DOCUMENT NUMBER: znz^ooi Pulled for Attorney-Client Privilege / Work Product Federal Register / Vol. 58, No. 195 / Tuesday, October 12, 1993 / Proposed Rules Issued in Renton. Washington, on October 5. 1993. Suzanne Stevens. Acting Manager, Transport Airplane Directorate. Aircraft Certification Service. |FR Doc. 93-24918 Filed 10-8-93: 8:45 am) BILLING CODE 4914-13-P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 5, 25,170, 171, and 174 [DocketNo. 92N-0181] RIN 0905—AD86 Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. SUMMARY: The Food and Drug Administration (FDA) is proposing to establish a process for determining when the likelihood or extent of migration to food of a substance used in a food-contact article is so trivial as not to require regulation of the substance as a food additive. Under this process. information about the proposed use of a substance will undergo an abbreviated review by FDATas opposed to the extensive review and formal issuance of a regulation normally required for food additives. In this document. FDA is proposing the criteria that it will use as part of this review in deciding whether to regulate the use of a substance as a food additive, as well as identifying the types of data that it will need to make this determination. DATES: Written comments by December 13. 1993. ADDRESSES: Submit written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Edward J. Machuga. Center for Food Safety and Applied Nutrition (HFS216). Food and Drug Administration. 200 C St. SW.. Washington. DC 20204. 202-254-9528. , SUPPLEMENTARY INFORMATION: I. Background In 1958, Congress amended the Federal Food, Drug, and Cosmetic Act (the act) to require premarket approval of food additives (sections 201 (s). 402(a)(2)(C), and 409 (21 U.S.C. 321(s). BFG16354 ^ fL X Z method approved by the Manager, Los those service bulletins after September 10. Angeles Aircraft Certification Office (ACO), 1990 (the effective date of AD 90-16-04, Amendment 39-6613), whichever occurs FAA, Transport Airplane Directorate. later, inspect for cracks in accordance with (2) Modification in accordance with those service bulletins. Repeat these paragraph (d) of this AD terminates the inspections thereafter at the intervals individual inspection requirements of the specified in the service bulletins listed in applicable service bulletin. Table 2.1 of the SARD, Revision A or (d) Prior to four years after September 10. Revision B. 1990, accomplish the structural (1) If any crack is found as a result of any modifications stipulated in the service inspection, prior to further flight, either bulletins specified in paragraph (c) of this accomplish the terminating modification in AD. accordance with the applicable service (e) Within the threshold for inspections bulletin, or repair in accordance with a specified in the service bulletins listed in method approved by the Manager. Los Table 2.2 of the SARD. Revision B. or within Angeles Aircraft Certification Office (ACO), one repetitive inspection period specified in FAA. Transport Airplane Directorate. those service bulletins after the effective date Note 3: Detection of any discrepancies of this AD. whichever occurs later, inspect other than cracking necessitates appropriate for cracks in accordance with those service corrective action in accordance with the bulletins. Repeat these inspections thereafter provisions of Part 43 of the Federal Aviation at the intervals specified in the service Regulations (FAR). bulletins listed in Table 2.2 of the SARD. (2) Modification in accordance with Revision B. paragraph (b) of this AD terminates the (1) If any crack is found during any individual inspection requirements of the inspection, prior to further flight, either applicable service bulletin. accomplish the terminating modification in (b) For service bulletins other than those accordance with the applicable service identified in paragraph (c) of this AD. prior bulletin, or repair in accordance with a to reaching the incorporation thresholds method approved by the Manager. Los listed in the SARD. Revision A or Revision Angeles Aircraft Certification Office (ACO). B. or prior to four years after September 10. 1990. whichever occurs later, accomplish the FAA, Transport Airplane Directorate. (2) Modification in accordance with structural modifications specified in the service bulletins listed under "STB No. Rev." paragraph (f) of this AD terminates the individual inspection requirements of the in Table 2.1 of the SARD. Revision A or applicable service bulletin. Revision B. (f) Prior to reaching the incorporation Note 4: The service bulletin revision levels thresholds listed in the SARD. Revision B, or lilted under ••Recommended Modification" "within four years after the effective date of— in Table 2.1 of the SARD. Revision B. are "acceptable revisions for modifications---------- this AD, whichever occurs later, accomplish the structural modifications specified tn the accomplished prior to September 10,1990. service bulletins listed in Table 2.2 of the Note 5: The modifications required by this SARD, Revision B. paragraph do not terminate the inspection Note 6:The service bulletin revision levels requirements of any other AD unless that AD listed under “Recommended Modification" specifies that any such modification in Table 2.2 of the SARD. Revision B. are constitutes terminating action for the acceptable revisions for modifications inspection requirements. accomplished prior to the effective date of (c) For McDonnell Douglas Service this AD. Bulletins A30-37, 30-38. 