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PANTPA are, accordingly, beyond the under the PANTPA and the Act. The Amendments to the CBP Regulations scope of this rulemaking which deals likely respondents are business Accordingly, the interim rule with implementing the preferential tariff organizations including importers, amending parts 10, 24, 162, 163, and treatment and other customs-related exporters and manufacturers. 178 of the CBP regulations (19 CFR parts provisions of the Act. Accordingly, it The estimated average annual burden 10, 24, 162, 163, and 178), which was would be inappropriate for CBP to associated with the collection of published at 78 FR 63052 on October address the comment. information in this final rule is 500 23, 2013, is adopted as a final rule. Conclusion hours. Comments concerning the accuracy of this burden estimate and R. Gil Kerlikowske, After further review of the matter, and suggestions for reducing this burden Commissioner. in light of the one comment, CBP has should be directed to the Office of Approved: May 14, 2014. determined to adopt as final, with no Management and Budget, Attention: Timothy E. Skud, changes, the interim rule published in Desk Officer for the Department of the Deputy Assistant Secretary of the Treasury. the Federal Register (78 FR 63052) on Treasury, Office of Information and October 23, 2013. Regulatory Affairs, Washington, DC [FR Doc. 2014–11576 Filed 5–20–14; 8:45 am] BILLING CODE 9111–14–P Executive Order 12866 20503. A copy should also be sent to the Trade and Commercial Regulations This document is not a regulation Branch, Regulations and Rulings, Office subject to the provisions of Executive of International Trade, U.S. Customs DEPARTMENT OF HEALTH AND Order 12866 of September 30, 1993 (58 and Border Protection, 90 K Street NE., HUMAN SERVICES FR 51735, October 1993), because it 10th Floor, Washington, DC 20229– Food and Drug Administration pertains to a foreign affairs function of 1177. Under the Paperwork Reduction the United States and implements an Act, an agency may not conduct or 21 CFR Part 172 international agreement, as described sponsor and a person is not required to above, and therefore is specifically respond to a collection of information, [Docket No. FDA–2009–F–0303] exempted by section 3(d)(2) of unless it displays a valid OMB control Executive Order 12866. number. Food Additives Permitted for Direct Regulatory Flexibility Act Addition to Food for Human Signing Authority Consumption; Advantame CBP Dec. 13–17 was issued as an This document is being issued in interim rule rather than a notice of AGENCY: Food and Drug Administration, proposed rulemaking because CBP had accordance with § 0.1(a)(1) of the CBP HHS. regulations (19 CFR 0.1(a)(1)) pertaining determined that the interim regulations ACTION: Final rule. involve a foreign affairs function of the to the authority of the Secretary of the United States pursuant to § 553(a)(1) of Treasury (or his/her delegate) to SUMMARY: The Food and Drug the Administrative Procedure Act approve regulations related to certain Administration (FDA or we) is (APA). Because no notice of proposed CBP revenue functions. amending the food additive regulations rulemaking was required, the provisions List of Subjects to provide for the safe use of advantame of the Regulatory Flexibility Act, as as a non-nutritive sweetener and flavor amended (5 U.S.C. 601 et seq.), do not 19 CFR Part 10 enhancer in foods generally, except apply. Accordingly, this final rule is not Alterations, Bonds, Customs duties meat and poultry. This action is in subject to the regulatory analysis and inspection, Exports, Imports, response to a petition filed by requirements or other requirements of 5 Preference programs, Repairs, Reporting Ajinomoto Co., Inc. U.S.C. 603 and 604. and recordkeeping requirements, Trade DATES: This rule is effective May 21, 2014. See section IX for further Paperwork Reduction Act agreements. information on the filing of objections. 19 CFR Part 24 The collections of information Submit either electronic or written contained in these regulations have Accounting, Customs duties and objections and requests for a hearing by previously been reviewed and approved inspection, Financial and accounting June 20, 2014. The Director of the Office by the Office of Management and procedures, Reporting and of the Federal Register approves the Budget (OMB) in accordance with the recordkeeping requirements, Trade incorporation by reference of certain requirements of the Paperwork agreements, User fees. publications listed in the rule as of May Reduction Act (44 U.S.C. 3507) under 21, 2014. 19 CFR Part 162 control number 1651–0117, which ADDRESSES: You may submit either covers many of the free trade agreement Administrative practice and electronic or written objections and requirements that CBP administers, and procedure, Customs duties and requests for a hearing identified by 1651–0076, which covers general inspection, Penalties, Trade agreements. Docket No. FDA–2009–F–0303, by any recordkeeping requirements. The of the following methods: collections of information in these 19 CFR Part 163 regulations are in §§ 10.2003, 10.2004, Administrative practice and Electronic Submissions and 10.2007 of title 19 of the Code of procedure, Customs duties and Submit electronic objections in the Federal Regulations (19 CFR 10.2003, inspection, Exports, Imports, Reporting following way: 10.2004, and 10.2007). This information and recordkeeping requirements, Trade • Federal eRulemaking Portal: http:// is required in connection with general agreements. www.regulations.gov. Follow the recordkeeping requirements (§ 10.2007), instructions for submitting comments. as well as claims for preferential tariff 19 CFR Part 178 treatment under the PANTPA and the Administrative practice and Written Submissions Act and will be used by CBP to procedure, Exports, Imports, Reporting Submit written objections in the determine eligibility for tariff preference and recordkeeping requirements. following way:

