36344 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

acted in bad faith, or whether special

circumstances make an award unjust.

(h) Agency review. Either the

applicant or complaint counsel may

seek review of the initial decision on the

fee application by filing a notice of

appeal under § 3.52(a), or the

Commission may decide to review the

decision on its own initiative, in

accordance with § 3.53. If neither the

applicant nor complaint counsel seeks

review and the Commission does not

take review on its own initiative, the

initial decision on the application shall

become a final decision of the

Commission 30 days after it is issued.

Whether to review a decision is a matter

within the discretion of the

Commission. If review is taken, the

Commission will issue a final decision

on the application or remand the

application to the Administrative Law

Judge for further proceedings.

(i) Judicial review. Judicial review of

final Commission decisions on awards

may be sought as provided in 5 U.S.C.

503(c)(2).

(j) Payment of award. An applicant

seeking payment of an award shall

submit to the Secretary of the

Commission a copy of the Commission’s

final decision granting the award,

accompanied by a statement that the

applicant will not seek review of the

decision in the United States courts.

The agency will pay the amount

awarded to the applicant within 60

days, unless judicial review of the

award or of the underlying decision of

the adjudicative proceeding has been

sought by the applicant or any party to

the proceeding.

By direction of the Commission.

Benjamin I. Berman,

Acting Secretary.

[FR Doc. 98–17803 Filed 7–2–98; 8:45 am]

BILLING CODE 6750–01–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 90F–0220]

Food Additives Permitted for Direct

Addition to Food for Human

Consumption; Acesulfame Potassium

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 acesulfame potassium

(ACK) as a nonnutritive sweetener in

nonalcoholic beverages. This action is

in response to a petition filed by

Hoechst Celanese Corp. (Hoechst).

DATES: This regulation is effective July

6, 1998; written objections and requests

for a hearing by August 5, 1998.

ADDRESSES: Submit written objections to

the Dockets Management Branch (HFA–

305), Food and Drug Administration,

5630 Fishers Lane, rm. 1061, Rockville,

MD 20852.

FOR FURTHER INFORMATION CONTACT:

Patricia A. Hansen, Center for Food

Safety and Applied Nutrition (HFS–

206), Food and Drug Administration,

200 C St. SW., Washington, DC 20204,

202–418–3093.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction

II. Evaluation of Safety

III. Evaluation of the Safety of the Petitioned

Use of the Additive

A. ACK—Background

B. ACK—New Information

C. Methylene Chloride

D. Special Conditions Relevant to Use in

Nonalcoholic Beverages

1. Hydrolysis Products—Consumer

Exposure

2. Hydrolysis Products—Evaluation of

Toxicological Information

a. Acetoacetamide-N-sulfonic acid

(AAS)

i. Genetic toxicity testing

ii. Subchronic toxicity studies in rats

and monkeys

iii. Reproduction and developmental

toxicity study in rats

iv. Assessment of AAS

b. Acetoacetamide (AAA)

i. Genetic toxicity testing

ii. Short-term and subchronic

toxicity studies in rats, rabbits, and dogs

iii. Developmental toxicity study in

rabbits

iv. Assessment of AAA—nonthyroid

endpoints

v. Assessment of AAA—thyroid

endpoints

vi. Consideration of whether more

testing of AAA is necessary

E. Summary of FDA’s Safety Evaluation

IV. Response to Comments

A. Summary of Comments

1. Center for Science in the Public

Interest’s (CSPI’s) First Submission

2. CSPI’s Second Submission

3. CSPI’s Third Submission

4. CSPI’s Fourth Submission

5. Hoechst’s Submission

6. Other Submissions

B. Analysis of Specific Issues Raised in the

Comments

1. AAA Test Results

2. ACK Test Results

a. The second rat study

i. Issues raised previously

ii. Issues not raised previously

b. The mouse study

i. Issues raised previously

ii. Issues not raised previously

c. The first rat study

Issues raised previously

C. Summary of FDA’s Response to

Comments

V. Conclusion of Safety

VI. Environmental Impact

VII. Paperwork Reduction Act

VIII. Objections

IX. References

I. Introduction

In a notice published in the Federal

Register of July 30, 1990 (55 FR 30983),

FDA announced that a food additive

petition (FAP 0A4212) had been filed by

Hoechst Celanese Corp. (Hoechst),

Route 202–206 North, Somerville, NJ

08876, proposing that § 172.800

Acesulfame potassium (21 CFR 172.800)

be amended to provide for the safe use

of acesulfame potassium (ACK) as a

nonnutritive sweetener in nonalcoholic

beverages, including beverage bases.

(Recently, Hoechst has reorganized; the

division of Hoechst now responsible for

ACK is known as Nutrinova, Inc., 25

Worlds Fair Dr., Somerset, NJ 08873.)

The present petition contains data and

other information relevant to the safety

of ACK under the proposed conditions

of use; the present petition also relies on

certain data and information contained

in previous petitions for ACK.

FDA’s food additive regulations were

first amended to permit the use of ACK

on July 28, 1988 (53 FR 28379, the ‘‘dry

uses final rule’’), in response to a

petition filed by Hoechst. In its original

evaluation of the safety of ACK, FDA

concluded that a review of animal

feeding studies showed that there is no

association between neoplastic disease

(cancer) and consumption of this

additive (53 FR 28379 at 28380 and

28381). The agency further concluded

that ACK was safe under the conditions

of use proposed in the initial petition,

and amended its food additive

regulations to permit the use of the

sweetener.

Following publication of the dry uses

final rule, the agency received timely

objections from the Center for Science

in the Public Interest (CSPI). CSPI

submitted four separate objections, two

of which asserted that the long-term

studies of ACK in rodents were

inadequate to evaluate ACK’s potential

carcinogenicity, and two of which

asserted that certain of these studies

showed that the additive was

potentially carcinogenic. CSPI requested

a stay of the regulation and also

requested a hearing on each of its

objections. FDA, after careful

consideration of CSPI’s objections,

found that none of the objections raised

issues of fact that justified granting a
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36345

1Stability studies of ACK in aqueous solutions

were also submitted in the original petition for

ACK.

hearing or otherwise provided a basis

for revoking the regulation. Thus FDA

denied both the request for a stay of the

regulation and a hearing, and confirmed

the effective date of the regulation. The

agency published a detailed response to

CSPI’s objections in the Federal

Register of February 27, 1992 (57 FR

6667).

Since its initial approval decision on

the use of ACK, FDA has approved the

following additional uses for ACK in

response to petitions: In baked goods

and baking mixes, including frostings,

icings, and fillings for baked goods; in

yogurt and yogurt-type products; in

frozen and refrigerated desserts; in

sweet sauces, toppings, and syrups; and

in alcoholic beverages (59 FR 61538, 59

FR 61540, and 59 FR 61543, December

1, 1994, and 60 FR 21700, May 3, 1995).

No objections were received in response

to the December 1, 1994, final rule.

However, CSPI filed timely objections to

the agency’s May 3, 1995, final rule

authorizing the use of ACK in alcoholic

beverages (60 FR 21700). The agency’s

response to those objections is

published elsewhere in this issue of the

Federal Register.

With respect to the present petition,

Hoechst’s original submission contained

data and information from several

toxicity studies of ACK, as well as data

and information regarding the stability

of ACK in aqueous solutions.1 Because

hydrolysis of ACK can occur under

certain conditions, the petitioner also

conducted toxicity studies of the

principal hydrolysis products of ACK.

In response to an issue raised by

FDA’s review, Hoechst submitted

additional information regarding ACK

hydrolysis products, including a report

prepared by a panel of experts in

various scientific disciplines who

independently evaluated the results of

certain toxicity studies of the ACK

hydrolysis products. Hoechst also

submitted an indepth analysis of the

potential health risk from one of the

ACK hydrolysis products,

acetoacetamide (AAA). FDA’s Center for

Food Safety and Applied Nutrition

(CFSAN) conducted its own indepth

analysis of the data and information on

AAA, and, in reaching a final decision

on this issue, also obtained the advice

of additional experts from within and

from outside the agency.

FDA notes that CSPI has submitted

comments on the present petition for

use of ACK in nonalcoholic beverages,

and has transmitted comments on that

petition from other interested parties as

well. Further, Hoechst has transmitted

additional comments from two of these

same parties. Several other comments

were also received. The agency’s

response to all comments on the present

petition is presented in section IV of

this document.

II. Evaluation of Safety

Under the general safety standard of

the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 348(c)(3)(A)), a

food additive cannot be approved for a

particular use unless a fair evaluation of

the data available to FDA establishes

that the additive is safe for that use.

FDA’s food additive regulations in

§ 170.3(i) (21 CFR 170.3(i)) define safe

as ‘‘a reasonable certainty in the minds

of competent scientists that the

substance is not harmful under the

intended conditions of use.’’

The food additives anticancer, or

Delaney, clause of the act (21 U.S.C.

348(c)(3)(A)) provides that no food

additive shall be deemed safe if it is

found to induce cancer when ingested

by man or animal. Importantly,

however, the Delaney clause applies to

the additive itself and not to impurities

in the additive. That is, where an

additive itself has not been shown to

cause cancer, but contains a

carcinogenic impurity, the additive is

properly evaluated under the general

safety standard using risk assessment

procedures to determine whether there

is a reasonable certainty that no harm

will result from the intended use of the

additive (Scott v. FDA, 728 F.2d 322

(6th Cir. 1984)).

III. Evaluation of the Safety of the

Petitioned Use of the Additive

A. ACK—Background

As previously noted, FDA’s original

evaluation of the safety of ACK

established that there was no

association between neoplastic disease

(cancer) and consumption of this

additive (53 FR 28379 at 28380 and

28381). That evaluation also established

a lifetime-averaged acceptable daily

intake (ADI) for ACK of 15 milligrams

per kilogram of body weight per day

(mg/kg bw/d), equivalent to 900 mg per

person per day (mg/p/d).

B. ACK—New Information

In the present petition, Hoechst

included several ACK toxicity studies

that had been conducted since the

agency’s original evaluation of the safety

of this additive. These included studies

on mutagenicity, antigenicity, and

potential for dermal and eye irritation;

an acute toxicity study in fish; and a

subchronic toxicity study in diabetic

rats.

The mutagenicity studies

demonstrated that ACK is not mutagenic

at histidine loci in Salmonella

typhimurium or at a tryptophan locus in

Escherichia coli. These results are

consistent with the negative results of

the mutagenicity and genetic toxicity

studies previously considered by FDA

in its original evaluation of the safety of

ACK. The results of all the ACK genetic

toxicity tests establish that ACK is not

genotoxic.

The results of the other ACK toxicity

studies listed above did not show

toxicologically significant ACK-related

adverse effects. Importantly, these ACK

toxicity studies contain no new

information that would change the

agency’s previous conclusion that there

is no association between neoplastic

disease and consumption of this

additive. Thus, FDA has evaluated the

safety of the petitioned use of ACK in

nonalcoholic beverages under the

general safety standard, considering all

available data.

In determining whether the proposed

use of an additive is safe, FDA

considers, among other things, whether

an individual’s lifetime-averaged

estimated daily intake (EDI) of the

additive will be less than the ADI

established from toxicological

information. Importantly, the new

studies on ACK listed above do not

contain any new information that would

cause the agency to alter the previously

determined ADI for ACK. Thus, FDA

concludes that the ADI for ACK is 15

mg/kg bw/d (equivalent to 900 mg/p/d).

The present petition contains

information regarding dietary

consumption of ACK-containing food

products, including nonalcoholic

beverages, and the agency has

considered consumer exposure to ACK

resulting from its use in nonalcoholic

beverages, as well as all currently listed

uses. FDA has calculated the mean EDI

from these combined uses to be 1.6 mg/

kg bw/d, which is equivalent to 96 mg/

p/d; and the 90th percentile EDI from

these combined uses to be 3.0 mg/kg

bw/d, which is equivalent to 180 mg/p/

d (Ref. 1). These levels of dietary

exposure to ACK, which represent

measures of the average and the high

chronic intake, respectively, are both

well below the ADI.

C. Methylene Chloride

Residual amounts of reactants and

manufacturing aids are commonly

found as contaminants in chemical

products, including food additives. In

its evaluation of the safety of ACK, FDA

reviewed both the safety of the additive
36346 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

and the safety of the chemical

impurities that may be present in the

additive from the manufacturing

process.

In the current manufacturing process

for ACK, methylene chloride, a

carcinogenic chemical, is used as a

solvent in the initial manufacturing

step. Subsequently, the product is

neutralized, stripped of methylene

chloride, and recrystallized from water.

Data submitted by the petitioner show

that methylene chloride could not be

detected in the final product at a limit

of detection of 40 parts per billion (ppb).

FDA has previously discussed the

significance of the use of methylene

chloride in the production of ACK. The

agency incorporates those discussions,

published in the Federal Register of

December 1, 1994 (59 FR 61538, 59 FR

61540, and 59 FR 61543) and of May 3,

1995 (60 FR 21700), in full, into the

agency’s safety determination on the

present petition.

Specifically, in evaluating the safety

of the uses of the additive that are

currently listed, FDA concluded, using

risk assessment procedures, that the

estimated upper-bound limit of

individual lifetime risk from the

potential exposure to methylene

chloride resulting from these uses of

ACK, together with the petitioned use of

ACK in nonalcoholic beverages, is 2.6 x

10-11, or less than 3 in 100 billion. The

agency also concluded that, because of

the numerous conservative assumptions

used in calculating this estimated

upper-bound limit of risk, this upperbound limit would be expected to be

substantially higher than any actual risk

(59 FR 61538 at 61539, 59 FR 61540 at

61542, 59 FR 61543 at 61544, and 60 FR

21700). FDA has received no new

information that would change the

agency’s previous conclusion.

Therefore, the agency concludes that

there is a reasonable certainty of no

harm from the exposure to methylene

chloride that might result from the

proposed use of ACK in nonalcoholic

beverages.

In conducting its evaluation, the

agency also considered whether a

specification is necessary to control the

amount of potential methylene chloride

impurity in ACK. At that time, FDA

concluded that there is no reasonable

possibility that methylene chloride will

be present in amounts that present a

health concern, and that there would

thus be no justification for requiring

manufacturers to monitor compliance

with a specification (59 FR 61538 at

61539, 59 FR 61540 at 61542, 59 FR

61543 at 61544, and 60 FR 21700).

Because no new information has been

received that would change FDA’s

previous conclusion regarding the need

for a specification, the agency affirms its

prior determination that a specification

for methylene chloride impurity in ACK

is unnecessary.

D. Special Conditions Relevant to Use in

Nonalcoholic Beverages

The use of ACK as a nonnutritive

sweetener in nonalcoholic beverages

may subject the sweetener to conditions

other than those considered in the

evaluation of the currently listed uses of

this additive. FDA has evaluated data in

the present petition and other

information regarding the stability of

ACK under a variety of conditions that

characterize the proposed use in

nonalcoholic beverages. Based on these

data and information, the agency

concludes that ACK is stable under

almost all circumstances expected to be

encountered for the proposed use in

nonalcoholic beverages.

However, FDA has determined that

there is a limited possibility that some

nonalcoholic beverages could be stored

under conditions that could lead to the

formation of ACK hydrolysis products.

Specifically, small amounts of

hydrolysis products may be formed in

highly acidic aqueous food products

(which would include some, though not

all, nonalcoholic beverages) under

conditions of prolonged storage at

elevated temperatures. As part of its

safety evaluation, FDA has reviewed

toxicological data and supporting

information regarding the hydrolysis

products of ACK, as well as estimates of

human dietary exposure to the

hydrolysis products. The substantive

aspects of the agency’s safety

assessment of the hydrolysis products,

as they relate to the use of ACK in

nonalcoholic beverages, are discussed in

detail in sections III.D.1 and 2 of this

document.

1. Hydrolysis Products—Consumer

Exposure

Both the present petition and the

petition supporting the initial approval

of ACK contain studies of the stability

of ACK in aqueous solutions. These

studies show that ACK hydrolyzes, in

strongly acidic or strongly basic aqueous

solutions, to acetoacetamide-N-sulfonic

acid (AAS). AAS subsequently

hydrolyzes to acetoacetamide (AAA).