53-16. 53-19, 53Note 7: The modifications required by this 25. 54-11. 54-27. 54-33. 55-2, and 57-7. paragraph do not terminate the inspection listed in Table 2.1 of the SARD, Revision A: and for .McDonnell Douglas Service Bulletins requirements of any other AD unless that AD specifies that any such modification A30—37. 30-38. 53-16. 53-19. 53-25. 54-11. constitutes terminating action for the 54-27. 55-2. and 57-7. listed in Table 2.1 of inspection requirements. the SARD. Revision B: Within the threshold for inspections listed under "S/B Change (g) An alternative method of compliance or Required" in Table 2.1 of the SARD. Revision adjustment of the compliance time that A or Revision B. or within one repetitive provides an acceptable level of safety may be inspection period specified under “STB used if approved by the Manager. Los Change Required" in Table 2.1 of the SARD. Angeles Aircraft Certification Office (ACO). Revision A or Revision B. after September 10. FAA. Transport Airplane Directorate. 1990. whichever occurs later, inspect for Operators shall submit their requests through cracks in accordance with a method an appropriate FAA Principal Maintenance approved by the Manager. Los Angeles Inspector, who may add comments and then Aircraft Certification Office (ACO). FAA. send it to the Manager, Los Angeles ACO. Transport Airplane Directorate. Repeat these Note 8: Information concerning the inspections thereafter at the intervals existence of approved alternative methods of specified under "STB Change Required" in compliance with this AD. if any. may be Table 2.1 of the SARD. Revision A or obtained from the Los Angeles ACO. Revision B. (h) Special flight permits may be issued in (1) If any crack is found during any accordance with FAR 21.197 and 21.199 to inspection, prior to further flight, either operate the airplane to a location where the accomplish the terminating modification in accordance with the applicable service requirements of this AD can be bulletin, or repair in accordance with a accomplished. 52719 Federal Register / Vol. 58, No. 195 / Tuesday, October 12, 1993 / Proposed Rules 342(a)(2)(C), and 348)). A "food additive,” as defined in section 201 (s) of the act, is: * ’ * any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; ’ * *). if such substance is not generally recognized, among experts qualified by scientific training or experience to evaluate its safety, as having been adequately shown through scientific procedures * * ’ to be safe under the conditions of its intended use * ' *. Under section 409(a) of the act, the use of a food additive is deemed unsafe unless it either conforms to the terms of a regulation prescribing its use or to an exemption for investigational use. Consequently, the safety of the substance under its intended conditions of use must be demonstrated, and a food additive regulation issued, before the substance can be used in food. Petitions submitted to establish that a use of a food additive is safe ordinarily contain or reference data from toxicological studies that demonstrate to a reasonable certainty that there will be no harm resulting from the specific use of the subject additive. In this regard, petitions must include information that will enable FDA to estimate the dietary concentration resulting from the intended use of the substance. They also address the potential for an------------------environmental impact resulting from the manufacture,Tiserand disposaTof the proposed food additive. l i l I I A strict interpretation' of the definition of "food additive" would make all substances that migrate, or may be expected to migrate, from foodcontact materials into food subject to premarket approval as food additives. However, agency personnel, in response to inquiries from manufacturers of foodcontact articles, have stated that certain specific uses of substances in foodcontact materials did not require regulation under the food additive provisions. Based on these responses, food additive petitions have not been submitted for use of substances that were expected to result in very low levels of migration and that did not raise any safety concerns. However, this system has never been formalized. In addition to submitting requests for exemptions from the food additive regulations for specific uses of specific substances, representatives of the food­ packaging and food-processing industries have suggested that FDA establish a threshold of regulation policy for such substances. For example, the Society of Plastics Industries submitted a citizen petition (Docket No. 77-0122) requesting that FDA modify § 170.3(e) (21 CFR 170.3(e)), the regulation that defines "food additive,” so that the use of a substance that does not result in detectable levels of migration into food-simulating solvents (using validated analytical methods