A proposal to amend part 39 of the Federal Aviation Regulations (14 CFR part 39) by superseding AD 2001-24-15, amendment 39-12532 (66 FR 64133, December 12, 2001), which is applicable to certain McDonnell Douglas Model DC-9-10, -30, and -40 series airplanes, and Model C-9 airplanes, was published in the Federal Register on March 18, 2002 (67 FR 11952). The action proposed to continue to require an inspection to detect chafing of the wiring of the attendants' work light of the aft cabin, and repair of chafed wiring; and modification and reidentification of the attendants' work light assemblies of the aft cabin; and to revise the applicability of the existing AD.

Interested persons have been afforded an opportunity to participate in the making of this amendment. No comments were submitted in response to the proposal or the FAA's determination of the cost to the public.

Note 3 in the final rule has been revised to more specifically define the general visual inspection.

New subparagraph (c)(2) of this AD has been added to explain that certain alternative methods of compliance that have been approved for AD 2001-24-15, amendment 39-12532, are approved for the corresponding requirements of this AD.

The applicability section of this AD has been revised to more clearly identify the affected airplanes.

The Cost Impact section of the proposed AD incorrectly identified 176 airplanes in the worldwide affected fleet. This figure has been revised in the final rule.

The FAA has determined that air safety and the public interest require the adoption of the rule with the changes previously described. The FAA has determined that these changes will neither increase the economic burden on any operator nor increase the scope of the AD.

There are approximately 387 Model DC-9-10, -30, and -40 series airplanes, and Model C-9 airplanes of the affected design in the worldwide fleet. The FAA estimates that 278 airplanes of U.S. registry will be affected by this AD.

The actions that are currently required by AD 2001-24-15 take approximately 1 work hour per airplane to accomplish, at an average labor rate of $60 per work hour. Based on these figures, the cost impact of the currently required actions is estimated to be $60 per airplane.

This AD adds no new actions or requirements, but only revises the applicability of the existing AD. Therefore, the estimated cost impact for this AD is unchanged.

The cost impact figure discussed above is based on assumptions that no operator has yet accomplished any of the requirements of this AD action, and that no operator would accomplish those actions in the future if this AD were not adopted. The cost impact figures discussed in AD rulemaking actions represent only the time necessary to perform the specific actions actually required by the AD. These figures typically do not include incidental costs, such as the time required to gain access and close up, planning time, or time necessitated by other administrative actions.

The regulations adopted herein will not have a substantial direct effect on the States, on the relationship between the national Government and the States, or on the distribution of power and responsibilities among the various levels of government. Therefore, it is determined that this final rule does not have federalism implications under Executive Order 13132.

For the reasons discussed above, I certify that this action (1) is not a “significant regulatory action” under Executive Order 12866; (2) is not a “significant rule” under DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and (3) will not have a significant economic impact, positive or negative, on a substantial number of small entities under the criteria of the Regulatory Flexibility Act. A final evaluation has been prepared for this action and it is contained in the Rules Docket. A copy of it may be obtained from the Rules Docket at the location provided under the caption ADDRESSES.

A proposal to amend 14 CFR part 39 to include an AD for ECF Model EC120B helicopters was published in the Federal Register on February 14, 2002 (67 FR 6886). That action proposed to require installing front and side covers to protect the yaw control.

The Direction General De L'Aviation Civile (DGAC), the airworthiness authority for France, notified the FAA that an unsafe condition may exist on this model helicopter. The DGAC advises of a yaw control jamming caused by an object that slid between the canopy and the cabin floor.

ECF has issued Alert Service Bulletin No. 67A005, dated July 30, 2001 (ASB), which specifies installing a front and side protection on the cabin floor to protect the yaw control. The DGAC classified this ASB as mandatory and issued AD No. 2001-386-007(A), dated September 5, 2001, to ensure the continued airworthiness of these helicopters in France.

This helicopter model is manufactured in France and is type certificated for operation in the United States under the provisions of 14 CFR 21.29 and the applicable bilateral agreement. Pursuant to the applicable bilateral agreement, the DGAC has kept the FAA informed of the situation described above. The FAA has examined the findings of the DGAC, reviewed all available information, and determined that AD action is necessary for products of this type design that are certificated for operation in the United States.

Interested persons have been afforded an opportunity to participate in the making of this amendment. No comments were received on the proposal or the FAA's determination of the cost to the public. The FAA has determined that air safety and the public interest require the adoption of the rule as proposed except that we have corrected the date of the DGAC AD in Note 4 from September 15, 2001 to September 5, 2001 and added “Eurocopter” to paragraph (a) of the AD. These changes will neither increase the economic burden on any operator nor increase the scope of the AD.

The FAA estimates that this AD will affect 44 helicopters of U.S. registry and will take 2 work hours per helicopter to accomplish the required actions. The average labor rate is $60 per work hour. Required parts will cost approximately $851 per helicopter. Based on these figures, we estimate the total cost impact of this AD on U.S. operators to be $42,724.

The regulations adopted herein will not have a substantial direct effect on the States, on the relationship between the national Government and the States, or on the distribution of power and responsibilities among the various levels of government. Therefore, it is determined that this final rule does not have federalism implications under Executive Order 13132.

For the reasons discussed above, I certify that this action (1) is not a “significant regulatory action” under Executive Order 12866; (2) is not a “significant rule” under DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and (3) will not have a significant economic impact, positive or negative, on a substantial number of small entities under the criteria of the Regulatory Flexibility Act. A final evaluation has been prepared for this action and it is contained in the Rules Docket. A copy of it may be obtained from the Rules Docket at the location provided under the caption ADDRESSES .

This amendment to part 95 of the Federal Aviation Regulations (14 CFR part 95) amends; suspends, or revokes IFR altitudes governing the operation of all aircraft in flight over a specified route or any portion of that route, as well as the changeover points (COPs) for Federal airways, jet routes, or direct routes as prescribed in part 95.

The specified IFR altitudes, when used in conjunction with the prescribed changeover points for those routes, ensure navigation aid coverage that is adequate for safe flight operations and free of frequency interference. The reasons and circumstances that create the need for this amendment involve matters of flight safety and operational efficiency in the National Airspace System, are related to published aeronautical charts that are essential to the user, and provide for the safe and efficient use of the navigable airspace. In addition, those various reasons or circumstances require making this amendment effective before the next scheduled charting and publication date of the flight information to assure its timely availability to the user. The effective date of this amendment reflects those considerations. In view of the close and immediate relationship between these regulatory changes and safety in air commerce, I find that notice and public procedure before adopting this amendment are impracticable and contrary to the public interest and that good cause exists for making the amendment effective in less than 30 days.

The FAA has determined that this regulation only involves an established body of technical regulations for which frequency and routine amendments are necessary to keep them operationally current. It, therefore—(1) is not a “significant regulatory action” under Executive Order 12866; (2) is not a “significant rule” under DOT Regulatory Policies and Procedures (44 FR 11034; February 26, 1979); and (3) does not warrant preparation of a regulatory evaluation as the anticipated impact is so minimal. For the same reason, the FAA certifies that this amendment will not have a significant economic impact on a substantial number of small entities under the criteria of the Regulatory Flexibility Act.

Congress passed and the President signed into law the Commodity Futures Modernization Act of 2000 (“CFMA”), amending the Commodity Exchange Act. 1 In order to more effectively implement its provisions, the Commission has reorganized its operating divisions. Under the reorganization plan, the Division of Trading and Markets and the Division of Economic Analysis have been reconfigured into two new divisions: The Division of Market Oversight and the Division of Clearing and Intermediary Oversight.

The Commission's rules in Chapter I of Title 17 of the Code of Federal Regulations contain numerous specific delegations of authority from the Commission to the Directors of the Division of Trading and Markets and/or the Division of Economic Analysis, and their respective designees. The Commission effective immediately is adopting new rule 140.100, which provides that all delegations of authority from the Commission to the Directors of the Division of Trading and Markets and/or the Division of Economic Analysis, and their respective designees, as currently set forth in Chapter I of Title 17 of the Code of Federal Regulations, are delegated jointly to the respective Directors of the Division of Market Oversight and the Division of Clearing and Intermediary Oversight, and their respective designees. 2 The conditions of, and limitations upon, the original delegations of authority remain unchanged.

The Commission has determined that this delegation of authority relates solely to agency organization, procedure and practice. Therefore, the provisions of the Administrative Procedure Act that generally require notice of proposed rulemaking and that provide other opportunities for public participation are not applicable. 3 The Commission further finds that, because the rules have no adverse effect upon a member of the public, there is good cause to make them effective immediately upon publication in the Federal Register .

In consideration of the foregoing and pursuant to the authority contained in the Commodity Exchange Act and in particular, sections 2(a) and 8a, 4 as amended by the Commodity Futures Modernization Act of 2000, appendix E of Public Law 106-554, 114 Stat. 2763 (2000), the Commission amends part 140 of title 17 of the Code of Federal Regulations as follows:

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

Neotame is the common or usual name for the chemical N -[ N -(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine-1-methyl ester (CAS Reg. No.165450-17-9). It is synthesized by reductive N -alkylation of L-phenylalanine-L-α-aspartyl methyl ester with 3,3-dimethylbutyraldehyde. According to the petitioner, neotame has a sweetening potency that is approximately 7,000 to 13,000 times that of sucrose, depending on its food application (Refs. 1 and 2).

The peptidyl linkage in neotame is stabilized by the N -alkyl substituent and is resistant to hydrolysis under typical use and storage conditions. Additionally, the N -alkyl substituent effectively prevents the common dipeptide cyclization reaction that results in the formation of a diketopiperazine derivative. The data from stability studies submitted by the petitioner show that the degradation of neotame in aqueous solutions is pH-, time-, and temperature-dependent. Based upon data from these stability studies on neotame, the agency concludes that minor decomposition of neotame could occur in neotame-containing foods only when stored under conditions that are not considered typical for a commercial product (Refs. 1 and 2).

