3118 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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

(§ 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3119

1The 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.

2On 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.

3This decision has been delegated to the

Commissioner of Food and Drugs, 21 CFR

5.10(a)(1).

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).

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

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.’’

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,
3120 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

4Statement 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.

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.

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 at¶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 in¶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 doseresponse study (the 12-week DR study)

of olestra on the status of vitamins¶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 doseresponse and vitamin restoration study

(the 26-week DR/VR study) to extend
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3121

5Free-living subjects maintain their normal diets

and eating patterns except for consumption of the

test article as instructed.

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 hardto-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).

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 (fatsoluble) 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
3122 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

BILLING CODE 4160–01–C
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 oilderived 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 oncecommon commercial practice of

rearranging fats and oils by basecatalyzed 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
3124 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

6These 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).

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 °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

°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 singleday 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 olestracontaining 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3125

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).

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 olestracontaining 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).

Second, CSPI asserted that consumers

usually eat an entire bag of chips at one

sitting, and that bags marked ‘‘singleserving’’ typically contain from threequarters 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 highvolume 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

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 90th 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 halflife 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
3126 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 monothrough 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 14Csucrose, 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 midrange 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3127

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.

10NRC requirements are actually

recommendations set at levels close to the amount

required for good health in the subject animals.

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).

3. Mini-Pig Studies

The absorption of a typical, mid-range

heated olestra was determined in

weanling mini-pigs. The weanling minipig 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 minipigs 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 minipigs (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 multigeneration 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 highdose 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).

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
3128 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 °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-bodyweight 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-tobody- 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3129

11Transcript, vol. 2, p. 135.

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.

14Transcript, vol. 2, p. 136. Discussion of this

concern also appears in the White Paper (Ref. 3)

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

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 Fischer344 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.

Dr. McConnell also noted that the

slides were reviewed by (1) Boardcertified pathologists in the contractor

lab performing the study (2) boardcertified 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 olestrarelated 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 olestrarelated effect because there was no other

lung pathology, there was no relation

between olestra exposure and time-toonset 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
3130 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

15Transcript, vol. 2, p. 111.

16Transcript, vol. 4, p. 113.

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

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 olestrarelated 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 olestrafed 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 organto-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 olestrarelated 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 fatsoluble.

(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 coadministration 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,
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 SpragueDawley 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 C14-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. Fortyeight 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 drugassociated 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

Exp. No. Subject No. male/female Age Range (years) Drug and treatment 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

bioavailability¶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 ‘‘midrange’’ 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
3132 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

17Transcript, vol. 4, p. 50.

18Transcript, vol. 4, p. 50.

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.

20Transcript, vol. p. 124.

21Transcript, vol. p. 124. 22Transcript, vol. p. 119.

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 highdose 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

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 underanticoagulated, 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 fatsoluble 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.

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 antipneumocystis 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.

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 highcarbohydrate 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.

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 micellemediated 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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-week vitamin D/K) 12-week dose response (12-week DR)

16-week vitamin E status in free-living subjects (16-week vitamin E) 12-week vitamin restoration (12-week VR)

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 β-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, doubleblind, 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 αtocopherol, 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
3134 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 olestracontaining 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 μg/

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 α-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 γ-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

23Serum 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

Treatment Group Olestra (g/d)

Vitamin A Vitamin E Vitamin D2

μg/g μg/d mg/g mg/d μg/g μg/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 β-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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3135

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.

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-α-tocopheryl

acetate) per g olestra. This level is

equivalent to 1.9 mg α-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 αtocopherol 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 α-tocopherol equivalents

per g of olestra is the appropriate

compensation level.

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 μg/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

μg 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 μg/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 μg/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 μg 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 γcarboxyglutamic 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

¶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 γ-carboxy glutamic

acid, plasma concentration of descarboxy 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
3136 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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.

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

μg) 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 μg vitamin K in the 8 g/d group

(4 μg/g olestra), 68 μg vitamin K in the

20 g/d group (3.2 μg/g olestra), and 82

μg vitamin K in the 32 g/d group (2.6

μg/g olestra). The petitioner averaged

these three results to yield an estimated

compensation level of 3.3 μg/g olestra.

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 β-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 β-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 doubleblind, placebo-controlled, parallel

design using 221 normal, healthy, freeliving 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 μg (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 Kdependent 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-α 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 freeliving 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, αtocopherol, β-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 αtocopherol concentration was reduced

by 6 percent, relative to control, in the

olestra group and by 4 percent in olestra

with added α-tocopheryl acetate group.

Serum concentrations of β-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

α-tocopheryl acetate/g olestra was not

sufficient to compensate for olestra’s

effect in this study and that olestra did
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3137

26A dose of 20 g is equivalent to the consumption

of two 1-oz servings of savory snacks at a single

meal.