The AAA that is formed is also subject

to hydrolysis; the eventual endproducts

are acetone, carbon dioxide, and

ammonia. Data and other information

submitted by the petitioner and

evaluated by the agency establish that

both AAS and AAA are transient

intermediates in the overall ACK

hydrolysis pathway and that no

significant buildup of AAS or AAA will

occur in ACK-sweetened nonalcoholic

beverages.

Studies in the two petitions also

establish that hydrolysis of ACK is

dependent on two other factors in

addition to pH: Time and temperature.

Prolonged storage at elevated

temperatures is required to produce

detectable amounts of AAS and,

particularly, its byproduct, AAA, even

in test solutions containing over 100

times the amount of ACK that would

ordinarily be used in a nonalcoholic

beverage. Specifically, data in the

petition show that such a concentrated,

buffered, carbonated solution of pH 3.0

(representative of the lower end of the

pH range for carbonated diet soft

drinks), after storage at 20 °C (68 °F) for

8 weeks, contained AAS at a level of

0.35 percent of the original ACK level.

Even with a sensitive analytical method

(limit of detection, circa (ca.) 1 ppb,

corresponding to 0.001 percent of the

original ACK level), no AAA was

detected in this system. More severe

storage conditions were required to

produce detectable levels of AAA (e.g.,

8 weeks storage at 30 °C (86 °F) or 50

weeks storage at 20 °C).

The combination of conditions

necessary to produce measurable

amounts of hydrolysis products in

beverages (i.e., low beverage pH and

extended storage at high temperatures)

is not expected to be frequently

encountered. The stability studies also

establish that AAA and AAS will not

build up in beverages over time.

Accordingly, FDA believes that any

consumer exposure to AAA and AAS

from consumption of ACK-sweetened

nonalcoholic beverages will be at

extremely low levels and also both

intermittent and infrequent.

Nevertheless, using data from the

stability studies and other information

regarding consumption patterns, FDA

has estimated a potential lifetimeaveraged ‘‘daily’’ dietary intake of ACK

hydrolysis products that might result

from consumption of ACK-sweetened

nonalcoholic beverages. In its

calculations, the agency has deliberately

incorporated several assumptions that,

taken together, will produce an

estimated ‘‘daily’’ intake that is likely to

be an overestimate rather than an

underestimate. First, FDA has assumed

that all nonalcoholic beverages ingested

by consumers will have been sweetened

only with ACK, that ACK will be used

at the highest levels characteristic of

each type of nonalcoholic beverage, and

that the consumer will have ingested

such beverages at the 90th percentile

consumption level. Second, FDA has

assumed certain values for beverage pH,
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36347

2FDA also considered the effect of extreme

temperature conditions on dietary exposure to ACK

hydrolysis products (see Ref. 2). However, the

agency has concluded that, for several reasons, it is

highly unlikely that beverages stored under

extremely high temperatures for extended periods

of time would be consumed on a continued basis.

First, most in-home or retail storage is under

refrigeration or other climate-controlled conditions.

Second, it is a common and usual practice in the

industry to discard diet beverages that have been

stored under extreme conditions (e.g., 50 to 55 °C,

equivalent to 120 to 130 °F) because the artificial

sweeteners currently in use undergo significant

decomposition that results in an unpalatable

product. FDA expects that this practice would also

be applied to beverages sweetened with ACK

because the decomposition of ACK that occurs

under such extreme conditions also results in an

unpalatable product. Finally, consumers do not

customarily store nonalcoholic beverages under

extreme conditions for lengthy periods, and would

not be expected to habitually consume the

unpalatable products that result from extended

storage at extremely high temperatures.

storage time, and storage temperature

that are also likely to produce an

overestimate of the ‘‘daily’’ intake of

ACK hydrolysis products. The basis for

the agency’s particular choice of

beverage pH, storage time, and storage

temperature is discussed in more detail

in the next two paragraphs.

FDA has chosen to use a pH of 3.0 in

its analysis because this pH is

representative of the lower end of the

range in which beverages containing

nonnutritive sweeteners are formulated.

The agency has chosen to use a storage

time of 8 weeks because FDA considers

8 weeks to be representative of a storage

period that is significantly longer than

the average storage period for

nonalcoholic beverages. Data in the

petition and in the agency’s files show

that ca. 90 percent of diet cola

(representative of beverages formulated

at low pH) is sold within 8 weeks of

bottling; these data also show that even

when additional flavor categories are

considered, ca. 90 percent of

nonalcoholic beverages are still sold

within 9.5 weeks of bottling, with an

average time from bottling to sale of just

under 4 weeks (Ref. 2).

With respect to temperature, FDA has

chosen to use 20 °C in its analysis

because this temperature is

representative of the high end of the

range of in-home or in-store storage

temperatures, when periods of both

refrigerated and room temperature

storage are taken into account.2 The

agency also reviewed climate data for

different geographical locations in the

United States, which were chosen to

cover the range of possible temperature

extremes for beverages stored under

ambient conditions (no temperature

control). This review shows that few

locations have annual average

temperatures above 20 °C (Ref. 2).

Accordingly, for all of the foregoing

reasons, the agency has used 20 °C as

representative of the temperature

conditions likely to be encountered over

an extended storage period.

FDA has calculated estimated dietary

exposure to AAS and AAA based upon

data reflecting the foregoing

assumptions regarding beverage

formulation and storage conditions (see

Ref. 2). The agency concludes that, for

the 90th percentile consumer of ACKsweetened nonalcoholic beverages,

exposure to AAS would be no more

than 2.5 micrograms (μg)/kg bw/d,

which is equivalent to 0.15 mg/p/d. In

estimating consumer exposure to AAA,

the agency incorporated an additional

conservative assumption: that AAA

would be present at a level

corresponding to one-half the limit of

detection (Ref. 3), even though it was

not actually detected. The agency

concludes that, for the 90th percentile

consumer of ACK-sweetened

nonalcoholic beverages, exposure to

AAA would be no more than 3.3

nanograms (ng)/kg bw/d, which is

equivalent to 0.2 μg/p/d.

2. Hydrolysis Products—Evaluation of

Toxicological Information

In support of the safety of ACK for use

as a nonnutritive sweetener in

nonalcoholic beverages, the petitioner

submitted toxicity studies of AAS and

AAA, the two principal hydrolysis

products of ACK. The agency’s

evaluation of these toxicological data

and other related information follows.

a. Acetoacetamide-N-sulfonic acid

(AAS). Hoechst submitted a set of

toxicity studies of AAS in support of the

safety of the proposed use of ACK in

nonalcoholic beverages including:

Short-term tests for genetic toxicity;

acute, short-term and subchronic

studies in rats; a subchronic study in

dogs; short-term and subchronic studies

in monkeys; an acute study in humans;

a reproduction and developmental

toxicity study in rats; and metabolism

studies in rats and humans. The key

studies of AAS relevant to FDA’s safety

decision regarding the petitioned use of

ACK are discussed in the next sections

of this document.

i. Genetic toxicity testing. AAS was

tested in several in vitro and in vivo

genetic toxicity tests. In the absence of

bioassay data, such tests are often used

to predict the carcinogenic potential of

the test compound.

AAS was not mutagenic at histidine

loci in Salmonella typhimurium (Ames

test), at a tryptophan locus in

Escherichia coli, nor at the HGPRT

locus in V79 cells treated in vitro. AAS

did not induce unscheduled

deoxyribonucleic acid (DNA) synthesis

in strain A 549 human cells exposed in

vitro. Finally, AAS was not clastogenic

in V79 cells exposed in vitro nor in

bone marrow cells of NMRI mice. The

agency concludes that results of these

tests establish that AAS is not

genotoxic.

ii. Subchronic toxicity studies in rats

and monkeys. The petitioner submitted

the results of a subchronic toxicity

study in which AAS was administered

in the diet to 30 Wistar rats/sex/group

at dose levels equivalent to 0, 800,

2,000, or 5,000 mg/kg bw/d for 90 days.

Twenty rats/sex/group were sacrificed

at the end of the dosing period. The

remaining ten rats/sex/group were

designated as ‘‘recovery’’ animals; that

is, there was an interval of

approximately 1 month between the

time dosing ended and the time of

sacrifice for these animals.

Increased relative kidney weights and

decreased relative pituitary weights

were observed in high-dose female rats.

The mid- and high-dose groups (2,000

and 5,000 mg/kg bw/d, respectively) of

male and female rats had softer feces,

decreased body weight gain, and doserelated increases in feed consumption

compared to controls. Other AASrelated effects observed in the animals

in the mid- and high-dose groups

included increased urine pH, and

changes in various clinical chemistry

parameters, some of which changes

resolved by the end of the recovery

period. Certain changes in the caecum

were also observed; however, these

effects had also resolved by the end of

the recovery period, and were judged by

FDA to be a probable physiological

adaptation to osmotic changes in the

gastrointestinal tract. Based on these

data, FDA concludes that the noobserved-effect level (NOEL) from this

study is 800 mg AAS/kg bw/d, the

lowest dose level tested in this study

(Ref. 4).

The petitioner also submitted the

results of a subchronic toxicity study of

AAS in Cynomologous monkeys. In this

study, four monkeys/sex/group were

administered gavage doses of 0, 100,

315, or 1,000 mg AAS/kg bw/d for 13

weeks. Marginal decreases in the

absolute and relative weights of various

organs in animals of the mid- and highdose groups were observed; however,

FDA does not consider these effects to

be of toxicological significance because

of the lack of corroborative evidence of

organ toxicity. The only toxicologically

significant effect observed in this study

was a dose-related increase in incidence

and severity of diarrhea in the mid- and

high-dose groups. Thus, FDA concludes

that the NOEL for AAS from this study
36348 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

3The petitioner also submitted results of genetic

toxicity tests of β-hydroxybutyramide (BHB), the

principal metabolite of AAA in humans. The Ames

test of BHB was well conducted and showed that

BHB is not mutagenic. Although several of the other

genetic toxicity tests of BHB had deficiencies, none

of these tests indicated that BHB is genotoxic.

is 100 mg/kg bw/d, the lowest dose level

tested (Ref. 4).

iii. Reproduction and developmental

toxicity study in rats. The petitioner

submitted the results of a twogeneration reproduction study with a

teratology phase conducted in SpragueDawley rats. In this study, AAS was

administered in the diet to 25 rats/sex/

group of the P- and F1-generation at

dose levels equivalent to 0, 164, 492, or

1,780 mg AAS/kg bw/d. No adverse

effects on reproduction or

developmental parameters were

observed at any dose level in this study.

Thus, FDA concludes that the NOEL for

this study is 1,780 mg AAS/kg bw/d, the

highest dose used in the study (Ref. 4).

iv. Assessment of AAS. No adverse

AAS-related effects were observed at

800 mg/kg bw/d in the subchronic rat

study, at 100 mg/kg bw/d in the

subchronic monkey study, and at 1,780

mg/kg bw/d and lower in the

reproduction/teratology study in rats.

The agency has no safety concerns about

AAS at its anticipated level of intake

(less than 2.5 μg/kg bw/day) because of

the substantial margin between this

level and the levels at which no adverse

effects were observed in these studies (a

margin of at least 40,000).

b. Acetoacetamide (AAA). Hoechst

submitted a set of toxicity studies of

AAA in support of the safety of ACK for

use in nonalcoholic beverages,

including short-term tests for genetic

toxicity; an acute study, two short-term

studies, and a subchronic study in rats;

an acute and two short-term studies in

dogs; a subchronic study in rabbits;

metabolism studies in rats, dogs,

hamsters, and humans; a developmental

toxicity study in rabbits; and several

other studies. The key studies of AAA

relevant to FDA’s safety decision

regarding the petitioned uses of ACK are

discussed in detail below.

i. Genetic toxicity testing. AAA was

tested in several in vitro and in vivo

genetic toxicity tests. As noted, in the

absence of bioassay data, such tests are

often used to predict the carcinogenic

potential of the test compound.

AAA was not mutagenic at the

HGPRT locus in V79 cells treated in

vitro nor at histidine loci in Salmonella

typhimurium (Ames test). AAA was not

clastogenic in V79 cells exposed in vitro

nor in bone marrow cells of NMRI mice.

In addition, AAA did not induce

unscheduled DNA synthesis in strain A

549 human cells exposed in vitro. The

agency concludes that the results of

these tests establish that AAA is not

genotoxic.3

ii. Short-term and subchronic toxicity

studies in rats, rabbits, and dogs. The

petitioner submitted the results of one

subchronic (90-day) and two short-term

toxicity studies of AAA in rats. One

short-term (30-day) study was designed

to determine appropriate doses for the

subsequent subchronic study. The

second short-term (14-day) study was

designed as a preliminary mechanistic

study; the second short-term study is

discussed in detail in section III.D.2.b.v

of this document.

In the subchronic study, AAA was

administered in the diet to 15 SPF

Wistar rats/sex/group at dose levels

equivalent to 0, 24, 157, 794, or 4,300

mg/kg bw/d for 13 weeks. The following

AAA-related adverse effects were

identified in the subchronic rat study:

(1) Reduced body weights of males and

females in the highest dose group over

the entire study; (2) anemia in female

rats in the highest dose group and male

rats in the two highest dose groups; (3)

increased numbers of both males and

females with centrilobular fatty liver in

the highest dose group; (4) increased

group mean relative liver weights for

male and female rats in the highest dose

group; as well as (5) various adverse

effects on the thyroid, which are

discribed in the next paragraph.

The adverse effects on the thyroid

observed in the subchronic rat study of

AAA were: (1) Dose-related increases in

the numbers of males and females with

grossly enlarged thyroids; (2) increased

relative thyroid weights for mid- and

high-dose males and females; (3) doserelated increases in the numbers of

males and females with follicular cell

hypertrophy and hyperplasia; and (4)

thyroid adenomas in one male rat in

each of the two highest dose groups. No

hypertrophy or hyperplasia was

associated with enlarged thyroids in

controls or in animals in the lowest dose

group (24 mg/kg bw/d).

With respect to endpoints in organs

other than the thyroid, no adverse

toxicological effects were observed at

doses corresponding to 157 mg/kg bw/

day and lower. However, based on the

gross and histopathological findings in

the thyroid, FDA concludes that the

NOEL from the subchronic rat study is

24 mg AAA/kg bw/d, the lowest dose

tested in this study.

The petitioner also submitted the

results of a subchronic study of AAA in

albino Himalayan rabbits. In this study,

six rabbits/sex/group were administered

0, 1,200, 6,000, or 30,000 mg AAA/kg

drinking water/day (equivalent to 0, 96,

499, or 2,192 mg AAA/kg bw/d for male

rabbits, and to 0, 93, 560, or 2,763 mg

AAA/kg bw/d for female rabbits). The

following effects were observed: (1)

Significantly increased testes weights

and signs of focal tubular

hypospermatogenesis in the testes of all

high-dose males; (2) significantly

increased thyroid weights in high-dose

males and females; and (3) thyroid

follicular cell hypertrophy and

hyperplasia in all high-dose males and

females. One mid-dose female and one

high-dose female in this study had

grossly enlarged thyroids; the mid-dose

female also had a thyroid follicular cyst

that may have been part of a

hyperplastic response.

With respect to endpoints in organs

other than the thyroid, no adverse

toxicological effects were observed at

doses corresponding to 499 mg/kg bw/

day and lower. However, based on the

evidence that the thyroid is a target

organ for AAA-related toxicity and the

finding of possible thyroid hyperplasia

in one female in the mid-dose group,

FDA concludes that the NOEL for AAA

in rabbits is 93 mg/kg bw/d, the lowest

dose tested in females in this study (Ref.

4).

The petitioner submitted the results of

two short-term (14-day) studies of AAA

in dogs. In the first short-term study,

two dogs/sex/group were gavaged with

0, 100, 500, or 2,500 mg AAA/kg bw/d

for 14 days. Thyroid follicular cell

hyperplasia was observed in males and

females in all dose groups.