The agency has determined the estimated daily intake (EDI) at the 90th percentile for neotame as a general-purpose sweetener to be 0.10 milligram per kilogram (mg/kg) body weight per day (bw/d) for consumers of all ages (eaters only) and 0.17 mg/kg bw/d for 2 to 5 year olds (eaters only). The corresponding mean intakes are 0.04 mg/kg bw/d and 0.05 mg/kg bw/d, respectively (Refs. 2 and 3).

In support of the safety of neotame, the petitioner submitted, within the two petitions, a combined total of 113 preclinical, clinical, and special studies, plus an additional 32 exploratory and screening studies in Food Master File No. 575. All pivotal preclinical studies were conducted in compliance with FDA's “good laboratory practice” regulations in 21 CFR part 58.

The preclinical (animal) studies include short-term, subchronic, and chronic dietary toxicity tests in the rat, mouse, and dog; multi-generation reproduction and developmental studies in the rat; teratology studies in the rat and rabbit; and lifetime/carcinogenicity studies in the rat and mouse. The genotoxicity of neotame, its metabolites, and decomposition products, are also evaluated in several tests using both in vitro and in vivo assay systems. Extensive metabolism and pharmacokinetic measurements were carried out in all animal species studied. The clinical (human) studies tested the response/acceptance to orally administered neotame in both men and women during short-term (e.g., acute, single-dosing) and longer-term (e.g., up to 13 weeks, repeat-dosing) periods. Pharmacokinetic (PK) measurements also were carried out in a number of these studies (Ref. 4).

Additionally, the petitioner provided three position papers in response to FDA questions. These position papers address: (1) The potential behavioral and neurotoxic effects of neotame, (2) the significance of elevated serum (hepatic) alkaline phosphatase activity in neotame-treated dogs as a measure of toxicity, and (3) body weight gain decrement in mice ingesting neotame. The key aspects of these position papers are discussed, as appropriate.

As a component of the toxicological testing program on neotame, the petitioner conducted an extensive series of metabolism and PK studies. These studies were designed to assess: (1) The absorption of neotame; (2) the elimination, distribution, and potential tissue accumulation of neotame; (3) the effects of neotame on drug metabolizing enzymes; and (4) the metabolites of neotame in rodents (rats and mice), dogs, rabbits, and humans.

a. Absorption of neotame . In all species studied, including humans, the agency finds that the absorption of ingested neotame occurs almost entirely in the small intestine. In the animal studies, the absorption of neotame was determined under fasting conditions using a dose level that was approximately 150 times greater than the 90th percentile estimated daily intake (EDI) of neotame for humans. Under these conditions, the amount of administered dose absorbed is reported to range from 18 to 38 percent in the rat, 15 to 44 percent in the rabbit, and 40 to 51 percent in the dog. These studies also indicate that, when mixed with the diet, the absorption of neotame is reduced. In the human clinical studies, the absorption of neotame approaches 100 percent in healthy male and female subjects when administered following an overnight fast and at dose levels ranging from one to five times the 90th percentile EDI. Individual absorption levels range from 68 to 126 percent (Ref. 5).

b. Elimination, distribution, and potential tissue accumulation of neotame . The agency estimates that approximately 40 percent of the systemic elimination of ingested neotame and metabolites occurs via the urine, and the remainder is eliminated via the fecal route. In a whole-body radiography study in the rat, following a gavaged dose of radiolabled neotame and serial sacrifice at timed intervals, post-dosing, the highest levels of radioactivity are associated with the intestinal tract, the liver, and the kidney. At final sampling, no residual radioactivity is detected in peripheral tissues, with some residual activity associated with the intestinal tract. No organs or tissues, including the brain, eye, and skin, concentrate or store radiolabled neotame or its metabolites.

Further evidence for the lack of accumulation of neotame at expected levels of human intake is found in the analysis of PK parameters evaluated during a 13-week dog study. In dogs consuming dietary neotame at dose levels of 1,200 to 2,000 mg/kg bw/d, there is an indication of saturation of an elimination pathway that could lead to possible accumulation. However, these levels are at least 10,000 times greater than the 90th percentile EDI (0.1 mg/kg bw/d) of neotame for humans. This effect is not seen in dogs from the next lower treatment group (600 mg/kg bw/d), a level approximately 6,000 times above the 90th percentile EDI. Based on these findings, the agency concludes there is no concern for possible accumulation of neotame or its metabolites at expected human intake levels (Refs. 4 and 5).

c. Effect of neotame on drug metabolizing enzymes . The rat is generally considered an appropriate animal model to assess the effects of xenobiotics on phase I (i.e., cytochrome P-450 or mixed-function amine oxidase microsomal enzyme systems 1 ) and phase II (i.e., conjugation or biotransformation reactions involving glucuronidation, sulfation, acetylation, or glutathione-S- transferase reactions) metabolism. Following a 14-day period during which dietary neotame was fed at 0 (control), 100, 300, or 1,000 mg/kg bw/d, rats were sacrificed and in vitro assays performed on isolated liver microsomal pellets. The agency concludes that, when compared against a positive control (phenobarbital, a known enzyme inducer), neotame does not induce P-450 microsomal mixed function oxidase metabolizing enzymes at any dose level administered during the in vivo phase of the study. In evaluating the effects of neotame on phase II metabolism, the agency notes that livers from rats in the 1,000 mg/kg bw/d treatment group show a statistically significant depression in phase II metabolism endpoints. However, at the next lower dose of 300 mg/kg bw/d, which is approximately 3,000 times the 90th percentile EDI for neotame for humans, there are no effects on these same endpoints (Ref. 5).

d. Metabolites of neotame . The initial step in the metabolism of neotame in rats, dogs, rabbits, and humans is de-esterification to N -[ N -(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine (DMB-Asp-Phe, coded in the petition as NC-00751) by Ca ++ -dependent pancreatic esterases or after absorption by plasma esterases. De-esterification of neotame is similar in all species studied, including humans, although in the rat and rabbit this conversion occurs at a faster rate than in the dog and human. The de-esterified metabolite (NC-00751) is rapidly cleared from the plasma and excreted via the bile duct or in urine (Ref. 5). A small percentage of NC-00751 may undergo peptide-bond hydrolysis to form metabolites of dimethylbutylaspartate. The 3,3-dimethylbutyl portion of DMB-Asp-Phe is then oxidized to 3,3-dimethyl-butyric acid. This is followed by conjugation with glucuronic acid or with carnitine (a minor pathway).

Methanol release results from the de-esterification of neotame and occurs more rapidly in the rat and rabbit than in the dog and human. The agency concludes that at the 90th percentile EDI for neotame, exposure to resultant methanol will be insignificant, i.e., not more than 0.008 mg/kg bw/d. This exposure level is of no toxicological concern because humans are exposed to much greater levels of methanol intake from their daily diets (Refs. 4 and 5).

Based on neotame metabolism studies in the rat and dog, FDA concludes that some intestinal microvillar peptidase activity occurs in the gut, which results in the formation of other minor plasma metabolites of neotame, including phenylalanine (Ref. 5). Further review indicates that approximately 13 to 17 percent of the total available phenylalanine in the ingested neotame is released into the plasma after absorption; the remainder is eliminated in feces and urine as DMB-Asp-Phe. The agency has estimated the amount of phenylalanine presented to the body from the ingestion of neotame. The phenylalanine content of neotame is 44 percent by weight. Given that the 90th percentile neotame EDI for a 60 kg adult is 0.10 mg/kg bw/d or 6 mg/d, and for a 2 to 5 year old (20 kg) child is 0.17 mg/kg bw/d or 3.4 mg/d, the estimated 90th percentile phenylalanine intake is 2.6 mg and 1.5 mg, respectively.

The agency notes that, for healthy adults, the daily dietary intake of phenylalanine may range from 2.5 to 10 grams per person per day (g/p/d), while that for a phenylketonuric (PKU) homozygous child (20 kg) may range from 0.4 to 0.6 g/p/d (Koch and Wenz 2 ). Thus, the amount of phenylalanine from the 90th percentile intake of neotame is trivial compared to that from the normal adult diet. Even for the PKU homozygous child, the incremental amount of phenylalanine intake that can be expected from neotame is insignificant, i.e., equivalent to no more than 0.3 to 0.4 percent of the daily phenylalanine intake of the PKU homozygous child (Ref. 5). The agency concludes that the potential intake of phenylalanine that may result from use of neotame as a general-purpose sweetener does not pose any safety concern (Refs. 4 and 5).

Based on reviews of the metabolism and pharmacokinetic studies on neotame, the agency concludes that the metabolism of neotame is qualitatively similar across all species studied. Furthermore, there is no evidence that, at expected levels of intake, neotame or its metabolites will accumulate in the body or that ingestion of neotame will have any adverse effect in the body on Phase I and II metabolism. The metabolites of neotame are well characterized, and the potential intakes of metabolites, such as methanol and phenylalanine, are of no toxicological consequence. Therefore, the agency's review of the metabolism and pharmacokinetic studies of neotame does not raise any safety concerns (Refs. 4 and 5).

FDA reviewed all studies and supplemental information submitted by the petitioner. During its review, the agency determined that certain studies were more important than others to a regulatory decision on neotame. This determination was based on the nature of the endpoints investigated in these studies (i.e., reproductive and developmental effects, long-term exposure, chronic toxicity, carcinogenic potential, and human tolerance), and on specific issues presented by these studies. The critical studies and issues presented by the studies are: (1) The 2-generation reproduction study in rats—neurotoxicity and behavioral effects, (2) the chronic (52-week) dog study—toxicological significance of increased serum (hepatic) alkaline phosphatase levels, (3) the 104-week mouse carcinogenicity study—body weight gain decrement effect, (4) the 104-week rat carcinogenicity study—body weight gain decrement effect at all dose levels tested, (5) the chronic (52-week) rat feeding study—body weight gain decrement effect, and (6) the human clinical trials—human tolerance to neotame.

a. A 2-generation reproduction study in the rat—neurotoxicity and behavioral effects . Reproductive performance and fertility were assessed over two generations in CD (cesarean derived) rats fed diets containing neotame at levels of 0 (control), 100, 300, or 1,000 mg/kg bw/d. Each treatment group consisted of 28 males and 28 females. Animals were mated, the resultant offspring weaned, and the F1 generation animals selected and allowed to mature for 10 weeks and then mated. The F2 litters were terminated, post-weaning. Under the conditions of this study, the agency concludes that neotame has no effects on the reproduction or fertility of rats exposed to neotame at levels up to 1,000 mg/kg bw/d for two generations. Nor are there any treatment effects on measures of physical development, e.g., pinna unfolding, hair growth, tooth eruption, or eye opening (Refs. 4 and 6).

