[Federal Register Volume 63, Number 64 (Friday, April 3, 1998)]
[Rules and Regulations]
[Pages 16417-16433]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-8750]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 87F-0086]
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Sucralose
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 sucralose as a
nonnutritive sweetener in food. This action is in response to a
petition filed by McNeil Specialty Products Co.
DATES: The regulation is effective April 3, 1998; written objections
and requests for a hearing by May 4, 1998. 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 certain
publications in Sec. 172.831(b) (21 CFR 172.831(b)), effective April 3,
1998.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Blondell Anderson, Center for Food
Safety and Applied Nutrition (HFS-206), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3106.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Evaluation of Safety
A. Estimated Daily Intake
B. Evaluation of Toxicological Testing Results
1. Pharmacokinetics and Metabolism
a. Comparative pharmacokinetics
b. Sucralose metabolism
2. Genotoxicity Testing
3. Reproductive/Developmental Toxicity Studies
a. Sucralose
i. Two-generation reproductive toxicity study in rats
(E056)
ii. Teratology study in rats (E030)
iii. Teratology studies in rabbits (El34)
b. Sucralose hydrolysis products
i. Two-generation reproductive toxicity study in rats
(E052)
ii. Teratology study in rats (E032)
c. Male fertility studies of sucralose and its hydrolysis
products in rats (E016, E038, E090, and E107)
4. Chronic Toxicity/Carcinogenicity Studies
a. Sucralose
i. Combined chronic toxicity/carcinogenicity study in rats
(E057)
ii. Carcinogenicity study in mice (E055)
iii. Chronic toxicity study in dogs (E051)
b. Sucralose hydrolysis products--carcinogenicity study in
rats (E053)
5. Special Toxicological Studies
a. Body weight gain (E058, E130, E143, E151, E160, E161)
i. The palatability hypothesis
ii. The agency's evaluation of the palatability hypothesis
iii. Resolution of the body weight gain decrement issue
[[Page 16418]]
b. Immunotoxicity study in rats (E162)
c. Neurotoxicity studies in mice and monkeys (E008 and E009)
d. Diabetic Studies (E156, E157, E168, E170, E171)
C. Acceptable Daily Intake Estimate for Sucralose
III. Comments
A. Determination of No-Observed-Effect Level and ADI
1. No-Observed-Effect Level in the Chronic Toxicity Study
2. No-Observed-Effect Level in Developmental Toxicity Studies
3. Derivation of ADI
B. Immunotoxic Potential of Sucralose
C. Mutagenicity of 1,6-DCF
D. Renal Effects
E. Fetal Edema
F. Bioaccumulation
G. Antifertility Effects
H. Neurotoxicity Effects
I. Exposure to Sucralose Hydrolysis Products
J. The Need for Studies in Special Populations
K. Labeling
IV. Conclusion
V. Environmental Effects
VI. References
VII. Objections
I. Introduction
In a notice published in the Federal Register of May 8, 1987 (52 FR
17475), FDA announced that a food additive petition (FAP 7A3987) had
been filed by McNeil Specialty Products Co. (McNeil), P.O. Box 3000,
Skillman, NJ 08558-3000 proposing that the food additive regulations be
amended to provide for the safe use of sucralose (1,6-dichloro-1,6-
dideoxy--D-fructofuranosyl-4-chloro-4-deoxy--D-
galactopyranoside) as a nonnutritive sweetener in food where standards
of identity do not preclude such use. (McNeil's address has since
changed to 501 George St., New Brunswick, NJ 08558-3000.)
The petitioner has requested the use of sucralose in 15 food
categories as described in Sec. 170.3 (21 CFR170.3(n)) as follows:
Baked goods and baking mixes (Sec. 170.3(n)(1)); beverages and beverage
bases (nonalcoholic) (Sec. 170.3(n)(3)); chewing gum
(Sec. 170.3(n)(6)); coffee and tea (Sec. 170.3(n)(7)); confections and
frostings (Sec. 170.3(n)(9)); dairy product analogs
(Sec. 170.3(n)(10)); fats and oils (Sec. 170.3(n)(12)); frozen dairy
desserts and mixes (Sec. 170.3(n)(20)); fruit and water ices
(Sec. 170.3(n)(21)); gelatins, puddings, and fillings
(Sec. 170.3(n)(22)); jams and jellies (Sec. 170.3(n)(28)); milk
products (Sec. 170.3(n)(31)); processed fruits and fruit juices
(Sec. 170.3(n)(35)); sugar substitutes (Sec. 170.3(n)(42)); and sweet
sauces, toppings, and syrups (Sec. 170.3(n)(43)). This final rule lists
all of the requested uses.
Sucralose has also been referred to as trichlorogalactosucrose or
4,1',6'-trichlorogalactosucrose. The Chemical Abstracts Service
Registry number (CAS Reg. No.) for sucralose is 56038-13-2. Sucralose
is a disaccharide that is made from sucrose in a five-step process that
selectively substitutes three atoms of chlorine for three hydroxyl
groups in the sugar molecule. It is produced at an approximate purity
of 98 percent. Sucralose is a free-flowing, white crystalline solid
that is soluble in water and stable both in crystalline form and in
most aqueous solutions; it has a sweetness intensity that is 320 to
1,000 times that of sucrose, depending on the food application.
Hydrolysis of sucralose can occur under conditions of prolonged
storage at elevated temperatures in highly acidic aqueous food
products. The hydrolysis products are the monosaccharides, 4-chloro-4-
deoxy-galactose (4-CG) and 1,6-dichloro-1,6-dideoxyfructose (1,6-DCF).
McNeil's original submission to FDA contained data and information
from toxicity studies in several animal species, other specific tests
in animals, and information from clinical tests in human volunteers.
The toxicity data base included: Short-term genotoxicity tests,
subchronic feeding studies, chronic toxicity/carcinogenicity studies in
rats and mice, a chronic toxicity study in dogs, reproductive toxicity
studies in rats, teratology studies in rats and rabbits, male fertility
studies in rats, and neurotoxicity studies in mice and monkeys. Other
specific tests conducted with animals included: Pharmacokinetics and
metabolism studies on sucralose in several species, mineral
bioavailability studies in rats, and several studies related to food
consumption and palatability in rats and dogs. Human clinical testing
addressed the pharmacokinetics and metabolism of sucralose, in addition
to its potential effects on carbohydrate metabolism. The petitioner
also submitted a report prepared by a panel of experts in various
scientific disciplines who independently evaluated and critiqued the
sucralose data base to identify areas of potential controversy.
During the course of the agency's evaluation of the sucralose
petition, McNeil submitted additional studies that had been conducted
in response to questions and concerns raised by the governmental
reviewing bodies of other countries. The additional studies included a
6-month gavage study in rats, two comparative pharmacokinetics studies
in rats and rabbits, an immunotoxicity feeding study in rats, and study
of unscheduled deoxyribonucleic acid (DNA) synthesis.
In response to an issue raised by FDA, the petitioner submitted a
6-month sucralose feeding study in rats, with a dietary restriction
design, to evaluate the toxicological significance of a body weight
gain decrement effect observed in sucralose-treated rats.
In anticipation of the potential wide use of sucralose in persons
with diabetes mellitus and to address concerns raised by a diabetic
association group in Canada, the petitioner performed a series of
clinical studies. Because of results observed in diabetic patients that
were treated with sucralose in a 6-month clinical study, the petitioner
requested (in 1995) that the agency withhold its final decision on the
safety of sucralose until that observation could be further
investigated. At that time, the petitioner initiated additional studies
with the main objective of evaluating the effects sucralose would have
on glucose homeostasis in patients with diabetes mellitus.
II. Evaluation of Safety
In the safety evaluation of a new food additive, the agency
considers both the projected human dietary exposure to the additive and
the data from toxicological tests submitted by the petitioner. Other
relevant information (e.g., published literature) is also considered.
The available data and information submitted in a food additive
petition must establish, to a reasonable certainty, that the food
additive is not harmful under the intended conditions of use.
A. Estimated Daily Intake
In determining whether the proposed use of an additive is safe, FDA
typically compares an individual's estimated daily intake (EDI) of the
additive to the acceptable daily intake (ADI) established from the
toxicity data. The agency determines the EDI by making 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. The proposed use levels of sucralose are supported by taste
panel testing that was reported in the petition. The petitioner also
submitted survey information on the consumption of the food types for
which the use of sucralose was requested.
The agency commonly uses the EDI for the 90th percentile consumer
of a food additive as a measure of high chronic exposure. For the
requested food uses of sucralose, the agency has determined the 90th
percentile EDI for consumers 2 years old and older (``all ages'') to be
98 milligrams per person per day (mg/p/d), equivalent to
[[Page 16419]]
approximately 1.6 mg per kilogram of body weight per day (mg/kg bw/d)
(Refs. 1 and 2).
Because sucralose may hydrolyze in some food products (although
only to a small extent and only under limited conditions), the
resulting hydrolysis products may also be ingested by the consumer.
Therefore, the agency has also calculated EDI's for the combined
hydrolysis products of sucralose. The 90th percentile EDI is 285
micrograms per person per day (g/p/d), equivalent to 4.7
g/kg bw/d (Refs. 1 and 2).
B. Evaluation of Toxicological Testing Results
The major studies relevant to the safety decision regarding the
petitioned uses of sucralose are discussed in detail in section II.B of
this document. The individual studies are identified by ``E'' numbers,
as designated by McNeil in the sucralose petition.
1. Pharmacokinetics and Metabolism
Studies were conducted to characterize and compare the metabolic
fate of sucralose in various animal species to that seen in humans in
order to assist in the selection of an appropriate animal model for
safety extrapolation to humans.
a. Comparative pharmacokinetics. The absorption, metabolism, and
elimination of sucralose have been studied in several different animal
species, including humans. Based on its evaluation of these studies,
the agency concludes that, in general, sucralose is poorly absorbed
following ingestion, with 36 percent or less of the dose absorbed in
rats (E004 and E137), mice (El46), rabbits (El24), dogs (E049 and
E123), and humans (E003, E033, and E128). Although there is consistency
among laboratory animal species in the routes of elimination of
sucralose when administered by the intravenous route (80 percent
urinary, 20 percent fecal), the amounts of sucralose absorbed and rates
of elimination after oral administration differ considerably (Ref. 3).
The agency estimates that about 5 percent of the ingested dose is
absorbed from the gastrointestinal system of rats, while that in
rabbits and mice ranged from 20 to 33 percent. Gastrointestinal
absorption of sucralose by the dog was in the range of 33 to 36
percent. Studies in human male volunteers showed absorption values in
the range of 11 to 27 percent, which is between the ranges observed for
rats (lower bound) and rabbits and mice (upper bound). In all of the
species tested, plasma disappearance curves are biphasic (E003, E004,
E049, E123, E128, E146, El63, and E164). With the exception of the
rabbit (El64), these curves are dominated by phase 1, with a half-life
of 2 to 5 hours. In the rabbit elimination is dominated by phase 2,
with a half-life of 36 hours (El64) (Ref. 3). The longer half-life of
sucralose in the rabbit was initially thought to be the result of
reingestion of sucralose. However, study E164, which was specifically
designed to address this question by controlling coprophagia, indicated
that sucralose elimination is intrinsically slower from the rabbit than
from other species tested (Refs. 3 and 4). Therefore, the agency
concludes that the pharmacokinetics of sucralose in the rabbit is
significantly different from that in humans and other tested species.
b. Sucralose metabolism. The majority of ingested sucralose is
excreted unchanged in the feces and most of what is absorbed appears
unchanged in the urine, with only minor amounts appearing as
metabolites (Refs. 3, 4, and 5). Mice (El46) and rats (El37) were found
to metabolize less than 10 percent of the absorbed sucralose, while
rabbits (El24) (20 to 30 percent), humans (El38 and E145) (20 to 30
percent), and dogs (El33) (30 to 40 percent) metabolize greater
quantities of the absorbed sucralose. Results from the submitted animal
and human pharmacokinetics data identified three major sucralose
metabolites (Ml, M2, and M3) in urine in addition to unchanged
sucralose. The metabolic profile of sucralose in rats was qualitatively
similar to that seen in humans. In addition to unchanged sucralose, two
sucralose metabolites, Ml and M2, were detected in the urine of rats
and humans after oral dosing of sucralose. The metabolic profile of
mice for sucralose differed from that of humans and the other tested
animals (rats, dogs, and rabbits) in that a unique urinary metabolite,
M3, was identified in addition to the presence of the Ml (trace
amounts) and M2 metabolites. A pronounced difference was observed in
the proportions of M2 and M3 excreted by male versus female mice: Males
produced more M2 than M3, while the opposite was true of female mice.