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• Mail/Hand delivery/Courier (for FAP 9A4778 had been transferred from aspartame that is approved as a paper submissions): Division of Dockets Ajinomoto Corporate Services LLC to sweetener in foods generally, except Management (HFA–305), Food and Drug Ajinomoto North America, Inc., One meat and poultry, in accordance with Administration, 5630 Fishers Lane, Rm. Parker Plaza, 400 Kelby St., Fort Lee, NJ current good manufacturing practice, in 1061, Rockville, MD 20852. 07024. an amount not to exceed that reasonably Instructions: All submissions received In an amended notice published in required to accomplish the intended must include the Agency name and the Federal Register of October 26, 2012 technical effect, in foods for which Docket No. FDA–2009–F–0303 for this (77 FR 65340), we announced that standards of identity established under rulemaking. All objections received will Ajinomoto Co., Inc., c/o Ajinomoto section 401 of the FD&C Act (21 U.S.C. be posted without change to http:// North America, Inc., One Parker Plaza, 341) do not preclude such use (21 CFR www.regulations.gov, including any 400 Kelby St., Fort Lee, NJ 07024, had 172.829). Data in the petition show that personal information provided. For amended its food additive petition to advantame has a sweetening potency detailed instructions on submitting also provide for the safe use of that is approximately 20,000 times that objections, see the ‘‘Objections’’ heading advantame as a non-nutritive sweetener of sucrose, depending on its food of the SUPPLEMENTARY INFORMATION and flavor enhancer in foods generally, application (Ref. 1). The petitioner has section. except in meat and poultry. proposed the use of advantame in food Docket: For access to the docket to II. Evaluation of Safety of Advantame at levels not in excess of that reasonably read background documents or required to produce its intended objections received, go to http:// Under section 409(c)(3)(A) of the technical effect. We have reviewed www.regulations.gov and insert the Federal Food, Drug, and Cosmetic Act results from taste panel studies that docket number, found in brackets in the (the FD&C Act) (21 U.S.C. 348(c)(3)(A)), investigated the sweetness profile of heading of this document, into the a food additive cannot be approved for advantame as a function of ‘‘Search’’ box and follow the prompts a particular use unless a fair evaluation concentration in a variety of foods, and and/or go to the Division of Dockets of the data available to FDA establishes these data demonstrate that advantame Management, 5630 Fishers Lane, Rm. that the additive is safe for that use. can be used at self-limiting levels in 1061, Rockville, MD 20852. ‘‘Safe’’ or ‘‘safety’’ in the context of food food (Refs. 1 and 2). FOR FURTHER INFORMATION CONTACT: additives means that there is ‘‘a Based upon data from stability studies Felicia M. Ellison, Center for Food reasonable certainty in the minds of on advantame, we concluded that Safety and Applied Nutrition (HFS– competent scientists that the substance advantame is stable under normal 265), Food and Drug Administration, is not harmful under the intended storage and use conditions. The stability 5100 Paint Branch Pkwy., College Park, conditions of use’’ (21 CFR 170.3(i)). To studies show that degradation of MD 20740–3835, 240–402–1264. establish with reasonable certainty that advantame is pH-, time-, and SUPPLEMENTARY INFORMATION: a food additive is not harmful under its temperature-dependent and is more intended conditions of use, we consider likely to occur from its use in low pH Table of Contents the projected human dietary exposure to foods (i.e., acidic foods) during I. Background the additive, the additive’s toxicological extended storage conditions. Under II. Evaluation of Safety of Advantame data, and other relevant information such extreme conditions, the principal A. Chemistry and Intake Considerations of (such as published literature) available degradation product is N-[N-[3-(3- Advantame to us. We compare an individual’s B. Overview of Advantame Safety Studies hydroxy-4-methoxyphenyl)propyl]-a- C. Toxicology/Safety Assessment of estimated daily intake (EDI) of the aspartyl]-L-phenylalanine (ANS-acid), Advantame additive from all food sources to an which is the de-esterified form of D. Estimating an Acceptable Daily Intake of acceptable intake level established by advantame. As is the case with neotame, Advantame toxicological data. The EDI is the N-alkyl substituent effectively III. Comments determined by projections based on the prevents the common dipeptide IV. Conclusion amount of the additive proposed for use cyclization reaction that results in the V. Public Disclosure in particular foods and on data formation of a diketopiperazine VI. Environmental Impact regarding the amount consumed from VII. Paperwork Reduction Act of 1995 derivative (Refs. 1 to 3). VIII. Section 301(ll) of the FD&C Act all food sources of the additive. We Further, there is no concern from IX. Objections commonly use the EDI for the 90th exposure to these degradation products X. References percentile consumer of a food additive under either normal or extended storage as a measure of high chronic dietary and use conditions (Refs. 2 and 4). I. Background intake. The petitioner determined the eaters- In a notice published in the Federal only EDI of advantame (i.e., the EDI for Register of July 21, 2009 (74 FR 35871), A. Chemistry and Intake Considerations the population of study subjects that we announced that Ajinomoto Co., Inc., of Advantame consumed one or more of the foods c/o Ajinomoto Corporate Services LLC, Advantame is the common or usual containing the additive) from its 1120 Connecticut Ave. NW., Suite 1010, name for the chemical N-[N-[3-(3- proposed use as a general-purpose Washington DC, 20036, had filed a food hydroxy-4- methoxyphenyl)propyl]-a- sweetener and flavor enhancer at the additive petition (FAP 9A4778). The aspartyl]-L-phenylalanine 1-methyl 90th percentile of consumption to be 10 petition proposed to amend the food ester, monohydrate (CAS Reg. No. milligrams per person per day (mg/p/d) additive regulations in part 172 Food 714229–20–6). The additive is a white for the total U.S. population (all ages) Additives Permitted for Direct Addition to yellowish crystalline powder that is and 8.1 mg/p/d for children (3 to 11 to Food for Human Consumption (21 an N-substituted derivative of the years old). The corresponding mean CFR part 172), to provide for the safe sweetener aspartame (21 CFR 172.804), estimated intakes are 4.9 mg/p/d and 4.6 use of advantame as a non-nutritive with the amino nitrogen of aspartame mg/p/d, respectively. We concur with sweetener in tabletop applications and alkylated with a 3-hydroxy-4-methoxy the petitioner’s exposure estimate for powdered beverage mixes. phenyl moiety. Advantame also is advantame (Ref. 2). In a letter dated August 24, 2012, the similar to the sweetener neotame, We also estimated the eaters-only EDI petitioner informed us that the care of another N-substituted derivative of of the principal degradation product

