sufficient to compensate for the olestra-induced 
decrease in 25-OHD<INF>2. FDA notes that in the 8-week VR study, 0.2 
<greek-m>g vitamin D<INF>2/g olestra slightly overcompensated for 
olestra's effects on vitamin D status, as measured by total 25-OHD 
levels. 

[[Page 3146]]
However, these values are based on only two compensation levels, and 
may be confounded by the fact that serum vitamin D levels continued to 
decrease over time in the study.
    The petitioner has also calculated, from the 1.1 percent olestra 
group of the 12-week DR pig study, that 13.0 IU vitamin D/g olestra 
(0.33 times the RDA per 10 g of olestra) would compensate for olestra's 
effects in that group. Although the design of that study also contains 
some weaknesses, FDA believes that the results of both the pig study 
and the 8-week human studies, considered together, support the need for 
a compensation level and provide an approximation of an appropriate 
level.
    Given the importance of vitamin D, FDA concludes that it is 
preferable to compensate consistent with olestra's demonstrated effects 
on vitamin D, rather than risk a deficiency (Ref. 58). FDA concludes 
that addition at levels of 12 IU vitamin D/g olestra (0.3 <greek-m>g/g 
olestra) or 0.3 times the RDA per 10 g of olestra, is adequate to 
compensate for any vitamin D that is lost due to diminished absorption 
caused by olestra. This level of vitamin D includes the amount that was 
observed to compensate for olestra's effects in the 12-week DR pig 
study and is slightly higher than the 0.2 <greek-m>g/g that was 
observed to be sufficient in the 8-week VR human study. During the 
Olestra Working Group meeting, the members of the Olestra Working Group 
unanimously agreed that FDA had appropriately evaluated the amount of 
vitamin D with which olestra should be compensated.
    This level of vitamin D compensation does not raise any toxicity 
concerns, even if olestra as actually consumed has no effect on the 
absorption of vitamin D, because it is generally accepted in the 
medical community that one would have to ingest five times the RDA (the 
RDA is 400 <greek-m>g of vitamin D) before toxicity effects begin to 
occur (Ref. 59). Thus, slight overcompensation with vitamin D would not 
cause health concerns. Assuming that the daily diet contains an RDA of 
vitamin D, olestra would have to contribute four times the RDA (or 
1,600 IU), which is equivalent to the amount added to about 13 oz of 
potato chips, to reach levels where toxicity effects begin. However, 
most of the vitamin D in olestra would not be bioavailable. Therefore, 
FDA is requiring compensation with 12 IU vitamin D/g olestra (0.3 
<greek-m>g/g olestra).
    e. Vitamin K.--i. Petitioner conclusions. The petitioner concluded 
that the effects of olestra on serum phylloquinone levels will not pose 
a potential public health concern, and therefore, compensation of 
olestra savory snacks with vitamin K is not necessary. The petitioner 
based this conclusion on: (1) The absence of olestra effects on the 
sensitive measures of vitamin K function under exaggerated conditions 
of the studies conducted in humans; (2) the presence in the U.S. diet 
of significantly more vitamin K than the single RDA fed in the studies 
in which no effects on sensitive measures were observed; (3) the fact 
that the dietary level of vitamin K associated with detectable effects 
on sensitive functional parameters is well below the RDA; and (4) the 
absence of either a dietary pattern consistent with, or clinical 
evidence for, the existence of subgroups within the U.S. population at 
risk of vitamin K deficiency.
    The petitioner concluded that functional measures of vitamin K 
status provide a reliable basis for public health decisions regarding 
this vitamin, because these measures provide a direct assessment of the 
ability of the vitamin K supplied to the tissues to maintain normal 
vitamin K function. Because, unlike vitamins A, D, and E, there are no 
significant phylloquinone stores in the body and serum concentrations 
of the vitamin fluctuate significantly throughout the day, these 
functional measures provide an integrated picture of the supply of 
vitamin K over a time period as short as 2 to 3 days. Fasting serum 
measures of phylloquinone, on the other hand, may not reflect the true 
status of vitamin K because of the very short half-life of the vitamin 
in the plasma (less than 2 hours). At any given time during the day, 
the serum concentration of phylloquinone may suggest low or inadequate 
vitamin K supply, while the tissues may be receiving more than adequate 
amounts to support maximal rates of carboxylation.
    The petitioner further concluded that urinary Gla excretion and 
plasma des-<greek-g>-carboxylated prothrombin (PIVKA-II) are the 
markers of vitamin K function that best reflect the integrated vitamin 
K status of the individual over time. If the phylloquinone supply from 
the diet falls below a level adequate to support maximal synthesis of 
vitamin K-dependent proteins in the body, PIVKA-II and urinary Gla will 
change to reflect the inadequate supply. The half-lives of prothrombin 
(Factor II) and of the vitamin K-dependent proteins which contribute 
the majority of the urinary Gla excretion (60 hours or more) are 
significantly longer than the half-life of phylloquinone in plasma 
(about 2 hours). Therefore, the petitioner argues, these functional 
measures provide a sensitive index of potential chronic effects on the 
adequacy of vitamin K in the diet. Urinary Gla is particularly 
important because it reflects carboxylation of vitamin K-dependent 
proteins in all tissues, including bone and kidney. Although the 
petitioner believes that compensation for vitamin K is unnecessary, the 
petitioner has evaluated olestra's effect on vitamin K by comparing 
serum vitamin K levels with vitamin K dietary intake at varying olestra 
levels, and has determined that 3.3 <greek-m>g vitamin K/g olestra will 
restore serum vitamin K levels to those of the control group. This 
level is less than one-half of the 80 <greek-m>g RDA, when contained in 
a 1-oz serving of savory snacks containing 10 g olestra. Because the 8-
week DR study was not designed to assess the olestra dose response for 
vitamin K, the compensation level calculated by the petitioner is only 
an estimate of an appropriate compensation level.
    ii. FDA conclusions. FDA concludes that the data from the 8-week 
human studies show that serum vitamin K levels were decreased by 
consumption of olestra, and that the lack of effect on functional 
assays could be attributable to the use of a subject population that is 
not at risk for vitamin K deficiency. Similarly, as noted, the lack of 
an olestra effect on prothrombin time in the pig studies may be 
explained by the insensitivity of the analytical method and 
oversupplementation of the test diet with vitamin K. While olestra may 
not pose a health risk due to moderate reductions in serum vitamin K 
levels for healthy adults consuming diets that, on average, provide 
them with the minimum RDA for fat-soluble vitamins and other nutrients, 
these reductions of vitamin K could be of concern for segments of the 
population at risk for vitamin K deficiency or where the control of 
blood clotting is more critical.
    There were no studies designed to assess the dose-response nature 
of olestra's effect on vitamin K. The pig studies are not useful in 
this case because of the uncertainty regarding the activity of 
menadione and phylloquinone in the swine diet and the likelihood that 
the NRC requirements for swine are much higher than actual need. In 
contrast, the 8-week DR study in humans is useful for estimating an 
appropriate compensation level because the diet contained approximately 
1 RDA of vitamin K and the dietary levels of vitamin K on the day 
before blood draws varied for each blood draw.
    FDA believes that the consequences of vitamin K depletion are 
sufficiently serious and their onset so sudden as to warrant addition 
of vitamin K to olestra-containing food. Also, it is well 

[[Page 3147]]
recognized in the medical community that large doses of vitamin K can 
be tolerated with no toxic effects.\34\ Thus, even if compensation with 
vitamin K is not necessary for all olestra consumers, such compensation 
poses no safety concern. FDA further believes it is appropriate to 
require compensation at a level somewhat higher than that calculated 
from the 8-week DR study, to provide a greater assurance of safety. 
Given that the RDA is 80 <greek-m>g/d and vitamin K exhibits no known 
toxicity, FDA recommended at the Olestra Working Group and the FAC 
meetings that a level of 8 <greek-m>g vitamin K/g olestra, or one times 
the RDA per 10 g of olestra, would provide an adequate compensation 
level of vitamin K and would not cause any concern over toxicity.

    \34\FDA is not aware of any toxic effects of phylloquinone. In 
addition large quantities are routinely given for certain specific 
situations. For example, infants usually receive a single dose of 
0.5 to 1.0 mg vitamin K injected intramuscularly shortly after birth 
to protect against bleeding.
---------------------------------------------------------------------------

    During the Olestra Working Group meeting, the members of the 
Olestra Working Group unanimously agreed that FDA had appropriately 
evaluated the amount of vitamin K with which olestra should be 
compensated. Although there was no disagreement among FAC members that 
slight overcompensation with vitamin K would not be of concern to the 
general public, a Working Group member\35\ and two presenters\36\ 
expressed concern about the effect that olestra consumption (whether or 
not compensated with vitamin K) would have on persons for whom blood 
clotting should be controlled, such as persons taking coumarin drugs.

    \35\Donna Richardson, J.D., R.N., Howard University, Midlantic 
Women's Health Initiative. Ms. Richardson is a member of the FAC 
(Transcript, vol. 3, p. 255).
    \36\Dr. Michael Jacobson, CSPI (Transcript, vol. 3, p. 179 and 
vol. 4, p. 15), and Dr. Ian Greaves, Associate Professor, and Deputy 
Director, Minnesota Center for Environmental and Health Policy, 
University of Minnesota School of Public Health. Dr. Greaves 
presented at the request of CSPI (Transcript, vol. 2, p. 267).
---------------------------------------------------------------------------

    Dr. John Suttie, a researcher in the vitamin K field,\37\ responded 
to these concerns. Dr. Suttie stated that monitoring of Coumadin 
therapy is a well-recognized problem, and that Coumadin doses must be 
titrated because of a number of adverse influences in such therapy. He 
and the petitioner\38\ stated that diet is usually not one of the 
primary factors of concern in anticoagulation therapy, even though 
dietary vitamin K intake can vary day-to-day by three- to four-fold. 
Dr. Suttie asserted that changes due to consumption of vitamin K-
compensated olestra would likely be within the normal range of dietary 
variation.

    \37\Dr. John Suttie is a biochemist and nutritionist at the 
University of Wisconsin. Dr. Suttie consulted with the petitioner 
and presented at its request. Transcript, vol. 3, p. 256.
    \38\Dr. John Peters, Procter and Gamble, Transcript vol. 1, p. 
147.
---------------------------------------------------------------------------

    FDA concurs with Dr. Suttie's statements and concludes that olestra 
should be compensated with 8 <greek-m>g vitamin K/g olestra. The 
majority of the FAC members also agreed that olestra should be 
compensated with vitamin K, and that the level selected by FDA is 
appropriate. FDA notes that if, in the future, the petitioner develops 
data that demonstrate that a lower level of compensation would be 
adequate, a petition could be submitted requesting an appropriate 
change in the required compensation level.
    f. Carotenoids.--i. Data and information regarding carotenoids. The 
human studies demonstrate that consumption of olestra affects serum 
carotenoid levels. The petitioner concludes, and FDA concurs, that 
supplementing olestra with vitamin A will compensate for olestra's 
effects on the provitamin A function of carotenoids. There was no 
disagreement with this conclusion during the discussions at the Olestra 
Working Group and FAC meetings. The petitioner also concluded that it 
is not necessary to compensate olestra with any carotenoids, as there 
are no established beneficial health effects (aside from their 
provitamin A role) and further, that olestra's effect on carotenoid 
availability in the body is likely to be much smaller than that shown 
in the 8-week studies.
    At the Olestra Working Group and FAC meetings, there was a thorough 
discussion of the possible beneficial health effects of carotenoids in 
preventing illnesses such as macular degeneration, prostate and lung 
cancer, and heart disease and whether olestra's effects on carotenoids 
would increase the risk of disease. In addition, the White Paper which 
was provided to the Committee, addressed the potential detrimental 
health impact of olestra's effect on carotenoids (Ref. 3). Information 
was also presented on whether carotenoids themselves have beneficial 
health effects, or whether it is other substances in the fruits and 
vegetables that provide the health benefits, and that carotenoids are 
serving solely as markers for fruit and vegetable consumption.
    In his presentation to the Olestra Working Group,\39\ Dr. Meir 
Stampfer, a professor of nutrition, stated that the results of an 
epidemiological study showed that higher levels of carotenoid intake, 
particularly lutein and zeaxanthin (which concentrate in the macula), 
have a marked protective effect against macular degeneration (Ref. 60). 
In addition, he stated that epidemiologic data show that individuals 
with high levels of lycopene intake were at a lower risk for developing 
prostate cancer a reduction that was statistically significant (Ref. 
61). Dr. Stampfer also stated that there are many epidemiologic studies 
showing that individuals with high levels of plasma or serum 
carotenoids have a lower risk of lung cancer. Written information 
provided to the Committee also discussed the role of carotenoids in 
preventing cataracts, cardiovascular disease, and stroke.\40\

    \39\Dr. Meir Stampfer is a professor of nutrition at Harvard 
University School of Public Health. Transcript, vol. 1, p. 154. CSPI 
also provided FDA with a letter from Dr. Stampfer and Dr. Walter 
Willett prior to the FAC meeting. Dr. Stampfer presented at the 
request of CSPI.
    \40\See for example Refs. 3 and 62.
---------------------------------------------------------------------------

    Dr. Alvan Feinstein critiqued the epidemiological data for 
carotenoids in his presentation to the FAC.\41\ Dr. Feinstein stated 
that the epidemiologic evidence is not conclusive that carotenoids 
reduce the incidence of cancer or any other disease. Dr. Feinstein 
stated that epidemiologic case-controlled or other observational 
studies are problematic because the baseline state of those studied is 
not identified. In the studies of macular degeneration and of various 
cancers, for example, the health or disease state of participants 
before exposure is not known and differences may not be noted or 
adjusted for. Also, the compared agents are ascertained in retrospect, 
after they were taken; that ascertainment may be inaccurate or biased 
by a knowledge of outcome events. In addition, epidemiological studies 
lack reliability in terms of participants' accounts of what they ate or 
did not eat in the past. Finally, in such epidemiologic studies it is 
difficult to determine and adjust for the agent of interest (e.g., 
carotenoids, fruits, vegetables, or lycopenes).

    \41\Transcript, vol. 1, p. 172.
---------------------------------------------------------------------------

    Dr. Feinstein stated that, given these limitations with 
epidemiological studies, researchers, in general, are very reluctant to 
draw causal conclusions from epidemiologic data and prefer to rely, 
whenever possible, on randomized trials. One reason that randomized, 
experimental trials are preferable for 

[[Page 3148]]
establishing cause and effect relationships is that the baseline state 
is clearly specified by the admission criteria, and the randomization 
produces an equal distribution for the differences in susceptibility to 
disease.
    Dr. Feinstein discussed the results of the randomized trials 
concerning the health effects of carotenoid. He stated that to date, 
there have been five randomized trials of the effects of carotenoid 
consumption on disease, and that the data thus far have shown no 
convincing beneficial effect. A 1994 study in Finland assessed the 
effects of dietary supplements containing <greek-b>-carotene versus 
placebo with lung and other cancers and identified a possible harmful 
effect of the carotenoid supplements.\42\ Other studies assessing the 
possible association between carotenoid supplement intake and 
nonmelanoma skin cancer (Ref. 64), and colorectal cancer (Ref. 65) also 
established no difference between the carotenoid and placebo groups in 
the selected outcome or in effects in the eye or coronary disease. 
Finally, a study examined the association between a combination of 
supplements (no placebos) and the death certificate diagnoses of cancer 
and found no statistically significant differences (Ref. 66).

    \42\Dr. Greaves mentioned that blood draws at the beginning of 
the Finland study showed that men in the lower quartile for serum 
<greek-b>-carotene in the blood had significantly higher incidence 
rates of lung cancer than the men with the high levels of <greek-b>-
carotene in blood (Ref. 63).
---------------------------------------------------------------------------

    The assessment of the significance of olestra's depletion of serum 
carotenoid should include consideration of the magnitude of the effect 
compared to variations in carotenoid utilization. Dr. James Olson, a 
professor of biochemistry,\43\ noted in his presentation to the Olestra 
Working Group, that in the broader context of the diet, the effects of 
olestra on carotenoid utilization when used in savory snacks will be 
relatively minor, because a number of other factors influence 
carotenoid utilization, including carotenoid stability, 
bioavailability, and absorption. In the presence unsaturated fatty 
acids such as vegetable oils, for example, carotenoid are very rapidly 
destroyed. Similarly, carotenoid bioavailability can vary from almost 
zero to about 50 percent, depending on the vegetable concerned, cooking 
practice, and the presence and type of oils in the GI tract. (For 
example, in butter fat or coconut oil, carotenoid are only about 50 
percent as well absorbed as in more unsaturated oils.) Inhibitors to 
carotenoid absorption also exist, including fiber, particularly acidic 
pectins, and high concentrations of vitamin E. Dr. Olson subsequently 
provided FDA with a published study that shows that the increase in 
plasma <greek-b>-carotene concentration 30 hours following consumption 
of a controlled meal containing 25 mg <greek-b>-carotene and 12 g 
citrus pectin was only half as large as the increase observed in the 
absence of citrus pectin (Ref. 67). Furthermore, Dr. Olson noted that 
competitions occur between various carotenoid for absorption; in 
particular, lutein, canthaxanthin, and <greek-b>-carotene mutually 
inhibit each other's absorption.

    \43\Dr. James Olson, Professor, Biochemistry and Biophysics 
Department of Iowa State University, researcher in the filed of 
carotenoid and vitamin A. Dr. Olson has consulted with the 
petitioner and presented at its request. Transcript, vol. 3, p. 190.
---------------------------------------------------------------------------

    Although olestra does affect carotenoid absorption, the petitioner 
asserted that only the more lipophilic carotenoid would likely be 
affected by olestra. The petitioner presented data regarding the 
octanol:water partition coefficients (PC's), a measurement of how fat-
soluble a substance is,\44\ for the various carotenoids, and noted that 
substances with a log<INF>10 PC above about 7.5 can be affected by 
olestra if they are consumed simultaneously with the olestra.\45\ Three 
of the four carotenoids monitored (<greek-a>-carotene, <greek-b>-
carotene, and lycopene) are the most lipophilic carotenoids with 
octanol:water PC's of approximately 17.6 each and would thus be 
expected to be the most affected by olestra. Indeed, the 8-week studies 
and 16-week vitamin E study show that the effects of olestra on the 
serum levels of these carotenoids are very similar. Lutein and 
zeaxanthin, which have more hydroxyl groups, are about 1,000 times less 
lipophilic (PC's of 14.82 and 14.95, respectively) than <greek-b>-
carotene (Ref. 68).

    \44\Octanol:water partition coefficients (PC's) are generally 
expressed on a log scale so that a substance with a PC of 12 is 10 
times as fat soluble as a substance with a PC of 11.
    \45\Transcript, vol. 2, p. 125.
---------------------------------------------------------------------------

    In addition, it is possible that serum carotenoid levels are not 
good indicators of carotenoid availability in the body. Dr. Olson 
pointed out that the plasma carotenoids amount to approximately one 
percent of the total tissue content of carotenoids. Plasma carotenoid 
concentrations can vary fairly rapidly within 1 to 4 weeks whereas 
tissue concentrations change much more slowly. Because protective 
aspects of carotenoids would be expressed at the intracellular level, 
plasma carotenoid concentrations, particularly in short-term studies, 
may not be very accurate indicators of useful carotenoid levels.\46\ 
Similarly, Dr. Leonard Cohen,\47\ in a presentation to the Olestra 
Working Group, also pointed out that serum measurements are single-
point at a certain time of the day, but that carotenoid levels have 
Circadian rhythms. Therefore, one cannot tell at one point of the day 
whether levels will be the same at another point of the day.

    \46\Transcript, vol. 3, p. 192.
    \47\Dr. Leonard Cohen, Section Head, Nutrition and 
Endocrinology, American Health Foundation. Transcript, vol. 3, p. 
149.
---------------------------------------------------------------------------

    Finally, Dr. Olson noted that five different conferences or 
reviewing groups have examined the relationship between carotenoids and 
disease: A U.K. Committee on the medical aspects of food policy (1987); 
the Life Science Research Offices of the Federated American Societies 
of Experimental Medicine in Biology; a European Union of Scientific 
Committees for Food (1992); an International Life Sciences Workshop on 
Antioxidants and Health (1993); and an FDA Conference on Antioxidant 
Nutrients (1993). He stated that all of these groups concluded that 
there is insufficient evidence to recommend specifically consumption of 
carotenoids, except to encourage the consumption of vegetables and 
fruit.
    After considering all the presentations and information submitted 
by CSPI in their White Paper (Ref. 3), a substantial majority of the 
Olestra Working Group felt that there is a reasonable certainty of no 
harm from olestra's effects on serum carotenoid levels.
    However, some members of the Olestra Working Group voiced concern 
about olestra's effects on carotenoid serum levels. Because of this 
concern, FDA subsequently consulted with scientists at the National 
Institutes of Health (NIH) and requested their views on whether 
olestra's effects on lipophilic carotenoids raise any significant 
public health issues with respect to the possible association between 
carotenoids and cancer risk\48\ and macular degeneration\49\ (Refs. 69 
and 70). The agency provided these scientists with copies of letters 
concerning carotenoids that the agency had received (including the 
letter from Dr.'s Willett and Stampfer (Ref. 62)), submissions by the 
petitioner, excerpts discussing carotenoids from the White Paper, and 
relevant sections of the Transcript from the Olestra Working Group and 
FAC meetings.

