[Federal Register Volume 67, Number 131 (Tuesday, July 9, 2002)]
[Rules and Regulations]
[Pages 45300-45310]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-17202]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket Nos. 98F-0052 and 99F-0187]


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

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 neotame as a 
nonnutritive sweetener in food. This action is in response to two 
petitions filed by Monsanto Co., which subsequently sold the rights to 
the petitions to the NutraSweet Co.

DATES: This rule is effective July 9, 2002. Submit objections and 
requests for a hearing by August 8, 2002. The Director of the Office of 
the Federal Register approves the incorporation by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51 of a certain 
publication in 21 CFR 172.829, as of July 9, 2002.

ADDRESSES: Submit written objections and requests for a hearing to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
objections to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Blondell Anderson, Center for Food 
Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740-3835, 202-418-3106.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Safety Evaluation of Neotame
A. Chemistry and Intake Considerations of Neotame
B. Nature and Extent of Neotame Safety Studies Database
C. Toxicology/Safety Assessment of Neotame
    1. Metabolism and Pharmacokinetics of Neotame
      a. Absorption of neotame
      b. Elimination, distribution, and potential tissue accumulation 
of neotame
      c. Effect of neotame on drug metabolizing enzymes
      d. Metabolites of neotame
    2. Critical Toxicology Studies and Issues
      a. A 2-generation reproduction study in the rat--neurotoxicity 
and behavioral effects
      b. Chronic (52-week) dog study--toxicological significance of 
elevated serum (hepatic) alkaline phosphatase levels
      c. A 104-week mouse carcinogenicity study--body weight gain 
decrement effect
      d. A 104-week rat carcinogenicity study--body weight gain 
decrement effect at all dose levels tested
      e. Chronic (52-week) rat feeding study--body weight gain 
decrement effect
      f. Clinical studies assessments--human tolerance to neotame
D. Estimating an Acceptable Daily Intake for Neotame
III. Comments
IV. Conclusion
V. Environmental Effects
VI. Paperwork Reduction Act of 1995
VII. References
VIII. Objections

I. Introduction

    FDA published notices in the Federal Register on February 10, 1998, 
and February 8, 1999 (63 FR 6762 and 64 FR 6100, respectively), 
announcing that food additive petitions, FAP 8A4580 and FAP 9A4643, had 
been filed by Monsanto Co., Skokie, IL 60077. The petitions propose 
amending the food additive regulations to provide for the safe use of 
neotame as a nonnutritive sweetener for tabletop use (FAP 8A4580) and 
for general-purpose use in food (FAP 9A4643) where standards of 
identity do not preclude such use. Subsequently, the rights to the 
petitions were sold to the NutraSweet Co., 699 North Wheeling Rd., 
suite 103, Mount Prospect, IL 60056. This document grants the petitions 
via a regulation approving the general-purpose food use of neotame.

II. Safety Evaluation

A. Chemistry and Intake Considerations of Neotame

    Neotame is the common or usual name for the chemical N-[N-(3,3-
dimethylbutyl)-L-[agr]-aspartyl]-L-phenylalanine-1-methyl ester (CAS 
Reg. No.165450-17-9). It is synthesized by reductive N-alkylation of L-
phenylalanine-L-[agr]-aspartyl methyl ester with 3,3-
dimethylbutyraldehyde. According to the petitioner, neotame has a 
sweetening potency that is approximately 7,000 to 13,000 times that of 
sucrose, depending on its food application (Refs. 1 and 2).
    The peptidyl linkage in neotame is stabilized by the N-alkyl 
substituent and is resistant to hydrolysis under typical use and 
storage conditions. Additionally, the N-alkyl substituent effectively 
prevents the common dipeptide cyclization reaction that results in the 
formation of a diketopiperazine derivative. The data from stability 
studies submitted by the petitioner show that the degradation of 
neotame in aqueous solutions is pH-, time-, and temperature-dependent. 
Based upon data from these stability studies on neotame, the agency 
concludes that minor decomposition of neotame could occur in neotame-
containing foods only when stored under conditions that are not 
considered typical for a commercial product (Refs. 1 and 2).
    The agency has determined the estimated daily intake (EDI) at the 
90th percentile for neotame as a general-purpose sweetener to be 0.10 
milligram per kilogram (mg/kg) body weight per day (bw/d) for consumers 
of all ages (eaters only) and 0.17 mg[sol]kg bw[sol]d for 2 to 5 year 
olds (eaters only). The corresponding mean intakes are 0.04 mg[sol]kg 
bw[sol]d and 0.05 mg[sol]kg bw[sol]d, respectively (Refs. 2 and 3).

B. Nature and Extent of Neotame Safety Studies Database

    In support of the safety of neotame, the petitioner submitted, 
within the two petitions, a combined total of 113 preclinical, 
clinical, and special studies, plus an additional 32 exploratory and 
screening studies in Food Master File No. 575. All pivotal preclinical 
studies were conducted in compliance with FDA's ``good laboratory 
practice'' regulations in 21 CFR part 58.
    The preclinical (animal) studies include short-term, subchronic, 
and chronic dietary toxicity tests in the rat, mouse, and dog; multi-
generation

[[Page 45301]]

reproduction and developmental studies in the rat; teratology studies 
in the rat and rabbit; and lifetime/carcinogenicity studies in the rat 
and mouse. The genotoxicity of neotame, its metabolites, and 
decomposition products, are also evaluated in several tests using both 
in vitro and in vivo assay systems. Extensive metabolism and 
pharmacokinetic measurements were carried out in all animal species 
studied. The clinical (human) studies tested the response/acceptance to 
orally administered neotame in both men and women during short-term 
(e.g., acute, single-dosing) and longer-term (e.g., up to 13 weeks, 
repeat-dosing) periods. Pharmacokinetic (PK) measurements also were 
carried out in a number of these studies (Ref. 4).
    Additionally, the petitioner provided three position papers in 
response to FDA questions. These position papers address: (1) The 
potential behavioral and neurotoxic effects of neotame, (2) the 
significance of elevated serum (hepatic) alkaline phosphatase activity 
in neotame-treated dogs as a measure of toxicity, and (3) body weight 
gain decrement in mice ingesting neotame. The key aspects of these 
position papers are discussed, as appropriate.

