[Federal Register Volume 79, Number 247 (Wednesday, December 24, 2014)]
[Rules and Regulations]
[Pages 77385-77387]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-30144]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. FDA-2009-F-0303]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; response to objections.

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SUMMARY: The Food and Drug Administration (FDA or we) is responding to 
objections we received on the final rule that amended the food additive 
regulations to provide for the safe use of advantame as a non-nutritive 
sweetener and flavor enhancer in foods generally, except in meat and 
poultry. After reviewing the objections to the final rule, we have 
concluded that they do not provide a basis for modifying or revoking 
the regulation. We are also confirming the effective date of May 21, 
2014, for the final rule.

DATES: The effective date of the final rule published on May 21, 2014 
(79 FR 29078), is confirmed: May 21, 2014.

FOR FURTHER INFORMATION CONTACT: Felicia M. Ellison, Center for Food 
Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740-3835, 240-402-1264.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of July 21, 2009 (74 FR 35871), we 
announced that a food additive petition (FAP 9A4778), had been filed by 
Ajinomoto Co., Inc., c/o Ajinomoto Corporate Services LLC, 1120 
Connecticut Ave. NW., suite 1010, Washington, DC 20036. The petition

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proposed to amend the food additive regulations in part 172, Food 
Additives Permitted for Direct Addition to Food for Human Consumption 
(21 CFR part 172), to provide for the safe use of advantame as a non-
nutritive sweetener in tabletop applications and powdered beverage 
mixes. Subsequently, in a letter dated August 24, 2012, the petitioner 
informed us that FAP 9A4778 had been transferred from Ajinomoto 
Corporate Services LLC to Ajinomoto North America, Inc., One Parker 
Plaza, 400 Kelby St., Fort Lee, NJ 07024.
    In an amended document published in the Federal Register of October 
26, 2012 (77 FR 65340), we announced that Ajinomoto Co., Inc., c/o 
Ajinomoto North America, Inc., One Parker Plaza, 400 Kelby St., Fort 
Lee, NJ 07024, had amended its food additive petition to provide for 
the safe use of advantame as a non-nutritive sweetener and flavor 
enhancer in foods generally, except in meat and poultry.
    In response to FAP 9A4778, we issued a final rule in the Federal 
Register on May 21, 2014 (79 FR 29078), permitting the safe use of 
advantame as a non-nutritive sweetener and flavor in foods generally, 
except in meat and poultry. This regulation is codified at Sec.  
172.803. We based our decision on data contained in the petition and in 
our files. In the preamble to the final rule (79 FR 29078 at 29079-
29084), we outlined the basis for our decision and stated that 
objections to the final rule and requests for a hearing were due within 
30 days of the publication date (i.e., by June 20, 2014).