The 2-generation study included tests of motor activity and cognitive function. General motor activity was measured in F1 offspring by counting breaks in a pair of infrared light beams over a 12-hour period, while cognitive function was assessed by recording swim times up to 60 seconds maximally in six consecutive trials per animal in a water-filled Y-maze (Ref. 7). While the petitioner concludes there were no significant treatment effects on motor activity in F1 male and female offspring, the agency's analyses of pertinent data show a statistically significant reduction in motor activity among F1 males from the 1,000 mg/kg bw/d neotame treatment group. No effects are noted on motor activity in F1 females at any dose level.

With regard to results from the swim-maze tests that were conducted in F1 offspring at approximately 24 to 28 days of age, both the petitioner and the agency conclude that there is a statistically significant increase in mean swimming time (an indicator of reduced performance) to the “correct” arm of the Y-maze in F1 males from the 1,000 mg/kg bw/d group. Specifically, this increased swim time is noted in two of six trials in the F1 males from the high dose group. While an increase in swim time is also noted for one of six trials in F1 males from the 300 mg/kg bw/d dose group, this singular observation is not accompanied by any other indication of treatment-related behavioral changes and therefore is not considered to be indicative of a biologically relevant effect. As with motor activity, there are no effects on cognitive performance (as measured by swim maze times) noted in F1 female offspring from any treatment group.

The F1 offspring from the 2-generation reproduction study also were subjected to specific tests that measured the development of auditory and visual responses. The agency's evaluation of results on auditory startle, pupil closure, and visual placing show no treatment-related effects in F1 males or females at any level of neotame tested.

The finding of statistically significant effects on two separate behavioral tests (i.e., motor activity and swim maze times) in F1 males from the 1,000 mg/kg bw/d dose group supports the conclusion that this dose is an effect level. Based on the findings from the studies of motor activity and cognitive function, the agency considers the 300 mg/kg bw/d dose to be a no observed adverse effect level (NOAEL) for these endpoints (Refs. 4 and 7).

Early in its evaluation of the neotame safety database, the agency determined that the petitioner should provide a more specific assessment addressing the potential neurotoxicity and behavioral effects of neotame. In response to the agency's request, the petitioner submitted a position paper entitled “Neotame Does Not Cause Any Behavioral or Neurotoxic Effects” (Ref. 8). This document contains summaries and discussions of data and information from two principal sources. The first involves several “key” preclinical studies (12 in all) and 4 clinical studies from the neotame studies database. The second source of information discussed in the position paper is a series of 20 publications that are primarily related to aspartame. Collectively, these 20 publications provide little information that is relevant to the agency's overall safety assessment of neotame and are not discussed further.

With regard to the “key” animal studies, the petitioner states in its position paper that these studies incorporated clinical observations/testing enhancements as “effective procedures for detecting neurotoxic effects.” During the ante mortem phase of the animal studies, these enhancements included detailed physical, behavioral, and clinical observations to detect signs of neurological disorder, behavioral abnormality, physiological dysfunction, and other signs of nervous system toxicity. Post mortem enhancements included extensive histopathological evaluations of brain, spinal cord, and peripheral nerves.

FDA has reviewed thoroughly all of the preclinical and clinical studies discussed in the position paper. With the exception of the 2-generation rat reproduction study in which statistically significant decreases in motor activity and statistically significant increases in swim times are observed in F1 offspring males at 1,000 mg/kg bw/d, the preclinical studies do not show behavioral or neurotoxic effects associated with the ingestion of neotame.

Based on available preclinical and clinical information from the neotame studies database, the agency concludes that there is no concern for potential neurotoxic or behavioral effects in humans from the ingestion of neotame as a general-purpose sweetener in foods. This conclusion is reinforced further by the NOAEL of 300 mg/kg bw/d established for motor activity and cognitive performance in F1 males from the 2-generation reproduction study, a dose level that is at least 3,000 times greater than the 90th percentile EDI of 0.1 mg/kg bw/d (Refs. 4 and 7).

b. Chronic (52-week) dog study—toxicological significance of elevated serum (hepatic) alkaline phosphatase . Beagle dogs were fed diets containing neotame at levels of 0 (control), 20, 60, 200, or 800 mg/kg bw/d over a 52-week period. Detailed data were collected on animal survival, growth, food intake, clinical chemistries, hematology, urinalyses, and gross organ pathology and histopathology. At the conclusion of the study, a limited number of dogs from the neotame treatment groups were placed on a control diet for an additional 4-week “reversibility period.” During the agency's review of this study, a question arose about the toxicological significance of increased serum alkaline phosphatase (ALP) levels (of hepatic origin) noted in female dogs from the 200 mg/kg bw/d dose group and in both sexes at the 800 mg/kg bw/d dose group. Other effects noted were statistically significant dose-related increases in absolute liver weights and in relative liver weights (liver to brain weight ratio) in female dogs in the 200 and 800 mg/kg bw/d dose groups. There was no evidence of histopathological changes in the liver, brain, sciatic nerve, and spinal cord or in other organs or tissues examined from neotame-treated dogs.

Because elevated serum ALP levels had also been observed in shorter duration studies (2-week and 13-week) in dogs ingesting neotame containing diets, the agency requested that the petitioner provide further clarification on this matter. In its response, the petitioner submitted a position paper entitled “Increases in Serum Alkaline Phosphatase in the Dog Are Not Associated with Target Organ Toxicity,” together with several publications related to hepatotoxicity and serum ALP activity (Ref. 9). In this position paper, the petitioner reasons that the increased serum ALP levels observed in neotame-treated dogs are not due to a hepatotoxic response, but to a “nonspecific, physiological response” to the high doses of neotame.

FDA conducted further statistical analyses on the liver weight parameters mentioned previously. Based on these analyses, the agency concludes that the means for these liver effects from the 200 and 800 mg/kg bw/d dose groups are statistically significantly higher than the means for the 0 (control), 20, and 60 mg/kg bw/d treatment groups. Furthermore, there are no statistically significant differences between the 0 (control), 20, and 60 mg/kg bw/d dose group means for any of the liver weight parameters that were evaluated.

From the review of the data from the 52-week dog study and the supplemental information submitted by the petitioner in its position paper, the agency concludes that the changes in serum ALP levels are most likely due to a nontoxic response to the higher levels (200 and 800 mg/kg bw/d) of administered neotame. This conclusion is based on the following: (1) There are no significant effects from neotame on other liver enzymes (e.g., alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase), (2) serum albumin levels are not decreased in neotame-treated dogs (a decrease would have been an indicator of chronic liver toxicity), (3) serum bilirubin levels are normal in both sexes at high doses of neotame (an increase would have been seen if cholestasis was occurring), and (4) the liver in both sexes and at all dose levels appears normal on histopathological examination. In this 52-week dog study, FDA establishes a no observed effect level (NOEL) of 60 mg/kg bw/d, based on liver effects (e.g., serum (hepatic) alkaline phosphatase and relative liver weights) as the most sensitive endpoints (Refs. 4 and 10).

c. A 104-week mouse carcinogenicity study—body weight gain decrement effect . CD-1 mice were fed neotame-containing diets for 104 weeks at levels of 0 (control), 50, 400, 2,000, or 4,000 mg/kg bw/d. Based on an evaluation of the histopathological data from this carcinogenicity study, FDA concludes that, under the conditions of the study, doses of neotame up to 4,000 mg/kg bw/d administered to male and female CD-1 mice for up to 2 years did not induce neoplastic lesions (Ref. 11).

Although there was no evidence of carcinogenicity in mice exposed to neotame for 104 weeks, during the agency's review of other endpoints, we noted negative effects on body weight gain (and thus body weight) in both sexes. In light of only small decreases in cumulative food consumption, the agency was concerned about the potential toxicological significance of the decrease in body weight gain. In response to the agency's request for further clarification on this issue, the petitioner submitted a position paper entitled “In the Mouse Carcinogenicity Study With Neotame Small Changes in Body Weight Gain at Some Intervals in Female Mice at 50 mg/kg bw Relative to Controls Are Due to a Decrease in Food Consumption” (Ref. 12). In its analysis, the petitioner states that the mouse is not a reliable model for determining the relationship between body weight gain and food consumption. Reasons cited include the small differences in body weight gain over a lifetime in mice, both in absolute terms and in proportion to initial body weights at the start of a study, and well-known difficulties in obtaining accurate measures of food intake for mice (e.g., mice frequently spill food from their food cups and contaminate their food with feces and urine). The petitioner reiterated its belief that the body weight gain decrements noted in mice during the 104-week study were due to a small but consistent reduction in food consumption which is attributable to poor diet palatability and should not be viewed as a toxicological response to neotame.

In further evaluation of this body gain weight decrement issue, FDA subjected the data on body weight, body weight gain, and adjusted (for neotame content) food intake to extensive statistical evaluation. Using an analysis of covariance model and pair-wise dose comparisons of body weights and body weight gain, the agency notes statistically significant effects for the 400, 2,000, and 4,000 mg/kg bw/d dose groups. Based on these analyses, the agency concludes that the body weight gain decrement effect in both male and female mice in the three highest dose groups is not accounted for by the small decreases in food consumption. However, in the 50 mg/kg bw/d treatment group, the effects on body weight and body weight gain are not statistically different from controls. Based on the detailed statistical evaluation of data pertinent to the body weight gain decrement noted in the 104-week dietary carcinogenicity study in mice, the agency establishes a NOEL of 50 mg/kg bw/d for this endpoint (Refs. 4 and 10).

d. A 104-week rat carcinogenicity study—body weight gain decrement effect at all dose levels tested . A 104-week rat carcinogenicity study (with an in utero phase) was conducted during which neotame was fed at 0 (control), 50, 500, or 1,000 mg/kg bw/d. Based on a thorough evaluation of the histopathological data from this carcinogenicity study, FDA concludes there is no evidence of neotame-induced neoplastic lesions in rats ingesting diets containing neotame at levels up to 1,000 mg/kg bw/d for 104 weeks (Ref. 11).