The metabolic profile of the rabbit for sucralose also showed
differences when compared to that seen in humans, rats, mice, or dogs.
In addition to unchanged sucralose, a small number of unidentified
metabolites (more polar than sucralose) were observed in rabbit urine,
but were not characterized (Refs. 3, 6 and 7). Dogs produced primarily
the M2 metabolite and only a trace amount of the Ml metabolite.
After repeated dosing, there was no evidence that sucralose induced
microsomal enzymes in rats (El44) (Ref. 7). There was also no evidence
of metabolic adaptation following chronic dosing with sucralose in rats
(E057e) (Ref. 3).
Based on the submitted pharmacokinetics data, the agency concludes
that the rabbit metabolism of sucralose is notably different from that
of humans in two important aspects: (1) A longer sucralose plasma half-
life, and (2) the presence of unique urinary sucralose metabolites.
Although pharmacokinetic differences between the other tested animals
(rats, mice, and dogs) and humans were not as pronounced, the profile
for rats was most similar to that for humans. The agency discusses the
relevance of these data for the selection of an appropriate animal
model in section II.C of this document.
2. Genotoxicity Testing
Sucralose and its hydrolysis products were tested in several in
vitro and short-term in vivo genotoxicity tests. In the absence of
bioassay data, such tests are often used to predict the carcinogenic
potential of the test compound. However, in the case of sucralose and
its hydrolysis products, chronic toxicity/carcinogenicity bioassay data
are also available.
Sucralose was shown to be nonmutagenic in an Ames test (E0ll) and a
rat bone marrow cytogenetic test (E013). Tests for the clastogenic
activity of sucralose in a mouse micronucleus test (E0l4) and a
chromosomal aberration test in cultured human lymphocytes (E012) were
inconclusive. Sucralose was weakly mutagenic in a mouse lymphoma
mutation assay (E014).
The hydrolysis product, 4-CG, was nonmutagenic in the Ames test
(E025) and mouse lymphoma assay (E026). 4-CG was nonclastogenic in the
chromosomal aberration assay (E0I2). Other assays (human lymphocytes
(E012), rat bone marrow (E027)) were inconclusive. Thus, no test on 4-
CG produced a genotoxic response.
The other hydrolysis product, 1,6-DCF, was not clastogenic in the
chromosomal aberration assay in rat bone marrow (E019). Results of
three other genotoxic tests were inconclusive: The chromosomal
aberration assay in cultured human lymphocytes (E012), the sex-linked
recessive lethal assay in Drosophila melanogaster (E021), and the
covalent DNA binding potential study in rats (El48). 1,6-DCF was
weakly mutagenic in the Ames test (E020) and the L5178Y TK+/-
assay (EO22 and E024). In an unscheduled DNA synthesis study (El65),
1,6-DCF did not induce DNA repair synthesis in isolated rat
hepatocytes.
[[Page 16420]]
An equimolar mixture of the hydrolysis products was not genotoxic
in the in vivo sister chromatid exchange assay in mice (E150) and was
inconclusive in a dominant lethal (mouse) test (E034).
As the foregoing discussion reflects, both sucralose and its
hydrolysis products showed weakly genotoxic responses in some of the
genotoxicity tests. More importantly, however, as demonstrated in the
2-year rodent bioassays (E053, E055, and E057), there was no evidence
of carcinogenic activity for either sucralose or its hydrolysis
products as discussed in sections II.B.4.a.i, II.B.4.a.ii, and
II.B.4.b.i of this document. Results from these chronic carcinogenicity
studies supersede the results observed in the genotoxicity tests
because they are more direct and complete tests of carcinogenic
potential (Refs. 5, 6, 8, 9, and 10).
3. Reproductive/Developmental Toxicity Studies.
Studies were performed in order to evaluate the toxic potential of
sucralose and its hydrolysis products on the reproductive systems of
mature male and female rats as well as on the postnatal maturation of
reproductive functions of offspring through two successive generations.
The objective of the teratology studies was to determine the potential
effects of sucralose and its hydrolysis products on the developing
fetus.
a. Sucralose--i. Two-generation reproductive toxicity study in rats
(E056). In this study, groups of 30 male and 30 female rats of the
Sprague-Dawley CD strain were fed sucralose at dose levels of 0.3, 1.0,
and 3.0 percent in the diet 10 weeks prior to breeding and throughout
two successive generations.
No treatment-related effects on any of the reproductive endpoints
(estrous cycles, mating performance, fertility index, gestation length,
gestation index) were observed in either generation. Litter size and
offspring viability were also unaffected by sucralose treatment.
Decreases in body weight gain of 11 to 25 percent and 2 to 12 percent
for adult rats were observed during both premating periods for the
first (F1) and second (F2) generations,
respectively. Slightly decreased food intake was also observed for both
generations (F0, 5 to 9 percent; F1, 3 to 5
percent).
Although significant decreases in the relative thymic weights were
noted in the F0 (male and female) and the F1
(male and female) rats in this study after dietary administration of
sucralose at the high-dose (3 percent) level, because of the nature of
the experimental design for reproductive studies, the agency cannot
evaluate the toxicological significance of this observation in this
study. Thymic and other lymphoidal effects are more appropriately
evaluated in immunologic studies that are designed to examine directly
parameters of immunologic functions. Such immunotoxicity studies on
sucralose are discussed in section II.B.5.b of this document.
Based upon the results of study E056, the agency concludes that
sucralose does not cause any reproductive effects in rats in doses up
to 3 percent in the diet (Refs. 5, 10, 11, and 12).
ii. Teratology study in rats (E030). Sucralose was administered by
gavage to groups of 20 pregnant Sprague Dawley CD rats at dose levels
of 500, 1,000, and 2,000 mg/kg bw/d from day 6 through day 15 of
gestation.
No treatment-related effects were noted in the dams at necropsy
with respect to the number of implantation sites, pre-implantation
losses, or post-implantation losses. The number of live young, as well
as fetal and placental weights, were also unaffected by treatment.
Neither body weight gain nor food consumption were affected by
treatment with sucralose.
Based upon the results of E030, the agency concludes that sucralose
did not cause maternal toxicity, embryo toxicity, or fetal toxicity;
nor did sucralose induce terata in rats at dose levels up to 2000 mg/kg
bw/d (Refs. 5 and 13).
iii. Teratology study in rabbits (El34). Sucralose was administered
by gavage to groups of 16 to 18 pregnant rabbits at dose levels of 0,
175, 350, and 700 mg/kg/d during days 6 to 19 of gestation. Uterine
contents of the females were examined at termination of the study (day
29 of gestation).
A total of 11 rabbits (1 in the control group, 4 in the 175 mg/kg
bw/d group, 2 in the 350 mg/kg bw/d group, and 4 in the 700 mg/kg bw/d
group) died or were killed in extremis (near death) because of reasons
unrelated to treatment. Two deaths occurred in the high-dose (700 mg/kg
bw/d) group that the agency considers treatment-related because they
were associated with symptoms (weight loss and reduced food intake)
occurring only at the highest dose. Three of the 12 surviving rabbits
in the high-dose group were eliminated from the study because they did
not become pregnant.
From the remaining nine pregnant rabbits in the high-dose group
only five animals successfully carried to term and produced viable
young. The other four females in this group aborted their fetuses.
Decreases in the mean number of viable young per litter were also
observed in this group. The mean number of post-implantation losses
also increased. Gastrointestinal tract disturbances were noted in high-
dose rabbits. These effects observed at the high-dose level were not
seen at either low- or mid-dose levels (Refs. 5, 14, and 15). While
maternal and fetal toxicity were observed at the high-dose level, there
was no evidence of frank terata at any of the tested dose levels. Thus
this study demonstrates that sucralose is not teratogenic in rabbits.
b. Sucralose hydrolysis products--i. Two-generation reproductive
toxicity study in rats (E052). Groups of 30 male and 30 female Sprague-
Dawley CD rats were fed an equimolar mixture of the sucralose
hydrolysis products (4-CG and 1,6-DCF) at dose levels of 0, 200, 600,
and 2,000 parts per million (ppm) in the diet for 10 weeks prior to
breeding and through two successive generations.
No treatment-related effects on estrus cycles, mating performance,
fertility, length of gestation, litter size, and offspring viability
were observed in either generation (F0 or F1
generation). During the 10-week premating period for both generations,
body weight gain of males was significantly reduced in the high-dose
(2,000 ppm) group only. Body weight gain of females was significantly
reduced in all treatment groups during this same period of time.
Decreased food intake was observed in the high-dose males and females
of the F0 generation. In both generations, reduction in
weight gain was observed in females during pregnancy and in offspring
from birth to weaning. No effect other than reduced body weight gain
was related to treatment (Refs. 5, 10, 14, and 16).
The agency concludes that the administration of the sucralose
hydrolysis products in the rat diet at levels up to 2,000 ppm caused no
alteration in the reproductive performance of the animals over two
generations (Refs. 5 and 16).
ii. Teratology study in rats (E032). An equimolar mixture of the
sucralose hydrolysis products was administered by gavage to groups of
20 pregnant Sprague-Dawley rats at dose levels of 30, 90, and 270 mg/kg
bw/d, from day 6 to 15 of gestation. The study was terminated on day 21
of gestation.
Results from this study showed no dose-related increase in the
incidence of terata among treated groups. Body weight gain of dams in
the high-dose group (270 mg/kg bw/d) was significantly reduced, whereas
weight gains in the low- and mid-dose dams were comparable to controls.
Decreased
[[Page 16421]]
fetal body weights and placental weights were observed at the high
dose.
The agency concludes that the sucralose hydrolysis products did not
produce terata in rats when administered at doses up to 270 mg/kg bw/d
(Refs. 10 and 13).
c. Male fertility studies on sucralose and its hydrolysis products
in rats (E016, E038, E090, and E107). Some chlorinated monosaccharides
have been reported to affect male fertility in rats by interfering with
spermatogenesis (Ref. 17). McNeil noted the structural similarity of
such compounds to the hydrolysis products of sucralose, and submitted a
series of antifertility studies on a series of chlorinated sugars,
including sucralose.
All of the studies were of similar design. Groups of male rats were
exposed for 14 days either by gavage or in the diet to 300 micromoles
(mol) of either sucralose or one of the chlorosucrose
compounds mentioned above. The antifertility compound, 6-chloro-6-
deoxyglucose, was used as the positive control in these studies.
Treated male and untreated female rats were mated 1 and 2 weeks after
treatment. Male mating performance and fertility were observed.
The agency has reviewed these studies and observes that the studies
were too short to cover the full cycle of spermatogenesis in rats
(Refs. 5 and 18). Because of their short duration, FDA concludes that
these studies, considered alone, are insufficient to assess the
antifertility potential of sucralose in male rats (Refs. 5 and 18).
However, the agency believes that further testing is not necessary
because the results from the two-generation reproduction studies
adequately address any toxicological concerns regarding the potential
antifertility effects of sucralose and its hydrolysis products. As
discussed previously, in the two-generation reproduction studies (E052
and E056), in which sucralose or its hydrolysis products were fed to
rats, no effects on fertility or other reproductive parameters were
observed in either male or female rats (see sections II.B.3.a.i and
II.B.3.b.i. of this document).
4. Chronic Toxicity/Carcinogenicity Studies
A combined chronic toxicity/carcinogenicity study (E057) in rats
and a carcinogenicity study in mice (E055) were conducted to study the
chronic toxicity and carcinogenic potential of sucralose when
administered to rodents over most of their lifetime. Because human
exposure to sucralose could possibly occur during in utero development,
an in utero phase was included in the rat study. A chronic (1-year)
study on sucralose was also performed in dogs (E051) in order to assess
the effects of sucralose administration in a nonrodent species. In
addition, a 2-year carcinogenicity study in rats (E053) was carried out
to study the chronic toxicity and carcinogenic potential of sucralose
hydrolysis products.
a. Sucralose--i. Combined chronic toxicity/carcinogenicity study in
rats (E057). This study consisted of a breeding phase, a
carcinogenicity phase, and a chronic toxicity phase. The
carcinogenicity and chronic toxicity phases were concurrently performed
in this study. The breeding phase of this study examined the potential
in utero effects of sucralose during development. During this phase
parental (F0) Sprague-Dawley CD rats, 70 males and 70
females per group, were fed diets containing 0, 0.3, 1, or 3 percent
sucralose for a 4-week period prior to mating and during gestation. One
male and one female weanling pup were selected from each of 50 litters
and allocated to the appropriate group of the carcinogenicity phase.