sensitive to at least 50 parts per billion (ppb)) would be exempt from regulation as a food additive unless there was scientific evidence to indicate that the substance presents a significant risk of harm to human health. However, FDA has been reluctant to adopt these or any other proposals in the absence of data clearly showing that substances present in the daily diet at concentrations at or below the proposed threshold level would not pose safety concerns. regulatory action against the substance as an unsafe food additive or against the company that makes the substance for introducing an adulterated food into interstate commerce. Therefore, in cases where it is not clear whether the use of a food-contact article would meet the food additive definition, FDA recommends that manufacturers seek a determination under the procedures that FDA is proposing to avoid the possibility of regulatory action. II. Need fora Threshold of Regulation for Substances Used in Food-Contact Articles The existing informal practice of determining by letter when a petition is needed for a particular use of a substance presents several problems. While agency personnel have been issuing these letters over the past three A Federal court also has addressed decades, the analytical methods used to the issue of whether the use of a fooddetect migration into food from indirect contact material involving insignificant food additives, such as packaging migration into food can be exempted materials, have become capable of from the food additive regulations. In detecting and measuring much smaller Monsanto v. Kennedy, 613 F. 2d 947 quantities. As a result, many of the food(D.C. Cir. 1979)), the Monsanto Co. contact uses for which no migration into contended that no migration of food was detectable using older acrylonitrile copolymer resulted from analytical methodologies, may now be the use of their beverage bottles that shown to result in measurable levels of contained the substance, and that, migration. Therefore, the basis for some therefore, the bottles did not have to be letters issued for use of a food-contact regulated as food additives. In its material showing "no detectable decision, the court stated that the migration” may no longer be valid. This Commissioner of Food and Drugs may practice, however, provides no determine that the level of migration mechanism by which the informal into food of a particular substance is so opinions rendered by agency employees negligible as to present no public health can be updated to reflect scientific concerns and, in such cases, may -developments.-----------------------------------decline to define the substance as a fob? A second problem with these opinion additive even though it comes within letters is that scientific laws of diffusion the strictly literal terms of the statutory predict that any two substances that are definition of a food additive (see 613 F. 2d at 955). The cpurt also stated that the in contact with one another will tend to diffuse into each other (Ref. 1). As a Commissioner has the discretion to result, even if migration cannot be decline to exercise this exemption detected, it is still likely to be occurring authority (id. at 956). at some level below the detection limit. The agency recognizes that, Therefore, one could argue that all foodhistorically, a number of companies have made their own determination that contact uses may reasonably be expected to result in migration of the a particular substance effectively does food-contact material into food. not migrate to food and thus is not a A third problem with the current food additive under its conditions of practice is that because the criteria for use. They have marketed the products data needed to evaluate such requests without recourse to the regulatory have never been published, the quality process. Nothing in the regulatory of the requests submitted to FDA for scheme presented in this proposed rule review varies considerably. In many would prevent a company from making cases, the original submission does not its own determination that a particular contain adequate data, and FDA has to use of a substance does not meet the request additional data to complete the definition of a food additive. However, review. As a result, many of these as always, the company makes such a requests for informal opinions have to determination at its own risk. If the be reviewed several times. These agency learns of the use of a substance from, for example, a competitor and multiple reviews compete for the resources necessary to review food reaches a different conclusion than the additive petitions. company, the agency may take BFG16355 ZOOOf'i.TZ 52720 52722 Federal Register / Vol. 58, No. 195 / Tuesday, October 12, 1993 / Proposed Rules concentration level as the threshold of regulation: (1) Because it is possible that a substance that has not been tested for carcinogenicity may later be found to be a carcinogen, FDA also has evaluated the likelihood of carcinogenic toxic effects associated with substances present in the diet at 0.5 ppb or less. FDA used potency data on a large number of known carcinogens to estimate the likely risk that could be expected if an