C. Toxicology/Safety Assessment of Neotame

1. Metabolism and Pharmacokinetics of Neotame
    As a component of the toxicological testing program on neotame, the 
petitioner conducted an extensive series of metabolism and PK studies. 
These studies were designed to assess: (1) The absorption of neotame; 
(2) the elimination, distribution, and potential tissue accumulation of 
neotame; (3) the effects of neotame on drug metabolizing enzymes; and 
(4) the metabolites of neotame in rodents (rats and mice), dogs, 
rabbits, and humans.
    a. Absorption of neotame. In all species studied, including humans, 
the agency finds that the absorption of ingested neotame occurs almost 
entirely in the small intestine. In the animal studies, the absorption 
of neotame was determined under fasting conditions using a dose level 
that was approximately 150 times greater than the 90th percentile 
estimated daily intake (EDI) of neotame for humans. Under these 
conditions, the amount of administered dose absorbed is reported to 
range from 18 to 38 percent in the rat, 15 to 44 percent in the rabbit, 
and 40 to 51 percent in the dog. These studies also indicate that, when 
mixed with the diet, the absorption of neotame is reduced. In the human 
clinical studies, the absorption of neotame approaches 100 percent in 
healthy male and female subjects when administered following an 
overnight fast and at dose levels ranging from one to five times the 
90th percentile EDI. Individual absorption levels range from 68 to 126 
percent (Ref. 5).
    b. Elimination, distribution, and potential tissue accumulation of 
neotame. The agency estimates that approximately 40 percent of the 
systemic elimination of ingested neotame and metabolites occurs via the 
urine, and the remainder is eliminated via the fecal route. In a whole-
body radiography study in the rat, following a gavaged dose of 
radiolabled neotame and serial sacrifice at timed intervals, post-
dosing, the highest levels of radioactivity are associated with the 
intestinal tract, the liver, and the kidney. At final sampling, no 
residual radioactivity is detected in peripheral tissues, with some 
residual activity associated with the intestinal tract. No organs or 
tissues, including the brain, eye, and skin, concentrate or store 
radiolabled neotame or its metabolites.
    Further evidence for the lack of accumulation of neotame at 
expected levels of human intake is found in the analysis of PK 
parameters evaluated during a 13-week dog study. In dogs consuming 
dietary neotame at dose levels of 1,200 to 2,000 mg[sol]kg bw[sol]d, 
there is an indication of saturation of an elimination pathway that 
could lead to possible accumulation. However, these levels are at least 
10,000 times greater than the 90th percentile EDI (0.1 mg[sol]kg 
bw[sol]d) of neotame for humans. This effect is not seen in dogs from 
the next lower treatment group (600 mg[sol]kg bw[sol]d), a level 
approximately 6,000 times above the 90th percentile EDI. Based on these 
findings, the agency concludes there is no concern for possible 
accumulation of neotame or its metabolites at expected human intake 
levels (Refs. 4 and 5).
    c. Effect of neotame on drug metabolizing enzymes. The rat is 
generally considered an appropriate animal model to assess the effects 
of xenobiotics on phase I (i.e., cytochrome P-450 or mixed-function 
amine oxidase microsomal enzyme systems\1\) and phase II (i.e., 
conjugation or biotransformation reactions involving glucuronidation, 
sulfation, acetylation, or glutathione-S- transferase reactions) 
metabolism. Following a 14-day period during which dietary neotame was 
fed at 0 (control), 100, 300, or 1,000 mg[sol]kg bw[sol]d, rats were 
sacrificed and in vitro assays performed on isolated liver microsomal 
pellets. The agency concludes that, when compared against a positive 
control (phenobarbital, a known enzyme inducer), neotame does not 
induce P-450 microsomal mixed function oxidase metabolizing enzymes at 
any dose level administered during the in vivo phase of the study. In 
evaluating the effects of neotame on phase II metabolism, the agency 
notes that livers from rats in the 1,000 mg[sol]kg bw[sol]d treatment 
group show a statistically significant depression in phase II 
metabolism endpoints. However, at the next lower dose of 300 mg[sol]kg 
bw[sol]d, which is approximately 3,000 times the 90th percentile EDI 
for neotame for humans, there are no effects on these same endpoints 
(Ref. 5).
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    \1\ Sipes, I. G. and Gandolfi, A. J., ``Biotransformation of 
Toxicants,'' chapter 4, pp. 88-109, in Casarett and Doull's 
Toxicology: The Basic Science of Poisons, 4th ed., edited by M. O. 
Amdur, J. Doul, and C. D. Klaassen, McGraw Hill, Inc., 1993.
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    d. Metabolites of neotame. The initial step in the metabolism of 
neotame in rats, dogs, rabbits, and humans is de-esterification to N-
[N-(3,3-dimethylbutyl)-L-[agr]-aspartyl]-L-phenylalanine (DMB-Asp-Phe, 
coded in the petition as NC-00751) by Ca\++\-dependent pancreatic 
esterases or after absorption by plasma esterases. De-esterification of 
neotame is similar in all species studied, including humans, although 
in the rat and rabbit this conversion occurs at a faster rate than in 
the dog and human. The de-esterified metabolite (NC-00751) is rapidly 
cleared from the plasma and excreted via the bile duct or in urine 
(Ref. 5). A small percentage of NC-00751 may undergo peptide-bond 
hydrolysis to form metabolites of dimethylbutylaspartate. The 3,3-
dimethylbutyl portion of DMB-Asp-Phe is then oxidized to 3,3-dimethyl-
butyric acid. This is followed by conjugation with glucuronic acid or 
with carnitine (a minor pathway).
    Methanol release results from the de-esterification of neotame and 
occurs more rapidly in the rat and rabbit than in the dog and human. 
The agency concludes that at the 90th percentile EDI for neotame, 
exposure to resultant methanol will be insignificant, i.e., not more 
than 0.008 mg[sol]kg bw[sol]d. This exposure level is of no 
toxicological concern because humans are exposed to much greater levels 
of methanol intake from their daily diets (Refs. 4 and 5).
    Based on neotame metabolism studies in the rat and dog, FDA 
concludes that some intestinal microvillar peptidase activity occurs in 
the gut, which results in the formation of other minor plasma 
metabolites of neotame, including phenylalanine (Ref. 5). Further 
review indicates that approximately 13 to 17

[[Page 45302]]

percent of the total available phenylalanine in the ingested neotame is 
released into the plasma after absorption; the remainder is eliminated 
in feces and urine as DMB-Asp-Phe. The agency has estimated the amount 
of phenylalanine presented to the body from the ingestion of neotame. 
The phenylalanine content of neotame is 44 percent by weight. Given 
that the 90th percentile neotame EDI for a 60 kg adult is 0.10 
mg[sol]kg bw[sol]d or 6 mg/d, and for a 2 to 5 year old (20 kg) child 
is 0.17 mg[sol]kg bw[sol]d or 3.4 mg/d, the estimated 90th percentile 
phenylalanine intake is 2.6 mg and 1.5 mg, respectively.
    The agency notes that, for healthy adults, the daily dietary intake 
of phenylalanine may range from 2.5 to 10 grams per person per day (g/
p/d), while that for a phenylketonuric (PKU) homozygous child (20 kg) 
may range from 0.4 to 0.6 g/p/d (Koch and Wenz\2\). Thus, the amount of 
phenylalanine from the 90th percentile intake of neotame is trivial 
compared to that from the normal adult diet. Even for the PKU 
homozygous child, the incremental amount of phenylalanine intake that 
can be expected from neotame is insignificant, i.e., equivalent to no 
more than 0.3 to 0.4 percent of the daily phenylalanine intake of the 
PKU homozygous child (Ref. 5). The agency concludes that the potential 
intake of phenylalanine that may result from use of neotame as a 
general-purpose sweetener does not pose any safety concern (Refs. 4 and 
5).
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    \2\ Koch, R. and Wenz E. J., ``Aspartame Ingestion by 
Phenylketonuric Heterozygous and Homozygous Individuals,'' chapter 
30, pp. 593-603, in Physiology and Biochemistry, edited by Stegink, 
L. D. and L. J. Filer, Jr., 1984.
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    Based on reviews of the metabolism and pharmacokinetic studies on 
neotame, the agency concludes that the metabolism of neotame is 
qualitatively similar across all species studied. Furthermore, there is 
no evidence that, at expected levels of intake, neotame or its 
metabolites will accumulate in the body or that ingestion of neotame 
will have any adverse effect in the body on Phase I and II metabolism. 
The metabolites of neotame are well characterized, and the potential 
intakes of metabolites, such as methanol and phenylalanine, are of no 
toxicological consequence. Therefore, the agency's review of the 
metabolism and pharmacokinetic studies of neotame does not raise any 
safety concerns (Refs. 4 and 5).
2. Critical Toxicology Studies and Issues
    FDA reviewed all studies and supplemental information submitted by 
the petitioner. During its review, the agency determined that certain 
studies were more important than others to a regulatory decision on 
neotame. This determination was based on the nature of the endpoints 
investigated in these studies (i.e., reproductive and developmental 
effects, long-term exposure, chronic toxicity, carcinogenic potential, 
and human tolerance), and on specific issues presented by these 
studies. The critical studies and issues presented by the studies are: 
(1) The 2-generation reproduction study in rats--neurotoxicity and 
behavioral effects, (2) the chronic (52-week) dog study--toxicological 
significance of increased serum (hepatic) alkaline phosphatase levels, 
(3) the 104-week mouse carcinogenicity study--body weight gain 
decrement effect, (4) the 104-week rat carcinogenicity study--body 
weight gain decrement effect at all dose levels tested, (5) the chronic 
(52-week) rat feeding study--body weight gain decrement effect, and (6) 
the human clinical trials--human tolerance to neotame.
    a. A 2-generation reproduction study in the rat--neurotoxicity and 
behavioral effects. Reproductive performance and fertility were 
assessed over two generations in CD (cesarean derived) rats fed diets 
containing neotame at levels of 0 (control), 100, 300, or 1,000 
mg[sol]kg bw[sol]d. Each treatment group consisted of 28 males and 28 
females. Animals were mated, the resultant offspring weaned, and the F1 
generation animals selected and allowed to mature for 10 weeks and then 
mated. The F2 litters were terminated, post-weaning. Under the 
conditions of this study, the agency concludes that neotame has no 
effects on the reproduction or fertility of rats exposed to neotame at 
levels up to 1,000 mg[sol]kg bw[sol]d for two generations. Nor are 
there any treatment effects on measures of physical development, e.g., 
pinna unfolding, hair growth, tooth eruption, or eye opening (Refs. 4 
and 6).
    The 2-generation study included tests of motor activity and 
cognitive function. General motor activity was measured in F1 offspring 
by counting breaks in a pair of infrared light beams over a 12-hour 
period, while cognitive function was assessed by recording swim times 
up to 60 seconds maximally in six consecutive trials per animal in a 
water-filled Y-maze (Ref. 7). While the petitioner concludes there were 
no significant treatment effects on motor activity in F1 male and 
female offspring, the agency's analyses of pertinent data show a 
statistically significant reduction in motor activity among F1 males 
from the 1,000 mg[sol]kg bw[sol]d neotame treatment group. No effects 
are noted on motor activity in F1 females at any dose level.
    With regard to results from the swim-maze tests that were conducted 
in F1 offspring at approximately 24 to 28 days of age, both the 
petitioner and the agency conclude that there is a statistically 
significant increase in mean swimming time (an indicator of reduced 
performance) to the ``correct'' arm of the Y-maze in F1 males from the 
1,000 mg[sol]kg bw[sol]d group. Specifically, this increased swim time 
is noted in two of six trials in the F1 males from the high dose group. 
While an increase in swim time is also noted for one of six trials in 
F1 males from the 300 mg[sol]kg bw[sol]d dose group, this singular 
observation is not accompanied by any other indication of treatment-
related behavioral changes and therefore is not considered to be 
indicative of a biologically relevant effect. As with motor activity, 
there are no effects on cognitive performance (as measured by swim maze 
times) noted in F1 female offspring from any treatment group.
    The F1 offspring from the 2-generation reproduction study also were 
subjected to specific tests that measured the development of auditory 
and visual responses. The agency's evaluation of results on auditory 
startle, pupil closure, and visual placing show no treatment-related 
effects in F1 males or females at any level of neotame tested.
    The finding of statistically significant effects on two separate 
behavioral tests (i.e., motor activity and swim maze times) in F1 males 
from the 1,000 mg[sol]kg bw[sol]d dose group supports the conclusion 
that this dose is an effect level. Based on the findings from the 
studies of motor activity and cognitive function, the agency considers 
the 300 mg[sol]kg bw[sol]d dose to be a no observed adverse effect 
level (NOAEL) for these endpoints (Refs. 4 and 7).
    Early in its evaluation of the neotame safety database, the agency 
determined that the petitioner should provide a more specific 
assessment addressing the potential neurotoxicity and behavioral 
effects of neotame. In response to the agency's request, the petitioner 
submitted a position paper entitled ``Neotame Does Not Cause Any 
Behavioral or Neurotoxic Effects'' (Ref. 8). This document contains 
summaries and discussions of data and information from two principal 
sources. The first involves several ``key'' preclinical studies (12 in 
all) and 4 clinical studies from the neotame studies database. The 
second source of information discussed in the position paper is a 
series of 20 publications that are primarily related to aspartame. 
Collectively, these 20 publications provide little information