Additional rats (30 per sex per group) were selected for the chronic
toxicity phase of this study.
Rats in each of the groups of this study were gang-housed, five
animals per sex per cage. After 52 weeks of sucralose treatment, an
interim sacrifice was performed on 15 males and 15 females from each
group of the chronic toxicity phase of the study. The remaining
surviving rats in this phase of the study were sacrificed at treatment
week 78. In the carcinogenicity phase, surviving rats were sacrificed
at week 104. In both phases of the study, classic toxicological
parameters such as mortality, body weight, hematology, clinical
chemistry, and organ weights were examined in treated and control rats.
Food consumption was calculated weekly from the total weight of food
consumed by each cage of rats. Histopathological examinations were
performed on representative tissues from control and high-dose rats.
Sucralose treatment had no effect on reproductive performance or on
fertility of the parental rats during the breeding phase. In both the
chronic toxicity and carcinogenicity phases of the study, survival of
rats was unaffected by sucralose treatment.
In the carcinogenicity phase, there was no evidence of treatment-
related neoplasia in any of the rats (Ref. 19). McNeil reported an
apparent increased incidence of male rats with hepatocellular clear
cell foci. FDA pathologists reviewed the liver histopathology slides
from this study that were obtained from McNeil. The agency's
pathologists observed that the increase in the incidence of male rats
with hepatocellular clear cell foci was only marginal and that there
was no concomitant increase in the severity of this lesion among the
treated animals. Therefore, the agency concludes that the occurrence of
hepatocellular clear cell foci was incidental and not treatment-related
(Refs. 5 and 20).
Renal pelvic mineralization and epithelial hyperplasia were noted
at higher incidences among treated rats in both the chronic toxicity
and the carcinogenicity phases of study E057. These changes were
observed primarily in the high-dose females. The degree of severity of
these lesions was reported as minimal or slight. McNeil concluded that
these changes are of no toxicological significance.
FDA evaluated these changes and noted that: (1) It is not unusual
to observe such lesions in aged rats, especially in females (Ref. 21).
In this study (E057), the rats were at or near the end of their
expected lifetime at the time of sacrifice; and (2) mineralization of
the renal pelvis represents a physiological adaptation secondary to
cecal enlargement. Cecal enlargement is often seen with other
substances that are poorly absorbed in the upper intestine and can be
expected in a study like this with a poorly absorbed substance like
sucralose (Refs. 21, 22, 23, 25, and 26). Based on the previously
mentioned reasons, FDA concludes that the renal pelvic mineralization
and epithelial hyperplasia observed are of no toxicological
significance (Refs. 6 and 26).
Decreased body weight gain was observed in all sucralose treated
animals in both the carcinogenicity and chronic toxicity phases of this
study. At the end of the carcinogenicity phase, mean body weight gain
in sucralose-fed rats was 13 to 26 percent less than that of the
control group. Food consumption in the treated groups during this phase
was 5 to 11 percent less than that of the control values. At the end of
the chronic toxicity phase, a reduction of 12 to 25 percent in the body
weight gain was observed in the treated rats relative to controls,
whereas food intake in the treated rats was reduced only 5 to 10
percent compared to controls.
McNeil postulated that this body weight gain decrement effect was
the result of reduced palatability of sucralose-containing diets.
However, based on the data in this study, as well as in all other rat
studies in the sucralose petition, the agency was unable to conclude
that reduced palatability, which affected food
[[Page 16422]]
consumption, fully accounted for the decreased body weight gain
observed in sucralose-fed rats (Ref. 27). Thus, the agency recommended
that McNeil perform additional testing to resolve the body weight gain
issue (Ref. 28). In the absence of such testing, FDA could not
determine a no-observed-effect level for this study (E057). The body
weight gain issue is discussed in detail in section II.B.5.a of this
document.
ii. Carcinogenicity study in mice (E055). In this study, Charles
River CD-1 mice, 52 animals per sex per group, were gang-caged (4 mice
per cage) and fed sucralose at 0, 0.3, 1.0, and 3.0 percent in the diet
for 104 weeks. At the termination of the study, survival and classic
toxicological parameters were examined for treated and control mice.
Survival rates were comparable for control and treated groups. Mean
body weight gains in both male and female mice in the high dose (3
percent) group were significantly reduced (21 to 25 percent) relative
to controls for the 104-week treatment period, without any significant
decreases in food consumption. Of other toxicological parameters
examined, significant decreases were observed only in the erythrocyte
counts of females in the high-dose group. There was no evidence of
treatment-related neoplasia in any of the sucralose-treated groups
(Ref. 19).
Based on the effects seen on body weight gain and the erythrocytic
counts at the high-dose level, the agency concludes that a dietary
level of 1 percent (equivalent to 1,500 mg/kg bw/d) was the no-
observed-effect level for sucralose (Refs. 5 and 29).
iii. Chronic toxicity study in dogs (E051). Groups of four male and
four female beagle dogs were fed sucralose at concentrations of 0, 0.3,
1.0, and 3.0 percent in the diet for 52 weeks. Parameters examined in
this study included mortality, body weight, food consumption,
hematology, clinical chemistry, urinalysis, and histopathology.
An increase in body weight gain of sucralose-treated male dogs
relative to controls was observed at all dose levels. However, this
increase in weight gain was accompanied by a general increase in food
consumption. All other parameters examined in this study were
comparable between treated and control animals.
Because there were no toxic effects seen at any dose tested, the
agency concludes that a dietary level of 3 percent (equivalent to 750
mg/kg bw/d) is the no-observed-effect level for sucralose in dogs
(Refs. 5 and 30).
b. Sucralose hydrolysis products--carcinogenicity study in rats
(E053). In this study, groups of 50 male and 50 female Sprague-Dawley
CD rats were administered an equimolar mixture of the hydrolysis
products (4-CG and 1,6-DCF) at concentrations of 0, 200, 600, and 2,000
ppm in the diet for 104 weeks.
There was no evidence of treatment-related neoplasia in any of the
dose groups in this study. A marginal increase in the incidence of
hepatocellular clear cell foci was reported in treated male and female
rats. The agency determined, however, that this was not a treatment-
related effect because there was no concomitant increase in severity of
the hepatic lesion (Refs. 19 and 20). Thus, the agency concludes that
the sucralose hydrolysis products are not carcinogenic to Sprague-
Dawley CD rats when administered as an equimolar mixture in the diet at
concentrations up to 2,000 ppm (Refs. 5, 19, and 31).
In this study, the mean body weight gain of the high-dose females
was significantly decreased (24 percent) relative to the control mean
after 104 weeks of treatment. Mean food consumption in these females
over the 104-week period was also reduced 14 percent compared to the
control group. The agency could not determine whether the body weight
gain decrement observed at the high-dose level in this study was fully
accounted for by decreased food intake. Therefore, the agency concludes
that, in rats, the mid-dose (600 ppm equivalent to 30 mg/kg bw/d) is
the no-observed-effect level for the hydrolysis products of sucralose
(Refs. 5 and 10).
5. Special Toxicological Studies
a. Body weight gain. As noted previously, the agency's review of
the rat data submitted in the original petition raised questions
regarding the effect of sucralose on body weight gain (Ref. 27).
Sucralose-fed rats in the subchronic and chronic studies showed
significant decreases in body weight gain with only small reductions in
food consumption (Ref. 27).
In particular, in the combined chronic toxicity/carcinogenicity rat
study (E057), decreases of 13 to 26 percent in body weight gain were
observed in sucralose-fed rats that had reductions in food consumption
of only 5 to 11 percent compared to controls (Ref. 27). Although the
treated rats ate less food, the reductions in food intake did not
appear to account fully for the decreased weight gain. McNeil contended
primarily that reduced palatability of the sucralose-containing diet
caused treated animals to eat less and thus gain less weight. McNeil
stated that, collectively, data obtained from the sucralose
acceptability study (El30 and E143), sucralose pair-feeding study
(E058), gavage study (El5l), and a diet spillage study (El54) supported
their claim that palatability fully accounted for the reduced body
weight gain (Ref. 32). Finally, McNeil also contended that this effect
was neither a toxic effect nor biologically significant. The studies
upon which McNeil relied are discussed followed by the agency's
discussion of its evaluation of those studies.
i. The Palatability hypothesis--(1) Acceptability studies in rats
(El30 and E143). Several studies were conducted to evaluate the
acceptability and palatability of sucralose when administered to rats
via drinking water or in the diet. Data from these rat studies showed
that sucralose was acceptable in drinking water at levels up to 3,200
ppm. However, reduced food consumption was seen in rats that were
administered sucralose in the diet at levels greater than 800 ppm.
(2) Pair-feeding study in rats (E058). Pair-feeding is an
experimental procedure where two groups of animals are fed the same
amount of diet. Thus, if there are differences in the body weight gain
of these two groups of animals, it is due to an effect of the test
substance and not due to differences in the amount of food consumed by
the two groups of animals.
There were five groups of female Sprague-Dawley CD rats in this
study. Initially, rats were grouped into various categories on the
bases of body weight. Twenty rats were randomly selected from each of
the weight categories and assigned to each of the five groups. One
group was fed 3 percent sucralose in the diet (unrestricted access) for
8 weeks. Animals in the pair-fed group were fed a daily amount of basal
diet equivalent to the mean food intake consumed on the previous day by
the 3-percent sucralose dose group. In a third group, an ad libitum
control group, rats received unrestricted access to basal diet. A
fourth group was administered sucralose by gavage in amounts equivalent
to that fed in the 3-percent dietary group. A fifth group served as a
control group for the sucralose-gavaged rats and received distilled
water by gavage.
Significant decreases in food consumption and body weight gain were
observed in both the 3-percent dietary administration group and its
pair-fed control group relative to ad libitum controls. Rats dosed with
sucralose by gavage consumed significantly more food and gained
significantly more weight than those receiving the water control.
[[Page 16423]]
(3) 4- to 13-week sucralose oral gavage study in rats (El5l).
Because administration by gavage circumvents effects due to dietary
administration of an unpalatable test material, McNeil performed a
study to investigate the effects of sucralose in rats, when
administered by gavage. In this study, groups of Sprague-Dawley rats,
10 per sex per group, were administered sucralose at doses of 2,000 mg/
kg bw/d for 13 weeks, 3,000 mg/kg bw/d for 9 weeks, or 4,000 mg/kg bw/d
for 4 weeks. Control rats (10 to 15 per sex) were sacrificed
concurrently at each of the time intervals along with the sucralose-
treated rats.
There were no treatment-related gross or histopathological changes
observed nor effects noted for urine and clinical chemistry parameters.
The average food consumption for all sucralose dosed rats was
consistently greater than that of the controls (104 to 108 percent of
the controls). Mean final body weights were also greater in the
sucralose treated rats compared to controls (103 to 109 percent).
(4) Diet spillage study in rats (El54). McNeil performed a study to
determine whether the decreased body weight gain observed in several of
the rat studies, including the combined chronic toxicity/
carcinogenicity study, was due, in part, to increased spillage of
sucralose-containing diet. If there was greater spillage of the
sucralose-containing diet than that seen in controls, then the
sucralose-treated animals were eating even less than they appeared to
consume. In this 8-week study, three groups of Sprague-Dawley rats (15
per sex per group) were individually housed and fed either basal diet
or basal diet containing sucralose at dose levels of 3 percent or 5
percent. Although overall diet spillage was significantly higher in the
sucralose-treated rats compared to controls, this difference existed
only for the first 2 weeks. Treated rats (both sexes) consumed 5 to 8
percent less food than controls. This decreased food intake was
associated with a 10 to 15 percent depression in weight gain.
ii. The agency's evaluation of the palatability hypothesis. From
its interpretation of the data in the acceptability studies (EI30 and
E143), pair-feeding study (E058), gavage study (El5l), and diet
spillage study (El54), McNeil identified three factors that the company
believed led to the decrement in body weight gain observed in the
combined chronic toxicity/carcinogenicity study in rats (E057): (1)
Decreased food consumption due to poor palatability and increased
spillage of the sucralose-containing diet; (2) inhibition of growth
potential in sucralose-fed F1 generation rats due to
decreased initial body weight resulting from decreased maternal weights
of the treated rats; and (3) magnification of the body weight gain
effect with increases in study duration.
