[Federal Register Volume 61, Number 193 (Thursday, October 3, 1996)]
[Rules and Regulations]
[Pages 51588-51593]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-25257]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 558
New Animal Drugs for Use in Animal Feeds; Oxytetracycline Type A
Medicated Articles
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the animal
drug regulations to reflect approval of a supplemental new animal drug
application (NADA) filed by Pfizer, Inc. The supplemental NADA provides
revised labeling for Pfizer's pioneer, Type A, oxytetracycline-
containing, medicated articles which brings the products into
compliance with the findings of the National Academy of Sciences/
National Research Council (NAS/NRC), Drug Efficacy Study Group's (DESI)
effectiveness evaluation and subsequent FDA conclusions. In addition,
the regulations are further amended to reflect approval, based on FDA's
DESI ``me-too'' policy, of one original NADA each filed by Pfizer and
PennField Oil Co. for Type A medicated articles that are copies of the
Pfizer pioneer products.
EFFECTIVE DATE: October 3, 1996.
FOR FURTHER INFORMATION CONTACT: Dianne T. McRae, Center for Veterinary
Medicine (HFV-102), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-594-1623.
SUPPLEMENTARY INFORMATION: Pfizer, Inc., 235 East 42d St., New York, NY
10017, filed a supplement to its approved NADA 8-804 which covers the
Type A medicated articles bearing the Terramycin
(oxytetracycline (OTC)) trade name on their labels. The articles
contain OTC quaternary salt expressed in terms of an equivalent amount
of OTC hydrochloride (HCl) (i.e., Terramycin 10, 20, 50, 50D,
100, 100D, 100SS, and 200). Pfizer also filed original NADA 95-143
which covers the Type A medicated articles OXTC 10, 30, 50,
50-S, 100, 100-S, 100MR, and 200. These articles contain OTC dihydrate
base expressed in terms of an equivalent amount of OTC HCl. PennField
Oil Co., 14040 Industrial Rd., Omaha, NE 68137, filed original NADA
138-938 which covers the Type A medicated articles Oxytetracycline 50,
100, and 100 MR (formulated for use in calf milk replacers or starter
feeds). These articles also contain OTC quaternary salt expressed in
terms of an equivalent amount of OTC HCl.
Pfizer Type A medicated articles covered by NADA 8-804 were the
subject of a NAS/NRC DESI evaluation of effectiveness (DESI 8622V). The
findings were published in the Federal Register of May 5, 1970 (35 FR
7089). NAS/NRC evaluated the articles as probably effective when used
for the control and treatment of specific diseases of livestock (swine,
cattle, sheep, rabbits, and mink) and poultry (broiler chickens, laying
chickens, and turkeys), and concluded that use may result in faster
gains and improved feed efficiency under appropriate conditions. NAS/
NRC stated that:
1. Labels and package inserts require extensive revision. There is
inadequate documentation of claims, excessive claims are made, and bold
conclusions are reached in the absence of sufficient controlled
experimental evidence.
2. Claims for growth promotion or stimulation are not allowed and
claims for faster gains and/or feed efficiency should be stated as
``may result in faster gains and/or improved feed efficiency under
appropriate conditions.''
3. Each disease claim should be properly qualified as ``appropriate
for use in (name of disease) caused by pathogens sensitive to (name of
drug) and if the disease cannot be so qualified the claim must be
dropped.''
4. The label claims ``for prevention of'' or ``to prevent'' should
be replaced with ``as an aid in the control of'' or ``to aid in the
control of.''
5. The label claim pertaining to egg production and hatchability
should be modified to read, ``May aid in maintaining egg production and
[[Page 51589]]
hatchability, under appropriate conditions, by controlling pathogenic
organisms.''
6. The labels should carry a warning that treated animals under the
conditions that prevail must actually consume sufficient medicated
water, or medicated feed, to constitute a therapeutic dose. As a
precaution, the labels should state what the desired oral dose is in
terms of animal weight per day for each species to serve as a guide to
effective use of the preparations in drinking water or feed.
7. The labels should declare the dosage for the treatment of
individual animals in terms of the amount of drug which should be given
per unit of animal weight.
The ``probably effective'' finding of NAS/NRC was subsequently
reviewed by FDA, resulting in an upgrade to ``effective'' status for
the control and treatment of bacterial diseases susceptible to OTC in
poultry, cattle, swine, sheep, and bees. FDA also made the following
conclusions:
1. The claims for hexamitiasis should be included under the
susceptible host.