Because adverse effects were observed

at all dose levels in the first study, the

petitioner performed a second shortterm (14-day) dog study using lower

doses. In the second study, three dogs/

sex/group were gavaged with 0, 4, 20, or

100 mg AAA/kg bw/d for 14 days; at the

end of the dosing period two males and

females from each group were

sacrificed. The remaining male and

female in each group were designated as

‘‘recovery’’ animals; that is, there was an

interval of approximately 1 month

between the time dosing ended and the

time of sacrifice for these two animals.

In this study, two of the males in the

high-dose group developed thyroid

follicular hyperplasia; no other males

and no females in this study were

reported to have thyroid abnormalities.

However, of the two high-dose males

that developed thyroid follicular

hyperplasia, one was a ‘‘recovery’’

animal, indicating that the effect of

AAA on the thyroid had persisted for 1

month after dosing ended. In an effort

to identify a possible mechanism for

AAA’s action on the thyroid in the

second dog study, the investigators
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36349

4 In reaching a safety decision on a food additive,

FDA typically uses NOEL’s determined from

studies of at least 90 days duration (a subchronic

study) and uses the term ‘‘NOEL’’ to refer

specifically to the no-observed-effect levels

determined from such studies. Results from studies

in which animals are exposed for shorter test

periods are typically used for different purposes

(e.g., to gather information for use in designing

longer studies). The short-term studies in dogs and

rats (14 days) are too short to determine a

subchronic NOEL.

5 Iodine is taken up by the thyroid and converted

to the thyroid hormone thyroxine, also known as T4

(which contains four iodine atoms) or to triiodothyronine, otherwise known as T3 (which

contains three iodine atoms). Thyroid hormone

production and release into circulation are

stimulated by TSH released by the pituitary in

response to decreases in circulating levels of T3 and

T4. The biological functions of T4 and T3 are

similar. The thyroid hormones are primarily

metabolized in the liver and, to a lesser extent, in

the kidneys. T4 can be converted to T3 (biologically

active) or to reverse T3 (inactive), and then to diiodothyronine (DIT).

Thyroid hypertrophy, hyperplasia and neoplasia

can be caused by a wide range of nongenotoxic

compounds. The common factor is prolonged

stimulation of the thyroid by TSH following

disruption of the normal feedback mechanism that

controls the serum level of TSH. This disruption of

thyroid hormone economy can be caused by

interference with iodide uptake and thyroid

hormone synthesis or secretion, interference with

the peripheral metabolism of T4 or T3, or increased

metabolism and excretion of thyroid hormones (see

Refs. 5 and 6).

6 ‘‘Ample information in experimental animals

indicates a relationship between inhibition of

thyroid-pituitary homeostasis and the development

of thyroid follicular cell neoplasms. This is

generally the case when there are long-term

reductions in circulating thyroid hormones which

have triggered increases in circulating thyroid

stimulating hormone * * *. The progression of

events leading to thyroid * * * neoplasms can be

reversed under certain circumstances by

reestablishing thyroid-pituitary homeostasis’’ (Ref.

6).

measured serum levels of thyroid

hormones T3 and T4 at the end of the

study; no compound-related changes in

serum T3 or T4 levels were observed.

(The investigators did not measure

levels of thyroid stimulating hormone

(TSH).)

FDA concludes that the results of the

short-term and subchronic toxicity

studies in rats, rabbits, and dogs

demonstrate that AAA has a

proliferative effect on the thyroid (i.e.,

diffuse follicular cell hypertrophy and

hyperplasia). The agency’s assessment

of the significance of the observed

thyroid lesions is discussed in detail in

section III.D.2.b.v of this document.

iii. Developmental toxicity study in

rabbits. The petitioner submitted an

embryotoxicity study of AAA in

Chinchilla rabbits in which groups of 16

rabbits were gavaged with 0, 100, 300,

or 1,000 mg AAA/kg bw/d on days 6

through 18 of pregnancy. FDA has

determined that there were no

toxicologically significant effects of

AAA on reproductive or developmental

parameters in this study; thus, the

NOEL for reproductive and

developmental effects is 1,000 mg AAA/

kg bw/d, the highest dose used in this

study (Ref. 4).

iv. Assessment of AAA—nonthyroid

endpoints. For organs other than the

thyroid, no AAA-related adverse effects

were observed at 157 mg/kg bw/d and

lower in the subchronic rat study, at 499

mg/kg bw/d and lower in the

subchronic rabbit study, and at 1,000

mg/kg bw/d and lower in the

developmental toxicity study in rabbits.

With respect to endpoints in organs

other than the thyroid, the agency has

no safety concerns about AAA at its

anticipated level of intake (less than 3.3

ng/kg bw/day) because of the substantial

margin between this level and the levels

at which no adverse effects were

observed in the studies discussed

previously (a margin of at least 5

million).

v. Assessment of AAA—thyroid

endpoints. No adverse AAA-related

effects on the thyroid were observed at

24 mg/kg bw/day in the subchronic rat

study, at 93 mg/kg bw/day in the

subchronic rabbit study, and at 20 mg/

kg bw/day and lower in the second

short-term dog study. Although the

study results permit FDA to identify

NOEL’s for certain thyroid endpoints in

the rat and rabbit subchronic studies,4

the major histological findings in these

studies, thyroid follicular cell

hypertrophy and hyperplasia, raise a

question regarding the possible

tumorigenic activity of AAA. Thyroid

follicular cell hypertrophy and

hyperplasia were also observed at

similar levels of AAA administration in

the dog studies, which studies were of

even shorter duration. The pronounced

thyroid follicular cell hypertrophy and

hyperplasia observed in rats, rabbits,

and dogs, considered together with the

occurrence of thyroid adenomas in two

males in the subchronic rat study,

suggest that AAA might induce thyroid

tumors if administered in long-term oral

studies (see Refs. 2 and 4).

In response to FDA’s concerns

regarding AAA’s thyroid effects, the

petitioner initially argued that

application of an appropriate safety

factor to the lowest NOEL for thyroid

endpoints was a suitable approach,

despite the possible tumorigenic activity

of AAA. Hoechst maintained that the

dose-related hypertrophy and

hyperplasia of the thyroid follicular

cells and, in a 90-day study, the

progression of some cells to adenomas

was consistent with a typical pattern of

morphological changes clearly

associated with sustained, elevated

levels of TSH,5 particularly in the rat.

Hoechst also maintained that AAA was

most likely to act on the thyroid gland

by inhibiting the enzyme

thyroperoxidase in follicular cells.

Thyroperoxidase is required for

synthesis of T3 and T4 in the thyroid;

therefore, inhibiting this enzyme would

lead to a reduction in the levels of T3

and T4 and, consequently, increased

serum levels of TSH (see Refs. 5 and 6).

As support for this hypothesis, Hoechst

referenced an extensive body of

scientific literature linking

thyroperoxidase inhibition (and

consequent elevated TSH levels) by

other compounds to thyroid lesions that

are similar in type, severity, and

timecourse of development, to the

thyroid lesions observed in the shortterm and subchronic studies of AAA

summarized previously in this

document. Hoechst asserted that

progression of the hypertrophy and the

hyperplasia associated with AAA would

be dependent on continued or chronic

stimulation of the thyroid gland by TSH,

again drawing upon comparisons with

other compounds whose similar effects

on the thyroid were mediated by

chronic TSH stimulation.6

In further support of its argument,

Hoechst submitted a set of publications

addressing various aspects of thyroid

function and toxicity, including thyroid

carcinogenicity; a report authored by the

‘‘Acesulfame K Scientific Expert Panel,’’

a group of experts retained by the

petitioner to perform an independent

safety evaluation of AAS and AAA (Ref.

7); and a letter from one of the experts

from the Acesulfame K Scientific Expert

Panel elaborating on the significance of

the thyroid effects of AAA (Ref. 8).

The petitioner also submitted the

results of a short-term study of AAA in

rats (the ‘‘preliminary mechanistic

study’’). In this study, 5 male rats per

group were fed diets containing 0, 50,

123, 410, 1,110, or 2,400 ppm AAA or

90 ppm methimazole (positive control)

for a period of 14 days. The following

AAA-induced thyroid effects were

observed in the preliminary mechanistic

study: (1) Significantly increased

absolute and relative thyroid weights in

all positive control rats and in all rats

fed diets containing 1,110 or 2,400 ppm

AAA; (2) grossly enlarged thyroids in all

positive control rats and in all rats fed

diets containing 1,110 or 2,400 ppm

AAA; (3) diffuse thyroid follicular cell

hypertrophy and hyperplasia in all

positive control rats and in all rats fed

diets containing 1,110 or 2,400 ppm

AAA; (4) significantly increased levels

of TSH in positive control rats, as well

as in rats fed 410, 1,110 or 2,400 ppm
36350 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

AAA; (5) significantly decreased levels

of T4 and reverse T3 in positive control

rats and in rats fed diets containing

1,110 or 2,400 ppm AAA; and (6)

significantly decreased T3 levels in

positive control rats and in rats fed diets

containing 2,400 ppm AAA (see Ref. 4).

In further support of its proposed

mechanism, Hoechst also submitted the

results of an in vitro investigation of the

action of AAA on canine

thyroperoxidase. In this study, AAA

was shown to inhibit enzyme activity in

a dose-related manner; the AAA

concentration at which 50 percent

enzyme inhibition occurred was

calculated by Hoechst to be 28.6

micromolar. Hoechst pointed to the

consistency between the results of both

the preliminary mechanistic study and

the thyroperoxidase inhibition study as

further evidence for the link it

hypothesized between thyroperoxidase

inhibition and the thyroid-related

effects observed in the oral toxicity

studies of AAA.

Hoechst also argued that a substance

acting through a TSH-dependent

mechanism would be expected to show

a threshold below which no excessive

stimulation of thyroid follicular cells

would occur. The petitioner

acknowledged that it is difficult to

actually determine thresholds for lowincidence effects because of the small

numbers of animals ordinarily used in

toxicity studies (see Ref. 8). However,

Hoechst cited the results of the

preliminary mechanistic study, the

results of the in vitro thyroperoxidase

inhibition study, and the results of the

short-term and subchronic oral studies

in rats, rabbits, and dogs as strong

evidence of the existence of a threshold

for AAA-induced thyroid effects. The

petitioner also pointed to the negative

results of the genetic toxicity tests of

AAA as further support for its argument

that a threshold level should exist,

below which administration of AAA

would not induce thyroid tumors. That

is, hypertrophy and hyperplasia and, by

extension, possible progression to

tumors, would occur only at AAA doses

high enough to increase circulating

levels of TSH, and not through a

genotoxic mechanism.

In summary, Hoechst proposed the

following nongenotoxic or ‘‘secondary’’

mechanism for the AAA-induced effects

observed in the thyroids of several

species: (1) At high doses, AAA acts to

disrupt thyroid hormone economy by

inhibiting thyroperoxidase activity and

thus decreasing serum levels of T3 and

T4; (2) the disruption in thyroid

hormone economy results in

hypersecretion of TSH by the pituitary;

(3) the elevated blood levels of TSH, if

sustained, result in hypertrophy and

hyperplasia of the thyroid follicular

cells and, eventually, thyroid tumors;

and (4) that AAA does not act through

a genotoxic mechanism to initiate a

neoplastic process.

Hoechst explicitly acknowledged that

there was a distinct possibility that

AAA, if tested in a 2-year rodent

bioassay, would induce thyroid tumors.

However, Hoechst also maintained that

thyroid tumors would occur only as a

result of chronic consumption of AAA

in amounts high enough to induce

excess TSH production. Hoechst argued

that because AAA would be consumed

only in extremely low amounts, well

below any value they believed likely for

the postulated threshold for stimulating

excess TSH production, it would be

appropriate to base an analysis of the

potential health risk from AAA on a

comparison between the NOEL’s for

certain thyroid endpoints and the

anticipated low levels of intake (a

‘‘safety factor’’ or ‘‘threshold concept’’

approach). Hoechst concluded that

because the NOEL’s for AAA’s thyroid

effects exceeded its dietary exposure

estimate by a factor of approximately 2

million, there would be essentially no

risk to human health from dietary

exposure to AAA resulting from

consumption of beverages sweetened

with ACK.

FDA agrees that the anticipated

human dietary exposure to AAA is

lower than the NOEL’s for AAA-related

thyroid hypertrophy and hyperplasia by

several orders of magnitude. FDA does

not agree, however, that Hoechst’s

approach of simply comparing these

NOEL’s with dietary exposure is

sufficient for evaluating the potential

health risk suggested by the AAArelated effects observed in the thyroid.

As previously noted, the AAA-related

histopathological findings in the thyroid

(i.e., hypertrophy and hyperplasia in

rats, rabbits, and dogs, together with

adenomas in two AAA-treated male rats

in the subchronic study) suggest that

AAA may induce thyroid tumors in

long-term studies. Hoechst’s ‘‘safety

factor’’ approach relies on the firm’s

proposed mechanism for AAA’s action

on the thyroid, which explicitly

incorporates a presumed threshold for

AAA’s thyroid effects. FDA has

concluded, however, that the available

data do not establish the mechanism

proposed by the petitioner. The

strengths and weaknesses in the data

submitted in support of Hoechst’s

proposed mechanism are discussed in

the following paragraphs.

FDA has determined that there is

strong evidence that AAA is not

genotoxic. The agency also

acknowledges that some of the results

from the preliminary mechanistic study

and the in vitro study of canine

thyroperoxidase are consistent with

Hoechst’s argument that AAA-induced

effects on the thyroid are mediated

through disruption of thyroid hormone

economy. In particular, because

inhibition of thyroperoxidase would

cause TSH serum levels to increase

rapidly, the results of the in vitro

thyroperoxidase inhibition study are

consistent with results of the

preliminary mechanistic study. The

preliminary mechanistic study also

provides some support for the

hypothesis that AAA-induced thyroid

effects in rats are mediated by doserelated perturbations in thyroid

hormone economy because decreased

circulating levels of T3 and T4 and

increased serum TSH levels were

associated with thyroid follicular cell

hypertrophy and hyperplasia in this

study.

However, a threshold level for

thyroperoxidase inhibition in vivo

cannot be determined from the available

data, which were obtained in an in vitro

system. In addition, a threshold level for

AAA-induced TSH induction cannot be

determined from the in vivo studies,

which were conducted with too few

animals. Finally, the in vivo studies of

AAA-induced effects on thyroid

hormone economy (the preliminary

mechanistic study in rats and the

second short-term dog study) were both

limited to 14 days duration; there are no

studies of the effects of longer periods

of exposure to AAA on thyroid hormone

economy.

Moreover, FDA has determined that

some of the data from the short-term

and subchronic toxicity studies appear

to be inconsistent with Hoechst’s

proposed mechanism. For example, as

discussed above, early AAA-related

changes in the thyroid (e.g.,

hypertrophy and hyperplasia), if

induced via the petitioner’s proposed

mechanism, would be expected to be

reversible. However, in the second 14-

day dog study, one of the two high-dose

animals with thyroid follicular

hyperplasia was a ‘‘recovery’’ animal

(i.e., an animal sacrificed 1 month after

dosing ended); the observation of

hyperplasia in a ‘‘recovery’’ animal

indicates that AAA’s effect on the

thyroid persisted for 1 month after

dosing ended. This raises the possibility

that the effect may persist for longer

than 1 month and may not be readily or

completely reversible.

Similarly, some of the data obtained

from the subchronic rat study are not

entirely consistent with certain features

of the mechanism proposed by Hoechst.
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36351

7 In the absence of information that would

support another approach, FDA uses simple linear

extrapolation from the dose-response information in

the experimental range to estimate the doseresponse outside the experimental range (that is, at

lower doses comparable to the anticipated human

exposure).

8 In the risk assessment of carcinogenic

constituents of food and color additives used

directly in food, FDA most often uses an estimate

of the lifetime-averaged daily dietary exposure to

the substance in question.

9Potency values at the thyroid and at other organ

sites are available for a large number of thyroid

tumorigens. In addition, the results of genetic

toxicity testing, short-term studies, and other

toxicity testing are available for many of the these

compounds. Mechanistic information, though not

complete in many cases, is also available for a

significant number of these compounds, as well as

information regarding structure-activity

relationships.

