Federal Register / Vol. 64, No. 166 / Friday, August 27, 1999 / Rules and Regulations 46841

DEPARTMENT OF HEALTH AND for the prevention of vitamin K additional information supporting HUMAN SERVICES deficiency and as a source of approval of the petitioned use, supplemental niacin when used at a rate specifically the GLP statement as Food and Drug Administration not to exceed 2 grams per ton (g/t) of described in § 571.1(k). FDA believes complete feed. Heterochemical Corp., this course of action is appropriate to 21 CFR Part 573 111 East Hawthorne Ave., Valley supplement the record. FDA will also [Docket No. 94F±0283] Stream, NY 11580, filed objections to clarify the reasons for approving the the final rule in its entirety alleging that FAP, and provide Heterochemical and Food Additives Permitted in the Feed the studies upon which the petition any other interested party with an and Drinking Water of Animals; relies failed to conform to good opportunity to proffer facts that Menadione Nicotinamide Bisulfite laboratory practices (GLP’s) or good demonstrate FDA’s basis for approving clinical practices (GCP’s), and that the FAP 2228 was incorrect. AGENCY: Food and Drug Administration, regulation promotes deception of the FDA is therefore republishing the HHS. consumer and misbranding of the final rule and providing an additional ACTION: Final rule; republication and product. Heterochemical’s objections 30 days for submission of objections or opportunity to file objections or are: of additional information in support of additional information. 1. The record of the studies fails to the objections that have already been establish that any of the nonclinical SUMMARY: filed. In accordance with its discretion The Food and Drug laboratory studies (including target Administration (FDA) is republishing, under section 409(f) of the act (21 U.S.C. animal safety) on which the regulation 348(f)), FDA is not staying the final rule. with additional information, a final rule is based were conducted in accordance that published in the Federal Register of FDA will consider a stay, however, if with GLP’s as described in part 58 (21 one is requested, after having evaluated January 2, 1996 (61 FR 5). The rule CFR part 58). The record also fails to amended the food additive regulations any objections or other information filed provide, alternatively, a reason for in response to this document. (animal use) to reflect approval of a food noncompliance as required by § 571.1(k) additive petition (FAP) filed by Vanetta (21 CFR 571.1(k)). Furthermore, the II. Administrative Record (U.S.A.) Inc. Objections to the final rule record does not provide a basis for were filed. FDA is not acting on the A. Question of Adherence to GLP’s (Part identifying the differences between the 58 and § 571.1(k)) objections in this document, but is practices used and those required by the clarifying the basis of approval of the GLP regulations, so as to permit an In filing an FAP, the petitioner is petition and providing additional evaluation of the studies’ integrity and required to provide data and information. The agency also is reliability (i.e., if the target animal safety information to support the safe use of providing a new 30-day period for the studies are flawed, there is no the product as required by section submission of objections or of information in support of the safety of 409(c)(1) of the act. The supporting data additional information in support of the the food additive) (Ref. 1). and information include full reports of objections that were previously filed. 2. The record of the studies fails to investigations made with respect to the FDA has not stayed the effective date of establish that any of the clinical studies safety of use of the additive, including the final rule, effective January 2, 1996. on which the regulation is based were information as to the methods and DATES: Objections, additional conducted in accordance with GCP’s as controls used in conducting the information in support of the previously illustrated in FDA’s Center for investigations. Part 58 prescribes GLP’s filed objections, or additional written Veterinary Medicine’s (CVM’s) guidance for conducting those nonclinical objections and requests for a hearing, document entitled ‘‘Guideline on the laboratory studies that are used to must be submitted by September 27, Conduct of Clinical Investigations: support or are intended for use to 1999. Responsibility of Clinical Investigators support FAP’s or marketing permits for ADDRESSES: Submit written objections and Monitors for Investigational New products regulated by FDA. Compliance and/or additional information in Animal Drug Studies,’’ October 1992 with GLP’s is intended to ensure the support of objections previously (the guidelines cited by the objection quality and integrity of the safety data submitted to the Dockets Management were supplanted by a revised document filed to support approval of an FAP. If Branch (HFA–305), Food and Drug in May 1997) (Ref. 2). nonclinical laboratory studies are Administration, 5630 Fishers Lane, rm. 3. Heterochemical objects to the involved, an FAP shall include, for each 1061, Rockville, MD 20852. regulation in that it establishes MNB as study, a statement that the study was FOR FURTHER INFORMATION CONTACT: a source of supplemental niacin and conducted in compliance with GLP Sharon A. Benz, Center