2. Appropriate claims regarding faster weight gains and improved
feed efficiency should be stated as ``For increased rate of weight gain
and improved feed efficiency (under appropriate conditions of use).''
Pfizer filed a supplement to NADA 8-804 that revised the labeling
of its products to comply with the findings of the NAS/NRC review and
FDA's conclusions concerning those findings. Pfizer's supplement to
NADA 8-804 also provides for transfer to 8-804 of its proprietary
claims previously approved, under NADA 38-439, for use of OTC in
lobster, catfish, Pacific salmon, and salmonids. The supplemental NADA
is approved as of March 14, 1996.
The Type A medicated articles covered by Pfizer's NADA 95-143
(containing OTC dihydrate base) and those covered by PennField's NADA
138-938 (containing OTC quaternary salt) have demonstrated
comparability to Pfizer's pioneer products (NADA 8-804,
Terramycin Premixes containing OTC quaternary salt equivalent
in activity to a concentration of OTC HCl declared in grams per pound
of premix) which were subject to the NAS/NRC evaluation of May 5, 1970.
Based on that comparability, original NADA's 95-143 and 138-938 are
approved as of May 30, 1996, and March 15, 1996, respectively, under
FDA's DESI ``me-too'' policy.
FDA has now completed the NAS/NRC DESI evaluation for OTC Type A
articles. Accordingly, FDA is revising Sec. 558.450 Oxytetracycline (21
CFR 558.450) to set out the NAS/NRC and FDA-approved conditions of use
for OTC articles. FDA also has replaced the claims for OTC articles
listed in Sec. 558.15(g)(1) (21 CFR 558.15(g)(1)) with a cross-
reference to Sec. 558.450. This change makes the Sec. 558.15(g)(1)
reference to OTC Type A articles the same as that for chlortetracycline
(CTC) which cross-refers to Sec. 558.128 (21 CFR 558.128), the DESI-
finalized claims for that product (see the Federal Register of July 9,
1996, 61 FR 35949).
The NAS/NRC DESI evaluation is concerned only with the drugs'
effectiveness and safety to the treated animals. Nothing herein will
constitute a bar to further proceedings with respect to questions of
safety of the drugs or their metabolites in food products derived from
treated animals.
Products that comply with the NAS/NRC findings and FDA's
conclusions regarding those findings are eligible for copying under the
Generic Animal Drug and Patent Term Restoration Act (GADPTRA) (see the
eighth in a series of policy letters issued to facilitate
implementation of GADPTRA that published in the Federal Register of
August 21, 1991 (56 FR 41561)). Accordingly, sponsors may now obtain
approval of abbreviated new animal drug applications (ANADA's) for
these OTC Type A medicated articles.
Also, the agency is revising Sec. 558.515(d)(2) (21 CFR
558.515(d)(2)) to make the claim language for the robenidine/OTC
combination consistent with the NAS/NRC DESI findings.
In the Federal Register of October 21, 1977 (42 FR 56264), the then
Bureau of Veterinary Medicine issued a notice of opportunity for a
hearing (NOOH) on a proposal to withdraw approval of certain NADA's
listed in Sec. 558.15, for most subtherapeutic uses of tetracycline
(CTC and OTC) in animal feed. The NOOH was issued in response to
scientific research suggesting that subtherapeutic use of such drugs
has contributed to the pool of antibiotic-resistant pathogenic
microorganisms in food animals. Furthermore, research indicated that
the drug resistance could be transferred to pathogenic organisms in
humans. The NOOH is still pending and approval of these supplements to
finalize the DESI review process for OTC Type A medicated articles does
not constitute a bar to subsequent action to withdraw approval on the
grounds cited in the outstanding NOOH.
In accordance with the freedom of information provisions of part 20
(21 CFR part 20) and Sec. 514.11(e)(2)(ii) (21 CFR 514.11(e)(2)(ii)), a
summary of safety and effectiveness data and information submitted to
support approval of these applications may be seen in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857, between 9 a.m. and 4 p.m.,
Monday through Friday.
Under section 512(c)(2)(F)(ii) and (c)(2)(F)(iii) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(ii) and
(c)(2)(F)(iii)), these approvals for food-producing animals do not
qualify for marketing exclusivity because the original and supplemental
applications do not contain reports of new clinical or field
investigations (other than bioequivalence or residue studies) and new
human food safety studies (other than bioequivalence or residue
studies) essential to the approvals and conducted or sponsored by the
applicants.
