Document ID: FDA-2020-N-0955-0006
Agency: fda
Document Type: Notice
Title: Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Revocation
of Approved Method
Posted Date: 2020-08-14T04:00Z

[Federal Register Volume 85, Number 139 (Monday, July 20, 2020)]
[Notices]
[Pages 43853-43858]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-15246]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-0832]

Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; 
Revocation of Approved Method

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA), Center for Veterinary 
Medicine (CVM), is proposing an order to revoke the approved method for 
detecting residues of carbadox, a carcinogenic new animal drug used in 
swine feed. An approved method is required by the Federal Food, Drug, 
and Cosmetic Act (FD&C Act), as implemented by regulation, to show that 
no residue of carcinogenic concern from a new animal drug persists in 
any edible tissue or in any food derived from treated animals. The 
currently approved method measures quinoxaline-2-carboxylic acid (QCA) 
as a marker residue to detect the presence of any residue of 
carcinogenic concern. CVM is proposing to revoke the approved method 
for carbadox based on our determination that it is inadequate to 
monitor residue of carcinogenic concern in compliance with FDA's 
operational definition of no residue because there is no established 
relationship between QCA measured by the approved method and the 
residue of carcinogenic concern.

DATES: Submit either electronic or written comments on the proposed 
order by September 18, 2020.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before September 18, 2020. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of September 18, 2020. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified as 
confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-0832 for ``Phibro Animal Health Corp.; Carbadox in Medicated 
Swine Feed; Revocation of Approved Method.'' Received comments, those 
filed in a timely manner (see ADDRESSES), will be placed in the docket 
and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at https://www.regulations.gov or at the Dockets 
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the

[[Page 43854]]

information you claim to be confidential with a heading or cover note 
that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The 
Agency will review this copy, including the claimed confidential 
information, in its consideration of comments. The second copy, which 
will have the claimed confidential information redacted/blacked out, 
will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management 
Staff. If you do not wish your name and contact information to be made 
publicly available, you can provide this information on the cover sheet 
and not in the body of your comments and you must identify this 
information as ``confidential.'' Any information marked as 
``confidential'' will not be disclosed except in accordance with 21 CFR 
10.20 and other applicable disclosure law. For more information about 
FDA's posting of comments to public dockets, see 80 FR 56469, September 
18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Diane Heinz, Center for Veterinary 
Medicine (HFV-6), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 240-402-5692, diane.heinz@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Introduction