    \48\Dr. Peter Greenwald, Director of the Division of Cancer 
Prevention and Control, National Cancer Institute, NIH.
    \49\Dr. Carl Kupfer, Director of the National Eye Institute, 
NIH.
---------------------------------------------------------------------------

    Regarding cancer risk, Dr. Peter Greenwald stated that the effects 
of olestra on carotenoid utilization under 

[[Page 3149]]
the conditions of use would be expected to be relatively minor, that 
the provitamin role of carotenoids is the only function that has been 
adequately documented, and that plasma carotenoid concentration (which 
were used in the reported epidemiological studies) probably is not a 
reliable indicator of tissue levels and may in fact be misleading. 
Therefore, he concluded that no significant health issue was raised by 
the reported effects of olestra on lipophilic carotenoids. Furthermore, 
he recommended against supplementing olestra with <greek-b>-carotene or 
other carotenoids at this time (Ref. 71).
    Regarding macular degeneration, Dr. Carl Kupfer stated that 
although theoretical considerations have raised the possibility that 
carotenoids might play some protective role in macular degeneration, 
there are currently no convincing clinical data to substantiate the 
hypothesis. Furthermore, he asserted that no clear eye health benefit 
has been demonstrated for carotenoids (Ref. 72).
    ii. FDA's evaluation of olestra's effects on carotenoids.
    On balance, having considered all the comments, data, and 
information that the agency has received on this subject, FDA has 
determined that the information currently available show that olestra's 
effects on the absorption of the lipophilic carotenoids is reasonably 
certain to be insignificant from a public health standpoint. First, FDA 
has determined that the available data do not establish any 
identifiable nutritional or prophylactic benefits for the carotenoids, 
either individually or collectively. Specifically, controlled 
randomized studies have been performed to test the potential cancer-
protective effects of carotenoid consumption and have shown no 
association between carotenoid consumption and cancer.\50\ Also, there 
have been no controlled studies to examine the association between 
carotenoid consumption and eye disease.

    \50\In fact, well-controlled studies indicate that there may be 
higher incidence of lung cancer in smokers consuming high levels of 
<greek-b>-carotene.
---------------------------------------------------------------------------

    The agency believes that its conclusion regarding the absence of 
harm from olestra's effect on some carotenoids, which conclusion is 
based on the scientific evidence currently available, is not 
inconsistent with the currently available epidemiological studies. This 
is because the epidemiologic studies show an association between diets 
rich in fruits and vegetables and decreased cancer risk and do not 
evaluate the association between carotenoids per se and lower disease 
risk. Thus, there is no direct evidence from these epidemiologic 
studies that carotenoids are the substances responsible for the 
protective effect. In fact, as noted by several experts, serum 
carotenoid levels may simply be markers for consumption of fruits and 
vegetables.
    The agency's determination that olestra's effects on the absorption 
of carotenoids is reasonably certain to be insignificant is bolstered 
by the fact that the actual magnitude of olestra's effects on 
carotenoid absorption is likely to be within the range of the normal 
variation due to diet and bioavailability because the percentage of 
consumed carotenoids that are actually available to the body is highly 
variable and affected by a number of factors. In fact, the agency 
believes that it is likely that olestra's effects on carotenoid 
absorption will likely be substantially less that those observed in the 
8-week studies and will be more similar to the effects observed in the 
16-week vitamin E study.\51\ Finally, the association between serum 
carotenoid levels and the availability of carotenoids at the cellular 
level is unclear. Hence, the relationship between olestra's effects on 
serum carotenoids and the body's utilization of carotenoids is also 
unclear.

    \51\While FDA finds that the petitioner's hypothesis that actual 
reductions in carotenoid levels will be affected by consumption 
patterns and will therefore be even less than those observed in the 
16-week vitamin E study is plausible, the actual magnitude of the 
effect is not supported with data at this time.
---------------------------------------------------------------------------

    Therefore, FDA has determined, based upon the scientific evidence 
that exists at this time, that there is currently no justification or 
need to require compensation of olestra-containing foods with specific 
carotenoids.\52\

    \52\This conclusion is consistent with the recommendations of 
the various conferences that have been held to examine the 
relationship between carotenoids and disease and is also consistent 
with FDA's decisions regarding health claims for antioxidant 
vitamins and cancer (58 FR 2622, January 6, 1993.)
---------------------------------------------------------------------------

C. Effects of Olestra on Water-soluble Nutrients that are Hard-to-
Absorb or Limited in the Diet

    The two 8-week clinical studies in the human and the two 12-week, 
the 26-week DR/VR, and the 39-week VR studies in the pig were used to 
assess olestra's potential effects on water-soluble nutrients. Iron, 
folate, vitamin B<INF>12, and zinc status were measured in both the pig 
and human studies. Vitamin B<INF>12 absorption was also measured in the 
human studies. Calcium status was measured only in the pig studies, 
because there are no non-invasive methods sufficiently sensitive to 
assess calcium status in humans. The human and pig studies are 
described in section V.B. of this document, and the methods used to 
measure the status of calcium, zinc, iron, folate, and vitamin B<INF>12 
are summarized in Table 4 (human studies) and Table 6 (pig studies).
1. Results and Conclusions from Human Studies
    a. Vitamin B<INF>12. In the 8-week human DR and VR studies, there 
was no change in serum measures of vitamin B<INF>12. However, 8 weeks 
is insufficient to observe effects in serum, and the presence of excess 
vitamin B<INF>12 in the diets likely reduced the sensitivity of the 
studies to evaluate vitamin B<INF>12 status. The petitioner also found 
that absorption of vitamin B<INF>12 did not change as a result of 
olestra consumption in either 8-week human study, as measured by the 
Schilling test. FDA notes that dietary levels of vitamin B<INF>12 were 
approximately 2.2 and 1.7 times the RDA in the DR and VR studies, 
respectively. However, this overfortification does not affect 
interpretation of the results of the Schilling test because the level 
of vitamin B<INF>12 in the diet is not a factor in the Schilling 
test.\53\ FDA concludes that the results of the Schilling test shows 
that olestra has no effect on vitamin B<INF>12 absorption in humans.

    \53\The Schilling test is an acute test that measures the 
absorption of a dose of radiolabeled vitamin B<INF>12
---------------------------------------------------------------------------

    b. Iron. Measures of iron status were performed in the 8-week VR 
study. The petitioner concluded that olestra had no effect on iron 
status, and that sporadic, statistically significant trends with 
olestra dose in one or more of the measures at one or more time points 
resulted from differences in status at baseline or from a general 
decrease in iron stores resulting from phlebotomy (drawing blood for 
analysis). FDA agrees with the petitioner's conclusion that there were 
no changes in all measures of iron stores, with the exception of serum 
ferritin levels for both treatment and control groups. FDA further 
concludes that the decreased serum ferritin levels were consistent with 
loss due to phlebotomy (Ref. 73).
    c. Folate. Folate status was monitored in the 8-week DR study in 
which folate was consumed at levels between 80 and 120 percent of its 
RDA. There was no olestra dose response on the indices for folate 
(serum and red blood cell folate concentration). FDA considers red 
blood cell folate levels to be excellent 

[[Page 3150]]
indicators of folate status.\54\ Thus, the agency agrees with the 
petitioner's conclusion that olestra consumption does not affect folate 
status.

    \54\Transcript, vol. 3, p. 117.
---------------------------------------------------------------------------

    d. Zinc. Zinc status was evaluated in the 8-week DR study. There 
was no olestra dose response on the indices for zinc that can be 
measured noninvasively in humans (serum and urinary concentration). FDA 
agrees with the petitioner's conclusion that there is no evidence that 
olestra affects zinc status. However, the agency notes that serum and 
urinary concentrations are not sensitive indicators of zinc status in 
humans. Although these data are not particularly sensitive indicators 
of zinc status, FDA finds that the data support a finding of no effect. 
However, FDA does not consider the data sufficiently sensitive to 
support, in and of themselves, a conclusion of no effect.
2. Results and Conclusions from Pig Studies
    Data from the studies of olestra consumption in pigs generally 
corroborate the findings from the human studies regarding the effect of 
olestra on iron and zinc status. Although, the results of the pig 
studies regarding vitamin B<INF>12, calcium, and folate, do not 
indicate any effect of olestra, these studies are of limited utility in 
assessing olestra's effects because of several weaknesses in study 
design, as discussed below.
    a. Vitamin B<INF>12. There were no statistically significant 
effects of olestra on liver vitamin B<INF>12 in the 12-week VR, the 26-
week VR/DR, and the 39-week VR pig studies. In the 12-week DR study, a 
statistically significant downward trend in liver vitamin B<INF>12 
levels, produced by a low value in the 7.7 percent olestra group, was 
observed. There were no statistically significant decreases in the 1.1 
percent, 2.2 percent, 3.3 percent, 4.4 percent, or 5.5 percent olestra 
groups. The low value in the 7.7 percent olestra group was not 
accompanied by an elevation in mean corpuscular volume, and thus, the 
petitioner concluded that this decrease did not represent a change in 
vitamin B<INF>12 status. (FDA notes that the downward trend was not 
found in other pig studies.)
    FDA concludes that the pig studies are limited in their usefulness 
in assessing olestra's effects on vitamin B12. FDA's principal 
reservation is that the level of vitamin B12 was measured only in the 
diet premix and not in the complete diets; such analysis of the premix 
is not as reliable as analysis of the complete diet because an 
accidental mixing error may have occurred or the vitamin may have been 
degraded or spared from degradation by an interaction with another 
ingredient during the mixing process or during storage. Accordingly, 
FDA finds that, although there was no consistent effect of olestra on 
vitamin B<INF>12, these pig studies are inadequate by themselves to 
evaluate olestra's effect on vitamin B<INF>12.
    b. Iron. A battery of tests (liver iron concentration, serum total 
iron binding capacity, and serum total iron concentration) conducted in 
the 12-week VR, 26-week DR/VR, and 39-week VR studies showed no adverse 
effects on iron status when olestra was fed at any level (up to 7.7 
percent of the diet). There were statistically significant decreases in 
liver iron values in the 12-week DR study in both the 5.5 percent and 
7.7 percent olestra groups. However, in these groups, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, and red blood 
cell count were unaffected by olestra consumption. The petitioner 
postulated that the trend in liver iron concentration was probably 
secondary to the poor vitamin A status of the animals, and thus, 
concluded that iron status was not affected by olestra.
    FDA notes that there was a large variability in liver iron values 
in all pig studies. FDA postulates that the variability in liver iron 
levels may have been due to several factors, such as blood loss from 
gastric ulcers, dewclaw lesions or abscesses, or differences in the 
amount of blood present in the liver after sacrifice. FDA further notes 
that the test diets were oversupplemented with iron in that the diets 
contained between 1.7 to 2.4 times the NRC requirements. FDA finds that 
these results make it possible to rule out gross effects on iron status 
but the foregoing factors make it difficult to exclude subtle effects 
in these studies (Ref. 56). Accordingly, FDA finds that the pig studies 
are inadequate by themselves to evaluate olestra's effect on iron.
    c. Folate. The petitioner stated that there were a few 
statistically significant differences in plasma folate concentration at 
week 4 in the 26-week DR/VR study, but the values in the olestra groups 
were greater than the control. There were no statistically significant 
changes in plasma folate in the two 12-week studies, nor in the 39-week 
VR study. Therefore, the petitioner concluded that folate status in 
pigs was not affected by olestra consumption.
    FDA finds that a conclusion on folate status cannot be drawn from 
the pig studies for several reasons. First, no measurements of folacin, 
either in the premix or in the diet as fed, were made in any of the 
studies. Second, folic acid was added to the diet, rather than 
folylpolyglutamates, the predominant form of folate in the American 
diet. Folic acid (folylmonoglutamate) is absorbed directly, while 
folylpolyglutamates must be cleaved by folylpolyglutamate hydrolase in 
the intestine prior to being absorbed. Therefore, folacin is not a 
hard-to-absorb nutrient when it is supplied as folic acid, as in these 
studies. Finally, plasma folate is not as sensitive a measure of folate 
status as red blood cell folate (the method used in the human studies). 
Therefore, FDA concludes that the pig studies are of limited utility in 
assessing olestra's effects on folate (Ref. 56).
    d. Zinc. There were no significant effects of olestra on liver, 
bone, or serum zinc levels in the 12-week DR study or the 26-week DR/VR 
study. The only significant differences from control values in these 
three measures of zinc status in the 12-week VR and 39-week VR studies 
were small (and probably spurious) increases in liver zinc in the 0.25 
percent low vitamin group in the 39-week VR study and in serum zinc in 
four olestra groups at week eight in the 12-week VR study. Accordingly, 
the petitioner concluded that liver, bone, and serum zinc 
concentrations were not affected by olestra in any of the pig studies.
    In general, FDA concurs with this conclusion, with some 
qualifications, as discussed below.
    Although they did not show any significant differences, the bone 
zinc measurements are less than an ideal means of assessment because 
the methodology used to analyze the bone has several flaws that limit 
the power and reliability of the results. (These flaws are discussed in 
the calcium section below.) Because of these methodological flaws, FDA 
concludes that the bone zinc measurements of the pig studies do not 
provide a completely reliable assessment of zinc status.
    FDA notes that liver and serum measurements of zinc, in controlled 
swine studies, are acceptable measurements of zinc status that have 
sensitivities comparable to properly performed bone measurements. A 
potential confounding factor in the assessment of zinc status in the 
pig studies is the amount of zinc in the test animal diets. FDA 
estimates that zinc consumption in the 12-week VR, 26-week DR/VR, and 
39-week VR studies exceeded the NRC requirements by at least 68 
percent. However, a review of the literature shows that serum and liver 
zinc measurements will reflect dietary zinc over a wide range of 
dietary 

[[Page 3151]]
concentrations in controlled swine studies. Therefore, FDA believes 
that this oversupplementation would not mask any effects of olestra on 
zinc status. FDA concludes, therefore, based on the results of the 
liver and serum measurements in these studies, that there is no 
evidence that consumption of olestra affects zinc status.
    e. Calcium. Bone ash and bone calcium levels were not affected by 
olestra consumption in the 12-week VR, 26-week DR/VR, or 39-week VR pig 
studies. The only change was seen in the 12-week DR study where bone 
ash but not bone calcium was less (60.6 <plus-minus> 2.0 vs. 61.1 
<plus-minus> 1.0 percent) in the 4.4 percent olestra dose group than in 
the control group (Refs. 74 and 75), a difference that was 
statistically significant. The other dose groups showed no 
statistically significant change in bone ash or bone calcium. The 
petitioner concludes that these results demonstrate that olestra 
consumption does not have an effect on calcium status.
    FDA concludes that the results from the pig studies are not useful 
for determining whether olestra has any subtle effects on calcium 
status; the results show only that there were no gross changes in 
calcium status. FDA's determination that these studies are seriously 
limited in their utility to determine calcium status changes is based 
on two factors: oversupplementation of calcium in the diet and flawed 
methodology in measuring bone ash and bone calcium.
    FDA believes that the bone ash measurements are not reliable 
because the test animals' diet was oversupplemented with calcium. 
Specifically, test animals received approximately 1.0 to 1.3 times the 
NRC calcium requirements during the 12-week studies (with the greater 
amounts during the last 7 weeks) (Refs. 76 and 53), and 1.2 to 1.7 
times the NRC requirement during the 26-week DR/VR and 39-week VR 
studies (Ref. 52). Based on published studies (Refs. 77 and 78), FDA 
believes that bone ash will reach maximum levels when dietary calcium 
is approximately 1.2 times the NRC requirement and adequate levels of 
phosphorus are provided (Ref. 56). Therefore, the supplementation above 
1.2 times the NRC requirement would mask any subtle effect on calcium 
absorption.
    In the 26-week DR/VR and 30-week studies, olestra would have to 
have inhibited the absorption of approximately 30 percent of the 
calcium before any adverse effects on bone ash would have been observed 
(Ref. 56). Thus, the bone ash data from these studies are not a 
stringent test of calcium status. Although the oversupplementation in 
the 12-week studies would not mask olestra effects on calcium as much 
as it would in the 26-week DR/VR and 39-week VR studies, methodological 
factors in obtaining the data on bone ash, as described below, in 
combination with the slight oversupplementation during the last 7 
weeks, make the calcium data only useful in determining whether there 
were gross effects of olestra on calcium status.
    Factors that CFSAN considers contributing to the limitations of the 
methodology that was used to evaluate bone ash include the following: 
(1) Only half of the bone selected for analysis (the L5 lumbar 
vertebra) was used, rather than using the whole bone; (2) after drying 
and grinding the half bone, an aliquot of the ground bone 
(approximately 1.5 g) was taken for fat extraction, rather than 
extracting the entire sample; (3) an aliquot (approximately 0.5 g) of 
the fat-free bone powder was ashed, rather than ashing the entire 
sample; and (4) ashing was performed at 500  deg.C for 8 hours, rather 
than more typical conditions of > 550  deg.C for > 12 hours (Ref. 79).
    Because of these methodological flaws, FDA concludes that the bone 
ash and bone calcium measurements performed in the pig studies do not 
provide a reliable assessment of calcium status.
    Although FDA finds that the data from the pig studies are of 
limited use in determining whether olestra affects the absorption of 
calcium because the test diet was overfortified with calcium and 
appropriate measures of bone were not made, FDA notes that the animals 
grew normally and all outward observations indicated that they had 
normal skeletal growth.
3. Overall Conclusions Regarding Olestra's Effects on Water-Soluble 
Nutrients
    The agency received no significant comments expressing concern 
about olestra's effects on water-soluble nutrients. Similarly, Dr. 
Connie Weaver, FDA's consultant on water-soluble nutrients, also found 
no basis for concern (Ref. 75). FDA's specific conclusions on these 
nutrients follow.
    a. Vitamin B<INF>12. FDA has determined that there is no need for 
compensation of olestra-containing foods with vitamin B<INF>12. In 
reaching this conclusion, the agency relied primarily on the 8-week 
human DR and VR studies in human to evaluate the effect of olestra on 
vitamin B<INF>12. Both studies showed no effect of olestra on vitamin 
B<INF>12  using the Schilling test, which is a sensitive test that is 
not affected by dietary vitamin B12 levels. The vitamin B<INF>12 
results of the pig studies are consistent with the results of the human 
studies. In the pig studies, no effect of olestra was seen in the 12-
week DR, the 26-week DR/VR, or 39-week VR studies. There was a 
statistically significant decrease in liver B<INF>12 levels in the 
highest olestra dose group (7.7 percent) in the earliest pig study (the 
12-week VR study). Because this result was not corroborated by results 
of any of the other studies, FDA concludes that, collectively, the data 
establish that olestra does not affect vitamin B<INF>12 absorption.
    b. Folate and iron. The results from the 8-week human studies 
establish that folate and iron status were not affected by olestra 
consumption. These studies were well designed, the methods used were 
sufficiently sensitive to evaluate olestra's effects, and the duration 
of the studies was long enough to see any such effect. Although there 
were limitations in the quality of the results of the pig studies with 
regard to folate and iron, in general, the results of the pig studies 
support the conclusion drawn from the human studies that olestra 
consumption does not adversely affect iron or folate status.
    c. Zinc. Zinc status was evaluated by three acceptable methods: 
serum and urinary zinc in the 8-week human studies, and serum and liver 
zinc in the pig studies. None of these analyses, in any of the studies, 
demonstrated an effect of olestra consumption on zinc status. The 
analysis for zinc in bone has methodological limitations. Therefore, 
although these results are consistent with the other zinc measurements, 
FDA is not relying on the bone results.
    FDA concludes that the totality of the results, in both the human 
and pig, using all three methods, provides strong evidence that olestra 
consumption does not affect zinc absorption. In addition, FDA is not 
aware of any hypothesis that would support an effect of olestra on zinc 
status.\55\ Therefore, FDA concludes that consumption of olestra does 
not affect zinc status.

    \55\At the Olestra Working Group meeting, Dr. Schneemna, FDA's 
overarching nutritional consultant, stated that the only mechanism 
she could envision of olestra to affect any water-soluble nutrient 
would be a general mechanism causing lower bioavailability for a 
variety of nutrient. Transcript, vol. 2, p. 97 and vol. 3, p. 130.
---------------------------------------------------------------------------

    d. Calcium. With respect to calcium, FDA concludes that there is no 
basis for concluding that calcium absorption would be adversely 
affected by olestra consumption. First, there is no plausible 
hypothesis for how olestra could affect calcium absorption other than 
by 

[[Page 3152]]
vitamin D depletion. Unlike the fat-soluble vitamins, calcium is water 
soluble and would not be expected to partition into olestra. Other 
mechanisms by which olestra might affect calcium absorption are: (1) by 
forming a physical barrier that would prevent calcium from reaching the 
mucosal cell surface, where it is absorbed; or (2) by decreasing GI 
transit time so drastically that there is little chance for calcium to 
make mucosal contact. However, these mechanisms would also be expected 
to affect the absorption of folate, vitamin B12, and iron, yet, 
importantly, as discussed above, these nutrients are unaffected by 
olestra consumption. Also, published studies (Refs. 80 and 81) indicate 
that olestra does not significantly alter gastric emptying or overall 
GI transit time.
    Further, it is likely that the effect of variations in calcium 
intake in the normal diet (especially as a result of dietary choices 
concerning calcium-rich foods such as dairy products) would be much 
greater than any effect from olestra consumption on calcium absorption 
(Ref. 75). Also, the compensatory homeostatic mechanisms the body has 
for calcium, and the fact that studies have shown that high-fat diets 
do not affect absorption of vitamin B<INF>12, folate, iron, or zinc, 
are additional reasons for reduced concern about the potential effect 
olestra on the absorption of calcium. Finally, studies of mineral oil 
(a substance much like olestra in that, like fats, it is non-polar and 
is not absorbed) in the published literature support the conclusion 
that any effect by olestra on calcium is likely to be vitamin D-
mediated rather than a direct effect on its absorption (Refs. 82 and 
83). Compensating for olestra's effects on vitamin D will thus preclude 
any effects of olestra consumption on calcium produced by vitamin D 
depletion.
    Thus, given the lack of effect on other water-soluble nutrients and 
the lack of any probable mechanism for olestra to affect calcium, FDA 
concludes that there is no basis for concern regarding olestra's 
effects on calcium status.