27The 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.

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.

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 doseresponse 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 fatsoluble 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

β-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-α-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 CaHPO4•2H2O
3138 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

and CaCO3, iron as FeSO4•7H2O, and

zinc as ZnSO4•7H2O. The

micronutrients were added directly to

the diet, separate from the olestra,

during diet preparation.

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.
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 1.201.1 1.35 1.80 1.901.1 1.65 2.40 2.604.4 1.65 2.40 2.604.4 2.40 4.20 4.604.4 3.15 6.00 6.607.7 2.05 3.80 4.157.7 3.45 6.60 7.307.7 4.85 9.40 10.45

1Expressed as multiples of the NRC requirements of pigs.
3140 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

28Unlike 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.

29The 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.

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. Abovebasal levels of vitamin E, in the form of

d-α-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

Percent olestra Vitamin A (IU/kg diet) Vitamin E (mg d-α-tocopherol acetate/g 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 dα-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 (αtocopherol), and vitamin D (25-

hydroxyvitamin D2 and 25-

hydroxyvitamin D3) and liver

measurements of vitamin A (total retinol

and retinyl esters) and vitamin E (αtocopherol).

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 doseresponse 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 doseresponse 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

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 μg

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.

The petitioner concluded and FDA

agrees that the results of the 39-week VR
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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-α-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).
3142 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 Study Olestra level (%) Vitamin E compensation (IU/g olestra) 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 higholestra 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-α 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 midand 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 γcarboxyglutamic acid, and plasma levels

of des-carboxylated or undercarboxylated 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 fatsoluble vitamins. Thus,

oversupplementation is significant
3144 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

30 Transcript, vol. 1, p. 84 and vol. 3, p. 234.

31Transcript, vol. 3, p. 234.

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 μg/kg, is in a cornsoybean 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 β-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 β-carotene eaten with

olestra would be decreased by 60

percent and absorption of β-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 β-carotene eaten with

olestra would be decreased by 60

percent, absorption of β-carotene eaten

at eating occasions either before or after

the olestra eating occasion would be

decreased by 30 percent, and absorption

of β-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 β-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.

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 freeliving 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 β-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 fatsoluble 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 olestracontaining 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 withmeal 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3145

32Transcript, vol. 3, pp. 220–225.

33 Dr. Patricia Rodier, is a senior scientist in the

Department of Obstetrics and Gynecology,

University of Rochester. Transcript, vol. 4, p. 99.

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

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).

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 α-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

α-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 sunlightinduced 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 μg

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 μg vitamin D2/

g olestra slightly overcompensated for

olestra’s effects on vitamin D status, as

measured by total 25-OHD levels.
3146 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 μg/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 μg/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 μg 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 μg/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-γcarboxylated 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 Kdependent proteins in the body,

PIVKA–II and urinary Gla will change to

reflect the inadequate supply. The halflives 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 μg 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 μg 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 olestracontaining food. Also, it is well
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3147

34FDA 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.

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).

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.

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.

40See for example Refs. 3 and 62.

41Transcript, vol. 1, p. 172.

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 μg/d and

vitamin K exhibits no known toxicity,

FDA recommended at the Olestra

Working Group and the FAC meetings

that a level of 8 μg 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.

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.

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 fourfold. Dr. Suttie asserted that changes

due to consumption of vitamin Kcompensated olestra would likely be

within the normal range of dietary

variation.

FDA concurs with Dr. Suttie’s

statements and concludes that olestra

should be compensated with 8 μg

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

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).

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
3148 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

42 Dr. Greaves mentioned that blood draws at the

beginning of the Finland study showed that men in

the lower quartile for serum β-carotene in the blood

had significantly higher incidence rates of lung

cancer than the men with the high levels of βcarotene in blood (Ref. 63).

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.

44Octanol: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.

45Transcript, vol. 2, p. 125.

46Transcript, vol. 3, p. 192.

47 Dr. Leonard Cohen, Section Head, Nutrition

and Endocrinology, American Health Foundation.

Transcript, vol. 3, p. 149.

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.

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 βcarotene 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).

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

β-carotene concentration 30 hours

following consumption of a controlled

meal containing 25 mg β-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 β-carotene mutually

inhibit each other’s absorption.

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 (α-carotene, β-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 β-carotene

(Ref. 68).

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 shortterm 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.

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.

Regarding cancer risk, Dr. Peter

Greenwald stated that the effects of

olestra on carotenoid utilization under
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3149

50 In fact, well-controlled studies indicate that

there may be higher incidence of lung cancer in

smokers consuming high levels of β-carotene.

51While 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.