unstudied compound were later found to be a carcinogen. These data were obtained from a carcinogenic potency data base, compiled by Gold et al. (Refs. 6 through 8), that included data on more than 3,500 long-term chronic animal studies of 975 chemicals. FDA restricted its analysis to the 477 animal carcinogens that were the subject of oral feeding studies showing a statistically significant increase in the incidence of animals with specific neoplasms (pco.oi) (Ref. 9). FDA limited its analysis to oral feeding studies because the route of exposure to food additives is by ingestion. FDA further restricted its analysis to the 477 animal carcinogens that were the subject of oral feeding studies showing a statistically significant increase in the incidence of animals with specific neoplasms (p<0.01) to ensure that it considered only the most reliable studies. In those cases where multiple studies had been carried out on a specific chemical, the carcinogenic potency chosen provide an adequate safety margin, however, the dietary concentration chosen as a level that presents no regulatory concern should be well below 1,000 ppb. Therefore, FDA is proposing in § 170.39(a)(2XO to establish a dietary concentration of 0.5 ppb as the threshold of regulation for substances used in food-contact articles. A 0.5 ppb threshold is 2,000 times lower than the dietary concentration at which the vast majority of studied compounds are likely to cause noncarcinogenic toxic effects and 200 times lower than the chronic exposure level at which potent pesticides induce toxic effects. FDA believes that these safety margins, which are larger than the 100 fold safety factor that is typically used in applying animal experimentation data to humans (21 Cr R 170.22), support a conclusion that substances consumed in dietary concentrations at or below 0.5 ppb are not of regulatory concern. FDA considered the following additional factors in reaching its tentative decision to establish a 0.5 ppb dietary sex/organ combination. Finally, in assessing the appropriate dietary concentration level to use as the threshold of regulation level, FDA has assumed that the distribution of carcinogenic potencies of the 477 chemicals studied is representative of all known and unknown carcinogens, and that it is very unlikely that an unstudied compound would both be a carcinogen and have an intrinsic carcinogenic potency far greater than the typical potency observed for the studied compounds. Based on the range of potencies exhibited by these 477 animal carcinogens, FDA has determined that most known carcinogens pose less than one in a million lifetime risk if*present in the daily diet at 0.5 ppb (Ref. 9). Therefore, FDA tentatively finds that establishing a 0.5 ppb dietary concentration level as the “threshold of regulation” for food-contact articles would result in negligible risk, even in the event that a substance that is exempted from regulation as a food additive were later shown to be a carcinogen. (2) FDA also tentatively concludes that establishing a 0.5 ppb dietary concentration level as the threshold of regulation is appropriate because it corresponds to a migration level that is above the detection limit for many of the analytical methods used to quantify migrants from food-contact materials. Thus, decisions will usually be made based on dietary concentrations that result from measurable migration into food or food-simulating solvents rather than on worst-case estimates of dietary concentration based on the detection limits of the methods used in the analysis. For example, assuming a consumption factor1 of 5 percent (the minimum value used by FDA in the absence of specific market volume data), a dietary concentration of 0.5 ppb corresponds to a migration level of 10 ppb. Although detection limits can vary considerably, the analytical methods used to detect migration of food-contact materials can seldom reliably quantify migrants below 1 to 2 ppb. (3) FDA tentatively concludes that exempting from regulation as food additives those food-contact materials whose use results in dietary concentrations of 0.5 ppb or less is also consistent with the latitude given to FDA In the Monsanto v. Kennedy decision. The court ruled that in order for the “component” element of the food additive definition in section 201 (s) of the act to be met, FDA would have to determine (with a fair degree of i migrates__ into food in more than insignificant amounts. The court further stated that “ * * * the Commissioner may determine, based on the evidence before _ him, that the level of migration into food of a particular substance is so negligible as to present no public health or safety concerns • • This authority derives from the administrative discretion, inherent in the statutory scheme, to deal appropriately with de minimis2 3 situations. Based on the study of the toxicological effects of a large number of chemicals that is discussed above, FDA tentatively concludes that the presence of a substance in the daily diet at or below 0.5 ppb is so negligible as to present no public health concerns. Therefore, FDA is proposing to adopt 1 The consumption factor for a food packaging material is that fraction of food in the diet that could be in contact with this material. 