    CVM is proposing to revoke the current approved method \1\ used to 
determine whether residues of carcinogenic concern of carbadox are 
present. That method measures QCA as the marker residue for the residue 
of carcinogenic concern. CVM is proposing to revoke the method because 
it does not adequately monitor the residue of carcinogenic concern in 
compliance with FDA's operational definition of no residue. See Sec.  
500.84(c)(3) (21 CFR 500.84(c)(3)).
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    \1\ The current approved method, ``Determination of Carbadox as 
Quinoxaline-2-carboxylic Residues in Swine Liver and Muscle Tissues 
after Drug Withdrawal,'' is available at https://www.fda.gov/media/136267/download.
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    The Delaney Clause of the FD&C Act generally prohibits the approval 
of carcinogenic animal drugs unless an exception applies. See section 
512(d)(1)(I) of the FD&C Act (21 U.S.C. 360b(d)(1)(I)). Under the 
``Diethylstilbestrol (DES) Proviso'' exception, a carcinogenic new 
animal drug may be approved if, among other things, no residue of such 
drug will be found by methods of examination prescribed or approved by 
the Secretary of Health and Human Services (HHS) by regulations in any 
edible portion of such animals after slaughter or in any food yielded 
by or derived from the living animals. FDA's sensitivity of the method 
regulations (``SOM regulations'') establish the requirements for 
satisfying the DES Proviso (part 500, subpart E (21 CFR part 500, 
subpart E)). The regulations require, among other things, approval of a 
``regulatory method'' to ensure that no residue of a carcinogenic drug 
will be found in edible portions of animals (Sec.  500.88 (21 CFR 
500.88)).
    When CVM approved the current regulatory method for carbadox in 
1998, our understanding of carbadox metabolism, based on the data 
available at the time, led us to conclude that the safety of carbadox 
residues could be assured by tracking the non-carcinogenic residue QCA 
alone. As a result, CVM did not direct the sponsor to submit a proposed 
regulatory method that complied with Sec.  500.88. Instead, CVM set a 
``tolerance'' for QCA based on our conclusion that carcinogenic 
residues, including desoxycarbadox (DCBX), a known carcinogenic 
metabolite of carbadox, depleted quickly (within 72 hours) while QCA 
residues depleted more slowly. However, CVM has reevaluated the current 
approved method because we have concluded, based on subsequent studies, 
that carcinogenic residues persist longer than previously known. In its 
reevaluation of the current approved method, CVM has determined that 
the current approved method cannot adequately monitor residue of 
carcinogenic concern because there is no established relationship 
between QCA and the residue of carcinogenic concern. That means that 
determining the concentration of QCA in animal tissue does not allow 
CVM to conclusively determine whether the residue of carcinogenic 
concern remains in the tissue. Thus, the current approved method does 
not comply with part 500, subpart E, and therefore does not satisfy the 
statutory requirement of section 512(d)(1)(I) of the FD&C Act. The 
importance of addressing the inadequacies of the current approved 
method is underscored by the new data that suggest that residues of 
carcinogenic concern of carbadox do not deplete in animal tissue as 
quickly as previously believed. As a result, we are proposing to revoke 
the currently approved method.
    If this proposed order to revoke the current approved method is 
finalized and this method is revoked, we intend to publish in the 
Federal Register a notice of opportunity for hearing (NOOH) proposing 
to withdraw approval of all new animal drug applications for use of 
carbadox based on the lack of an approved method for measuring residues 
as required by part 500, subpart E. See section 512(d)(1)(I) of the 
FD&C Act. Elsewhere in this issue of the Federal Register, FDA is 
withdrawing the April 12, 2016, NOOH \2\ (81 FR 21559) for its proposal 
to withdraw approval of all new animal drug applications for use of 
carbadox in medicated swine feed. (A correction to the April 12, 2016, 
NOOH was published in the Federal Register on April 21, 2016 (81 FR 
23499).)
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    \2\ See https://www.federalregister.gov/documents/2016/04/12/2016-08327/phibro-animal-health-corp-carbadox-in-medicated-swine-feed-opportunity-for-hearing.
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II. Background

A. Regulation of Carcinogenic New Animal Drugs

    Under the Delaney Clause of the FD&C Act, FDA generally cannot 
approve a new animal drug application (NADA) if the drug that is the 
subject of that application induces cancer in humans or animals 
(section 512(d)(1)(I) of the FD&C Act). An exception to this general 
rule is commonly known as the ``DES Proviso,'' \3\ which allows for the 
approval of a carcinogenic new animal drug where CVM finds that under 
the approved conditions of use: (1) The drug will not adversely affect 
the animals treated with the drug and (2) no residues of the drug will 
be found by an approved regulatory method in any edible tissues of, or 
in any foods yielded by, the animal (section 512(d)(1)(I) of the FD&C 
Act).
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    \3\ The ``DES Proviso'' refers to Diethylstilbestrol, a 
carcinogenic hormone widely used in beef-cattle feed at the time the 
Delaney Clause was enacted.
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    As part of an NADA, CVM requires that the sponsor include a 
description of practicable methods for determining the quantity, if 
any, of the new animal drug in or on food and any substance formed in 
or on food because of its use, and the proposed tolerance or withdrawal 
period or other use restrictions to ensure that the proposed use of 
this drug will be safe (Sec.  514.1(b)(7) (21 CFR

[[Page 43855]]

