Federal Register, Volume 61 Issue 20 (Tuesday, January 30, 1996)

[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]]

_______________________________________________________________________

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.

-----------------------------------------------------------------------

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 B12
b. Iron
c. Folate
d. Zinc
2. Results and Conclusions from Pig Studies
a. Vitamin B12
b. Iron
c. Folate
d. Zinc-
e. Calcium
3. Overall Conclusions Regarding Olestra's Effects on Water-Soluble
Nutrients
a. Vitamin B12
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.
---------------------------------------------------------------------------

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.
---------------------------------------------------------------------------

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).
---------------------------------------------------------------------------

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.
---------------------------------------------------------------------------

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.
---------------------------------------------------------------------------

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 C16 and C18 fatty acids
in soybean oil.
Identical analytical techniques showed that similar types
(C29-C35 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^{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
^{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 CO2, or the lipid
fraction was extracted and analyzed for intact olestra by HPLC. Urine,
feces, expired CO2, and the carcass were analyzed for ^{14C.
The urine was analyzed for ^{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 CO2. 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,
F0 dams were mated for a reproduction (F1A) phase and then
were mated again for a teratology (F1B ) phase. After the growth
period, the F1A offspring were mated for the F2A and F2B
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^{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 B12, 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 B12, 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 B12, 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 B12; and on
the bioavailability of -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 D2 (25-OHD2)
concentration, carotenoid bioavailability, and vitamin B12
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 -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 B12 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 g/day (two RDA) of vitamin D2 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 -tocopherol concentration
Vitamin D Serum concentration of 25-OHD2, 25-hydroxyvitamin D3
(25-OHD3), and 1,25-dihydroxyvitamin D (1,25-(OH)2D)
Vitamin K Serum phylloquinone concentration, urinary excretion of
-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 B12 Schilling test, serum vitamin B12, serum vitamin B12
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 D2 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 D2
-----------------------------------------------------------------------------
Treatment Group Olestra (g/d) g/ g/ g/ 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 -
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--tocopheryl
acetate) per g olestra. This level is equivalent to 1.9 mg -
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 -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 -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 D2) and endogenous (vitamin D3) produced
in the body via sunlight-catalyzed dermal synthesis. The nature of the
dose-response effect of olestra on dietary vitamin D2 was
determined by measuring serum levels of 25-OHD2, which is derived
only from dietary vitamin D. Serum levels of 25-OHD3 (from
dermally synthesized vitamin D3), 1,25-(OH)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-OHD2. At the
end of the study, the reductions in 25-OHD2 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-OHD3 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 D2 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-OHD2 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 D2 in the 8-week VR study could be offset
by adding 0.07 times the RDA of vitamin D2 per 1 oz serving of
savory snack containing 10 g olestra (equivalent to .07 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 D2
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-OHD2 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 g vitamin D2/g olestra reduced the decrease
in total serum 25-OHD (which was due to both olestra and test diet
effects). At the 0.2 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 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 D2 consumption was not excessive and the effect of
olestra had levelled off within 4 weeks. FDA concludes that these
results show that 0.2 g vitamin D2/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
K1) 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 -
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 -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 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 g vitamin K in the 8 g/d group (4
g/g olestra), 68 g vitamin K in the 20 g/d group (3.2
g/g olestra), and 82 g vitamin K in the 32 g/d group
(2.6 g/g olestra). The petitioner averaged these three results
to yield an estimated compensation level of 3.3 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 -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 -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 g (800 IU) ergocalciferol
(vitamin D2), 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 K1), serum
Simplastin/Ecarin 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-OHD2, 25-OHD3, and 1,25-
(OH)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-OHD2
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-OHD2 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-OHD2 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 K1 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- 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, -tocopherol, -
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 -tocopherol concentration
was reduced by 6 percent, relative to control, in the olestra group and
by 4 percent in olestra with added -tocopheryl acetate group.
Serum concentrations of -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 -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 B12, 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 B12, 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 -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--tocopheryl acetate. Dietary vitamin D was
supplied as ergocalciferol (vitamin D2). 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 B12 was provided as cyanocobalamin, calcium as a
mixture of CaHPO42H2O