While the agency accepted the physiological and nutritional
principles presented by McNeil, the agency concluded that McNeil's
arguments did not explain fully the magnitude of the decrement in body
weight gain in the sucralose-fed rats of the combined chronic toxicity/
carcinogenicity study (E057) for the following reasons.
The agency disagreed with the petitioner's contention that in the
combined chronic toxicity/carcinogenicity study (E057), a consistent
decrease in food consumption was demonstrated at all dose levels. The
agency determined that this study (E057) did not adequately measure
food consumption and did not adequately account for diet spillage.
Furthermore, the agency determined that in many of the sucralose rat
studies food consumption decreases were not of sufficient magnitude to
account for the observed body weight gain decrements seen in the
sucralose-fed rats of these studies (Ref. 27). Inadequacies in the
measuring of food consumption and the monitoring of spilled diets also
confounded the interpretation of the pair-feeding study (E058) (Refs.
10 and 27).
The agency also disagreed that decreased initial body weights
accounted for the weight gain decrement in sucralose treated rats in
study E057. Although maternal weights were slightly decreased (93 to 97
percent of controls) on day 1 of lactation, this small difference was
not large enough to sufficiently explain the body weight differences of
the lactating pups (Ref. 27). In fact, maternal weights of the
sucralose-fed rats were not significantly different from those of the
control rats during days 14 to 21 of lactation (Ref. 27). Differences
in initial body weights of the F1 pups (4 to 8 percent
decreases) of the combined chronic/carcinogenicity study (E057) were
not sufficient to explain the magnitude of the final body weight gain
decrements of these rats (Ref. 27).
Finally, although FDA agreed with the general principle that long-
term food intake disparity will result in increasing differences in
body weight gain over time, FDA concluded that this principle alone did
not account for the degree of magnification of body weight gain
decrement compared to the small reductions in food consumption seen in
the sucralose studies (Ref. 27).
Based on the foregoing reasoning, FDA concluded that the
acceptability studies (El30 and E143), pair-feeding study (E058), 4- to
13-week gavage study (El5l), and the diet spillage study (El54) did not
adequately explain the magnitude of decreased body weight gain relative
to the level of reduced food consumption, in the combined chronic/
carcinogenicity study (E057). The agency thus concluded that McNeil had
failed to explain satisfactorily the observed body weight gain
decrement and that additional study data were needed to resolve this
issue (Ref. 28). McNeil subsequently conducted two studies (E160 and
E161) in rats to resolve the body weight gain decrement issue.
iii. Resolution of the body weight gain decrement issue--(1)
Sucralose dietary administration and dietary restriction study in rats
(El60). McNeil agreed to perform an additional sucralose feeding study
(the diet restriction study, E160) to attempt to resolve the body
weight gain decrement issue and to test the petitioner's palatability
hypothesis. The specific purpose of the study was twofold: To determine
whether the weight gain decrement observed in the sucralose-fed rats of
the combined chronic toxicity/carcinogenicity study (E057) could be
explained solely by decreased food consumption; and to establish a
``no-observed-effect'' level for the body weight gain decrement effect
after chronic administration of sucralose.
In study E160, Sprague-Dawley CD rats were divided into eight
groups (20 animals per sex per group). Three groups were fed ad libitum
basal diet that contained 0, 1, or 3 percent sucralose. Three groups
were fed restricted amounts of basal diet at levels that were 85, 90,
or 95 percent of that eaten by the ad libitum controls. Two other
groups were fed restricted diets (90 percent of ad libitum controls)
that also contained sucralose at a concentration of 1 percent or 3
percent. The groups were as follows:
Group 1 Control--basal diet ad libitum
Group 2 Control--basal diet 95 percent of Group 1
Group 3 Control--basal diet 90 percent of Group I
Group 4 Control--basal diet 85 percent of Group 1
Group 5 1-percent sucralose--ad libitum
Group 6 3-percent sucralose--ad libitum
Group 7 1-percent sucralose--90 percent of Group 1
Group 8 3-percent sucralose--90 percent of Group I
[[Page 16424]]
Special experimental designs, including single-housing of the test
animals, accurate weighing of spilled diet, and utilization of special
feed jars, were incorporated into this study to ensure the highest
level of accuracy in the measuring and reporting of food intake. Body
weight, body weight gain, food consumption, and food conversion
efficiency data were collected for each of the groups. Overall survival
was unaffected by the feeding of sucralose at doses up to 3 percent for
the duration of the study. The agency evaluated the data from this
study using two separate statistical procedures. In the first
comparison, data from control groups 1 to 4 were combined and fitted
(separately for males and females) with a polynomial regression model
that showed final body weight gain as a function of initial body weight
and food consumption. Data for each of the sucralose groups were also
fitted with this mathematical model and compared to the data from the
combined control groups.
In the second comparison, mean food consumption was calculated for
each sucralose group. Using the regression models, FDA calculated the
expected body weight gain for animals at the mean food consumption for
both the combined control groups and the sucralose groups. The
calculated body weight for each sucralose group was then compared to
the combined control group at the mean food consumption.
For both sexes, with both statistical procedures, the 3-percent
sucralose groups (Groups 6 and 8) showed significant decrements in body
weight gain relative to the combined control groups (Ref. 33).
Decrements of 3.9 to 6.3 percent were observed in the mean body weights
of the 3-percent sucralose-fed groups after adjustment for food
consumption and initial body weight differences. Thus food consumption
only partially accounted for the weight gain decrement observed in the
3-percent sucralose-fed rats. Weight decrements in the males of the 3-
percent dose group stabilized by 15 weeks; in the females, differences
stabilized at 20 weeks. Therefore, FDA concludes that the duration of
this study (26 weeks) was sufficient to evaluate weight gain decrement
effects.
In both the 1-percent sucralose group and the 1-percent sucralose
with l0-percent diet restriction group, adjusted mean body weights were
comparable to those of the combined control data (Ref. 33). Therefore,
FDA determined that reduced food consumption accounted fully for weight
gain differences in the 1-percent sucralose-fed group.
Based upon the data from this study, the agency concludes that
treatment with sucralose at 1 percent in the diet had no effect on body
weight gain in rats. The same data establish that rats fed sucralose at
a concentration of 3 percent of the diet did show significant decreases
in weight gain which were attributable to the test substance. The
agency further concludes that, based upon this study, the 1-percent
dose level (equivalent to the 500 mg/kg bw/d dose in study E057) is the
no-observed-effect level for the body weight gain effect observed in
sucralose-treated rats in this study (Ref. 34).
(2) Sucralose toxicity study by oral (gavage) administration to
Sprague-Dawley CD rats for 26-weeks (El6l). McNeil submitted a 26-week
gavage study (El6l) in rats that was designed to: (1) Provide further
support for their contention that the body weight gain decrement seen
in sucralose fed rats could be explained solely by decreased food
intake caused by the reduced palatability of sucralose-containing diet;
(2) confirm the data in the 4- to 13-week sucralose oral gavage study
(EI51); and (3) to address inadequacies in the experimental design of
the 4- to 13-week sucralose oral gavage study (El5l).
In this 26-week study, sucralose was administered orally to
Sprague-Dawley CD rats, 20 rats per sex per group, by gavage at dosages
of 0, 750, 1,500, or 3,000 mg/kg bw/d. Rats in the control group were
gavaged with purified water. Body weight, water consumption, and food
consumption data were recorded for all groups. Routine hematological
and clinical chemistry parameters were measured. Organ weight data also
were recorded. Histopathological examinations were performed on
representative vital tissues from the control and high-dose groups.
Histopathological examinations were performed also on all abnormal
tissues.
Seven deaths occurred during the study that were attributed either
to spontaneous causes not related to treatment or technical trauma
during dosing: 2 males, 0 mg/kg bw/d dose; 1 male and 2 females, 1,500
mg/kg bw/d dose; and 1 male and 1 female, 3,000 mg/kg bw/d dose.
Overall body weights of the animals in the sucralose-treated groups
were not significantly different from those of the control group during
the length of the study. The mean food consumption in the sucralose-
gavaged rats was similar to that seen in the controls, except in the
high-dose males. Food intake for the high-dose males was 3.9 percent
greater than that of the control rats.
After making adjustments for initial body weight and food
consumption, the agency performed a statistical analysis on the final
body weight data using polynomial regression analysis. This analysis
showed that the adjusted final body weight of the high-dose males was
significantly decreased (4.6 percent; p = 0.035) relative to that of
the control group. The adjusted mean body weights of all other groups
were not significantly different from the controls.
Water consumption was significantly increased in the sucralose-
treated rats relative to controls. There were no treatment-related
effects seen in any of the hematological or clinical chemistry
parameters tested. Cecal enlargement was the only effect of sucralose
that was dose-related among both sexes of the sucralose-gavaged rats.
As discussed previously in section II.B.4.i of this document, this
effect is a normal physiological adaptation to poorly absorbed dietary
components and not related to toxicity. The relative kidney weight of
the high-dose group also was significantly increased when compared to
the control group. However, this kidney effect was not associated with
any toxicologically significant renal histopathology. Additionally, the
plasma electrolytes of the sucralose-treated rats in this study were
comparable to that seen in control animals.
As with the diet restriction study (El60), decreased body weight
gain was observed in the sucralose-treated rats of the high-dose group.
The agency concludes that the mid-dose (1,500 mg/kg bw/d) is the no-
observed-effect level for the body weight gain effect observed in this
study (El6l) (Refs. 35 and 36).
b. Immunotoxicity study in rats. As reported by McNeil and as noted
in the agency's review of the sucralose data, thymus, spleen, and
hematological changes were observed in rats at the high-dose levels in
some of the short-term and long-term sucralose feeding studies. For
example, when rats were fed sucralose in a 4- to 8-week range-finding
study (E031) the following effects were noted: Decreased thymus and
spleen weights, lymphocytopenia, and cortical hypoplasia of the spleen
and thymus. In the two-generation reproductive toxicity study (E056),
decreased thymus weights were noted in the F0 and
F1 generations of the high-dose sucralose (3 percent in the
diet) group. McNeil stated that the above effects were secondary to the
palatability-related reduction in food consumption in treated rats.
In an effort to provide more specific and detailed assessment of
the immunotoxic potential of sucralose, the petitioner conducted a 28-
day oral immunotoxicity study (El62) of
[[Page 16425]]
sucralose in rats. In this study, groups of male and female Sprague-
Dawley rats (13 per sex per group) were administered sucralose by
gavage at dose levels of 750, 1,500, and 3,000 mg/kg bw/d for 28 days.
Additional groups (13 per sex per group) of rats formed a gavage
control group, an ad libitum diet control group, a dietary sucralose
(3,000 mg/kg bw/d) group, and a diet restricted (90 percent of ad
libitum control) group.
Immunotoxicological parameters examined in this study were: Thymus
and spleen weights at study termination; standard histopathology
evaluation of the spleen, thymus, bone marrow, and lymph nodes; and
total and differential white blood cell counts. The study also examined
the following specific immunologic parameters: Bone marrow cellularity,
immunoglobulin subtypes, splenic lymphocyte subsets, and splenic
natural killer cell activity.
Significant decreases were observed in the mean thymus weight of
the males in the high dose (3,000 mg/kg bw/d) gavage group. Thymus
weight was not significantly affected by sucralose when administered to
rats by gavage at either 1,500 or 750 mg/kg bw/d; nor was it affected
in the sucralose-fed group or the diet restricted group. No
morphological changes in thymus or any other lymphoid tissues were
observed in any of the sucralose treated groups.
In the mid-dose (1,500 mg/kg bw/d) sucralose-gavaged male rats,
there appeared to be a trend toward decreasing white blood cell and
lymphocyte counts with increasing dose levels of sucralose, but the
trend did not reach statistical significance. No significant
differences were seen in other immunologic parameters in the sucralose
gavage groups relative to the control gavage group. However, because of
the large variation seen in the data from the gavaged animals at the
mid-dose, the agency finds that the study is inconclusive regarding
treatment-related effects for these parameters at the mid-dose.
The agency concludes that the highest dose (3,000 mg/kg bw/d)
tested in the gavage groups showed an effect based on the significant
changes in thymus weight. Because of the difficulty in interpreting
data from the mid-dose animals, the agency has determined that the low
dose, 750 mg/kg bw/d, is the no-observed-effect level for the
immunological endpoints examined in this study (Ref. 37).
c. Neurotoxicity testing in mice and monkeys (E008 and E009). The
chlorinated monosaccharide, 6-chloro-6-deoxy-D-glucose (6-CG), is known
to be neurotoxic to laboratory animals (Refs. 38 and 39). Because
sucralose is a chlorinated disaccharide, McNeil conducted two
neurotoxicity studies, one in mice (E008) and one in monkeys (E009).