52This 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.)

53The Schilling test is an acute test that measures

the absorption of a dose of radiolabeled vitamin B12

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 β-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 cancerprotective 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.

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.

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

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 watersoluble 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.

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
3150 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

54Transcript, vol. 3, p. 117.

indicators of folate status. 54 Thus, the

agency agrees with the petitioner’s

conclusion that olestra consumption

does not affect folate status.

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-toabsorb 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3151

55At 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.

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 °C for 8 hours, rather

than more typical conditions of > 550 °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.

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
3152 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

56Eight g/d olestra intake approximates the

lifetime average 90th-percentile intake for snack

eaters.

vitamin D depletion. Unlike the fatsoluble 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.

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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3153

57Reporting 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.

58Transcript, vol. 2, p. 185.

59Statement of Dr. Michael Jacobson, CSPI,

Transcript, vol. 1, p. 171.

60Statements 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.

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 olestracontaining 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 diarrhealike 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.

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

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

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 olestraconsuming 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
3154 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

61Passive 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.

62The 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.

63Transcript, vol. 4, p. 163.

64Statement of Dr. Joanne Lupton, Transcript,

vol. 2, p. 222.

‘‘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.

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

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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 multicenter 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
3156 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

65Statement of Dr. Myra Karstadt, CSPI,

Transcript, vol. 3, p. 9.

66Statement of Dr. Herbert Needleman, Professor

of Psychiatry and Pediatrics, University of

Pittsburgh School of Medicine. Transcript, vol. 3, p.

14.

67Statement 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.

68Statement of Captain Charles Hargrove, M.D.,

Transcript, vol. 2, p. 225.

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-yearold 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

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.)

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

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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3157

69Statement 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.

70Microflora-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).

71Statement of Dr. Joanne Lupton, Transcript,

vol. 4, p. 87.

potato chips with olestra by children is

analogous to ‘‘toddlers’ diarrhea,’’ one

of the causes of which is excess fruitjuice consumption. Dr. Kleinman

observed that just as the number of

stools per day decreases when¶

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

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.

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 microflorarelated 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

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
3158 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

72Transcript, 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.

73Statement of Dr. Joanne Lupton, Transcript,

vol. 2, pp. 216–226.

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

75Transcript, vol. 1, p. 112.

76Statement of Dr. Larry Johnson, Professor of

Medicine and Director of the Digestive Diseases

Division, Uniformed Health Service University,

Transcript, vol. 4, p. 83.

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 (14Cfatty 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

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.

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 microfloraassociated 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.

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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3159

77Statement of Dr. Joanne Lupton, Transcript,

vol. 3, p. 89.

78Letter from Drs. A. R. Colon and J. S. DiPalma,

Georgetown University Medical Center, read at the

FAC meeting; Transcript, vol. 3, p. 19.

79Statement of the petitioner, Transcript, vol. 1,

p. 141.

80Transcript, vol. p. 97.

81Statement of Joanne Lupton, Transcript, vol. 3,

p. 24.

82Statements of Drs. Charles Hargrove and Dr.

William Klish, Transcript, vol. 2, pp. 226 and 260,

respectively.

stool is going to be but that there is no

evidence of dehydration, or electrolyte

imbalance in those subjects reporting

‘‘diarrhea’’. 77

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

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 olestrainduced 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 continuously¶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 reducedcalorie 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).

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 microflorarelated 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
3160 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

83Under 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.

84FDA’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.

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.

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

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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3161

85Transcript, vol. 3, p. 91.

86Transcript, vol. 3, p. 93.

87Transcript, vol. 3, p. 52.

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.

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

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
3162 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

88Transcript, vol. 3, p. 90.

89Transcript, vol. 3, p. 218, 259, 261.

90Transcript, vol. 3, p. 263.

91Transcript, vol. 3, p. 271.

92Transcript, vol. 3, p. 258.

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.

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

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

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 olestracontaining 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.
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3163

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.

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 ¶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 olestracontaining 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 wellreasoned 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

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
3164 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 publichealth 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 fooddrug interactions; in this instance, betacarotene 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 drugfood 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 betacarotene 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
3166 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 fatsoluble 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

requiring¶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 olestracontaining 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

¶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,
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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 α-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 μg vitamin K11/g olestra (1.0 X RDA per 10 g olestra)
3168 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

94The 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.

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 olestracontaining 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 olestracontaining 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 olestracontaining 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.

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 § 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 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. BactoUnidisk, 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 §§ 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 § 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 ¶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.
3170 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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.

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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 § 172.867 is added to subpart

I to read as follows:

§ 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
3172 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations

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 μg

vitamin K1 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
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Rules and Regulations 3173

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 §§ 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