[[Page 3138]]
and CaCO3, iron as FeSO47H2O, and zinc as
ZnSO47H2O. 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-OHD2, 25-OHD3, and 1,25-
(OH)2D
Vitamin K Prothrombin time
Folate Plasma concentration
Vitamin B12 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)^{1 Vitamin E (x NRC)^{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 D2 (ergocalciferol), while vitamin A was in the form of
retinyl palmitate. Above-basal levels of vitamin E, in the form of d-
-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--
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 D2. 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
D2 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-
-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 D2 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 (-
tocopherol), and vitamin D (25-hydroxyvitamin D2 and 25-
hydroxyvitamin D3) and liver measurements of vitamin A (total
retinol and retinyl esters) and vitamin E (-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 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--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-OHD2; the serum
concentration of 25-OHD2 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 D3
synthesized in the skin.
The petitioner also concluded that in the 12-week VR study, serum
concentration of 25-OHD2 increased in a dose-response manner as
the amount of vitamin D2 added to the basal diet was increased, at
all levels of olestra. However, interpretation of the serum 25-
OHD2 data at the mid- and high-olestra levels (4.4 and 7.7
percent) was confounded because the proportion of 25-OHD3 in the
serum decreased with increasing levels of olestra at these treatment
levels. The petitioner has suggested, that this decrease in serum 25-
OHD3 may have resulted from the effect of the high levels of
olestra on the reabsorption of biliary vitamin D3. Reduced
reabsorption of biliary vitamin D3 would tend to increase the
serum concentration of 25-OHD2 because of diminished vitamin
D3 competition for the liver 25- hydroxylase.
Using the serum 25-OHD2 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-OHD2 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 D3 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-OHD2 by 20
percent at week 26. At week 16, serum 25-OHD2 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-OHD2 by the same magnitude as in the
26-week DR/VR study, while serum 25-OHD3, total serum 25-OHD, and
serum 1,25-(OH)2D were not affected. Serum 25-OHD2 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-OHD3 levels and very low
25-OHD2 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-OHD3 levels. Because a definitive cause for
these elevated serum 25-OHD3 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-OHD2 increased in a dose-response manner as
the amount of vitamin D2 added to the basal diet was increased, at
all levels of olestra. FDA further agrees with the petitioner that the
decrease in serum 25-OHD3 observed in the mid- and high-level
groups may have resulted from olestra's effects on the reabsorption of
biliary vitamin D3. However, FDA also believes that the serum 25-
OHD2 levels may have been confounded by the daily 2-minute
exposure to UV light, which caused an increase in serum levels of 25-
OHD3 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 D2 because of the apparent interaction between serum 25-
OHD3 and 25-OHD2 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 D2, 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 -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 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 -
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 -carotene eaten with olestra would
be decreased by 60 percent and absorption of -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 -carotene eaten with
olestra would be decreased by 60 percent, absorption of -
carotene eaten at eating occasions either before or after the olestra
eating occasion would be decreased by 30 percent, and absorption of
-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 -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 -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
-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 -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 D2 concentration do not warrant compensation with
vitamin D. As support, the petitioner cites the absence of changes in
serum 1,25-OH2D concentration in the pig studies as evidence that
olestra has no significant effect on overall vitamin D status despite
the decrease in dietary vitamin D2 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
g vitamin D2/g olestra (0.07 times the RDA per 10 g of
olestra) would be sufficient to compensate for the olestra-induced
decrease in 25-OHD2. FDA notes that in the 8-week VR study, 0.2
g vitamin D2/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 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 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 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
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--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 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 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 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 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 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 -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
-carotene in the blood had significantly higher incidence
rates of lung cancer than the men with the high levels of -
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 -carotene concentration 30 hours following consumption
of a controlled meal containing 25 mg -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 -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 log10 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 (-carotene, -
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 -
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 -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
-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 B12, and zinc status were measured in both the pig
and human studies. Vitamin B12 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 B12
are summarized in Table 4 (human studies) and Table 6 (pig studies).
1. Results and Conclusions from Human Studies
a. Vitamin B12. In the 8-week human DR and VR studies, there
was no change in serum measures of vitamin B12. However, 8 weeks
is insufficient to observe effects in serum, and the presence of excess
vitamin B12 in the diets likely reduced the sensitivity of the
studies to evaluate vitamin B12 status. The petitioner also found
that absorption of vitamin B12 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 B12 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 B12 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 B12 absorption in humans.

\53\The Schilling test is an acute test that measures the
absorption of a dose of radiolabeled vitamin B12
---------------------------------------------------------------------------

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 B12, 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 B12. There were no statistically significant
effects of olestra on liver vitamin B12 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 B12
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 B12 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 B12, these pig studies are inadequate by themselves to
evaluate olestra's effect on vitamin B12.
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 2.0 vs. 61.1
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 B12. FDA has determined that there is no need for
compensation of olestra-containing foods with vitamin B12. 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 B12. Both studies showed no effect of olestra on vitamin
B12 using the Schilling test, which is a sensitive test that is
not affected by dietary vitamin B12 levels. The vitamin B12
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 B12 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 B12 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 B12, 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^{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 CO2, 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 (^{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 ^{14CO2, ^{14CH4, or
^{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 -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 g vitamin K11/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 B12,
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 B12) 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
Paper on Olestra,'' Center for Science in the Public Interest,
November 3, 1995.
4. ``Toxicological Principles for the Safety Assessment of
Direct Food Additives and Color Additives Used in Food,'' Draft,
(Redbook II), U.S. Food and Drug Administration, 1993.
5. Memorandum from M. DiNovi, FDA to J. Gordon, FDA, June 28,
1989.
6. Memorandum from M. DiNovi, FDA to J. Gordon, FDA, April 17,
1989.
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]]