 Effect of Olestra on the Gastrointestinal (GI) Tract

A. Introduction

    Because olestra is not digested or absorbed and passes unchanged 
through the GI tract, it has the potential to affect GI physiology and 
function. Therefore, the petitioner conducted several studies to assess 
olestra's potential to affect the GI tract.
    For example, the petitioner assessed the potential for olestra to 
elicit GI symptoms such as cramping, bloating, loose stools, and 
diarrhea-like symptoms by collecting adverse effect reports in studies 
designed primarily to assess potential effects of olestra on absorption 
of nutrients from the diet. The petitioner also collected data on GI 
symptoms in a human study (the oil loss study) designed to set a 
specification for olestra stiffness (i.e., viscosity). (The oil loss 
study sought to establish the viscosity that would prevent olestra from 
separating from other fecal contents in the colon and leaking past the 
anal sphincter (passive oil loss)). Other studies addressed the 
potential for olestra to cause GI symptoms in the young and in patients 
with inflammatory bowel disease (IBD). The study in patients with IBD 
also assessed the potential for olestra to adversely affect disease 
activity. Finally, the petitioner conducted several studies to assess 
the potential for olestra to affect the normal metabolic activity of 
intestinal micro flora and the potential for olestra to affect the 
absorption, synthesis, and excretion of bile acids.

B. Effect of Olestra on GI Symptoms

1. Study of GI Symptoms in 8-week Studies in Normal Subjects
    Data on GI symptoms were collected in the two 8-week human clinical 
studies conducted to determine olestra's potential to affect 
nutritional status. The design and methodology of these studies are 
described above in detail in Section IV.B.1.a.The petitioner believes 
that data from the two 8-week studies are particularly useful in 
understanding the potential for olestra to produce GI symptoms because 
the olestra doses used were large (up to 32 g/d) and were consumed 
every day, the studies were lengthy (8 weeks), and details of the GI 
symptoms were recorded by the subjects for each day they reported 
symptoms. Specifically, subjects were questioned daily about changes in 
their health, including GI symptoms. If a GI symptom was experienced, a 
subject completed a detailed questionnaire which asked about the type, 
severity, and duration of symptoms experienced. To facilitate 
collection of GI symptom data, the questionnaire provided a list of 
common GI symptoms along with general definitions of each. This served 
to remind subjects of other possible symptoms in addition to the one 
that first prompted completion of the GI symptom report.
    The petitioner noted two considerations relevant to the evaluation 
of the GI symptom reports. First, the subjects were prompted every day 
to report symptoms and were provided with a list of commonly 
experienced GI symptoms; this would be expected to amplify the 
reporting of GI symptoms, relative to data collected under unprompted 
conditions. In addition, the collected symptom data will closely 
reflect actual incidence, rather than capturing only those symptoms 
that subjects judged significant enough to report. Second, the 
petitioner stated that the two 8-week studies were not intended to 
examine GI symptoms under real-life consumption conditions where snacks 
are not consumed every day with every meal and where people may 
moderate intake if they experience GI symptoms; therefore, the GI 
symptom data from these studies may have exaggerated what will occur in 
young, healthy adults consuming olestra snacks under real life 
conditions.
    a. Petitioner's evaluation of GI symptoms. Because the two 8-week 
studies were run under nearly identical protocols, the petitioner 
combined the GI symptom data from the two studies for analysis. GI 
symptoms were reported by subjects in all groups, including placebo. 
The petitioner stated that the number of people reporting GI symptoms 
in the two 8-week studies increased in a dose responsive manner with 
olestra dose. The number of individuals who ate eight g/d olestra\56\ 
for 8 weeks and reported at least one GI symptom (62 percent) was 
greater than the number who ate a corresponding amount of a 
triglyceride for 8 weeks and reported at least one GI symptom (45 
percent). The petitioner noted that the GI symptoms reported by the 
control and 8 g/d groups of subjects were essentially not different in 
severity, length of episodes, or total number of symptom days (number 
of days on which symptoms occurred times the number of symptoms). The 
petitioner also noted that GI symptoms reported by subjects who 
consumed larger amounts of olestra (20 g/d or 32 g/d) were of the same 
kind and severity as those reported by subjects in the placebo and 
eight g/d olestra groups; however, the total number of symptom days was 
greater in the two groups consuming the higher levels of olestra.

    \56\Eight g/d olestra intake approximates the lifetime average 
90<SUP>th-percentile intake for snack eaters.
---------------------------------------------------------------------------

    The petitioner concluded that none of the GI symptoms reported by 
subjects eating either triglyceride or olestra at any level (8, 20, or 
32 g/d) were clinically significant. According to the petitioner, the 
GI symptoms spontaneously abated and recurred during the course of the 
study in all 

[[Page 3153]]
groups and stopped within 5 days after the study ended. The petitioner 
also stated that the GI symptoms experienced by an individual eating 
olestra-containing foods are self-limiting in the sense that the 
symptoms either stopped in the face of continued consumption of such 
foods or ceased when the individual stopped eating the olestra-
containing food or reduced the amount consumed. The number of subjects 
reporting symptoms at any given time and the severity of the symptoms 
remained essentially constant over time among the different treatment 
groups, indicating that symptoms did not worsen with prolonged 
consumption of olestra. In addition, clinical laboratory data collected 
at the time subjects were reporting symptoms did not show clinically 
significant effects such as hemoconcentration, electrolyte imbalance, 
or increased urinary creatinine or specific gravity.
    The petitioner stated that the symptoms were, on average, mild to 
moderate in all groups. As an indication of the mildness of the 
symptoms, the petitioner stated that few individuals reporting GI 
symptoms in the two 8-week studies dropped out of the studies because 
of the symptoms. (Four of a total of 115 subjects in the 20 and 32 g 
olestra per day groups dropped out; out of these 4, only 1 was 
attributed to GI symptoms experienced (heartburn)).
    Although most of the symptoms were reported as mild on average, the 
petitioner stated that at least one symptom described as severe was 
reported by some subjects: 5 percent (placebo), 10 percent (8 g/d 
olestra), 26 percent (20 g/d olestra), and 22 percent (32 g/d olestra). 
All severe symptoms reported by the placebo and eight g/d olestra 
groups were limited to 1 day. For the 20 g/d olestra group, the maximum 
duration of severe symptoms was 2 days, and for the 32 g/d group, it 
was 4 days. According to the petitioner, GI symptoms reported by people 
eating 20 or 32 g/d olestra are similar to those reported by people 
eating high amounts of common food ingredients that elicit GI symptoms. 
The petitioner asserted that high fiber diets produce GI symptoms such 
as stomach cramps, loose stools, diarrhea, bloating, and flatulence. 
Therefore, the petitioner concluded that persons eating olestra-
containing foods, even at levels beyond the expected consumption from 
snacks, are unlikely to experience GI symptoms that are different from 
those they might normally experience consuming other foods or from 
dietary changes.
    b. FDA's evaluation of the GI symptoms. Unlike the petitioner, in 
its original analysis, FDA evaluated the adverse effects reports from 
the two studies separately, because there did not appear to be any 
reason or need to combine the two date sets. In analyzing the two 
studies, FDA, however, did combine reports of loose stools and diarrhea 
(Ref. 84), for the following reason. The petitioner defined loose 
stools as bowel movements that were unformed but not watery, and 
diarrhea-like stools as watery stools that were difficult to control 
and had little or no solid material.\57\ However, the difference was 
between loose stools and diarrhea-like stools may not have always been 
clear to the subjects. Further, substantial fluid and electrolyte 
losses could potentially result from either form of stools. Thus, FDA 
believes that it is preferable to combine these two reported effects 
for analysis.

    \57\Reporting of diarrhea was based on subjects' perception of 
diarrhea. There was no measurement of water-content made. However, 
subjects' electrolyte levels were monitored. FDA recognizes that the 
effect observed may not be diarrhea in the clinical sense but is 
using that term in this preamble because it is the term used in the 
study report.
---------------------------------------------------------------------------

    In its presentation of the GI symptom data to the Olestra Working 
Group and the FAC, FDA did combine the data from the two studies; 
combining the data is acceptable for the following reasons: (1) Both 
studies used the same olestra dosages (placebo, 8 g/d, 20 g/d, and 32 
g/d); (2) similar criteria were used in both studies for selecting and 
excluding study subjects; (3) the studies were of the same duration; 
and (4) the same methods were used to monitor for adverse GI 
experiences. By pooling the data, the statistical power of the study 
increased.\58\

    \58\Transcript, vol. 2, p. 185.
---------------------------------------------------------------------------

    At the Olestra Working Group and FAC meetings, there was some 
discussion regarding the advisability of pooling data from the two 
studies. For example, CSPI stated in their White Paper that the two 
studies were analyzed separately because one of the studies had a very 
high rate of GI problems in the control group that masked the 
difference between the placebo and the 8 g/d groups and also because 
the second study had a low level of GI problems in the control 
group.\59\ Others stated that not only could the studies be combined, 
but that the conclusions were the same whether or not the data were 
pooled, i.e., there was increased reporting of GI effects with 
increasing olestra doses.\60\

    \59\Statement of Dr. Michael Jacobson, CSPI, Transcript, vol. 1, 
p. 171.
    \60\Statements of Dr. David Allison, Dr. Joann Lupton, and Dr. 
Karl Klontz. Dr. Allison is an Associate Research Scientist at New 
York Obesity Research Center, Saint Luke/Roosevelt Hospital. He was 
a temporary member of the FAC. Dr. Lupton is an Associate Professor 
of Human Nutrition at Texas A&M. She was FDA's consultant on GI 
issues. Dr. Karl Klontz is with FDA. Transcript, vol. 3, pp. 49-54.
---------------------------------------------------------------------------

    FDA's analysis of the data from the two 8-week studies showed there 
was a dose-response effect for olestra with respect to two endpoints, 
reported diarrhea/loose stools and fecal urgency. For example, in the 
8-week DR study, the percentage of subjects who experienced loose 
stools or diarrhea (at any time during the study) was 19 percent 
(control group), 45 percent (8 g/d olestra group), 74 percent (20 g/d 
olestra group), and 67 percent (32 g/d olestra group). In general, 
whether the data from the two studies were analyzed separately or 
together, the incidence of GI symptoms in the eight g/d olestra group 
was not statistically different from that of the control group; the 
differences in the incidences of GI symptoms between the control group 
on the one hand and the 20 or 32 g/d olestra groups were statistically 
significant.
    Although FDA agrees that, in general, the GI symptoms started and 
stopped in all groups, FDA notes that, in some olestra-fed subjects, 
the GI symptoms persisted for a long period of time. For example, over 
the course of the 56 days, two study subjects in the 20 g/d olestra 
group reported loose stools for 38 and 40 days, respectively, and 
another subject in the same group reported experiencing fecal urgency 
and loose stools for 55 days. In the 32 g/d olestra group, three 
subjects reported loose stools for more than 50 days. FDA agrees that 
these GI symptoms cease when olestra is no longer consumed. However, 
FDA believes it is important that consumers know that the GI symptoms 
they are experiencing may be due to consumption of olestra. This need 
for information is discussed in section VII of this document.
    As noted, the petitioner contends that the nature and severity of 
the GI symptoms observed among the olestra-consuming participants were 
comparable to symptoms experienced by persons consuming diets moderate 
or high in fiber. FDA does not agree. While high-fiber diets have been 
associated with increased gas manifested as belching, flatulence, and 
mild abdominal distention, diarrhea and staining of underwear 
(discussed in following section) have not commonly been reported (Refs. 
85 and 86).
    Finally, FDA concurs with the petitioner that there was no evidence 
in either study that subjects experiencing olestra-related symptoms 
described as 

[[Page 3154]]
``diarrhea'' also experienced significant fluid and electrolyte loss.
2. GI Symptoms in the Oil Loss Study
    The petitioner conducted an oil loss study.\61\ This study had 
three objectives to determine: (1) The minimum olestra stiffness that 
would control passive oil loss, as measured by underwear staining, to 
the level experienced by a triglyceride placebo group; (2) the 
relationship between olestra stiffness\62\ and the occurrence of oil in 
the toilet (OIT); and (3) whether the stiffness of olestra affected the 
incidence of common GI symptoms experienced by the subjects.

    \61\Passive oil loss can occur when people consume large amounts 
of nonabsorbable oil that is liquid at body temperature, such as 
mineral oil or liquid olestra; liquid oil separates from other fecal 
material in the colon and leaks past the anal sphincter. The 
petitioner observed that early formulations of olestra caused 
passive oil loss, but that oil loss could be decreased by increasing 
the stiffness of olestra at body temperature. Stiffer olestra has 
less of a tendency to separate from the fecal matrix.
    \62\The stiffness of olestra was characterized by measuring a 
rheological parameter called the thixotropic area, which is 
determined by measuring the shear stress on olestra as the shear 
rate is first increased and then decreased. The area between the 
ascending and descending shear stress versus rate curves is the 
thixotropic area. Olestra that is liquid at body temperature has 
thixotropic areas approaching zero. Highly saturated olestra that is 
largely solid at body temperature has thixotropic areas well above 
100 kiloPascals/sec (kPa/s). In practical terms, olestra with a 
stiffness of 18 kPa/s had a consistency similar to a typical catsup 
at room temperature; olestra with a stiffness of 50 kPa/s has a 
consistency similar to mayonnaise; olestra with a stiffness of 103 
kPa/s is similar to cold margarine.
---------------------------------------------------------------------------

    The oil loss study was a double-blind, placebo controlled, parallel 
design study with seven groups of 18 to 44 year old male and female 
subjects (173 to 182 per group). Six groups consumed 34 g/d of olestra 
of varying stiffness (18, 45, 50, 66, 78, or 103 Kpa/s) in potato chips 
for 5 days. A placebo group consumed an equivalent amount of potato 
chips prepared with triglycerides. All groups consumed the potato chips 
as part of a normal diet.
    At the end of the 5 days, the subjects completed a questionnaire 
answering specific questions about underwear staining due to passive 
oil loss and incidence of oil droplets in the toilet (OIT) following 
defecation. In addition, reports of adverse GI experiences (e.g., 
diarrhea, abdominal pain, indigestion) were collected during the 
consumption period as well as the 3 days following the treatment phase.
    a. Effect of olestra stiffness on passive oil loss. From the 
results of this study, the petitioner concluded that the incidence of 
passive oil loss in subjects who consumed olestra with a stiffness less 
than or equal to 45 kPa/s (i.e., those in the two lowest treatment 
groups) was significantly increased relative to the incidence reported 
by the subjects consuming triglycerides (the placebo group). The 
incidence of passive oil loss in subjects consuming olestra of greater 
that 50 kPa/s was not significantly different from the incidence 
reported by subjects in the placebo group. FDA's analysis of these data 
agreed with the petitioner's analysis.
    At the Olestra Working Group and FAC meeting, CSPI stated that 
their analysis showed that there are statistically significant 
increases of passive oil loss above control with olestra at the higher 
stiffness levels.\63\ However, no details on how the data were analyzed 
were given. FDA had the data from the passive oil loss study analyzed 
independently by Dr. Joanne Lupton, FDA's consultant on GI issues. Dr. 
Lupton's analysis was consistent with FDA's analysis, i.e., there would 
be an increase in passive oil loss in subjects consuming olestra having 
a stiffness of under 50 kPa/s but not in subjects consuming olestra 
with stiffness of 50 kPa/s or higher.\64\

    \63\Transcript, vol. 4, p. 163.
    \64\Statement of Dr. Joanne Lupton, Transcript, vol. 2, p. 222.
---------------------------------------------------------------------------

    Therefore, FDA concurs with the petitioner's conclusion that there 
would not be an increased incidence of passive oil loss in subjects 
consuming olestra of a stiffness greater than or equal to 50 kPa/s 
(Ref. 87). FDA also notes that passive oil loss is not a hazard to 
health or otherwise an adverse effect per se and that the purpose of 
conducting the study was to determine the stiffness specification of 
olestra above which passive oil loss would not occur.
    b. Effect of olestra stiffness on OIT. The petitioner stated that 
the incidence of reported OIT was significantly increased in all 
olestra groups relative to the incidence in the placebo group. The 
incidence of OIT in the 18 kPa/s olestra group was also significantly 
greater than the incidence in any other olestra group. However, there 
was no consistent trend in the incidence of OIT reported by the 
subjects who consumed olestra of stiffness greater or equal to 45 kPa/
s.
    FDA agrees that the incidence of OIT was significantly greater in 
all olestra treatment groups (13.5 percent to 32 percent) compared to 
the placebo group (4.7 percent). FDA also agrees that there was no 
predictive relationship between olestra stiffness and OIT when the 
stiffness was greater or equal to 45 kPa/s (Ref. 87).
    c. Effect of olestra stiffness on GI symptoms. With respect to GI 
symptoms, the petitioner stated that 9 percent of the subjects in the 
placebo group and from 10 percent to 16 percent of the subjects in the 
olestra groups reported GI symptoms including (in decreasing order of 
occurrence) gas/stomach gurgle, diarrhea, abnormal (loose, soft) 
stools, abdominal pain, and indigestion/heartburn. The petitioner 
concluded that there was no consistent trend with olestra stiffness in 
the number of GI symptoms reported. The petitioner also concluded that, 
consistent with the results of other studies, the GI symptoms do not 
present a safety concern because: (1) When they occur, the symptoms are 
generally mild or moderate in severity; (2) they subside when olestra 
consumption is stopped; and (3) they do not differ substantially from 
the GI symptoms normally experienced when diets high in fiber are 
consumed.
    FDA agrees with the petitioner that there was no trend in reported 
GI effects based on olestra stiffness. However, the percentage of 
subjects who reported at least one of the eight gastrointestinal 
effects assessed was significantly greater in four of the six olestra 
stiffness treatment groups (18, 66, 78, 103 kPa/s) compared to the 
placebo group (Ref. 87).
    In addition, the percentage of subjects in the olestra groups 
reporting GI symptoms in response to directed questions was 0 percent 
to 19 percent greater than the percentage of subjects reporting 
symptoms in the placebo group. The GI effects that were reported 
significantly more often in some of the olestra groups compared to the 
placebo group were urgent bowel movements, difficulty wiping, and soft 
stools (Ref. 87).
    An increase in the number of daily bowel movements over that 
occurring in the placebo group was reported by subjects in all of the 
olestra stiffness treatment groups except one (45 kPa/s). Twenty-seven 
percent of subjects in the placebo group reported an increased number 
of bowel movements per day compared to a range of 35 to 48 percent for 
olestra recipients (Ref. 87).
    FDA agrees that, when reports of loose stools and diarrhea are 
analyzed separately, with only one exception, no statistically 
significant increase in either loose stools or diarrhea-like stools was 
reported among olestra recipients versus placebo recipients. However, 
as is the case with analysis of the GI symptoms in the two 8-week 
studies, FDA believes that it is appropriate to combine reports of 
loose stools and diarrhea for analysis. This is because the difference 
between loose stools and diarrhea-like stools may not have always been 
clear to the study 

[[Page 3155]]
subjects and may be simply variable manifestations of the same effect. 
When reports of loose stools and diarrhea like stools are combined, the 
analysis shows that during the 5 day study, 42.3 percent (447/1056) of 
olestra recipients experienced loose stools or diarrhea-like stools 
compared to 33.1 percent (57/172) of placebo group subjects; this 
difference is statistically significant (P=0.03). (Ref. 87).
    Finally, FDA notes that, in general, the results of analysis of the 
GI symptoms data in the oil loss study are consistent with those 
obtained in the 8-week studies. In addition, FDA agrees that, like the 
GI symptoms reported in the 8-week studies, GI symptoms in the oil loss 
study subside when olestra consumption is stopped. As discussed above, 
however, FDA does not agree with the petitioner that the GI symptoms 
experienced with olestra consumption are similar to those experienced 
with high fiber consumption.
3. Study of Selected Fecal Parameters in Subjects Consuming Olestra
    a. Study design. The petitioner conducted a study designed to 
examine fecal composition of subjects reporting diarrhea when consuming 
olestra. Normal healthy males and females (18 to 60 years of age) were 
selected for the study from a population of subjects who had reported 
GI symptoms while consuming olestra in previous product acceptance 
studies. The study consisted of two phases. A screening phase was 
conducted to identify subjects who reported GI symptoms from olestra 
consumption. The second phase was a study phase during which the 
identified subjects ate different amounts of olestra and GI symptoms 
were recorded and fecal measurements were made.
    The screening phase was a 4-week, cross-over design with two 
treatment groups, 0 and 20 g/d olestra. Fifty-two adults who had 
reported GI symptoms in previous olestra studies were recruited for the 
study. The olestra was substituted for 20 g of triglyceride in the 
three daily meals with roughly one-third of the dose provided in each 
meal. The study participants were acclimated to the study procedures 
during a 3-day baseline period in which they ate placebo meals. They 
were then divided into two groups and ate either placebo meals or meals 
providing 20 g/d olestra for 5 days. After a 7-day washout period, the 
subjects again ate placebo meals (containing triglycerides) for 3 days, 
and then crossed-over to olestra or placebo meals for 5 days. After the 
second treatment period, the subjects were monitored for a 4-day 
washout period. All meals during baseline, treatment, and washout 
periods were eaten under supervision at the clinical site.
    The frequency, duration, and severity of nine predefined GI 
symptoms were documented daily by the subjects, starting at the 
beginning of the baseline period and continuing through the final 4-day 
washout period. Diarrhea was defined as ``excessive frequency of very 
loose/watery stools that are extremely difficult or impossible to 
control.'' Loose stools were defined as ``a bowel movement that is 
easier to pass than normal, but is not watery and unformed.''
    At the completion of the screening phase, those subjects who 
reported an increase in the frequency, severity, or duration of GI 
symptoms during the olestra period, relative to the placebo period, 
were selected to take part in the study phase. Eighteen subjects met 
the selection criteria.
    The study phase was a crossover, placebo-controlled, single-blind 
(subject) design with three treatment groups, 0, 10, and 20 g/d 
olestra. Each subject received each treatment for 7 days. The treatment 
periods were separated by 7-day washout periods. Subjects ate all 
treatment meals under supervision at the clinical site, and ate their 
habitual diets at home during the washout periods.
    GI symptoms were ascertained during the treatment periods and the 
first 4 days of the washout periods by GI assessment records completed 
daily by the subjects. For each GI symptom episode, the subject 
recorded the date, time of day, and intensity. The intensity scale for 
GI symptoms was graded as follows: 0 (none); 1 (slight); 2 (mild); 3 
(moderate); and 4 (severe). Total fecal collections were made for the 
last 3 days of each treatment period and the daily collections were 
pooled. To complete the study and have data included in the analyses, a 
subject had to provide at least one fecal sample for each 3-day 
collection period.
    Stools were collected into plastic containers and immediately 
frozen. Wet weight, volume, and density measurements were made on each 
stool. Fecal samples from each subject during the 3-day collection 
period were then pooled. Three-day pooled fecal samples for each 
subject were analyzed for water concentration, dry weight, olestra 
analysis, Na, K, Cl, total and individual bile acids, free fatty acids, 
triglycerides, and total lipids.
    b. Petitioner conclusions. Of the 15 subjects completing the study, 
6 subjects reported diarrhea while eating 20 g/d olestra. The 
petitioner concludes that this study further confirms that the diarrhea 
reported by subjects consuming olestra does not present potential for 
harm. This conclusion is based on the observation that there was no 
significant increase in stool weight, water content, or number of bowel 
movements per day for subjects reporting diarrhea while consuming 
olestra at 20 g/d.
    c. FDA conclusions. The number of subjects who reported diarrhea 
increased with increasing dose of olestra; three subjects (20 percent) 
reported diarrhea while eating 0 g/d olestra, six (40 percent) subjects 
while eating 10 g/d olestra, and 11 (69 percent) while eating 20 g/d 
olestra. The difference in incidence of reported diarrhea between the 
20 g/d and 0 g/d consumption levels was statistically significant. In 
addition, the mean number of diarrheal bowel movements per subject 
reporting any diarrhea and the severity of the diarrhea both increased 
with increasing olestra consumption. Although there was an increase in 
the number of subjects reporting loose stools with increasing olestra 
dose, this increase was not statistically significant. FDA concludes 
that these results are qualitatively similar to the results of the 8-
week studies.
    Measurements of the concentration of stool water and electrolytes 
(Na, K, and Cl) suggest these parameters did not differ in persons 
reporting diarrhea during the 20 g/d olestra period from those of their 
nondiarrheal stools during the placebo period. However, it was not 
possible to analyze stool electrolyte values by individual stools or by 
individual days because the stools were pooled from the 3-day 
collection period, as is normally done when measuring fecal parameters. 
FDA notes that there appears to be an increase weight of stools in 
those subjects reporting diarrhea when eating 20 g/d olestra that is 
not completely accounted for by the presence of olestra in the stools. 
FDA concludes that the results of this study indicate that there is no 
difference in stool composition (e.g., water and electrolyte content) 
between those subjects consuming olestra who reported diarrhea and 
those who did not (Ref. 88).
4. Study in Patients with Inflammatory Bowel Disease
    The petitioner conducted a multi-center study in both ulcerative 
colitis (UC) patients and Crohn's disease (CD) patients. The objective 
of the study was to assess whether the presence of olestra in the GI 
tract exacerbates conditions in which the GI epithelium is compromised. 
Inflammatory bowel 