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(ANS-acid), related impurities that may C. Toxicology/Safety Assessment of a-aspartyl]-L-phenylalanine; (4) the be formed during the manufacture of Advantame phenylalanine cleavage product of ANS9801-acid (HF–1), N-[3-(3-hydroxy- advantame, and related degradation 1. Pharmacokinetics and Metabolism of 4-methoxyphenyl)propyl]-L-a-aspartic products that may be formed under Advantame certain conditions in food. The eaters- acid; and (5) 3-(3-hydroxy-4- only EDI of the principal degradation The petitioner conducted methoxyphenyl) propylamine (HU–1). product, related impurities, and related pharmacokinetic and metabolism ANS9801-acid represented 40 percent studies in the rat, dog, and humans to degradation products at the 90th or more of the excreted metabolic support the safety of advantame for products in all species tested. HF–1 and percentile of consumption is 0.10 mg/p/ human use. The studies were designed HU–1 were other minor metabolites. d, 0.15 mg/p/d, and 0.20 mg/p/d, to address the metabolic fate (i.e., These metabolites likely are derived respectively, for the total U.S. absorption, distribution, metabolism, from ANS9801-acid in the intestines. In population (all ages); and 0.08 mg/p/d, and excretion) of advantame. humans, HF–1 and ANS9801-acid were 0.12 mg/p/d, and 0.16 mg/p/d, a. Absorption of advantame. the only metabolites identified in feces, respectively for children (3 to 11 years Pharmacokinetic parameters estimated at 30 ± 12 percent and 52 ± 13 percent old) (Ref. 2). from advantame study data show that of the dose, respectively. Other We also estimated the eaters-only absorption of advantame and its (uncharacterized) metabolites accounted dietary exposure to both advantame and metabolites occurs almost entirely in the for 0 to 3 percent of the dose in feces. its degradation products for other small intestine, and that the amount ANS9801-acid represented 43 percent of subpopulations, including various age absorbed can approach 15 percent in urinary radioactivity, with HU–1 and humans. Advantame absorption rates groups of children, and have concluded HF–1 representing 35 percent and 19 varied 2- to 4-fold between individuals. that the exposure estimated for the U.S. percent of the urinary radioactivity, The rat and dog appeared to absorb less respectively. The remaining 2 to 3 population (all ages) represents the advantame than humans (8 to 15 upper-bound cumulative dietary percent of urinary radioactivity percent as compared to humans). consisted of uncharacterized exposure to advantame and its Absorption of advantame was limited by metabolites. Overall, 82 to 100 percent degradation products from food (Ref. 2). rapid intestinal hydrolysis of the methyl of the radioactivity was accounted for in B. Overview of Advantame Safety ester in all species. these studies, which is within the Studies b. Distribution of advantame. The acceptable range of recoveries for petitioner conducted studies with pharmacokinetic studies. In support of the safety of advantame, radiolabelled advantame to identify Methanol and phenylalanine both are the petitioner submitted 37 preclinical which organs might accumulate released during the metabolism of (animal), clinical (human subjects), and advantame or its metabolites if advantame. The metabolism studies specialty toxicology studies, along with absorbed. In the rat, the radiolabelled provided by the petitioner indicated several additional exploratory or advantame was found primarily in the that most advantame residues excreted screening studies. All pivotal preclinical organs of absorption (gastrointestinal in the feces and urine are in the form (GI) tract), metabolism (liver), and studies were conducted in accordance of the metabolite ANS9801-acid. At the excretion (GI tract, kidneys, and urinary with our Good Laboratory Practice EDI for advantame, it is unlikely that bladder). Low levels of radioactivity (GLP) regulations appearing in 21 CFR even 100 percent conversion of were observed in all other tissues. advantame to methanol or part 58, or in accordance with other Distribution of radiolabelled advantame phenylalanine would affect internationally accepted GLP standards. in the dog was studied after oral dosing physiological levels of methanol or The preclinical studies included in and was dominated by high phenylalanine. Therefore, we conclude vivo short-term, sub-chronic, and concentrations of radioactivity in the that the amounts of methanol and chronic studies in the rat, mouse, rabbit, organs of absorption, followed by phenylalanine released from and dog, including reproductive and excretory organs, such as the liver and metabolism of advantame do not developmental studies in the rat and kidneys. There was very little represent a safety concern (Ref. 5). rabbit. The safety data also included radioactivity detected in other tissues. d. Excretion of advantame. neurotoxicity and immunotoxicity In a study using radiolabelled Advantame and its metabolites were studies in the rat; pharmacokinetic advantame in pregnant rats, low levels rapidly eliminated from the rat and studies in the mouse, rat, and dog; of radioactivity were observed in the human. The findings were similar in carcinogenicity studies in the mouse placenta, with no radioactivity observed dogs, with the exception of the and rat; and a series of in vitro in the fetuses. Based on these findings, excretion of the metabolite ANS-a-SO4, we conclude there is no concern for which was eliminated more slowly. mutagenicity and genotoxicity studies. possible accumulation of advantame or Advantame has an approximate half-life The petitioner also submitted studies its metabolites at expected human (the amount of time required for a assessing tolerance in the rabbit and intake levels. quantity of a substance to fall to half its dog, and palatability in the mouse. c. Metabolism of advantame. Data initial value) of less than 60 minutes In addition, the petitioner submitted from metabolism studies using after absorption in humans. The four clinical studies that examined radiolabelled advantame in the rat, dog, metabolite ANS9801-acid has a half-life tolerance, absorption, distribution, and human volunteers showed five of 3 to 5 hours in humans. Ultimately, metabolism, and excretion (ADME) of metabolites: (1) The methyl ester 90 to 95 percent of absorbed advantame advantame in human subjects. Subjects hydrolysis product (ANS9801-acid); (2) is excreted in the feces and urine within in the ADME studies included healthy a sulfate conjugate of ANS9801-acid 24 hours of absorption. Based on the adult males and females, as well as (ANS-a-SO4), N-[N-[3-(3-sulfoxy-4- review findings from the metabolism adult males and females with type 2 methoxyphenyl)propyl]-L-a-aspartyl]-L- and pharmacokinetic studies on diabetes. phenylalanine; (3) de-methyoxylated advantame, there is no indication that metabolite of ANS9801-acid (RF–1), N- advantame or its metabolites will [N-[3-(3,4-dihydroxyphenyl)propyl]-L- accumulate in humans. In addition,