Hoechst has advanced, as part of its

argument, the observation that rodents

are more susceptible to TSH-mediated

thyroid effects than other species, and

that male rats are ‘‘particularly

vulnerable.’’ However, FDA notes that

the available data do not show clear

differences, between rats and dogs, in

sensitivity to AAA-induced effects. For

example, the NOEL for AAA-induced

thyroid effects in rats in the subchronic

study and the level at which no AAAinduced effects were observed in the

second dog study are approximately the

same. In addition, although FDA’s

review of the subchronic rat study

showed that male rats may have been

slightly more susceptible to AAA’s

thyroid effects than female rats, the

differences were again small.

FDA concludes that, for several

reasons, the petitioner’s proposed

mechanism has not been established.

First, as noted, some of the results of the

short-term and subchronic feeding

studies (e.g., persistence of thyroid

effects in recovery animal in the dog

study; the lack of a clear difference, in

sensitivity to AAA, between rats and

dogs and between male and female rats)

appear to be inconsistent with the

proposed mechanism. Second, the data

on AAA’s effects on thyroid hormone

economy are limited to short-term

exposures of a relatively small number

of animals; as previously noted, these

limited data do not permit the

determination of a threshold for AAA’s

effects. Thus, FDA has determined that

although the mechanism proposed by

Hoechst is plausible, it has not been

established. Because Hoechst’s

approach to evaluating the health risk

from AAA (a comparison of the NOEL’s

for certain thyroid endpoints with

dietary AAA exposure) relies explicitly

on the firm’s proposed mechanism, and

the proposed mechanism has not been

established, FDA concludes that

Hoechst’s approach is not sufficient for

an evaluation of the health risk from

AAA.

vi. Consideration of whether more

testing of AAA is necessary—(1)

Statement of the issue. Because the

findings in the short-term and

subchronic toxicity studies of AAA

suggest that AAA could induce thyroid

tumors in a long-term study, FDA

carefully considered whether conduct of

such a study was necessary to evaluate

the safety of ACK for use in

nonalcoholic beverages. In particular,

given the likely human dietary exposure

to AAA, FDA considered whether the

possibility that AAA might induce

tumors in a long-term bioassay raised

sufficient concern such that testing of

the hypothesis should be required. Said

differently, the issue was whether a

long-term oral study of AAA, a

hydrolysis product expected to be

present at extremely low levels (if at all)

in only certain nonalcoholic beverages,

is needed to evaluate the safety of the

petitioned use of the food additive,

ACK. In addressing this question, FDA

determined that it was critical to assess

both the likely putative tumorigenic

(neoplastic) potency of AAA and the

likely patterns of dietary exposure to

AAA resulting from consumption of

ACK-sweetened nonalcoholic beverages.

As discussed in detail in the rest of

this section, FDA considered several

approaches to assessing the risk from

AAA, and determined both that longterm testing of AAA is unnecessary and

that the petitioned use of ACK in

nonalcoholic beverages is safe.

(2) Risk assessment. The usual

process of quantitative risk assessment

is characterized by four steps. First, a

possible toxicological hazard is

identified. Second, mathematical

modelling techniques are applied to the

dose-response information from a

toxicity study in order to estimate the

probability, or, usually, an upper-bound

limit on the probability, of the toxic

effect of the substance at any given dose

level (see for example, Refs. 9 through

11).7 Typically, in a risk assessment of

a carcinogen, this dose-response

information is taken from tumor

incidence data from a long-term animal

study; most often, this long-term study

is conducted in a rodent species. Third,

the likely human dietary exposure to the

substance is estimated. This estimate of

dietary exposure may consider such

factors as the age groups likely to be

exposed and the type, magnitude, and

duration of the anticipated exposures.8

Finally, the information from the first

three steps is combined to characterize

the risk associated with the potential

human exposure to the substance in

question.

In the present case, as in the usual

risk assessment process, a possible

hazard, thyroid carcinogenicity, has

been identified. There are similarities

between the thyroid effects produced by

oral administration of AAA in shortterm and subchronic toxicity studies

and those produced by oral

administration of other substances

known to induce thyroid tumors in

long-term rodent studies. Thus, there is

the possibility that AAA would also

induce tumors if tested in a long-term

rodent study and, thus, may ultimately

present a carcinogenic hazard to

humans.

The risk assessment process used in

the present case differs from the usual

process, however, in that AAA has not

been demonstrated to be an animal (or

human) carcinogen. That is, doseresponse information from a long-term

oral study of AAA in animals has not

been used because such a study has not

been conducted. As an alternative, FDA

has used information from the many

existing long-term oral studies of known

thyroid tumorigens to assess the

probable carcinogenic potency (or range

of probable potencies) of AAA that

might be determined, were a

carcinogenicity study of AAA

conducted in a rodent species. The

agency believes this is a sound approach

because of the substantial amount of

information available for a large number

of thyroid tumorigens.9

As in the usual risk assessment

process for a known carcinogenic

constituent of a food or color additive,

a potential life-time averaged ‘‘daily’’

human dietary exposure to the

substance in question (in this case,

AAA, a putative tumorigen) has been

estimated. In calculating this estimate,

FDA has used estimates of the likely

human dietary exposure to ACK, in

conjunction with information from

analytical testing conducted on model

solutions under exaggerated conditions,

to estimate a potential lifetime-averaged

level of daily dietary exposure to AAA.

FDA’s exposure estimate is conservative

in that it incorporates numerous

assumptions and default values for

certain parameters that, when

combined, yield a value for ‘‘daily’’

dietary exposure to AAA that is likely

to overestimate rather than

underestimate such exposure. By

combining the information regarding

potential human dietary exposure with

the information regarding the likely

tumorigenic potency (or range of

probable potencies) of AAA, FDA has

characterized the potential human

carcinogenic risk from AAA resulting
36352 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

10The CPDB summarizes results of

carcinogenicity bioassays published in the open

literature and in technical reports of the NTP. The

NTP data base, also known as the NCI/NTP data

base, contains the results of mouse and rat

carcinogenicity studies conducted by NCI/NTP. The

published review that was used by Hoechst

summarized the results of 343 selected

carcinogenicity studies conducted by NCI/NTP; in

this subset of the NCI/NTP data base, 14 percent of

the studies in male rats, 11 percent of the studies

in female rats, 8 percent of the studies in male mice

and 9 percent of the studies in female mice were

identified as having positive or equivocal,

chemically-related thyroid proliferative lesions.

(The studies from the NCI/NTP data base are also

included in the CPDB.) IRIS is an electronic data

base prepared and maintained by the U.S.

Environmental Protection Agency (EPA); it contains

information on human health effects that may result

from exposure to various chemicals in the

environment.

11Hoechst’s estimate of consumer exposure to

AAA (3.5 ng/kg bw/d) is essentially the same as

FDA’s estimate (3.3 ng/kg bw/d, equivalent to 0.2

μg/p/d). FDA has determined that both Hoechst’s

and the agency’s estimate of AAA dietary exposure,

because of the particular assumptions used in

deriving them, are likely to overestimate rather than

underestimate exposure.

12The potencies of the AAA surrogates are

properly described as tumorigenic potencies; the

tumors observed in rodents are more often benign,

rather than malignant, follicular cell tumors. In both

the petitioner’s and the agency’s comparative risk

assessments, the distribution of tumorigenic

potencies of AAA surrogates is used to estimate the

putative tumorigenic potency of AAA. This putative

tumorigenic potency of AAA is then used as a

direct substitute for a hypothetical human cancer

potency in the comparative risk assessments.

from the consumption of ACKsweetened nonalcoholic beverages.

The petitioner and the agency have

separately analyzed the likely health

risk suggested by the AAA-related

thyroid findings in the short-term

studies, by considering both estimates of

the tumorigenic potency of AAA and

the likely patterns of dietary exposure to

AAA resulting from consumption of

ACK-sweetened nonalcoholic beverages.

In the course of its analysis, scientists

from FDA’s Center for Food Safety and

Applied Nutrition consulted with

several scientists (hereafter referred to

as ‘‘the FDA consultants’’), from both

within and outside the agency, with

expertise in various scientific

disciplines relevant to the agency’s

analysis. Details of the petitioner’s

analysis and the agency’s analysis

(including relevant comments from the

FDA consultants) are discussed in the

following paragraphs.

(3) Hoechst’s analysis. In response to

the agency’s reservations regarding

Hoechst’s initial, threshold-based

approach to evaluating the potential

health risk from AAA, Hoechst

performed two additional ‘‘extremecase’’ or ‘‘worst-case’’ comparative risk

assessments. In both assessments,

Hoechst assumed that AAA would

induce thyroid tumors in a long-term

study, even though AAA has not been

shown to be a tumorigen. In contrast to

the firm’s initial approach, neither of

Hoechst’s comparative risk assessments

was predicated on a threshold for

AAA’s thyroid effects. That is, both of

Hoechst’s comparative risk assessments

assumed that some risk of neoplastic

disease would be present at all levels of

exposure to AAA.

In presenting its assessments of the

tumorigenic potential of AAA, Hoechst

continued to argue strongly for the

mechanism it had proposed to account

for AAA’s thyroid effects. Hoechst used

several features of its proposed

mechanism to select the set of chemicals

against which to compare AAA and

estimate AAA’s tumorigenic potential;

Hoechst’s selection of these surrogates

for AAA is described in the following

paragraphs.

Using data from lifetime studies of

thyroid tumorigens that Hoechst

identified as acting with similar effect

and through a mechanism similar to the

one it had proposed for AAA, Hoechst

estimated AAA’s putative thyroid tumor

potency. According to Hoechst, these

estimates of AAA’s putative thyroid

tumor potency, coupled with an

estimate of dietary exposure, would

provide ‘‘comparative risk assessments’’

of AAA’s potential to induce thyroid

tumors. Hoechst drew upon several

recognized sources to identify the

thyroid tumorigens that it chose as

surrogates for AAA. These sources

included a publication analyzing target

organs for more than 500 chemicals in

the Carcinogen Potency Database

(CPDB), a published review of the

information in the data base maintained

by the National Toxicology Program

(NTP), the Integrated Risk Information

System (IRIS), and a well known

literature source on thyroid follicular

cell carcinogenesis (Refs. 6 and 12

through 14).10 From the group of thyroid

tumorigens identified using these

sources, Hoechst selected those for

which long-term rodent bioassays had

been conducted and in which the test

substance displayed tumorigenic

activity in either the thyroid alone or, if

tumorigenic at other organ sites as well,

with greater potency at the thyroid than

at other sites. From this subset of

thyroid tumorigens, only those

compounds that Hoechst identified as

both nonmutagenic and active in

inhibiting thyroperoxidase (both of

which are critical elements of Hoechst’s

proposed mechanism) were retained as

AAA surrogates. Applying these criteria,

Hoechst identified four compounds:

Amitrole, methimazole,

propylthiouracil, and sulfamethazine.

Hoechst used the same estimated

dietary exposure in both of its

comparative risk assessments. In

calculating this estimate, Hoechst used

data on ACK stability and nonalcoholic

beverage consumption patterns,

incorporating several conservative

assumptions similar to those used by

FDA and described previously. Hoechst

estimated the high-level consumer’s

potential ‘‘daily’’ dietary exposure to

AAA to be 3.5 ng/kg bw/day. Hoechst

asserted that this estimate of potential

‘‘daily’’ dietary exposure was likely to

overestimate significantly the actual

exposure because of the numerous

conservative assumptions used in

deriving the estimate.11

In its first comparative risk

assessment, Hoechst assumed that the

putative induction of thyroid tumors by

AAA would be directly related to an

AAA-induced increase in serum levels

of TSH. Using the literature sources

listed previously, Hoechst identified

three compounds (methimazole,

propylthiouracil, and sulfamethazine)

that the firm asserted have

approximately the same quantitative

effect on circulating TSH levels as AAA

had on TSH levels in the preliminary

mechanistic study in rats. Hoechst then

estimated a hypothetical cancer potency

for AAA by interpolating between the

established tumorigenic potencies of

these three substances;12 the

hypothetical cancer potency for AAA in

this assessment was 2.3 x 10-3 (mg/kg

bw/day)-1. When coupled with the

firm’s estimated ‘‘daily’’ dietary

exposure of 3.5 ng/kg bw/day, Hoechst’s

estimated upper-bound limit of lifetime

human cancer risk, in its first

assessment, was 8.1 x 10-9.

In the second of Hoechst’s

nonthreshold risk assessments, the

putative induction of thyroid tumors by

AAA was assumed to be directly related

to AAA-induced inhibition of

thyroperoxidase (and thus, indirectly, to

elevated serum TSH levels). Hoechst

identified four substances (amitrole,

methimazole, propylthiouracil, and

sulfamethazine) for which it maintained

that the induction of thyroid tumors in

animals is known to occur as a result of

thyroperoxidase inhibition. Hoechst

then estimated a hypothetical cancer

potency for AAA by calculating a

weighted average of the established

tumorigenic potencies of these four

substances. In this second comparative

risk assessment, Hoechst estimated the

hypothetical potency of AAA as 4.0 x

10-2 (mg/kg bw/day)-1. When coupled

with the firm’s estimated ‘‘daily’’

dietary exposure of 3.5 ng/kg bw/day,

Hoechst’s estimated upper-bound limit
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36353

13Taken together, the six plots of the 1996 CPDB

include results of 5,002 experiments on 1,230

chemicals. The agency notes that of the 91

compounds in the CPDB that were reported to

induce thyroid tumors in rodents, only three

(methimazole, deltamethrin, and sulfamethazine)

produced thyroid tumors only. Of the remaining 88

compounds, 70 percent had a higher cancer potency

for tumors other than thyroid tumors. Thus, the

majority of compounds that have been found to

induce thyroid tumors (by any mechanism) have

also been found to induce tumors at other sites, for

which the estimated cancer potency is higher than

the potency estimated for thyroid tumors alone (see

Ref. 2).

14One of the FDA consultants noted that some,

but not all thyroid peroxidase inhibitors lead to

tumors at sites other than the thyroid, especially the

liver of mice. This consultant further commented

that ‘‘* * * FDA is on strong ground to look at the

potency for tumors other than thyroid, as well as

looking at those for the thyroid.’’ Including the

higher potencies for tumors other than thyroid

tumors in FDA’s assessment is, however, a

conservative measure in that the data in the studies

of AAA submitted to the petition do not suggest

that there are other likely target organs for

neoplasia.

of lifetime human cancer risk, in its

second assessment, was approximately

1.4 x 10-7.

The petitioner argued that both its

estimates of AAA’s upper-bound limit

of lifetime human cancer risk were well

below the level ordinarily regarded by

FDA as commensurate with negligible

risk. The petitioner also argued that any

actual risk would be far lower than

these estimated upper-bound limits of

risk because of the numerous

conservative assumptions used in

calculating these estimates.

In addition, the petitioner noted that

humans are less sensitive than rats to

thyroid effects induced through TSHdependent mechanisms. Hoechst

referenced scientific literature in

support of its contention that, although

chronic TSH stimulation induces

thyroid hypertrophy and hyperplasia in

humans as well as in rodents, humans

are less likely to develop tumors

following chronic stimulation by TSH.

Specifically, they noted that prolonged

TSH stimulation is known to lead to

thyroid enlargement or goiter in

humans, but rarely leads to thyroid

tumors (Refs. 15 and 16). Hoechst also

maintained that the rat’s significantly

higher baseline TSH levels and more

rapid metabolism of the hormone leave

rats more vulnerable than humans to the

development of thyroid tumors in

response to chemically induced

increases in circulating TSH levels (see

Refs. 8 and 17). Hoechst argued that the

lower sensitivity of human thyroid

follicular cells to elevated TSH levels

would further reduce the likely

magnitude of any actual thyroid tumor

risk to humans from exposure to any

AAA in ACK-sweetened nonalcoholic

beverages.

(4) FDA’s analysis. FDA has carefully

evaluated the petitioner’s comparative

risk assessments. The agency agrees that

it is reasonable to perform an ‘‘extremecase’’ risk assessment of AAA in order

to evaluate the potential health concern

raised by the thyroid findings in the

short-term studies of AAA. To this end,

FDA conducted its own analysis of the

potential health risk from the low levels

of AAA that may be ingested as a result

of the consumption of ACK-sweetened

nonalcoholic beverages. FDA’s two

principal comparative risk assessments

of AAA, like the petitioner’s, are

essentially modified carcinogenic risk

assessments; however, in several

respects the agency’s approach differs

from the petitioner’s.