[[Page 3156]]
disease (IBD) represents an extreme example of such a condition. In the 
study the petitioner conducted, 45 IBD patients with at least a 2-year 
history of diagnosed disease, who were in remission (21 UC and 24 CD), 
were given 20 g/d of olestra in cookies and potato chips for 4 weeks. 
Forty-four control subjects were given cookies and potato chips 
prepared with conventional vegetable triglycerides. At the end of the 
4-week consumption period, the disease status of each patient was 
assessed and classified as in remission, worsened, or relapsed. Four 
weeks after the end of the consumption period, the patients were 
contacted by telephone and asked about the status of their disease. If 
judged appropriate, they were seen by the investigator. In addition, 
bowel permeability was assessed at the beginning and end of the 
consumption period by measuring urinary excretion of polyethylene 
glycol (PEG).
    The petitioner stated that IBD patients are good surrogates in 
which to determine whether olestra will have an adverse impact on a 
wide range of GI diseases involving acute and chronic inflammation, 
ulcerations, and possibly a compromised intestinal barrier. The 
petitioner also asserted that this patient population was chosen 
because UC and CD are thought to be exacerbated by a range of stimuli, 
some of which may be dietary in nature. According to the petitioner, 
IBD patients in remission are also good models for people who are 
asymptomatic but who may have underlying predisposing conditions or 
subclinical GI diseases which, when exacerbated, may become active.
    FDA agrees that a study in persons with IBD is useful to assess 
whether olestra may have adverse health effects on potentially 
sensitive subpopulations with bowel disease. FDA believes that persons 
with IBD are an appropriate target population for such a study because 
the disease is prevalent, because the acute disease status of such 
patients can be significantly influenced by factors that change bowel 
habits, and because such patients can have increased bowel permeability 
which, if further increased, could have long-range health significance.
    The petitioner concluded that, in the placebo group, out of 44 
subjects, 40 remained in remission, disease activity worsened for 4, 
and none relapsed. For the olestra group, out of 45, 41 remained in 
remission, disease activity worsened for three and one relapsed. The 
petitioner concluded that the relapse was not test-related. Further, 
hematologic parameters indicative of disease activity were not 
different between the groups. The one relapse was not unexpected and is 
consistent with the spontaneous relapse rate among IBD patients (about 
30 percent per year (Ref. 89), or about 1 per month for the population 
size studied). There was no increase in bowel permeability in either 
the UC or CD patients. Because there was no difference between olestra 
and placebo groups in the number of patients whose disease activity 
worsened during the study, the petitioner concluded that consumption of 
20 g/d olestra for 4 weeks did not affect disease activity of the IBD 
patients.
    FDA notes that for any study with a small number of subjects and 
relatively low background relapse rate (e.g., 2.5 percent per month 
projected in the control group), an effect of treatment (olestra) 
compared with control (triglyceride) would be seen only if the effect 
was large (Ref. 90). Thus, the study can be used to address the 
possibility that consumption of 20 g of olestra per day will 
consistently--about 30 percent of the time - exacerbate IBD. The study 
gives some reassurance that consumption of olestra at 20 g/d for up to 
31 days would not cause a large detrimental effect in special 
populations such as UC and CD patients. This study was too small and 
too brief, however, to rule out a moderate detrimental effect (e.g., 
relapse rates that are two or three times those of control) (Ref. 91).
5. GI Symptoms in Young Children
    GI symptoms in the young were reported in three studies. Two of 
these, a study in 5 to 8-year-old children that lasted 7 days and 
another in 3 to 5-year-old children that lasted 5 days, were designed 
to address the potential effects of olestra on GI symptoms. The third 
study, while conducted to determine whether children (2 to 5 years of 
age) adjusted their energy intake in response to variations in the 
proportion of energy from dietary fats, also provided information on GI 
symptoms. In this third study, children consumed olestra for five 2-day 
periods over 5 weeks.
    After reviewing the reports on GI symptoms from these studies, the 
petitioner concluded that there were no differences in incidence of any 
GI symptoms among treatment groups, and no significant health effects 
from consumption of olestra by children.
    Potential GI effects in the young were discussed at the meetings of 
the Olestra Working Group and FAC. CSPI commented that the studies on 
children were too short to provide enough meaningful data on 
gastrointestinal problems.\65\ In addition, Dr. Herbert Needleman 
stated that he had reviewed the petitioner's two 8-week studies and 
CSPI's White Paper on olestra and that he had concluded that olestra 
had not been demonstrated to safe for consumption by children.\66\

    \65\Statement of Dr. Myra Karstadt, CSPI, Transcript, vol. 3, p. 
9.
    \66\Statement of Dr. Herbert Needleman, Professor of Psychiatry 
and Pediatrics, University of Pittsburgh School of Medicine. 
Transcript, vol. 3, p. 14.
---------------------------------------------------------------------------

    On the other hand, Dr. William Klish\67\ stated that he had 
reviewed all the relevant data on olestra and concluded stated that 
olestra should in no way be considered harmful to children. Dr. Klish 
added that, while children are born with an immature gastrointestinal 
tract, their digestive and absorptive physiology, as well as 
gastrointestinal motility, are similar to that of an adult at about 1 
year of age and therefore, the adult data on olestra can be 
extrapolated to children. Dr. Klish also noted that the feeding of a 
nonabsorbable oil to children has been occurring without adverse 
effects for at least the last 50 years in the form of mineral oil to 
treat constipation, a symptom seen frequently in children. (Mineral oil 
was normally given in doses of about 15 g to about 45 g/d for months or 
years in the child who is chronically constipated.)

    \67\Statement of Dr. William Klish, Professor of Pediatrics at 
Baylor College of Medicine, Head of the Section of Gastroenterology 
and Nutrition at the Texas Children's Hospital in Houston, TX. 
Transcript, vol. 2, p. 260.
---------------------------------------------------------------------------

    Dr. Charles Hargrove, a pediatric gastroenterologist with whom FDA 
consulted regarding pediatric GI issues, stated that, in view of the 
physiologic maturity of the GI tract by 9 to 12 months of age, there 
should be no serious harmful effect in the toddler/preschool child if 
the consumer parent has appropriate labeling information to associate 
potential GI symptoms with olestra. He added that the differential 
diagnosis for numerous GI upsets in the young, i.e., loose stools, 
stomach cramps, would have to be expanded to include olestra despite 
the apparently low incidence of the latter, and that physicians should 
be made aware of olestra's potential to induce loose stools, for 
example, as they should be aware that apple or grape juice can produce 
loose stools in some toddlers.\68\

    \68\Statement of Captain Charles Hargrove, M.D., Transcript, 
vol. 2, p. 225.
---------------------------------------------------------------------------

    Dr. Ronald Kleinman, a pediatric gastroenterologist and a member of 
the Olestra Working Group concluded that olestra does not pose any 
danger to health in the young. He added that the effect of excessive 
consumption of 

[[Page 3157]]
potato chips with olestra by children is analogous to ``toddlers' 
diarrhea,'' one of the causes of which is excess fruit-juice 
consumption. Dr. Kleinman observed that just as the number of stools 
per day decreases whenpara. consumption of the fruit juice decreases, 
stools will begin to firm up once consumption of olestra-containing 
foods decreases. Dr. Kleinman noted that as is the case for many 
constituents of foods and foods currently available, some individuals 
who are intolerant to olestra or foods containing olestra include 
children, and that children, like adults, can relate symptoms to foods 
and will be able to stop eating such foods when they have reached a 
level of intolerance for it.\69\

    \69\Statement of Dr. Ronald Kleinman, Chief of the Pediatric GI 
and Nutrition Unit, Massachusetts General Hospital and Associate 
Professor of Pediatrics, Harvard Medical Center Dr. Kleinman was a 
temporary member of the FAC. Transcript, vol. 4, p. 177 and 192.
---------------------------------------------------------------------------

    FDA notes that, in general, the GI symptoms seen in the studies in 
children conducted by the petitioner are consistent with those seen in 
the 8-week studies in adults discussed above. Although the short 
duration of the studies in children makes it difficult to compare the 
GI effects to those seen in the 8-week studies in a meaningful way, FDA 
has concluded that the data regarding GI effects obtained in adults can 
be extrapolated to the young and that this approach is fully consistent 
with the expert views provided at the Olestra Working Group and FAC 
meetings. FDA also notes that despite CSPI's criticism that the studies 
in children were not of adequate length, CSPI did not contradict the 
basis for the agency's conclusion that extrapolation from studies in 
adults is appropriate.

C. Effect of Olestra on Intestinal Microflora Metabolism

    Olestra passes intact through the colon where it has the potential 
to affect adversely the normal metabolic activity of the intestinal 
microflora. The indigenous microflora of the colon carry out a variety 
of reductive, degradative, and hydrolytic processes that are important 
to the host. Therefore, it is important to know whether consumption of 
olestra affects microflora populations, alters fermentation processes 
or normal microflora metabolism of host-produced substrates, or acts as 
a substrate for microflora.
1. Effect of Olestra on Breath Gas and Microflora-Associated 
Characteristics
    The petitioner used an analysis of breath hydrogen as a noninvasive 
technique for studying microbial fermentation in the human colon under 
``normal'' and ``high'' dietary fiber intakes (within the range 
recommended as ``healthy'' fiber intake in the United States), with and 
without olestra. An analysis of breath methane was also used in this 
study to provide additional information on microbial fermentation 
activity in methanogenic individuals.
    In addition, because normal metabolic function of colonic 
microflora can be assessed by measurement of several endpoints of 
metabolic activity (microflora-associated characteristics\70\), the 
petitioner measured microflora-associated characteristics to provide 
additional information on the effect of the presence of olestra in the 
colon on normal bacterial metabolism.

    \70\Microflora-associated characteristics include degradation of 
beta-aspartylglycine and mucin, conversion of cholesterol and 
bilirubin to their respective metabolites, inactivation of trypsin, 
and production of short-chain fatty acids (SCFA).
---------------------------------------------------------------------------

    The breath gas study was a parallel, double-blind, placebo-
controlled study 5 weeks in length. The subjects were 97 normal healthy 
males and females from 18 to 58 years of age. Subjects were randomly 
assigned to four treatment groups. Following an 8-day baseline period 
during which subjects consumed a placebo breakfast low in dietary 
fiber, they were fed breakfast meals daily containing moderate (7 g) or 
high (24 g) levels of fiber, with 24 g of either olestra or 
triglyceride for 28 days. Breath gas and fecal samples were collected 
at the end of the baseline period and at the end of the test period. 
The breath gas samples were analyzed for hydrogen and methane. The 
fecal samples were examined for viable microbial counts and direct 
microscopic cell counts for fecal bacteria. (Fecal bacteria have been 
demonstrated to be directly representative of the indigenous human 
intestinal microflora and their metabolic activities.) In addition, the 
fecal samples were analyzed for microflora-associated characteristics.
    The petitioner concluded that, although there was a trend toward 
lower breath hydrogen production in the olestra groups (20 percent 
reduction in the olestra high fiber group compared to placebo high 
fiber group) there were no statistically significant differences in 
cumulative breath hydrogen production between olestra and placebo 
groups. Further, the petitioner stated that olestra did not affect the 
total number of direct or viable counts of the fecal microflora. The 
petitioner also stated that olestra had no statistically significant 
effect on cumulative breath methane production following consumption of 
either the moderate or high fiber meal and that breath methane 
production values for individuals in the olestra groups were similar to 
individual values in the respective placebo groups.
    According to the petitioner, olestra had no effect on fecal 
microbial counts, and did not interfere with the normal degradation of 
beta-aspartylglycine, mucin, or trypsin. The concentration and 
distribution of short chain fatty acids (SCFA) was not consistently or 
significantly affected by olestra, indicating the absence of an adverse 
effect on microbial metabolism. Finally, the petitioner stated that 
urobilinogen and coprostanol concentrations were not adversely affected 
by olestra consumption. The petitioner concluded that the results of 
this study demonstrate that olestra will not interfere with normal 
intestinal fermentation of dietary fiber.
    FDA notes that the best direct information on microbial imbalances 
of concern would have been adequate direct microscopic cell counts and 
viable cell counts. Although these tests were performed, the data 
cannot be used due to improper handling of the samples (Ref. 92). The 
study did show that the microflora-associated characteristics that are 
generated by the majority of the bacterial genera found in the colon 
(e.g., the proteases, peptidases) and production of SCFA were not 
affected or only slightly affected by the presence of olestra in the GI 
tract. However, FDA's analysis of the data further shows lowering of 
hydrogen breath gas in some subjects, appearance of undergraded mucin 
in some subjects, a reduction of microbial formation of coprostanol 
from cholesterol, and reduced bilirubin conversion in those subjects 
consuming olestra (Ref. 92). FDA notes that these variations in 
microflora-associated characteristics are not different from those 
observed from dietary changes, for example, from low to high fiber 
diets, and that there are large variations in normal healthy subjects 
with respect to microflora-related parameters (Ref. 93). In addition, 
although there was some dampening of hydrogen production when olestra 
was added to a high-fiber diet, this dampening was not significant.\71\

    \71\Statement of Dr. Joanne Lupton, Transcript, vol. 4, p. 87.
---------------------------------------------------------------------------

2. Potential for Intestinal Microflora to Metabolize Olestra
    The petitioner stated that the pivotal studies that demonstrate 
that olestra is not metabolized by microflora in the GI tract are a 
clinical study in humans and the rat absorption and metabolism 

[[Page 3158]]
studies. The clinical study showed no production of radiolabeled 
metabolic breakdown products, and no changes in either olestra fatty 
acid composition or ester distribution following incubation of 
radiolabeled olestra with fecal microflora from humans who consumed 7 
g/d olestra for up to 31 days.
    As noted, in the rat absorption studies, virtually all radiolabel 
was recovered in feces and GI contents, with insignificant amounts 
recovered as metabolic byproducts in CO<INF>2, urine, and tissues after 
animals were fed olestra for 28 days and then dosed with radiolabeled 
olestra.
    The petitioner also submitted a published study (Ref. 94) that 
demonstrates that olestra is not metabolized by the microflora of the 
GI tract. In this study, radiolabeled (<SUP>14C-fatty acids) olestra 
was incubated for 72 hours in either minimal or organically enriched 
anaerobic media inoculated with feces from seven healthy subjects who 
had consumed 9 g/d of olestra for 3 to 4 weeks. The petitioner stated 
that no significant quantities of <SUP>14CO<INF>2, <SUP>14CH<INF>4, or 
<SUP>14C-volatile fatty acids were detected during the incubation, 
indicating that olestra was not metabolized by colonic microflora. At 
the Olestra Working Group and FAC meetings, the petitioner also pointed 
out that human gut microflora have never adapted to breakdown fat or 
cellulose. In addition, the petitioner reasoned that because the 
breakdown of fat requires beta oxidation, which requires oxygen, it is 
unlikely that in the anaerobic environment of the human intestine, 
microorganisms will adapt to metabolize olestra.\72\

    \72\Transcript, vol. 1, p. 152. Accordingly, the petitioner 
concluded that there was no evidence of degradation of the olestra 
(i.e., no change in ester distribution or fatty acid composition) by 
intestinal microflora.
---------------------------------------------------------------------------

    FDA notes that there is a hypothetical possibility that an organism 
capable of metabolizing olestra at a low level could arise among the 
intestinal microflora (Ref. 95). The in vitro study on minimal medium 
did suggest that olestra might be metabolized by microflora at a low 
level when olestra is the only carbon source (Ref. 95). Such conditions 
are unlikely to exist in the intestinal tract. Because of the 
possibility that olestra might be metabolized, FDA asked Dr. Joann 
Lupton, a consultant for FDA who specializes in the effect of diet on 
the GI tract, to review the breath gas and in vitro studies. Dr. Lupton 
did not observe any metabolism of olestra by microflora.\73\ Dr. Lupton 
concluded that because no long chain fatty acids were released from the 
olestra, and because the olestra was actually recovered without any 
change in chain length or degree of saturation, olestra is not 
metabolized by the microflora (Refs. 96 and 97). Further, given the 
findings in the human and animal material balance studies (discussed in 
section III.A of this document), which showed that olestra was excreted 
quantitatively and was unchanged in the feces, FDA believes that the 
available evidence shows that there is no metabolism of olestra by the 
intestinal microflora.

    \73\Statement of Dr. Joanne Lupton, Transcript, vol. 2, pp. 216-
226.
---------------------------------------------------------------------------

D. Effect of Olestra on Bile Acid Metabolism

    The petitioner submitted several published and unpublished studies 
in animals and humans to demonstrate that consumption of olestra will 
have no meaningful effect on the absorption, synthesis or excretion of 
bile acids. The studies included: (1) A 2-year rat study where olestra 
was fed at 5 percent of the diet and total fecal bile acid excretion 
was measured after 1, 2, and 24 months; (2) a study in rats on the 
effect of olestra on the absorption of chenodeoxycholic acid, one of 
the more lipophilic bile acids; (3) studies on the effect of olestra on 
bile acid excretion in humans ingesting 8 to 40 g/d olestra for 30 days 
or 90 g/d olestra for 37 to 55 days; (4) a study in rats on olestra s 
effect on biliary acid profiles; and (5) a study examining the effect 
of olestra on bile acid pool size and bile composition in African Green 
Monkeys.
    The petitioner stated that olestra had no effect on the rate of 
recovery or the amount of chenodeoxycholic acid, that neither bile acid 
synthesis nor excretion are affected by olestra, that the absorption of 
bile acids is not affected by olestra, and that olestra had no effect 
on biliary or fecal bile acid profiles.
    FDA reviewed the studies and, although some of the studies have 
limitations in experimental design or execution, has concluded that the 
studies as a whole show that olestra would not be expected to produce 
major changes in bile acid metabolism and absorption (Ref. 98).

E. Overall Conclusions on Effects on the GI Tract

    The issues of potential concern with respect to the effect of 
olestra on the GI tract are: (1) The potential for loose stools or 
diarrhea to result in electrolyte and fluid loss; (2) whether the GI 
effects have the potential to interfere with normal daily life of 
consumers, (3) whether the GI effects seen are of special concern to 
subpopulations where proper fluid control is important (e.g., 
individuals with underlying cardiovascular or GI diseases, the young 
and the elderly); and (4) whether changes observed in microflora-
associated characteristics associated with olestra consumption are 
meaningful to health.
    These issues were discussed at the meetings of the Olestra Working 
Group and the FAC. After presentation and discussion of the data 
relating to the potential GI effects that olestra may cause, most 
members of the Olestra Working Group and FAC, including all of the 
gastroenterologists, felt that there was reasonable certainty of no 
harm with respect to the potential for olestra to cause GI effects.\74\ 
These members felt that, while olestra may cause certain GI effects, 
including loose stools, these effects are not adverse effects because 
they do not threaten health. For example, effects described as 
``diarrhea'' were not diarrhea in the medical sense because they were 
not associated with water loss or electrolyte imbalance.