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given the rapid rates of excretion, there a 4-week and a 13-week rat study, that in the same volunteers. We concluded is no indication that advantame or its evaluated the immunotoxicity potential that the oral administration of metabolites will accumulate in the body of advantame. Findings related to advantame was tolerable in healthy from the proposed uses of advantame various immune responses in these rat adult male subjects when administered (Ref. 3). The potential intake of the studies initially appeared to represent as a single dose at each dose level primary metabolite, the ANS9801-acid, potential immunotoxicity responses without the occurrence of any as well as other minor metabolites is of (Ref. 7). After further evaluation, we treatment-related adverse events during no toxicological consequence. determined that the lymphocyte a subsequent 7-day observation period Therefore, we conclude that the reduction observed in the studies was (Ref. 10). Based on this study, we metabolism and pharmacokinetic due to individual animal variations and concluded that advantame is well studies of advantame do not raise any not to treatment with advantame. We tolerated in healthy human males. safety concerns (Ref. 5). also evaluated the reported low thymic The second clinical study was weights in the high-dose groups of both conducted to characterize the metabolic 2. Neurotoxicity and Immunotoxicity sexes for the 4-week study and profile of advantame in urine and feces Assessment of Advantame concluded that this change was in human subjects. This study The petitioner investigated the consistent with a non-specific high-dose investigated the absorption, metabolism, potential neurotoxicity of advantame in stress response because it was limited to and excretion of radiolabelled rats. Within each of the standard the high-dose groups and affected only advantame after a single oral dose at toxicology studies submitted, the a few animals. We reviewed the 0.25 mg/kg bw in six healthy adult male petitioner also reported physical, seemingly dose-related degenerative volunteers. In this study, systemic behavioral, and clinical observations for changes in the thymuses of the 13-week absorption of advantame was reported each animal, followed by extensive female groups and determined that this to be in the range of 9 to 30 percent (Ref. histological evaluations of brain, spinal change likely was incidental because it 10). We concluded that data on the cord, and peripheral nerves. Data on was not reported in either the 4-week or pharmacokinetic profile of advantame critical prenatal neurological 2-year rat studies. Overall, we from this study, although limited, was development were examined in the in concluded that the immunological useful in our evaluation of the safety of utero phase of the carcinogenicity/ findings observed in the two rat studies advantame. Based on this study, we chronic toxicity studies in rats. No did not have any toxicological have no safety concerns with the treatment-related neurotoxicological significance as there was no evidence of absorption, metabolism, or excretion of effects or abnormal behaviors were seen a treatment-related immunotoxic advantame as it was well tolerated in in animals that were exposed to response (Ref. 8). Based on these human subjects. advantame in these studies. evaluations, we concluded that The third clinical study was In addition to examining various advantame did not cause conducted to investigate the tolerability general endpoints related to immunotoxicological effects within the of repeated daily consumption of a 30 neurological systems within standard context of these rat studies (Ref. 4). mg dose of advantame (equivalent to toxicology studies, the petitioner The petitioner conducted an 0.375 mg/kg bw/day to 0.5 mg/kg bw/ conducted a neurobehavioral study in additional immunotoxicity study in the day) over a period of 4 weeks using six which rats were fed diets containing 10, same rat strain used in the 4-week and healthy subjects of each sex. The study 100, or 1,000 milligrams per kilogram 13-week rat studies. In this study, rats also included a placebo control group body weight (mg/kg bw) of advantame. were fed diets containing 0 mg/kg bw consisting of six healthy subjects of each One group of rats was fed a diet (control); 1,500 mg/kw bw; 5,000 mg/kg sex that received diets without containing 3 mg/kg bw of amphetamine bw; and 15,000 mg/kg bw of advantame advantame. Based on results of the sulfate as a positive control. Locomotor for 4 weeks. Groups of 10 rats of each study, we concluded that, although activity of the rats was measured for 10 sex were examined at the end of there were apparent small differences in minutes at each dose interval beginning treatment, as well as after a 30-day blood plasma values of the main with the pre-dose period followed by recovery period. No treatment-related metabolite of advantame, ANS9801- measurements performed at 30, 60, 180, effects were detected in the various acid, the differences were not due to and 300 minutes post-dose. The study immunological parameters examined, randomization procedures of the study authors concluded that there were no including lymphocyte counts, thymus and, instead, were reflective of within- significant effects of advantame on weights, immunophenotyping of subject variability inherent in the spontaneous locomotor activity at any lymphocytes, and lymphocyte subjects of the study (Ref. 10). We dose level under the conditions of the proliferation assay, in the study. Based concluded advantame was well study. on these data, we concluded that tolerated in these subjects and that there Based on the lack of effect on rat advantame did not produce any were no safety concerns. locomotor activity of advantame given immunotoxic effects under the The fourth clinical study was at the highest dose, we concluded that conditions of this study (Ref. 9). conducted as a double blind, placebo- the No Observed Effect Level (NOEL) controlled study in diabetic subjects under the conditions of this study was 3. Human Clinical Studies designed to investigate the tolerability 1,000 mg/kg bw (Ref. 6). Given the lack The petitioner submitted four human of repeated daily consumption of a 30 of signs of neurotoxicity, as well as an clinical studies as part of the safety data mg dose (equivalent to 0.375 mg/kg bw/ absence of histopathological change in for advantame to demonstrate tolerance day to 0.5 mg/kg bw/day) of advantame the central nervous system (brain and of the sweetener in humans. The first fed daily for 12 weeks, using 18 diabetic spinal cord) and peripheral nerves in clinical study was conducted to subjects of each sex per group. Diabetic any of the treated animals, we conclude investigate the tolerability of advantame subjects in the placebo-controlled group that the neurotoxicity studies of when administered orally to healthy received diets without advantame. advantame do not raise safety concerns adult males at dose levels of 0.1 mg/kg Based on the results of this study, we (Ref. 4). bw, 0.25 mg/kg bw, and 0.35 mg/kg bw. noted that there were no clinically The petitioner presented data for two The study also investigated the significant changes identified. We general, repeat-dose toxicology studies, pharmacokinetic profile of advantame concluded that advantame was tolerated