9. Memorandum from M. DiNovi, FDA to F. O. Fields, FDA, June 6,
1994.
10. Memorandum from M. DiNovi, FDA to J. Gordon, FDA, October 3,
1990.
11. Memorandum from M. DiNovi, FDA to F. O. Fields, FDA,
February 5, 1993.
12. Memorandum from M. DiNovi, FDA to H. Thorsheim, FDA, March
13, 1995.
13. Memorandum from M. DiNovi, FDA to H. Thorsheim FDA, May 4,
1995.
14. Mattson, F. H. and Volpenhein, R.A., ``Hydrolysis of Fully
Esterified Alcohols Containing from One to Eight Hydroxyl Groups by
the Lipolytic Enzymes of Rat Pancreatic Juice,'' Journal of Lipid
Research, 13:325-328, 1972.
15. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
July 6, 1993.
16. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
August 1, 1993.
17. Memorandum from L. S. Pellicore, FDA, to F.O. Fields, FDA,
August 2, 1993.
18. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
August 4, 1993.
19. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
August 5, 1993.
20. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
January 25, 1995.
21. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
July 28, 1995.
22. Memorandum from L. S. Pellicore, FDA, to F. O. Fields, FDA,
July 28, 1995.
23. Memorandum from E. J. Matthews, FDA to F. O. Fields, FDA,
December 16, 1993.
24. Memorandum from T. F. X. Collins, FDA, to F. O. Fields, FDA,
October 23, 1993.
25. Memorandum from J. J. Welsh, FDA, to L. S. Pellicore, FDA,
March 1, 1994.
26. Memorandum from M. J. Bleiberg, FDA, to F. O. Fields, FDA,
February 8, 1993.
27. Goodman, D. G., J. M. Ward, R. A. Squire, K. C. Chu, and M.
S. Linhart, ``Neoplastic and Nonneoplastic Lesions in Aging F344
Rats,'' Toxicology and Applied Pharmacology, 48:237-248, 1979.
28. Memorandum from F. S. D. Lin, FDA, to R. Lorentzen, FDA,
February 4, 1988.
29. Memorandum from R. W. Moch, FDA, to F. O. Fields, FDA, April
5, 1993.
30. Harada, T., R. P. Maronpot, R. W. Morris, K. A. Stitzel, and
G. A. Boorman, ``Morphological and Stereological Characterization of
Hepatic Foci of Cellular Alteration in Control Fischer 344 Rats,''
Toxicology and Pathology 17(4):579-593, 1989.
31. Harada, T., R. R. Maronpot, R.W. Morris, and G. A. Boorman,
``Observations on Altered Hepatocellular Foci in National Toxicology
Program 2-Year Carcinogenicity Studies in Rats,'' Toxicology and
Pathology, 17(4):690-708, 1989.
32. Maronpot, R. R., T. Harada, A. S. K. Murthy, and G. A.
Boorman, ``Documenting Foci of Hepatocellular Alteration in 2-Year
Carcinogenicity Studies: Current Practices of the National
Toxicology Program,'' Toxicology and Pathology, 17(4):675-684, 1989.
33. Mahon, D. C., ``Altered Hepatic Foci in Rat Liver as Weight
of the Evidence of Carcinogenicity: The Canadian Perspective,''
Toxicology and Pathology, 17(4):709-715, 1989.
34. Squire, R. A., ``Evaluation and Grading of Rat Liver Foci in
Carcinogenicity Tests,'' Toxicology and Pathology, 17(4):685-
689,1989.
35. Moch, R. W. and T. P. O'Neill, ``Hepatocellular Foci-A
Regulator's Gordian,'' Toxicology and Pathology, 17(4):724-728,
1989.
36. Lang, P. L., ``Spontaneous Neoplastic Lesions in the Crl:CD-
1(1CR)BR Mouse,'' Charles River Breeding Laboratories, Wilmington,
MA, February 1, 1987.
37. Maita, K., M. Hirano, T. Harada, K. Mitsumori, A. Yoshida,
K. Takahashi, N. Nakashima, T. Kitazawa, A. Enomoto, K. Inui, and Y.
Shirasu, ``Mortality, Major Cause of Morbidity and Spontaneous
Tumors in CD-1 Mice,'' Toxicology and Pathology, 16(3):340-349,
1988.
38. Memorandum from M. J. Bleiberg, FDA, to F. O . Fields, FDA,
November 1994.
39. Memorandum from M. A. Bryant, FDA to N. Beru, August 17,
1995.
40. Memorandum from M. J. Bleiberg, FDA, to J. Gordon, FDA,
August 8, 1990
41. Memorandum from J. M. Collins, FDA to F. O. Fields, FDA,
April 12, 1994.
42. Musa, M. M. and L. L. Lyman, ``Absorption and Disposition of
Warfarin: Effects of Food and Liquids,'' Current Therapeutic
Research, 20:630-633, 1976.
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.
58. Memorandum of Conference, August 1, 1995.
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
g vitamin K^{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}}}}}}}}}}}}}