514.1(b)(7))). Carcinogenic drugs, such as carbadox, must also meet the 
requirements in part 500, subpart E (Sec.  514.1(b)(7)(ii)). These SOM 
regulations set out the requirements for demonstrating that no residues 
of the drug will be found by an approved regulatory method in any 
edible tissues of or in any foods obtained from the animal, as required 
to comply with the DES Proviso.
    Specifically, the SOM regulations require CVM to determine if any 
animal drug or any of its metabolites is a carcinogen (Sec.  
500.84(a)). For the drug and each metabolite that FDA decides should be 
regulated as a carcinogen,\4\ CVM calculates, based on submitted 
assays, the concentration of the test compound in the total diet of the 
test animal that corresponds to a maximum lifetime risk of cancer in 
the test animal of 1 in 1 million (Sec.  500.84(c)(1)). CVM designates 
the lowest concentration (i.e., the concentration of the most potent 
carcinogen) thus calculated as the So (Sec.  500.84(c)(1)). 
The So corresponds to a concentration of residue of 
carcinogenic concern in the total human diet that represents no 
significant increase in the risk of cancer to people (Sec.  500.82(b) 
(21 CFR 500.82(b))). The residue of carcinogenic concern includes all 
compounds in the total residue of a demonstrated carcinogen excluding 
any compounds determined by CVM not to present a carcinogenic risk 
(Sec.  500.82(b)). CVM treats unidentified residues of a carcinogenic 
drug as carcinogenic (Sec.  500.82(b) (definition of ``Residue of 
carcinogenic concern'')). Because FDA relies on the So from 
the most potent carcinogen, this approach ensures that use of the drug 
does not present a significant increase in the risk of cancer when 
considering all residues in edible tissues.
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    \4\ See Sec.  500.82(b) (defining ``residue of carcinogenic 
concern'' as all compounds in the total residue of a demonstrated 
carcinogen excluding any compounds judged by FDA not to present a 
carcinogenic risk).
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    Because the total human diet is not derived only from food-
producing animals, the SOM regulations make adjustments for human food 
intake of edible tissues and determine the concentration of residue of 
carcinogenic concern in a specific edible tissue (such as muscle, 
liver, kidney, milk, or eggs) that corresponds to no significant 
increase in the risk of cancer to the human consumer. CVM assumes for 
purposes of these regulations that this value will correspond to the 
concentration of residues in a specific edible tissue that corresponds 
to a maximum lifetime risk of cancer in the test animals of 1 in 1 
million. This value is designated as the Sm (Sec. Sec.  
500.82(b) and 500.84(c)(1)). By limiting concentration of residue of 
carcinogenic concern to a value at or below the Sm, a 
consumer can eat a specific edible tissue every day for an entire 
lifetime without increasing his or her cancer risk by more than 1 in 1 
million.
    Based on data submitted by a sponsor, CVM selects a target tissue 
(the edible tissue selected to monitor for residues in the target 
animals) and a marker residue \5\ and designates the concentration of 
the marker residue that the regulatory method must be able to detect in 
the target tissue (Sec.  500.86(a) through (c) (21 CFR 500.86(a) 
through (c))). This value, termed the Rm, is the 
concentration of a marker residue in the target tissue when the residue 
of carcinogenic concern is equal to Sm, that ensures that 
the residue of carcinogenic concern does not exceed Sm in 
each of the edible tissues when the marker residue is not detectable 
(Sec. Sec.  500.82(b) and 500.86(c)). When the marker residue is at or 
below the Rm, the residue of carcinogenic concern in the 
human diet does not exceed So (Sec.  500.86(c)).
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    \5\ The marker residue is the residue whose concentration is in 
a known relationship to the concentration of the residue of 
carcinogenic concern in the last tissue to deplete to the 
Sm (Sec.  500.82(b)).
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    A sponsor must submit a regulatory method that is able to detect 
the marker residue at or below the Rm (Sec. Sec.  500.88(b) 
and 500.84(c)(2) (the Limit of Detection (LOD) for the regulatory 
method must be less than or equal to Rm.)). Under the SOM 
regulations, a method must be able to confirm the identity of the 
marker residue in the target tissue at a minimum concentration 
corresponding to the Rm. FDA will determine the LOD from the 
submitted analytical method validation data (Sec.  500.88(b)).\6\ If a 
method cannot be developed that can detect the marker residue at or 
below the Rm, the requirements of the SOM regulations are 
not satisfied, and FDA cannot approve the drug. See 21 U.S.C. 
360b(d)(1)(I); Sec.  500.88.
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    \6\ As discussed above, the Delaney Clause prohibits the use of 
carcinogenic animal drugs unless an exception, such as the DES 
Proviso, applies. See section 512(d)(1)(I) of the FD&C Act. The DES 
Proviso requires that, among other things, no residue of such drug 
will be found (by methods of examination prescribed or approved by 
the Secretary of HHS by regulations) in any edible portion of such 
animals after slaughter or in any food yielded by or derived from 
the living animals. FDA's SOM regulations establish the process by 
which a carcinogenic new animal drug may satisfy the DES Proviso. 
The SOM regulations were revised in 2002 to delete the operational 
definition of the term ``no residue'' and to make conforming 
amendments to other parts of the regulations. The LOD of the method 
replaced the Rm as the ``no residue'' determinant.
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B. History of Carbadox Approvals