[[Page 45303]]

that is relevant to the agency's overall safety assessment of neotame 
and are not discussed further.
    With regard to the ``key'' animal studies, the petitioner states in 
its position paper that these studies incorporated clinical 
observations/testing enhancements as ``effective procedures for 
detecting neurotoxic effects.'' During the ante mortem phase of the 
animal studies, these enhancements included detailed physical, 
behavioral, and clinical observations to detect signs of neurological 
disorder, behavioral abnormality, physiological dysfunction, and other 
signs of nervous system toxicity. Post mortem enhancements included 
extensive histopathological evaluations of brain, spinal cord, and 
peripheral nerves.
    FDA has reviewed thoroughly all of the preclinical and clinical 
studies discussed in the position paper. With the exception of the 2-
generation rat reproduction study in which statistically significant 
decreases in motor activity and statistically significant increases in 
swim times are observed in F1 offspring males at 1,000 mg[sol]kg 
bw[sol]d, the preclinical studies do not show behavioral or neurotoxic 
effects associated with the ingestion of neotame.
    Based on available preclinical and clinical information from the 
neotame studies database, the agency concludes that there is no concern 
for potential neurotoxic or behavioral effects in humans from the 
ingestion of neotame as a general-purpose sweetener in foods. This 
conclusion is reinforced further by the NOAEL of 300 mg[sol]kg bw[sol]d 
established for motor activity and cognitive performance in F1 males 
from the 2-generation reproduction study, a dose level that is at least 
3,000 times greater than the 90th percentile EDI of 0.1 mg[sol]kg 
bw[sol]d (Refs. 4 and 7).
    b. Chronic (52-week) dog study--toxicological significance of 
elevated serum (hepatic) alkaline phosphatase. Beagle dogs were fed 
diets containing neotame at levels of 0 (control), 20, 60, 200, or 800 
mg[sol]kg bw[sol]d over a 52-week period. Detailed data were collected 
on animal survival, growth, food intake, clinical chemistries, 
hematology, urinalyses, and gross organ pathology and histopathology. 
At the conclusion of the study, a limited number of dogs from the 
neotame treatment groups were placed on a control diet for an 
additional 4-week ``reversibility period.'' During the agency's review 
of this study, a question arose about the toxicological significance of 
increased serum alkaline phosphatase (ALP) levels (of hepatic origin) 
noted in female dogs from the 200 mg[sol]kg bw[sol]d dose group and in 
both sexes at the 800 mg[sol]kg bw[sol]d dose group. Other effects 
noted were statistically significant dose-related increases in absolute 
liver weights and in relative liver weights (liver to brain weight 
ratio) in female dogs in the 200 and 800 mg[sol]kg bw[sol]d dose 
groups. There was no evidence of histopathological changes in the 
liver, brain, sciatic nerve, and spinal cord or in other organs or 
tissues examined from neotame-treated dogs.
    Because elevated serum ALP levels had also been observed in shorter 
duration studies (2-week and 13-week) in dogs ingesting neotame 
containing diets, the agency requested that the petitioner provide 
further clarification on this matter. In its response, the petitioner 
submitted a position paper entitled ``Increases in Serum Alkaline 
Phosphatase in the Dog Are Not Associated with Target Organ Toxicity,'' 
together with several publications related to hepatotoxicity and serum 
ALP activity (Ref. 9). In this position paper, the petitioner reasons 
that the increased serum ALP levels observed in neotame-treated dogs 
are not due to a hepatotoxic response, but to a ``nonspecific, 
physiological response'' to the high doses of neotame.
    FDA conducted further statistical analyses on the liver weight 
parameters mentioned previously. Based on these analyses, the agency 
concludes that the means for these liver effects from the 200 and 800 
mg[sol]kg bw[sol]d dose groups are statistically significantly higher 
than the means for the 0 (control), 20, and 60 mg[sol]kg bw[sol]d 
treatment groups. Furthermore, there are no statistically significant 
differences between the 0 (control), 20, and 60 mg[sol]kg bw[sol]d dose 
group means for any of the liver weight parameters that were evaluated.
    From the review of the data from the 52-week dog study and the 
supplemental information submitted by the petitioner in its position 
paper, the agency concludes that the changes in serum ALP levels are 
most likely due to a nontoxic response to the higher levels (200 and 
800 mg[sol]kg bw[sol]d) of administered neotame. This conclusion is 
based on the following: (1) There are no significant effects from 
neotame on other liver enzymes (e.g., alanine aminotransferase, 
aspartate aminotransferase, gamma glutamyl transferase), (2) serum 
albumin levels are not decreased in neotame-treated dogs (a decrease 
would have been an indicator of chronic liver toxicity), (3) serum 
bilirubin levels are normal in both sexes at high doses of neotame (an 
increase would have been seen if cholestasis was occurring), and (4) 
the liver in both sexes and at all dose levels appears normal on 
histopathological examination. In this 52-week dog study, FDA 
establishes a no observed effect level (NOEL) of 60 mg[sol]kg bw[sol]d, 
based on liver effects (e.g., serum (hepatic) alkaline phosphatase and 
relative liver weights) as the most sensitive endpoints (Refs. 4 and 
10).
    c. A 104-week mouse carcinogenicity study--body weight gain 
decrement effect. CD-1 mice were fed neotame-containing diets for 104 
weeks at levels of 0 (control), 50, 400, 2,000, or 4,000 mg[sol]kg 
bw[sol]d. Based on an evaluation of the histopathological data from 
this carcinogenicity study, FDA concludes that, under the conditions of 
the study, doses of neotame up to 4,000 mg[sol]kg bw[sol]d administered 
to male and female CD-1 mice for up to 2 years did not induce 
neoplastic lesions (Ref. 11).
    Although there was no evidence of carcinogenicity in mice exposed 
to neotame for 104 weeks, during the agency's review of other 
endpoints, we noted negative effects on body weight gain (and thus body 
weight) in both sexes. In light of only small decreases in cumulative 
food consumption, the agency was concerned about the potential 
toxicological significance of the decrease in body weight gain. In 
response to the agency's request for further clarification on this 
issue, the petitioner submitted a position paper entitled ``In the 
Mouse Carcinogenicity Study With Neotame Small Changes in Body Weight 
Gain at Some Intervals in Female Mice at 50 mg[sol]kg bw Relative to 
Controls Are Due to a Decrease in Food Consumption'' (Ref. 12). In its 
analysis, the petitioner states that the mouse is not a reliable model 
for determining the relationship between body weight gain and food 
consumption. Reasons cited include the small differences in body weight 
gain over a lifetime in mice, both in absolute terms and in proportion 
to initial body weights at the start of a study, and well-known 
difficulties in obtaining accurate measures of food intake for mice 
(e.g., mice frequently spill food from their food cups and contaminate 
their food with feces and urine). The petitioner reiterated its belief 
that the body weight gain decrements noted in mice during the 104-week 
study were due to a small but consistent reduction in food consumption 
which is attributable to poor diet palatability and should not be 
viewed as a toxicological response to neotame.
    In further evaluation of this body gain weight decrement issue, FDA 
subjected the data on body weight, body weight gain, and adjusted (for 
neotame content)