The positive control in these studies, 6-CG, produced strong clinical
signs of neurotoxicity, as well as severe morphological changes in the
tissues of the central nervous system (CNS). Animals receiving
sucralose or an equimolar mixture of sucralose hydrolysis products at
doses up to 1,000 mg/kg bw/d did not exhibit any clinical signs of
neurotoxicity or morphological changes in CNS tissues (Refs. 5 and 40).
The agency concludes that the lack of neurotoxic effects by both
sucralose and its hydrolysis products at the tested dose levels in
these studies provides assurance that sucralose used as a food additive
under the proposed conditions of use will not produce neurotoxic
effects.
d. Diabetic studies in humans (EI56, E157, E168, E170, E171). In an
effort to provide an assessment of any potential effect sucralose use
would have on the diabetic population, the petitioner performed a
series of clinical studies on diabetic patients. The results obtained
from those studies are discussed in this section of this document.
A single-dose cross-over study (E156) was performed in 13 insulin-
dependent (IDDM or Type I diabetics) and 13 non-insulin dependent
(NIDDM or Type II diabetics) patients to evaluate the effects of a
single dose of sucralose (1,000 mg) on short-term glucose homeostasis.
Fasting plasma glucose area under the curve (AUC) and fasting serum C-
peptide AUC were measured after the consumption of a standardized
liquid breakfast meal. This study showed that neither plasma glucose
nor serum C-peptide levels were affected by this single dose
administration of sucralose in these patients. From this study the
agency concludes that sucralose does not adversely affect short-term
glycemic control in persons with diabetes mellitus (Ref. 41 ).
A 6-month clinical study (E157) was performed investigating the
effect of sucralose (667 mg/d through oral administration) on glucose
homeostasis in patients with NIDDM (Type II diabetes). The study was
divided into a screening phase, a testing phase, and a followup phase.
Forty-one patients participated in the testing phase of the study. The
41 patients were divided into two groups: 20 patients whose diabetes
was managed by insulin and 21 managed by oral hypoglycemic agents
(OHA's). Each of these two groups were further subdivided into a
sucralose group and a placebo group. Percent concentration of
glycosylated hemoglobin (HbA1c) was the primary measure of long-term
glycemic control in this study. In addition, the following parameters
of glucose homeostasis were measured: (1) Fasting levels of plasma
glucose, serum C-peptide, and serum insulin; and (2) postprandial
measures of plasma glucose, serum C-peptide, and serum insulin. These
parameters were measured after 0, 1, 3, and 6 months of treatment with
either sucralose or a placebo (cellulose).
The results from this study showed a small but statistically
significant increase in the glycosylation of hemoglobin (HbA1c) from
baseline levels in the sucralose-treated group compared to that seen in
the placebo group (dataset 1: mean difference of 0.007 percent, p =
0.005; dataset 2: mean difference of 0.006 percent, p = 0.012) (Ref.
42). This HbA1c effect was observed in the sucralose-treated group at 1
month of treatment and did not significantly increase to higher levels
throughout the remainder of the study (mean difference range of 0.006
to 0.008 percent, p 0.0043). Overall, during the test phase
of the study, no statistically significant changes from baseline were
observed in any of the secondary measurements of glucose homeostasis
(ie., plasma glucose and serum C-peptide and insulin concentrations).
Because of the small patient group sizes in this study, the ultimate
clinical significance of the observed HbA1c effect could not be
determined (Ref. 42). However, generally speaking, increases in
glycosylation in hemoglobin imply lessening of control of diabetes.
Thus, the petitioner performed studies E168 and E170 in an attempt to
provide an explanation for the observed HbA1c effect.
In study E168 McNeil performed a series of tests to determine
whether the increased HbA1c levels observed in study E157 were an
artifact of measurement (e.g. interferences related to methodology) or
a direct effect of sucralose on the rate of hemoglobin glycation. These
tests included a reanalysis of blood samples from study E157 for
glycohemoglobin levels; an investigation of the procedures used to
measure glycated hemoglobin; and an analysis of the effects of
sucralose on glycation of hemoglobin in hemolysates versus intact
erythrocytes. Results from these tests confirmed that in E157, HbA1c
levels were increased in the sucralose-treated diabetic patients and
showed that sucralose had no direct effect on the rate of hemoglobin
glycation.
In study E170, red cell preparations from the blood of diabetic and
non-diabetic patients were treated with
[[Page 16426]]
sucralose (100 mg per liter) to investigate the rate of formation of
glycated hemoglobin in the blood. The results of this study showed that
sucralose did not affect the rate of formation of glycated hemoglobin
(Ref. 42). Thus, there was no evidence that a physicochemical or other
influence by sucralose might explain the increased glycation of
hemoglobin.
Because studies E168 and E170 did not provide an explanation for
the HbA1c effect observed in study E157, study E171 was performed as a
repeat study of E157 with a better experimental design, in that E171
had larger patient group sizes and stronger statistical power (90
percent versus 80 percent in study E157) to detect an effect by
sucralose on hemoglobin glycation. The 3-month duration for study E171
was deemed adequate because the increased HbA1c levels that were seen
at one month of treatment in study E157 did not increase any further at
any of the later time points tested in the study. In study E171, 136
NIDDM patients were divided into two groups based on their diabetic
therapy (64 taking insulin and 72 on OHA's). Each of these two groups
were subdivided equally into a sucralose and placebo group. The study
was divided into a screening phase, a testing phase, and a followup
phase. Glycosylated hemoglobin (HbA1c) was the primary measure of
glucose homeostasis; in addition, the secondary parameters, fasting
plasma glucose and serum C-peptide, were measured. Serum insulin levels
were not measured in this study.
Results from study E171 showed no statistically significant changes
from baseline in the HbA1c levels or any of the other measured
parameters of glucose homeostasis in the sucralose-treated groups
relative to the placebo control group. The agency concludes from the
results of this study that sucralose (667 mg/d) has no effect on long-
term glucose homeostasis (as measured by HbA1c) in patients with NIDDM
(Refs. 43 and 44). The agency further concludes that the small but
statistically significant decline in glycemic control that was observed
in the sucralose-treated groups in study E157 was not a clinically
significant effect because this effect was not duplicated in a repeat
study (study E171) that had a greater statistical power (Ref. 43).
Therefore, based upon the clinical studies of sucralose, FDA
concludes that sucralose does not adversely affect glucose homeostasis
in patients with diabetes mellitus.
C. Acceptable Daily Intake Estimates for Sucralose
Based on a comprehensive review of the sucralose data base, the
agency has selected the rat as the most appropriate experimental model
to establish a safe level of sucralose for human ingestion. This
selection was based on the following considerations:
(1) The pharmacokinetics data show that the sucralose metabolite
profile in rats was qualitatively comparable to that in humans.
(2) In the combined chronic toxicity/carcinogenicity rat study
(E057) with sucralose, the animals were exposed in utero, which
maximizes the toxicological testing sensitivity.
(3) The combined chronic toxicity/carcinogenicity rat studies
(E057) and the carcinogenicity study in rats (E053) were designed to
test the toxic potential of sucralose and its hydrolysis products for a
duration approximating the lifespan of the species. The agency
historically uses life-time studies for safety evaluation of this type
of food additive. Such testing effectively allows for the assessment of
chronic toxicity including the carcinogenic potential of sucralose.
(4) The majority of the sucralose toxicological data base consists
of rat studies, thereby allowing a more comprehensive safety evaluation
of sucralose in that species. For these reasons, the agency concludes
that the combined chronic toxicity/carcinogenicity study (E057) in
rats, interpreted in light of the no-observed-effect level established
in other studies (El60, E161, and E162), provides the most appropriate
basis for establishing the ADI for sucralose (Refs. 4 and 10). Data in
study E057 showed that sucralose was not carcinogenic to rats at
concentrations up to 3 percent (1,500 mg/kg bw/d). No toxicologically
significant changes in hematology, clinical chemistry, organ weights,
or urinalysis were observed in the sucralose-treated rats in this
study. Macroscopic and microscopic examinations of the tissues from
these sucralose-treated rats revealed no significant treatment-related
toxicological effects.
The only treatment-related effect seen in the sucralose-fed rats of
this study was decreased body weight gain at the 3-percent dose level.
The relationship of this effect to treatment at the 3-percent dose
level was corroborated by the diet restriction study (El60). In the
diet restriction study (El60), the 1-percent dose level (equivalent to
500 mg/kg bw/d dose in study E057) was established as the no-observed-
effect level of sucralose for the observed body weight gain decrement
effect (Refs. 10 and 34).
Using the no-observed-effect level of 500 mg/kg bw/d and applying a
100-fold safety factor, the agency has determined an ADI of 5 mg/kg bw/
d for sucralose. This ADI estimate is well above the 90th-percentile
EDI for sucralose of 1.6 mg/kg bw/d (Refs. 10 and 45).
The agency concludes that the 2-year rat carcinogenicity study
(E053) on the sucralose hydrolysis products established a no-observed-
effect level at the 0.6 percent dose level (equivalent to 30 mg/kg bw/
d). Therefore, the agency has no safety concerns about the sucralose
hydrolysis products at their anticipated levels of intake (0.0048 mg/kg
bw/d) because of the substantial margin of safety between these levels
and the no-observed-effect level.
III. Comments
The agency received several comments on McNeil's sucralose
petition. Several comments supported amending the food additive
regulations for the safe use of sucralose (Ref. 47). Other comments,
principally from Malkin Solicitors (Malkin, formerly Malkin-Janners)
and the Center for Science in the Public Interest (CSPI) (Refs. 48 and
49) raised several issues which they claimed McNeil's petition had not
addressed. The issues raised by the comments and the agency's responses
are discussed in this section of this document.
In addition, CSPI submitted a draft report from Life Science
Research Limited of Suffolk, England entitled ``An investigation of
diet spillage among rats fed diet containing sucralose.'' This draft
report was provided to CSPI by an individual who stated that the study
was undertaken by McNeil but was uncertain that the study report had
been submitted to FDA. The diet spillage study in rats (El54) was
subsequently submitted to the agency by McNeil in March, 1992. As
discussed in section II.B.5.a.i. of this document, the agency concludes
that the study raises no unique issue and contributes very little to
the resolution of the issue of decreased food intake by sucralose-
treated rats.
A. Determination of No-Observed-Effect Level and ADI
1. No-Observed-Effect Level in the Chronic Toxicity Study
Malkin pointed to decreases in body weight gain of 13 to 20
percent, 19 to 24 percent, and 20 to 26 percent observed in animals in
the three treatment groups compared to control animals in the combined
chronic/
[[Page 16427]]
carcinogenicity study in rats (E057) and claimed that, because
decreases in body weight of greater than 10 percent can be interpreted
as an indication of toxicity, a no-observed-effect level was not
established in this study. Malkin cited several observations from
studies in the McNeil petition that suggest that the decreased body
weight gain was not due solely to poor palatability as McNeil asserted.
In addition, Malkin contended that the petitioner overstated the
actual doses in the combined chronic toxicity/carcinogenicity study
(E057) in rats because the diets were formulated with a constant
percentage of sucralose throughout the study. Thus, the actual dose per
body weight was variable depending on food consumption and the weight
of the animal. Therefore, the dosage received later in life is lower
than that received by the young, and Malkin contended that depending on
which dosage was used, the no-observed-effect level and the ADI can
vary significantly.
FDA agrees in part with certain assertions made in the Malkin
comment but disagrees with the overall significance of the findings
identified by Malkin. Specifically, as discussed previously, the agency
also found that the data in the original petition were not adequate to
determine whether the body weight gain decrement was due solely to a
palatability-induced decrease in food consumption or whether the weight
gain decrement was due to effects mediated by sucralose. Therefore, the
petitioner conducted an additional, carefully controlled weight gain
study (diet restriction study, E160, which was submitted after the
Malkin comment was received) to resolve the body weight gain decrement
issue. Based on this study, the agency concludes that sucralose has a
treatment-related effect on body weight gain when fed orally to rats at
a concentration of 3 percent (Refs. 10, 28, 33, 34, and 46). Also the
agency agrees with the comment that the decrements in body weight gain
observed in the combined chronic carcinogenicity study (E057) cannot be
explained solely by differences in food intake due to reduced
palatability of the sucralose-containing diet. The mechanism by which
sucralose affects body weight gain in rats is unknown. The agency
concludes, however, that a no-observed-effect level for sucralose, as
discussed previously, was demonstrated in the diet restriction study
(EI60).