The agency has carefully considered the potential environmental
effects of approving supplemental NADA 8-804. FDA has concluded that
the action will not have a significant impact on the human environment,
and that an environmental impact statement is not required. The
agency's finding of no significant impact and the evidence supporting
that finding, contained in an environmental assessment, may be seen in
the Dockets Management Branch (address above) between 9 a.m. and 4
p.m., Monday through Friday.
The agency has determined under 21 CFR 25.24(d)(1)(i) that approval
of original NADA's 95-143 and 138-938 is the type of action that does
not individually or cumulatively have a significant effect on the human
environment. Therefore, neither environmental assessments nor
environmental impact statements are required.
List of Subjects in 21 CFR Part 558
Animal drugs, Animal feeds.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Center for Veterinary Medicine, 21 CFR part 558 is
amended as follows:
PART 558--NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS
1. The authority citation for 21 CFR part 558 continues to read as
follows:
Authority: Secs. 512, 701 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 360b, 371).
Sec. 558.15 [Amended]
2. Section 558.15 Antibiotic, nitrofuran, and sulfonamide drugs in
the feed of animals is amended in the
[[Page 51590]]
table, in paragraph (g)(1) to read as follows:
a. In the entry for ``Pfizer, Inc., PennField Oil Co., VPO, Inc.,
and Purina Mills, Inc.'', by removing ``, VPO, Inc., and Purina Mills,
Inc.'';
b. Under the ``Species'' column of this entry, by removing
``Chickens and turkeys.'' and adding in its place ``Sec. 558.450.'';
c. All of the subentries for Pfizer, Inc., PennField Oil Co.,
represented by ``Do.'' are removed;
d. The ``Pfizer, Inc.'' entry for oxytetracycline for sheep,
including the three subentries represented by ``Do.'' are removed;
e. The ``Pfizer, Inc.'' entry for oxytetracycline for chickens,
including the first subentry represented by ``Do.'' is removed.
3. Section 558.450 is revised to read as follows:
Sec. 558.450 Oxytetracycline.
(a) Approvals. Type A medicated articles:
(1) 10, 20, 30, 50, 100, and 200 grams per pound to 000069 in
Sec. 510.600(c) of this chapter.
(2) 50 and 100 grams per pound to 053389 in Sec. 510.600(c) of this
chapter.
(b) Special considerations. (1) In accordance with Sec. 558.5
labeling shall bear the statement: ``FOR USE IN DRY ANIMAL FEED ONLY.
NOT FOR USE IN LIQUID FEED SUPPLEMENTS.''
(2) The articles in paragraph (a)(1) of this section contain an
amount of mono-alkyl (C8-C18) trimethylammonium
oxytetracycline expressed in terms of an equivalent amount of
oxytetracycline hydrochloride or an amount of oxytetracycline dihydrate
base expressed in terms of an equivalent amount of oxytetracycline
hydrochloride.
(3) The articles in paragraph (a)(2) of this section contain an
amount of mono-alkyl (C8-C18) trimethylammonium
oxytetracycline expressed in terms of an equivalent amount of
oxytetracycline hydrochloride.
(c) Related tolerances. See Sec. 556.500 of this chapter.
(d)(1) Conditions of use. It is used in feed as follows:
Table 1
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Oxytetracycline amount Combination Indications for use Limitations Sponsor
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(i) 10 to 20 grams per Sheep; increased rate 000069,
ton (g/ton) of weight gain and 053389
improved feed
efficiency.
(ii) 10 to 50 g/ton 1. Chickens; increased Do not feed to chickens do
rate of weight gain producing eggs for
and improved feed human consumption.
efficiency.
2. Growing turkeys; Do not feed to turkeys do
increased rate of producing eggs for
weight and improved human consumption.
feed efficiency.
3. Swine; increased do
rate of weight and
improved feed
efficiency.
(iii) 100 g/ton Turkeys; control of Feed continuously for 7 do
hexamitiasis caused by to 14 days (d); do not
Hexamita meleagridis feed to turkeys
susceptible to producing eggs for
oxytetracycline. human consumption.
(iv) 100 to 200 g/ton Chickens; control of Feed continuously for 7 do
infectious synovitis to 14 d; do not feed
caused by Mycoplasma to chickens producing
synoviae; control of eggs for human
fowl cholera caused by consumption; in low
Pasteurella multocida calcium feed, withdraw
susceptible to 3 d before slaughter.
oxytetracycline.