[[Page 45304]]

food intake to extensive statistical evaluation. Using an analysis of 
covariance model and pair-wise dose comparisons of body weights and 
body weight gain, the agency notes statistically significant effects 
for the 400, 2,000, and 4,000 mg[sol]kg bw[sol]d dose groups. Based on 
these analyses, the agency concludes that the body weight gain 
decrement effect in both male and female mice in the three highest dose 
groups is not accounted for by the small decreases in food consumption. 
However, in the 50 mg[sol]kg bw[sol]d treatment group, the effects on 
body weight and body weight gain are not statistically different from 
controls. Based on the detailed statistical evaluation of data 
pertinent to the body weight gain decrement noted in the 104-week 
dietary carcinogenicity study in mice, the agency establishes a NOEL of 
50 mg[sol]kg bw[sol]d for this endpoint (Refs. 4 and 10).
    d. A 104-week rat carcinogenicity study--body weight gain decrement 
effect at all dose levels tested. A 104-week rat carcinogenicity study 
(with an in utero phase) was conducted during which neotame was fed at 
0 (control), 50, 500, or 1,000 mg[sol]kg bw[sol]d. Based on a thorough 
evaluation of the histopathological data from this carcinogenicity 
study, FDA concludes there is no evidence of neotame-induced neoplastic 
lesions in rats ingesting diets containing neotame at levels up to 
1,000 mg[sol]kg bw[sol]d for 104 weeks (Ref. 11).
    During its review of the 104-week rat carcinogenicity study, the 
agency noted effects on body weight gain (and thus body weight) in both 
sexes of neotame-treated rats at all dose levels tested. Statistically 
significant decreases in cumulative body weight gains were observed at 
various intervals throughout the study. At week interval 0 to 52, 
cumulative body weight gains were 9 to 11 percent less and 13 to 19 
percent less, respectively, in neotame-treated male and female rats, 
than in control animals. Similar effects were noted at week intervals 0 
to 78 and 0 to 104, i.e, cumulative body weight gains ranging from 10 
to 13 percent less in treated males and 17 to 20 percent less in 
treated females. In reporting this information, the petitioner suggests 
that the lower body weights and lower body weight gains among neotame-
treated rats can be attributed to reduced food intake due to reduced 
palatability of the diets containing neotame.
    The agency, however, based on an analysis of the food intake data, 
concludes that the decreases in adjusted (for neotame content) food 
intake among the neotame-treated rats are small and do not fully 
explain the magnitude of the differences in body weight and body weight 
gain observed in these animals at week 52 and thereafter up to week 
104. In view of the significant body weight gain decrement effect 
observed in all neotame treatment groups during the 104-week rat 
carcinogenicity study, a NOEL cannot be established. Lacking a suitable 
explanation for this effect based on decreased food intake (as argued 
by the petitioner), the agency considered the body weight gain 
decrement effect unresolved by the 104-week rat study (Refs. 4 and 10).
    e. Chronic (52-week) rat feeding study--body weight gain decrement 
effect. In order to resolve the body weight gain decrement issue in 
rats, the agency carried out a thorough analysis of data from a 52-week 
rat feeding study. This study employed a wide range of neotame dose 
levels, two of which were below the lowest dose tested in the 104-week 
rat carcinogenicity study (as discussed in section II.C.2.d of this 
document). The results of this analysis are presented in the following 
paragraphs.
    In the chronic (52-week) rat feeding study (with an in utero phase) 
rats received neotame at 0 (control), 10, 30, 100, 300, or 1,000 
mg[sol]kg bw[sol]d. Except for body weight and body weight gain, there 
were no statistically significant treatment-related effects of neotame 
during this 52-week feeding study. With respect to both body weight and 
body weight gain, female rats appear to be more sensitive than males.
    In regard to body weight, at the end of the 52-week study, body 
weights in females from the 100, 300, and 1,000 mg[sol]kg bw[sol]d 
groups were statistically significantly lower than those of control 
female rats. However, the body weights of females from the 10 and 30 
mg[sol]kg bw[sol]d groups were not statistically different from control 
females. Among males, only the 100 mg[sol]kg bw[sol]d group had 
statistically significant body weight differences from control male 
rats.
    As for cumulative body weight gains during the 0 to 52-week 
interval, statistically significant decreases are noted in treated 
females, compared to controls, only from the 300 and 1,000 mg[sol]kg 
bw[sol]d treatment groups. While the body weight gains in females from 
the 100 mg[sol]kg bw[sol]d are lower than in control female rats, this 
difference is not statistically significant. Compared with controls, 
there are no significant differences in cumulative body weight gains in 
females from the two lowest treatment groups (10 and 30 mg[sol]kg 
bw[sol]d) for the 0 to 52-week interval. Cumulative body weight gains 
in male rats from the 30, 100, 300, and 1,000 mg[sol]kg bw[sol]d 
neotame treatment groups, while somewhat lower than controls, are not 
statistically different. As noted in the 104-week carcinogenicity 
study, female rats in the 52-week dietary study were more sensitive to 
body weight gain decrement effects than males.
    FDA performed a detailed analysis of the results from the 52-week 
dietary rat study and concludes that this study provides an adequate 
basis to assess the body weight gain decrement effect noted in the 104-
week carcinogenicity rat study for four reasons. First, the range of 
neotame dose levels studied in the 52-week study is comparable to the 
doses tested in the 104-week study. Second, in each study, the female 
rat is more sensitive. Third, a parallel comparison of the 52-week 
study and the first 52 weeks of the carcinogenicity study shows that 
the body weight gain decrement effect was of a similar order of 
magnitude in both studies. Fourth, the magnitude of decrease in body 
weight gain occurring during week interval 0 to 52 in the 104-week 
study does not worsen during the last half of the study. These 
observations add strength to the utility of the 52-week dietary rat 
study in resolving any concern about the body weight gain decrement 
effect and in establishing a NOEL of 30 mg[sol]kg bw[sol]d for this 
endpoint (Refs. 4 and 10).
    f. Clinical studies assessments--human tolerance to neotame. The 
petitioner submitted the results of six human clinical trials that 
investigated the ingestion of neotame under varied conditions, 
including acute-single exposure, acute-repeat exposure, and short-term 
(2-week) and longer-term (13-week) daily exposure. Five of these trials 
employed healthy adult subjects, while one trial evaluated non-insulin 
dependent diabetes mellitus (Type II diabetic) adult subjects. In each 
of these trials, subject tolerance to neotame intake was determined by 
physical examinations, vital signs, electrocardiograms, routine 
clinical laboratory measurements (e.g., hematology, clinical 
chemistries, and urinalysis), and self-assessments of adverse 
experiences.
    The levels of neotame administered in these clinical trials ranged 
from 1 to 15 times the 90th percentile EDI level of 0.1 mg[sol]kg 
bw[sol]d or 6 mg per person per day (mg/p/d).
    The agency concludes that in all six trials there are no treatment-
related effects reported for any of the parameters examined. Although 
headache was the most frequently noted adverse experience, the 
incidence of

[[Page 45305]]

headache is comparable for the treated and control groups and is not 
considered to be associated with neotame intake. Results from ancillary 
pharmacokinetic measurements in several of the clinical trials do not 
raise any safety concerns. In the trial with Type II diabetic subjects, 
no adverse effects are noted in any of the subjects. Under the 
conditions of that trial, the agency concludes that the ingestion of 
neotame at levels up to 1.5 mg[sol]kg bw[sol]d does not produce 
significant changes in either fasting-state glucose or insulin levels 
in Type II diabetic subjects.
    Based on reviews of these clinical trials, the agency concludes 
that the ingestion of neotame at levels up to 1.5 mg[sol]kg bw[sol]d 
(15 times the 90th percentile EDI) for a period as long as 13 weeks is 
well tolerated by healthy male and female subjects. The agency also 
concludes that in the study with Type II diabetic subjects, the intake 
of neotame at levels up to 1.5 mg[sol]kg bw[sol]d does not have 
significant effects on fasting plasma glucose or insulin levels in 
study subjects (Refs. 4 and 13).

D. Estimating an Acceptable Daily Intake for Neotame

    In determining an acceptable daily intake (ADI) for a new food 
additive, the agency relies on a comprehensive evaluation of all 
relevant studies and information submitted by the petitioner. As the 
agency's evaluation of the neotame safety studies database progressed, 
four studies with attendant issues emerged as having the greatest 
impact in reaching a safety decision; these studies are highlighted in 
table 1 of this document.

                         Table 1.--Summary of Study Data Pertinent to Establishing an Acceptable Daily Intake Value for Neotame
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           NOEL (mg[sol]kg
              Study Information                           Pivotal Endpoint                    bw[sol]d)           Safety Factor\A\       ADI (mg/p/d)
--------------------------------------------------------------------------------------------------------------------------------------------------------
2-Generation Reproduction (Rat)               Motor Activity and Cognitive Function                  (300)\B\            1,000                   18
                                               in F1 Males
52-week (Dog)                                 Serum (Hepatic) ALP Levels and Relative                     60               100                   36
                                               Liver Weights in Females
104-week (Mouse)                              Body Weight Gain Decrement in Both                          50               100                   30
                                               Sexes
52-week (Rat)                                 Body Weight Gain Decrement in Females                       30               100                   18
--------------------------------------------------------------------------------------------------------------------------------------------------------
\A\ Safety factors typically applied by the agency in establishing an ADI based on effects from a reproductive toxicity study or from a chronic study
  are 1000 and 100, respectively.
\B\ The value reported is the NOAEL as discussed in Section II.C.2.a of this document.