    Currently, there are three approved NADAs for use of carbadox in 
medicated swine feed, either alone or in combination with other 
approved new animal drugs. Carbadox, a quinoxaline derivative, is a 
synthetic antimicrobial used to manufacture medicated feeds that are 
administered ad libitum to swine. Phibro Animal Health Corp. (Phibro), 
GlenPointe Centre East, 3d Floor, 300 Frank W Burr Blvd., Suite 21, 
Teaneck, NJ 07666, is currently the sponsor of all three approved 
NADAs.
1. NADA 041-061
    NADA 041-061, originally approved in 1972 (37 FR 20683, October 3, 
1972), provides for the use of MECADOX 10 (carbadox) Type A medicated 
article to manufacture single-ingredient Type C medicated swine feeds 
at the rate of 10 to 25 grams per ton (g/ton) of feed for increased 
rate of weight gain and improved feed efficiency; and at 50 g/ton of 
feed for control of swine dysentery (vibrionic dysentery, bloody 
scours, or hemorrhagic dysentery), control of bacterial swine enteritis 
(salmonellosis or necrotic enteritis caused by Salmonella 
choleraesuis), and for increased rate of weight gain and improved feed 
efficiency. Currently, the withdrawal period for these uses of carbadox 
is 42 days (Sec.  558.115(d)(1)(ii) and (d)(2)(ii) (21 CFR 
558.115(d)(1)(ii) and (d)(2)(ii))).
    In January 1998, FDA approved a supplemental application to NADA 
041-061. Based on the review of the data submitted in support of this 
supplemental application, CVM concluded: (1) The parent compound 
carbadox is rapidly metabolized and carcinogenic residues of the drug 
do not persist in any edible tissues beyond 72 hours postdosing; (2) 
unextracted residues of carbadox are noncarcinogenic residues related 
to the noncarcinogenic metabolite QCA; (3) extractable QCA is the only 
residue detectable in the edible tissues 72 hours postdosing; and (4) 
thus QCA is a reliable marker residue for carbadox and its 
metabolites.\7\ Despite the requirement in Sec.  500.86 that an 
Rm, instead of a tolerance, be established for a 
carcinogenic drug, CVM assigned a ``tolerance of 30 ppb [parts per 
billion] for QCA in swine liver'' as a means of

[[Page 43856]]

``assur[ing] that all residues of carcinogenic concern are well below 
their respective So in all edible tissues'' \8\ because, 
based on the conclusions listed above, CVM believed, at the time of the 
1998 supplemental approvals, that a tolerance would adequately protect 
public health. For a ``Regulatory Method,'' CVM approved a method that 
used a ``gas chromatographic assay with electron capture detection.'' 
\9\ However, this method was not published in the Federal Register as 
provided in Sec.  500.88, and the method that had been published for 
the 1972 approval was removed from the Code of Federal Regulations. 
Nevertheless, since the January 1998 approval of the supplemental NADA, 
CVM and the sponsor have treated the current approved method as the 
method of examination prescribed or approved by the Secretary of HHS by 
regulations for purposes of applying section 512(d)(1)(I) of the FD&C 
Act, the Delaney Clause, to carbadox.
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    \7\ FDA, Freedom of Information (FOI) Summary, NADA 041-061, 
MECADOX 10 (carbadox) Type A medicated article, supplemental 
approval January 30, 1998. Available at https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/308.
    \8\ Id. at 13.
    \9\ Id.
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    In October 1998, FDA approved an additional supplemental NADA for 
NADA 041-061, changing the withdrawal period for carbadox medicated 
feeds from 70 days to 42 days. This supplemental NADA was approved 
based on the previous approval of a tolerance of 30 parts per ppb for 
QCA and a residue depletion study using the approved QCA analytical 
method that showed residues of QCA in liver depleted below 30 ppb by 42 
days.\10\
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    \10\ FDA, FOI Summary, NADA 041-061, MECADOX 10 (carbadox) Type 
A medicated article, supplemental approval October 5, 1998. 
Available at https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1673.
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2. NADA 092-955
    NADA 092-955, originally approved in 1975 (40 FR 45164, October 1, 
1975), provides for the use of MECADOX 10 (carbadox) Type A medicated 
article with BANMINTH (pyrantel tartrate) Type A medicated article to 
manufacture two-way, combination drug Type C medicated swine feeds at 
50 g/ton of feed plus pyrantel tartrate at 96 g/ton of feed for control 
of swine dysentery (vibrionic dysentery, bloody scours, or hemorrhagic 
dysentery), control of bacterial swine enteritis (salmonellosis or 
necrotic enteritis caused by S. choleraesuis), as an aid in the 
prevention of migration and establishment of large roundworm (Ascaris 
suum) infections, and as an aid in the prevention of establishment of 
nodular worm (Oesophagostomum) infections. The withdrawal period for 
the use of this drug combination is 70 days (Sec.  558.115(d)(3)(ii)).
3. NADA 141-211
    NADA 141-211, originally approved in 2004 (69 FR 51173, August 18, 
2004), provides for the use of MECADOX 10 (carbadox) Type A medicated 
article with TERRAMYCIN 50, TERRAMYCIN 100, or TERRAMYCIN 200 
(oxytetracycline) Type A medicated articles to manufacture two-way, 
combination drug Type C medicated swine feeds at 10 to 25 g/ton of feed 
plus oxytetracycline at levels in feed to deliver 10 mg carbadox per 
pound of body weight for treatment of bacterial enteritis caused by 
Escherichia coli and S. choleraesuis susceptible to oxytetracycline, 
for treatment of bacterial pneumonia caused by Pasteurella multocida 
susceptible to oxytetracycline, and for increased rate of weight gain 
and improved feed efficiency. The withdrawal period for the use of this 
animal drug combination is 42 days (Sec.  558.115(d)(4)(ii)).