II. Objections and Requests for a Hearing

    Section 409(f)(1) of the Federal Food, Drug, and Cosmetic Act (the 
FD&C Act) (21 U.S.C. 348(f)(1)) provides that, within 30 days after 
publication of an order relating to a food additive regulation, any 
person adversely affected by such order may file objections, 
``specifying with particularity the provisions of the order deemed 
objectionable, stating reasonable grounds therefor, and requesting a 
public hearing upon such objections.''
    Under 21 CFR 171.110, objections and requests for a hearing are 
governed by part 12 (21 CFR part 12) of FDA's regulations. Under Sec.  
12.22(a), each objection must meet the following conditions: (1) Must 
be submitted on or before the 30th day after the date of publication of 
the final rule; (2) must be separately numbered; (3) must specify with 
particularity the provision of the regulation or proposed order 
objected to; (4) must specifically state each objection on which a 
hearing is requested; failure to request a hearing on an objection 
constitutes a waiver of the right to a hearing on that objection; and 
(5) must include a detailed description and analysis of the factual 
information to be presented in support of the objection if a hearing is 
requested; failure to include a description and analysis for an 
objection constitutes a waiver of the right to a hearing on that 
objection.
    Following publication of the final rule permitting the use of 
advantame as a non-nutritive sweetener and flavor enhancer in foods 
generally, except meat and poultry, we received 12 submissions with 
objections to the rule within the 30-day objection period. The majority 
of these submissions were letters expressing concern regarding one or 
more of the following issues: (1) Labeling of products containing 
advantame, and (2) advantame being mistaken for aspartame. A few of the 
letters also expressed general opposition to the final rule, or 
objected to the rule based on adverse effects believed to have been 
caused by aspartame, and not advantame. None of these letters requested 
a hearing, nor provided evidence in support of any of these objections 
that could be considered factual information (Sec.  12.22(a)(5)). 
Therefore, these objections do not justify the modification or 
revocation of the regulation. We will not discuss these submissions 
further.
    There was one submission that raised a specific objection. The 
letter was from the Natural Resources Defense Council (NRDC) (letter to 
Docket No. FDA-2009-F-0303, June 20, 2014). The letter from NRDC did 
not request a hearing on their objection. Therefore, NRDC has waived 
its right to a hearing on their objection (see Sec.  12.22(a)(4)). The 
only remaining question under Sec.  12.24(a) is whether NRDC's 
objection, and the information submitted in support of the objection, 
establish that the regulation authorizing the use of advantame should 
be modified or revoked. As discussed in detail in section III, we have 
concluded that NRDC has not established a basis for modification or 
revocation of the regulation authorizing the use of advantame.

III. Analysis of Objection

    The objection raised by NRDC asserts that FDA did not comply with 
section 409 of the FD&C Act in our evaluation of the advantame petition 
because, they claim, we did not conduct a fair evaluation of the data 
before the Agency as required by section 409(c)(3) of the FD&C Act and 
did not consider the relevant safety factors as required by section 
409(c)(5). Specifically, NRDC states that advantame and the sweetener 
aspartame are structurally related and that FDA has stated that 
``advantame actually contains a small amount of aspartame.'' NRDC 
asserts that when we were considering potential effects of advantame, 
we considered the health effects of aspartame but did not consider the 
potential impacts of advantame on the hypothalamus despite having 
evidence that aspartame significantly altered that part of the brain. 
In support of their claim, NRDC cites five animal studies that they 
state are in FDA's possession and indicate aspartame affects the 
hypothalamus. NRDC requests that since the brain tissues from the key 
advantame animal studies were preserved, FDA should withdraw its 
approval of advantame until those tissues are examined for alteration 
of the hypothalamus and the implications on a child's developing brain 
are fully considered. In addition, NRDC claims that we did not comply 
with Executive Order 13045 regarding protection of children from 
environmental health risks and safety risks by not assessing the safety 
of advantame on a child's brain development.
    The issue of whether aspartame poses a risk of hypothalamic adverse 
effects, including endocrine dysfunction, was thoroughly addressed in 
the Commissioner's final decision on aspartame published in the Federal 
Register on July 24, 1981 (46 FR 38285). In that decision, the 
Commissioner affirmed the safety of aspartame as a nutritive sweetener 
and concluded that there is a reasonable certainty that human 
consumption of aspartame at projected consumption levels will not pose 
a risk to the brain, including endocrine function. We are not aware of 
any new relevant evidence to the contrary. NRDC has not provided any 
evidence that the effects on the hypothalamus in the aspartame studies 
they cited are toxicologically significant at the expected levels of 
intake of aspartame and, further, they have not provided evidence of 
the relevancy of this information to the safety of advantame.
    We disagree with NRDC's characterization of the relationship 
between advantame and aspartame. While advantame is structurally 
related to aspartame, and aspartame is used as one of the starting 
chemicals in the manufacture of advantame, which is what FDA was 
referring to in the language quoted by NRDC, the two sweeteners are 
chemically different and are metabolized differently in the human body. 
When aspartame is consumed, it is metabolized into its two