Regarding the dosage calculations, the agency considers it
inappropriate to limit the dosage calculation to any one time point in
the study (Ref. 46). The agency normalizes the data and in doing so
takes into consideration the increased dosage during the growing phase
and the lower dosage during adulthood to provide an average intake. In
reviewing the achieved dosages provided in study E057, the agency
found that male rats achieved an average high dose of 1.3 g/kg
bw/d, while females achieved an average high dose of 1.7 g/kg bw/d. The
average of the two equals 1.5 g/kg bw/d. Thus, the agency concludes
that this dose was calculated using the standard techniques for
calculating a lifetime dose and is not an overstatement of the actual
dose.
2. No-Observed-Effect Level in Developmental Toxicology Studies
Malkin stated that the ``Two-Generation Reproduction Study of
Sucralose in Rats'' (E056) did not establish a no-observed-effect level
because of dose-related reductions in pup body weight and statistically
significant, dose-related decreases in body weight gain in pups from
day 1 through weaning in two generations (F1 and
F2). In addition, Malkin stated that there was a recurring
dose-related increase in relative kidney weights.
The purpose of this reproduction study (E056) was to assess the
potential effects of sucralose on reproduction. The experimental design
of such studies limits the measuring of food consumption by the pups,
especially during lactation (Refs. 10, 40, and 50). However, precise
food consumption measurements are essential to evaluate the potential
for a substance to affect body weight gain. Therefore, study E056
cannot be used to draw conclusions about body weight gain. Moreover,
body weight gain effects were comprehensively studied in other studies
(El60 and E161). As discussed previously, FDA disagrees with this
comment. Regarding the increased kidney weights, microscopic
examination of the kidneys of rats in the subchronic studies (El5l and
E161) revealed no histopathological changes and therefore, FDA
determined that these increases in relative kidney weight in these rats
were not toxicologically significant.
Malkin also asserted that the no-observed-effect level in the
teratology study in rabbits (El34) is 350 mg/kg bw/d rather than 700
mg/kg bw/d proposed by the petitioner.
Although no frank terata were observed at any of the tested doses
in this study (El34), the agency finds that toxicity elicited at the
high dose (700 mg/kg bw/d) prevented the use of this dose to assess
teratological effects. Therefore, as discussed previously, the agency
agrees that the no-observed-effect level in the rabbit teratology study
is 350 mg/kg bw/d (Refs. 40 and 50).
3. Derivation of ADI
CSPI challenged the derivation of the ADI for sucralose (15 mg/kg
bw/d) conducted by the Food and Agriculture Organization/World Health
Organization (FAO/WHO) Joint Expert Committee on Food Additives (JECFA)
and by McNeil. CSPI contended that the appropriate ADI ranges from 0.2
to 8 mg/kg bw/d depending on the study used to derive the ADI. CSPI
used a large number of safety factors ranging from 10 to 1,000 to
derive the ADI from each of the studies which included: (1) The 8-week
dose range-finding study (E031); (2) the two-generation reproduction
toxicity study (E056); and (3) the long-term feeding studies in the rat
(2 years) (E057), the mouse (2 years) (E055), and the dog (1 year)
(E051). In addition, CSPI cited the clinical study (E047) as supporting
the animal-derived ADI's.
As discussed in section II.C of this document, FDA has evaluated
all the studies in McNeil's petition and has concluded that the
combined chronic toxicity/carcinogenicity study in rats (E057),
interpreted in light of the data in the diet restriction study (El60)
and the 26-week gavage study (El6l), provides the most appropriate
basis for establishing the ADI for sucralose. This study (E057)
provides a no-observed-effect level of 500 mg/kg bw/d; these results
are corroborated by data from the diet restriction study (El60) in rat.
Applying a 100-fold safety factor (21 CFR 170.22) results in an ADI for
sucralose of 5 mg/kg bw/d (Ref. 10).
The combined chronic toxicity/carcinogenicity rat study (E057)
provides certain distinct advantages over other studies in the
sucralose petition in terms of establishing an ADI. The agency did not
use the 8-week range-finding (E031) or two generation reproduction
(E056) studies because they were too brief and, compared to chronic
studies, they lack the capability to measure general toxicity. The 1-
year chronic toxicity study in dogs (E051) showed no toxic effect at
any dose tested and thus, provides no basis for concluding that the ADI
should be lower than that established in the rat study. Although the 2-
year carcinogenicity study in mice (E055) established a higher no-
observed-effect level of 1,500 mg/kg bw/d, it did not include an in
utero exposure of the animals to sucralose. Finally, the agency notes
that the purpose of the clinical study (EO47) was to assess tolerance
and acceptance of sucralose and, thus, it was not designed nor intended
to
[[Page 16428]]
assess the toxicity of this compound (Refs. 10 and 51). Thus, use of
the combined toxicity/carcinogenicity study in rats (E057) to establish
the ADI for sucralose is sound and scientifically preferred.
B. Immunotoxic Potential of Sucralose
The Malkin comments claimed that the following observations may
have significance relative to the potential immunotoxicity of
sucralose: (1) Dose-related decreases in thymus weights with concurrent
decreases in white blood cell or lymphocyte counts (lymphocytopenia) in
the 1-year chronic toxicity study in dogs (E051); (2) dose-related
decreases in thymus weight that were seen in the parental rats and
offspring in the two-generation reproduction study (E056); and (3)
decreased spleen weights at the two highest dosages in the 4- to 13-
week sucralose oral gavage rat study (El5l). Malkin further asserted
that these findings are important in view of published data that
establish that the immune system is a target organ for some chlorinated
compounds. Malkin also contended that these alleged immunotoxic effects
cannot be explained by decreased food consumption and that a more
direct evaluation of immunotoxicity potential should be done for
sucralose (Ref. 48).
CSPI also questioned whether sucralose has a toxic effect on the
thymus. In their comment, CSPI discussed various effects that were
demonstrated in the 4- to 8-week range-finding study in rats (E031),
i.e., splenic hypoplasia of lymphoid tissues, cortical hypoplasia of
the thymus, and decreased spleen, adrenal, and thymus weights. CSPI
also cited the lymphocytopenia that was observed in rodents and dogs in
the sucralose studies (Ref. 49).
From a comparative analysis of thymus weight data, body weight
data, and food consumption data in the sucralose rat studies, CSPI
concluded that the relative thymus weight in sucralose-fed rats is much
more severely affected than in diet restricted animals (Ref. 48). CSPI
further asserted that thymus histopathology was not evaluated in all of
the sucralose studies. CSPI also questioned the appropriateness of the
reevaluation of the thymic histopathological examinations by McNeil in
the 4- to 8-week range-finding study (E031). Finally, CSPI asserted
that adequate studies of immune system function, including a clinical
study, should be conducted (Ref. 49).
After the Malkin and CSPI comments were received by FDA, McNeil
conducted a 28-day oral immunotoxicity study in rats (EI62) in which a
number of immunological parameters were examined. In this study,
sucralose was administered by gavage at dose levels of 750, 1,500, and
3,000 mg/kg bw/d and also in the diet at a level of 3,000 mg/kg bw/d.
As discussed in section IIB.5 of this document, the only treatment-
related effect observed in this study was decreased thymus weight. FDA
determined that a dose level of 750 mg/kg bw/d was the no-observed-
effect level for this study (Ref. 37). This no-observed-effect level is
1.5 times higher than the no-observed-effect level established from
body weight gain decrements observed in studies E057 and E160, which
studies FDA used to determine an ADI of 5 mg/kg bw/d for sucralose. The
ADI assures that the proposed use levels of sucralose pose no safety
concerns regarding immunotoxicity.
In addition, other studies of sucralose lacked evidence of
immunotoxic effects. In the combined chronic toxicity/carcinogenicity
rat study (E057), a dose of 500 mg/kg bw/d demonstrated no
immunodeficiencies in rats exposed in utero, during lactation, and
through their entire lifespan. Likewise, no immunotoxic effects were
demonstrated in any of the clinical chemistry parameters nor were
immunotoxic effects observed in the histopathological examinations of
the sucralose-gavaged rats in the 26-week gavage study (EI61), in which
sucralose was administered at doses up to 3000 mg/kg bw/d. This study
is discussed in section II.B.5.a.ii of this document.
Therefore, the agency concludes that the available animal data
provide adequate evidence that sucralose will not be immunotoxic to
humans at the projected level of dietary exposure (Refs. 40 and 50).
C. Mutagenicity of 1,6-DCF
Malkin claimed that data in the sucralose petition showed that 1,6-
DCF, a sucralose hydrolysis product, is mutagenic in the Ames assay and
is a more potent mutagen than unhydrolyzed sucralose in the mouse
lymphoma assay. Further, Malkin stated that the mutagenic potential of
1,6-DCF is established by its ability to alkylate 4-(paranitrobenzene)-
pyridine in an assay which has been used to demonstrate the alkylating
nature of carcinogenic hydrocarbons, some of which were known to bind
covalently to DNA, and by the association of 1,6-DCF with DNA in all
tissues including the testes. Thus, Malkin asserted that it is
imperative to demonstrate in vivo that 1,6-DCF does not covalently bind
to DNA or other chromosomal proteins in germ cells (Ref. 48). CSPI also
asserted that the DNA-binding capacity and mutagenic potential of 1,6-
DCF should be carefully reviewed (Ref. 49).
As discussed in section II.B.2 of this document, the data from the
genotoxic studies are of limited toxicological significance because the
results of the mutagenic testing were equivocal and because such tests
are used primarily as a guide to assess the need for more powerful
bioassays. While 1,6-DCF was weakly mutagenic in the Ames test (E020)
and the L5178Y TK+/assay (E022, E024), the results from the combined
chronic toxicity/carcinogenicity study (E057) and the carcinogenicity
study on an equimolar mixture 4-CG and 1,6-DCF (E053) establish that
sucralose and its hydrolysis products do not elicit tumor formation.
Because of the longer exposure duration and greater testing sensitivity
of carcinogenicity bioassays, such as E057 and E053, the negative
results in these carcinogenicity bioassays of sucralose and its
hydrolysis products (E057 and E053) supersede the equivocal results
obtained in the genotoxicity studies on sucralose and its hydrolysis
products cited by the Malkin and the CSPI comment (Refs. 5 and 50).
D. Renal Effects
CSPI asserted that McNeil's hypothesized etiology of sucralose-
induced rat renal changes (i.e., secondary to cecal enlargement and not
likely to be significant at low intake) should be proved and that the
renal changes observed in the female rats should be interpreted as
being of toxicological significance. Also, the comment asserted that
the available data are insufficient to conclude that the
nephrocalcinosis (deposition of calcium in the kidney) is only an
indirect consequence of cecal enlargement (Ref. 49).
First, nephrocalcinosis is not uncommon in the rat, particularly
the female rat (Refs. 21, 22, and 23). Investigators have reported the
incidence of renal calcification as high as 100 percent in female rats
used as controls with a complete absence of this condition in male rats
fed the identical diet (Ref. 21). Because mice and other rodent models
do not experience the condition, FDA believes that the rat, especially
the female rat, is uniquely sensitive to the development of
nephrocalcinosis and, therefore, is an inappropriate surrogate for man
with respect to this pathologic endpoint.
Second, as discussed in section II.B.4.a.i of this document, the
agency
[[Page 16429]]
recognizes that a number of poorly or slowly absorbed compounds mediate
changes in physiologic function that result in renal mineralization, as
observed in this study (Refs. 6, 21, and 26). In response to the
feeding of poorly absorbed compounds, like sucralose, cecal enlargement
in association with renal changes occurs frequently in old rats (Refs.
21 and 26). Increased calcium absorption and excretion, pelvic
nephrocalcinosis, increased water retention, and alterations of the gut
microflora occur as physiologic adaptive responses to changes in
osmolality in the gut that lead to cecal enlargement (Refs. 21, 22, and
23). Therefore, cecal enlargement is a physiologic adaptive change
rather than a toxic effect (Ref. 26).
Third, in the carcinogenicity study of sucralose hydrolysis
products (EO53), which was concurrently conducted in the same
laboratory with study E057, the incidence of nephrocalcinosis in the
control group was 33 percent (Ref. 26). This incidence is comparable to
that observed in the mid- (32 percent) and high- (30 percent) dose
treated groups in the combined chronic toxicity/carcinogenicity
sucralose study (EO57). The agency concludes that the nephrocalcinosis
is not toxicologically significant for the foregoing reasons.