C. Post-Approval Information Regarding Carcinogenic Residues

    After the 1998 supplemental approval, FDA has subsequently 
evaluated data regarding the persistence of carbadox residues in swine 
treated with carbadox, including residues of carbadox, DCBX, and QCA. 
Based on a review of this data, FDA has concluded that: (1) 
Carcinogenic residues persist in animal tissue more than 72 hours 
postdosing and (2) QCA is not the only residue detectable in animal 
tissue after 72 hours postdosing.
    For the 2003 Joint Food and Agriculture Organization/World Health 
Organization Expert Committee on Food Additives (JECFA) meeting, the 
sponsor provided data in which it reported that DCBX is measurable 
quantitatively (in specific amounts) at 15 days postdosing (the last 
sampling timepoint in the study) (Ref. 1). Based on those studies, 
which showed the persistence of genotoxic, carcinogenic residues, JECFA 
could not determine an amount of residues of carbadox in human food 
that would have no adverse health effects in consumers. Following that 
meeting, the Codex Committee on Residues of Veterinary Drugs in Foods 
withdrew the maximum residue levels for carbadox, and carbadox has been 
removed from the market in many foreign jurisdictions, including the 
European Union (Ref. 2), Canada (Ref. 3), and Australia (Ref. 4).
    Pursuant to section 512(l)(1) of the FD&C Act, FDA ordered Phibro 
to provide it with data related to the persistence of DCBX in edible 
tissues and the appropriateness of QCA as a marker residue. Phibro 
responded, among other submissions, with the same data provided to the 
2003 JECFA. CVM reviewed the 2003 JECFA data and determined that the 
data show qualitatively (in non-specific amounts) that carbadox and 
DCBX are present in liver tissue samples at 48 hours and at 15 days 
withdrawal, respectively. CVM concluded that the mass spectrometry 
chromatograms and the reported DCBX concentration data provide 
qualitative confirmation of the presence of DCBX at 15 days withdrawal 
in the samples exposed to digestive enzymes.
    CVM has also reviewed data submitted by the sponsor, including data 
from a 2008 study discussed in its Request for a Hearing in response to 
the 2016 NOOH and studies it submitted in July 2016. In general, 
proprietary data (such as the 2008 and 2016 studies conducted by 
Phibro) are considered confidential commercial information and 
therefore cannot be shared publicly in this proposed order. Based on 
its review of these data, CVM concluded that the known carcinogenic 
residues (carbadox and DCBX) persist beyond 72 hours and that QCA is 
not the only residue detectable after 72 hours. Furthermore, the 
sponsor has not provided data to establish a relationship between QCA 
and the residue of carcinogenic concern, which include carbadox and 
DCBX, nor have they provided data to establish the residue level of QCA 
at which the residue of carcinogenic concern in the diet of people 
represents no significant increase in the risk of cancer to people. 
Without these data, CVM cannot establish the Rm and the 
sponsor cannot demonstrate ``no residue'' of carcinogenic concern as 
required by the SOM regulations in part 500, subpart E, as implementing 
the FD&C Act at 21 U.S.C. 360b(d)(1)(I).