During its review of the 104-week rat carcinogenicity study, the agency noted effects on body weight gain (and thus body weight) in both sexes of neotame-treated rats at all dose levels tested. Statistically significant decreases in cumulative body weight gains were observed at various intervals throughout the study. At week interval 0 to 52, cumulative body weight gains were 9 to 11 percent less and 13 to 19 percent less, respectively, in neotame-treated male and female rats, than in control animals. Similar effects were noted at week intervals 0 to 78 and 0 to 104, i.e, cumulative body weight gains ranging from 10 to 13 percent less in treated males and 17 to 20 percent less in treated females. In reporting this information, the petitioner suggests that the lower body weights and lower body weight gains among neotame-treated rats can be attributed to reduced food intake due to reduced palatability of the diets containing neotame.

The agency, however, based on an analysis of the food intake data, concludes that the decreases in adjusted (for neotame content) food intake among the neotame-treated rats are small and do not fully explain the magnitude of the differences in body weight and body weight gain observed in these animals at week 52 and thereafter up to week 104. In view of the significant body weight gain decrement effect observed in all neotame treatment groups during the 104-week rat carcinogenicity study, a NOEL cannot be established. Lacking a suitable explanation for this effect based on decreased food intake (as argued by the petitioner), the agency considered the body weight gain decrement effect unresolved by the 104-week rat study (Refs. 4 and 10).

e. Chronic (52-week) rat feeding study—body weight gain decrement effect . In order to resolve the body weight gain decrement issue in rats, the agency carried out a thorough analysis of data from a 52-week rat feeding study. This study employed a wide range of neotame dose levels, two of which were below the lowest dose tested in the 104-week rat carcinogenicity study (as discussed in section II.C.2.d of this document). The results of this analysis are presented in the following paragraphs.

In the chronic (52-week) rat feeding study (with an in utero phase) rats received neotame at 0 (control), 10, 30, 100, 300, or 1,000 mg/kg bw/d. Except for body weight and body weight gain, there were no statistically significant treatment-related effects of neotame during this 52-week feeding study. With respect to both body weight and body weight gain, female rats appear to be more sensitive than males.

In regard to body weight, at the end of the 52-week study, body weights in females from the 100, 300, and 1,000 mg/kg bw/d groups were statistically significantly lower than those of control female rats. However, the body weights of females from the 10 and 30 mg/kg bw/d groups were not statistically different from control females. Among males, only the 100 mg/kg bw/d group had statistically significant body weight differences from control male rats.

As for cumulative body weight gains during the 0 to 52-week interval, statistically significant decreases are noted in treated females, compared to controls, only from the 300 and 1,000 mg/kg bw/d treatment groups. While the body weight gains in females from the 100 mg/kg bw/d are lower than in control female rats, this difference is not statistically significant. Compared with controls, there are no significant differences in cumulative body weight gains in females from the two lowest treatment groups (10 and 30 mg/kg bw/d) for the 0 to 52-week interval. Cumulative body weight gains in male rats from the 30, 100, 300, and 1,000 mg/kg bw/d neotame treatment groups, while somewhat lower than controls, are not statistically different. As noted in the 104-week carcinogenicity study, female rats in the 52-week dietary study were more sensitive to body weight gain decrement effects than males.

FDA performed a detailed analysis of the results from the 52-week dietary rat study and concludes that this study provides an adequate basis to assess the body weight gain decrement effect noted in the 104-week carcinogenicity rat study for four reasons. First, the range of neotame dose levels studied in the 52-week study is comparable to the doses tested in the 104-week study. Second, in each study, the female rat is more sensitive. Third, a parallel comparison of the 52-week study and the first 52 weeks of the carcinogenicity study shows that the body weight gain decrement effect was of a similar order of magnitude in both studies. Fourth, the magnitude of decrease in body weight gain occurring during week interval 0 to 52 in the 104-week study does not worsen during the last half of the study. These observations add strength to the utility of the 52-week dietary rat study in resolving any concern about the body weight gain decrement effect and in establishing a NOEL of 30 mg/kg bw/d for this endpoint (Refs. 4 and 10).

f. Clinical studies assessments—human tolerance to neotame . The petitioner submitted the results of six human clinical trials that investigated the ingestion of neotame under varied conditions, including acute-single exposure, acute-repeat exposure, and short-term (2-week) and longer-term (13-week) daily exposure. Five of these trials employed healthy adult subjects, while one trial evaluated non-insulin dependent diabetes mellitus (Type II diabetic) adult subjects. In each of these trials, subject tolerance to neotame intake was determined by physical examinations, vital signs, electrocardiograms, routine clinical laboratory measurements (e.g., hematology, clinical chemistries, and urinalysis), and self-assessments of adverse experiences.

The levels of neotame administered in these clinical trials ranged from 1 to 15 times the 90th percentile EDI level of 0.1 mg/kg bw/d or 6 mg per person per day (mg/p/d).

The agency concludes that in all six trials there are no treatment-related effects reported for any of the parameters examined. Although headache was the most frequently noted adverse experience, the incidence of headache is comparable for the treated and control groups and is not considered to be associated with neotame intake. Results from ancillary pharmacokinetic measurements in several of the clinical trials do not raise any safety concerns. In the trial with Type II diabetic subjects, no adverse effects are noted in any of the subjects. Under the conditions of that trial, the agency concludes that the ingestion of neotame at levels up to 1.5 mg/kg bw/d does not produce significant changes in either fasting-state glucose or insulin levels in Type II diabetic subjects.

Based on reviews of these clinical trials, the agency concludes that the ingestion of neotame at levels up to 1.5 mg/kg bw/d (15 times the 90th percentile EDI) for a period as long as 13 weeks is well tolerated by healthy male and female subjects. The agency also concludes that in the study with Type II diabetic subjects, the intake of neotame at levels up to 1.5 mg/kg bw/d does not have significant effects on fasting plasma glucose or insulin levels in study subjects (Refs. 4 and 13).

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

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

Thirty comments were submitted to FDA's Dockets Management Branch in response to the filing of the two neotame food additive petitions (25 for FAP 8A4580 and 5 for FAP 9A4643). The issues raised in the comments are identified and grouped into the following subject categories.

The majority of the comments compared neotame to aspartame. In these comparisons, the comments assumed that neotame produces the same metabolic breakdown products as aspartame and thus would be responsible for the same health effects they allege to be associated with aspartame, which is the subject of a food additive regulation (21 CFR 172.804). In response to these comments, FDA points out that neotame is chemically and metabolically different (see section II.A of this document and Ref. 1, and section II.C.1 of this document, respectively) from aspartame even though they are structurally related. Therefore, the comments' assertions about neotame are without basis. Because the comments do not provide the agency with any information regarding the safety of neotame, they will not be discussed further.

Several comments objected to the tabletop use petition on the basis that the petitioner's EDI for neotame is inaccurate, implying that it is too low. In determining an EDI, FDA makes projections based on the amount of the additive proposed for use in particular foods and on data regarding the consumption levels of these particular foods, commonly using the 90th percentile as a measure of high chronic exposure. The agency concludes that the 90th percentile EDI calculated for neotame, as discussed in section II.A of this document, accurately reflects the exposure to neotame as a general-purpose sweetener in all foods (except for meats and poultry), including tabletop use (Ref. 2).

One comment noted that the petitioner assumes that neotame will replace 50 percent of aspartame's current applications and argued that this assumption may be limited unduly and not sufficiently conservative. FDA agrees with the comment on this point, and disagrees with the petitioner's use of the 50 percent replacement factor in their estimation of exposure to neotame. The agency conservatively assumes that this new sweetener will replace all existing uses of aspartame (Ref. 14) and uses this estimate in its safety evaluation.

One comment stated that there is no NOEL established by the 104-week rat carcinogenicity study for neotame, because all doses show adverse effects on growth. The comment also asserted that the data contained in this study do not support the petitioner's explanation that decreases in body weights in the treated rats are due to reduced palatability of the neotame-containing diets. In addition, the comment indicated that the petitioner did not supply any gavage, pair-feeding, or dietary restriction studies to prove that the body weight gain decrements are due to palatability and not toxicity. The comment also claimed that a safe usage level for neotame cannot be determined from the safety database provided in the neotame food additive petitions.

FDA agrees that a NOEL cannot be established based on the 104-week rat carcinogenicity study, in view of the body weight gain (decrement) effect. The agency also notes that, while neotame may have had some influence on diet palatability, the decreases in food intake (adjusted for neotame content) among neotame-treated rats of both sexes in the 104-week study are too small to explain the magnitude of the body weight gain decrement that occurred in rats from the neotame treatment groups (see section II.C.2.d of this document and Refs. 4 and 10). FDA disagrees, however, about the necessity for additional testing requested by the comment to resolve the body weight gain decrement issue. While the proposed studies might address mechanistic relationships between food consumption and weight gain, the agency believes that they will not provide meaningful data to explain the magnitude of differences in body weight and body weight gain in neotame-treated rats from the 104-week study in view of the small decreases in food consumption noted in these animals. In addition, FDA believes that a safe usage level for neotame can be established from the database provided by the petitioner. As discussed in section II.C.2.e of this document, the results in the 52-week rat dietary toxicity study provide a strong scientific basis to resolve concerns over the body weight gain decrement effect (Refs. 4, 10, and 15). Based on the 52-week rat study and using body weight gain decrement as the most sensitive endpoint for toxicity, the agency is able to establish a NOEL for neotame of 30 mg/kg bw/d. From this NOEL, FDA derives an ADI for neotame of 18 mg/p/d (see table 1 in section II.D of this document and Ref. 4).