3This doctrine is expressed in Latin as be minimis non curat lex (the law does not concern irsejf with trifles). BFG16357 21740004 of toxicological oral feeding studies, it is possible to predict the likely range of toxic potency for an unstudied compound based on an analysis of the toxic potencies of a large number of representative compounds. Analysis of the data on 18,000 acute oral feeding studies in rats and mice found that all of the acute toxic effects occurred above 1,000 ppb (Ref. 4). Because of the large number and wide variety of chemicals used in this analysis, it is representative of the substances used in the manufacture of food-contact articles. Therefore, this analysis can be used to predict the upper-bound dietary concentration at which an unstudied chemical (i.e., one that has not been the subject of toxicological feeding studies) is unlikely to cause acute toxic effects. The agency also considered the toxic effects that result from chronic exposure to chemical substances. The results of 2year chronic oral feeding studies on 220 compounds have shown that only 5 of the 220 chemicals exhibited toxic effects below 1,000 ppb. All 5 of the chemicals that were toxic at levels below 1,000 ppb were pesticides, compounds that would, based on their pesticidal activity, be expected to be more toxic than most substances (Ref. 5). However, even among these 5 pesticides, none exhibited toxic effects at dietary concentrations below 100 ppb. Based on the results of these analyses, the agency believes that it is reasonable to expect that the noncarcinogenic toxic effects caused by the majority of________ unstudied compounds would be Federal Register / Vol. 58, No. 195 / Tuesday, October 12, 1993 / Proposed Rules carcinogens and that do not contain carcinogenic impurities, unless the impurity has a TOso value of more than 6.25 mg/kg bodvweight/day (proposed § 170.39(a)(1)). ' FDA’s tentative decision to only review substances known to contain carcinogenic impurities under the proposed regulation if the carcinogenic impurity is shown to have a TDso value greater than 6.25 mg/kg bodyweight/day is conservative. However, FDA tentatively concludes that such conservatism is appropriate because of the limited showing that need be made for such substances. It will only be necessary to show that based on results reported in the scientific literature or on results of a chronic feeding study that has been previously reviewed by the agency, the TDso value for the impurity exceeds the specified level. If such a showing is made, that is the end of the inquiry about the impurity. This approach is in marked contrast to FDA’s review of petitions for food additives that appear to contain a carcinogenic impurity. In such cases, the agency carries out an in-depth review of the data to determine whether the impurity should be classified as a carcinogen. If FDA concludes that the impurity is a carcinogen, the agency uses risk assessment procedures to determine whether there is reasonable certainty that no harm will result from the use of the food additive containing the impurity. The quantitative risk assessment carried out by the agency is based on the cumulative dietary emc-ijnpunty resulting from the intended use of the food additive under review and from other regulated uses of the additive. The carcinogenic potency used in the risk assessment is that estimated by the agency based on a thorough review of the data available on the carcinogenic impurity. B. Selection of o Threshold of Regulation for :he Use of Direct Food Additives in Food-contcct A,rticles As mentioned above. FDA has tentatively concluded that there are certain limited types of situations in which the use of a substance in a foodcontact article that would result in a dietary concentration greater than 0.5 ppb should still qualify for an exemption from regulation as an indirect food additive. If a substance that is currently regulated for direct addition to food is intended to be used in a food-contact article, and if the dietary concentration of the substance resulting from the proposed indirect use is very small compared to the acceptable daily intake (ADI) for the substance based on data in FDA's files, the agency will consider granting an exemption from regulation for this use of the substance even if the dietary concentration will exceed 0.5 ppb. Because these substances will have already been the subject of acceptable safety studies that have established the level of use of the substance that is safe. FDA believes that the threshold for such substances can be established based not on a specific level of dietary concentration but on a specific percentage of the ADI, that is, 1 percent or less of the ADI for the substance (proposed § 170.39(a)(2)(ii)). This level of exposure would contribute only a small fraction of the ADI of a substance and would be well within the margin of safety for those direct food additives with small cumulative dietary exposures. For substances with high cumulative dietary exposures resulting from currently regulated direct food additive uses, a level of exposure that is 1 percent of the