    \74\Transcript, vol. 3, p. 78 and vol. 4, p. 196.
---------------------------------------------------------------------------

    On the question of whether the ``diarrhea'' experienced by subjects 
was diarrhea in the medical sense, the petitioner presented additional 
data on fecal water content to the Olestra Working Group.\75\ (The 
study from which these data were derived is described in more detail in 
section VI.3. of this document). According to the petitioner, the 
results of the study showed that, even in olestra-consumers 
experiencing what they described as diarrhea, these subjects had no 
change in the stool water content, and also, no change in electrolytes 
or the pH of the stool; the only difference was that the stools of 
these subjects had more lipid, which was completely accounted for by 
the olestra consumed. Dr. Lawrence Johnson, a gastroenterologist member 
of the Olestra Working Group, agreed with the petitioner's analysis and 
stated that when one looks at stool by weight, the gross weight will 
increase because olestra is not absorbed and increases the weight of 
the stool. (Increased stool weight is one criterion for diarrhea.) Dr. 
Johnson added that one would next determine whether fat or fluid is 
responsible for stool weight increase. He noted that the amount of 
fluid in the stool was about 200 cc, which is the amount that would be 
in stool in normal physiologic amounts.\76\ Dr. Joanne Lupton, the FDA 
consultant on GI issues, added that, in looking at the clinical data, 
the larger the proportion of the stool that is olestra, the softer the 

[[Page 3159]]
stool is going to be but that there is no evidence of dehydration, or 
electrolyte imbalance in those subjects reporting ``diarrhea''.\77\

    \75\Transcript, vol. 1, p. 112.
    \76\Statement of Dr. Larry Johnson, Professor of Medicine and 
Director of the Digestive Diseases Division, Uniformed Health 
Service University, Transcript, vol. 4, p. 83.
    \77\Statement of Dr. Joanne Lupton, Transcript, vol. 3, p. 89.
---------------------------------------------------------------------------

    In addition, at the Olestra Working Group and FAC meetings, the 
question of whether olestra in the feces represented steatorrhea was 
raised. Drs. A. R. Colon and J. S. DiPalma\78\ stated that initial 
human studies on olestra revealed steatorrhea, in addition to diarrhea, 
as an apparent dose-related side effect and that there were no data 
that assessed 72-hour fecal fat excretion or dose-steatorrhea 
correlations. In response to a question of whether the effects seen 
with olestra are steatorrhea and not diarrhea, the petitioner stated 
that the effects seen with olestra are unrelated to steatorrhea, which, 
according to the petitioner, is the presence of unabsorbed free fatty 
acids in the lower bowel which results in an osmotic and an 
inflammatory and irritative response in the bowel.\79\ The petitioner 
stated that the only identified change between feces from subjects 
consuming olestra and those consuming triglyceride was that the lipid 
content of the stool in the olestra group was increased, an expected 
result because olestra is not absorbed and is excreted in the feces. 
The petitioner added that their analysis showed that there was no 
additional lipid in the stool of subjects consuming olestra.\80\ Dr. 
Joanne Lupton agreed that the available data do not reflect any 
steatorrhea.\81\

    \78\Letter from Drs. A. R. Colon and J. S. DiPalma, Georgetown 
University Medical Center, read at the FAC meeting; Transcript, vol. 
3, p. 19.
    \79\Statement of the petitioner, Transcript, vol. 1, p. 141.
    \80\Transcript, vol. p. 97.
    \81\Statement of Joanne Lupton, Transcript, vol. 3, p. 24.
---------------------------------------------------------------------------

    FDA notes that steatorrhea (the passage of large amounts of fat in 
stool) usually occurs in conjunction with pancreatic disease and 
malabsorption syndrome. FDA has reviewed the data on the lipid content 
in feces of subjects consuming olestra and concludes that there was no 
evidence of steatorrhea in any subject in the study (Ref. 99). Most 
members also felt that consumers can deal with the GI effects of 
olestra in the same manner as similar effects caused by other 
foodstuffs in the food supply, i.e., by limiting intake of the material 
causing the effect. For this reason, most members felt that foods 
containing olestra should be labeled in a manner to alert consumers to 
the potential GI effects of olestra but also in a manner that will not 
preclude the consumers from seeking health care for more serious 
concerns. (Labeling for olestra is discussed in more detail in section 
VII. of this document.)
    Based upon the available data and information, FDA concludes that 
consumption of olestra causes GI symptoms such as bloating, loose 
stools, abdominal cramps, and diarrhea-like symptoms. There is no clear 
association between the onset of these effects and time of ingestion. 
In some cases, the effects occurred the few first days of consuming 
olestra products; in others, such products were consumed for several 
weeks before effects were seen. In addition, there were some people in 
whom the effects never were reported. With some consumers, the olestra-
induced effects were seen at low olestra doses and with others, it took 
a higher dose to elicit the effects. In addition, the agency notes that 
few individuals reporting GI symptoms in the olestra clinical studies 
dropped out of the studies because of the symptoms and that study 
subjects were able to carry out their daily functions while they were 
on the studies.
    While olestra caused GI effects such as those mentioned above, 
there is no evidence that these effects represent adverse health 
consequences. The effect of olestra on stool consistency is similar to 
that produced by liquid petrolatum, which softens fecal contents and 
interferes with the development of firm, well-formed stools. The 
``diarrhea'' experienced by the study subjects was not diarrhea in the 
medical sense because it was not associated with loss of water or 
electrolytes. Indeed, those subjects who experienced loose stools or 
diarrhea continuouslypara.for several weeks during olestra consumption 
did not show any evidence of fluid loss such as hemoconcentration or 
electrolyte imbalance. This is consistent with published studies (Refs. 
80 and 81) that show that olestra does not significantly alter gastric 
emptying or overall GI transit time.
    With respect to whether olestra's potential to cause diarrhea-like 
symptoms or loose stools raises concern for special subpopulations 
where proper fluid and electrolyte control is important, FDA notes 
that, as discussed above, the soft stool and ``diarrhea'' appear to be 
caused by disruption of the fecal matrix and are not associated with 
clinical signs of fluid loss, which is the case in classical diarrhea. 
Therefore, FDA has determined that there is no basis to conclude that 
these subpopulations would be at special risk due to consumption of 
olestra.
    FDA recognizes that nutritionists generally do not recommend 
reduced-calorie products for consumption by children. Nevertheless, 
there is the potential that olestra-containing products may be eaten by 
children. Although the studies FDA reviewed with respect to the effect 
of olestra on GI symptoms in the young were not sufficiently long, FDA 
notes that the GI physiology of children older than approximately 9 
months is comparable to that of adults\82\ (Ref. 100). Therefore, FDA 
concludes that there is no basis to conclude that the effect of olestra 
on the GI tract would be any different in children than in adults, and 
thus, the results of studies conducted in adults to address the effects 
of olestra consumption on the GI tract can be extrapolated to the young 
(Ref. 101).

    \82\Statements of Drs. Charles Hargrove and Dr. William Klish, 
Transcript, vol. 2, pp. 226 and 260, respectively.
---------------------------------------------------------------------------

    With respect to differences seen in microflora-associated 
characteristics as a result of olestra consumption, FDA notes that such 
variations are no different than those observed with other dietary 
changes (for example, from low to high fiber diets), and that there are 
large variations in normal healthy subjects with respect to microflora-
related parameters. Also, FDA believes that the available evidence 
shows that there will be no significant metabolism of olestra by the 
intestinal microflora. Therefore, FDA concludes that, collectively, the 
data do not establish an adverse effect of olestra consumption on 
microbial metabolism or function.
    Notwithstanding the fact that FDA finds no safety concerns with 
respect to the effect of olestra on the GI tract, FDA believes that it 
is important for consumers to be aware of the GI symptoms associated 
with ingestion of olestra-containing foods so that they are able to 
associate olestra with the GI symptoms that it may cause. This 
information would also preclude unnecessary concerns and inappropriate 
medical treatment. Appropriate labeling for olestra-containing foods is 
discussed in section VII. of this document.

VII. Labeling of Foods Containing Olestra

    As discussed above, because olestra is not absorbed and passes 
through the GI tract intact, it affects the absorption of certain fat-
soluble vitamins and nutrients, which partition into it. Olestra also 
has the potential to cause certain GI effects such as abdominal 
cramping and loose stools. The agency has considered whether these 
effects warrant special labeling of foods containing olestra. As 
discussed in detail below, FDA has determined that 

[[Page 3160]]
foods containing olestra shall be labeled with the following statement:
    This Product Contains Olestra. Olestra may cause abdominal 
cramping and loose stools. Olestra inhibits the absorption of some 
vitamins and other nutrients. Vitamins A, D, E, and K have been 
added.

A. Labeling Authority

    Under the act, the agency has the mandate to ensure that labeling 
provides truthful and nonmisleading information to consumers. Thus, the 
law provides the agency with authority to require specific label 
statements when needed for reasons other than to ensure the safe use of 
food.\83\ Specifically, section 409(c)(3)(B) of the act (21 U.S.C. 348 
(c)(3)(B)) prohibits FDA from approving a food additive if the proposed 
use would result in the misbranding of food within the meaning of the 
act (21 U.S.C. 348(c)(3)(B)). Under section 403(a)(1) of the act (21 
U.S.C. 343(a)(1)), a food is misbranded if its labeling is false or 
misleading in any particular.

    \83\Under section 409(c)(1)(A) of the act (21 U.S.C. 
348(c)(1)(A)), the agency has the authority to prescribe the 
conditions of safe use of a food additive, including the authority 
to require label statements needed to ensure safety. Thus, in a food 
additive regulation, the agency may rely on this provision for 
requiring statements to appear on labels of products containing food 
additives. In the case of olestra, however, FDA is not requiring the 
labeling of olestra-containing foods in order to ensure the safe use 
of olestra.
---------------------------------------------------------------------------

    Section 201(n) of the act (21 U.S.C. 321(n)) amplifies what is 
meant by ``misleading'' in section 403(a)(1) of the act. Section 201(n) 
of the act states that in determining whether labeling is misleading, 
the agency shall take into account not only representations made about 
the product, but also the extent to which the labeling fails to reveal 
facts material in light of such representations made or suggested in 
the labeling or material with respect to consequences which may result 
from use of the article to which the labeling relates under the 
conditions of use prescribed in the labeling or under such conditions 
of use as are customary or usual (see 21 CFR 1.21). Thus the omission 
of certain material facts from the label or labeling of a food causes 
the product to be misbranded within the meaning of 21 U.S.C. 343(a)(1) 
and 321(n). In general, the agency believes the concept of ``material 
fact'' is one that must be applied on a case-by-case basis. The agency 
has required special labeling in cases where information is necessary 
to ensure that consumers are aware of special health risks associated 
with consumption of a particular product. For example, although protein 
products intended for use in weight reduction are not inherently 
unsafe, FDA requires a warning statement for such products that states, 
in part, that very low calorie protein diets may cause serious illness 
or death. Another example of required information is the use of the 
term ``milk derivative'' following the ingredient declaration of sodium 
caseinate when used in a product labeled ``non dairy'' (21 CFR 
101.4(d)).
    FDA believes that such a labeling statement is appropriately 
established as part of the rulemaking for a food additive approval 
under section 409 of the act. As noted, under section 409(c)(3)(B) of 
the act a food additive regulation cannot issue if the available data 
show that ``the proposed use of the additive would *** result in *** 
misbranding of food within the meaning of the Act.'' Thus, the status 
of foods containing a particular additive, in terms of misbranding 
under the act, is always an issue to be considered and determined by 
the agency for each food additive petition. (In most cases, the 
proposed use of the additive presents no issue regarding misbranding of 
foods that contain the additive.) Accordingly, the notice of filing of 
a food additive petition published under 21 U.S.C. 348(b)(5) 
necessarily includes notice that proper labeling under the act of foods 
containing such additive is a question before the agency. In the case 
of olestra, the notice of filing published in the Federal Register of 
June 23, 1987 (52 FR 23606), was a public announcement that the olestra 
food additive petition had been filed, and that all issues regarding 
the approval of the proposed use, including the proper labeling of 
foods containing olestra, would be considered by FDA.\84\

    \84\FDA's regulation regarding the failure to reveal material 
facts, (21 CFR 1.21), states that ``affirmative disclosure of 
material facts *** may be required, among other appropriate 
regulatory procedures, by *** regulations in this chapter 
promulgated pursuant to section 701(a) of the act; or direct court 
enforcement action (emphasis added).'' Thus, establishing a 
requirement for a label statement for olestra-containing foods as 
part of a section 409 proceeding is consistent with 21 CFR 1.21.
---------------------------------------------------------------------------

    As discussed below, FDA has determined that all foods containing 
olestra should bear a label disclosing olestra's GI effects and its 
effects on nutrients, and disclosing that certain vitamins have been 
added back. The agency believes that these labeling statements can be 
imposed as final requirements as part of the food additive petition 
process of section 409 of the act, and that it is important that once 
approved, products containing olestra be properly labelled so as not to 
be misbranded. Thus, FDA is imposing an immediately effective labeling 
requirement. However, the agency acknowledges the importance of the 
opportunity for interested members of the public to express their views 
on the labeling for olestra. In addition, the petitioner, Procter & 
Gamble, intends conduct focus group testing of the required olestra 
label (Ref. 103). Accordingly, the labeling requirement for foods 
containing olestra, while immediately effective, is an interim 
requirement only. The agency requests comments on this label from 
interested persons, on such issues as the need for such labeling, the 
adequacy of its content, the agency's word choice, and the 
configuration of the label. Three copies of such comments shall be 
submitted to the Dockets Management Branch (address above) April 1, 
1996. FDA will then evaluate and respond to any comments received, as 
well as any studies or other information from focus group testing 
conducted by the petitioner. As noted below, under section 409(f)(1) of 
the act, interested persons have the opportunity to file objections to 
the final rule; such objections shall be filed within 30 days of the 
final rule, and shall conform to certain requirements in terms of 
format and content, which are articulated below. Commenters on the 
labeling for olestra who intend their comments to be treated and 
function as objections under section 409(f)(1) of the act shall conform 
to the time restrictions, format, and content requirements for 
objections. Any labeling comments received more than 30 days from the 
date of this final rule and any comments not otherwise conforming to 
the requirements for objections shall be considered by FDA as simply a 
comment and not an objection under 409(f)(1) of the act and addressed 
by the agency accordingly.-
    In these circumstances, FDA has concluded that it is appropriate 
for the agency to establish labeling requirements for olestra-
containing foods that are effective concurrent with the promulgation of 
a final rule regulating the additive.

B. Labeling with Respect to GI Effects

    As discussed in section VI. of this document, consumption of 
olestra may cause GI symptoms such as abdominal cramping and loose 
stools. However, there is no evidence that these effects represent 
adverse health consequences. As noted, the effect of olestra on stool 
consistency is similar to that produced by mineral oil, which softens 
fecal contents and interferes with the development of firm, well-formed 
stools. Further, the ``diarrhea'' experienced by the study subjects was 
not diarrhea in the usual medical sense because it was not associated 
with loss 

[[Page 3161]]
of water or electrolytes. Nonetheless, while the agency has concluded 
that based upon the evaluation of the available evidence there are no 
safety concerns with respect to the effect of olestra on the GI tract, 
the agency believes that consumers should be provided with information 
to enable them to associate olestra with the GI symptoms that it may 
cause. The agency believes that providing this information to consumers 
would preclude unnecessary concerns about the origin of GI effects, 
were they to be observed, and may also prevent unnecessary or 
inappropriate medical treatment of those symptoms. Accordingly, FDA has 
determined that the relationship between GI symptoms and consumption of 
foods containing olestra is a fact that is material in light of the 
consequences of consuming olestra in savory snacks. In such 
circumstances, this relationship must be disclosed to consumers 
consistent with sections 201(n) and 403(a)(1) of the act.

C. Labeling with Respect to Effects on Nutrients

    As discussed in section V. of this document, olestra interferes 
with the absorption of the fat-soluble vitamins A, E, D, and K and 
therefore, these vitamins will be required to be added to olestra-
containing foods to compensate for that amount of the vitamins that is 
not absorbed due to olestra's effects. As required under section 
403(i)(2) of the act, these vitamins will be declared in the ingredient 
listing.
    The added vitamins, however, may not be considered in determining 
nutrient content of the food for the nutritional label or for any 
nutrient claims, express or implied. This is because the added vitamins 
will simply compensate for the amounts lost due to decreased absorption 
of the vitamins from other foods but will not contribute significant 
amounts of these vitamins to the diet. In other words, the purpose of 
adding the four fat-soluble vitamins is to ensure that no significant 
change in vitamin availability (neither decrease nor increase) occurs.
    Olestra also decreases absorption of some lipophilic carotenoids, 
which can lead to lower serum levels of those nutrients. As noted, the 
agency has concluded that supplementing olestra with vitamin A will 
compensate for olestra's effects on the provitamin A function of 
carotenoids. Except for the provitamin A function (which is taken care 
of by addition of vitamin A), other specific health benefits for 
carotenoids have not been established.
    As noted, labeling may be considered misleading not only if it 
fails to reveal facts that are material in light of consequences which 
may result from use of a food, but also if it fails to reveal facts 
that are material in light of representations made. As discussed above, 
FDA concludes that no consequences will result from inhibition of 
lipophilic nutrients by olestra because vitamins A, D, E and K will be 
added back to compensate. However, the mandatory listing of these 
vitamins on the ingredient statement could confuse consumers by 
implying that the food would provide significant amounts of these 
vitamins. Therefore, FDA is requiring a statement indicating that 
olestra inhibits the absorption of vitamins and other nutrients to set 
the context for why they are added. FDA is including the term other 
nutrients because any nutrient that is as lipophilic as these vitamins 
would also be affected, although there is currently no basis for adding 
them back. Thus, in light of the disclosure in the ingredient statement 
that vitamins A, D, E, and K have been added, FDA has determined that 
the label statement explaining such compensation must be made.
    FDA is not requiring a specific statement on carotenoids in this 
labeling statement because doing so could falsely imply that their 
decreased absorption is known to be of significance. As stated 
previously, the current evidence does not show that inhibition of 
carotenoid absorption would result in any significant health 
consequences. This decision is consistent with FDA's policy for 
nutrient content claims, as required by 21 CFR 101.54. In that 
regulation, claims that a food is a ``good source'' of, ``high'' in, or 
contains ``more'' of a nutrient can be made only if the difference is 
significant with respect to a recommended daily intake (RDI) or daily 
reference value (DRV) for a nutrient, as established by regulation, so 
that consumers are not confused by implications that are of no 
nutritional significance. Such claims may not be made for substances 
for which a RDI or DRV has not been established. FDA believes that its 
policy concerning when a company may state that a food provides more of 
a nutrient should guide FDA in when it requires a company to disclose 
that a food would decrease availability of a nutrient. Therefore, FDA 
concludes that the label of foods containing olestra should not state 
that olestra inhibits the availability of carotenoids because to do so 
may imply that the inhibition of carotenoid absorption is of 
nutritional significance.

D. FAC Discussions Regarding Labeling

1. GI Effects
    Both the Olestra Working Group and the FAC discussed the importance 
of labeling that would disclose the association between olestra and the 
additive's potential GI effects. The FAC members agreed with the agency 
that it is important that consumers be able to associate the GI effects 
that olestra may cause with the additive. Committee members, however, 
recommended some amendments to a tentative label statement discussed at 
the FAC meeting (``Foods containing olestra may cause intestinal 
discomfort or a laxative effect'').
    First, members of the Committee suggested\85\ that the label read 
``Olestra may cause***'' instead of ``Foods containing olestra may 
cause***'' to make clear that the GI effects experienced are caused by 
the additive, olestra. The agency agrees that the suggested change 
results in a clearer and more succinct label, and thus is following 
this suggestion.

    \85\Transcript, vol. 3, p. 91.
---------------------------------------------------------------------------

    Second, some Committee members felt that significant increases in 
the frequency of GI effects were seen only at the higher olestra doses 
(20 and 32 g olestra/day) in the 8-week studies (see discussion in 
section VI.B.1 of this document) and therefore, that the label 
statement should be amended to state that it is excess consumption of 
olestra that may cause the GI symptoms.\86\ Others felt that a test of 
trends might show a dose-response effect, i.e., that the more olestra 
one consumes the more one experiences symptoms; in addition, 
significant differences might be observed at eight g/d olestra if the 
power of the study was increased sufficiently.\87\

    \86\Transcript, vol. 3, p. 93.
    \87\Transcript, vol. 3, p. 52.
---------------------------------------------------------------------------

    The agency agrees that there is a clear dose response effect with 
respect to olestra's ability to elicit GI effects. The agency also 
agrees that the lack of statistical difference between the placebo 
group and the eight g/d group in the two 8-week studies might be due 
only to the lack of power of the studies. In addition, the agency notes 
that consumption of 20 g/day olestra (equivalent to two 1-oz bags of 
potato chips, for example), for which there was a clearly significant 
difference from the placebo group with respect to GI effects, may not 
be considered excessive consumption by many consumers. As noted above, 
a scenario-driven estimate of 20 g/p/d, based on consumption of 2 oz of 
chips per day is a reasonable 

[[Page 3162]]
estimate of a ``short-term'' high consumer. Therefore, the agency does 
not agree that the label statement should be amended to indicate that 
only excessive consumption could lead to GI symptoms.
    Third, some Committee members expressed concern that the presence 
of a label statement could lead some consumers to disregard GI symptoms 
caused by factors other than olestra consumption and that erroneous 
attribution to olestra might unnecessarily cause them to delay 
consulting their healthcare provider.\88\ Therefore, several Committee 
members recommended that a second sentence be added to the proposed 
label to advise consumers that they should consult their healthcare 
provider should symptoms persist after consumption of olestra-
containing foods ceases.