    Based on the NOAEL or NOEL identified for the most sensitive 
endpoint in each of the four studies, ADI values were determined 
ranging from a high of 36 mg[sol]p[sol]d to a low of 18 mg[sol]p[sol]d. 
In taking a conservative approach, the agency concludes that the 
appropriate ADI for neotame is 18 mg[sol]p[sol]d (Ref. 4). This level 
is three times higher than the 90th percentile EDI for neotame of 6 
mg[sol]p[sol]d.

III. Comments

    Thirty comments were submitted to FDA's Dockets Management Branch 
in response to the filing of the two neotame food additive petitions 
(25 for FAP 8A4580 and 5 for FAP 9A4643). The issues raised in the 
comments are identified and grouped into the following subject 
categories.
Aspartame
    The majority of the comments compared neotame to aspartame. In 
these comparisons, the comments assumed that neotame produces the same 
metabolic breakdown products as aspartame and thus would be responsible 
for the same health effects they allege to be associated with 
aspartame, which is the subject of a food additive regulation (21 CFR 
172.804). In response to these comments, FDA points out that neotame is 
chemically and metabolically different (see section II.A of this 
document and Ref. 1, and section II.C.1 of this document, respectively) 
from aspartame even though they are structurally related. Therefore, 
the comments' assertions about neotame are without basis. Because the 
comments do not provide the agency with any information regarding the 
safety of neotame, they will not be discussed further.
Estimated Daily Intake
    Several comments objected to the tabletop use petition on the basis 
that the petitioner's EDI for neotame is inaccurate, implying that it 
is too low. In determining an EDI, FDA makes projections based on the 
amount of the additive proposed for use in particular foods and on data 
regarding the consumption levels of these particular foods, commonly 
using the 90th percentile as a measure of high chronic exposure. The 
agency concludes that the 90th percentile EDI calculated for neotame, 
as discussed in section II.A of this document, accurately reflects the 
exposure to neotame as a general-purpose sweetener in all foods (except 
for meats and poultry), including tabletop use (Ref. 2).
    One comment noted that the petitioner assumes that neotame will 
replace 50 percent of aspartame's current applications and argued that 
this assumption may be limited unduly and not sufficiently 
conservative. FDA agrees with the comment on this point, and disagrees 
with the petitioner's use of the 50 percent replacement factor in their 
estimation of exposure to neotame. The agency conservatively assumes 
that this new sweetener will replace all existing uses of aspartame 
(Ref. 14) and uses this estimate in its safety evaluation.
No Observed Effect Level, Body Weight, and Body Weight Gain Effects
    One comment stated that there is no NOEL established by the 104-
week rat carcinogenicity study for neotame, because all doses show 
adverse effects on growth. The comment also asserted that the data 
contained in this study do not support the petitioner's explanation 
that decreases in body weights in the treated rats are due to reduced 
palatability of the neotame-containing diets. In addition, the comment 
indicated that the petitioner did not supply any gavage, pair-feeding, 
or dietary restriction studies to prove that the body weight gain 
decrements are due to palatability and not toxicity. The comment also 
claimed that a safe usage level for neotame cannot be determined from 
the safety database provided in the neotame food additive petitions.
    FDA agrees that a NOEL cannot be established based on the 104-week 
rat carcinogenicity study, in view of the body weight gain (decrement) 
effect. The agency also notes that, while neotame may have had some 
influence

[[Page 45306]]

on diet palatability, the decreases in food intake (adjusted for 
neotame content) among neotame-treated rats of both sexes in the 104-
week study are too small to explain the magnitude of the body weight 
gain decrement that occurred in rats from the neotame treatment groups 
(see section II.C.2.d of this document and Refs. 4 and 10). FDA 
disagrees, however, about the necessity for additional testing 
requested by the comment to resolve the body weight gain decrement 
issue. While the proposed studies might address mechanistic 
relationships between food consumption and weight gain, the agency 
believes that they will not provide meaningful data to explain the 
magnitude of differences in body weight and body weight gain in 
neotame-treated rats from the 104-week study in view of the small 
decreases in food consumption noted in these animals. In addition, FDA 
believes that a safe usage level for neotame can be established from 
the database provided by the petitioner. As discussed in section 
II.C.2.e of this document, the results in the 52-week rat dietary 
toxicity study provide a strong scientific basis to resolve concerns 
over the body weight gain decrement effect (Refs. 4, 10, and 15). Based 
on the 52-week rat study and using body weight gain decrement as the 
most sensitive endpoint for toxicity, the agency is able to establish a 
NOEL for neotame of 30 mg[sol]kg bw[sol]d. From this NOEL, FDA derives 
an ADI for neotame of 18 mg[sol]p[sol]d (see table 1 in section II.D of 
this document and Ref. 4).
Serum Alkaline Phosphatase and Liver Toxicity
    Several comments expressed concerns regarding potentially adverse 
effects of neotame based on changes observed in serum ALP levels in 
dogs consuming high doses of neotame (i.e., 200 mg[sol]kg bw[sol]d and 
higher) in both 13-week and 52-week feeding studies. Additional 
comments suggested that neotame is hepatotoxic, as evidenced by effects 
on other endpoints, such as changes in absolute and/or relative liver 
weight, changes in serum cholesterol and triglycerides, and neotame-
related cholestasis.
    The agency notes that most of these comments focused on effects 
observed in the 13-week dog study. In its review of the subchronic (13-
week) dog study, the agency observed the liver effects referenced in 
the comments (Ref. 16). Ordinarily, in the absence of a longer duration 
study, the agency would have given more weight to the results of the 
13-week dog study. However, a chronic (52-week) dog study was also 
submitted in support of the safety of neotame, and that study provides 
for a more complete manifestation of the target organ toxicity in 
neotame-treated dogs.
    While the agency considers the 13-week dog study useful for 
obtaining preliminary toxicological information (i.e., identification 
of target organs) and for determining the appropriate range of doses of 
neotame that would be fed in the 52-week dog study, the 52-week study 
provides a stronger basis for assessing the potential chronic toxicity 
of neotame in the dog. Because the results from this longer-term study 
supersede those of the 13-week study and because all of the effects 
noted in the shorter-term study occurred at levels of exposure well 
above the NOEL established by the 52-week study, the agency concludes 
that no further discussion is needed in response to issues raised in 
comments concerning the 13-week dog study.
    Several comments asserted that elevated serum ALP levels observed 
in the neotame-treated dogs in the 52-week dog study indicate liver 
toxicity. As discussed in section II.C.2.b of this document, FDA 
recognizes that in the 52-week dog study elevated serum ALP levels are 
observed in both sexes of dogs from as early as 13 weeks until the end 
of the study at neotame dose levels of 200 and 800 mg[sol]kg bw[sol]d. 
However, the agency disagrees with comments that these elevated serum 
ALP levels are evidence of hepatic toxicity. While an increase in serum 
ALP may be an indicator of liver toxicity, such a conclusion cannot be 
substantiated in the absence of additional corroborative changes. 
Specifically, hepatic damage may result in increased levels of other 
liver enzymes, such as alanine aminotransferase, aspartate 
aminotransferase, or gamma glutamyl transferase. None of these liver 
enzymes was elevated in the neotame-treated dogs. Also, a decrease in 
blood albumin levels may indicate chronic liver toxicity. Blood albumin 
levels in dogs from all neotame dose groups were normal and comparable 
to control values. Furthermore, an elevation in serum bilirubin 
indicates cholestasis; serum bilirubin levels were unaffected by 
neotame treatment.
    Increased cholesterol levels are another indication of altered 
liver function. Plasma cholesterol and triglyceride levels in dogs from 
the 52-week study, although somewhat variable, were well within the 
normal range for dogs and unaffected by neotame treatment. 
Additionally, histopathological examinations of livers from dogs from 
the neotame-treated groups did not reveal any evidence of necrosis, 
blockage of bile flow, or any other abnormalities that were not 
detected in control animals. Collectively, these observations support 
the agency's conclusion that data from the 52-week study do not show 
evidence of hepatic toxicity in dogs administered neotame (Refs. 4, 17, 
and 18).
    Several comments asserted that neotame-related liver toxicity is 
not reversible, as is implied by the petitioner, based primarily on the 
increases in both serum ALP levels and relative liver weights in the 
dog studies. The agency concludes that the reversibility of these 
effects is not relevant to a safety decision regarding chronic 
ingestion of neotame. While FDA agrees, as noted in section II.C.2.b of 
this document, that increases in serum ALP levels and relative liver 
weights occur in dogs from the 200 and 800 mg[sol]kg bw[sol]d neotame 
groups in the 52-week study, neither of these parameters is affected at 
the lower levels tested (20 or 60 mg[sol]kg bw[sol]d). By considering 
serum ALP and relative liver weights as the most sensitive endpoints of 
potential neotame toxicity, the agency determines for the 52-week dog 
study that 60 mg[sol]kg bw[sol]d is an appropriate NOEL (Refs. 4, 10, 
and 17).
Liver as a Target Organ for Neotame Toxicity
    One comment emphasized the importance of the liver in animal growth 
and glucose homeostasis. This comment asserted, based on analyses of 
the neotame safety studies database, that neotame affects growth in 
both rats and dogs, and appears to affect glucose homeostasis in 
persons with diabetes. Based upon these findings, along with the 
elevated serum ALP levels in neotame-treated dogs and the structure of 
neotame, the comment concluded that it was important to rule out the 
liver as a target organ.
    In regard to the effect of neotame on body weight gain in the rat, 
the agency has established a NOEL of 30 mg[sol]kg bw[sol]d, based on 
the 52-week rat feeding study, as summarized in section II.C.2.e of 
this document. We discuss our analyses of the 52-week rat feeding study 
and our resolution of the body weight gain effect in more detail in 
Refs. 10 and 15.
    In regard to the effect of neotame on body weight and body weight 
gain in the 52-week dog feeding study, the effect occurred only in male 
dogs and only in the highest neotame dose group (i.e., 800 mg[sol]kg 
bw[sol]d) during weeks 1 to 5 and 7 to 8 (Ref. 18). At all other dose 
levels tested (i.e., 20, 60, and 200 mg[sol]kg bw[sol]d), there were no 
statistically significant effects on body weight or body weight gain in 
either sex. Furthermore, as discussed in