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constituent amino acids, phenylalanine and aspartic acid, and a small 
amount of methanol. By contrast, the primary metabolite of advantame is 
the de-esterified form of advantame, namely N-[N-[3-(3-hydroxy-4-
methoxyphenyl)propyl]-[alpha]-aspartyl]-L-phenylalanine. Because 
chemically these two sweeteners are different compounds, FDA's safety 
decision on advantame was based solely on studies conducted on 
advantame. Therefore, we did not consider the health effects of 
aspartame in our safety decision on advantame.
    Regarding concerns about possible effects of advantame on the 
hypothalamus, the hypothalamus is involved with endocrine control via 
the pituitary gland. Therefore, any long-lasting hypothalamic changes 
would affect the pituitary gland. For this reason, we recommend in our 
guidance ``Toxicological Principles for the Safety Assessment of Direct 
Food Additives and Color Additives Used in Food'' that the pituitary 
gland from subchronic and long-term animal studies be assessed for 
treatment-related changes. Consistent with our guidance, the pituitary 
gland was one of the organs evaluated in the animal studies on 
advantame that were considered in the final rule, and there was no 
evidence of toxicologically significant changes.
    As previously noted, NRDC has requested that we withdraw our 
approval of advantame until we examine the brain tissues from the key 
advantame animal studies that were preserved for alteration of the 
hypothalamus and fully consider the implications on a child's 
developing brain. NRDC has claimed that several studies on a different 
substance showed effects on the hypothalamus, but has not provided any 
information to support its view that additional histopathological 
examination of brain tissue samples is necessary to establish the 
safety of advantame. During our evaluation of the advantame petition, 
we thoroughly reviewed all of the data provided by the petitioner on 
the safety of advantame, including the results from a two-generation 
study in rats, a chronic (52-week) dog study, a 104-week mouse 
carcinogenicity study, and a combined 104-week rat carcinogenicity 
feeding study with in utero and chronic (52-week) phases, which 
included extensive histological evaluations of the brain, including the 
hypothalamus. In evaluating these studies, we applied the appropriate 
safety factors to extrapolate the findings from these animal studies to 
humans as required by section 409(c)(5) of the FD&C Act. We also 
considered the potential intake of advantame at both the mean and 90th 
percentile of consumption for various age groups, including children. 
Based on this exposure and toxicological information, the estimated 
levels of daily intake for even high consumers of advantame were far 
below (approximately 200 times) the acceptable daily intake level, 
establishing that advantame is safe for the general population, 
including children.
    NRDC's objection to the advantame final rule does not provide any 
new evidence or identify any evidence that we overlooked in our 
evaluation that would call into question FDA's determination of safety 
for advantame. Moreover, NRDC has not provided a basis for concluding 
that the information we evaluated is inadequate to support a finding 
that the use of advantame as a non-nutritive sweetener in food is safe. 
Therefore, this objection does not provide a basis for us to reconsider 
our decision to issue the final rule on advantame.

IV. Summary and Conclusion

    Section 409 of the FD&C Act requires that a food additive be shown 
to be safe before marketing. Under 21 CFR 170.3(i), a food additive is 
``safe'' if ``there is a reasonable certainty in the minds of competent 
scientists that the substance is not harmful under the intended 
conditions of use.'' In our May 21, 2014, final rule approving the use 
of advantame, we concluded that the data presented by the petitioner to 
establish safety of the additive demonstrate that advantame is safe for 
its intended use in food.
    The petitioner has the burden to demonstrate the safety of the 
additive to gain FDA approval. However, once we make a finding of 
safety, the burden shifts to an objector, who must come forward with 
evidence that calls into question our conclusion (see section 409(f)(1) 
of the FD&C Act). After evaluating the objection from NRDC, we have 
concluded that the objection does not provide any basis for us to 
reconsider our decision to issue the final rule permitting the use of 
advantame as a non-nutritive sweetener and flavor enhancer in foods 
generally, except meat and poultry. Accordingly, we are not making any 
changes in response to the objection.
    Therefore, we have determined that the final rule should not be 
modified or revoked based on the objections. Thus, we are confirming 
May 21, 2014, as the effective date of the regulation.

    Dated: December 18, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014-30144 Filed 12-23-14; 8:45 am]
BILLING CODE 4164-01-P