for Veterinary authorizes labeling the product as a requirements set forth under part 58, or Medicine (HFV–228), Food and Drug source of supplemental niacin. Based on if the study was not conducted in Administration, 7500 Standish Pl., a low level of niacin supplementation, compliance with the GLP’s, a brief Rockville, MD 20855, 301–827–6656. the firm contends that the labeling statement with the reason for SUPPLEMENTARY INFORMATION: promotes deception of the consumer noncompliance. and results in misbranding of food In FAP 2228, Vanetta submitted a I. Background within the meaning of the Federal Food, journal article (Ref. 1) supporting In the Federal Register of January 2, Drug, and Cosmetic Act (the act). approval of its petition. The studies 1996, FDA published a final rule that The preamble of the January 2, 1996, reported in the article were not amended the food additive regulations final rule stated that FDA evaluated the conducted in accordance with GLP’s, (animal use) to reflect approval of an data presented in the petition and and Vanetta did not submit a statement FAP (FAP 2228) filed by Vanetta concluded that use of the product is of the reason for noncompliance. (U.S.A.) Inc., 1770 East Market St., York, safe. The final rule stated that the food Accordingly, FDA is reopening the PA 17402. The final rule provides for additive regulations would be amended administrative record to include a the safe use of menadione nicotinamide as requested in the FAP. FDA is now statement from Vanetta on the reasons bisulfite (MNB) as a nutritional republishing the final rule to clarify its for the studies’ noncompliance with supplement in chicken and turkey feeds basis for approval, and to provide GLP’s, as required under § 571.1(k).

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B. Clarification of the Record demonstrating that inclusion of MNB in The approved conditions of use, as The objections Heterochemical filed chick diets improved blood clotting specified in the MNB regulation (21 CFR in response to FDA’s approval of MNB when compared to negative controls. 573.625(b)), state that MNB can be used point out that the basis for the agency’s The improvements observed in the as a ‘‘nutritional supplement in chicken decision was not clear. The study were similar to those seen when and turkey feeds for both the prevention administrative record for FAP 2228 another accepted source of vitamin K of vitamin K deficiency and as a source included various agency comments on activity was added to experimental of supplemental niacin.’’ The conditions of use appropriately the studies reported in the journal diets. The highest level of menadione compare the levels of vitamin K activity article by Oduho et al. The objector utilized in this study, 0.4 milligram from menadione and nicotinamide by interpreted the comments to mean that (mg)/kg diet, approaches that stating that MNB can prevent a vitamin the studies were invalid and thus did recommended by the National Research K deficiency, but is simply a source of not support approval of the FAP. Council, 0.5 mg/kg, for the type of birds niacin. As noted previously, niacin can Contrary to the objector’s interpretation, used in this experiment (Ref. 7). The serve as a generic name for all pyridine- the agency’s comments on the Oduho adequacy of 0.4 mg to meet the birds’ 3-carboxylic acids that exhibit studies did not question their validity, nutritional requirement is demonstrated nicotinamide activity (Ref. 3). By using and do not invalidate the agency’s final by the fact that the prothrombin times the different terms, the conditions of use decision that MNB is safe and achieves of 17 and 19 seconds for MNB and establish that MNB provides different its intended technical effect. However, menadione dimethylpyrimidinol levels of vitamin K and niacin activities. the objections made it clear that the bisulfite (MPB), an accepted source of The directions for use on the product agency needed to make additional vitamin K activity (21 CFR 573.620), fall label specify the minimum amount of comments to clarify the record. very close to the normal range for menadione and niacin in MNB, and do 1. Target Animal Safety chickens, which has been reported to so in units commonly used in the feed FAP 2228 included the Oduho article vary from 20 to 25 seconds (Ref. 8). The industry (Ref. 9). Animal nutritionists to support safety of MNB. The Oduho Oduho article reported the normal routinely mix feed ingredients to obtain article included what was described as prothrombin range for chicks to be 12 to a complete, balanced animal diet, and a chronic study (Ref. 1). The results 25 seconds. The bioavailability of the the composition of this diet normally reported in the article indicated that vitamin K activity, supplied by the changes with an animal’s weight and MNB is a safe and effective source of menadione component of MNB, did not age (Ref. 7). Therefore, users of the vitamin K and niacin activities. Niacin differ significantly from that of the product will refer to the minimum can serve as a generic name for all positive control substance, MPB. Both amounts specified on the MNB label pyridine-3-carboxylic acids that exhibit MNB and MPB were bioequivalent as an and mix feed accordingly with MNB nicotinamide activity (Ref. 3). Only active source of menadione. and other sources of niacin to provide