[[Page 45307]]

section II.C.2.b of this document, the agency relies on more sensitive 
endpoints, i.e., serum ALP levels and relative liver weights, for 
establishing a NOEL for neotame from the 52-week dog study.
    The agency also disagrees with the comment's assertion that neotame 
appears to affect glucose homeostasis in persons with diabetes. We 
explain our basis for concluding that neotame does not appear to affect 
glucose homeostasis in persons with diabetes later in this document, in 
the discussion entitled ``Type II Diabetes Study.''
    As for changes in serum ALP levels, the agency does not consider 
these to be a manifestation of hepatic toxicity in the 52-week dog 
study. Our reasons for discounting the toxicological significance of 
the changes in serum ALP are discussed previously (see section II.C.2.b 
of this document and the fourth subject category in section III ``Serum 
Alkaline Phosphatase and Liver Toxicity'').
    The comment asserted that ``[t]he structure of neotame suggests 
that the metabolic formation of nitrosamines by gut microflora is 
possible as well as formation in some food products.'' The agency 
acknowledges that a number of nitrosamine compounds are potent 
hepatotoxins and hepatocarcinogens. The agency also recognizes that 
neotame contains a secondary amine that could hypothetically form 
nitrosoneotame in the presence of a nitrosating agent. However, there 
is no scientific evidence presented in this comment to demonstrate that 
the presence of neotame in food leads to the formation of 
nitrosoneotame either through chemical reaction in food products or by 
metabolic processes in the gut upon ingestion (Ref. 14). Furthermore, 
the petitioner addressed this issue using many maximizing assumptions 
concerning the formation and potency of the hypothetical 
nitrosoneotame. In particular, the petitioner assumed that 
nitrosoneotame would be formed and that it would be as potent a 
carcinogen as dimethylnitrosamine. Based on this scenario, the 
petitioner concluded that the amounts of nitrosamine that could be 
formed would be extremely small, that any hypothetical risk would be 
trivial, and that additional analyses were not necessary. After 
evaluating the petitioner's reasoning, FDA agrees with this conclusion 
(Refs. 1 and 14). Furthermore, as noted in sections II.C.2.c and 
II.C.2.d of this document, there is no evidence of chronic liver 
toxicity or pre-neoplastic or neoplastic liver lesions in lifetime 
carcinogenicity feeding studies in rats and mice ingesting neotame in 
amounts up to 1,000 mg[sol]kg bw[sol]d and 4,000 mg[sol]kg bw[sol]d, 
respectively. Thus, the agency concludes that the hypothetical 
formation of nitrosamine compounds from neotame poses no safety 
concerns.
    Finally, the agency recognizes that one cannot absolutely rule out 
the liver as a target organ for the toxic effects of neotame when it is 
ingested at exaggerated dose levels. However, as discussed in the 
agency's response to this comment, and elsewhere in this document, the 
agency concludes that at expected levels of dietary intake of neotame 
there is no concern for potential toxic effects to the liver.
Systemic Exposure/Body Weight Gain
    One comment stated that ``[t]he long-term studies conducted in the 
dog species show definite signs of toxicity which, through close 
inspection of the pharmacokinetic data generated in the study and 
specific PK metabolism studies, is shown to be related to systemic 
exposure of the parent compound.'' Subsequently, the comment referred 
to ``a non-linear increase in systemic exposure of the parent compound 
and its metabolite over the dose range studied.'' The comment asserted 
that this nonlinear increase in systemic exposure to the parent 
compound and its metabolite is related to decreases in body weight gain 
in the dog.
    In response, the agency notes that the analysis of PK parameters 
(i.e., area under the curve, and maximum concentration) discussed in 
the comment is based on data from the 13-week dog study, which the 
agency does not consider to be a long-term study as claimed in the 
comment. In the agency's review of this study (Ref. 16), decreased body 
weight gains were observed in dogs of both sexes at dietary neotame 
intakes of 600 and 2,000 mg[sol]kg bw[sol]d (the 2,000 mg[sol]kg 
bw[sol]d dose level was reduced on day 15 to 1,200 mg[sol]kg bw[sol]d 
for the remainder of the 13-week study). These extremely high dose 
levels are 6,000 to 20,000 times greater than the 90th percentile EDI 
for neotame. At lower levels of neotame intake (i.e., 60 and 200 
mg[sol]kg bw[sol]d), there were no effects on body weight gain in 
either sex. In considering the PK parameters derived from blood 
concentration data from the dogs fed these lower levels of neotame, the 
agency concludes (Ref. 19) that there was no evidence of increased 
systemic exposure to neotame or its metabolites. (It should be noted 
that PK measurements in the dog were evaluated only in the 13-week 
subchronic study.)
    Moreover, as mentioned in Refs. 4, 10, and 17, a chronic (52-week) 
neotame dog feeding study was conducted. Because of its longer 
duration, the 52-week study is more definitive than the subchronic (13-
week) dog study for assessing the toxicity of neotame. In the 52-week 
dog study, decreased body weight gains were noted only at the highest 
dose tested (800 mg[sol]kg bw[sol]d) and not at any of the lower dose 
levels (20, 60, and 200 mg[sol]kg bw[sol]d).
Bile Salt Metabolism and Excretion
    One comment pointed out that neotame produced discolored feces 
(white and gray) at the highest doses tested (200 and 800 mg[sol]kg 
bw[sol]d) in the 52-week dog study. This comment suggested that the 
change in fecal color was due to neotame's effect on bile salt 
metabolism and excretion. The agency agrees that dogs from the 800 
mg[sol]kg bw[sol]d treatment group frequently excreted gray or white 
feces. However, there were only two incidences of gray feces from 
animals in the 200 mg[sol]kg bw[sol]d treatment group (a female on day 
322 and a male on day 328), and no changes in appearance of feces from 
dogs in the 20 or 60 mg[sol]kg bw[sol]d treatment groups. There was 
also one incident of white feces observed for a female in the control 
group on day 70 of the study. Based on this evidence, as well as 
information in section II.C.2.e of this document, the agency concludes 
that there is no evidence to support a correlation between fecal color 
and liver toxicity in dogs fed neotame-containing diets during the 52-
week study (Ref. 20).
Developmental (Teratology) Studies
    One comment claimed that the dose levels of neotame tested in the 
definitive rabbit developmental (teratology) study were too low. The 
agency disagrees. FDA's evaluation of this study shows that there are 
statistically significant decreases in feed consumption and maternal 
body weights during the gestation period. Thus, the highest dose in the 
study (500 mg[sol]kg bw[sol]d) was sufficient to achieve maternal 
toxicity (Refs. 4 and 6). In addition, FDA notes that this study 
satisfies dose selection criteria recommended in the agency's Redbook 
guidelines (Ref. 21).
    Another comment raised concern over post-implantation effects of 
neotame based on a maternal toxicity range-finding study in the rabbit. 
Because of the study's limitations, the agency does not share this 
concern. While a range-finding study may aid in identifying a 
compound's potential target organ effects, the primary objective of 
such a study is to establish appropriate dose levels to be further 
evaluated in a more definitive toxicity study. In the study in 
question, the agency notes that only six animals were used in each dose 
group, too few for an adequate assessment of

[[Page 45308]]

the developmental (teratogenic) potential of a compound (Ref. 21). In 
the definitive rabbit developmental (teratology) study, a total of 25 
mated females were assigned to the control and high-dose groups, and 20 
each in the low- and mid-dose groups (Ref. 6). This larger number of 
animals allows for a more accurate assessment of the teratogenic 
potential of neotame in the rabbit as well as increasing the 
statistical power of the study. In the definitive rabbit teratology 
study, there were no significant dose-dependent, post-implantation 
effects due to neotame treatment.
    One comment argued that neotame-induced effects on post-
implantation loss, fetal size, and limb development in rabbits in the 
teratology study may be masked by the quality of the study and the high 
background incidence of these effects. The comment disagreed with the 
petitioner's interpretation of the data on post-implantation and other 
fetal observations. In particular, the comment asserted that the 
petitioner's interpretation of data was scientifically flawed because 
the petitioner made comparisons between treatment groups and the 
concurrent control group whose incidence percentages, according to the 
comment, were higher than those incidence percentages typically seen in 
historical control data.
    FDA disagrees with this assessment. By using concurrent control 
animals, the study avoided the inherent variability that may be 
introduced into data analyses when historical control data are used in 
place of concurrent control data. Potential sources of variability from 
the use of historical control data include: (1) Differences in animal 
husbandry and animal room environment, (2) differences in diet 
compositions, (3) differences in times of study conduct, (4) 
differences in the sources of nutrients in animal diets, (5) 
differences in skills and experience of technicians or scientists, and 
(6) genetic drifts, as discussed in Haseman et al., 1989\3\ and Roe, 
1994.\4\ Therefore, the agency concludes that, within the definitive 
rabbit study, in the absence of compelling evidence to the contrary, it 
is more appropriate to compare results between treated and concurrent 
control animals than to compare results between treated animals and 
historical control data. The agency also notes that the study followed 
the Redbook guidelines. Additionally, the agency finds no dose-
dependent effects on post-implantation data when this study's treated 
and concurrent control groups are compared (Refs. 6 and 21).
---------------------------------------------------------------------------