Like Hoechst, FDA assumed that AAA

would be tumorigenic if tested in a longterm bioassay. The agency also

assumed, as did Hoechst in its

comparative risk assessments, that there

is no threshold for AAA’s presumed

tumorigenic activity. However, in

contrast to Hoechst, FDA did not rely on

assumptions regarding AAA’s

mechanism of action on the thyroid.

Although FDA believes that it is

plausible that AAA may induce thyroid

tumors in long-term studies through the

mechanism hypothesized by the

petitioner, the data supporting the

petitioner’s hypothesis are limited in

several key areas. First, as noted, there

are no studies demonstrating long-term

effects of AAA on thyroid hormone

economy; thus, FDA, in its comparative

risk assessments, did not assume a

quantitative correlation between TSH

induction and AAA’s putative thyroid

tumorigenic potency. Second, there is

no direct evidence of AAA-induced

effects on thyroperoxidase activity in

vivo; consequently, FDA did not assume

that AAA’s putative potency would be

similar to potencies of thyroid

carcinogens known or asserted to act

through inhibition of thyroperoxidase

activity.

To provide assurance that the risk

presented by AAA is not

underestimated, FDA included in its set

of AAA surrogates all substances it

identified, using the 1996 CPDB (see

Ref. 18), as having induced tumors in

the thyroid, including substances that

also induced tumors in other organs,

regardless of the relative potencies

involved.13 This set of surrogates

includes both genotoxic and

nongenotoxic substances. Because the

potency distribution for genotoxic

chemicals is shifted to higher potencies

than the potency distribution for

nongenotoxic chemicals, FDA’s set of 91

surrogates includes substances of higher

potency than those in Hoechst’s set of

4 surrogates (Ref. 2). FDA included this

frank and deliberate conservatism to

ensure that neither the putative potency

of AAA nor the attendant estimate of

AAA’s potential carcinogenic risk

would be underestimated.

In the first of FDA’s comparative risk

assessments, the agency used potency

values from the distribution of the

thyroid tumor potencies of the 91

surrogates. FDA chose this approach

because the data from the short-term

and subchronic studies of AAA in rats,

rabbits, and dogs identify the thyroid as

the potential target organ for putative

AAA-induced tumors and do not

suggest other likely target organs. The

distribution of thyroid tumor potencies

for the 91 surrogates has a peak, or

‘‘most probable’’ value, of 7.0 x 10-3

(mg/kg bw/day)-1. FDA used this

potency value as an estimate for the

likely potency of AAA. This potency,

coupled with the agency’s estimated

‘‘daily’’ dietary exposure to AAA of 3.3

ng/kg bw/day, yields an estimated

upper-bound limit of lifetime risk from

AAA of 2.3 x 10-8 (Ref. 2). This

hypothetical upper-bound limit of

lifetime risk from AAA is well below

the level that FDA ordinarily considers

commensurate with negligible risk.

To provide further assurance that

AAA’s potential risk was not being

underestimated, the agency performed a

second risk assessment. In this second

assessment, FDA hypothesized that

AAA might, in addition to inducing

thyroid tumors, induce tumors at sites

other than the thyroid and that AAA’s

potency at these other sites could be

higher than for tumors induced at the

thyroid.14 In essence, this scenario

describes the most adverse outcome of

a long-term bioassay with AAA, were

such a bioassay actually conducted.

Thus, FDA’s second risk assessment

included an assumption of the most

adverse outcome for a study testing the

hypothesis that AAA causes thyroid

tumors so that the potential risk posed

by AAA would not be underestimated.

In this assessment, to estimate AAA’s

most likely tumorigenic potency, FDA

used the peak, or ‘‘most probable value’’

value from the distribution of highest

tumor potencies at any organ site for

FDA’s 91 surrogates. Using this estimate

of the putative tumorigenic potency of

AAA (2.0 x 10-2 (mg/kg bw/d)-1) and the

agency’s conservative estimate of

‘‘daily’’ dietary exposure to AAA of 3.3

ng/kg bw/d, FDA estimated the upperbound limit of lifetime human cancer

risk from exposure to AAA to be 6.6 x

10-8 (Ref. 2). This hypothetical upperbound limit of lifetime risk from AAA,

like the value obtained in FDA’s first
36354 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

15One of the FDA consultants also provided two

additional approaches to calculating a conservative

upper-bound limit of lifetime human cancer risk,

one that made use of a feature of the petitioner’s

proposed mechanism for AAA’s action on the

thyroid and one that did not. The estimates of

AAA’s upper-bound carcinogenic risk derived by

these two additional approaches were 8.0 x 10-8 and

3.3 x 10-8, respectively (see Ref. 2). Both of the

consultant’s estimates for the upper-bound risk

from AAA, like the upper-bound risks calculated by

FDA (2.3 x 10-8 and 6.6 x 10-8) and by the petitioner

(8.1 x 10-9 and 1.4 x 10-7), are very low.

16FDA notes that approaches to modifying risk

assessments for intermittent exposures to

carcinogens generally reduce the estimated risk

substantially (see for example, Refs. 19 and 20).

Such modification can be particularly important for

carcinogens that are nongenotoxic. In general,

continuous exposure to such substances for a

prolonged period of time is needed before tumors

develop; removal of the carcinogen from the diet for

a significant portion of that time, will stop

progression toward tumor development and may

even result in partial or complete reversal of the

treatment-related preneoplastic changes (see Ref. 6).

If AAA were to induce thyroid tumors, and if it

were to do so through a nongenotoxic or indirect

mechanism, the intermittent nature of the exposure

to AAA from consumption of ACK-sweetened

nonalcoholic beverages would reduce the risk from

AAA so that it is even more likely to be

significantly less than the value estimated by the

agency’s method, and perhaps to be zero. On this

point, one of the FDA consultants also commented

that explicit consideration of the expected

intermittent nature of any dietary exposure to AAA

was particularly important in placing the

calculations of AAA’s estimated risk into

perspective.

risk assessment, is well below the level

ordinarily considered by FDA as

commensurate with negligible risk.

Based on its risk assessments, the

agency believes that AAA is highly

unlikely to pose more than a negligible

cancer risk to consumers. For example,

even if, in FDA’s first risk assessment,

AAA’s thyroid tumor potency were as

high as that of the 90th percentile most

potent compound in FDA’s set of AAA

surrogates, the estimated upper-bound

limit of lifetime risk from AAA, using

all of the conservative features and

assumptions described previously,

would still be less than 7 x 10-7. To

produce the same estimate of upperbound risk from AAA using the

approach in FDA’s second risk

assessment, AAA’s potency at any organ

site would have to approach that of the

90th percentile most potent compound

in FDA’s set of AAA surrogates. The

agency considers these potency levels

highly unlikely for several reasons.

First, AAA’s potency at the thyroid

would need to approach that of

methimazole, the positive control in the

preliminary mechanistic study. That

AAA would be as potent as

methimazole is unlikely, however, given

the fact that almost 100-fold greater

doses of AAA than of methimazole were

needed to induce comparable degrees of

thyroid follicular cell hypertrophy and

hyperplasia, the presumed precursors to

any thyroid neoplasia (see Ref. 2).

Second, the thyroid tumorigens in the

set of 91 surrogates with potencies in

this range (approaching the 90th

percentile and above) are almost all

genotoxic or have strong structural

indicators of genotoxicity while the

results of the genetic toxicity tests of

AAA show that AAA is not genotoxic.

As previously noted, the potency

distribution for genotoxic compounds is

shifted to higher values than the

potency distribution of nongenotoxic

compounds; thus, the probability that

AAA, a nongenotoxic compound, will

be more potent than the most potent

genotoxic compounds in FDA’s set of

AAA surrogates is extremely low (see

Ref. 2).

As noted previously, the agency’s

comparative risk assessments were

based on numerous conservative

assumptions so that any risk from AAA

would not be underestimated; FDA

believes that any actual risk from AAA

would be substantially lower than either

of its estimates of the upper-bound limit

of lifetime risk. The agency also notes

that all of the FDA consultants agreed

that the numerous conservative

assumptions used in the agency’s

comparative risk assessments were

likely to lead to an overestimate, rather

than an underestimate, of the risk from

AAA.15

The conservative nature of FDA’s risk

estimates was amplified by the agency’s

assumption, in its comparative risk

assessments, that consumers would be

subject to ‘‘chronic’’ or ‘‘daily’’ dietary

exposure to AAA through consumption

of ACK-sweetened nonalcoholic

beverages. In fact, frequent exposure to

AAA is unlikely because few containers

of beverages are likely to be stored

under the conditions necessary to

produce significant quantities of AAA.

Thus, any actual dietary exposure to

AAA through consumption of ACKsweetened beverages is likely to be at

very low levels, to be intermittent, and

to be infrequent.16

In summary, the agency has used

information from the many long-term

oral studies of known thyroid

tumorigens to estimate the range of

possible tumorigenic potencies of AAA;

this estimate has then been used to

represent the tumorigenic potency for

AAA that might be determined by a

carcinogenicity study of AAA in a

rodent species. FDA has combined this

information with a conservative

estimate of ‘‘daily’’ dietary exposure to

AAA in order to assess the risk that

might be posed to individuals

consuming ACK-sweetened beverages.

FDA’s risk assessments for AAA all

yield upper-bound limits of lifetime risk

that are not only very low, but are also

expected to be substantially higher than

any actual risk from AAA.

(5) Resolution of the issue. FDA has

carefully evaluated the data from the

available short-term and subchronic oral

toxicity tests of AAA. As previously

noted, the findings in these studies

suggested that AAA might induce

thyroid tumors in a long-term oral

study, raising the question of AAA’s

possible carcinogenic risk. Thus, FDA

has considered whether conduct of a

long-term study was necessary to assess

the possible carcinogenic risk from

AAA.

FDA has concluded that, for several

reasons, it is not necessary to require the

conduct of a long-term study of AAA.

First, the primary purpose of such a

study would be to determine whether

AAA actually induced thyroid tumors.

As an alternative, in its assessment of

the potential health risk of AAA, the

agency has simply chosen to assume

that AAA would, indeed, induce

thyroid tumors in a long-term study,

thus obviating the first purpose of such

a study.

The second purpose of a long-term

study of AAA, in the event that AAA

were found to be tumorigenic, would be

to determine AAA’s tumorigenic

potency. As an alternative, in its risk

assessments for AAA, FDA has

conservatively estimated AAA’s

putative potency by considering the

range of potencies of the many known

thyroid tumorigens (AAA surrogates) for

which long-term testing has been

conducted. As noted previously, FDA

believes this is a sound approach

because the results of the short-term

tests of AAA indicate the thyroid as a

likely target organ for the assumed

neoplasia, and because of the

substantial amount of chemical and

toxicological information available for a

large number of thyroid tumorigens.

FDA has also used several deliberate

conservatisms in constructing its set of

surrogates in order to ensure that AAA’s

putative potency and any attendant

estimate of AAA’s hypothetical cancer

risk are not underestimated: (1) FDA’s

set of surrogates includes genotoxic

compounds which, as a group, are

generally more potent than

nongenotoxic compounds (AAA is

nongenotoxic); (2) FDA’s set of AAA

surrogates also includes compounds for

which genetic toxicity testing data are

not available, but which have features in

their chemical structures that are widely

recognized as strong indicators of

mutagenicity/carcinogenicity and, thus,

are expected to be of higher potency

than nongenotoxic compounds; and (3)
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36355

17CSPI uses the term ‘‘petition’’ to refer to its

request for a stay of the dry uses final rule.

18 In its January 29, 1996, letter, CSPI indicated

that it intended to submit a detailed analysis of the

ACK safety data at a future date.

19CSPI mentioned histologic changes in the

thyroid glands of rats, rabbits, and dogs, referring

specifically to ‘‘hypertrophic and neoplastic

changes’’ when AAA was administered at high dose

levels in short-term studies. As previously noted in

this document, AAA-related thyroid follicular cell

hypertrophy occurred in all three animal species;

adenomas occurred only in two male rats in a

subchronic study.

FDA’s set of surrogates includes thyroid

tumorigens that are tumorigenic at sites

other than the thyroid and with higher

potency than at the thyroid. Using

information regarding the AAA

surrogates and the distribution of their

potencies, FDA estimated a range of

hypothetical carcinogenic potencies for

AAA. Thus, by conservatively

estimating the range of likely

tumorigenic potencies for AAA, FDA

believes that it has obviated the need to

determine AAA’s potency through longterm testing.

Using the estimates of AAA’s likely

tumorigenic potency, the agency

performed several comparative risk

assessments for AAA, combining the

estimates of AAA’s potency with a

deliberately exaggerated estimate of

dietary exposure to AAA to assess the

possible risk from the compound; these

conservative estimates of AAA’s

hypothetical upper-bound limit of

cancer risk are very low. As previously

noted, the risk estimates calculated by

the FDA consultant and by Hoechst,

though derived using different

assumptions about the range of possible

potencies for AAA, are also very low. In

addition, the conservative nature of all

of the risk estimates for AAA is

amplified by the assumption that

consumers would be subject to

‘‘chronic’’ or ‘‘daily’’ exposure to AAA

through consumption of ACKsweetened nonalcoholic beverages

when, in fact, such exposure is likely to

be both intermittent and infrequent.

FDA’s risk assessments show that,

even assuming that AAA were

carcinogenic in a long-term test, the

hypothetical upper-bound of risk

associated with an exaggerated estimate

of dietary exposure to the compound

would be extremely small. Because of

the numerous conservatisms used in

calculating these upper-bound limits of

risk, FDA concludes that any actual risk

from AAA would be far lower than

these limits and, in fact, negligible. In

this way, the results of FDA’s risk

assessments corroborate the agency’s

determination that a long-term study of

AAA is not necessary to assess the

potential risk to the public health from

consumption of this compound.

Thus, based on the available data and

information, including the risk

assessments described previously, FDA

concludes that there is a reasonable

certainty that no harm will result from

the exposure to AAA that might result

from the proposed use of ACK in

nonalcoholic beverages. Accordingly,

the agency has determined that

requiring the petitioner to conduct

further testing of AAA is not necessary

and would not serve a useful purpose

from the public health perspective.

E. Summary of FDA’s Safety Evaluation

The safety of ACK has been

thoroughly tested and the data have

been carefully reviewed by the agency.

FDA has considered the data and

information submitted in the present

petition as well as other information in

its files, including data and information

in previous petitions for ACK.

The agency has determined that the

toxicological data on ACK establish that:

(1) There is no association between

neoplastic disease (cancer) and

consumption of the additive and (2) the

ADI for the additive is 15 mg/kg bw/

day. FDA has also determined that the

estimated dietary exposure to ACK from

all currently permitted uses of the

additive as well as the proposed use in

nonalcoholic beverages (1.6 mg/kg bw/

day for the mean consumer, 3.0 mg/kg

bw/day for the 90th percentile

consumer) is well below the ADI. In

addition, the agency has concluded that

there is a reasonable certainty of no

harm from the exposure to methylene

chloride (a chemical used in the

manufacture of ACK) that might result

from all currently permitted uses of the

additive as well as the proposed use in

nonalcoholic beverages.

Finally, FDA has considered the

special conditions that are relevant to

the proposed use in nonalcoholic

beverages. In this regard, FDA has

considered toxicological data and other

information, including estimates of

dietary exposure, regarding AAS and

AAA, the principal hydrolysis products

of ACK. Based on the data and

information described previously in this

document, including FDA’s comparative

risk assessments for AAA, the agency

has concluded that there is a reasonable

certainty of no harm from the exposure

to AAS and AAA that might result from

the proposed use of ACK in

nonalcoholic beverages.

Thus, based on a full and fair

evaluation of the relevant data and

information, FDA concludes that the

proposed use of ACK in nonalcoholic

beverages is safe.

IV. Response to Comments

During the course of FDA’s evaluation

of the present petition, the agency

received several sets of comments on

the petition. FDA received multiple

submissions from CSPI, who also

transmitted comments from other

interested parties. Later, Hoechst

transmitted additional remarks from two

of these same parties. Several letters

were also received from trade groups

and other organizations.

