[Federal Register Volume 64, Number 166 (Friday, August 27, 1999)]
[Rules and Regulations]
[Pages 46841-46843]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-22314]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 573

[Docket No. 94F-0283]


Food Additives Permitted in the Feed and Drinking Water of 
Animals; Menadione Nicotinamide Bisulfite

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule; republication and opportunity to file objections 
or additional information.

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SUMMARY:  The Food and Drug Administration (FDA) is republishing, with 
additional information, a final rule that published in the Federal 
Register of January 2, 1996 (61 FR 5). The rule amended the food 
additive regulations (animal use) to reflect approval of a food 
additive petition (FAP) filed by Vanetta (U.S.A.) Inc. Objections to 
the final rule were filed. FDA is not acting on the objections in this 
document, but is clarifying the basis of approval of the petition and 
providing additional information. The agency also is providing a new 
30-day period for the submission of objections or of additional 
information in support of the objections that were previously filed. 
FDA has not stayed the effective date of the final rule, effective 
January 2, 1996.
DATES: Objections, additional information in support of the previously 
filed objections, or additional written objections and requests for a 
hearing, must be submitted by September 27, 1999.
ADDRESSES:  Submit written objections and/or additional information in 
support of objections previously submitted to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:  Sharon A. Benz, Center for Veterinary 
Medicine (HFV-228), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-6656.

SUPPLEMENTARY INFORMATION: 

I. Background

     In the Federal Register of January 2, 1996, FDA published a final 
rule that amended the food additive regulations (animal use) to reflect 
approval of an FAP (FAP 2228) filed by Vanetta (U.S.A.) Inc., 1770 East 
Market St., York, PA 17402. The final rule provides for the safe use of 
menadione nicotinamide bisulfite (MNB) as a nutritional supplement in 
chicken and turkey feeds for the prevention of vitamin K deficiency and 
as a source of supplemental niacin when used at a rate not to exceed 2 
grams per ton (g/t) of complete feed. Heterochemical Corp., 111 East 
Hawthorne Ave., Valley Stream, NY 11580, filed objections to the final 
rule in its entirety alleging that the studies upon which the petition 
relies failed to conform to good laboratory practices (GLP's) or good 
clinical practices (GCP's), and that the regulation promotes deception 
of the consumer and misbranding of the product. Heterochemical's 
objections are:
    1. The record of the studies fails to establish that any of the 
nonclinical laboratory studies (including target animal safety) on 
which the regulation is based were conducted in accordance with GLP's 
as described in part 58 (21 CFR part 58). The record also fails to 
provide, alternatively, a reason for noncompliance as required by 
Sec. 571.1(k) (21 CFR 571.1(k)). Furthermore, the record does not 
provide a basis for identifying the differences between the practices 
used and those required by the GLP regulations, so as to permit an 
evaluation of the studies' integrity and reliability (i.e., if the 
target animal safety studies are flawed, there is no information in 
support of the safety of the food additive) (Ref. 1).
    2. The record of the studies fails to establish that any of the 
clinical studies on which the regulation is based were conducted in 
accordance with GCP's as illustrated in FDA's Center for Veterinary 
Medicine's (CVM's) guidance document entitled ``Guideline on the 
Conduct of Clinical Investigations: Responsibility of Clinical 
Investigators and Monitors for Investigational New Animal Drug 
Studies,'' October 1992 (the guidelines cited by the objection were 
supplanted by a revised document in May 1997) (Ref. 2).
    3. Heterochemical objects to the regulation in that it establishes 
MNB as a source of supplemental niacin and authorizes labeling the 
product as a source of supplemental niacin. Based on a low level of 
niacin supplementation, the firm contends that the labeling promotes 
deception of the consumer and results in misbranding of food within the 
meaning of the Federal Food, Drug, and Cosmetic Act (the act).
     The preamble of the January 2, 1996, final rule stated that FDA 
evaluated the data presented in the petition and concluded that use of 
the product is safe. The final rule stated that the food additive 
regulations would be amended as requested in the FAP. FDA is now 
republishing the final rule to clarify its basis for approval, and to 
provide additional information supporting approval of the petitioned 
use, specifically the GLP statement as described in Sec. 571.1(k). FDA 
believes this course of action is appropriate to supplement the record. 
FDA will also clarify the reasons for approving the FAP, and provide 
Heterochemical and any other interested party with an opportunity to 
proffer facts that demonstrate FDA's basis for approving FAP 2228 was 
incorrect.
    FDA is therefore republishing the final rule and providing an 
additional 30 days for submission of objections or of additional 
information in support of the objections that have already been filed. 
In accordance with its discretion under section 409(f) of the act (21 
U.S.C. 348(f)), FDA is not staying the final rule. FDA will consider a 
stay, however, if one is requested, after having evaluated any 
objections or other information filed in response to this document.