    \3\ Haseman, J. K., Huff, J. E., Rao, G. N., and Eustis, S. I., 
``Sources of Variability in Rodent Carcinogencity,'' Fundamental and 
Applied Toxicology, vol. 12(4), pp. 793-804, 1989.
    \4\ Roe, F. J. C., ``Historical Histopathological Control Data 
for Laboratory Rodents: Valuable Treasure or Worthless 
Trash?''Laboratory Animals, vol. 28(2), pp. 148-154, (London), 1994.
---------------------------------------------------------------------------

    In further response to this comment, the agency concludes that the 
manner in which the comment has analyzed the data from the rabbit 
developmental study is incorrect. More specifically, the comment 
compared control and treated groups on a per-fetus, rather than on a 
per-litter incidence basis. As recognized by authoritative sources\5\ 
\6\ \7\ the maternal animal, not the developing organism, is randomly 
and independently assigned to control and treatment groups during the 
gestation period. Therefore, the analyses of effects should be reported 
as incidence-per-litter or as number and percent of litters with 
particular endpoints. Because the comment's analysis is based on 
inappropriate per-fetus comparisons, its conclusions are inherently 
flawed. Furthermore, the agency finds that the comparisons between the 
concurrent control and treated groups, on a percent per-litter basis, 
show no treatment-related effects on the litter incidence of any fetal 
endpoint examined in the rabbit developmental (teratology) study (Refs. 
6 and 21).
---------------------------------------------------------------------------

    \5\ FDA, ``Guidelines for Developmental Toxicity Studies,'' 
chapter IV.C.b, section III.D, Redbook 2000 Toxicology Principles 
for the Safety of Food Ingredients (http://www.cfsan.fda.gov/
[tilde]redbook/redivc96.html).
    \6\ Tyl, R. W. and M. C. Merr, ``Developmental Toxicity Testing-
Methodology,'' chapter 7, pp. 217, Handbook of Developmental 
Toxicology, edited by R. D. Hood, CRC Press, New York, NY, 1997.
    \7\ Kimmel, C. A. and G. I. Kimmel, ``Principles of 
Developmental Toxicity Risk Assessment,'' chapter 21, pp. 671-672, 
Handbook of Developmental Toxicology, edited by R. D. Hood, CRC 
Press, New York, NY, 1997.
---------------------------------------------------------------------------

    One comment focused on the dosimetric and pharmacokinetic aspects 
of the rabbit developmental (teratology) study. The comment asserted 
that if a higher dose level, e.g., 1,000 mg[sol]kg bw[sol]d, rather 
than 500 mg[sol]kg bw[sol]d, had been used as the top dose in this 
definitive study, higher systemic exposure and greater toxicity would 
have occurred in the neotame-treated rabbits. As noted earlier with 
regard to the levels of neotame tested in this study, the agency finds 
that overall study design and dose selection were sufficient to achieve 
maternal toxicity. FDA believes that it is irrelevant if greater 
toxicity were to occur at a higher dose level than the highest dose 
used in the rabbit developmental (teratology) study. The highest dose 
used was sufficient to achieve maternal toxicity, based on 
statistically significant decreases in both feed intake and body weight 
gain, at the 500 mg[sol]kg bw[sol]d dose level. Furthermore, there is 
an appropriate NOEL for these effects (Refs. 6 and 21).
    This comment also suggested that decreases in food intake and 
maternal body weight gain noted in the dams from the 500 mg[sol]kg 
bw[sol]d dose group were due to (tissue) accumulation of neotame. Based 
on a review of the PK data from the definitive rabbit developmental 
study, the agency concludes that these data do not suggest that 
bioaccumulation of neotame or its metabolites would occur even at a 
dose level of 500 mg[sol]kg bw[sol]d (Ref. 22). With regard to a 
possible relationship between (tissue) accumulation of neotame and 
decreases in feed intake and maternal body weight gain, the agency 
finds that a mechanistic explanation is unnecessary for an adequate 
evaluation of the study because the agency has determined an 
appropriate NOEL for these effects. As noted previously in section 
II.C.1.b of this document, based on the evaluation of other neotame 
feeding studies in the rat and dog, FDA concludes that there is no 
concern for the potential bioaccumulation of neotame or its metabolites 
at expected human intake levels.
Type II Diabetes Study
    One comment criticized several aspects of the Type II diabetes 
study. The comment stated that the design of this study was not 
adequate to detect small differences resulting from neotame treatment 
in the parameters examined. It cited the following inadequacies: 
Limited statistical power, parameters measured only under the quiescent 
metabolic condition of extended fasting, short duration, and no meal 
test. Despite these deficiencies, the comment recommended inclusion of 
the Type II diabetes study in the safety evaluation, because no other 
studies in the neotame safety database investigated the effects of 
neotame on glucose homeostasis in patients or animals with diabetes. 
Finally, the comment concluded that results from the Type II diabetes 
study were strongly suggestive of a treatment-related effect of neotame 
on fasting glucose control.
    FDA agrees that although the experimental design of the Type II 
diabetes study limits its utility for assessing the potential effects 
of neotame on glucose homeostasis in Type II diabetics, it should be 
included in the safety evaluation of neotame (Ref. 23). Based on 
findings obtained during a directed clinical investigator site 
inspection and audit of study records at the facility responsible for 
this clinical

[[Page 45309]]

trial, FDA concludes that the study was well-executed, irrespective of 
previously noted design limitations (Ref. 23).
    The agency disagrees with the comment's conclusion that results 
from the trial with Type II diabetic subjects are strongly suggestive 
of a treatment-related effect of neotame on glucose control. FDA 
performed a detailed evaluation of the study data on fasting glucose 
pharmacodynamic parameters including: (1) Area under the effect curve, 
(2) area under curve, (3) percent perturbation, and (4) normal 
variations in glucose concentrations. Based on these analyses, the 
agency finds that under the conditions of the study, there were no 
significant changes in these parameters in study subjects that are 
attributable to neotame (Ref. 23). Overall, FDA concludes that under 
the conditions of the Type II diabetic study, blood glucose 
concentrations in Type II diabetic subjects following neotame treatment 
(at levels ranging from 5 to 15 times the 90th percentile EDI of 0.1 
mg[sol]kg bw[sol]d) are comparable to those in the same subjects when 
given a placebo, and that any changes noted are within the normal range 
of variation and not the result of neotame treatment (Ref. 23).
Methanol and Phenylalanine Formation
    Several comments expressed concern that harmful levels of methanol 
and phenylalanine may result from ingesting neotame-containing foods 
and beverages. FDA disagrees with these comments. Methanol release 
results from the de-esterification of neotame, which occurs more 
rapidly in the rat and rabbit than in the dog and human (see section 
II.C.1.d of this document). The agency concludes that, at the 90th 
percentile EDI of neotame, the resultant exposure to methanol would be 
extremely low, approximately 0.008 mg[sol]kg bw[sol]d (Ref. 5). Humans 
are exposed to much higher levels of methanol intake from their daily 
diet. For example, the methanol content of fruit juices ranges from 64 
mg/liter (L) in orange juice to 326 mg/L in apricot juice. In contrast, 
the methanol content of neotame-sweetened carbonated beverages is 
estimated to be 1.37 mg/L.
    Similarly, FDA concludes that the potential intake of phenylalanine 
from the use of neotame will be extremely low in comparison to that 
present in the daily diet. Based upon data cited by Koch and Wenz, 1984 
(see footnote 2 in section II.C.1.d of this document), the agency notes 
that the daily dietary intake of phenylalanine for a healthy individual 
may range from 2.5 to 10 g/p/d. The daily intake of phenylalanine for a 
PKU homozygous child with a body weight of 20 kg is reported to range 
from 0.4 to 0.6 g/p/d or 400 to 600 mg[sol]p[sol]d (Ref. 5).
    Using a conservative approach (Refs. 4 and 5), the agency 
calculates that the amount of phenylalanine exposure expected from the 
90th percentile intake (0.1 mg[sol]kg bw[sol]d) of neotame (Ref. 2) by 
a 60 kg adult is 2.64 mg[sol]p[sol]d. FDA finds this amount of exposure 
trivial in contrast to that expected from the normal adult diet. For 
the PKU homozygous child, the additional phenylalanine intake expected 
from the 90th percentile ingestion of neotame (i.e., 0.17 mg[sol]kg 
bw[sol]d) (Ref. 3) by a 20 kg individual is 1.50 mg[sol]p[sol]d, an 
incremental amount that is equivalent to no more than 0.3 to 0.4 
percent of the PKU homozygous child's normal daily phenylalanine 
intake. From these conservative estimates, the agency concludes that 
the potential intake of phenylalanine that may result from use of 
neotame as a general-purpose sweetener does not pose any safety concern 
(Refs. 4 and 5).