Nequinate 18.16 g/ton Chickens; control of do 000069
(0.002%) infectious synovitis
caused by M. synoviae;
control of fowl
cholera caused by P.
multocida susceptible
to oxytetracycline; as
an aid in the control
of coccidiosis caused
by Eimeria tenella, E.
necatrix, E.
acervulina, E. maxima,
E. brunetti, and E.
mivati.
(v) 200 g/ton Turkeys; control of Feed continuously for 7 000069,
infectious synovitis to 14 d; withdraw 5 d 053389
caused by M. synoviae before slaughter; do
susceptible to not feed to turkeys
oxytetracycline. producing eggs for
human consumption.
(vi) 400 g/ton Chickens; control of Feed continuously for 7 do
chronic respiratory to 14 d; do not feed
disease (CRD) and air to chickens producing
sac infection caused eggs for human
by M. gallisepticum consumption; in low
and Escherichia coli calcium feeds,
susceptible to withdraw 3 d before
oxytetracycline. slaughter.
[[Page 51591]]
Monensin 90 to 110 g/ Chickens; control of do 000069
ton CRD and air sac
infection caused by M.
gallisepticum and E.
coli susceptible to
oxytetracycline; and
as an aid in the
prevention of
coccidiosis caused by
E. necatrix, E.
tenella, E.
acervulina, E.
brunetti, E. mivati,
and E. maxima.
Nequinate 18.16 g/ton Chickens; control of do do
(0.002%) CRD and air sac
infection caused by M.
gallisepticum and E.
coli susceptible to
oxytetracycline; as an
aid in prevention of
coccidiosis caused by
E. tenella, E.
necatrix, E.
acervulina, E. maxima,
E. brunetti, and E.
mivati.
(vii) 500 g/ton Chickens; reduction of Feed continuously for 5 000069,
mortality due to air d; do not feed to 053389
sacculitis (air-sac- chickens producing
infection) caused by eggs for human
E. coli susceptible to consumption; withdraw
oxytetracycline. 24 hours before
slaughter; in low
calcium feeds withdraw
3 d before slaughter.
Monensin 90 to 110 g/ Chickens; reduction of do 000069
ton mortality due to air
sacculitis (air-sac-
infection) caused by
E. coli susceptible to
oxytetracycline; as an
aid in the prevention
of coccidiosis caused
by E. necatrix, E.
tenella, E.
acervulina, E.
brunetti, E. mivati,
and E. maxima.
Salinomycin 40 to 60 g/ Chickens; reduction of do 000069,
ton mortality due to air 012799
sacculitis (air-sac-
infection) caused by
E. coli susceptible to
oxytetracycline;
prevention of
coccidiosis caused by
E. necatrix, E.
tenella, E.
acervulina, E.
brunetti, E. mivati,
and E. maxima.
(viii) 0.05 to 0.1 Calves (up to 250 lb); Feed continuously; in 000069,
milligram/pound (mg/lb) for increased rate of milk replacers or 053389
of body weight daily. weight gain and starter feed.
improved feed
efficiency.
(ix) 10 mg/lb of body 1.Calves and beef and Feed continuously for 7 do
weight daily. nonlactating dairy to 14 d; in feed or
cattle; treatment of milk replacers;
bacterial enteritis withdraw 5 d before
caused by E. coli and slaughter.
bacterial pneumonia
(shipping fever
complex) caused by P.
multocida susceptible
to oxytetracycline.
2. Calves (up to 250 Feed continuously for 7 do
lb); treatment of to 14 d; in milk
bacterial enteritis replacers or starter
caused by E. coli feed; withdraw 5 d
susceptible to before slaughter.
oxytetracycline.
3. Sheep; treatment of Feed continuously for 7 do
bacterial enteritis to 14 d; withdraw 5 d
caused by E. coli and before slaughter.
bacterial pneumonia
caused by P. multocida
susceptible to
oxytetracycline.
[[Page 51592]]
4. Swine; treatment of Feed continuously for 7 do
bacterial enteritis to 14 d; withdraw 5 d
caused by E. coli and before slaughter.
Salmonella
choleraesuis
susceptible to
oxytetracycline and
treatment of bacterial
pneumonia caused by P.
multocida susceptible
to oxytetracycline.
5. Breeding swine; Feed continuously for do
control and treatment not more than 14 d;
of leptospirosis withdraw 5 d before
(reducing the slaughter.
incidence of abortion
and shedding of
leptospirae) caused by
Leptospira pomona
susceptible to
oxytetracycline.