ADI would be within the margin of error for the estimated daily intake, which invariably is based on one or more worst-case assumptions, and would, therefore, not significantly affect the cumulative dietary exposure, even in the event that a particular substance has been granted exemptions for several different types of uses in food-contact articles. IV. Process for Evaluating Requests for Exemption From Regulation as a Food Additive FDA proposes to establish the following criteria to evaluate requeststo exempt substances from regulation as food additives: 1. The substance must not have been shown to be a carcinogen in humans or animals and must not contain a carcinogenic impurity with a TDjo value of less than 6.25 mg/kg bodyweight/day, and there must be no reason, based on the chemical structure of the substance, to suspect that the substance is a carcinogen (proposed § 170.39(a)(1)). Known carcinogens would be excluded from review under the proposed regulation because the use of carcinogens as food additives is prohibited by the Delaney Clause (section 409(c)(3)(A) of the act). 2. The substance must: (a) Not migrate, and not be expected to migrate, into food at levels that result in dietary concentrations that are above 0.5 ppb, corresponding to dietary exposures above 1.5 micrograms/person/day (based on a diet of 1,500 grams of solid food and 1,500 grams of liquid food per BFG16358 21740005 this level as the threshold of regulation in § 170.39. Known or suspected carcinogens would be excluded from review under the proposed regulation because the use of carcinogens as food additives is prohibited by the Delaney Clause (section 409(c)(3)(A) of the act). However, in Scott v. FDA, 728 F. 2d 322 (6th Cir. 1984). the court stated that a food additive that has not been shown to cause cancer, but that contains a carcinogenic impurity, may properly be evaluated under the general safety clause of the statute using risk assessment procedures to determine if there is reasonable certainty that no harm will result from the use of the substance. FDA has used risk assessment procedures to determine under what conditions a substance containing a carcinogenic impurity could be used in a food-contact article and pose no safety concerns. A widely used measure of a carcinogenic response in the scientific literature is the so-called ‘‘TDso.” that is, the feeding dose that causes cancer in 50 percent of test animals. FDA has calculated a theoretical TDso threshold at which carcinogenic impurities would present less than a one in a million risk, a level of risk generally considered to be very low, when present in the diet at 0.5 ppb. In using these risk assessment procedures, FDA assumed a linear relationship between the feeding dose and the carcinogenic response. Based on a linear dose/response relationship,_____ FDA determined that carcinogenic irnpuT-ities-i percent of test animals at feeding levels above 6.25 milligrams (mg) per kilogram (kg) bodvweight per day (i.e., TDso values above 6.25 mg/kg bodyweight/ day) will pose less than a one in a million hypothetical upper-bound lifetime risk if present in the daily diet at levels of 0.5 ppb (Ref. 10). If a chemical with a TDso value above 6.25 mg/kg bodyweight/day is present as an impurity in a substance that is exempted from regulation because its dietary concentration is 0.5 ppb or less, the level of the chemical in the diet as a result of the use of the exempted substance would obviously be considerably less than 0.5 ppb. Therefore, the hypothetical upperbnund lifetime risk of cancer from an impurity that is carcinogenic and that has a TDso value greater than 6.25 mg/ kg bodyweight/day would be expected to be well below one in a million and to pose effectively no safety concern. Based on this risk assessment, FDA proposes to limit its review under proposed § 170.39 to those substances that have not been shown to be 52723 Federal Register / Vol. 58, No. 195 / Tuesday, October 12, 1993 1 Proposed Rules person per day)3, and, therefore, not pose a public health or safety concern; (b) be currently regulated for direct Jdition into food and be used in a manner that would result in exposure levels that are less than 1 percent of the ADI as determined by safety data in FDA files {proposed § 170.39(a)(2)). 3. The substance must have no technical effect in or on the food to which it migrates (proposed § 170.39(a)(3)). FDA tentatively finds that there is no basis on which to exempt a substance that is added directly or indirectly to food at a level at which it has a technical effect in that food. 4. The use of the substance must not have a significant adverse impact on the environment (proposed § 170.39(a)(4]). To have the use of a substance in a food-contact article reviewed under this proposed regulation, a company would submit its request to the Division of Petition Control (HFS-216), Food and Drug Administration, 200 C St. SW., Washington, DC 20204 (proposed § 170.39(d)). The agency recognizes that it is impossible to foresee all of the safety issues that may be revealed by scientific information not presently available. Therefore, in proposed § 170.39(b), FDA is reserving the right to decline to grant