[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]
[[Page 46841]]
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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).
[[Page 46842]]
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