    \88\Transcript, vol. 3, p. 90.
---------------------------------------------------------------------------

    Data submitted in the petition show that GI symptoms caused by 
olestra do not persist more than 2 days after consumption of olestra 
ceases. Thus, the agency agrees that persistent GI symptoms are 
unlikely to be related to consumption of olestra. Nevertheless, the 
agency believes that it should not require a label to bear information 
about medical advice unrelated to the food in the package.
    Finally, some Committee members questioned whether it is 
appropriate to refer to the stool softening effect of olestra as a 
``laxative effect.''-As discussed above, the effect of olestra on stool 
consistency is similar to that produced by mineral oil, an over the 
counter laxative that works by lubricating the intestinal tract, 
softening the fecal contents, and facilitating the passage of feces. 
However, unlike mineral oil, olestra would be consumed for a purpose 
other than its potential laxative effect. In this case, FDA believes 
that requiring use of the term laxative may imply the therapeutic use 
of a laxative.
    Therefore, instead of the term ``laxative effect,'' the agency 
believes it is more appropriate to use ``may cause loose stools'' on 
the label to indicate clearly to consumers, olestra's potential to 
affect stool consistency.
2. Fat-Soluble Vitamins and Carotenoids
    Some Committee members felt that consumers, upon seeing vitamins A, 
E, D, and K in the ingredient listing of olestra-containing foods, 
could be confused into thinking that the product is fortified with 
these vitamins. Therefore, they suggested that the ingredient list 
ought to contain a parenthetical note explaining that the vitamins were 
added to restore what would be lost due to olestra's interference with 
vitamin absorption.\89\ Other Committee members recommended that the 
agency handle this issue consistent with similar prior cases.\90\

    \89\Transcript, vol. 3, p. 218, 259, 261.
    \90\Transcript, vol. 3, p. 263.
---------------------------------------------------------------------------

    With respect to olestra's potential to decrease the bioavailability 
of carotenoids, most members of the Committee agreed with the agency 
that, given the current state of knowledge, the observed degree of 
reduction in carotenoid bioavailability does not raise concern. Given 
this conclusion, most Committee members further agreed that the effect 
of olestra on the bioavailability of carotenoids is not a fact material 
in light of consequences that may result from consumption of foods 
containing olestra and therefore, does not warrant disclosure on the 
labels of such foods.\91\ Others felt that it was necessary to inform 
consumers that consumption of olestra may lower serum carotenoid 
levels.\92\

    \91\Transcript, vol. 3, p. 271.
    \92\Transcript, vol. 3, p. 258.
---------------------------------------------------------------------------

    The agency notes that there are no prior cases on which to base how 
labeling with respect to the vitamins that are added to olestra-
containing foods might be handled. The agency has not previously 
approved an additive which interferes with the absorption of vitamins 
to a degree that necessitates requiring that foods containing the 
additive be compensated with such vitamins to mitigate the effect of 
olestra.
    As stated above, the agency believes that consumers who see the 
added vitamins listed on the ingredient listing could be misled and 
believe that the food is fortified with the vitamins unless they are 
given information explaining why the vitamins are added to the olestra-
containing food. Therefore, the agency believes that the fact that the 
olestra inhibits vitamin absorption and that vitamins have been added 
back are material facts that should be disclosed to consumers.

E. Agency Conclusions Regarding Labeling of Foods Containing Olestra

    Based on the entire record before the agency, FDA has concluded 
that foods containing olestra should bear the following label 
statement:
    This Product Contains Olestra. Olestra may cause abdominal 
cramping and loose stools. Olestra inhibits the absorption of some 
vitamins and other nutrients. Vitamins A, D, E and K have been 
added.
    In the absence of such labeling, the agency would consider olestra-
containing foods to be misbranded (21 U.S.C. 343(a) and 321(n)). FDA 
believes that this information will be used by consumers both in their 
decisions on purchases and to help them adjust their consumption to 
minimize side effects. To ensure that the required labeling statement 
will be readily recognized and easy to read, FDA is requiring a 
standardized format that specifies among other things, type style and 
type size. FDA's recent experience with graphic requirements for the 
new Nutrition Facts label, as well as focus group discussions of the 
new Nutrition Facts label requirements, show that messages put in a 
boxed area help consumers distinguish the message from other 
information as well as draw attention to it (see 60 FR 67176 at 67181, 
December 28, 1995). Therefore, FDA is requiring that the message on the 
label of olestra-containing foods be surrounded by a box. Additionally, 
FDA is also specifying the minimum type size to ensure proper 
prominence. FDA welcomes any comments on the adequacy of this label 
requirement, including the format, as it reassesses this interim rule.
    The agency would not object to any additional truthful 
nonmisleading information that a manufacturer may wish to include in 
the label statement, including, for example, a telephone number that 
consumers can call to obtain additional information regarding GI 
effects caused by olestra or olestra's effect on the absorption of fat-
soluble nutrients.

VIII. Response to Comments

    FDA received approximately 2,300 comments on the olestra petition. 
Comments were received from health care professionals, scientists, 
nutritionists, members of academia, consumer organizations, and 
professional associations as well as individual consumers. These 
comments, together with the Olestra Working Group and the FAC 
deliberations on the issues raised by the comments, have been taken 
into account in FDA's final decision on the olestra petition.
    Most of the comments opposing olestra's approval (about 2,000 
comments) were from individual consumers who identified themselves as 
members of CSPI and simply stated that fat substitutes must be 
absolutely safe and urged the agency to reject the ``petition to 
approve the unsafe fat substitute olestra.'' These comments did not 
provide any factual information or any rationale to support the opinion 
expressed. Because these comments raise no factual issue, they will not 
be discussed further.

[[Page 3163]]

    Most of the remaining comments opposing olestra's approval (the 
majority of which were form letters with some of the writers declaring 
affiliation with CSPI) expressed similar views on one or more of the 
following issues that were discussed extensively at the meetings of the 
Olestra Working Group and the FAC: (1) The potential for olestra to 
cause GI effects (including the nature of the GI effects); (2) the 
potential for olestra to deplete fat soluble vitamins, carotenoids, and 
other phytochemicals, and para.whether such depletion increases the 
risk for certain cancers and other diseases such as coronary heart 
disease, stroke, macular degeneration, and other eye diseases; (3) 
whether adding vitamins to olestra-containing foods to compensate for 
depletion is efficacious or raises vitamin toxicity issues; (4) whether 
olestra, with or without supplemented vitamin K, interferes with 
coumadin therapy; (5) whether labeling with respect to GI issues and 
nutrient issues should be required for foods containing olestra 
(including the nature of the information that should be included in the 
label statement); (6) adequacy of the length of the studies to assess 
long term effects of olestra consumption and whether adequate studies 
have been conducted in special populations; (7) whether liver lesions 
seen in two rat studies and lung tumors in one mouse study are 
meaningful to human health; (8) whether vitamin A-supplemented olestra 
raises teratogenic concerns; and (9) whether the petitioner's estimates 
of olestra intake from savory snacks are credible.
    Because the agency's analysis of these comments has already been 
incorporated at the appropriate places throughout this document, that 
analysis will not be repeated here. Comments raising issues that have 
not been previously discussed in this document and the agency's 
responses are given below.
    The agency also received many comments supporting the approval of 
olestra. These comments were from individual consumers as well as 
scientists, clinicians, and nutritionists. Several of the comments 
cited problems with obesity in the population and the need for a fat 
replacer such as olestra and that the health benefits from lower fat 
intake far outweigh the perceived adverse side effects. These comments 
stated that under the intended conditions of use, olestra is safe and 
that it provides those who wish to use products made with olestra with 
an option for low fat, low saturated fat salty snacks. One comment 
signed by nine scientists and clinicians countered point-by-point 
arguments made in the CSPI White Paper; the comment added that their 
in-depth review of the olestra research program shows that olestra is 
safe for use as a fat replacer. Other comments stated that the Olestra 
Working Group and FAC meetings were conducted in an open and fair 
manner, that the meetings permitted a thorough exchange of scientific 
information, that all issues were adequately addressed, and that the 
commenters concurred with the majority of the FAC members who concluded 
that olestra was safe for its intended use.

A. Comments on Procedures

    CSPI made several comments about the agency's process for review of 
the olestra petition. None of these procedural comments raise issues 
regarding the olestra safety data. Nevertheless, because the agency 
greatly values public participation and has provided a substantial 
opportunity for such participation regarding FDA's review of the 
olestra petition, FDA is addressing these procedural comments in this 
preamble. Importantly, however, none of these comments, even if 
correct, undermines the agency's safety determination here.
    1. One comment from CSPI stated that the period allotted for 
comments following the Olestra Working Group and FAC meetings of 
November 14 through 17, 1995, was unjustifiably brief. The comment 
added that the comment period was too brief a time for review of 
transcripts and other data to prepare a thoughtful and complete 
postmeeting comment. The comment suggested that an additional 50 days 
be provided for comment.
    The point raised by this comment is moot because FDA granted CSPI 
additional time (Ref. 105) to prepare its comments. The agency notes 
that CSPI did submit extensive comments prepared after the Olestra 
Working Group and FAC meetings on December 1, 1995, the date for 
submission of comments announced in the Federal Register of November 
16, 1995 (60 FR 57586), the deadline to which CSPI objected. The agency 
granted CSPI additional time because the agency accepted CSPI's 
representation that it needed additional time to obtain and review a 
new study presented by the petitioner at the Olestra Working Group and 
FAC meeting, and to prepare comments on the study. The data were 
delivered to CSPI on December 8, 1995, with the letter extending the 
time for submission of comments (Ref. 105). FDA notes that CSPI 
submitted additional comments on December 21, 1995, but that these 
additional comments did not mention the new study.
    2. One comment from CSPI asserted that FAC members could not reach 
well-reasoned positions because they did not receive copies of CSPI's 
White Paper until noon on Friday, November 17, 1995.
    The agency believes that both Working Group and FAC members had 
sufficient access to CSPI's White Paper and the organization's views 
and thus, FDA does not agree with this comment. FDA distributed copies 
of a revised draft that the agency had received from CSPI the week 
preceding the November meetings to each Olestra Working Group member, 
guest, or consultant prior to convening of the Olestra Working Group 
meeting. Nine FAC members served on the Olestra Working Group and 
received copies of the CSPI White Paper. Also, several other FAC 
members attended part or all of the Olestra Working Group meeting and 
therefore, heard CSPI's presentations and responses to questions during 
the Working Group meeting. Thus, the assertion that no Committee member 
had access to or time to consider CSPI's views prior to noon on Friday, 
November 17, 1995, is incorrect.\93\

    \93\In addition, CSPI itself selectively sent a draft of the 
White Paper document to 11 of the standing 18 FAC members who 
participated in the Friday, November 17, 1995, meeting. (This direct 
distribution was squarely contrary to the applicable regulations, 21 
CFR 14.35(d).) Of the other seven, two were also members of the 
Working Group and received copies of the revised draft on the first 
day of that meeting. Three of the seven attended the Working Group 
meeting (and therefore heard CSPI's oral presentations). Only 2 of 
the 18 FAC members potentially were unaware of CSPI's written or 
oral views until the public hearing on the morning of Friday, 
November 17, 1995.
---------------------------------------------------------------------------

    Finally, it is important to consider the roles of the FAC and the 
Olestra Working Group. The Olestra Working Group was composed of FAC 
members with expertise directly relevant to the safety issues for 
olestra and of additional temporary members with needed expertise not 
available from standing FAC members. FDA fully expected that this 
specialized subgroup would conduct the focused consideration of the 
olestra petition; under the FAC charter, however, subgroup views can 
only be passed on to FDA through the full FAC. Thus, the purpose of the 
FAC meeting was to apprise FAC members of the Working Group discussion, 
and for the FAC to consider whether to pass the Working Group views on 
to FDA, to pass the views on with additional commentary, or to return 
the matter to the Working Group for further discussion.
    3. One comment from CSPI challenged the way in which 

[[Page 3164]]
    consultants and special, temporary members were appointed to the 
Olestra Working Group and FAC. CSPI contended that FDA failed to 
consider experts on vitamin K and carotenoids that CSPI had suggested 
for the Olestra Working Group, and that FDA did not appoint any other 
experts in those subject areas to either the Working Group or the FAC. 
CSPI alleged that therefore, the FAC was ill-prepared to discuss these 
matters.
    The agency carefully considered CSPI's suggested experts on 
carotenoids and vitamin K. However, several of these experts had 
already provided written views on the issues to CSPI (apparently in 
response to a solicitation by CSPI). Statements by some of these 
experts were included as part of CSPI's mailing to selected FAC 
members, and statements by some or all of these experts were included 
in materials distributed during the Olestra Working Group and FAC 
meetings. Because the individuals appear to have had previously 
established views regarding olestra, FDA concluded that they could not 
appropriately be included in the Olestra Working Group. Furthermore, 
there is no reason to believe that the nutrition (10 members or 
consultants) and toxicology (3 members) experts participating at the 
Committee meeting were not able to comprehend or interpret the 
information and views on carotenoids and vitamin K presented orally or 
in writing by experts on behalf of either CSPI or the petitioner.
    4. Another comment from CSPI argued that Dr. Fergus Clydesdale was 
an inappropriate choice as chair of the Olestra Working Group, 
asserting that Dr. Clydesdale had a pro-industry stance.
    First, it is significant to note that CSPI does not allege that Dr. 
Clydesdale conducted the Olestra Working Group meeting unfairly or did 
not allow for an open and orderly exchange of views. Second, FDA notes 
that all advisory committee members undergo an evaluation for conflicts 
of interest with respect to specific issues to be presented to a 
committee. Dr. Clydesdale was subjected to that review, and his 
participation was ultimately determined to be consistent with the 
applicable conflict of interest laws and regulations.
    5. A comment from CSPI asserted that FDA's interpretation of 
conflict of interest is too restrictive in that it only applies to 
interests in the petitioner or its competitors. CSPI would disqualify 
any member who holds strong views, pro or con, regarding the food 
industry or food additives.
    FDA believes that the agency's policies, procedures, and practices 
comport with the applicable conflicts of interest laws and regulations 
and thus, disagrees with CSPI's comment on this point.
    6. CSPI also claimed that the amount of time Olestra critics were 
allotted at the Olestra Working Group and Committee meetings was 
insufficient in contrast to the ``ample amounts'' of time given to the 
petitioner and to FDA staff.
    FDA disagrees with this comment for several reasons. -First, the 
agency believes that the appropriate question is whether there was 
ample opportunity for public participation, not whether a particular 
participant had enough time. Second, CSPI was provided with substantial 
opportunities to present its views to both the Olestra Working Group 
and Committee, much more than customarily provided to any single group 
or individual during advisory committee public hearings and much more 
than that provided to any other group or individual during the public 
hearing portions of the meetings.
    FDA notes that at a typical advisory committee meeting concerning a 
product approval application or petition, FDA presents its analysis of 
the data, and the applicant/petitioner is permitted to ``defend'' its 
application or petition. Although there is always a public hearing 
portion to the meeting, the bulk of the meeting is devoted to Committee 
discussion, including questioning by committee members of FDA, the 
applicant/petitioner, or other presenters.
    FDA policy is to provide a minimum of 1 hour of public hearing time 
at each advisory committee hearing. Because of the substantial interest 
in olestra, and because FDA desired comments focussed on specific 
issues, considerably more public hearing time that the minimum was 
allotted. (A total of nearly 6 hours of public hearing time occurred 
during the Olestra Working Group and FAC meetings.) A significant 
portion of that time was allotted to CSPI or other participants who 
presented views consistent with those of CSPI. In addition to time 
specifically allotted to it, CSPI was permitted to respond to questions 
posed by the Working Group and the FAC. Finally, CSPI participated in 
an unscheduled public hearing session along with the petitioner near 
the close of the FAC meeting.
    7. One comment urged that the FAC should be reconstituted because 
of a perceived strong pro-industry orientation of its members and Dr. 
Clydesdale (chair of the Working Group), and the ``lack of consumer 
health activists.'' The comment added that advisory committees should 
include ``a preponderance of public-health advocates'' in order to 
provide the best advice to the agency.
    FDA disagrees with this comment. FDA appoints Committee members 
based on their scientific, medical, or other technical expertise, 
members are screened before each meeting with respect to conflict of 
interest in the particular matters to be brought before them, and 
members are expected to provide an unbiased evaluation of the 
information presented to them. Furthermore, consumer representatives 
were members of both the Working Group and the FAC, members who were 
nominated by a consumer consortium for consideration by FDA. Finally, 
the FACA requires that advisory committees be fairly balanced. The 
agency believes that both the Working Group and the FAC meet this 
standard. Thus, FDA does not agree with this comment.
    8. One comment from CSPI stated that the Committee could not 
formulate well-reasoned positions because CFSAN staff failed to provide 
Committee members with a study published in the American Journal of 
Clinical Nutrition 2 months earlier demonstrating that 3 g of olestra 
caused remarkable declines in serum carotenoid levels, and a second 
study published in the New England Journal of Medicine in early 
November that found a strong correlation between low lycopene levels in 
blood and optic neuropathy. In addition, the comment stated that CFSAN 
staff failed to mention that olestra caused premature liver foci in 
rats and a statistically significant increase in lung tumors in male 
mice and further failed to provide any evidence that carotenoids may 
reduce the risk of cancer, cardiovascular diseases, and age-related 
macular degeneration.
    The agency disagrees with this comment in its entirety. First, with 
regard to the first published study, the agency notes that the effect 
of olestra on serum carotenoids was discussed at length at the Olestra 
Working Group and FAC meeting. Not only were the results of the study 
cited by the comment presented by CSPI, a study conducted by the 
petitioner showing olestra effects on serum carotenoids that were much 
greater than those shown in the cited study were presented by FDA.
    With regard to the second published study, FDA notes that CSPI and 
other presenters submitted and presented detailed information regarding 
the potential relationship between carotenoids and disease, and after 
consideration of this information, most Olestra Working Group and FAC 
members determined that there is a reasonable certainty of no harm with 


[[Page 3165]]
respect to olestra's effects on serum carotenoids.
    Finally, with regard to liver foci and lung tumors, FDA presented 
data on olestra's effect on liver foci in rats and in on lung tumors in 
male mice. In addition, this topic was thoroughly discussed at the 
Olestra Working Group and FAC meetings.

B. Substantive Comments

    9. One comment questioned whether an acceptable daily intake (ADI) 
based on a ``no observed-effect level'' has been established for 
olestra. One comment asserted that even applying even a minimal safety 
factor of 10 to the 8 g/d consumption level tested by the petitioner, 
and at which carotenoids were depleted by up to 60 percent within 2 
weeks after the start of olestra consumption, would preclude the 
approval of olestra for use in snack foods, because the estimated daily 
intake (EDI) would greatly exceed the 0.8 g/d ADI.
    The agency acknowledges that it has not established a numerical 
value for an ADI for olestra. First, as noted earlier, safety factors 
are applied to toxic effects observed in animal studies; the purpose of 
the safety factor is to allow for any discrepancy when extrapolating 
from animals to humans. Because olestra is intended for use as a 
macroingredient, it is not possible to feed it to test animals at 
sufficiently high amounts to elicit toxic effects and thereby establish 
an ADI using the traditional 100-fold safety factor. The agency notes, 
however, that no toxic effects were observed when test animals were fed 
olestra at up to 10 percent of the diet. Furthermore, as discussed at 
length in this preamble, the clinical data establishing the safety of 
olestra for its intended use are nutrition studies conducted in humans 
to which the traditional 100-fold safety factor is not applied.
    With respect to olestra's effect to decrease serum carotenoid 
levels, the agency has concluded, as discussed in detail above, that 
based upon the available data, this effect does not represent an 
adverse health effect and therefore, cannot appropriately be used for 
establishing an ADI for olestra.
    10. A comment stated that the NCI and other public health leaders 
have been encouraging Americans to eat at least five servings a day of 
fruits and vegetables. The comment added that this advice is grounded, 
in part, on the presence of carotenoids in fruits and vegetables and 
the belief of senior scientists at the NCI and elsewhere on 
chemoprotective activities of carotenoids and similar nutrients. The 
comment asserted that if FDA were to approve olestra, it would be 
undercutting NCI's scientific judgement and stand in favor of 
protecting public health. Another comment stated, specifically with 
respect to the carotenoids and their potential importance, that the 
issue receive an impartial review by the National Research Council or a 
specially convened advisory group of researchers in the carotenoid 
field.
    FDA agrees with the comments that the issue with respect to the 
potential importance of carotenoids deserves special attention. This is 
why FDA convened a working group for olestra and the full FAC to 
examine the issue along with others. The Olestra Working Group and the 
full FAC were supplemented with appropriate experts in the field of 
nutrition; in addition, noted experts in the carotenoid field as well 
as epidemiology experts who could speak to the epidemiological data on 
carotenoids and incidence of diseases such as cancer and macular 
degeneration made presentations to the Olestra Working Group and FAC. 
Finally, because of significant discussion of this issue and because 
the agency received additional comments since the Olestra Working Group 
and FAC meetings on the potential chemoprotective function of 
carotenoids, FDA consulted with Dr. Greenwald at NCI and Dr. Kupfer at 
the NEI regarding whether olestra's effects on carotenoids raise any 
significant health issues (Refs. 69 and 70). FDA provided letters 
concerning carotenoids that the agency had received and excerpts 
discussing carotenoids from: (1) Submissions from the petitioner, (2) 
the White Paper, (3) FDA's briefing document for the Olestra Working 
Group, and (4) the transcript of the Olestra Working Group and FAC 
meetings to Dr.'s Greenwald and Kupfer.
    After reviewing the data, Dr. Greenwald concluded that there is no 
significant public health issue raised by the effects of olestra on 
lipophilic carotenoids and that supplementing olestra with beta 
carotene or other carotenoids was not warranted (Ref. 71). Dr. Kupfer 
from NEI concluded that although theoretical considerations have raised 
the possibility that carotenoids might play some protective role in 
macular degeneration, there are currently no convincing clinical data 
to support the hypothesis, and there are no demonstrated eye health 
benefits for carotenoids (Ref. 72). Given the NIH conclusions, FDA does 
not agree that FDA would be undercutting NCI's scientific judgement if 
it were to approve olestra. Further, FDA notes that by approving 
olestra, FDA is not contradicting or undercutting the NCI advice to eat 
fruits and vegetables.
    11. One comment stated that 30-300 mg/day of beta-carotene was used 
to prevent or lessen the photosensitivity characteristic of the disease 
erythropoietic protoporphyria (EPP). The comment added that if a 
significant amount of the beta-carotene taken by the EPP patients, who 
also eat foods containing olestra, is not absorbed, the patients will 
suffer from photosensitivity and will have to curtail markedly the 
activities the beta-carotene ingestion would permit. The comment added 
that it was not enough to theorize that supplementation of olestra with 
carotenoids will cure the problem and suggested the design of two 
studies on the effect of olestra on the absorption of beta-carotene, 
which should be conducted and evaluated before approval of olestra is 
considered.
    The comment raises the issue of food-drug interactions; in this 
instance, beta-carotene is being used as a drug, i.e., to treat 
patients with EPP. Food-drug interactions are generally handled through 
labeling for the drug product or through advice of the physician 
prescribing the drug. The agency fully intends to apprise physicians 
regarding the effect of olestra on the absorption of beta-carotene and 
other lipophilic carotenoids so that physicians will in turn be able to 
advise EPP patients appropriately. Further, because the agency believes 
that this potential drug-food interaction problem can be adequately 
addressed through education of physicians and their patients, the 
agency does not agree that the suggested studies on the effect of 
olestra on the absorption of supplemented beta-carotene are necessary.
    12. One comment cited an association between retinitis pigmentosa 
and steatorrhea and asserted that olestra causes steatorrhea and that 
chronic consumption of olestra may result in retinitis pigmentosa. The 
comment also stated that the studies show that vitamin supplementation 
results in reversal of the condition.
    The agency does not agree that olestra causes steatorrhea; the 
basis for that conclusion is discussed above. However, the agency 
acknowledges that loss of fat soluble vitamins due to the presence of 
olestra in the GI tract has the potential for harm. For this reason, 
the agency is requiring, as a condition of safe use, that olestra be 
supplemented with vitamins A, D, E and K in such a way that the 
bioavailability of these vitamins from the diet remains unchanged. 
Thus, any potential consequence of decreased absorption of 

