[Federal Register Volume 63, Number 128 (Monday, July 6, 1998)]
[Rules and Regulations]
[Pages 36344-36362]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-17700]
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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.
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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 Sec. 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
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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.
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\1\ Stability studies of ACK in aqueous solutions were also
submitted in the original petition for ACK.
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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 Sec. 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
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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 upper-bound 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 deg.C
(68 deg.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 deg.C (86 deg.F) or 50 weeks storage at
20 deg.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 lifetime-averaged ``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,
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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 deg.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 deg.C (Ref. 2).
Accordingly, for all of the foregoing reasons, the agency has used 20
deg.C as representative of the temperature conditions likely to be
encountered over an extended storage period.
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\2\ FDA 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 deg.C, equivalent to 120 to 130 deg.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.
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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 ACK-sweetened nonalcoholic
beverages, exposure to AAS would be no more than 2.5 micrograms
(g)/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 g/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 dose-related
increases in feed consumption compared to controls. Other AAS-related
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 no-observed-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 high-dose 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
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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 two-generation reproduction study
with a teratology phase conducted in Sprague-Dawley 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
g/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\
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\3\ The petitioner also submitted results of genetic toxicity
tests of -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.
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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) dose-
related 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 short-term (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
[[Page 36349]]
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).
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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 short-term 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\
---------------------------------------------------------------------------
\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 tri-iodothyronine, 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 di-iodothyronine (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).
---------------------------------------------------------------------------
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
[[Page 36350]]
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 low-incidence 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 AAA-related 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 dose-related 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.
[[Page 36351]]
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 AAA-induced 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 long-term 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.
---------------------------------------------------------------------------
\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 dose-
response 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.
---------------------------------------------------------------------------
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 short-term 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, dose-response 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\
---------------------------------------------------------------------------
\9\ Potency 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.
---------------------------------------------------------------------------
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
[[Page 36352]]
from the consumption of ACK-sweetened 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
``extreme-case'' 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.
---------------------------------------------------------------------------
\10\ The 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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\11\ Hoechst'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 g/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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\12\ The 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.
---------------------------------------------------------------------------
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
[[Page 36353]]
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 TSH-dependent 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 ``extreme-case'' 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 long-term 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.
---------------------------------------------------------------------------
\13\ Taken 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).
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\14\ One 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.
---------------------------------------------------------------------------
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 upper-bound limit of lifetime human cancer risk
from exposure to AAA to be 6.6 x 10-8 (Ref. 2). This
hypothetical upper-bound limit of lifetime risk from AAA, like the
value obtained in FDA's first
[[Page 36354]]
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 upper-bound 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\
---------------------------------------------------------------------------
\15\ One 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.
---------------------------------------------------------------------------
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 ACK-sweetened beverages is
likely to be at very low levels, to be intermittent, and to be
infrequent.\16\
---------------------------------------------------------------------------
\16\ FDA 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.
---------------------------------------------------------------------------
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)
[[Page 36355]]
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 long-term 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 ACK-sweetened 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
petition\17\ [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.
---------------------------------------------------------------------------
\17\ CSPI uses the term ``petition'' to refer to its request for
a stay of the dry uses final rule.
---------------------------------------------------------------------------
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 AAA\19\ 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
[[Page 36356]]
further discussion of this submission is warranted.
---------------------------------------------------------------------------
\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.
\19\ CSPI 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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\20\ FDA 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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\21\ The 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.
---------------------------------------------------------------------------
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).''
---------------------------------------------------------------------------
\22\ Several 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.
---------------------------------------------------------------------------
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.''
---------------------------------------------------------------------------
\23\ The 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 long-term
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).
---------------------------------------------------------------------------
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
[[Page 36357]]
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\
---------------------------------------------------------------------------
\25\ This 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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\26\ One 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).
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\27\ FDA 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.
---------------------------------------------------------------------------
CSPI implies that, in order for long-term toxicity
(carcinogenicity) testing to be valid, it must conform to NTP
``requirements.'' FDA does not agree. The NTP document cited by
CSPI\28\
[[Page 36358]]
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).
---------------------------------------------------------------------------
\28\ This document is entitled ``Specifications for the Conduct
of Studies to Evaluate the Toxic and Carcinogenic Potential of
Chemical, Biological and Physical Agents in Laboratory Animals for
the National Toxicology Program (NTP).''
---------------------------------------------------------------------------
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 Sec. 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 guidance\29\
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.
---------------------------------------------------------------------------
\29\ Other 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).
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\30\ CSPI 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.
---------------------------------------------------------------------------
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
dose-related.'' 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 long-term studies of ACK were
conducted.\31\
---------------------------------------------------------------------------
\31\ One 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.)
---------------------------------------------------------------------------
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
[[Page 36359]]
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 high\32\ and questioned whether this study or the other long-term
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.
---------------------------------------------------------------------------
\32\ CSPI 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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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
[[Page 36360]]
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.
---------------------------------------------------------------------------
\34\ As 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.
---------------------------------------------------------------------------
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 time-to-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 time-to-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
[[Page 36361]]
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.
---------------------------------------------------------------------------
\35\ Several 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).
---------------------------------------------------------------------------
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.
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\37\ Because 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).
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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 Sec. 172.800 should be amended as set forth
below.
In accordance with Sec. 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 Sec. 171.1(h),
the agency will delete from the documents any materials that are not
available for public disclosure before making the documents available
for inspection.
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
[[Page 36362]]
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:
Sec. 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