Several comments expressed concerns regarding potentially adverse effects of neotame based on changes observed in serum ALP levels in dogs consuming high doses of neotame (i.e., 200 mg/kg bw/d and higher) in both 13-week and 52-week feeding studies. Additional comments suggested that neotame is hepatotoxic, as evidenced by effects on other endpoints, such as changes in absolute and/or relative liver weight, changes in serum cholesterol and triglycerides, and neotame-related cholestasis.

The agency notes that most of these comments focused on effects observed in the 13-week dog study. In its review of the subchronic (13-week) dog study, the agency observed the liver effects referenced in the comments (Ref. 16). Ordinarily, in the absence of a longer duration study, the agency would have given more weight to the results of the 13-week dog study. However, a chronic (52-week) dog study was also submitted in support of the safety of neotame, and that study provides for a more complete manifestation of the target organ toxicity in neotame-treated dogs.

While the agency considers the 13-week dog study useful for obtaining preliminary toxicological information (i.e., identification of target organs) and for determining the appropriate range of doses of neotame that would be fed in the 52-week dog study, the 52-week study provides a stronger basis for assessing the potential chronic toxicity of neotame in the dog. Because the results from this longer-term study supersede those of the 13-week study and because all of the effects noted in the shorter-term study occurred at levels of exposure well above the NOEL established by the 52-week study, the agency concludes that no further discussion is needed in response to issues raised in comments concerning the 13-week dog study.

Several comments asserted that elevated serum ALP levels observed in the neotame-treated dogs in the 52-week dog study indicate liver toxicity. As discussed in section II.C.2.b of this document, FDA recognizes that in the 52-week dog study elevated serum ALP levels are observed in both sexes of dogs from as early as 13 weeks until the end of the study at neotame dose levels of 200 and 800 mg/kg bw/d. However, the agency disagrees with comments that these elevated serum ALP levels are evidence of hepatic toxicity. While an increase in serum ALP may be an indicator of liver toxicity, such a conclusion cannot be substantiated in the absence of additional corroborative changes. Specifically, hepatic damage may result in increased levels of other liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, or gamma glutamyl transferase. None of these liver enzymes was elevated in the neotame-treated dogs. Also, a decrease in blood albumin levels may indicate chronic liver toxicity. Blood albumin levels in dogs from all neotame dose groups were normal and comparable to control values. Furthermore, an elevation in serum bilirubin indicates cholestasis; serum bilirubin levels were unaffected by neotame treatment.

Increased cholesterol levels are another indication of altered liver function. Plasma cholesterol and triglyceride levels in dogs from the 52-week study, although somewhat variable, were well within the normal range for dogs and unaffected by neotame treatment. Additionally, histopathological examinations of livers from dogs from the neotame-treated groups did not reveal any evidence of necrosis, blockage of bile flow, or any other abnormalities that were not detected in control animals. Collectively, these observations support the agency's conclusion that data from the 52-week study do not show evidence of hepatic toxicity in dogs administered neotame (Refs. 4, 17, and 18).

Several comments asserted that neotame-related liver toxicity is not reversible, as is implied by the petitioner, based primarily on the increases in both serum ALP levels and relative liver weights in the dog studies. The agency concludes that the reversibility of these effects is not relevant to a safety decision regarding chronic ingestion of neotame. While FDA agrees, as noted in section II.C.2.b of this document, that increases in serum ALP levels and relative liver weights occur in dogs from the 200 and 800 mg/kg bw/d neotame groups in the 52-week study, neither of these parameters is affected at the lower levels tested (20 or 60 mg/kg bw/d). By considering serum ALP and relative liver weights as the most sensitive endpoints of potential neotame toxicity, the agency determines for the 52-week dog study that 60 mg/kg bw/d is an appropriate NOEL (Refs. 4, 10, and 17).

One comment emphasized the importance of the liver in animal growth and glucose homeostasis. This comment asserted, based on analyses of the neotame safety studies database, that neotame affects growth in both rats and dogs, and appears to affect glucose homeostasis in persons with diabetes. Based upon these findings, along with the elevated serum ALP levels in neotame-treated dogs and the structure of neotame, the comment concluded that it was important to rule out the liver as a target organ.

In regard to the effect of neotame on body weight gain in the rat, the agency has established a NOEL of 30 mg/kg bw/d, based on the 52-week rat feeding study, as summarized in section II.C.2.e of this document. We discuss our analyses of the 52-week rat feeding study and our resolution of the body weight gain effect in more detail in Refs. 10 and 15.

In regard to the effect of neotame on body weight and body weight gain in the 52-week dog feeding study, the effect occurred only in male dogs and only in the highest neotame dose group (i.e., 800 mg/kg bw/d) during weeks 1 to 5 and 7 to 8 (Ref. 18). At all other dose levels tested (i.e., 20, 60, and 200 mg/kg bw/d), there were no statistically significant effects on body weight or body weight gain in either sex. Furthermore, as discussed in section II.C.2.b of this document, the agency relies on more sensitive endpoints, i.e., serum ALP levels and relative liver weights, for establishing a NOEL for neotame from the 52-week dog study.

The agency also disagrees with the comment's assertion that neotame appears to affect glucose homeostasis in persons with diabetes. We explain our basis for concluding that neotame does not appear to affect glucose homeostasis in persons with diabetes later in this document, in the discussion entitled “Type II Diabetes Study.”

As for changes in serum ALP levels, the agency does not consider these to be a manifestation of hepatic toxicity in the 52-week dog study. Our reasons for discounting the toxicological significance of the changes in serum ALP are discussed previously (see section II.C.2.b of this document and the fourth subject category in section III “Serum Alkaline Phosphatase and Liver Toxicity”).

The comment asserted that “[t]he structure of neotame suggests that the metabolic formation of nitrosamines by gut microflora is possible as well as formation in some food products.” The agency acknowledges that a number of nitrosamine compounds are potent hepatotoxins and hepatocarcinogens. The agency also recognizes that neotame contains a secondary amine that could hypothetically form nitrosoneotame in the presence of a nitrosating agent. However, there is no scientific evidence presented in this comment to demonstrate that the presence of neotame in food leads to the formation of nitrosoneotame either through chemical reaction in food products or by metabolic processes in the gut upon ingestion (Ref. 14). Furthermore, the petitioner addressed this issue using many maximizing assumptions concerning the formation and potency of the hypothetical nitrosoneotame. In particular, the petitioner assumed that nitrosoneotame would be formed and that it would be as potent a carcinogen as dimethylnitrosamine. Based on this scenario, the petitioner concluded that the amounts of nitrosamine that could be formed would be extremely small, that any hypothetical risk would be trivial, and that additional analyses were not necessary. After evaluating the petitioner's reasoning, FDA agrees with this conclusion (Refs. 1 and 14). Furthermore, as noted in sections II.C.2.c and II.C.2.d of this document, there is no evidence of chronic liver toxicity or pre-neoplastic or neoplastic liver lesions in lifetime carcinogenicity feeding studies in rats and mice ingesting neotame in amounts up to 1,000 mg/kg bw/d and 4,000 mg/kg bw/d, respectively. Thus, the agency concludes that the hypothetical formation of nitrosamine compounds from neotame poses no safety concerns.

Finally, the agency recognizes that one cannot absolutely rule out the liver as a target organ for the toxic effects of neotame when it is ingested at exaggerated dose levels. However, as discussed in the agency's response to this comment, and elsewhere in this document, the agency concludes that at expected levels of dietary intake of neotame there is no concern for potential toxic effects to the liver.

One comment stated that “[t]he long-term studies conducted in the dog species show definite signs of toxicity which, through close inspection of the pharmacokinetic data generated in the study and specific PK metabolism studies, is shown to be related to systemic exposure of the parent compound.” Subsequently, the comment referred to “a non-linear increase in systemic exposure of the parent compound and its metabolite over the dose range studied.” The comment asserted that this nonlinear increase in systemic exposure to the parent compound and its metabolite is related to decreases in body weight gain in the dog.

In response, the agency notes that the analysis of PK parameters (i.e., area under the curve, and maximum concentration) discussed in the comment is based on data from the 13-week dog study, which the agency does not consider to be a long-term study as claimed in the comment. In the agency's review of this study (Ref. 16), decreased body weight gains were observed in dogs of both sexes at dietary neotame intakes of 600 and 2,000 mg/kg bw/d (the 2,000 mg/kg bw/d dose level was reduced on day 15 to 1,200 mg/kg bw/d for the remainder of the 13-week study). These extremely high dose levels are 6,000 to 20,000 times greater than the 90th percentile EDI for neotame. At lower levels of neotame intake (i.e., 60 and 200 mg/kg bw/d), there were no effects on body weight gain in either sex. In considering the PK parameters derived from blood concentration data from the dogs fed these lower levels of neotame, the agency concludes (Ref. 19) that there was no evidence of increased systemic exposure to neotame or its metabolites. (It should be noted that PK measurements in the dog were evaluated only in the 13-week subchronic study.)

Moreover, as mentioned in Refs. 4, 10, and 17, a chronic (52-week) neotame dog feeding study was conducted. Because of its longer duration, the 52-week study is more definitive than the subchronic (13-week) dog study for assessing the toxicity of neotame. In the 52-week dog study, decreased body weight gains were noted only at the highest dose tested (800 mg/kg bw/d) and not at any of the lower dose levels (20, 60, and 200 mg/kg bw/d).

One comment pointed out that neotame produced discolored feces (white and gray) at the highest doses tested (200 and 800 mg/kg bw/d) in the 52-week dog study. This comment suggested that the change in fecal color was due to neotame's effect on bile salt metabolism and excretion. The agency agrees that dogs from the 800 mg/kg bw/d treatment group frequently excreted gray or white feces. However, there were only two incidences of gray feces from animals in the 200 mg/kg bw/d treatment group (a female on day 322 and a male on day 328), and no changes in appearance of feces from dogs in the 20 or 60 mg/kg bw/d treatment groups. There was also one incident of white feces observed for a female in the control group on day 70 of the study. Based on this evidence, as well as information in section II.C.2.e of this document, the agency concludes that there is no evidence to support a correlation between fecal color and liver toxicity in dogs fed neotame-containing diets during the 52-week study (Ref. 20).