D. Statutory Authority To Propose Order

    Under 5 U.S.C. 554(e) (section 5(d) of the Administrative Procedure 
Act (APA)), an agency, in its sound discretion, may issue a declaratory 
order to terminate a controversy or remove uncertainty. The APA defines 
``order'' as the whole or a part of a final disposition, whether 
affirmative, negative, injunctive, or declaratory in form, of an agency 
in a matter other than rulemaking but including licensing (5 U.S.C. 
551(6)). The APA defines ``adjudication'' as agency process for the 
formulation of an order (5 U.S.C. 551(7)). FDA's regulations, 
consistent with the APA, define ``order'' to mean the final agency 
disposition, other than

[[Page 43857]]

the issuance of a regulation, in a proceeding concerning any matter 
(Sec.  10.3(a) (21 CFR 10.3(a)). Our regulations also define 
``proceeding and administrative proceeding'' to mean any undertaking to 
issue, amend, or revoke a regulation or order, or to take or not to 
take any other form of administrative action, under the laws 
administered by FDA (Sec.  10.3(a)). Moreover, our regulations 
establish that the Commissioner of Food and Drugs may initiate an 
administrative proceeding to issue, amend, or revoke an order (21 CFR 
10.25(b)).
    On our own initiative, we are proposing to formulate a 5 U.S.C. 
554(e) declaratory order to remove uncertainty regarding the approved 
method for carbadox that measures QCA as a marker residue. An order is 
the most appropriate method to revoke the approved method because there 
is no rule to amend. The current approved method is not currently 
published in the Federal Register, contrary to Sec.  500.88, and the 
method that had been published for the 1972 approval was removed from 
the Code of Federal Regulations in 1998. The FD&C Act does not provide 
the procedure we must use to determine whether a method of examination 
that was never published in regulation satisfies the regulatory 
requirements of part 500, subpart E. Thus, we are choosing to issue a 
declaratory order to remove uncertainty.

III. Discussion

    CVM proposes to revoke the approved method for carbadox that 
measures QCA as the marker residue. The currently approved method 
cannot adequately monitor residue of carcinogenic concern because there 
is no established relationship between QCA and the residue of 
carcinogenic concern. Thus, the current approved method does not comply 
with part 500, subpart E, and therefore does not satisfy the statutory 
requirement of section 512(d)(1)(I) of the FD&C Act.
    When CVM approved a supplemental NADA for carbadox in 1998, it did 
not require the sponsor to provide data establishing a known 
relationship between the concentration of the marker residue (QCA) and 
the concentration of the residue of carcinogenic concern (Sec.  
500.86(a) through (c)). At the time of the 1998 supplemental NADA 
approval, CVM did not believe that such information was necessary 
because of previous conclusions that it had made about the persistence 
of carcinogenic residue in the edible tissues of animals dosed with 
carbadox. Results from subsequent studies have led CVM to reexamine the 
conclusions made in 1998. CVM concludes, based on data from these 
studies, that it is necessary to establish a known relationship between 
the marker residue and the residue of carcinogenic concern, as required 
by regulation. Accordingly, CVM is proposing to revoke the current 
approved method because it is inadequate to monitor the residue of 
carcinogenic concern.