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at daily doses up to 0.5 mg/kg bw/day 104-week mouse carcinogenicity study, rodent species. The only clinical sign in people with type 2 diabetes. and (4) a combined 104-week rat related to advantame treatment was the We raised concerns about the carcinogenicity feeding study with in observation of pale feces in all high- experimental design (e.g., sample size utero and chronic (52-week) phases. dose and some mid-dose dogs of both and the randomization procedures) in a. Two-generation reproduction study sexes. We established a NOAEL for this some of the clinical studies (Ref. 10). in the rat. Reproductive performance study at the 50,000 ppm dose of However, overall, we ultimately and fertility were assessed over two advantame, the highest dose tested, concluded that advantame was well- generations in rats fed diets containing equivalent to 2,058 mg/kg bw/day in tolerated in healthy males when fed a advantame at levels of 2,000 ppm, male dogs and 2,139 mg/kg bw/day in single dose of advantame at dose levels 10,000 ppm, or 50,000 ppm. The female dogs (Refs. 4 and 12). We also of 0.1 mg/kg bw/day to 0.5 mg/kg bw/ parental rats received the advantame concluded that systemic toxicity in the day. The third and fourth clinical diet for 10 weeks before pairing and test animals associated with advantame studies showed that advantame was during mating. Parental and first administration was not apparent. tolerated in healthy males and females generation female rats continued to c. The 104-week mouse and type 2 diabetic males and females receive the advantame treatment carcinogenicity study. The when repeatedly fed a dose of 0.375mg/ throughout gestation, lactation, and carcinogenicity potential of advantame kg bw/day to 0.5 mg/kg bw/day for 4 until death. A control group of rats was evaluated in mice (64/sex/group). weeks. The doses administered in the received the untreated basal diet for the The mice were fed diets containing third and fourth studies were same period of time. The first generation advantame at levels of 0 ppm, 2,000 approximately 3-fold higher than the contained 25 male and 25 females from ppm, 10,000 ppm, or 50,000 ppm for EDI for consumers of all ages at the 90th each of the parent groups and received 104 weeks beginning when they were percentile of consumption (Ref. 10). advantame at the same dietary approximately 6 weeks old. One Pharmacokinetic evaluations of concentrations as their parents hundred seventy-three male and 177 advantame were conducted on blood throughout the study until termination. female mice died or were euthanized at plasma samples from the human Direct treatment of the first generation the point of near death over the study subjects that received single and repeat rats began at 4 weeks of age for 10 weeks period. A statistically significant effect dose administrations of advantame. Data before pairing and mating for the second of treatment on the distribution of from these analyses showed that generation litters. The first generation deaths in the various dosing groups advantame was undetectable in plasma continued treatment until termination compared to the controls was not samples 4 hours after its administration. after the second generation litters were reported. The study’s authors noted that The repeat dosing studies showed weaned. the high death rate was not altered by variation in the plasma levels of Under the conditions of this study, the administration of advantame and ANS9801-acid for some subjects. The advantame administration to rats did that no specific factors that contributed significance of this variability could not not produce any effects on mortality, to this rate were greater in number in be determined because of the small body weight, estrous cycle, sperm the experimental groups compared to number of subjects examined. However, motility, mating, fertility, duration of the control groups. the variable ANS9801-acid levels were gestation, outcome of parturition, litter We noted a low survival rate of the not associated with any clinically size, sex ratio, pup birth weights, test animals, a common finding in 2- significant, treatment-related toxicity in survivability of pups, motor activity of year bioassays using the CD–1 mouse, these subjects. pups, organ weights, or histopathology and a number of various clinical signs Clinically significant treatment- in either generation. However, at the in both the control and treated mice related toxicities or adverse events were 50,000 ppm dose level, statistically (Ref. 13). Our evaluation of the mouse not noted in the advantame-treated significant increased feed consumption survival data revealed no evidence of groups in any of these clinical studies. in the advantame treated rats compared premature deaths that were due to Overall, the clinical studies showed that to the control rats during the maturation treatment and none of the findings oral administration of advantame was phases (before pairing) of parental males indicated a proliferative response as the tolerated in humans fed up to 30 mg per and first generation males and females cause of early death in these mice. We day (Ref. 10). was reported. This increased feed considered the data available up to the consumption, in the absence of any 92-week observation period and 4. Critical Toxicology Studies effect on feed conversion efficiency and determined that 25 or more surviving We reviewed all studies and body weight gain, was not considered animals per group was adequate to supplemental information submitted by toxicologically significant (Refs. 4 and evaluate the carcinogenic potential for the petitioner. During our review, we 11). Based upon the findings, we advantame. We concluded that none of determined that certain studies were established a No Observed Adverse the clinical signs observed correlated more pivotal in supporting a regulatory Effect Level (NOAEL) at the 50,000 ppm consistently with a histomorphological decision on the petitioned uses of dose for advantame-treated rats in this diagnosis or were an indication of advantame. We based our determination study. treatment-related toxicity (Ref. 14). on the experimental design of the b. Chronic (52-week) study in dogs. The Center for Food Safety and studies as well as the types of the Chronic toxicity of advantame was Applied Nutrition’s Cancer Assessment studies’ endpoints. We gave greater evaluated in beagle dogs that were fed Committee (CAC) evaluated data from weight to the studies that examined the diets containing advantame at levels of the 104-week mouse study for the reproductive and developmental effects, 0 ppm, 2,000 ppm, 10,000 ppm, and carcinogenic potential of advantame. long-term exposure, chronic toxicity, 50,000 ppm over a 52-week period using The CAC concluded that oral carcinogenicity potential, and four dogs/per sex/per group. Two administration of advantame at doses up investigations of specific toxicological additional dogs per sex were assigned to to 50,000 ppm for 104 weeks did not issues presented by these studies. The each dose group as part of a 6-week produce any treatment-related tumors or critical studies were: (1) A two- recovery phase without advantame. This any evidence of increased incidences of generation reproduction study in rats; study was performed to evaluate tumors in mice (Ref. 15). We established (2) a chronic (52-week) dog study; (3) a systemic toxicity of advantame in non- a NOEL for female mice of 10,000 ppm