One comment claimed that the dose levels of neotame tested in the definitive rabbit developmental (teratology) study were too low. The agency disagrees. FDA's evaluation of this study shows that there are statistically significant decreases in feed consumption and maternal body weights during the gestation period. Thus, the highest dose in the study (500 mg/kg bw/d) was sufficient to achieve maternal toxicity (Refs. 4 and 6). In addition, FDA notes that this study satisfies dose selection criteria recommended in the agency's Redbook guidelines (Ref. 21).

Another comment raised concern over post-implantation effects of neotame based on a maternal toxicity range-finding study in the rabbit. Because of the study's limitations, the agency does not share this concern. While a range-finding study may aid in identifying a compound's potential target organ effects, the primary objective of such a study is to establish appropriate dose levels to be further evaluated in a more definitive toxicity study. In the study in question, the agency notes that only six animals were used in each dose group, too few for an adequate assessment of the developmental (teratogenic) potential of a compound (Ref. 21). In the definitive rabbit developmental (teratology) study, a total of 25 mated females were assigned to the control and high-dose groups, and 20 each in the low- and mid-dose groups (Ref. 6). This larger number of animals allows for a more accurate assessment of the teratogenic potential of neotame in the rabbit as well as increasing the statistical power of the study. In the definitive rabbit teratology study, there were no significant dose-dependent, post-implantation effects due to neotame treatment.

One comment argued that neotame-induced effects on post-implantation loss, fetal size, and limb development in rabbits in the teratology study may be masked by the quality of the study and the high background incidence of these effects. The comment disagreed with the petitioner's interpretation of the data on post-implantation and other fetal observations. In particular, the comment asserted that the petitioner's interpretation of data was scientifically flawed because the petitioner made comparisons between treatment groups and the concurrent control group whose incidence percentages, according to the comment, were higher than those incidence percentages typically seen in historical control data.

FDA disagrees with this assessment. By using concurrent control animals, the study avoided the inherent variability that may be introduced into data analyses when historical control data are used in place of concurrent control data. Potential sources of variability from the use of historical control data include: (1) Differences in animal husbandry and animal room environment, (2) differences in diet compositions, (3) differences in times of study conduct, (4) differences in the sources of nutrients in animal diets, (5) differences in skills and experience of technicians or scientists, and (6) genetic drifts, as discussed in Haseman et al., 1989 3 and Roe, 1994. 4 Therefore, the agency concludes that, within the definitive rabbit study, in the absence of compelling evidence to the contrary, it is more appropriate to compare results between treated and concurrent control animals than to compare results between treated animals and historical control data. The agency also notes that the study followed the Redbook guidelines. Additionally, the agency finds no dose-dependent effects on post-implantation data when this study's treated and concurrent control groups are compared (Refs. 6 and 21).

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

One comment focused on the dosimetric and pharmacokinetic aspects of the rabbit developmental (teratology) study. The comment asserted that if a higher dose level, e.g., 1,000 mg/kg bw/d, rather than 500 mg/kg bw/d, had been used as the top dose in this definitive study, higher systemic exposure and greater toxicity would have occurred in the neotame-treated rabbits. As noted earlier with regard to the levels of neotame tested in this study, the agency finds that overall study design and dose selection were sufficient to achieve maternal toxicity. FDA believes that it is irrelevant if greater toxicity were to occur at a higher dose level than the highest dose used in the rabbit developmental (teratology) study. The highest dose used was sufficient to achieve maternal toxicity, based on statistically significant decreases in both feed intake and body weight gain, at the 500 mg/kg bw/d dose level. Furthermore, there is an appropriate NOEL for these effects (Refs. 6 and 21).

This comment also suggested that decreases in food intake and maternal body weight gain noted in the dams from the 500 mg/kg bw/d dose group were due to (tissue) accumulation of neotame. Based on a review of the PK data from the definitive rabbit developmental study, the agency concludes that these data do not suggest that bioaccumulation of neotame or its metabolites would occur even at a dose level of 500 mg/kg bw/d (Ref. 22). With regard to a possible relationship between (tissue) accumulation of neotame and decreases in feed intake and maternal body weight gain, the agency finds that a mechanistic explanation is unnecessary for an adequate evaluation of the study because the agency has determined an appropriate NOEL for these effects. As noted previously in section II.C.1.b of this document, based on the evaluation of other neotame feeding studies in the rat and dog, FDA concludes that there is no concern for the potential bioaccumulation of neotame or its metabolites at expected human intake levels.

One comment criticized several aspects of the Type II diabetes study. The comment stated that the design of this study was not adequate to detect small differences resulting from neotame treatment in the parameters examined. It cited the following inadequacies: Limited statistical power, parameters measured only under the quiescent metabolic condition of extended fasting, short duration, and no meal test. Despite these deficiencies, the comment recommended inclusion of the Type II diabetes study in the safety evaluation, because no other studies in the neotame safety database investigated the effects of neotame on glucose homeostasis in patients or animals with diabetes. Finally, the comment concluded that results from the Type II diabetes study were strongly suggestive of a treatment-related effect of neotame on fasting glucose control.

FDA agrees that although the experimental design of the Type II diabetes study limits its utility for assessing the potential effects of neotame on glucose homeostasis in Type II diabetics, it should be included in the safety evaluation of neotame (Ref. 23). Based on findings obtained during a directed clinical investigator site inspection and audit of study records at the facility responsible for this clinical trial, FDA concludes that the study was well-executed, irrespective of previously noted design limitations (Ref. 23).

The agency disagrees with the comment's conclusion that results from the trial with Type II diabetic subjects are strongly suggestive of a treatment-related effect of neotame on glucose control. FDA performed a detailed evaluation of the study data on fasting glucose pharmacodynamic parameters including: (1) Area under the effect curve, (2) area under curve, (3) percent perturbation, and (4) normal variations in glucose concentrations. Based on these analyses, the agency finds that under the conditions of the study, there were no significant changes in these parameters in study subjects that are attributable to neotame (Ref. 23). Overall, FDA concludes that under the conditions of the Type II diabetic study, blood glucose concentrations in Type II diabetic subjects following neotame treatment (at levels ranging from 5 to 15 times the 90th percentile EDI of 0.1 mg/kg bw/d) are comparable to those in the same subjects when given a placebo, and that any changes noted are within the normal range of variation and not the result of neotame treatment (Ref. 23).

Several comments expressed concern that harmful levels of methanol and phenylalanine may result from ingesting neotame-containing foods and beverages. FDA disagrees with these comments. Methanol release results from the de-esterification of neotame, which occurs more rapidly in the rat and rabbit than in the dog and human (see section II.C.1.d of this document). The agency concludes that, at the 90th percentile EDI of neotame, the resultant exposure to methanol would be extremely low, approximately 0.008 mg/kg bw/d (Ref. 5). Humans are exposed to much higher levels of methanol intake from their daily diet. For example, the methanol content of fruit juices ranges from 64 mg/liter (L) in orange juice to 326 mg/L in apricot juice. In contrast, the methanol content of neotame-sweetened carbonated beverages is estimated to be 1.37 mg/L.

Similarly, FDA concludes that the potential intake of phenylalanine from the use of neotame will be extremely low in comparison to that present in the daily diet. Based upon data cited by Koch and Wenz, 1984 (see footnote 2 in section II.C.1.d of this document), the agency notes that the daily dietary intake of phenylalanine for a healthy individual may range from 2.5 to 10 g/p/d. The daily intake of phenylalanine for a PKU homozygous child with a body weight of 20 kg is reported to range from 0.4 to 0.6 g/p/d or 400 to 600 mg/p/d (Ref. 5).

Using a conservative approach (Refs. 4 and 5), the agency calculates that the amount of phenylalanine exposure expected from the 90th percentile intake (0.1 mg/kg bw/d) of neotame (Ref. 2) by a 60 kg adult is 2.64 mg/p/d. FDA finds this amount of exposure trivial in contrast to that expected from the normal adult diet. For the PKU homozygous child, the additional phenylalanine intake expected from the 90th percentile ingestion of neotame (i.e., 0.17 mg/kg bw/d) (Ref. 3) by a 20 kg individual is 1.50 mg/p/d, an incremental amount that is equivalent to no more than 0.3 to 0.4 percent of the PKU homozygous child's normal daily phenylalanine intake. From these conservative estimates, the agency concludes that the potential intake of phenylalanine that may result from use of neotame as a general-purpose sweetener does not pose any safety concern (Refs. 4 and 5).

The agency has evaluated all the data and other information submitted by the petitioner in support of the safe use of neotame as a general-purpose sweetener and concludes that there is a reasonable certainty that no harm will result from the use of neotame as proposed. In accordance with a memorandum of understanding (MOU) between the Food Safety and Inspection Service (FSIS), United States Department of Agriculture, and FDA (65 FR 51758, August 25, 2000), a restriction from use “in meat and poultry” appears in the neotame regulation. This restriction is required when the petitioner does not specify whether the food additive is intended for such use. At this time, FSIS has not made a determination on the use of neotame in or on meat or poultry. Therefore, FDA concludes that the food additive regulations should be amended as set forth in this document.

In accordance with § 171.1(h) (21 CFR 171.1(h)), the petitions and the documents that FDA considered and relied upon in reaching its decision to approve the petitions are available for inspection at the Center for Food Safety and Applied Nutrition by appointment with the information contact person. As provided in § 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.

The agency has carefully considered the potential environmental effects of this action. FDA has concluded that the action will not have a significant impact on the human environment, and that an environmental impact statement is not required. The agency's finding of no significant impact and the evidence supporting that finding, contained in an environmental assessment, may be seen in the Dockets Management Branch (see ADDRESSES ) between 9 a.m. and 4 p.m., Monday through Friday.