[[Page 3166]]
fat-soluble vitamins will be offset by the vitamin compensation 
required by the final rule.
    13. Some comments stated that approval of the petition will result 
in unnecessary medical care associated with olestra's GI effects. 
Another comment questioned whether FDA has evaluated the potential 
impact of olestra on the health care delivery system, specifically, on 
the cost of office visits and diagnostic procedures by primary care 
physicians and gastroenterologists who evaluate GI disturbances that 
may occur from the use of the additive. The comment added that it 
seemed ill advised for FDA to approve the introduction of a product 
which may increase expenditures for healthcare.
    The agency does not agree that approval of the petition will result 
in unnecessary medical care associated with olestra's GI effects and 
therefore, does not agree that use of the additive will lead to 
increased costs associated with medical care for these effects. This is 
because the agency has determined that foods containing olestra shall 
be labeled so that consumers will be able to associate olestra with the 
GI symptoms that it may cause. The agency believes that this will 
significantly reduce or eliminate any unnecessary or inappropriate 
medical treatment. Therefore, the agency does not believe that it is 
necessary to evaluate the potential impact of olestra on the cost to 
the health care delivery system.
    14. One comment stated that while a general reduction in fat 
intake, especially saturated fat, is desirable, it seems unlikely that 
substituting olestra for part of the fat in a few products will have, 
or can be shown to have substantial benefit and added that benefits 
should be substantial to warrant the use of materials like olestra. 
Other comments stated that when GI disturbances are considered in 
conjunction with depletion of fat-soluble vitamins that are critical to 
the maintenance of health and depletion of other fat-soluble materials 
whose importance is not yet fully understood, the potential benefits 
that could result form the use of olestra are outweighed by the risk to 
the public health.
    The agency notes that, unlike approval of drugs, the law applicable 
to the approval of food additives does not permit consideration of, or 
require a showing of, benefits. As stated above, before a food additive 
can be approved, it has to be established that there is a reasonable 
certainty that the additive will not be harmful under the prescribed 
conditions of use. Further, as discussed in detail above, the agency 
does not agree that the GI symptoms that may occur due to consumption 
of foods containing olestra represent risk to the public health. 
Similarly, as discussed above, because the agency is requiringpara.that 
olestra be supplemented with the affected vitamins, the agency does not 
agree that olestra's potential to decrease the absorption of fat-
soluble vitamins and other nutrients with purported uses represent risk 
to the public health.
    Finally, the agency notes that the petitioner is not required to 
show that olestra has health or other benefits for consumers of the 
additive. Likewise, FDA is not permitted to consider such benefits in 
its evaluation of the safety of olestra for its intended use.
    15. Several comments stated that once approved for use in savory 
snacks, olestra will be used in everything and urged the agency to 
prevent its use in other products such as fat-free cakes and fast-food 
fries.
    The agency notes that the final rule that is being promulgated 
restricts the use of olestra for only in prepackaged ready-to-eat 
savory (i.e., salty or piquant but not sweet) snacks. Use of olestra in 
any other foods, including fat-free cakes and fast-food fries, is not 
permitted. Any additional use will require an evaluation of that use 
through a food additive petition in accordance with 21 CFR 171.1.
    16. Two comments expressed concern that olestra may cause allergic 
reactions in many people and, therefore, should not be approved.
    These comments did not provide any data to substantiate the 
assertion that olestra would be an allergen. FDA does not agree with 
these comments. FDA notes that, in general, food allergens are known to 
be protein or glycoprotein in nature. Olestra, composed of six, seven, 
or eight fatty acids esterified to sucrose, is neither a protein nor a 
glycoprotein and does not contain these substances even as minor 
constituents. Therefore, the agency believes that olestra is unlikely 
to cause any allergic reactions and finds that these comments are 
without merit.
    17. One comment stated that unless olestra can be converted into an 
acceptable energy source for livestock/poultry and pet rations or 
properly removed from the environment, a major disposal problem would 
result. The comment added that since olestra has no energy value, 
neither the spent frying olestra nor the waste savory snacks will be 
recycled. The comment asserted that this issue needs to be addressed 
prior to approval of olestra.
    The agency agrees that the question of whether disposal of olestra 
or olestra-containing products raises environmental concerns needs to 
be addressed before olestra can be approved. In fact, the National 
Environmental Policy Act (NEPA) mandates that FDA review the 
environmental consequences of its actions. In accordance with NEPA, FDA 
required the submission of, and reviewed, an environmental assessment 
(EA) for olestra prepared by the petitioner. Among other things, the EA 
addresses whether disposal of olestra or olestra-containing products 
has the potential to cause adverse environmental effects. As discussed 
below, the agency has consulted with the U.S. Environmental Protection 
Agency (EPA), has reviewed the petitioner's EA, and has concluded that 
approval of olestra will not have any para.significant adverse 
environmental impacts from its manufacture, use, or disposal.

IX. Environmental Impact Considerations

    The petitioner submitted an environmental assessment (EA) with its 
food additive petition for the use of olestra as a replacement for fats 
and oils in food. In May 1987, shortly after the food additive petition 
was filed, FDA was contacted by EPA regarding olestra. EPA was 
interested in whether the use of olestra would have an adverse effect 
on water quality and wastewater treatment processes. FDA agreed to 
consult with EPA regarding olestra and give EPA an opportunity to 
comment on the petitioner's environmental submission after FDA had 
completed its evaluation. In July 1990, the petitioner submitted a 
request to limit the intended use of olestra to substitution for 
conventional fat in the preparation of savory snacks. At that time, the 
petitioner submitted a revised EA for the limited use of olestra in 
savory snacks.
    The expected route of environmental introduction for olestra is 
through wastewater treatment systems and, subsequently, to aquatic and 
terrestrial environments. The petitioner performed studies on primary 
and secondary wastewater treatment processes which demonstrated that 
olestra does not have an adverse effect on the effective functioning of 
wastewater treatment plants. The petitioner provided studies on the 
fate and effects of olestra in aquatic and terrestrial systems which 
establish that, at the expected concentrations, olestra would not have 
an adverse effect upon organisms exposed in the water column, in 
sediments, or in soil following land application of sewage sludge. 
After analysis of the information provided, 

[[Page 3167]]
FDA tentatively concluded that approval of this petition would not 
cause significant environmental effects.
    Before reaching a final conclusion on the environmental effects of 
olestra, however, FDA requested that EPA review the information 
provided by the petitioner on the potential effect of olestra on 
wastewater treatment systems; exposed aquatic organisms, such as fish 
and sediment dwelling animals; soil physical and chemical properties 
subsequent to sewage sludge applications; and possible effects 
resulting from an accidental spill or treatment plant malfunction. EPA 
concluded that these issues had been satisfactorily addressed by the 
petitioner in the EA for the olestra food additive petition, and did 
not raise any environmental objection to the use of olestra in savory 
snacks. In light of the consultations with EPA, and based upon its own 
review, FDA has concluded that adverse environmental effects are not 
expected to result from the manufacture of olestra or from production 
or consumption of savory snacks containing olestra.
    Accordingly, the agency has concluded that the action will not have 
a significant impact on the human environment and that an environmental 
impact statement is not required. The agency's finding of no 
significant impact and the evidence supporting that finding, contained 
in an environmental assessment, may be seen in the Dockets Management 
Branch (address above) between 9 a.m. and 4 p.m., Monday through 
Friday.

X. FDA's Overall Conclusions

    The question before FDA regarding olestra is whether the additive 
is safe for its intended use as a fat substitute in savory snacks. (21 
U.S.C. 409(c)(3)(a).) To determine that olestra is safe, the agency 
must conclude, based upon a fair evaluation of the evidence of record, 
that there is a reasonable certainty that olestra is not harmful under 
the intended conditions of use. (21 CFR 170.3(i).) This determination 
of reasonable certainty of no harm necessarily involves the application 
of scientific judgement. Under the act, the agency has a duty to deny 
approval to an additive that has not been shown to be safe within the 
meaning of the act; the agency has a parallel duty to permit the 
marketing of those additives where the available scientific record 
establishes safety.
    It is not uncommon for an agency safety decision regarding a 
regulated product, including a food additive, to be very difficult. The 
decision regarding the food additive olestra is one such decision. The 
difficulty presented by the olestra food additive petition results from 
a relatively unique intersection of a number of factors, including the 
following.
    First, the volume of available safety evidence for olestra is 
enormous, all of which FDA was obligated to review, evaluate, and 
synthesize. Second, as a macro-ingredient, olestra is intended to 
replace a sizeable portion of the diet, and thus, will likely be 
consumed in relatively large amounts; this alone sets olestra apart 
from almost all food additives previously reviewed by FDA. Third, 
olestra presents a number of questions regarding nutritional effects, 
most of which have not been presented previously to FDA. Fourth, much 
of the pivotal scientific safety evidence for olestra comes from 
studies in humans; human studies, even well conducted ones like those 
for olestra, are necessarily limited in terms of the number of subjects 
that can reasonably be tested in a clinical trial conducted prior to 
marketing, the length of the trial, and the endpoints measured. 
Finally, under the act, once approved, olestra may be consumed by the 
entire U.S. population of 250 million people. This potentially 
widespread consumption for olestra does not, of course, set it apart 
from other foods and food additives. It does, however, distinguish this 
decision from those that FDA makes regarding drug and medical device 
products.
    It is important to emphasize that the coalescing of the foregoing 
factors does not preclude an agency decision at this time; it does, 
however, make the determination challenging. Similarly, it is worth 
noting that because of the challenge presented by olestra, the agency 
used an expanded approach to its evaluation of the petition, and 
established and utilized the internal Regulatory Decision Team, sought 
out and utilized the expertise of five subject-specific experts, and 
held a lengthy public meeting of the agency's Food Advisory Committee 
and a subgroup of that Committee (the Olestra Working Group) to foster 
an open and public discussion of the safety issues presented by 
olestra.
    Consistent with the act and its applicable standards, FDA has 
conducted an evaluation and synthesis of the evidence of record 
concerning olestra, including the proceedings of the FAC and comments 
submitted to the agency. In this process, FDA has applied its best 
scientific judgement, aided by the scientific judgement of the experts 
and public participants who contributed to the evaluation process. As 
the foregoing discussion makes clear, and as the proceedings of the FAC 
illustrate, olestra presents a number of important scientific 
questions. For some questions, there is arguably evidence, including 
support from recognized experts, on both sides of the question, 
ultimately requiring FDA to evaluate and weigh the data currently 
available and apply its scientific judgement. The agency has, as a 
result of this process, determined that there is a reasonable certainty 
that no harm will result from the use of olestra in savory snacks.
    Based upon a fair evaluation of the evidence of record, FDA 
concludes that olestra is not toxic, carcinogenic, genotoxic, or 
teratogenic. Olestra is essentially not absorbed or metabolized. 
Heating olestra, as would occur in the commercial preparation of snacks 
made using olestra, does not increase the absorption of the additive. 
FDA further concludes that the studies conducted show that olestra has 
an effect on the absorption of vitamins A, E, D, and K. FDA also 
concludes that it is possible to supplement foods containing olestra 
with all four vitamins in such a way as to compensate for the amounts 
that are not absorbed from the diet due to the action of olestra. FDA 
concludes that the amounts that should be provided are those listed 
below:

       TABLE 10.--COMPENSATION LEVELS FOR VITAMINS A, D, E, AND K       
------------------------------------------------------------------------
                 Vitamin                         Compensation level     
------------------------------------------------------------------------
Vitamin A................................  51 retinol equivalents/g     
                                            olestra as retinyl palmitate
                                            or retinyl acetate)(170 IU/g
                                            olestra or 0.34 X RDA/10 g  
                                            olestra                     
Vitamin E................................  1.9 mg <greek-a>-tocopherol  
                                            equivalents/g olestra (0.94 
                                            X RDA/10 g olestra)         
Vitamin D................................  12 IU vitamin D/g olestra    
                                            (0.3 X RDA per 10 g olestra)
Vitamin K................................  8 <greek-m>g vitamin K<INF>11/g   
                                            olestra (1.0 X RDA per 10 g 
                                            olestra)                    
------------------------------------------------------------------------


[[Page 3168]]


    As discussed previously, in order to avoid confusion about the 
purpose of the added vitamins in olestra-containing foods, FDA is 
requiring a label statement to indicate that olestra affects the 
absorption of some nutrients and that in order to compensate for 
olestra's effects on vitamins A, D, E, and K, these vitamins have been 
added.
    As discussed above, at present, carotenoids have no identifiable 
health benefit role (except for the provitamin A role of beta 
carotene.) Further, randomized studies have failed to show an 
association between selective carotenoid repletion and cancer. Although 
epidemiological studies show an association between diets rich in 
fruits and vegetables (including those that contain carotenoids) and 
decreased cancer risk, there is no direct evidence that carotenoids 
themselves are responsible for or contribute in a significant way to 
that protective benefit. In addition, the level of effects on 
carotenoids from olestra may well be within the normal variation due to 
diet and bioavailability. In light of the current state of the 
scientific evidence, FDA believes that there is a reasonable certainty 
of no harm from olestra's effects on carotenoid absorption. 
Accordingly, the agency concludes that there is currently no 
justification or need to require compensation of olestra-containing 
foods with specific carotenoids.
    Regarding water soluble nutrients, given the totality of the study 
results, FDA concludes that there is a reasonable certainty that 
olestra will not cause any harmful effects on vitamin B<INF>12, 
calcium, iron, zinc, or folate or other water soluble nutrients. 
Collectively, the clinical data on the water-soluble vitamins that are 
hard to absorb (folate and vitamin B<INF>12) show that olestra does not 
affect the absorption of these nutrients. Similarly, the data on two of 
the nutrients that are limited in the diet (iron and zinc) show that 
olestra does not interfere with their absorption.
    Although the data on the third nutrient that is limited in the 
diet, calcium, are not sufficiently rigorous to detect possible subtle 
changes, the lack of any plausible argument for expecting an effect, 
the lack of any olestra effect on folate, iron, or zinc, the fact that 
supplementation with vitamin D will preclude any vitamin D-mediated 
calcium depletion, and the insignificance of any subtle effect compared 
to variations in the human diet, lead FDA to conclude that there is a 
reasonable certainty that olestra will not have any harmful effect on 
calcium absorption.
    With respect to the potential effect of olestra on the GI tract, 
FDA concludes that the effects seen do not represent significant 
adverse health consequences and therefore, do not preclude approval of 
the petition. However, while FDA believes that there are no direct 
safety concerns with respect to olestra's potential effect on the GI 
tract, FDA concludes that the GI symptoms associated with ingestion of 
olestra-containing foods are material fact information within the 
meaning of 201(n) of the act. Disclosing this information on food 
labels will enable consumers to associate olestra with any GI effects 
that it may cause. Consequently, FDA is requiring that such information 
be disclosed on the label of foods containing olestra to preclude 
consumers from being misled about consequences which may result from 
the consumption of the olestra-containing foods. Therefore, in the 
final rule, FDA concludes that foods containing olestra should bear an 
appropriate label statement.
    In summary, FDA concludes that all safety issues have been 
addressed adequately and that based upon the currently available 
evidence, the use of olestra in savory snacks will be safe when used in 
accordance with the final rule.
    FDA's determination will permit the use of olestra in savory 
snacks. In order for olestra to be lawfully used in other foods (e.g., 
cakes and pies), a new food additive petition would need to be filed 
and approved. In conjunction with that review, the agency would then 
conduct a separate and independent safety evaluation of the additional 
proposed uses.
    Procter and Gamble has notified FDA that the company will be 
conducting additional studies of olestra exposure (both amounts 
consumed and patterns of consumption) and the effects of olestra 
consumption (Ref. 103).
    FDA believes that Procter and Gamble's plans to continue to study 
the consumption and effects of olestra are both prudent and 
responsible. It is likewise prudent and responsible for FDA to evaluate 
the results of such studies as it monitors the on-going marketing and 
distribution of olestra. Only with data from the broader marketing of 
olestra can the agency, be in the position to evaluate in the future 
whether there continues to be reasonable certainty of no harm from the 
use of olestra in savory snacks. Therefore, as a condition of approval, 
Procter and Gamble is to conduct the studies that it has identified in 
its letter to FDA (Ref. 103), consistent with the timetables identified 
in that letter. Furthermore, consistent with the terms of that letter, 
Procter and Gamble is to provide the Food and Drug Administration with 
access to all data, information, and reports of those studies as such 
information becomes available.
    It is the agency's responsibility as a public health agency to 
review and evaluate the data generated by Procter and Gamble's studies, 
as well as any new data that bear on the safety of olestra (such as 
data and information on the health significance of carontenoids)\94\ to 
determine whether there continues to be a basis for a reasonable 
certainty that the use of olestra in savory snacks is not harmful. 
Thus, consistent with the agency's continuing obligation to oversee the 
safety of the food supply, FDA will, within 30 months of this approval, 
review and evaluate any new data and information bearing on the safety 
of olestra and present such information to the agency's Food Advisory 
Committee (or a working group of the FAC). To the extent that 
additional data and information bearing on olestra's safety are 
submitted to and reviewed by the agency, FDA will, in its discretion, 
hold any additional meetings of the FAC that may be necessary to 
consider such information.

    \94\The record of this proceeding, particularly the meeting of 
the Olestra Working Group and the FAC, demonstrates that the 
question of the role of carotenoids in disease prevention or health 
maintenance is an issue of intense interest and the focus of 
continuing scientific study and evaluation. It is thus likely that 
there will be additional scientific data and information that bears 
on the question of the role of carotenoids in the future.
---------------------------------------------------------------------------

     This future meeting of the FAC (and any subsequent FAC meetings) 
will be open public meetings with an opportunity for participation by 
FDA, Procter and Gamble, and interested members of the public, and will 
provide an opportunity for public discussion and deliberation of the 
newly developed data regarding olestra.
    As an indication of the agency's view of the importance of this 
review, evaluation, and public discussion by the FAC of future data on 
olestra, as well as an indication of the depth of the agency's 
commitment to do so, the final rule established by this decision 
includes a statement concerning FDA's commitment in this regard. FDA 
has used the word ``will'' in Sec. 172.867(f) with respect to the 
agency's commitment to conduct such review and evaluation. The agency 
has thus legally bound itself to institute this review and evaluation. 
(See CNI v. Young, 818 F.2d 943 (D.C. Cir. 1987).)
    The decision embodied in this document necessarily articulates 
certain 

[[Page 3169]]
baseline parameters concerning the safety data for olestra, 
particularly parameters with respect to the finding of a reasonable 
certainty of no harm. These parameters include the exposure to olestra 
(both amount of consumption and patterns of consumption), and the 
nature, severity, incidence, and prevalence of any effects of olestra 
consumption, including any effects on fat-soluble nutrients and any 
gastrointestinal effects. If, as a result of the agency's review and 
evaluation and its consultation with the FAC, FDA determines that the 
results reflected in the new data and information are not consistent 
with the parameters that form the basis of this decision, or the agency 
otherwise concludes that the available safety evidence for olestra 
shows that there is no longer reasonable certainty of no harm from the 
use of this substance, FDA will institute appropriate regulatory 
proceedings.
    It is important to recognize that to institute a proceeding to 
limit or revoke the approval of olestra, FDA would not be required to 
show that olestra is unsafe. Rather, the agency would only need to show 
that based upon new evidence, FDA is no longer able to conclude that 
the approved use of olestra is safe, i.e., that there is no longer a 
reasonable certainty of no harm from the use of the additive. Further, 
in any proceeding to withdrawal or limit the approval of olestra, 
Procter and Gamble would have the burden to establish the safety of the 
additive. 21 CFR 12.87(c).
    Imposing a condition of approval such as this is not without 
precedent in the area of food additive approvals. At the time that FDA 
reinstated the approval of the artificial sweetener, aspartame, the 
Commissioner of Food and Drugs required that the petitioner for 
aspartame (G.D. Searle & Co.) develop data and other information on the 
actual use levels of the additive so that the estimated use levels of 
aspartame that formed the basis of the agency's safety decision could 
be compared with levels of actual use. (46 FR 38283, 38303; July 24, 
1981).
    This condition of approval is not, and should not be interpreted 
as, an indication that FDA has somehow not determined that there is a 
reasonable certainty that no harm will result from the use of olestra 
in savory snacks. As discussed in great detail above, the agency has 
determined, based upon a fair evaluation of the evidence in the record 
at this time, that such certainty exists. Having so concluded, however, 
the agency cannot responsibly ignore its continuing obligation to 
monitor the safety of the food supply and hence, has imposed the 
condition of approval set forth above.
    As noted, olestra presents several new challenges. It is a is a 
macro-ingredient that it not metabolized, one of the first of its type 
to be subject to FDA review. In addition, olestra's effects on nutrient 
absorption are not routinely presented by food additives reviewed by 
FDA. The safety decision for olestra is in large part based on the data 
from human studies. These studies are more than sufficient to provide a 
basis to conclude that olestra is safe. The agency recognizes, however, 
that olestra has the potential to be consumed by the bulk of the U.S. 
population of 250 million. In these circumstances, FDA believes that it 
is not only consistent with the agency's mandate under the act to 
protect the public health to condition the approval of olestra on the 
conduct of future studies, see United States v. Bacto-Unidisk, 394 U.S. 
784 (1969), but it is also the most responsible course for the agency 
to take in these circumstances.
    The Procter and Gamble Co. has made a commitment to the agency that 
it will conduct the studies outlined in the letter to FDA (Ref. 103), 
and FDA doubts neither the company's independent interest in conducting 
these studies nor the good faith of its commitment to the agency to do 
so. Nevertheless, FDA believes that it is important to articulate here 
the agency's view of the consequences of a failure of the company to 
adhere to its commitment. That is, if Procter and Gamble does not 
conduct the identified studies and does not conduct them according to 
the articulated timetable, FDA will consider the approval set forth in 
this document to be void ab initio and will institute appropriate 
proceedings, judicial or otherwise, consistent with that view.