when doses exceed 1,000 times the The agency noted that the levels of all nutritional needs based on the chick’s vitamin K requirement did the nicotinamide utilized in Oduho weight and age of the animals being fed. article’s authors report morbidity or experiment number 2 are below those Finally, the agency notes that the mortality. The data generated by the accepted as nutritionally adequate. MNB label follows the Association of chronic study, where up to 6 g of However, this study did demonstrate American Feed Control Officials menadione per kilogram (kg) complete that the nicotinamide portion of the (AAFCO) format, which the agency feed were fed to chick’s, support the MNB molecule was available to the concluded was acceptable. AAFCO, safety of the substance. chicks, i.e., that it is bioavailable to a primarily composed of State regulatory Although this chronic study was of similar extent as pure nicotinamide, officials, has developed a set of model relatively short duration (14 days), the which served as a control in the study. regulations concerning feed labeling. agency believes that it is sufficient to In addition, the low level of FDA generally concurs with the AAFCO support its conclusion that MNB is safe. nicotinamide supplementation is closer model regulations although these model The agency evaluated the results of the to the level of this vitamin supplied by regulations are not binding. Feed study in conjunction with the following MNB with the mandated 2 g per ton manufacturers routinely follow the and other available information that complete feed restriction. Both the model regulations when labeling feed further supported its final determination amount of nicotinamide supplied by and are familiar with the AAFCO that MNB is safe and achieves its MNB and other dietary sources of this requirements. intended technical effect. MNB compound will be utilized to formulate III. Opportunity for Objection hydrolyzes into menadione and a diet which meets the animal’s niacin nicotinamide. Menadione is prior nutritional requirements. A food additive shall, with respect to sanctioned as a source of vitamin K Vanetta amended its petition and any particular use or intended use of activity (Ref. 4), and nicotinamide submitted a preliminary report on such additive, be deemed to be unsafe, (niacinamide) is generally recognized as clinical studies conducted at the unless it and its use or intended use safe as a nutrient and/or dietary University of Georgia. This report conform to the terms of an exemption supplement under 21 CFR 582.5535 and supported the utility of MNB as a source that is in effect for investigational use, section 201(s) of the act (21 U.S.C. of vitamin K activity. Because the or there is in effect, and it and its use 321(s)). Both components have a long bioavailabilities of both the menadione or intended use are in conformity with, history of safe use in animal diets (Refs. and nicotinamide components of MNB a regulation issued under section 409(a) 4 and 5). were established by the Oduho article, of the act. With respect to any intended 2. Utility and the utility of MNB as a source of use of a food additive, a person may file Menadione and many of its vitamin K activity was confirmed in the a petition with the appropriate center derivatives have vitamin K activity. This University of Georgia experiments, the within FDA proposing the issuance of a vitamin has several biological functions, utility portion of the amended petition regulation prescribing the conditions one of the most important being in was acceptable. under which said additive may be safely blood clot formation (Ref. 6). The 3. Conditions of Use and Directions for used. The petition shall, in addition to Oduho article included a study Use any explanatory or supporting data,

VerDate 18-JUN-99 08:52 Aug 26, 1999 Jkt 183247 PO 00000 Frm 00028 Fmt 4700 Sfmt 4700 E:\FR\FM\A27AU0.076 pfrm04 PsN: 27AUR1 Federal Register / Vol. 64, No. 166 / Friday, August 27, 1999 / Rules and Regulations 46843 contain the name of the food additive, (superseded by ‘‘Guidance for Industry No. DEPARTMENT OF HOUSING AND its chemical name and composition, a 58,’’ May 1997). URBAN DEVELOPMENT statement of the conditions of the 3. National Research Council, Vitamin proposed use of such additive, together Tolerance of Animals, National Academy 24 CFR Part 103 with all directions, recommendations, Press, 1987. 4. ‘‘Food Additive Status of Vitamin K and suggestions proposed for the use of Active Substances in Animal Food’’ (48 FR [Docket No. FR±4433±F±02] such additive with specimens of 16748, April 19, 1983). proposed labeling. The petition shall 5. Title 21 CFR 121.101, ‘‘Substances that RIN 2529±AA86 also contain relevant data bearing on the are generally recognized as safe,’’ 1974 (21 physical or other technical effect the CFR part 582, 1998). Fair Housing Complaint Processing; additive is intended to produce, the 6. Suttie, J. W., ‘‘Vitamin K,’’ Handbook of Plain Language Revision and quantity of the additive required to Vitamins, edited by L. J. Machlin, Marcel Reorganization produce the desired effect, a description Dekker, Inc., 1991. of practicable methods for determining 7. National Research Council, The AGENCY: Office of the Assistant the quantity of the additive in or on Nutritional Requirements of Poultry, National Secretary for Fair Housing and Equal Academy