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

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

Any person who will be adversely affected by this regulation may at any time file with the Dockets Management Branch (see ADDRESSES ) written objections by August 8, 2002. Each objection shall be separately numbered, and each numbered objection shall specify with particularity the provisions of the regulation to which objection is made and the grounds for the objection. Each numbered objection on which a hearing is requested shall specifically so state. Failure to request a hearing for any particular objection shall constitute a waiver of the right to a hearing on that objection. Each numbered objection for which a hearing is requested shall include a detailed description and analysis of the specific factual information intended to be presented in support of the objection in the event that a hearing is held. Failure to include such a description and analysis for any particular objection shall constitute a waiver of the right to a hearing on the objection. Three copies of all documents are to be submitted and are to be identified with the docket number found in brackets in the heading of this document. Any objections received in response to the regulation may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

The temporary regulations that are the subject of these corrections are under sections 1502 and 172 of the Internal Revenue Code.

An interim final rule on Sub-Acute Care Program; Uniform Skilled Nursing Facility Benefit; Home Health Care Benefit; Adopting Medicare Payment Methods for Skilled Nursing Facilities and Home Health Care Providers was published on Thursday, June 13, 2002 (67 FR 40597) added a new § 199.4(e)(21) on home health services. A final rule on Revisions to Coverage Criteria for Transplants, Cardiac and Pulmonary Rehabilitation and Ambulance Services was published on June 25, 2002 (67 FR 42717) also added a new § 199.4(e)(21) on Pulmonary rehabilitation. This document corrects the paragraph designation.

In FR Doc 02-15913 published on June 25, 2002 (67 FR 41721) make the following correction: On page 41721, in the second column, redesignate paragraph (e)(21) as paragraph (e)(22).

We did not publish a notice of proposed rulemaking (NPRM) for this regulation. Under 5 U.S.C. 553(b)(B), the Coast Guard finds that good cause exists for not publishing a NPRM. Publishing a NPRM, which would incorporate a comment period before a final rule could be issued, would be contrary to public safety interests since immediate action is needed to minimize potential danger to the public because there will be numerous spectator craft in the area.

For the same reason, under 5 U.S.C. 553(d)(3), the Coast Guard finds that good cause exists for making this rule effective less than 30 days after publication in the Federal Register .

On May 7, 1998, the Coast Guard published a Notice of Proposed Rulemaking in the Federal Register (63 FR 25187), seeking comments on the establishment of permanent special local regulations for the Deerfield Beach Super Boat Race. No comments were received during the comment period. On June 26, 1998, the Coast Guard published a final rule in the Federal Register (63 FR 34813) creating the permanent special local regulations in 33 CFR 100.733. The published rule is effective on the third Sunday in July.

However, this year the third Sunday in July will put the race the weekend before the mini-lobster season. The race organizers are moving the race date up one week this year to avoid conflict with vessels and people preparing for the mini-lobster season.

Super Boat International Productions Inc., is sponsoring a high-speed power boat race that will take place on July 14, 2002 in the Alantic Ocean off Deerfield Beach, Florida. Approximately 35 race boats, ranging in length from 24 to 50 feet, will participate in the event. There will also be approximately 200 spectator craft. The race boats will be competing at high speeds with numerous spectator craft in the area, creating a hazard in the navigable waterways. These regulations will create a regulated area offshore of Deerfield Beach that will only allow participant vessels to enter and establish a spectator craft area.

The permanent special local regulations in 33 CFR § 100.733 have been in place since 1998. The rule is effective on the third Sunday in July. However, this year the third Sunday in July will put the race the weekend before the mini-lobster season. The race organizers are moving the race date this year to avoid conflict with vessels and people preparing for the mini-lobster season.

This rule is not a “significant regulatory action” under section 3(f) of Executive Order 12866, Regulatory Planning and Review, and does not require an assessment of potential costs and benefits under section 6(a)(3) of that Order. The Office of Management and Budget has not reviewed it under that Order. It is not “significant” under the regulatory policies and procedures of the Department of Transportation (DOT) (44 FR 11040, February 26, l979).

The Coast Guard expects the economic impact of this proposed rule to be so minimal that a full Regulatory Evaluation under paragraph 10e of the regulatory policies and procedures of Department of Transportation is unnecessary because vessels will be able to transit around the regulated area and entry into the regulated area is prohibited for only 6 hours on the day of the event.

Under the Regulatory Flexibility Act (5 U.S.C. 601-612), we have considered whether this rule would have a significant economic impact on a substantial number of small entities. The term “small entities” comprises small businesses, not-for-profit organizations that are independently owned and operated and are not dominant in their fields, and governmental jurisdictions with populations of less than 50,000.

The Coast Guard certifies under 5 U.S.C. 605(b) that this rule will not have a significant economic impact on a substantial number of small entities because small entities will be able to transit around the regulated area and entry into the regulated area is prohibited for only 6 hours on the day of the event.

A regulated area encompasses all waters within a box established by joining the following points:

A spectator area is established in the vicinity of the regulated area for spectator traffic and encompasses all waters within a box established by joining the following points:

All coordinates reference Datum NAD: 83.

Entry into the regulated area by non-participant persons or vessel is prohibited unless authorized by the Coast Guard Patrol Commander. After the completion of scheduled races and the departure of participants from the regulated area, traffic may resume normal operations at the discretion of the Coast Guard Patrol Commander. The Coast Guard Patrol Commander may also permit traffic to resume normal operations between scheduled racing events.

Under section 213(a) of the Small Business Regulatory Enforcement Fairness Act of 1996 (Pub. L. 104-121), we offered to assist small entities in understanding the rule so that they could better evaluate its effects on them and participate in the rulemaking process.

Small businesses may send comments on the actions of Federal employees who enforce, or otherwise determine compliance with, Federal regulations to the Small Business and Agriculture Regulatory Enforcement Ombudsman and the Regional Small Business Regulatory Fairness Boards. The Ombudsman evaluates these actions annually and rates each agency's responsiveness to small business. If you wish to comment on actions by employees of the Coast Guard, call 1-888-REG-FAIR (1-888-734-3247).

This rule calls for no new collection of information under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

A rule has implications for federalism under Executive Order 13132, Federalism, if it has a substantial direct effect on State or local governments and would either preempt State law or impose a substantial direct cost of compliance on them. We have analyzed this rule under that Order and have determined that it does not have implications for federalism.

The Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1531-1538) requires Federal agencies to assess the effects of their discretionary regulatory actions. In particular, the Act addresses actions that may result in the expenditure by a State, local, or tribal government, in the aggregate, or by the private sector of $100,000,000 or more in any one year. Although this rule will not result in such an expenditure, we do discuss the effects of this rule elsewhere in this preamble.

This rule will not effect a taking of private property or otherwise have taking implications under Executive Order 12630, Governmental Actions and Interference with Constitutionally Protected Property Rights.

This rule meets applicable standards in sections 3(a) and 3(b)(2) of Executive Order 12988, Civil Justice Reform, to minimize litigation, eliminate ambiguity, and reduce burden.

We have analyzed this rule under Executive Order 13045, Protection of Children from Environmental Health Risks and Safety Risks. This rule is not an economically significant rule and does not create an environmental risk to health or risk to safety that may disproportionately affect children.

This rule does not have tribal implications under Executive Order 13175, Consultation and Coordination with Indian Tribal Governments, because it does not have a substantial direct effect on one or more Indian tribes, on the relationship between the Federal Government and Indian tribes, or on the distribution of power and responsibilities between the Federal Government and Indian tribes.

We have analyzed this rule under Executive Order 13211, Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use. We have determined that it is not a “significant energy action” under that Order because it is not a “significant regulatory action” under Executive Order 12866 and is not likely to have a significant adverse effect on the supply, distribution, or use of energy. It has not been designated by the Administrator of the Office of Information and Regulatory Affairs as a significant energy action. Therefore, it does not require a Statement of Energy Effects under Executive Order 13211.

We have considered the environmental impact of this rule and concluded that under figure 2-1, paragraph 34(h), of Commandant Instruction M16475.lD, this rule is categorically excluded from further environmental documentation. A “Categorical Exclusion Determination” is available in the docket for inspection or copying where indicated under ADDRESSES.

The Coast Guard published a final rule in the Federal Register on August 17, 1987, (52 FR 30671) establishing a safety zone for the waters within 1330 yards of Ammunition Island, latitude 61°07′5″ N, longitude 146°18′ W, (NAD 83) and the vessel moored or anchored at Ammunition Island, Port Valdez, Alaska (33 CFR 165.1703). The zone is needed to protect the safety of persons and vessels operating in the vicinity during ammunition and explosives loading and offloading operations.

It was recently discovered that the listed position for Ammunition Island was incorrect. The Coast Guard is correcting the listed position for Ammunition Island to latitude 61°07′28″ N, 146°18′29″ W (NAD 83).

Outline of This Document: The contents of this preamble are listed in the following outline:

This final rule may affect the following entities: (1) Persons in charge of vessels or facilities that may release CERCLA hazardous substances into the environment; and (2) entities that plan for or respond to such releases.

EPA does not intend for this table to be exhaustive, but rather to provide a guide for readers regarding entities likely to be affected by this action. Other entities not listed in the table may also be affected. You can determine whether your organization is affected by examining the changes being made to 40 CFR part 302. If you have questions about the applicability of this action to a particular entity, consult the contact names and phone numbers listed in the preceding FOR FURTHER INFORMATION CONTACT section of this preamble.

The Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), 42 U.S.C. 9601 et seq. , as amended, gives the Federal government broad authority to respond to releases or threats of releases of hazardous substances from vessels and facilities. The term “hazardous substance” is defined in section 101(14) of CERCLA by reference to various Federal environmental statutes.

Under CERCLA section 103(a), the person in charge of a vessel or facility from which a CERCLA hazardous substance has been released in a quantity that equals or exceeds its reportable quantity (RQ) must immediately notify the National Response Center (NRC) of the release. A release is reportable if an RQ or more is released within a 24-hour period (see 40 CFR 302.6). In addition to the reporting requirements under CERCLA section 103, section 304 of the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. 11001 et seq. , requires owners or operators of certain facilities to report releases of extremely hazardous substances and CERCLA hazardous substances to State and local authorities (see 40 CFR 355.40). After the release of a hazardous substance in a quantity equal to or greater than its RQ, facility owners or operators must immediately notify the community emergency coordinator for each local emergency planning committee for any area likely to be affected by the release, and the State emergency response commission of any State likely to be affected by the release.