(x) 25 mg/lb of body Turkeys; control of Feed continuously for 7 do
weight complicating bacterial to 14 d; withdraw 5 d
organisms associated before slaughter; do
with bluecomb not feed to turkeys
(transmissible producing eggs for
enteritis; coronaviral human consumption.
enteritis) susceptible
to oxytetracycline.
(xi) 25 mg/head/day Calves (250 to 400 lb); do
increased rate of
weight gain and
improved feed
efficiency.
(xii) 75 mg/head/day Growing cattle (over do
400 lb); increased
rate of weight gain;
improved feed
efficiency, and
reduction of liver
condemnation due to
liver abscesses.
(xiii) 0.5 to 2.0 g/head/ Cattle; prevention and Feed 3 to 5 d before do
day treatment of the early and after arrival in
stages of shipping feedlots.
fever complex.
(xiv) 200 mg/colony Honey bees; control of Remove at least 6 weeks do
American foulbrood prior to main honey
caused by Bacillus flow.
larvae and European
foulbrood caused by
Streptococcus pluton
susceptible to
oxytetracycline.
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(2) It is used in fish feed as follows:
Table 2
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Oxytetracycline amount Combination Indications for use Limitations Sponsor
----------------------------------------------------------------------------------------------------------------
(i) 250 mg/kilogram of Pacific salmon for For salmon not over 30 000069
fish/d (11.35 g/100 lb marking of skeletal g body weight;
of fish/d). tissue. administer as sole
ration for 4
consecutive days in
feed containing
oxytetracycline
hydrochloride or mono-
alkyl (C8-C18)
trimethyl ammonium
oxytetracycline; fish
not to be liberated
for at least 7 d
following the last
administration of
medicated feed.
(ii) 2.5 to 3.75 g/100 1. Salmonids; control Administer as mono- 000069
lb of fish/d. of ulcer disease alkyl (C8-C18)
caused by Hemophilus trimethyl ammonium
piscium, furunculosis oxytetracycline in
caused by Aeromonas mixed ration for 10 d;
salmonicida, bacterial do not liberate fish
hemorrhagic septicemia or slaughter fish for
caused by A. food for 21 d
liquefaciens, and following the last
pseudomonas disease. administration of
medicated feed; do not
administer when water
temperature is below 9
C (48.2 F).
[[Page 51593]]
2. Catfish; control of Administer as mono- 000069
bacterial hemorrhagic alkyl (C8-C18)
septicemia caused by trimethyl ammonium
A. liquefaciens and oxytetracycline in
pseudomonas disease. mixed ration for 10 d;
do not liberate fish
or slaughter fish for
food for 21 d
following the last
administration of
medicated feed; do not
administer when water
temperature is below
16.7 C (62 F)
(iii) 1 g/lb of Lobsters; control of Administer as sole 000069
medicated feed. gaffkemia caused by ration for 5
Aerococcus viridans. consecutive days in
feed containing
monoalkyl (C8-C18)
trimethyl ammonium
oxytetracycline;
withdraw medicated
feed 30 d before
harvesting lobsters.
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(3) Oxytetracycline may be used in accordance with the provisions
of this section in the combinations provided as follows:
(i) Robenidine hydrochloride in accordance with Sec. 558.515.
(ii) Lasalocid as in Sec. 558.311.
4. Section 558.515 is amended by revising paragraph (d)(2) to read
as follows:
Sec. 558.515 Robenidine hydrochloride.
* * * * *
(d) * * *
(2) For broiler chickens--(i) Amount per ton. Robenidine
hydrochloride, 30 grams (0.0033 percent) plus oxytetracycline, 400
grams.
(ii) Indications for use. As an aid in the prevention of
coccidiosis caused by Eimeria mivati, E. brunetti, E. tenella, E.
acervulina, E. maxima, and E. necatrix; control of CRD and air sac
infection caused by Mycoplasma gallisepticum and Escherichia coli
susceptible to oxytetracycline.
(iii) Limitations. Feed continuously for 7 to 14 days; do not feed
to chickens producing eggs for human consumption; withdraw 5 days
before slaughter; do not use in feeds containing bentonite; feed must
be used within 50 days of manufacture; oxytetracycline as provided by
No. 000069 of this chapter.
Dated: September 16, 1996.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 96-25257 Filed 10-2-96; 8:45 am]
BILLING CODE 4160-01-F