Press, 1994. Opportunity, HUD. food and any substance formed in or on 8. Swenson, M. J. ‘‘Physiological properties food because of its use, and full reports and cellular and chemical constituents of ACTION: Final rule. of investigations made with respect to blood,’’ Duke’s Physiology of Domestic the safety of the use of the additive, Animals, edited by M. J. Swenson, Cornell SUMMARY: This final rule adopts an including information as to the methods University Press, 1977. interim rule, published in the Federal and controls used in conducting the 9. Official Publication, Association of Register on April 14, 1999, that revised investigations. American Feed Control Officials, Inc., 1998. HUD’s regulations concerning the Any party who will be adversely List of Subjects in 21 CFR Part 573 processing of fair housing complaints. affected by this regulation may at any DATES: Effective Date: September 27, time on or before September 27, 1999, Animal feeds, Food additives. 1999. file with the Dockets Management Therefore, under the Federal Food, FOR FURTHER INFORMATION CONTACT: Roy Drug, and Cosmetic Act and under Branch (address above) written Rodriguez, Acting Director, Office of authority delegated to the Commissioner objections thereto. Each objection shall Enforcement, Office of Fair Housing and of Food and Drugs, FDA is republishing be separately numbered, and each Equal Opportunity, U.S. Department of numbered objection shall specify with in its entirety the text of the final Housing and Urban Development, 451 particularity the provisions of the regulation that appeared in the Federal Seventh Street, SW., Washington, DC regulation to which objection is made Register of January 2, 1998. This 20410–2000; telephone (202) 708–0836 and the grounds for the objection. Each republication of the final rule does not (this is not a toll-free number). Hearing numbered objection on which a hearing amend the regulation in any way. or speech impaired individuals may is requested shall specifically so state. access this number via TTY by calling Failure to request a hearing for any PART 573ÐFOOD ADDITIVES the toll-free Federal Information Relay particular objection shall constitute a PERMITTED IN FEED AND DRINKING Service at (800) 877–8339. waiver of the right to a hearing on that WATER OF ANIMALS SUPPLEMENTARY INFORMATION: objection. Each numbered objection for 1. The authority citation for 21 CFR which a hearing is requested shall part 573 continues to read as follows: I. Background include a detailed description and analysis of the specific factual Authority: 21 U.S.C. 321, 342, 348. On April 14, 1999, HUD published in the Federal Register an interim rule (64 information intended to be presented in 2. Section 573.625 is republished as FR 18538) that revised HUD’s fair support of the objection in the event follows: that a hearing is held. Failure to include housing complaint processing such a description and analysis for any § 573.625 Menadione nicotinamide regulations. The interim rule revised particular objection shall constitute a bisulfite. these regulations in two ways. First, the waiver of the right to a hearing on the The food additive may be safely used sections of HUD’s regulations that objection. Three copies of all documents as follows: addressed the filing of complaints were shall be submitted and shall be (a) Product. The additive is 1,2,3,4- rewritten using plain language. Plain identified with the docket number tetrahydro-2-methyl-1, 4-dioxo-2- language is an approach to writing that found in brackets in the heading of this naphthalene sulfonic acid with 3- promotes responsive, accessible, and document. Any objections received in pyridine carboxylic acid amine (CAS understandable written communication. response to the regulation may be seen No. 73581–79–0). Second, the sections of HUD’s in the Dockets Management Branch (b) Conditions of use. As a nutritional regulations that addressed the between 9 a.m. and 4 p.m., Monday supplement in chicken and turkey feeds investigation of complaints were moved through Friday. for both the prevention of vitamin K to another place in the regulations. We deficiency and as a source of revised these regulations to make the IV. References supplemental niacin. procedures for filing housing 1. Oduho, G. W., T. K. Chung, and D. H. (c) Limitations. Not to exceed 2 grams discrimination complaints easier to Baker, ‘‘Menadione nicotinamide bisulfite is per ton of complete feed. To assure safe understand. a bioactive source of vitamin K and niacin use, the label and labeling shall bear The interim rule solicited comments activity for chicks,’’ Journal of Nutrition, 123: adequate directions for use. from the public on these revisions and 737–743, 1993. included a 60-day public comment 2. ‘‘Guideline on the Conduct of Clinical Dated: August 11, 1999. period. The public comment period Investigations: Responsibility of Clinical Stephen F. Sundlof, Investigators and Monitors for Investigational closed on June 14, 1999. We received no Director, Center for Veterinary Medicine. New Animal Drug Studies’’ (‘‘Guideline No. comments on the interim rule. This final 39,’’ U.S. Department of Health and Human [FR Doc. 99–22314 Filed 8–26–99; 8:45 am] rule adopts the interim rule without Services, FDA, CVM, October 1992) BILLING CODE 4160±01±F change.

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