Section 102(b) of CERCLA establishes RQs of one pound (“statutory RQs”) for releases of most CERCLA hazardous substances. Under section 102(a) of CERCLA, the Administrator of EPA has the authority to adjust these RQs by regulation (“adjusted RQs”). The list of CERCLA hazardous substances and RQs is codified in Table 302.4 of 40 CFR 302.4.

EPA and other Federal agencies periodically review the regulations they administer to identify those rules that are obsolete or unduly burdensome. For example, on June 29, 1995, EPA published a final rule (60 FR 33912) eliminating a number of legally obsolete regulations. Now we are taking another step in the ongoing review of our rules. EPA has reviewed 40 CFR part 302 and is correcting typographical errors in the table of hazardous substances. We also are revising regulatory text to make it more concise, conform more closely to statutory language, and eliminate text that is redundant or legally obsolete. All of these changes are editorial and do not affect any substantive aspects of the CERCLA release reporting program.

Because these corrections are editorial, EPA does not anticipate that any costs will be associated with this rulemaking. Rather, we expect that these corrections will serve to reduce confusion among the regulated community and government authorities about release reporting regulations contained in 40 CFR part 302 and, therefore, reduce the burden of complying with these regulations.

EPA is publishing this rule without prior proposal because we view these changes as noncontroversial amendments and anticipate no adverse comment. Section 553 of the Administrative Procedure Act, 5 U.S.C. 553(b)(3)(B), provides that, when an agency for good cause finds that notice and public procedure is impracticable, unnecessary, or contrary to the public interest, the agency may issue a rule without providing notice and an opportunity for public comment. EPA has determined that there is good cause for making today's rule final without prior proposal and opportunity for comment because the removals and revisions contained in this final rule are editorial and do not affect any substantive aspects of the CERCLA release reporting program. Thus, notice and public comment procedure are unnecessary. EPA finds that this constitutes good cause under 5 U.S.C. 553(b)(3)(B). For the same reason, EPA has also determined that it has good cause under 5 U.S.C. 553(d) to make the rule effective upon publication.

The following section describes the specific corrections that EPA is making to 40 CFR part 302 in today's rulemaking.

EPA believes that listing abbreviations in 40 CFR 302.2 is unnecessary, because these terms: (1) Are defined elsewhere in 40 CFR part 302 (as is the case with “CASRN” and “kg”); (2) are not used in this CFR part (as in the case of “lb” for pound); or (3) would more appropriately be defined when the term is first used (such as “RQ” and “RCRA”). For these reasons, EPA is removing and reserving 40 CFR 302.2.

The definition of “release” in 40 CFR 302.3 was, at the time we codified it in the CFR in 1985, the same as the statutory definition of this term in CERCLA section 101(22). The Superfund Amendments and Reauthorization Act of 1986 (SARA), however, changed the statutory definition; for this reason, we are revising the definition of “release” in 40 CFR 302.3 to reflect these amendments, which included language regarding abandonment or discarding of containers. EPA proposed this change in a July 19, 1988, proposed rule (53 FR 27268) and did not receive any adverse comments on this issue.

In addition, the definition of “reportable quantity” in 40 CFR 302.3 is being changed to add the abbreviation “(RQ)” so that the term is defined when first used in 40 CFR part 302.

Section 302.5(b) refers to toxicity identified in the Resource Conservation and Recovery Act (RCRA) regulations at 40 CFR 261.24. In 1990, EPA revised 40 CFR 261.24 as well as Table 302.4 to delete references to the terms “extraction procedure” and “EP” toxicity. To be consistent with these changes, EPA is revising paragraph (b) of 40 CFR 302.5 to delete references to “EP” toxicity.

An additional Washington phone number ((202) 267-2675), a facsimile number ((202) 267-2165), and a telex number (892427) are being added to the list of National Response Center (NRC) phone numbers in paragraph (a) of 40 CFR 302.6.

The penalty description in 40 CFR 302.7(a)(3) was, at the time we codified it in the CFR in 1985, consistent with the penalty provisions in CERCLA section 103(b). In 1986, however, SARA changed CERCLA section 103(b) to include language regarding submission of false information. EPA proposed this change in the July 19, 1988 proposed rule and did not receive any adverse comments on this issue. Thus, EPA is revising paragraph (a)(3) of 40 CFR 302.7 to conform to the revised language of CERCLA section 103(b).

The reference to paragraph (a) in 40 CFR 302.8(e)(1)(iv)(H) and 40 CFR 302.8(f)(4)(viii) is incorrect, and is being changed to reference paragraph (b).

Because corrections and other changes to Table 302.4 that are described below are numerous and pervasive, we are reprinting Table 302.4 in its entirety in today's rule. We hope that this reprint of Table 302.4 will prove to be a useful resource for the public and the regulated community until such time as the revised volume of 40 CFR part 302 that contains these changes is published. Amendatory instruction 5 in today's direct final rule accounts for the removal of the previous version of Table 302.4, and its replacement with the version published in today's final rule.

Three columns in Table 302.4 of 40 CFR 302.4 contain information that is duplicated elsewhere in the table or is no longer relevant to the listing of hazardous substances and reportable quantities. For this reason, EPA is deleting these columns from Table 302.4 in today's rulemaking.

We believe that deleting these columns will serve to: (1) Simplify the table and reduce confusion among the regulated community and government authorities about its use; (2) reduce the number of typographical and other errors that are introduced into the table; and (3) allow the table to be printed in a “portrait” rather than “landscape” format, resulting in a reduction in the number of CFR pages. A description of each of the columns identified for deletion is included below.

EPA lists substances in Table 302.4 by the names used in certain other environmental statutes (e.g., RCRA, the CWA, or the Clean Air Act (CAA)) or in their implementing regulations. When the substance is known by different names in different regulatory programs, EPA lists these names as separate entries in Table 302.4's Hazardous Substance column. In addition, Appendix A to Table 302.4 lists these synonyms together, by Chemical Abstracts Service Registry Number (CASRN).

Because the synonyms are all listed alphabetically in the Hazardous Substance column, and because Appendix A provides a per-substance grouping of all these synonyms, the Regulatory Synonyms column includes only unnecessary duplicative information. Therefore, EPA is deleting this column from Table 302.4 in today's final rule.

When Table 302.4 was first published in the Federal Register in 1985, the Statutory RQ column served a useful purpose because (1) CWA hazardous substances generally had different statutory RQs than other CERCLA hazardous substances; and (2) the Agency had not yet adjusted many of the statutory RQs for these substances.

Today, however, all of the statutory RQs for the CWA hazardous substances have been adjusted and, for any new substance added to Table 302.4, the statutory RQ is always one pound. When new substances are added to the list, footnote “##” is added to the Final RQ Pounds column indicating that the substance has a one-pound statutory RQ; thus, the Statutory RQ column provides only redundant or obsolete information. In addition, this column can be a source of errors; for example, at least seven substances have had incorrect information in the Statutory RQ column. EPA is deleting the Statutory RQ column from Table 302.4 in today's final rule.

The “Final RQ Category” column was used in Table 302.4 in the first CERCLA reporting program final rule on April 4, 1985, because members of the regulated community were familiar with a similar association between letter categories and numerical RQs (X = 1 pound, A = 10 pounds, B = 100 pounds, etc.) in the Clean Water Act (CWA) hazardous substance regulations (40 CFR part 117). The CWA categories, however, correspond to ranges of aquatic toxicity, while the CERCLA categories are simply another way of expressing the RQ value. EPA originally proposed the CWA categories (A, B, C, and D) in 1975, based on the hazardous material classification system for a 1973 international convention. A 1978 final rule for CWA RQs added another category (X).

The Category column provides little or no useful information on the CERCLA list of hazardous substances in Table 302.4, because the next column gives the RQ in pounds. Today, the category is a source of errors and confusion. For example, prior to today's rulemaking, the category for six substances was incorrectly listed as X, even though the RQs are 10, 100, or 1000 pounds. EPA is deleting the Category column from Table 302.4 in today's final rule.

Because EPA is removing the Regulatory Synonyms, Statutory Code, and Final RQ Category columns from Table 302.4 in today's rulemaking, we are revising the note that precedes Table 302.4 to remove references to these columns. The revised note will also identify Appendix A to Section 302.4 as a source for identifying regulatory synonyms of substances that appear on the CERCLA list of hazardous substances.

EPA has identified other errors in Table 302.4. The majority of these errors are either typographical or the result of inadvertent omissions; the scope of what is regulated and how it is regulated will not change. Therefore, these corrections qualify for the “good cause” exemption as “minor or technical amendments.”

The most commonly found errors in Table 302.4 are inadvertent discrepancies between an individual hazardous substance name that appears on the CERCLA list and the same name as it appears in other statutes (i.e., RCRA section 3001, CWA sections 307 and 311, and CAA section 112) and their implementing regulations. In today's rule, EPA is making corrections to the hazardous substance names of a number of CERCLA entries to make them consistent with names that appear in these other regulatory lists. Many of these corrections are simple and involve, for example, the deletion of an unnecessary hyphen or the addition of parentheses. In addition, to help make each entry more readable, we are changing all of the CASRNs listed in Table 302.4 to include hyphens in the appropriate places (e.g., changing “50000” to “50-00-0” for formaldehyde). Other types of corrections to Table 302.4 included in today's rule that require more explanation are described below.

The most commonly found errors in the entries for hazardous waste streams (i.e., F- and K-waste streams) in Table 302.4 are inadvertent discrepancies between the waste stream description that appears on the CERCLA list and the description for the same waste stream as it appears in the RCRA regulations at 40 CFR 261.31 and 261.32. In the years since Table 302.4 was first published in the CFR in 1985, EPA has amended the descriptions of several waste streams in the RCRA regulations, but did not make conforming changes to these entries in 40 CFR 302.4. EPA does not intend to retain two different descriptions of the same waste stream in the RCRA and CERCLA regulations; thus, we are removing obsolete descriptions of certain waste streams from Table 302.4 and replacing them with the current descriptions from 40 CFR part 261. Some of these corrections are simple; other types of corrections that require more explanation are described below.