E. Fetal Edema
Malkin stated that the teratology study of sucralose in rats (E030)
indicates an apparent increase in the incidence of subcutaneous edema
in fetuses. Malkin noted that the expected occurrence of fetal edema at
the Life Science Research Limited (LSRL) laboratory of Essex, England,
where the McNeil teratology study was conducted, was 12 percent. In
contrast, Malkin asserted that the historical incidences of
subcutaneous fetal edema for Charles River CD rats is approximately
0.03 percent and the incidence based on data derived from nine United
States teratology laboratories is 0.007 percent. Malkin concluded that
the unusually large background incidence of edema seen at LSRL may mask
a treatment-related increase in subcutaneous edema (Ref. 48).
The agency believes that the most appropriate historical control
values to use in considering the significance of a response in an
animal bioassay are those pertaining to the identical strain of animal
used in the study and drawn from the testing laboratory used for the
study (Refs. 40 and 50). It is inappropriate to compare data from
Charles Rivers CD rats that were bred in two different countries
because, due to genetic divergence, different ranges of normalcy as
well as spontaneous malformations are likely to exist for each colony
(Ref. 50).
The rat teratology study in question (E030) was conducted in an
LSRL laboratory, utilizing a Charles River rat derived in England. The
historical control data from LSRL showed the incidence of subcutaneous
fetal edema in Charles River rats to range from 0 to 32 percent. In the
teratology study in rats (E030), which was performed in England, the
reported incidences of subcutaneous fetal edema were 15.6, 20.9, 20.5,
and 25.6 percent for the control, low, mid, and high dosages,
respectively. These incidences fall within the LSRL historical control
range (Ref. 40). Additionally, the slightly increased incidences in
subcutaneous fetal edema in the sucralose treated rats raised by the
Malkin comment (E030) were not statistically different when compared to
their concurrent controls (Refs. 13, 40, and 50). Thus, the incidences
of subcutaneous fetal edema identified by the Malkin comment are
considered by FDA to be of no toxicological significance.
F. Bioaccumulation
The Malkin comment raised three issues concerning the possible
bioaccumulation of sucralose. First, Malkin disputed McNeil's
calculation of an ``effective half-life'' of 13 hours for sucralose.
Instead, Malkin asserted that sucralose has a ``terminal half-life'' of
24 hours in healthy humans, which is, Malkin asserts, indicative of the
potential for sucralose to accumulate in the body of consumers.
Further, Malkin stated that the remaining 4 to 7 percent of
radioactivity not excreted 5 days after a single dose of sucralose in
humans indicates that sucralose may never be totally excreted from the
body, even for periodic users. Second, Malkin pointed to data on
sucralose metabolism in dogs (EI23) which show that 20 percent of the
oral dose was not recovered 4 days after dosing with 36Cl
labeled sucralose and claimed that this residual radioactivity
represents either potential bioaccumulation, extensive in vivo
dechlorination, or both. Finally, Malkin stated that there was a
potential for sucralose to accumulate in the fetus because of its
extremely slow elimination from fetal tissue.
The available pharmacokinetics data in the petition do not allow
the agency to draw definitive conclusions regarding bioaccumulation of
sucralose and its metabolites. However, the available evidence on the
physicochemical properties of sucralose, such as low lipid solubility
and high water solubility, is not representative of compounds that
manifest a high potential for bioaccumulation (Refs. 50 and 53). In
addition, sucralose is relatively poorly absorbed from the gut in
humans in that only 11 to 27 percent of the administered dose is
absorbed. Finally, there is little or no evidence of direct tissue
toxicity from sucralose in the mouse, rat, and dog, even when
administered at high doses for 1 to 2 years. In a practical sense, the
absence of tissue toxicity is more important because even if sucralose
had accumulated to some limited degree in these animals, no organ
toxicity was demonstrated in any of the long-term studies (E055, E057,
and E051).
G. Antifertility Effects
Malkin asserted that antifertility effects were observed with
unidentified degradation products of sucralose (Ref. 48). In evidence
of this assertion, Malkin pointed to results of a study (E004)
conducted by McNeil in which sucralose and/or its metabolites
distribute to and have a long residual time in testes. Malkin cited a
literature publication by Ford and Waites (Ref. 17) where sucralose was
shown to inhibit the oxidation of glucose and decrease the
concentration of adenosine triphosphate in epididymal spermatozoa.
Malkin further asserted that these observations must be reviewed in the
context of the known antifertility effects of other chlorosugars (Ref.
48).
The results obtained in study E004 were discounted by the
petitioner because there were indications that the sucralose sample
used in the study were degraded. A subsequent repeat test (study E107)
that was performed by McNeil showed sucralose had no effect on the
glycolytic activity of sperm from male rats.
The agency concludes from stability data contained in the sucralose
petition that sucralose is stable under the proposed conditions of use
(Refs. 52 and 53). Therefore, the agency would not expect significant
amounts of degradation products to be formed from the proposed uses of
sucralose.
The agency has previously discussed in this preamble the studies
mentioned in the Malkin's comment. With regard to the Malkin comment
claiming accumulation of sucralose and its metabolites in testes, the
available pharmacokinetics data in the sucralose petition do not allow
the agency to draw definitive conclusions regarding the bioaccumulation
of sucralose and its metabolites. However, neither of the two-
generation reproduction studies (E052 and E056) showed any reproductive
toxicity that was
[[Page 16430]]
treatment-related. Again, this absence of reproductive toxicity is
directly relevant to the Malkin comment about antifertility effects and
demonstrates that any speculation about bioaccumulation is of no
practical significance.
The agency noted insufficiencies in the antifertility studies on
sucralose and its hydrolysis products, specifically in their duration,
and therefore concludes that they are inadequate to assess the
antifertility potential of sucralose (Refs. 5, 18, and 54). More
importantly, however, results from the two-generation reproduction
studies (E052 and E056) do adequately address any potential
toxicological concern regarding the antifertility potential of
sucralose and its hydrolysis products. Evidence presented in the
reproduction studies supports the conclusion that sucralose and its
degradation products do not possess antifertility properties (Refs. 5,
12, and 18).
H. Neurotoxicity Effects
Malkin stated that neurotoxic effects of some chlorosugars have
been reported and pointed out that 6-chloro-6-deoxyglucose (6-CG) is
used as a positive control for CNS neuropathology and neuromuscular
deficits (Ref. 48). Therefore, Malkin stated that neurobehavioural
studies of sucralose should be assessed in an appropriate study.
FDA has evaluated the petitioner's neurotoxicity studies, E008
(mice) and E009 (monkey), which compared the potential neurotoxic
effects of sucralose or its hydrolysis products with the positive
control 6-CG (Refs. 38 and 39). As discussed in section II.B.5.c of
this document, FDA finds that neither mice nor monkeys showed
neurological effects after receiving sucralose or equimolar mixtures of
sucralose hydrolysis products at levels as high as 1000 mg/kg bw/d for
21 and 28 days respectively.
I. Exposure to Sucralose Hydrolysis Products
Malkin stated that in acidic drinks such as powdered cherry drinks
(storage temperature, 35 deg.C) and carbonated soft drinks (storage
temperature, 22 deg.C), sucralose concentrations decrease by 4 percent
to 20 percent after a 6-month storage and if, as the petitioner states,
the disappearance of sucralose results in the appearance of
stoichiometric amounts of the hydrolysis products 4-CG and 1,6-DCF,
human exposure to these hydrolysis products will be significantly
greater than the 10 mg/kg body weight claimed by the petitioner (Ref.
48).
The agency notes that even if the decomposition noted after 6
months at 35 deg.C (an 18 percent decrease of sucralose) was accepted
as representative of actual use, the probable exposure to hydrolysis
products would not change appreciably from the current estimate of 285
g/p/d (90th percentile, 4.8 g/kg bw/d) because
beverages account for only 13 percent of the estimated exposure to
sucralose. Nonetheless, the agency does not believe that such abusive
storage conditions should be assumed when considering chronic exposure
(Refs. 52 and 53). The data for storage at 20 deg.C, and for storage
at 35 deg.C for up to 3 months show no decomposition of sucralose
within experimental error. The sucralose content of carbonated
beverages also does not change significantly under typical storage
conditions. Finally, the no-observed-effect level established for the
hydrolysis products is 30,000 g/kg bw/d, so there is an
adequate safety margin to allow for additional decomposition of
sucralose to the hydrolysis products.
J. The Need for Studies in Special Populations
CSPI stated that, although McNeil showed that sucralose does not
affect insulin secretion and action, and glucose metabolism in normal
human subjects (E046), non-diabetic rats, and non-diabetic dogs, there
are no clinical studies of type I and II diabetics or the ``diabetic''
rat. CSPI contended that sucralose will be in heavy use by diabetics
and that before approving sucralose, the agency should require the
results of testing of the effects of sucralose in diabetics (Ref. 49).
First, FDA believes that these comments do not preclude the
conclusion that the proposed uses of sucralose are safe. The EDI
(discussed in section II.A of this document) of sucralose (90th
percentile) established by the agency would include those levels
expected to be ingested by diabetics (Refs.1, 2, 53, and 55). The 90th
percentile level of consumption used by FDA is an amount equivalent to
the sweetness that would be provided by the total amount of sugars
commonly added to the diet. Thus, the estimates of heavy consumption of
sucralose used by FDA would cover estimated intake of sucralose by
diabetics who might preferentially select sucralose-containing
products.
Second, after this comment was received by FDA, McNeil did perform
studies on sucralose in diabetic individuals. Specifically, McNeil has
submitted a series of studies (E156, E157, E168, E170, and E171) that
investigated the short-term and long-term effects of sucralose on
glucose homeostasis in patients with IDDM and NIDDM. These studies were
previously discussed in detail earlier in this document. Based upon the
data from these studies, the agency concludes that sucralose has no
adverse health effects on short-term or long-term glucose homeostasis
or any other adverse effect in diabetic patients (Refs. 41, 43, 44,
45). The sucralose exposure tested in the diabetic study E171, where no
effect on glycemic control in diabetics was observed, is seven times
higher than the 90th percentile EDI estimate expected from the proposed
uses of sucralose. This 90th percentile exposure estimate represents
the expected use of sucralose by the heavy eater population and also
encompasses the level that is expected to be ingested by the diabetic
population (Ref. 5).
Additionally, none of the data in the animal studies in the
sucralose data base that examined the effect of sucralose on
carbohydrate/glucose metabolism provided any evidence to suggest that
diabetics would be at any greater risk than the general human
population (Ref. 46). These studies show that: (1) Sucralose has no
influence on insulin secretion by rats or humans; (2) sucralose has no
effect on postprandial or fasting blood glucose levels in animals or
humans; (3) sucralose causes no changes in intestinal absorption of
glucose or fructose; (4) sucralose has no effect on glucose utilization
or on any of the key enzymes modulating glucose metabolism or storage;
(5) administration of sucralose results in no clinical or pathological
symptoms similar to those observed in diabetes mellitus; and (6)
because sucralose has no influence on insulin's action on blood glucose
levels, it would not be anticipated to result in difficulties with
insulin-based management of diabetes. Therefore, on the basis of the
data in the clinical studies and other available information in the
sucralose database, the agency has no safety concerns regarding the use
of sucralose by diabetic individuals.
Another comment by Malkin speculated that the chlorinated galactose
component of sucralose may have an effect on individuals with
diminished ability to metabolize galactose (galactosemic individuals).
Malkin further speculated that 4-chlorogalactose, a sucralose
degradation product, may act as a substrate for enzymes that metabolize
galactose in normal individuals, or may inhibit galactosyltransferase,
an enzyme largely
[[Page 16431]]
responsible for the production of milk in humans.
As discussed previously, from the review of the stability data
submitted in the sucralose petition, the agency would not expect
significant amounts of degradation products to be formed as a result of
the proposed uses of sucralose. Therefore, exposure to degradation
products from the use of sucralose would be minimal and would be of no
toxicological significance.
In another comment, Malkin criticized the petitioner's metabolism
data because the data were obtained from healthy adults and did not
address metabolism or safety in children, diabetics, or the obese.
First, as noted, the petitioner did conduct several studies of
sucralose use in diabetics. Moreover, there are no data that would
suggest any particular reason to expect an increased potential for
adverse effects in children and obese people and other subpopulations.