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advantame in the diet (based on abilities to mate and give birth also were in this context, refers to the exposure of decreased weight gain at 50,000 ppm) evaluated in the parent rats. The the developing embryo-fetus within the and a NOEL of 50,000 ppm advantame numbers of offspring, sex ratios, and womb (uterus) of the mother (Parental in the diet for male mice, equivalent to litter weights were recorded for the first F0 females).) Two animals died during 5,693 mg/kg bw/day (Ref. 16). generation offspring. the course of the treatment phase. These d. Combined 104-week rat Results from the in utero phase of the deaths, however, were not dose related. carcinogenicity study with in utero rat study showed that: (1) Fertility, One male in the high-dose group died phase and toxicity phase. This study growth, and survival in the parent rats during the recovery phase. included three phases: (1) An in utero was unaffected by advantame treatment; The CAC evaluated data from the 104- reproduction phase; (2) a 52-week (2) body weights and feed consumption week rat carcinogenicity study for the chronic toxicity phase; and (3) a 104- in the treated parent groups were carcinogenic potential of advantame. week oral carcinogenicity phase. In each similar to that seen in the control rats; The CAC concluded that oral of the study phases, rats were fed diets and (3) initial body weights of the first administration of advantame at doses up containing advantame at levels of 2,000 generation rats that were selected for to 50,000 ppm for 104 weeks did not ppm, 10,000 ppm, or 50,000 ppm. The either the carcinogenicity study or the produce any treatment-related tumors or control groups of rats received a similar 52-week toxicity study were not affected any evidence of increased incidences of diet without advantame for the same by exposure to advantame during tumors in rats (Ref. 15). We established period of time. The in utero preconception, in utero, or during a NOAEL for this study of 50,000 ppm reproduction phase of this study was weaning. advantame in the diet, equivalent to an designed to generate and assess The chronic toxicity phase of this achieved dose of 3,279 and 4,025 mg/kg populations of rats that had been study consisted of three advantame bw/day in males and females, exposed to advantame prior to mating, treatment groups of first generation rats respectively (Ref. 16). We also during mating, and throughout gestation selected from the in utero study, with 20 concluded that advantame treatment did and lactation up to weaning and the of each sex per group. The rats were fed not result in an increased incidence of start of the main chronic and diets containing advantame at levels of tumors in rats. carcinogenicity studies. Four-week-old 2,000 ppm, 10,000 ppm, and 50,000 Based on our review of the previously offspring produced during the parent ppm. A group of untreated first mentioned critical studies, we mating were used to populate the first generation rats not exposed to concluded that there is no cause for generation that was subsequently used advantame was selected to serve as concern regarding the carcinogenicity in the 104-week carcinogenicity study controls for this 52-week phase of the potential of advantame as proposed for and in the 52-week chronic toxicity rat study. An additional 10 rats of each sex its use as a non-nutritive sweetener and study. Offspring that did not meet the were added to the control group and the flavor enhancer in foods. survival criteria or had abnormal 10,000 ppm and 50,000 ppm treatment bodyweights were not used, and where groups to provide animals for a 6-week D. Estimating an Acceptable Daily possible, the numbers of surviving recovery phase without advantame Intake of Advantame offspring per litter were reduced by following their initial advantame In determining an acceptable daily random selection to four males and four exposure period (week 0 to week 52). intake (ADI) for a new ingredient, we females per litter. Adult parent males The study’s authors reported no effect rely on a comprehensive evaluation of were killed after mating; adult parent of the administration of advantame on all relevant studies and information females were killed after litters were mortality, maternal body weight gain submitted by the petitioner. Four weaned. Body weights, feed and feed consumption, fertility, or on studies had the greatest impact in our consumption, and survival rates were the growth and survival of offspring reaching a safety decision. These studies evaluated in the parent rats. The during the in utero phase. (‘‘In utero,’’ are highlighted in table 1.

TABLE 1—SUMMARY OF STUDY DATA PERTINENT TO ESTABLISHING AN ACCEPTABLE DAILY INTAKE VALUE FOR ADVANTAME

Pivotal 1 NOEL 2 NOAEL 3 Study Dose range (ppm) Endpoint (ppm) (ppm)

Rat two-generation reproductive study ...... 0, 2,000, 10,000, 50,000 ...... ND 10,000 50,000 Dog 52-week study ...... 0, 2,000, 10,000, 50,000 ...... ND 10,000 50,000 Mouse 2-year bioassay ...... 0, 2,000, 10,000, 50,000 ...... ND 10,000 50,000 Rat 2-year bioassay with in utero and 1-year chron- 0, 2,000, 10,000, 50,000 ...... ND 10,000 50,000 ic phase. 1 ND = None Detected. 2 NOEL = No Observed Effect Level. 3 NOAEL = No Observed Adverse Effect Level.

Based on our review of the studies chronic exposure, potential toxicity, and total number of animals in each dose summarized in table 1, we determined potential carcinogenicity of advantame. group (20 animals of each sex per group the most appropriate study for Therefore, the data from the 1-year for the chronic phase with 10 additional establishing an ADI for advantame was chronic phase of this study was chosen animals of each sex for groups in the the combined 104-week rat to determine the ADI. The primary recovery phase), and the high overall carcinogenicity study with in utero and reasons for selecting it were its length animal survival rate. In addition, the chronic (52-week) phases. This study (52-weeks) and the inclusion of a 6- results from the 2-year phase showed no was of sufficient length and overall week recovery phase (control, 10,000 indication that advantame is complexity to produce information on ppm, and 50,000 ppm dose groups), the carcinogenic.