II. Administrative Record

A. Question of Adherence to GLP's (Part 58 and Sec. 571.1(k))

    In filing an FAP, the petitioner is required to provide data and 
information to support the safe use of the product as required by 
section 409(c)(1) of the act. The supporting data and information 
include full reports of investigations made with respect to the safety 
of use of the additive, including information as to the methods and 
controls used in conducting the investigations. Part 58 prescribes 
GLP's for conducting those nonclinical laboratory studies that are used 
to support or are intended for use to support FAP's or marketing 
permits for products regulated by FDA. Compliance with GLP's is 
intended to ensure the quality and integrity of the safety data filed 
to support approval of an FAP. If nonclinical laboratory studies are 
involved, an FAP shall include, for each study, a statement that the 
study was conducted in compliance with GLP requirements set forth under 
part 58, or if the study was not conducted in compliance with the 
GLP's, a brief statement with the reason for noncompliance.
    In FAP 2228, Vanetta submitted a journal article (Ref. 1) 
supporting approval of its petition. The studies reported in the 
article were not conducted in accordance with GLP's, and Vanetta did 
not submit a statement of the reason for noncompliance. Accordingly, 
FDA is reopening the administrative record to include a statement from 
Vanetta on the reasons for the studies' noncompliance with GLP's, as 
required under Sec. 571.1(k).

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B. Clarification of the Record

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

III. Opportunity for Objection

    A food additive shall, with respect to any particular use or 
intended use of such additive, be deemed to be unsafe, unless it and 
its use or intended use conform to the terms of an exemption that is in 
effect for investigational use, or there is in effect, and it and its 
use or intended use are in conformity with, a regulation issued under 
section 409(a) of the act. With respect to any intended use of a food 
additive, a person may file a petition with the appropriate center 
within FDA proposing the issuance of a regulation prescribing the 
conditions under which said additive may be safely used. The petition 
shall, in addition to any explanatory or supporting data,

[[Page 46843]]

contain the name of the food additive, its chemical name and 
composition, a statement of the conditions of the proposed use of such 
additive, together with all directions, recommendations, and 
suggestions proposed for the use of such additive with specimens of 
proposed labeling. The petition shall also contain relevant data 
bearing on the physical or other technical effect the additive is 
intended to produce, the quantity of the additive required to produce 
the desired effect, a description of practicable methods for 
determining the quantity of the additive in or on food and any 
substance formed in or on food because of its use, and full reports of 
investigations made with respect to the safety of the use of the 
additive, including information as to the methods and controls used in 
conducting the investigations.
    Any party who will be adversely affected by this regulation may at 
any time on or before September 27, 1999, file with the Dockets 
Management Branch (address above) written objections thereto. 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 shall be 
submitted and shall 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.

IV. References

    1. Oduho, G. W., T. K. Chung, and D. H. Baker, ``Menadione 
nicotinamide bisulfite is a bioactive source of vitamin K and niacin 
activity for chicks,'' Journal of Nutrition, 123: 737-743, 1993.
    2. ``Guideline on the Conduct of Clinical Investigations: 
Responsibility of Clinical Investigators and Monitors for 
Investigational New Animal Drug Studies'' (``Guideline No. 39,'' 
U.S. Department of Health and Human Services, FDA, CVM, October 
1992) (superseded by ``Guidance for Industry No. 58,'' May 1997).
    3. National Research Council, Vitamin Tolerance of Animals, 
National Academy Press, 1987.
    4. ``Food Additive Status of Vitamin K Active Substances in 
Animal Food'' (48 FR 16748, April 19, 1983).
    5. Title 21 CFR 121.101, ``Substances that are generally 
recognized as safe,'' 1974 (21 CFR part 582, 1998).
    6. Suttie, J. W., ``Vitamin K,'' Handbook of Vitamins, edited by 
L. J. Machlin, Marcel Dekker, Inc., 1991.
    7. National Research Council, The Nutritional Requirements of 
Poultry, National Academy Press, 1994.
    8. Swenson, M. J. ``Physiological properties and cellular and 
chemical constituents of blood,'' Duke's Physiology of Domestic 
Animals, edited by M. J. Swenson, Cornell University Press, 1977.
    9. Official Publication, Association of American Feed Control 
Officials, Inc., 1998.

List of Subjects in 21 CFR Part 573

    Animal feeds, Food additives.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, FDA is 
republishing in its entirety the text of the final regulation that 
appeared in the Federal Register of January 2, 1998. This republication 
of the final rule does not amend the regulation in any way.

PART 573--FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF 
ANIMALS

    1. The authority citation for 21 CFR part 573 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 342, 348.

    2. Section 573.625 is republished as follows:


Sec. 573.625   Menadione nicotinamide bisulfite.

    The food additive may be safely used as follows:
    (a) Product. The additive is 1,2,3,4-tetrahydro-2-methyl-1, 4-
dioxo-2-naphthalene sulfonic acid with 3-pyridine carboxylic acid amine 
(CAS No. 73581-79-0).
    (b) Conditions of use. As a nutritional supplement in chicken and 
turkey feeds for both the prevention of vitamin K deficiency and as a 
source of supplemental niacin.
    (c) Limitations. Not to exceed 2 grams per ton of complete feed. To 
assure safe use, the label and labeling shall bear adequate directions 
for use.

    Dated: August 11, 1999.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 99-22314 Filed 8-26-99; 8:45 am]
BILLING CODE 4160-01-F