The Malkin comment did not present any data or evidence that suggest
that these subpopulations are at special risk. In the absence of such
data, the agency determines an additive's safety based on studies
conducted in healthy test animals at doses far in excess of the maximum
anticipated exposure in humans. In addition, in setting an ADI, the
agency uses a 100-fold safety factor after determining the highest no-
adverse-effect level. The agency uses a 100-fold safety factor as a
means to account for differences between animals and humans and to
account for differences in sensitivity among humans. For these reasons,
the agency believes that studies aimed at addressing effects in the
subpopulations indicated are not warranted.
K. Labeling
In response to a November 22, 1991 (56 FR 58910), request by FDA
for comments on a proposed monograph for sucralose for inclusion in the
Food Chemicals Codex, Malkin stated that the name sucralose is
inaccurate, deceptive, and will mislead consumers because of the close
similarity to the name sucrose, a product for which sucralose might be
a replacement. Because sucralose is a chlorinated version of a
disaccharide, Malkin contended that the common name should not
misrepresent the makeup of the material. Malkin cited Sec. 102.5(a) and
(c) (21 CFR 102.5(a) and (c)) and contended that the common name should
indicate that the material is a disaccharide, reflect the presence of
chlorine, and avoid confusion with sucrose. Malkin stated that the name
used by the FAO/WHO JEFCA ``trichlorogalactosucrose'' or a similarly
accurate name such as trichlorofructogalactose should be used.
Section 403(i)(2) of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 343(i)(2)) deems a food that is fabricated from two or more
ingredients to be misbranded unless its label bears the common or usual
name for each ingredient. Section 102.5(a) states, in part, that: ``The
common or usual name of a food, which may be a coined term, shall
accurately identify or describe, in as simple and direct terms as
possible, the basic nature of the food or its characterizing properties
or ingredients. The name shall be uniform among all identical or
similar products and may not be confusingly similar to the name of any
other food that is not reasonably encompassed within the same name.''
Section 102.5(c) addresses the need for the common or usual name of a
food to include a statement of the presence or absence of any
characterizing ingredients or components, whether such ingredients need
to be added, whether the absence or presence has a bearing on price,
and similar issues that may cause a consumer to purchase a product that
is not what it appears to be.
Sucralose is a single ingredient and has no other characterizing
ingredients or components that are added or removed. Thus,
Sec. 102.5(c) does not govern the question of what is the appropriate
name for this additive.
Under Sec. 102.5(a), a substance may be described by a coined term
provided that it accurately identifies, in as simple and direct terms
as possible, the nature of the food, i.e., the food additive sucralose.
While the names suggested by Malkin may be suitable for describing the
nature of the substance to a chemist, they are not the most direct and
simple terms for the average consumer. FDA recognizes that the precise
chemical names of additives may not be helpful for consumers and has
permitted the use of a simple coined name that consumers can
understand. For example, none of the three intense sweeteners currently
allowed in food, saccharin, aspartame, and acesulfame potassium, are
described by their specific chemical names. This causes no confusion,
however. The important issue is whether the name is commonly used for
the substance and whether that name could be misleading for some
reason.
Although Malkin states that the name trichlorogalactosucrose is
used by JEFCA for this additive, that organization has since the
comment was submitted accepted sucralose as the preferred name.
Additionally, the additive is regulated under the name sucralose in
both Canada and Australia. Thus, it is consistent with the
international marketplace, including other English speaking countries,
to describe the additive by the name sucralose. Similarly, the Food
Chemicals Codex has also published a monograph under the name
sucralose. For these reasons, the agency concludes that the name
sucralose is the common name, accurately identifies the additive, and
will not mislead consumers.
IV. Conclusion
The agency has evaluated all the data in the petition and other
information and concludes that the proposed uses of sucralose are safe.
Therefore the agency 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 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.
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 (address above) between 9 a.m. and 4 p.m., Monday
through Friday.
VI. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum, from DiNovi, Chemistry Review Branch, to
Anderson, Novel Ingredients Branch, September 21, 1993.
2. Memorandum, from DiNovi, Food and Color Additives Review
Section, to Anderson, Direct Additives Branch, May 18, 1989.
3. Memorandum from Roth, HFS-506, to Review Staff Office of
Premarket Approval, October 26, 1994.
4. Memorandum, from Roth, HFS-506, to Anderson, Division of
Product Policy, October 26, 1994.
[[Page 16432]]
5. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, August 8, 1990.
6. Addendum memorandum, from Graham, Additives Evaluation
Branch, to Anderson, Direct Additives Branch, April 12, 1991.
7. Memorandum, from Griffiths, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, August 22, 1988.
8. Addendum memorandum, from Graham, Additives Evaluation
Branch, to Anderson, Direct Additives Branch, August 12, 1991.
9. Memorandum, from Dunkel, Genetic Toxicology Branch, to
McLaughlin, Direct Additives Branch, May 23, 1984.
10. Memorandum, from Whiteside, Additives Evaluation Branch No.
2, to Anderson, Novel Ingredients Branch, May 26, 1995.
11. Memorandum, from Whiteside, Additives Evaluation Branch No.
2., to Anderson, Direct Additives Branch, January 21,1994.
12. Memorandum, from Collins, Mammalian Reproduction and
Teratology Team, to Gryder, Additives Evaluation Branch, August 15,
1987.
13. Memorandum, from Welsh, Whole Animal Toxicology Branch, to
McLaughlin, Direct Additives Branch, February 1, 1984.
14. Addendum Memorandum, from Whiteside, Additives Evaluation
Branch, to Anderson, Direct Additives Branch, November 12, 1991.
15. Memorandum, from Collins, Mammalian Reproduction and
Teratology Team, to Gryder, Additives Evaluation Branch, October 2,
1987.
16. Memorandum, from Welsh, Mammalian Reproduction and
Teratology Team, to Bleiberg, Division of Toxicology, July 15, 1986.
17. Ford, W. C. L., and G. M. H. Waites, ``A Reversible
Contraceptive Action of Some 6-chloro-6-deoxy Sugars in the Male
Rat,'' Journal of Reproduction and Fertility, 52:153-157, 1978.
18. Memorandum, from Whitby, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, December 20, 1988.
19. Memorandum, Cancer Assessment Committee, October 20, 1987,
January 26, April 6, and July 13, 1989.
20. Memorandum, from Dua, Division of Pathology, to Lin,
Additives Evaluation Branch, February 11, 1992.
21. Lord, G. H., and P. M. Newberne, ``Renal Mineralization--A
Ubiquitous Lesion in Chronic Rat Studies,'' Food Chemistry and
Toxicology, 28:449-455, 1990.
22. Newberne, P. M, M. W. Conner, and P. Estes, ``The Influence
of Food Additives and Related Materials on Lower Bowel Structure and
Function,'' Toxicologic Pathology, 16:184-197, 1988.
23. Vaughan, O. W., and L. J. Filer, ``The Enhancing Action of
Certain Carbohydrates on the Intestinal Absorption of Calcium in the
Rat,'' Journal of Nutrition, 71:10-14, 1960.
24. United Nations (UN) Environmental Programme, International
Labour Organization, World Health Organization, Food and Agriculture
Organization of the U.N., ``Principles for the Safety Assessment of
Food Additives and Contaminants in Food,'' Geneva: World Health
Organization, 1987 (Environmental Health Criteria, 70), pp. 41-42.
25. De Groot, A. P., and V. J. Feron, ``Effects of Very High
Dietary Levels of Lactose on the Kidneys of Rats.'' In: Report R4812
Central Institute for Nutrition and Food Research (CIVO/TNO). Zeist,
the Netherlands: CIVO/TNO; October 1975/March 1976: 1-6.
26. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, April 1, 1991.
27. Memorandum, from Sucralose Working Group, to Rulis, Novel
Ingredients Branch, August 3, 1992.
28. Memorandum, from Sucralose Working Group, to Pauli, Novel
Ingredients Branch, December 21, 1992.
29. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, May 11, 1987.
30. Memorandum, from Bleiberg, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, October 20, 1987.
31. Memorandum, from Graham, Additives Evaluation Branch, to
Direct Additives Branch, August 3, 1987.
32. Submission to FAP 7A3987, McNeil Specialty Products, May 5,
1992.
33. Memorandum, from Barton, Experimental Design and Evaluation
Branch, to Anderson, Novel Ingredients Branch, April 26, 1994.
34. Memorandum, from Whiteside, Additives Evaluation Branch No.
2, to Anderson, Novel Ingredients Branch, June 29, 1994.
35. Memorandum, from Whiteside, Additives Evaluation Branch No.
2, to Anderson, Novel Ingredients Branch, July 8, 1994.
36. Memorandum, from Barton, Experimental Design and Evaluation
Branch, to Anderson, Novel Ingredients Branch, March 18, 1994.
37. Memorandum, from Hinton, Biochemical and Analytical Branch,
to Anderson, Novel Ingredients Branch, March 7, 1995.
38. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, February 17, 1988.
39. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, April 12, 1988.
40. Addendum Memorandum, from Whiteside, Additives Evaluation
Branch No. 2, to Anderson, Novel Ingredients Branch, May 26, 1995.
41. Memorandum, from Wilcox, Epidemiology Branch, to Anderson,
Novel Ingredients Branch, October 7, 1994.
42. Memorandum, from Whiteside, Scientific Support Branch, to
Anderson, Novel Ingredients Branch, November 13, 1997.
43. Memorandum, from Fleming, Center for Drug Evaluation and
Research, to Anderson, Novel Ingredients Branch, August 21, 1997.
44. Memorandum, from Barton, Division of Mathematics, to
Anderson, August 28, 1997.
45. Addendum Memorandum, from Whiteside, Scientific Support
Branch, to Anderson, Novel Ingredients Branch, November 13, 1997.
46. Memorandum, from Yetley/Einhorn, Clinical Nutrition Branch,
to Anderson, Director Additives Branch, January 8, 1990.
47. Comments, from supporters of the petition, to Dockets
Management Branch.
48. Comments, from Malkin Solicitors.
49. Comments, from Center for Science in the Public Interest
(CSPI).
50. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, December 13, 1990.
51. Memorandum, from Whiteside, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, November, 12, 1991.
52. Memorandum, from DiNovi, Food and Color Additives Review
Section, to Anderson, Direct Additives Branch, December 6, 1990.
53. Memorandum, from Modderman, Food and Color Additives Review
Section, to Anderson, Direct Additives Branch, May 20, 1988.
54. Memorandum, from Graham, Additives Evaluation Branch, to
Anderson, Direct Additives Branch, December 27, 1988.
55. Memorandum, from Glinsmann, Clinical Nutrition, to Anderson,
June 18, 1991.
VII. Objections
Any person who will be adversely affected by this regulation may at
any time on or before May 4, 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 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.
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by reference, Reporting and
recordkeeping requirements.
[[Page 16433]]
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 172.831 is added to subpart I to read as follows:
Sec. 172.831 Sucralose.
The food additive sucralose may be safely used as a sweetening
agent in foods 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 under the following conditions:
(a) Sucralose is the chemical 1,6-dichloro-1,6-dideoxy--D-
fructofuranosyl-4-chloro-4-deoxy--D-galactopyranoside (CAS
Reg. No. 56038-13-2).
(b) The additive meets the specifications of the ``Food Chemical
Codex,'' 4th ed. (1996), pp. 398-400, which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
are available from the the Division of Product Policy (HFS-206), Center
for Food Safety and Applied Nutrition, Food and Drug Administration,
200 C St. SW., Washington, DC 20204-0001, or may be examined at the
Center for Food Safety and Applied Nutrition's Library, 200 C St. SW.,
rm. 3321, Washington, DC 20204-0001, or the Office of the Federal
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
(c) The additive may be used as a sweetener in the following foods:
(1) Baked goods and baking mixes;
(2) Beverages and beverage bases;
(3) Chewing gum;
(4) Coffee and tea;
(5) Dairy product analogs;
(6) Fats and oils (salad dressing);
(7) Frozen dairy desserts;
(8) Fruit and water ices;
(9) Gelatins, puddings, and fillings;
(10) Jams and jellies;
(11) Milk products;
(12) Processed fruits and fruit juices;
(13) Sugar substitutes (for table use);
(14) Sweet sauces, toppings, and syrups;
(15) Confections and frostings.
(d) 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: March 30, 1998.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
[FR Doc. 98-8750 Filed 4-1-98; 8:45 am]
BILLING CODE 4160-01-F