A. Summary of Comments

1. Center for Science in the Public

Interest’s (CSPI’s) First Submission

The first of CSPI’s submissions was a

letter, dated October 18, 1990, in which

CSPI referred to the organization’s 1988

objections to FDA’s initial approval of

the use of ACK (the dry uses final rule).

CSPI asked that FDA not consider

expanding the permitted uses of ACK

‘‘without first resolving [CSPI’s]

objections, hearing request, and

petition17 [sic].’’ As noted previously in

this document, FDA considered the

issues raised by CSPI in its objections

and responded, in detail, to those

objections in the Federal Register of

February 27, 1992 (57 FR 6667). After

reviewing the objections, the agency

concluded that no genuine issues of

material fact had been raised that would

justify either a hearing or a stay of the

regulation and, accordingly, denied

CSPI’s requests. Because the agency has

responded to CSPI’s objections to the

dry uses final rule and to the

organization’s related requests, no

further discussion of CSPI’s first

submission is warranted.

2. CSPI’s Second Submission

CSPI’s second submission was a

letter, dated January 29, 1996, in which

CSPI asserted that the long-term toxicity

testing of ACK was inadequate and that

ACK was ‘‘possibly carcinogenic.’’ Once

again, CSPI referred to its previous

objections to the dry uses final rule, and

urged FDA to deny the present petition

and to require the petitioner to conduct

additional carcinogenicity testing of

ACK. CSPI did not, however, supply

any substantive information to support

these requests.18 In its letter, CSPI also

mentioned certain results from the

toxicity tests of AAA19 in support of its

request for additional carcinogenicity

testing of ACK, but did not supply any

substantive information that had not

already been considered by FDA or any

explanation of how the AAA test results

related to the organization’s request for

additional testing of ACK. Because CSPI

did not provide any substantive

information to support its requests, no
36356 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

20FDA has assumed that the NTP nomination

package is the detailed analysis of the safety data

on ACK that CSPI indicated, in its letter of January

29, 1996, that it would send to the agency at a

future date.

21The administrative record for the dry uses final

rule contains all of the Hoechst study reports

submitted in support of the original petition for

ACK, other data and supporting information, FDA

review memoranda, and other documents. Hoechst

submitted reports for 6 genetic toxicity tests, 2 acute

toxicity studies, a subchronic toxicity study, 4

reproduction or developmental toxicity studies, 3

long-term studies in rodents referred to previously

in this document, a 2-year study in dogs, 11

metabolism studies, and 7 other specialized studies.

22Several of the letters to CSPI and to FDA raised

specific issues regarding the procedures used in, or

the interpretation of results from, the long-term

studies of ACK in rodents. None provided any new

data or other information that had not already been

considered by the agency. FDA’s analysis of the

specific issues raised in these letters is discussed

later in this document.

23The ten complete documents in CSPI’s

‘‘standard data set’’ were six FDA review

memoranda, including the final review

memorandum from FDA’s Cancer Assessment

Committee; the dry uses final rule (53 FR 28379);

FDA’s response to CSPI’s objections to the dry uses

final rule (57 FR 6667); and two letters addressed

to Hoechst from an independent pathology lab,

supplying additional information regarding

histopathology data (one letter in regard to a longterm study in rats, the other in regard to a long-term

study in mice). The other items in CSPI’s ‘‘standard

data set’’ consisted primarily of narrative sections

from, or excerpts from various tables (e.g., mortality

data, tumor incidence data) included in, the study

reports for the three long-term feeding studies of

ACK in rodents.

24 Judging from their remarks, some of CSPI’s ten

consultants may have been under the impression

that all of the data and information on ACK had

been made available to them. For example, one of

these individuals stated: ‘‘I agree strongly with

[CSPI’s] evaluation that the available data on this

compound is at best incomplete * * * I could not

find any information related to mutagenicity or

other genotoxicity or any studies on reproduction

and development.’’ Another of CSPI’s consultants

also made similar remarks regarding the apparent

lack of ACK genetic toxicity data.

However, as noted previously in this document,

the ACK toxicity data base submitted to the original

petition for ACK included the results of six genetic

toxicity tests and four studies of reproductive or

developmental toxicity. The agency concluded that

the results of the genetic toxicity tests did not

indicate ACK-induced genotoxic effects and that the

results of the reproduction and teratology studies

produced no evidence of ACK-related teratogenic or

adverse reproductive effects (see 53 FR 28379 at

28380).

further discussion of this submission is

warranted.

3. CSPI’s Third Submission

CSPI’s third submission consisted of a

letter to FDA, dated May 29, 1996, in

which CSPI reiterated its concerns about

the carcinogenicity testing of ACK, and

also included copies of the materials the

organization had submitted to the

National Toxicology Program (NTP) in

nominating ACK for ‘‘chronic toxicity

(carcinogenicity) testing’’ by NTP

(‘‘CSPI’s NTP nomination package’’).

CSPI’s NTP nomination package

consisted of a cover letter, dated May

29, 1996, and a narrative describing

CSPI’s rationale for nominating ACK for

testing under the NTP program (a

document entitled ‘‘Summary of Data on

Acesulfame Potassium’’), including a

list of nine references and seven

attachments.20

The seven attachments in CSPI’s NTP

nomination package were three FDA

review memoranda; the final report for

a subchronic toxicity study of ACK in

rats; a letter from Hoechst responding to

FDA questions regarding histopathology

data from two of the long-term studies

of ACK in rodents; and two FDA

memoranda, each summarizing a

different meeting of Hoechst and FDA

representatives. The agency notes that

the attachments are all copies of

publicly available documents contained

in the administrative record for the dry

uses final rule. The agency also notes,

however, that CSPI did not provide NTP

with all of the information from the

administrative record for the dry uses

final rule.21 Specifically, CSPI did not

provide NTP with the reports on the

long-term studies of ACK in rats or

mice, the reports of the genetic toxicity

studies of ACK, or any of the review

memoranda from FDA’s pathologists or

FDA’s Cancer Assessment Committee.

The narrative describing CSPI’s

rationale for nominating ACK for NTP

testing raised various issues with

respect to the three long-term ACK

feeding studies in rodents that were

submitted in the original ACK petition.

FDA’s analysis of the specific issues

raised in CSPI’s third submission is

discussed in section IV.B.2 of this

document.

4. CSPI’s Fourth Submission

CSPI’s fourth submission consisted of

a letter, dated July 31, 1996, addressed

to the Director of FDA’s CFSAN, in

which the organization reiterated its

concerns regarding the long-term testing

of ACK and also mentioned its

nomination of ACK for chronic toxicity

(carcinogenicity) testing by NTP. In

addition, CSPI cited certain of the

results from the toxicity testing of AAA

and urged FDA to require the petitioner

to conduct long-term testing of AAA.

CSPI again asked FDA to deny the

present petition and to revoke ‘‘all

existing regulations permitting the use

of acesulfame potassium.’’

In support of its requests, CSPI

enclosed copies of letters from ‘‘ten

experts in the fields of carcinogenesis,

toxicology, and statistics’’ who had, at

CSPI’s request, ‘‘reviewed the Hoechst

test protocols and results’’ (hereinafter,

these individuals will be referred to as

‘‘CSPI’s ten consultants’’). Seven of the

letters were addressed to CSPI; the

authors of these particular letters

expressed support for CSPI’s

nomination of ACK for testing under the

NTP program. Three of the letters were

addressed to the Commissioner of the

Food and Drug Administration. The

authors of these three letters urged FDA

to require additional carcinogenicity

tests of ACK; one of the authors also

urged FDA not to approve the present

petition.22 CSPI claimed that ‘‘[b]ased

on the experts’ conclusions regarding

Hoechst’s tests, it is clear that Hoechst

has failed to demonstrate a ’reasonable

certainty of no harm’ for the use of

acesulfame potassium in soft drinks (or

other foods).’’

In partial response to CSPI’s letter of

July 31, 1996, FDA requested copies of

the materials supplied to CSPI’s ten

consultants and on which, presumably,

the consultants had based their

comments. CSPI responded by

submitting copies of materials that it

characterized as ‘‘a standard data set,’’

consisting of ten complete documents

and selected portions of several other

documents (19 items altogether) drawn

from the administrative record for the

dry uses final rule.23 Based on the

‘‘standard data set’’ submitted by CSPI,

it appears that the ten consultants were

not provided, however, with all of the

Hoechst study reports and other

relevant supporting information, nor

were they provided with all of the FDA

review memoranda filed in the

administrative record for the prior

approvals of ACK.24 For example,

neither the results of the ACK genetic

toxicity testing nor FDA’s final

pathology review memorandum (Ref.

21), which articulated FDA’s resolution

of the outstanding questions regarding

missing data and incomplete initial

reporting of histopathology results

raised in earlier FDA review

memoranda, were included in CSPI’s

‘‘standard data set.’’

As previously noted, most of the

letters from CSPI’s ten consultants did

not raise specific issues regarding either

the long-term testing of ACK or other

safety data relevant to FDA’s evaluation

of the present petition; only one

consultant provided detailed criticism

of FDA’s interpretation of the data.

FDA’s analysis of the few specific points

raised in letters from the ten consultants

is discussed below, along with FDA’s

analysis of the issues raised in CSPI’s

NTP nomination package.

5. Hoechst’s Submission

In response to the letters from CSPI’s

ten consultants, Hoechst transmitted to

FDA copies of letters from two CSPI
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36357

25This book, co-edited by a Hoechst scientist and

a professor at a German university, discusses

various studies of ACK submitted in the original

petition, including genetic toxicity studies, acute

studies, the three long-term feeding studies in

rodents referred to previously in this document, a

subchronic feeding study, reproduction and

teratology studies, metabolism studies and others.

The book also discusses several additional studies

of ACK (e.g., additional genetic toxicity studies),

conducted after FDA’s initial approval decision,

that were submitted to the present petition and

have been discussed previously in this document.

26One of these individuals referred to AAA as a

‘‘metabolic breakdown product.’’ FDA notes,

however, that AAA has not been shown to be a

metabolite of ACK. As discussed previously in this

document, the ACK toxicity data base submitted to

the original petition for ACK included the results

of 11 metabolism studies. FDA carefully evaluated

the results of these studies and concluded that they

revealed no evidence that ACK was metabolized (53

FR 28379 at 28380, see also Ref. 4).

27FDA notes that, in the subchronic study, ACK

was administered at dose levels of 0, 1.0, 3.0, or

10.0 percent in the diet. ACK-related reductions in

body weight of greater than 10 percent, along with

various other effects, were observed in the 10

percent dose group. Body weight reductions were

also observed in the 3 percent dose group, but such

reductions were less than 10 percent. Based on the

findings in the 10 percent and 3 percent dose

groups, Hoechst chose to use 3 percent as the

highest dose level in the long-term study; there are

no data to suggest that 5 percent was required.

28This document is entitled ‘‘Specifications for

the Conduct of Studies to Evaluate the Toxic and

Continued

consultants to whom the firm had

provided supplementary information

regarding the toxicity testing of ACK. In

their letters, these two individuals

stated that, after reviewing additional

information provided to them by

Hoechst, they had concluded that the

long-term testing of ACK was adequate

and that the test results did not indicate

that ACK was a carcinogen.

Hoechst also submitted to FDA copies

of the materials it had provided to the

two CSPI consultants for review. These

materials included several documents

from the administrative record for the

dry uses final rule as well as a copy of

the dry uses final rule. Also included in

Hoechst’s information package was a

copy of a document entitled ‘‘Executive

Summary,’’ a document that, according

to Hoechst, was a summary of

toxicology information on ACK that had

been submitted to Health Canada as part

of a petition for the use of ACK; and a

book, entitled Acesulfame Potassium.25

Because the additional letters from

these two particular consultants

provided no data or other substantive

information, FDA regards them solely as

further elaboration of the earlier remarks

from the two individuals in question.

No further discussion of any of these

remarks is necessary.

6. Other Submissions

FDA also received several letters from

trade groups and other organizations

urging FDA to approve the present

petition. Because none of these letters

provided any substantive information,

no further discussion of these

submissions is necessary.

B. Analysis of Specific Issues Raised in

the Comments

1. AAA Test Results

CSPI, in its fourth submission, and

two of CSPI’s ten consultants,

commented on the results of short-term

toxicity tests of ACK’s breakdown

product, AAA, and raised the issue of

AAA’s possible carcinogenic

potential.26 FDA agrees that the results

of the short-term studies of AAA raised

concerns that required resolution. As

discussed previously, the agency

carefully evaluated the data from the

short-term toxicity tests of AAA, along

with other data and information from

the petition and in its files. As

discussed previously, FDA has

concluded that AAA is highly unlikely

to pose a significant cancer risk to

individuals consuming ACK-sweetened

beverages; none of the information in

the comments provides a basis to

reconsider that conclusion. Because the

agency’s detailed analysis of the issue of

AAA’s possible carcinogenic potential

has already been presented (see sections

III.D.2.b.v and vi of this document), that

analysis will not be repeated here. The

agency’s analysis of the remaining

issues raised in the comments on the

present petition follows.

2. ACK Test Results

In its NTP nomination package, CSPI

again raised some of the same questions

regarding the adequacy of, and the

results from, the long-term testing of

ACK that it raised in its previous

objections to the dry uses final rule;

CSPI also raised some new points with

respect to the safety testing of ACK.

CSPI’s NTP nomination package is

clearly addressed to NTP and is not

written as a comment, per se, on the

present petition; the narrative in CSPI’s

NTP nomination package focuses on the

differences between the designs of, and

procedures used in, the long-term

feeding studies of ACK and specific

elements of NTP study designs or other

‘‘NTP standards.’’ Nevertheless, FDA

has assumed that CSPI’s NTP

nomination package constitutes the

‘‘detailed analysis of the safety data on

ACK’’ that CSPI had intended to send to

the agency at a future date and that FDA

had indicated it would treat as a

comment on the present petition. Thus,

FDA has attempted to extract from

CSPI’s NTP nomination package those

remarks on specific issues that could be

construed as comments on the present

petition.

As noted previously, there is

considerable overlap between the

specific issues raised by certain of

CSPI’s ten consultants and those raised

by CSPI. Because CSPI’s NTP

nomination package provides the most

detailed discussion of specific issues,

those remarks will be the focus of FDA’s

response. Where the other parties have

raised additional points or points that

differ substantively from those raised by

CSPI, FDA will indicate that in its

discussion.

a. The second rat study. In its original

evaluation of the safety of ACK, FDA

reviewed a long-term study conducted

in CPB–WU Wistar rats in which ACK

was administered at 0, 0.3, 1.0, or 3.0

percent in the test diet (the ‘‘second rat

study’’). In the preamble to the dry uses

final rule, the agency concluded that

this study was adequate for an

evaluation of a food additive and that it

demonstrated the safety of acesulfame

potassium (see 53 FR 28379 at 28380).

Implicit in FDA’s determination of the

adequacy of the second rat study was

that the dosing levels in this study were

appropriate (see 57 FR 6667 at 6669).

i. Issues raised previously—(1)

Appropriateness of the dosing. CSPI’s

NTP nomination package asserts that

the second rat study was inadequate

because the highest dose tested (3

percent in the diet) was too low. To

support its assertion, CSPI compares the

dosing regimen used in the second rat

study with NTP ‘‘requirements’’: ‘‘NTP

requires that long-term feeding studies

be carried out at the minimally toxic

dose (MTD), which is functionally

equivalent to the maximum tolerated

dose * * *.’’ CSPI also states that ‘‘NTP

requires that when a test chemical is

administered in the diet, the high dose

should not exceed 5 percent of the diet,

but use of a 5 percent dose could meet

NTP standards. Since rats in the

subchronic test tolerated 10 percent

acesulfame potassium in the diet with

what were reported as only minimal

effects* * *, 5 percent should have

been the highest dose tested in the two

rat studies.’’27 CSPI’s submission does

not, however, contain or identify any

data or other evidence to establish that

the dosing used in the second rat study

was, in fact, too low to permit an

assessment of ACK’s carcinogenic

potential.

CSPI implies that, in order for longterm toxicity (carcinogenicity) testing to

be valid, it must conform to NTP

‘‘requirements.’’ FDA does not agree.