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Based on the NOAEL for the 1-year VII. Paperwork Reduction Act of 1995 hearing on that objection. If you request chronic toxicity study, we concluded This final rule contains no collection a hearing, your objection must include that the appropriate ADI for advantame of information. Therefore, clearance by a detailed description and analysis of is 1,970 mg/p/d (Ref. 4). This level is the Office of Management and Budget the specific factual information you significantly higher than the EDI for under the Paperwork Reduction Act of intend to present in support of the advantame of 10 mg/p/d for humans of 1995 is not required. objection in the event that a hearing is all ages at the 90th percentile. held. If you do not include such a VIII. Section 301(ll) of the FD&C Act description and analysis for any III. Comments Our review of this petition was particular objection, you waive the right We received two comments in limited to section 409 of the FD&C Act. to a hearing on the objection. response to the advantame food additive This final rule is not a statement It is only necessary to send one set of petition. One comment merely regarding compliance with other documents. Identify documents with the expressed support for the petitioned use sections of the FD&C Act. For example, docket number found in brackets in the of advantame, providing that safety is the Food and Drug Administration heading of this document. Any shown and the substance is properly Amendments Act of 2007, which was objections received in response to the declared when used as an ingredient in signed into law on September 27, 2007, regulation may be seen in the Division food. The other comment stated that amended the FD&C Act to, among other of Dockets Management between 9 a.m. they did not object to the petition, but things, add section 301(ll) of the FD&C and 4 p.m., Monday through Friday, and rather to the use of advantame as a Act (21 U.S.C. 331(ll)). Section 301(ll) of will be posted to the docket at http:// flavoring substance in food prior to a the FD&C Act prohibits the introduction www.regulations.gov. premarket approval for use as a or delivery for introduction into X. References sweetener and flavor enhancer without interstate commerce of any food that declaring advantame as an ingredient on contains a drug approved under section The following references have been the food label. Because this comment is 505 of the FD&C Act (21 U.S.C. 355), a placed on display in the Division of not relevant to the safety of advantame, biological product licensed under Dockets Management (see ADDRESSES) it has no bearing on our evaluation of section 351 of the Public Health Service and may be seen by interested persons the advantame petition. Act (42 U.S.C. 262), or a drug or between 9 a.m. and 4 p.m., Monday biological product for which substantial through Friday, and are available IV. Conclusion clinical investigations have been electronically at http:// www.regulations.gov. We have evaluated the data and other instituted and their existence has been information submitted by the petitioner made public, unless one of the 1. Memorandum from H. Lee, Division of in support of the safe use of advantame exemptions in section 301(ll)(1) to (ll)(4) Petition Review, CFSAN, FDA to F. of the FD&C Act applies. In our review Ellison, Division of Petition Review, as a general-purpose sweetener and CFSAN, FDA, July 28, 2009. flavor enhancer in food and conclude of this petition, we did not consider whether section 301(ll) of the FD&C Act 2. Memorandum from H. Lee, Division of that there is a reasonable certainty that Petition Review, CFSAN, FDA to F. the substance is not harmful under the or any of its exemptions apply to food Ellison, Division of Petition Review, petitioned conditions of use. Therefore, products containing this food additive. CFSAN, FDA, December 26, 2012. we conclude that the food additive Accordingly, this final rule should not 3. Memorandum from H. Lee, Division of regulations should be amended as set be construed to be a statement that a Petition Review, CFSAN, FDA to F. forth in this document. product containing this food additive, if Ellison, Division of Petition Review, introduced or delivered for introduction CFSAN, FDA, November 24, 2009. V. Public Disclosure into interstate commerce, would not 4. Memorandum from T. S. Thurmond, violate section 301(ll) of the FD&C Act. Division of Petition Review, CFSAN, In accordance with § 171.1(h) (21 CFR Furthermore, this language is included FDA to F. Ellison, Division of Petition Review, CFSAN, FDA, May 14, 2013. 171.1(h)), the petition and the in all food additive final rules that documents that we considered and 5. Memorandum from W. Roth, Division of pertain to food and therefore should not Food Contact Notification, CFSAN, FDA relied upon in reaching our decision to be construed to be a statement of the approve the petition will be made to F. Ellison, Division of Petition Review, likelihood that section 301(ll) of the CFSAN, FDA, January 22, 2013. FOR available for public disclosure (see FD&C Act applies. 6. Memorandum from T. Walker, Division of FURTHER INFORMATION CONTACT). As Petition Review, CFSAN, FDA to F. provided in § 171.1(h), we will delete IX. Objections Ellison, Division of Petition Review, from the documents any materials that If you will be adversely affected by CFSAN, FDA, December 8, 2011. are not available for public disclosure. one or more provisions of this 7. Memorandum from S.K. Park, Division of regulation, you may file with the Petition Review, CFSAN, FDA to F. VI. Environmental Impact Ellison, Division of Petition Review, Division of Dockets Management (see CFSAN, FDA, April 18, 2011. We have carefully considered the ADDRESSES) either electronic or written 8. Memorandum from S. Francke-Carroll and potential environmental effects of this objections. You must separately number S. Mog, Senior Science and Policy Staff, action and have concluded that it will each objection, and within each CFSAN, FDA to T.S. Thurmond, S.K. not have a significant impact on the numbered objection you must specify Park, and C. Whiteside, Division of human environment, and that an with particularity the provision(s) to Petition Review, CFSAN, FDA, March environmental impact statement is not which you object, and the grounds for 17, 2011. required. FDA’s finding of no significant your objection. Within each numbered 9. Memorandum from S. Francke-Carroll and impact and the evidence supporting that objection, you must specifically state S. Mog, Senior Science and Policy Staff, CFSAN, FDA to C. Whiteside, T.S. finding, contained in an environmental whether you are requesting a hearing on Thurmond, and S.K. Park, Division of assessment, may be seen in the Division the particular provision that you specify Petition Review, CFSAN, FDA, March 1, of Dockets Management (see ADDRESSES) in that numbered objection. If you do 2013. between 9 a.m. and 4 p.m., Monday not request a hearing for any particular 10. Memorandum from C. Whiteside, through Friday. objection, you waive the right to a Division of Petition Review, CFSAN,