A. CVM's Conclusions in the January 1998 Approval

    In reviewing residue chemistry information for the supplemental 
NADA for carbadox in January 1998, CVM relied on studies conducted by 
the sponsor \11\ and academic researchers \12\ to establish an 
So and an Sm for the most potent of the 
carcinogenic compounds. As part of the supplemental NADA, the sponsor 
submitted toxicology studies, including carcinogenicity bioassays with 
carbadox, DCBX, and hydrazine (another carcinogenic metabolite of 
carbadox).\13\ These studies indicated that DCBX was the most potent of 
the three identified carcinogenic residues of carbadox.\14\ Based on 
the carcinogenicity of DCBX, CVM calculated an So of 0.061 
ppb for total residue of carcinogenic concern for carbadox in the total 
diet. CVM calculated an Sm value for the residue of 
carcinogenic concern in muscle at 0.305 ppb, in liver at 0.915 ppb, and 
in kidney and fat at 1.830 ppb.\15\
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    \11\ Pfizer, Inc. was the sponsor for carbadox until 2001. The 
current sponsor is Phibro Animal Health.
    \12\ Summaries of these studies can be found in the FDA FOI 
Summary, NADA 041-061, MECADOX 10 (carbadox) Type A medicated 
article, supplemental approval January 30, 1998, available at 
https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/308; and, in the 1990 evaluation of carbadox by the 
Joint FAO/WHO Expert Committee on Food Additives, available at 
http://www.fao.org/fileadmin/user_upload/vetdrug/docs/41-3-carbadox.pdf (accessed on October 11, 2019).
    \13\ FDA, FOI Summary, NADA 041-061, MECADOX 10 (carbadox) Type 
A medicated article, supplemental approval January 30, 1998. 
Available at https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/308.
    \14\ Id.
    \15\ Id.
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    Based on information submitted as part of the supplemental NADA 
approved in January 1998, CVM made conclusions about how long 
carcinogenic residues persist in the edible tissues of swine after 
treatment with carbadox and about the appropriate marker residue to 
select to monitor carbadox use. As stated in the FOI summary for the 
January 1998 approval of the supplemental NADA,\16\ CVM concluded the 
data:
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    \16\ Id.

Show that carbadox, desoxycarbadox and hydrazine do not persist in 
edible tissue as detectable residues beyond 72 hours. The agency's 
evaluation of these data, and the new information provided by the 
sponsor, demonstrate that following administration, parent carbadox 
is rapidly metabolized; that the metabolism of carbadox is similar 
among species; that the in vivo metabolism of the compounds of 
carcinogenic concern is also rapid and irreversible such that the 
resulting metabolic products cannot regenerate compounds of 
carcinogenic concern; that the unextractable residues are related to 
non-carcinogenic compounds, quinoxaline-2-carboxylic acid (QCA) and 
quinoxaline-2-carboxaldehyde; and that QCA is the only residue 
detectable in the edible tissues beyond 72 hours post dosing. Thus, 
the agency concludes that the unextractable bound residue is not of 
carcinogenic concern and that QCA is a reliable marker residue for 
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carbadox.

    CVM made the following conclusions during the review of the 
supplemental NADA for carbadox approved in January 1998:
    1. Carcinogenic residues do not persist in animal tissue beyond 72 
hours postdosing.
    2. Extractable QCA is the only residue detectable in edible tissues 
72 hours postdosing.
    3. Unextractable residues are noncarcinogenic residues related to 
QCA.
    4. QCA is a reliable marker residue for carbadox and its 
metabolites.
    5. No residue of carcinogenic concern, even below the 
So, is detectable by any method after 72-hours postdosing.
    Because of these conclusions, CVM did not require the sponsor to 
submit data to meet the requirements of the part 500, subpart E 
regulations despite the fact that carbadox is a carcinogen. These 
regulations require CVM to designate an Rm (the residue 
level at which the residue of carcinogenic concern in the diet of 
people represents no significant increase in the risk of cancer to 
people) based on a known relationship between the marker residue and 
the residue of carcinogenic concern. In addition, the sponsor must 
provide a regulatory method that can detect the marker residue at or 
below the Rm.\17\ CVM

[[Page 43858]]

instead established a tolerance of 30 ppb for QCA, and granted the 
supplemental approval for carbadox. Subsequent to the 1998 supplemental 
approval, CVM has evaluated additional information that undermines its 
previous conclusions that carcinogenic residues deplete within 72 hours 
and that QCA is the only residue detectable at 72 hours postdosing. 
These new data reinforce the inadequacy of the currently approved 
method and clarify the need for a method that satisfies the 
requirements of part 500. See, supra, Section II.C.
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    \17\ Under Sec.  500.86, the necessary steps to meet the 
operational definition of ``no residue'' are: (1) Measure the 
depletion of the residue of carcinogenic concern until its 
concentration is at or below the Sm (0.915 ppb) in liver; 
(2) measure the depletion of the marker residue until the 
concentration of the residue of carcinogenic concern is at or below 
the Sm; (3) use the information in (1) and (2) to 
establish an Rm; and, (4) according to the regulations as 
they existed in 1998, develop a method that could detect the marker 
residue of the drug, as long as the marker residue would only be 
detected at or below the Rm under the proposed conditions 
of use. According to the current regulations, step (4) requires the 
development of a method that complies with the operational 
definition of no residue (the method's LOD is less than or equal to 
the Rm).
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B. The Current Approved Method for Carbadox That Measures QCA as the 
Marker Residue for Carbadox Is Inadequate