The NTP document cited by CSPI28
36358 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

Carcinogenic Potential of Chemical, Biological and

Physical Agents in Laboratory Animals for the

National Toxicology Program (NTP).’’

29Other guidelines, such as those issued by EPA

or the Organization for Economic Cooperation and

Development (OECD), are also frequently used as

resources in the design, conduct, and evaluation of

toxicological tests (see for example, Ref. 22).

30CSPI specifically noted that the NTP document

stipulates the use of five dose groups in addition

to controls. FDA notes that the use of five dose

groups is not a requirement, either for the scientific

validity of the test, or for utility of the test in

reaching a regulatory decision. FDA’s own Redbook

recommends (but does not require) the use of at

least three dose groups in addition to controls;

EPA’s guidelines for subchronic toxicity testing

contain a similar recommendation.

31One of CSPI’s consultants criticized the

petitioner’s use of historical control data,

commenting that the ‘‘historical database’’ is

‘‘actually very small.’’ CSPI’s consultant did not,

however, provide any information to indicate that

FDA made inappropriate use of the relevant

historical control data. (As previously noted, FDA’s

final pathology review memorandum, which

discusses the agency’s use of the historical control

data, was apparently not included in the materials

supplied by CSPI to its ten consultants.)

establishes standardized protocol

elements and reporting formats for

certain toxicity and carcinogenicity tests

conducted by contract laboratories

under the auspices of the NTP program.

The NTP document does not establish

criteria for evaluating the scientific

validity of toxicity and carcinogenicity

tests in general, nor does it establish

regulatory requirements with respect to

safety decisions on food additives. The

NTP document provides specifications

that must be met in order for the results

of a particular toxicity study to be

included in the NCI/NTP data base

(described previously in this document).

FDA notes that the agency’s own

guidelines, ‘‘Toxicological Principles for

the Safety Assessment of Direct Food

Additives and Color Additives Used in

Food’’ (the FDA Redbook), do not

establish regulatory requirements or

requirements for establishing the

scientific validity of testing. Rather, the

Redbook represents the agency’s best

advice to manufacturers of food and

color additives on how to satisfy the

legal safety standard of ‘‘reasonable

certainty * * * that a substance is not

harmful’’ (see § 170.3(i)); and contains

general toxicological principles that are

to be applied using good scientific

judgment.

It is important to note that although

the details provided in the NTP

document differ from those provided in

the Redbook, a study that follows either

the NTP ‘‘specifications’’ or the

Redbook guidance29 and is conducted in

accordance with good laboratory

practices will generally be appropriate

for use in a safety evaluation. Strict

adherence to any particular set of

guidelines is not necessary, however, to

ensure either scientific validity or

suitability for a regulatory safety

decision. Accordingly, in reaching a

final decision on the safety of a food

additive, FDA considers all of the

relevant data and information available,

including the design of, and results

from, toxicity testing. The suitability

and validity of any particular toxicity

study submitted in support of a food

additive is evaluated on its own merits,

using good scientific judgment, by FDA.

The agency notes that, in its

objections to the dry uses final rule,

CSPI raised the same issue regarding the

adequacy of the dosing in the second rat

study, and FDA addressed this issue in

its response to CSPI’s objections (57 FR

6667 at 6668 and 6669). The agency

incorporates that discussion, in full,

into the safety determination on the

present petition. Because CSPI has

presented no new evidence to support

its opinion regarding the adequacy of

the dosing in this study, nor identified

evidence that the agency overlooked in

its previous evaluations, FDA reaffirms

its earlier determination that the dosing

in the second rat study was adequate for

an assessment of the carcinogenic

potential of acesulfame potassium (57

FR 6667 at 6669, see also 53 FR 28379,

28380).

With respect to dosing, one of CSPI’s

consultants asserted that the dose range

in the second rat study was too narrow,

citing ‘‘[the] increased tumorigenesis at

even the ‘lowest’ dose used * * *.’’

FDA has previously concluded,

however, that the data from the second

rat study do not establish an association

between tumors and treatment with

ACK (53 FR 28379 at 28380 and 28381).

The issue of tumor incidence in the

second rat study is also discussed later

in this document.

CSPI, in its NTP nomination package,

also implies that the second rat study is

inadequate because the subchronic

testing of ACK, used as an aid in

determining doses for the second rat

study, did not conform in each and

every respect to the standardized

elements in the NTP guidelines.

Specifically, CSPI stated that a

subchronic study was not conducted in

the same strain of rat as that used in the

second rat study; CSPI also disagrees

with the use, in the subchronic study,

of fewer dose groups than the number

NTP ‘‘requires.’’30

FDA disagrees. First, the agency notes

that the purposes of subchronic testing

are generally acknowledged to be

twofold: To identify likely target organs

in longer-term studies and to aid in

determining doses for the longer-term

testing. Second, as previously noted, the

NTP document does not establish

scientific or regulatory requirements for

either subchronic or long-term toxicity

testing, including carcinogenicity

testing. In particular, the NTP document

does not establish a subchronic testing

regimen that must be followed in order

for long-term testing to be valid.

Moreover, FDA is not aware of any

relevant guideline, including the NTP

document, that states that deviations

from the guidelines for a subchronic

toxicity study conducted to determine

appropriate dose levels in a subsequent

carcinogenicity study necessarily

invalidates the results of the

carcinogenicity study.

Because CSPI has not provided any

substantive information to support its

assertions regarding the effect of the

design of the ACK subchronic study on

the validity of the long-term testing of

ACK, it has provided no basis for FDA

to reconsider its conclusions regarding

the second rat study. Thus, FDA

reaffirms its earlier conclusions that the

dosing in the second rat study was

appropriate for an assessment of the

carcinogenic potential of ACK and that

the study was suitable for a safety

assessment of ACK (57 FR 6667 at 6669,

see also 53 FR 28379 at 28380).

(2) Incidence of mammary tumors. In

its NTP nomination package, CSPI

stated that there was an increased

incidence of mammary tumors in

treated females in the second rat study.

CSPI also claimed that ‘‘* * * FDA

discounted these data because [the]

incidence was not strongly doserelated.’’ CSPI thus implies that the lack

of a strong dose-response was the only

reason FDA concluded, in its previous

evaluation, that the incidence of

mammary tumors in female rats in the

second rat study was not ACK-related.

CSPI also criticizes the agency’s use of

historical control data in evaluating the

results of the second rat study and

asserts that more information on

‘‘animals or test conditions’’ (e.g., diets,

animal husbandry) should have been

obtained by FDA before using the data

from ‘‘previous studies’’ conducted at

the testing laboratory where the longterm studies of ACK were conducted.31

The agency notes that CSPI has

previously raised these particular points

in its objections to the dry uses final

rule, and that FDA has previously

addressed these points at length in

responding to CSPI’s objections (57 FR

6667 at 6674 and 6675). Specifically, in

the original safety evaluation of ACK,

FDA gave careful and detailed

consideration to the incidence of

mammary gland tumors in female rats in

the second rat study. After a review of
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36359

32CSPI presents some figures for the incidence of

pneumonia in the rats in the second study that are

apparently derived from information in the final

report for this study, a document not included in

CSPI’s NTP nomination package.

33 In its NTP nomination package, CSPI remarks:

‘‘* * * the likelihood that animals were of different

ages when exposure to the test agent began, and that

female animals may have been considerably older

than males, makes it difficult to know what to make

of the data.’’ While CSPI speculates, at length, on

the ages of the animals in the subchronic study,

CSPI does not provide any substantive information

to support its claims regarding the long-term study,

nor does the organization provide an explanation of

the significance of its allegations.

all the data, the agency concluded that

mammary gland neoplasms were not

associated with treatment with ACK.

The preamble to the dry uses final rule

cited several reasons for this conclusion,

including the lack of a dose response.

However, the agency also took into

account the lack of evidence of

progressive stages of mammary gland

neoplasms and certain information

obtained from historical control data (53

FR 28379 at 28381, see also Ref. 21).

With respect to the use of historical

control data, the agency notes that, as in

its objections to the dry uses final rule,

CSPI mischaracterizes the information

on historical controls and fails to

acknowledge the detailed information

on this point that FDA has evaluated. In

its response to CSPI’s objections, the

agency noted that the historical control

data were from the same type of studies

conducted in the same laboratory, with

the same strain of rat, under similar

conditions, with continuity of

pathological standards, and,

furthermore, were from the same time

period as the long-term studies

evaluated in FDA’s original review (57

FR 6667 at 6672 and Ref. 8 of that

document). CSPI has presented no new

information to support its allegation that

FDA made inappropriate use of the

relevant historical control data.

In summary, CSPI has presented no

new evidence that would change the

agency’s previous conclusion that the

occurrence of mammary gland

neoplasms was not associated with

treatment with ACK, and FDA

incorporates its earlier discussion of the

results of the second rat study, in full,

into the safety determination on the

present petition. Because CSPI has

presented no new evidence to support

its opinion nor identified evidence that

the agency overlooked in its previous

evaluations, FDA reaffirms its earlier

determination that the data from the

second rat study do not establish an

association between the occurrence of

neoplasms and treatment with ACK (53

FR 28379 at 28380 and 28381).

ii. Issues not raised previously—(1)

Incidence of respiratory disease. In its

NTP nomination package, CSPI claims

that the incidence of respiratory disease

in the animals used in the second rat

study was too high32 and questioned

whether this study or the other longterm studies of ACK in rodents were

adequate: ‘‘The poor health of the

animals used in the Hoechst studies

raises the question as to whether any of

the test results in the subchronic and

chronic studies were good enough to be

used.’’ However, CSPI’s submission

neither identifies nor contains any data

or other evidence that establish that the

second rat study was, in fact, rendered

inadequate for an assessment of ACK’s

carcinogenic potential by the incidence

of respiratory disease in the test

animals.

In its original evaluation of the safety

of ACK, FDA carefully considered all of

the data and information relevant to an

evaluation of the long-term testing of

ACK, including the general health of,

and the incidence of respiratory disease

in, test animals. In the case of the

second rat study, FDA determined that

the mortality rate was low in all dose

groups and the signs of chronic

respiratory disease randomly distributed

(Refs. 21 and 23). Only in the case of the

first rat study did FDA conclude that the

incidence of respiratory disease in test

animals confounded the test results to

such an extent that such incidence

contributed to a finding that the study

was inadequate for assessing the safety

of ACK (53 FR 28379 at 28380, see also

Ref. 24). Because CSPI has not presented

any new evidence to support its

allegation nor has the organization

identified evidence that the agency

overlooked in its previous evaluations,

FDA reaffirms its earlier determination

that the second rat study was adequate

for an assessment of the carcinogenic

potential of acesulfame potassium.

(2) Assignment of animals to test

groups. CSPI’s NTP nomination package

also raises a question regarding the

procedure used to assign animals to the

various test groups in the second rat

study. CSPI implies that improper

assignment procedures were used,

which confounded the results of the

second rat study. CSPI does not,

however, provide any data or other

information to support its speculation.33

In its original evaluation of the safety

of ACK, FDA carefully considered all of

the data and information relevant to an

evaluation of the long-term testing of

ACK, including the question of whether

the assignment procedures or other

aspects of the study designs

compromised the suitability of the

studies for an assessment of ACK’s

carcinogenic potential (Ref. 23). FDA

concluded that the second rat study was

adequate for an assessment of ACK’s

carcinogenic potential (Ref. 24, see also

53 FR 28379, 28380, and 57 FR 6667 at

6669). Because CSPI, in support of its

allegations, has neither presented

evidence that has not already been

evaluated by the agency nor identified

evidence that the agency overlooked in

its previous evaluations, FDA reaffirms

its earlier conclusion that the second rat

study was adequate for an assessment of

ACK’s carcinogenic potential.

b. The mouse study. In concluding

that ACK had been shown to be safe,

FDA reviewed a long-term study

conducted in Swiss mice in which ACK

was administered at 0, 0.3, 1.0, or 3.0

percent in the test diet (‘‘the mouse

study’’). FDA concluded that the results

of this study showed no association

between neoplastic disease and

treatment with ACK (53 FR 28379 at

28380). In the preamble to the dry uses

final rule, the agency explicitly

discussed the adequacy of the mouse

study with respect to study duration.

FDA concluded that the length of the

study was adequate because it had been

conducted for the majority of the

animals’ lifespan (53 FR 28379 at 28380;

see also 57 FR 6669 at 6670). Implicit

in FDA’s determination of the mouse

study’s adequacy was that the dosing

levels in this study were appropriate (57

FR 6667).

i. Issues raised previously—(1)

Adequacy of the study length. In its NTP

nomination package, CSPI asserts that

the mouse study was inadequate

because the study was too short. To

support its assertion, CSPI again refers

to NTP ‘‘requirements’’: ‘‘NTP generally

requires that long-term studies on rats

and mice be carried out for a 104-week

period. Hoechst’s study in mice lasted

only 80 weeks.’’ CSPI also presents

some figures for survival levels in the

various test groups (apparently derived

from information in the final report for

the mouse study, a document not

included in CSPI’s NTP nomination

package) and remarks that ‘‘survival of

the mice was very high at 80 weeks.’’

CSPI implies that the survival statistics

suggest that the study was not

conducted for the majority of the

animals’ lifespan. However, CSPI

provides no data or other evidence to

support its view.

FDA disagrees with CSPI’s comments

regarding the length of the mouse study.

First, as previously noted in this

document, the NTP document cited by

CSPI does not establish either scientific

or regulatory requirements. Second, in

its original evaluation of the safety of

ACK, FDA carefully considered all of

the data and information relevant to an
36360 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

34As noted previously in this document, CSPI

questions, in its NTP nomination package, the

health of the test animals in all of the long-term

studies of ACK in rodents. However, CSPI also cites

the high survival rates of the test animals in the

mouse study in support of some of the

organization’s criticisms of this study. The agency

notes that CSPI’s positions regarding animal health

and survival rates in the mouse study are not

entirely consistent.

evaluation of the long-term testing of

ACK, including the duration of, and

survival data from, the mouse study. As

previously noted, FDA concluded that

length of the study was adequate

because it had been conducted for the

majority of the animals’ lifespan (see 53

FR 28379 at 28380, see also Ref. 24.)

Specifically, the agency found that at

the time the study was conducted,

survival of the Swiss strain of mice

tended to decline severely between 18

and 24 months of age; thus, at that time,

80 weeks was representative of a time

period corresponding to the majority of

the animals’ lifespan (Ref. 24).

CSPI previously raised this issue in its

objections to the dry uses final rule, and

the agency previously discussed this

issue in responding to CSPI’s objections

(57 FR 6667). FDA incorporates that

discussion, in full, into the safety

determination on the present petition.

Because CSPI has not identified any

evidence that the agency overlooked in

its previous evaluations, FDA reaffirms

its earlier determination that the mouse

study was of adequate duration for an

assessment of the carcinogenic potential

of ACK.

(2) Appropriateness of dosing. CSPI,

in its NTP nomination package,

comments on the appropriateness of the

dosing in the mouse study: ‘‘* * * the

high survival at 80 weeks of mice fed

3% acesulfame potassium in the diet

suggests that a higher dose might have

been more in keeping with NTP

recommendations.’’ CSPI provides no

other further explanation of the

significance of its remarks, nor does it

provide any data or other information

that would establish that the dosing in

the mouse study was too low to permit

an assessment of ACK’s carcinogenic

potential. CSPI previously questioned

the adequacy of the dosing in the mouse

study in its objections to the dry uses

final rule, and the agency previously

discussed this issue in responding to

CSPI’s objections (57 FR 6667). FDA

incorporates that discussion, in full,

into the safety determination on the

present petition. Because CSPI has

presented no new evidence to support

its opinion nor identified evidence that

FDA overlooked in its previous

evaluations, FDA reaffirms its earlier

determination that the dosing in the

mouse study was appropriate for an

assessment of the carcinogenic potential

of acesulfame potassium (see 57 FR

6667 at 6669).

ii. Issues not raised previously—(1)

Incidence of respiratory disease. In its

NTP nomination package, CSPI notes

that respiratory infections occurred in

the mice, but offers no specific

supporting information.34 In particular,

CSPI neither identifies nor provides any

data or other evidence regarding the

actual incidence of respiratory

infections in the mice, nor does it

provide any information that would

establish that the mouse study was

rendered inadequate for an assessment

of ACK’s carcinogenic potential by the

alleged incidence of respiratory disease

in the test animals.