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FDA to F. Ellison, Division of Petition Additive Safety (HFS–200), Center for DEPARTMENT OF DEFENSE Review, CFSAN, FDA, February 7, 2013. Food Safety and Applied Nutrition, 11. Memorandum from A. Khan, Division of 5100 Paint Branch Pkwy., College Park, Office of the Secretary Petition Review, CFSAN, FDA to F. Ellison, Division of Petition Review, MD 20740. Copies may be examined at [DOD–2012–OS–0105] the Food and Drug Administration’s CFSAN, FDA, June 22, 2010. RIN 0720–AB58 12. Memorandum from T. Walker, Division of Main Library, 10903 New Hampshire Petition Review, CFSAN, FDA to F. Ave., Bldg. 2, Third Floor, Silver Spring, 32 CFR Part 199 Ellison, Division of Petition Review, MD 20993, 301–796–2039, or at the CFSAN, FDA, December 27, 2011. National Archives and Records TRICARE Revision to CHAMPUS DRG- 13. Memorandum from I. Chen, Division of Based Payment System, Pricing of Petition Review, CFSAN, FDA to F. Administration (NARA). For Ellison, Division of Petition Review, information on the availability of this Hospital Claims material at NARA, call 202–741–6030 or CFSAN, FDA, May 24, 2010. AGENCY: Office of the Secretary, 14. Memorandum from S. Francke-Carroll go to: http://www.archives.gov/federal- Department of Defense. and S. Mog, Senior Science and Policy register/cfr/ibr-locations.html. Staff, CFSAN, FDA to C. Whiteside and ACTION: Final rule. A. Khan, Division of Petition Review, (1) Assay for advantame, not less than CFSAN, FDA, March 17, 2011. 97.0 percent and not more than 102.0 SUMMARY: This Final rule changes 15. Memorandum from A. Khan, Division of percent on a dry basis. TRICARE’s current regulatory provision Petition Review, CFSAN, FDA to F. (2) Free N-[N-[3-(3-hydroxy-4- for inpatient hospital claims priced Ellison, Division of Petition Review, methoxyphenyl)propyl]-a-aspartyl]-L- under the DRG-based payment system. CFSAN, FDA, March 3, 2012. Claims are currently priced by using the phenylalanine, not more than 1.0 16. CFSAN Cancer Assessment Committee rates and weights that are in effect on a percent. Full Committee Review, Carcinogenicity beneficiary’s date of admission. This Evaluation of Advantame, April 27, (3) Total other related substances, not 2012. Final rule changes that provision to more than 1.5 percent. price such claims by using the rates and List of Subjects in 21 CFR Part 172 (4) Lead, not more than 1.0 milligram weights that are in effect on a Food additives, Incorporation by per kilogram. beneficiary’s date of discharge. reference, Reporting and recordkeeping (5) Water, not more than 5.0 percent. DATES: requirements. Effective Date: This Final rule is (6) Residue on ignition, not more than effective June 20, 2014. Therefore, under the Federal Food, 0.2 percent. Drug, and Cosmetic Act and under Applicability Date: This rule applies authority delegated to the Commissioner (7) Specific rotation, determined at to claims with a discharge date of ° ¥ ¥ ° of Food and Drugs, 21 CFR part 172 is 20 C [a]D: 45.0 to 38.0 calculated October 1, 2014, or later from hospitals amended as follows: on a dry basis. paid by TRICARE under the Inpatient (c) The food additive advantame may Prospective Payment System/Diagnosis- Related Groups-based payment system. PART 172—FOOD ADDITIVES be safely used as a sweetening agent and PERMITTED FOR DIRECT ADDITION flavor enhancer in foods generally, FOR FURTHER INFORMATION CONTACT: Ms. TO FOOD FOR HUMAN except in meat and poultry, in Amber Butterfield, TRICARE CONSUMPTION accordance with current good Management Activity, Medical Benefits and Reimbursement Office, telephone ■ manufacturing practice, in an amount 1. The authority citation for 21 CFR (303) 676–3565. part 172 continues to read as follows: not to exceed that reasonably required to achieve the intended technical effect, SUPPLEMENTARY INFORMATION: Authority: 21 U.S.C. 321, 341, 342, 348, in foods for which standards of identity 371, 379e. I. Dates established under section 401 of the ■ The effective date above is the date 2. Add § 172.803 to subpart I to read Federal Food, Drug, and Cosmetic Act as follows: that the policies herein take effect and do not preclude such use. are considered to be officially adopted. § 172.803 Advantame. (d) If the food containing the additive The applicability date, which is (a) Advantame is the chemical N-[N- purports to be or is represented to be for different than the effective date, is the [3-(3-hydroxy-4- special dietary use, it must be labeled in date on which the policies adopted in methoxyphenyl)propyl]-a-aspartyl]-L- compliance with part 105 of this this rule shall apply to claims from phenylalanine 1-methyl ester, chapter. hospitals paid by TRICARE under the monohydrate (CAS Reg. No. 714229– Inpatient Prospective Payment System/ Dated: May 15, 2014. 20–6). Diagnosis-Related Groups-based (b) Advantame meets the following Leslie Kux, payment system, and must be specifications when it is tested Assistant Commissioner for Policy. implemented. according to the methods described or [FR Doc. 2014–11584 Filed 5–19–14; 11:15 am] II. Executive Summary and Overview referenced in the document entitled BILLING CODE 4160–01–P ‘‘Specifications and Analytical Methods A. Purpose of the Final Rule for Advantame’’ dated April 1, 2009, by the Ajinomoto Co. Inc., Sweetener 1. Need for the Regulatory Action Department 15–1, Kyobashi 1-chome, This Final rule amends the TRICARE/ Chuo-ku, Tokyo 104–8315, Japan. The CHAMPUS regulatory provision (32 Director of the Office of the Federal CFR 199.14(a)(1)(i)(C)(3)) of pricing Register approves this incorporation by inpatient hospital claims that are reference in accordance with 5 U.S.C. reimbursed under the DRG-based 552(a) and 1 CFR part 51. Copies are payment system from the beneficiary’s available from the Office of Food date of admission, to pricing such

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