    Under section 512(d)(1)(I) of the FD&C Act, carcinogenic new animal 
drugs, such as carbadox, must have a method of detection, prescribed or 
approved by regulation, to ensure that no residue of carcinogenic 
concern persists in any edible tissue or other food derived from a 
treated animal. CVM has implemented this statutory requirement through 
its SOM regulations in part 500, subpart E, which require that each 
carcinogenic new animal drug have a marker residue with a known 
relationship to the residue of carcinogenic concern. This relationship 
is necessary to establish a concentration of the marker residue (the 
Rm) that ensures any residue of carcinogenic concern in a 
specific edible tissue is below the level corresponding to maximum 
lifetime risk of cancer in the test animal of 1 in 1 million (the 
Sm), based on calculations that consider the entire diet 
(the So). The approved method must have a limit of detection 
less than or equal to the Rm.
    Although CVM approved the current method for carbadox as part of 
the supplemental NADA in January 1998 and designated the Sm 
and So, we did not require the sponsor to provide data 
showing the relationship between QCA and the residue of carcinogenic 
concern and therefore did not designate an Rm. Nor did we 
require the sponsor to identify a regulatory method with a limit of 
detection less than or equal to the Rm. Without an 
Rm and an appropriate regulatory method for detecting when 
the marker residue falls below the Rm, it is impossible to 
determine that the residue of carcinogenic concern falls below the 
Sm and So at the established withdrawal period. 
Accordingly, it is impossible, based on information currently 
available, to use the current approved method to ensure compliance with 
the operational definition of no residue.
    Furthermore, based on studies conducted since 1998, CVM has 
reevaluated the conclusions that originally led us to determine that 
assignment of a tolerance of 30 ppb for QCA in swine liver would assure 
that the residue of carcinogenic concern would remain below their 
respective So in all edible tissues. CVM concludes, based on 
its review of the data, that carcinogenic residues persist longer than 
previously known. Because there is no regulatory method that detects 
when the residue of carcinogenic concern falls below the limit of 
detection for the Rm, the current approved method is 
inadequate for monitoring compliance with FDA's operational definition 
of no residue. See Sec.  500.84(c)(3). Accordingly, the approved method 
for carbadox does not satisfy the statutory or regulatory requirements.

IV. Conclusion

    In the January 1998 approval of the supplemental NADA for carbadox, 
CVM previously determined that carbadox and its metabolites, including 
DCBX, induce cancer in animals but that no such residues of the drug 
would be found in edible tissues after the preslaughter withdrawal 
period by the approved regulatory methods of examination. However, the 
failure to establish an Rm or a relationship between QCA 
residues and residue of carcinogenic concern in animal tissue during 
the 1998 process leads CVM to now conclude that the current approved 
method does not meet the requirements of the FD&C Act and the SOM 
regulations and is inadequate to monitor carbadox residues in 
compliance with FDA's operational definition of no residue. New 
information available to CVM since the approval of the January 1998 
supplemental NADA reinforces the importance of having an approved 
regulatory method that complies with the SOM regulations. Therefore, we 
are proposing to revoke the current approved method.

V. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. Su[aacute]rez, A.F. and Arnold, D., Addendum to the carbadox 
monograph prepared by the 36th meeting of the Committee and 
published in the FAO Food and Nutrition Paper 41/3, Rome 1991. 
Available at: http://www.fao.org/fileadmin/user_upload/vetdrug/docs/41-15-carbadox.pdf (accessed on April 7, 2020).
2. Evaluations of the Joint FAO/WHO Expert Committee on Food 
Additives (JECFA). Carbadox. Available at: https://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=2176 
(accessed on April 7, 2020).
3. Internet Archive of Health Canada, Drug and Health Products (June 
2008), https://web.archive.org/web/20080609050022/ http://www.hc-sc.gc.ca/dhp-mps/vet/faq/faq_mrl-lmr-eng.php (accessed on April 7, 
2020).
4. Australian Pesticides and Veterinary Medicines Authority, 
``Substances not permitted for use on food-producing animals in 
Australia,'' https://apvma.gov.au/node/11626 (accessed on April 7, 
2020).

    Dated: July 9, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-15246 Filed 7-17-20; 8:45 am]
BILLING CODE 4164-01-P