FDA notes that, in its original

evaluation of the safety of ACK, the

agency carefully considered all of the

data and information relevant to an

evaluation of the long-term testing of

ACK, including the health of the test

animals (Ref. 23). CSPI has presented no

evidence to support its claim that has

not already been evaluated by the

agency nor identified evidence that the

agency overlooked in its previous

evaluations. Thus, FDA reaffirms its

earlier conclusion that the mouse study

was suitable for an assessment of ACK’s

carcinogenic potential (see 53 FR 28379

at 28380, and 57 FR 6667 at 6669).

(2) Histopathology data. CSPI also

criticizes aspects of the

histopathological examinations in the

mouse study. CSPI specifically

compares the extent of the

histopathology review of tissues from

animals from the low and mid-dose test

groups with ‘‘NTP requirements.’’ CSPI

implies that the histopathology review

was not extensive enough and, thus,

obscured the results of the mouse study.

CSPI does not, however, provide any

data or other information that would

establish that the histopathological

examinations of tissues from the

animals in the mouse study were

inadequate for an assessment of ACK’s

carcinogenic potential.

FDA notes that, in its original

evaluation of the safety of ACK, the

agency carefully considered all of the

data and information relevant to an

evaluation of the long-term testing of

ACK, including the histopathology data

from the mouse study. FDA concluded

both that the mouse study was adequate

for an assessment of ACK’s carcinogenic

potential and that the results of the

study showed no association between

neoplastic disease and treatment with

ACK (53 FR 28379 at 28380 and 57 FR

6667 at 6669, see also Ref. 24). Again,

because CSPI has presented no evidence

to support its assertions that has not

already been evaluated by the agency

nor has CSPI identified evidence that

the agency overlooked in its previous

evaluations, FDA reaffirms its prior

conclusion that the mouse study was

suitable for an assessment of ACK’s

carcinogenic potential.

(3) Time-to-tumor. In its NTP

nomination package, CSPI also claims

that the data in the mouse study showed

that ACK caused tumors: ‘‘[i]n the

mouse study, there was an early timeto-tumor reported for first tumors in

treated animals relative to first tumors

in controls.’’ However, CSPI provides no

additional data or other information to

support this claim, nor does it provide

further explanation of the significance

of this alleged time-to-tumor

differential.

In the original safety evaluation of

ACK, FDA carefully considered all of

the data in the mouse study, including

data in the study report that showed an

apparent ACK-related decreased timeto-tumor for first tumors. After an

interim review of all the data, the

agency concluded that the only finding

of possible significance was an increase

in lymphocytic leukemia in female mice

in the highest dose group (Ref. 25). After

detailed consideration of this reported

finding, FDA concluded that this

finding was not treatment-related and

that no increase in neoplastic disease of

the lymphoreticular system could be

attributed to ACK (Ref. 24).

Because CSPI has presented no new

evidence to support its opinion nor

identified evidence that the agency

overlooked in its previous evaluations,

it has provided no basis for FDA to

change its previous conclusions

regarding the results of the mouse study.

Thus, FDA reaffirms its earlier

determination that the data from the

mouse study do not establish an

association between neoplasia and

treatment with ACK (see 53 FR 28379 at

28380 and 57 FR 6667 at 6669).

c. The first rat study. In its evaluation

of the original petition for the use of

ACK, the agency reviewed a long-term

study conducted in CIVO-bred Wistar

rats in which ACK was administered at

0, 0.3, 1.0, or 3.0 percent in the diet (the

‘‘first rat study’’). In the preamble to the

dry uses final rule, the agency

concluded that the data from this study

did not establish a carcinogenic effect of

ACK (53 FR 28379 at 28380). However,

the agency further concluded, because

of deficiencies and confounding factors

in this study (e.g., a high incidence of

respiratory disease in the test animals),

that it was ‘‘inadequate for assessing the

carcinogenic potential of the test

compound or for any other purposes of
Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations 36361

35Several of CSPI’s ten consultants made similar

remarks. None of these individuals, however,

provided any substantive information in support of

their remarks.

36 Importantly, as in its objections to the dry uses

final rule, CSPI mischaracterizes the information on

historical controls and fails to acknowledge the

information on this point that FDA evaluated. The

agency has previously discussed, in detail, its use

of historical control data in the evaluation of the

first rat study in responding to CSPI’s objections to

the dry uses final rule. In its response to CSPI’s

objections, the agency noted that the historical

control data were from the same type of studies

conducted in the same laboratory, with the same

strain of rat, under similar conditions, with

continuity of pathological standards, and,

furthermore, were from the same time period as the

first rat study (57 FR 6667 at 6672).

37Because the first rat study was inadequate for

use in assessing the carcinogenic potential of ACK,

the petitioner conducted a second long-term study

in a different strain of rat. This second rat study did

not show lymphoreticular tumors in the lungs (53

FR 28379 at 28380).

a safety evaluation’’ (53 FR 28379 at

28381).

Issues raised previously. In its NTP

nomination package, CSPI asserts that,

despite the prevalence of chronic

respiratory disease in the test animals in

the first rat study, the test results were

suggestive of a carcinogenic effect of

ACK.35 Specifically, CSPI claims that

the data in the first rat study showed a

dose-dependent effect on incidence of

lymphoreticular cancers of pulmonary

origin and on time-to-tumor. In support

of its claims, CSPI cites a single FDA

interim review memorandum (Ref. 23).

CSPI also asserts that the agency made

inappropriate use of historical control

data in evaluating the results of the first

rat study.36 With respect to the use of

historical control data, CSPI merely

expresses its opinion that more

information on ‘‘animals and test

conditions’’ (e.g., diets and animal

husbandry) should have been obtained

by FDA before using the data from

‘‘previous studies’’ conducted at the

testing laboratory where the long-term

studies of ACK were conducted.

The agency notes that the issue of a

possible dose-dependent effect of ACK

on the incidence of lymphoreticular

tumors and on time-to-tumor was raised

by CSPI in its letter to FDA dated

September 23, 1987, and this issue was

addressed by the agency in the preamble

to the dry uses final rule (53 FR 28379).

Specifically, the agency noted that, in

the first rat study, there was a slightly

higher incidence, and earlier

appearance, of lymphoreticular tumors

in dosed rats than in the concurrent

control group. However, the agency

concluded that under the circumstances

of severe chronic respiratory disease,

sampling limitations, and the very high

rate of spontaneously-occurring lung

tumors in this strain of rat, no

conclusions could be made regarding

any effect of ACK on the lungs (53 FR

28379 at 28380; see also Ref. 24).37 FDA

also notes that CSPI previously raised

this particular issue in its objections to

FDA’s original approval decision on

ACK, and the agency discussed these

issues, at length, in responding to CSPI’s

objections (57 FR 6667 at 6671 and

6672). FDA incorporates those

discussions, in full, into the safety

determination on the present petition.

Because CSPI has presented no new

evidence to support its opinion nor

identified evidence that the agency

overlooked in its previous evaluations

that would change the outcome of those

evaluations, FDA reaffirms its earlier

determination that the data from the

first rat study do not establish a

carcinogenic effect of ACK.

C. Summary of FDA’s Response to

Comments

In determining that ACK is safe for

use in nonalcoholic beverages, FDA

carefully considered all of the data and

information in the present petition, as

well as other information in its files,

including relevant information from

previous petitions for ACK. FDA has

also carefully considered all of the

issues raised in the comments on the

present petition.

As previously noted in this document,

many of the specific issues raised in the

comments on the present petition are

the same as those raised in earlier

objections to the dry uses final rule, and

the agency has previously considered

and responded to these issues in detail

(see 57 FR 6667). Also as noted, the

comments supply no new information

that would change any of the agency’s

prior conclusions on any of the issues

previously raised. Likewise, with

respect to specific issues raised in the

comments on the present petition that

have not been raised previously, the

comments neither provide new

evidence nor identify evidence that FDA

has overlooked that would change the

agency’s conclusion that the use of ACK

in nonalcoholic beverages is safe.

Because no outstanding issues in the

comments undermine FDA’s

determination of safety, FDA is denying

the requests that: (1) The petitioner be

required to conduct additional testing of

ACK or AAA, (2) the present petition be

denied, and (3) all existing regulations

permitting the use of ACK in food be

revoked.

V. Conclusion of Safety

FDA has evaluated the data in the

petition, published scientific literature,

and other relevant material from its files

and concludes that the use of ACK in

nonalcoholic beverages is safe.

Therefore, the agency concludes that

§ 172.800 should be amended as set

forth below.

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 Center for Food Safety

and Applied Nutrition 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.

VI. Environmental Impact

The agency has carefully considered

the potential environmental effects of

this action. FDA 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.

VII. Paperwork Reduction Act

This final rule contains no collections

of information. Therefore, clearance by

the Office of Management and Budget

under the Paperwork Reduction Act of

1995 is not required.

VIII. Objections

Any person who will be adversely

affected by this regulation may at any

time on or before August 5, 1998, 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
36362 Federal Register / Vol. 63, No. 128 / Monday, July 6, 1998 /Rules and Regulations

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.

IX. References

The following sources are referred to

in this document. References marked

with an asterisk (*) 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.

References without an asterisk are not

on display; they are available as

published articles, books, and reports.

*1. Memorandum, from M. DiNovi,

Chemistry Review Branch, to P. Hansen,

Biotechnology Policy Branch, dated April 28,

1994.

*2. Memorandum to the file FAP 0A4212,

from M. DiNovi, K. Ekelman, and P. Hansen,

dated June 3, 1998.

*3. Memorandum, from M. DiNovi,

Chemistry Review Branch, to P. Hansen,

Biotechnology Policy Branch, dated

November 9, 1994.

*4. Memorandum, from K. Ekelman,

Division of Health Effects Evaluation, to P.

Hansen, Regulatory Policy Branch, dated

June 2, 1998.

5. Green, W. L., ‘‘Mechanisms of Action of

Antithyroid Compounds,’’ pp. 77–87 in: The

Thyroid, edited by S. C. Werner and S. H.

Ingbar, Harper & Row, New York, 1978.

6. Hill, R. N. et al., ‘‘Thyroid Follicular Cell

Carcinogenesis,’’ Fundamental and Applied

Toxicology, 12:629–697, 1989.

*7. Report, Borzelleca, J. F., C. C. Capen,

M. S. Christian, and B. N. LaDu, ‘‘Summary

and Consensus of the Acesulfame K

Scientific Expert Panel on the Safety of

Acetoacetamide-N-Sulfonic Acid and

Acetoacetamide,’’ dated October 13, 1992.

*8. Letter, from C.C. Capen, Ohio State

University, to J. Simplicio, Hoechst-Celanese

Corp., dated December 6, 1991.

9. Gaylor, D. W., and R. L. Kodell, ‘‘Linear

Interpolation Algorithm for Low Dose

Assessment of Toxic Substances,’’ Journal of

Environmental Pathology and Toxicology,

4:305–315, 1980.

10. National Academy of Sciences/National

Research Council, ‘‘Risk Assessment in the

Federal Government: Managing the Process,’’

Washington, DC, 1983.

11. Lorentzen, R. J., ‘‘FDA Procedures for

Carcinogenic Risk Assessment,’’ Food

Technology, pp. 108–111, 1984.

12. Gold, L.S. et al., ‘‘Target Organs in

Chronic Bioassays of 533 Chemical

Carcinogens,’’ Environmental Health

Perspectives, 93:233–246, 1991.

13. McConnell, E. E., ‘‘Thyroid Follicular

Cell Carcinogenesis: Results from 343 2–Year

Carcinogenicity Studies Conducted by the

NCI/NTP,’’ Regulatory Toxicology and

Pharmacology, 16:177–188, 1992.

14. IRIS (1995), Cincinnati: Office of Health

and Environmental Assessment,

Environmental Criteria and Assessment

Office, EPA.

15. Curran, P. G., and L. J. DeGroot, ‘‘The

Effect of Hepatic Enzyme-Inducing Drugs on

Thyroid Hormones and the Thyroid Gland,’’

Endocrine Reviews, 12(2):135–150, 1991.

16. Donaich, I., ‘‘Aetiological

Considerations of Thyroid Carcinoma,’’ vol.

6, pp. 55–72, in: Tumors of the Thyroid

Gland, edited by D. Smithers, E & S

Livingstone, Edinburgh, 1970.

17. Capen, C. C. and S. L. Martin,

‘‘Mechanisms that Lead to Disease in the

Endocrine System in Animals,’’ Toxicologic

Pathology, 17:234–249, 1989.

18. Handbook of Carcinogenic Potency and

Genotoxicity Databases, edited by L. S. Gold

and E. Zeiger, CRC Press, Boca Raton, FL,

1997.

19. Goddard, M. J., D. J. Murdoch, and D.

Krewski, ‘‘Temporal Aspects of Risk

Characterization,’’ Inhalation Toxicology,

7:1005–1018, 1995.

20. Kodell, R. L., D. W. Gaylor, and J. J.

Chen, ‘‘Using Average Lifetime Dose Rate for

Intermittent Exposures to Carcinogens,’’ Risk

Analysis, 7:339–345, 1987.

*21. Memorandum, from F. Hines,

Diagnostic Pathology Branch, to L. Taylor,

Additives Evaluation Branch, dated June 6,

1986.

22. ‘‘Health Effects Test Guidelines,’’ U.S.

EPA, June, 1996.

*23. Memorandum, from L. Taylor,

Additives Evaluation Branch, to P.

McLaughlin, Petitions Control Branch, dated

November 17, 1982.

*24. Memorandum, Cancer Assessment

Committee (CAC) (covers conferences of

November 21, 1983, February 21, 1985,

December 12, 1985, and June 17, 1986, and

information in Ref. 25 of this document).

*25. Memorandum, from L. Taylor,

Additives Evaluation Branch, to Cancer

Assessment Committee, dated June 19, 1986.

List of Subjects in 21 CFR 172

Food additives, 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: 21 U.S.C. 321, 341, 342, 348,

371, 379e.

2. Section 172.800 is amended by

adding paragraph (c)(13) to read as

follows:

§ 172.800 Acesulfame potassium.

* * * * *

(c) * * *

(13) Nonalcoholic beverages,

including beverage bases.

* * * * *

Dated: June 29, 1998.

Michael A. Friedman,

Acting Commissioner of Food and Drugs.

[FR Doc. 98–17700 Filed 6–30–98; 10:34 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 93F–0286]

Food Additives Permitted for Direct

Addition to Foods for Human

Consumption; Acesulfame Potassium

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule; response to

objection, confirmation of effective date.

SUMMARY: The Food and Drug

Administration (FDA) is overruling the

objection that it has received on the

final rule that amended the food

additive regulations to provide for the

safe use of acesulfame potassium (ACK)

as a nonnutritive sweetener in alcoholic

beverages. After reviewing the objection

to the final rule, the agency has

concluded that the objection does not

provide a basis for revoking the

amendment to the regulation. Therefore,

FDA is confirming the effective date for

the final rule. The final rule was issued

in response to a food additive petition

filed by Hoechst Celanese Corp.

DATES: The effective date of the final

rule published at 60 FR 21700 is

confirmed as May 3, 1995.

FOR FURTHER INFORMATION CONTACT:

Patricia A. Hansen, Center for Food

Safety and Applied Nutrition (HFS–

206), Food and Drug Administration,

200 C St. SW., Washington, DC 20204,

202–418–3093.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of May 3, 1995

(60 FR 21700), FDA issued a final rule

amending its regulations to permit the

use of acesulfame potassium (ACK) as a

nonnutritive sweetener in alcoholic

beverages (the ‘‘alcoholic beverages final

rule’’). This amendment of the

regulation, codified at 21 CFR

172.800(c)(12), was issued in response

to a food additive petition (FAP No.

3A4391) filed by Hoechst Celanese

Corp. FDA based its decision to permit

the use of ACK in alcoholic beverages

on the data in this petition and other

relevant information in its files,

including data and information from