IV. Conclusion

    The agency has evaluated all the data and other information 
submitted by the petitioner in support of the safe use of neotame as a 
general-purpose sweetener and concludes that there is a reasonable 
certainty that no harm will result from the use of neotame as proposed. 
In accordance with a memorandum of understanding (MOU) between the Food 
Safety and Inspection Service (FSIS), United States Department of 
Agriculture, and FDA (65 FR 51758, August 25, 2000), a restriction from 
use ``in meat and poultry'' appears in the neotame regulation. This 
restriction is required when the petitioner does not specify whether 
the food additive is intended for such use. At this time, FSIS has not 
made a determination on the use of neotame in or on meat or poultry. 
Therefore, FDA concludes that the food additive regulations should be 
amended as set forth in this document.
    In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petitions 
and the documents that FDA considered and relied upon in reaching its 
decision to approve the petitions are available for inspection at the 
Center for Food Safety and Applied Nutrition by appointment with the 
information contact person. 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.

V. Environmental Effects

    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 (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday.

VI. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VII. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES), and you may review them between 9 
a.m. and 4 p.m., Monday through Friday.

    1. Memorandum from DiNovi, Division of Product Manufacture and 
Use, Chemistry Review Team, to Anderson, Division of Product Policy, 
March 31, 1998.
    2. Memorandum from DiNovi, Division of Product Manufacture and 
Use, Chemistry Review Team, to Anderson, Division of Product Policy, 
August 12, 1999; addendum memorandum to the August 12, 1999, 
memorandum from DiNovi, Division of Biotechnology and GRAS 
Notification Review, to Anderson, Division of Petition Review, 
February 28, 2002.
    3. Memorandum from DiNovi, Division of Product Manufacture and 
Use, Chemistry Review Team, to Anderson, Division of Product Policy, 
December 14, 2000.
    4. Memorandum from Biddle, Lin, Whiteside, Division of Health 
Effects Evaluation, to Anderson, Division of Product Policy, January 
31, 2001; addendum memorandum to the January 31, 2001, memorandum 
from Whiteside, Division of Petition Review, to Anderson, Division 
of Petition Review, February 28, 2002.
    5. Memorandum from Bleiberg, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, January 31, 
2001; addendum memorandum to the January 31, 2001, memorandum from 
Biddle, Division of Petition Review, to Anderson, Division of 
Petition Review, February 28, 2002.
    6. Memorandum from Welsh, Scientific Support Branch, to 
Anderson, Division of Product Policy, January 31, 2001.
    7. Memorandum from Mattia, Scientific Support Branch, to 
Anderson, Division of Product Policy, January 31, 2001; addendum 
memorandum to the January 31, 2001, memorandum from Biddle, Division 
of Petition Review, to Anderson, Division of Petition Review, April 
12, 2002.
    8. Position paper from The NutraSweet Co., ``Neotame Does Not 
Cause Any Behavioral or Neurotoxic Effects.''
    9. Position paper from The NutraSweet Co., ``Increases in Serum 
Alkaline Phosphatase in

[[Page 45310]]

the Dog Are Not Associated With Target Organ Toxicity.''
    10. Memorandum from Whiteside, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, January 21, 
2001.
    11. Memorandum of Conference from the Center for Food Safety and 
Applied Nutrition--Cancer Assessment Committee, August 16, 2000.
    12. Position paper from The NutraSweet Co., `` In the Mouse 
Carcinogenicity Study with Neotame Small Changes in Body Weight Gain 
at Some Intervals in Female Mice at 50 mg[sol]kg bw Relative to 
Controls are Due to a Decrease in Food Consumption.''
    13. Memorandum from Chen, Scientific Support Branch, to 
Anderson, Division of Product Policy, July 19, 2000.
    14. Memorandum from DiNovi, Division of Product Manufacture and 
Use, Chemistry Review Team, to Anderson, Division of Product Policy, 
January 10, 2001.
    15. Memorandum from Whiteside, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, January 31, 
2001.
    16. Memorandum from Ikeda, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, May 28, 1999.
    17. Memorandum from Ikeda, Division of Health Effects 
Evaluation, to Biddle, Division of Health Effects Evaluation, 
January 31, 2001.
    18. Memorandum from Ikeda, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, June 16, 2000; 
addendum memorandum to the June 16, 2000, memorandum from Whiteside, 
Division of Petition Review, to Anderson, Division of Petition 
Review, February 28, 2002.
    19. Memorandum from Bleiberg, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, February 5, 
2001.
    20. Memorandum from Ikeda, Division of Health Effects 
Evaluation, to Anderson, Division of Product Policy, February 5, 
2001.
    21. Memorandum from Shackleford, Division of Heath Effects 
Evaluation, to Anderson, Division of Product Policy, February 12, 
2001.
    22. Memorandum from Roth, Division of Health Effects Evaluation, 
to Anderson, Division of Product Policy, February 28, 2001.
    23. Memorandum from Park, Roth, and Klontz, Division of Health 
Effects Evaluation, to Anderson, Division of Product Policy, January 
30, 2001.

VIII. Objections

    Any person who will be adversely affected by this regulation may at 
any time file with the Dockets Management Branch (see ADDRESSES) 
written objections by August 8, 2002. Each objection shall be 
separately numbered, and each numbered objection shall specify with 
particularity the provisions of the regulation to which objection is 
made and the grounds for the objection. Each numbered objection on 
which a hearing is requested shall specifically so state. Failure to 
request a hearing for any particular objection shall constitute a 
waiver of the right to a hearing on that objection. Each numbered 
objection for which a hearing is requested shall include a detailed 
description and analysis of the specific factual information intended 
to be presented in support of the objection in the event that a hearing 
is held. Failure to include such a description and analysis for any 
particular objection shall constitute a waiver of the right to a 
hearing on the objection. Three copies of all documents are to be 
submitted and are to 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.

List of Subjects in 21 CFR Part 172

    Food additives, Incorporation by reference, Reporting and 
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
172 is amended as follows:

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

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

    Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.
    2. Section 172.829 is added to subpart I to read as follows:


Sec. 172.829  Neotame.

    (a) Neotame is the chemical N-[N-(3,3-dimethylbutyl)-L-[agr]-
aspartyl]-L-phenylalanine-1-methyl ester (CAS Reg. No. 165450-17-9).
    (b) Neotame meets the following specifications when it is tested 
according to the methods described or referenced in the document 
entitled ``Specifications and Analytical Methods for Neotame'' dated 
April 3, 2001, by the NutraSweet Co., 699 North Wheeling Rd., Mount 
Prospect, IL 60056. The Director of the Office of the Federal Register 
has approved the incorporation by reference of this material in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available 
from the Office of Food Additive Safety (HFS-200), Center for Food 
Safety and Applied Nutrition, 5100 Paint Branch Pkwy., College Park, MD 
20740. Copies may be examined at the Center for Food Safety and Applied 
Nutrition's Library, 5100 Paint Branch Pkwy., rm. 1C-100, College Park, 
MD 20740, or at the Office of the Federal Register, 800 North Capitol 
St. NW., suite 700, Washington, DC 20001.
    (1) Assay for neotame, not less than 97.0 percent and not more than 
102.0 percent on a dry basis.
    (2) Free dipeptide acid (N-[N-(3,3-dimethylbutyl)-L-[agr]-
aspartyl]-L-phenylalanine), not more than 1.5 percent.
    (3) Other related substances, not more than 2.0 percent.
    (4) Lead, not more than 2.0 milligrams per kilogram.
    (5) Water, not more than 5.0 percent.
    (6) Residue on ignition, not more than 0.2 percent
    (7) Specific rotation, determined at 20  deg.C [[agr]]D: 
-40.0 deg. to 43.4 deg. calculated on a dry basis.
    (c) The food additive neotame may be safely used as a sweetening 
agent and flavor enhancer in foods generally, except in meat and 
poultry, in accordance with current good manufacturing practice, in an 
amount not to exceed that reasonably required to accomplish the 
intended technical effect, in foods for which standards of identity 
established under section 401 of the Federal Food, Drug, and Cosmetic 
Act do not preclude such use.
    (d) When neotame is used as a sugar substitute tablet, L-leucine 
may be used as a lubricant in the manufacture of tablets at a level not 
to exceed 3.5 percent of the weight of the tablet.
    (e) If the food containing the additive purports to be or is 
represented to be for special dietary use, it shall be labeled in 
compliance with part 105 of this chapter.

    Dated: July 2, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-17202 Filed 7-5-02; 10:41 am]
BILLING CODE 4160-01-S