XI. Administrative Record and Inspection of Documents

    The administrative record for this final rule consists of the food 
additive petition (FAP 7A3997), all documents filed in that petition, 
and any items cited in this preamble.
    In accordance with Secs. 171.1(h) (21 CFR 171.1(h)), the petition 
and the documents that FDA considered and relied upon in reaching its 
decision to approve the petition are available for inspection at the 
CFSAN (address above) by appointment with the information contact 
person listed above. As provided in Sec. 171.1(h), the agency will 
delete from the documents any materials that are not available for 
public disclosure before making the documents available for inspection.

XII. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before February 29, 1996 file with the Dockets 
Management Branch (address above) written objections thereto. Each 
objection shall be separately numbered, and each numbered objection 
shall specify with particularity the provisions of the regulation to 
which objection is made and the grounds for the objection. Each 
numbered objection on which a hearing is requested shall specifically 
so state. Failure to request a hearing for any particular objection 
shall constitute a waiver of the right to a hearing on that objection. 
Each numbered objection for which a hearing is requested shall include 
a detailed description and analysis of the specific factual information 
intended to be presented in support of the objection in the event that 
a hearing is held. Failure to include such a description and analysis 
for any particular objection shall constitute a waiver of the right to 
a hearing on the objection. Three copies of all documents shall be 
submitted and shall be identified with the docket number found in 
brackets in the heading of this document. Any objections received in 
response to para.the regulation may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.
    FDA will publish notice of the objections that the agency has 
received or lack thereof in the Federal Register.

XIII. 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. Charge to Olestra Working Group, Draft, Nov. 13, 1995.
    2. Transcript of meeting of the Olestra Working Group (vols. 1-
3) and Food Advisory Committee (vol. 4), Alexandria, VA, November 14 
through 17, 1995.
    3. Myra Karstadt, Ph.D. and Michael F. Jacobson, Ph.D., ``White 
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    7. Memorandum from M. DiNovi, FDA to J. Gordon, FDA, July 14, 
1989.
    8. Memorandum from M. DiNovi, FDA to J. Gordon, FDA, January 17, 
1991. 

[[Page 3170]]

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1995.
    40. Memorandum from M. J. Bleiberg, FDA, to J. Gordon, FDA, 
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April 12, 1994.
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    43. Memorandum of Meeting, May 3, 1995.
    44. Memorandum from J. Judd, USDA to G. N. Biddle, FDA, August 
7, 1995.
    45. Memorandum of Telephone Conversation between J. Judd, USDA, 
and H. Thorsheim, FDA, September 17 and 18, 1995.
    46. Memorandum from M. S. Calvo, FDA to J. Gordon, FDA, August 
8, 1989.
    47. Memorandum from M. Jenkins, FDA to G. Biddle, FDA, August 
14, 1995.
    48. Memorandum from R. Chanderbhan, FDA, to K. N. Biddle, FDA, 
July 11, 1995.
    49. Memorandum from C. Barton, FDA to H. Thorsheim, FDA, May 23, 
1995.
    50. Memorandum from C. Barton, FDA to H. Thorsheim, FDA, May 18, 
1995.
    51. Memorandum from C. Barton, FDA to H. Thorsheim, FDA, May 19, 
1995.
    52. Memorandum from R. Lovell, FDA to H. Thorsheim, FDA, March 
21, 1995.
    53. Memorandum from Randall Lovell, FDA to F. O. Fields, FDA, 
March 22, 1994.
    54. Memorandum from Randall Lovell, FDA to F. O. Fields, FDA, 
January 27, 1995.
    55. Matschiner, J. T. and W. V. Taggart, ``Bioassay of Vitamin K 
by Intracardial Injection in Deficient Adult Male Rats,'' Journal of 
Nutrition, 94:57-59, 1968.
    56. Memorandum from R. Lovell, FDA to H. Thorsheim, FDA, 
September 13, 1995.
    57. Rothman, K. J., L. L. Moore, M. R. Singer, U.S.D.T. Nguyen, 
S. Mannino, and A. Milunsky, ``Teratogenicity of High Vitamin A 
Intake,'' New England Journal Medicine, 333:1369-1373, 1995.
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    59. Recommended Dietary Allowances, National Research Council, 
National Academy of Sciences Press; pp. 96 and 97.
    60. Seddon M. J., et. al., ``Dietary Carotenoids, Vitamins A, C, 
and E, and Advanced Age-Related Macular Degeneration,'' Journal of 
the American Medical Association, 272:1413-1420, 1994.
    61. Giovannucci E., et. al., ``Intake of Carotenoids and Retinol 
in Relation to Risk of Prostate Cancer,'' Journal of the National 
Cancer Institute 87:1767-1776, 1995.
    62. Letter from W. Willett and M. Stampfer, Harvard School of 
Public Health to D. Kessler, FDA, November 1, 1995.
    63. The Alpha-tocopherol Beta-carotene Cancer Prevention Study 
Group, ``The Effect of Vitamin E and Beta Carotene on the Incidence 
of Lung Cancer and Other Cancers in Male Smokers,'' New England 
Journal of Medicine, 330:1029-1035, 1994.
    64. Greenberg, E. R., et.al., ``A Clinical Trial of Beta 
Carotene to Prevent Basal-Cell and Squamous-Cell Cancers of the 
Skin,'' New England Journal of Medicine, 323:789-795, 1990.
    65. Greenberg, E. R., et.al., ``A Clinical Trial of Antioxidant 
Vitamins to Prevent Coloractal Adenoma,'' New England Journal of 
Medicine, 331:141-147, 1994.
    66. Blot, W. J. et.al., ``Nutrition Intervention Trials in 
Linxian, China: Supplementation with Specific Vitamin/Mineral 
Combinations, Cancer Incidence, and Disease Specific Mortality in 
the General Population,'' Journal of the National Cancer Institute, 
85:16-30, 1993.
    67. Rock, C. L. and M. E. Swendseid, ``Plasma -Carotene Response 
in Humans after Meals Supplemented with Dietary Pectin,'' American 
Journal Clinical Nutrition, 55:96-99, 1992.
    68. Letter from J. Peters, Procter & Gamble to H. Thorsheim, 
FDA, January 16, 1996.
    69. Letter from J. E. Vanderveen, FDA to P. Greenwald, NCI, 
November 30, 1995.
    70. Letter from J. E. Vanderveen, FDA to C. Kupfer, NEI, 
December 4, 1995.
    71. Letter from P. Greenwald, NCI, to J. Vanderveen, FDA, 
December 5, 1995.
    72. Letter from C. Kupfer, NEI to J. Vanderveen, FDA, January 
17, 1995.
    73. Letter from S. R. Lynch, VAMC to J. Vanderveen, FDA, June 
19, 1995.
    74. Memorandum from C. Barton, FDA to O. Fields, FDA, September 
20, 1993.
    75. Memorandum of Meeting, May 31, 1995.
    76. Memorandum from M. S. Calvo, FDA and W.V. Rumpler, USDA to 
F. O. Fields, October 13, 1993.
    77. Maxson, P. F. and D. C. Mahan, ``Dietary Calcium and 
Phosphorus Levels for Growing Swine from 18 to 56 Kilograms Body 
Weight,'' Journal of Animal Science, 56:1124-1134, 1983.
    78. Cromwell, G. L., V. W. Hays, C. W. Scherer, and J. R. 
Overfield, ``Effects of Dietary Calcium and Phosphorus on 
Performance and Carcass, Metacarpal and Turbinate Characteristics of 
Swine,'' Journal of Animal Science, 34:746-751, 1972.
    79. Memorandum from L. Lutwak, FDA to K. Biddle, FDA, January 6, 
1995.
    80. Cortot, A., S. F. Phillips, and J. Malagelada, ``Parallel 
Gastric Emptying of Nonhydrolyzable Fat and Water after a Solid-
Liquid Meal in Humans,'' Gastroenterology, 82:877-881, 1982.
    81. Aggarwal, A. M., M. Camilleri, S. F. Phillips, T. G. 
Schlagheck, M. L. Brown, and G. M. Thomforde, ``Olestra, a 
Nondigestible, Nonabsorbable Fat/Effects on Gastrointestinal and 
Colonic Transit,'' Digestive Diseases and Sciences, 38:1009-1014, 
1993.
    82. Smith, M. C. and H. Spector, ``Calcium and Phosphorus 
Metabolism in Rats and 

[[Page 3171]]
Dogs as Influenced by the Ingestion of Mineral Oil,'' Journal of 
Nutrition, 20:19-30, 1940.
    83. Smith, M. C. and H. Spector, ``Further Evidence of the Mode 
of Action of Vitamin D,'' Journal of Nutrition, 20:197-202, 1940.
    84. Memorandum from K. Klontz, FDA to F. O. Fields, FDA, January 
11, 1995.
    85. Anderson, J. W., L. Story, B. Sieling, W. J. L. Chen, M. S. 
Petro, J. Story, ``Hypocholesterolemic Effects of Oat-Bran or Bean 
Intake for Hypercholesterolemic Men,'' American Journal of Clinical 
Nutrition, 40:1146-1155, 1984.
    86. Stasse-Wolthuis, M., et.al., ``The Effect of a Natural High-
Fiber Diet on Serum Lipids, Fecal Lipids, and Colonic Function,'' 
American Journal of Clinical Nutrition, 32:1881-1888, 1979.
    87. Memorandum from K. Klontz, FDA to F. O. Fields, FDA, August 
9, 1994.
    88. Memorandum from K. Klontz, FDA to H. Thorsheim, FDA, 
December 26, 1995.
    89. Jalan, K. N., et. al., ``An Experience of Ulcerative 
Colitis. III. Long Term Outcome,'' Gastroenterology, 59:598-609, 
1970.
    90. Memorandum of Conference, October 4, 1994.
    91. Memorandum from S. Fredd, FDA to F. O. Fields, FDA, January 
3, 1995.
    92. Memorandum from R. Pertel, FDA to N. Beru, FDA, September 6, 
1995.
    93. Memorandum of Meeting, May 26, 1995.
    94. Nuck, B. A., T. G. Schlagheck, and R. W. Federle, 
``Inability of the Human Fecal Microflora to Metabolize the 
Nonabsorbable Fat Substitute, Olestra,'' Indian Journal of Pathology 
and Microbiology, 13:328-334, 1994.
    95. Memorandum from R. Pertal, FDA to N. Beru, FDA, September 6, 
1995.
    96. Letter from J. Lupton, Texas A&M to L. Pellicore, FDA, 
December 15, 1995.
    97. Memorandum of telephone conversation between L. Pellicore, 
FDA, and J. Lupton, Texas A&M, January 17, 1995.
    98. Memorandum from R. Chanderbhan, FDA, to G. N. Biddle, FDA, 
August 24, 1995.
    99. Memorandum for the Record, January 18, 1996.
    100. Memorandum of Meeting, June 16, 1995.
    101. Memorandum of Conference, June 26, 1995.
    102. Swinyard, E. A. (1990) Gastrointestinal Drugs In: 
Remington's Pharmaceutical Sciences, 18th Edition. A. R. Gennaro 
(ed.). Mack Publishing Co., Easton, PA, pp 783-799).
    103. Letter from Procter & Gamble, to FDA, January 24, 1996.
    104. Letter from W. Schultz, FDA to M. Jacobson, CSPI, December 
8, 1995.

List of Subjects in 21 CFR 172

    Food additives, Incorporation by reference, 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 
172 is amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR 
HUMAN CONSUMPTION

    1. The authority citation for 21 CFR part 172 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371, 
379e).

    2. New Sec. 172.867 is added to subpart I to read as follows:


Sec. 172.867  Olestra.

    Olestra, as identified in this section, may be safely used in 
accordance with the following conditions:
    (a) Olestra is a mixture of octa-, hepta-, and hexa-esters of 
sucrose with fatty acids derived from edible fats and oils or fatty 
acid sources that are generally recognized as safe or approved for use 
as food ingredients. The chain lengths of the fatty acids are no less 
than 12 carbon atoms.
    (b) Olestra meets the following specifications:
    (1) The total content of octa-, hepta-, and hexa-esters is not less 
than 97 percent as determined by a method entitled ``Determination of 
Olestra by Size Exclusion Chromatography,'' dated December 19, 1995, 
which is incorporated by reference in accordance with 5 U.S.C. 552(a) 
and 1 CFR part 51. Copies are available from the Office of Premarket 
Approval, Center for Food Safety and Applied Nutrition (HFS-200), Food 
and Drug Administration, 200 C St. SW., Washington, DC, or may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
200 C St. SW., rm. 3321, Washington, DC, or at the Office of the 
Federal Register, 800 North Capitol Street, NW., suite 700, Washington, 
DC.
    (2) The content of octa-ester is not less than 70 percent as 
determined by a method entitled ``Measurement of the Relative Ester 
Distribution of Olestra Test Material'' dated December 19, 1995, which 
is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 
CFR part 51. Copies are available from the Office of Premarket 
Approval, Center for Food Safety and Applied Nutrition (HFS-200), Food 
and Drug Administration, 200 C St. SW., Washington, DC, or may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
200 C St. SW., rm. 3321, Washington, DC, or at the Office of the 
Federal Register, 800 North Capitol Street, NW., suite 700, Washington, 
DC.
    (3) The content of hexa-ester is not more than 1 percent as 
determined by the method listed in paragraph (b)(2) of this section.
    (4) The content of penta-ester is not more than 0.5 percent as 
determined by the method listed in paragraph (b)(2) of this section.
    (5) The unsaturated fatty acid content is not less than 25 percent 
(thus not more than 75 percent saturated fatty acid) and not more than 
83 percent as determined by a method entitled ``Measurement of the 
Fatty Acid Composition of Olestra Test Material,'' dated December 19, 
1995, which is incorporated by reference in accordance with 5 U.S.C. 
552(a) and 1 CFR part 51. Copies are available from the Office of 
Premarket Approval, Center for Food Safety and Applied Nutrition (HFS-
200), Food and Drug Administration, 200 C St. SW., Washington, DC, or 
may be examined at the Center for Food Safety and Applied Nutrition's 
Library, 200 C St. SW., rm. 3321, Washington, DC, or at the Office of 
the Federal Register, 800 North Capitol Street, NW., suite 700, 
Washington, DC.
    (6) The content of C12 and C14 fatty acids is each not more than 1 
percent, and total C20 and longer fatty acids is not more than 20 
percent. C16 and C18 fatty acids make up the remainder with total 
content not less than 78 percent as determined by the method listed in 
paragraph (b)(5) of this section.
    (7) The free fatty acid content is not more than 0.5 percent as 
determined by a method entitled ``Free Fatty Acids'' published in the 
Official Methods and Recommended Practices of the American Oil 
Chemists' Society, 3d Ed. (1985) vol. 1, which is incorporated by 
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies 
are available from the American Oil Chemists Society, 1608 Broadmoor 
Dr., Champaign, IL 61821, or may be examined at the Center for Food 
Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321, 
Washington, DC, or at the Office of the Federal Register, 800 North 
Capitol Street, NW., suite 700, Washington, DC.
    (8) The residue on ignition (sulfated ash) is not more than 0.5 
percent.
    (9) Total methanol content is not more than 300 parts per million 
as determined by the ``Total Available Methanol Method,'' dated 
December 19, 1995, which is incorporated by reference in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the 
Office of Premarket Approval, Center for Food Safety and Applied 
Nutrition (HFS-200), Food and Drug Administration, 200 C St. SW., 
Washington, DC or may be examined at the Center for Food Safety and 
Applied Nutrition's Library, 200 C St. SW., rm. 3321, Washington, DC, 
or at the Office of the Federal Register, 800 North 

[[Page 3172]]
Capitol Street, NW., suite 700, Washington, DC.
    (10) The total heavy metal content (as Pb) is not more than 10 
parts per million.
    (11) Lead is not more than 0.1 part per million, as determined by a 
method entitled ``Atomic Absorption Spectrophotometric Graphite Furnace 
Method,'' Food Chemicals Codex, 3d Ed. 3d Supp. p. 168 (1992), which is 
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR 
part 51. Copies are available from the National Research Council Press, 
2101 Constitution Ave. NW., Washington, DC, or may be examined at the 
Center for Food Safety and Applied Nutrition's Library, 200 C St. SW., 
rm. 3321, Washington, DC, or at the Office of the Federal Register, 800 
North Capitol Street, NW., suite 700, Washington, DC.
    (12) Water is not more than 0.1 percent, as determined by a method 
entitled ``Moisture,'' Official Methods and Recommended Practices of 
the American Oil Chemists' Society, 4th Ed. (1989), vol. 1, which is 
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR 
part 51. Copies are available from the American Oil Chemists Society, 
1608 Broadmoor Dr., Champaign, IL 61821, or may be examined at the 
Center for Food Safety and Applied Nutrition's Library, 200 C St. SW., 
rm. 3321, Washington, DC, or at the Office of the Federal Register, 800 
North Capitol Street, NW., suite 700, Washington, DC.
    (13) Peroxide value is not more than 10 meq/kg as determined by a 
method entitled ``Peroxide Value,'' Official Methods and Recommended 
Practices of the American Oil Chemists' Society, 4th Ed. (1989) vol. 1, 
which is incorporated by reference in accordance with 5 U.S.C. 552(a) 
and 1 CFR part 51. Copies are available from the American Oil Chemists 
Society, 1608 Broadmoor Dr., Champaign, IL 61821, or may be examined at 
the Center for Food Safety and Applied Nutrition's Library, 200 C St. 
SW., rm. 3321, Washington, DC, or at the Office of the Federal 
Register, 800 North Capitol Street, NW., suite 700, Washington, DC.
    (14) The stiffness is not less than 50 kiloPascals/second, as 
determined by a method entitled ``Method for Measurement of the 
Stiffness of Olestra,'' dated December 19, 1995, which is incorporated 
by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. 
Copies are available from the Office of Premarket Approval, Center for 
Food Safety and Applied Nutrition (HFS-200), Food and Drug 
Administration, 200 C St. SW., Washington, DC, or may be examined at 
the Center for Food Safety and Applied Nutrition's Library, 200 C St. 
SW., rm. 3321, Washington, DC, or at the Office of the Federal 
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
    (c) Olestra may be used in place of fats and oils in prepackaged 
ready-to-eat savory (i.e., salty or piquant but not sweet) snacks. In 
such foods, the additive may be used in place of fats and oils for 
frying or baking, in dough conditioners, in sprays, in filling 
ingredients, or in flavors.
    (d) To compensate for any interference with absorption of fat 
soluble vitamins, the following vitamins shall be added to foods 
containing olestra: 1.9 milligrams alpha-tocopherol equivalents per 
gram olestra; 51 retinol equivalents per gram olestra (as retinyl 
lacetate or retinyl palmitate); 12 IU vitamin D per gram olestra; and 8 
<greek-m>g vitamin K<SUP>1 per gram olestra.
    (e)(1) The label of a food containing olestra shall bear the 
following statement in the manner prescribed in paragraph (e)(2) of 
this section:
    This Product Contains Olestra. Olestra may cause abdominal 
cramping and loose stools. Olestra inhibits the absorption of some 
vitamins and other other nutrients. Vitamins A, D, E, and K have 
been added.
    (2) The statement required by paragraph (e)(1) of this section 
shall:
    (i) Appear either on the principal display panel or on the 
information panel of the label;
    (ii) Be enclosed by a 0.5 point box rule with 2.5 points of space 
around the statement.
    (iii) Utilize at least one point leading;
    (iv) Have type that is kearned so the letters do not touch;
    (v) Be all black or one color type, printed on a white or other 
neutral contrasting background whenever possible;
    (vi) Utilize a single easy-to-read type style such as Helvetica 
Regular and upper and lower case letters; and
    (vii) Be in type size no smaller than 8 point.
    (3) The sentence ``This Product Contains Olestra.'' shall be 
highlighted by bold or extra bold type, such as Helvetica Black. The 
label shall appear as follows:

BILLING CODE 4160-01-F

[[Page 3173]]
[GRAPHIC][TIFF OMITTED]TR30JA96.001



BILLING CODE 4160-01-C
    (4) Vitamins A, D, E, and K present in foods as a result of the 
requirement in paragraph (d) of this section shall be declared in the 
listing of ingredients. Such vitamins shall not be considered in 
determining nutrient content for the nutritional label or for any 
nutrient claims, express or implied.-
    (5) Olestra shall not be considered as a source of fat or calories 
for purposes of Secs. 101.9 and 101.13 of this chapter.
    (f) Consistent with its obligation to monitor the safety of all 
additives in the food supply, including olestra, the Food and Drug 
Administration will review and evaluate all data and information 
bearing on the safety of olestra received by the agency after the 
effective date of this regulation, and will present such data, 
information, and evaluation to the agency's Food Advisory Committee 
within 30 months of the effective date of this regulation. The purpose 
of such presentation will be to receive advice from the Committee on 
whether there continues to be reasonable certainty that use of olestra 
in compliance with this regulation is not harmful. The agency will hold 
such additional Food Advisory Committee meetings on olestra as the 
agency determines, in its discretion, to be necessary. Based upon the 
results of this entire process, the FDA will initiate any appropriate 
regulatory proceedings.

    Dated: January 24, 1996.
David A. Kessler,
Commissioner of Food and Drugs.
[FR Doc. 96-1584 Filed 1-25-96; 8:45 am]
BILLING CODE 4160-01-F