[Federal Register Volume 81, Number 70 (Tuesday, April 12, 2016)]
[Notices]
[Pages 21559-21573]
[FR Doc No: 2016-08327]

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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;
Opportunity for Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of opportunity for hearing.

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SUMMARY: The Food and Drug Administration (FDA), Center for Veterinary
Medicine (CVM), is proposing to withdraw approval of all new animal
drug applications (NADAs) providing for use of carbadox in medicated
swine feed. This action is based on CVM's determination that the use of
carbadox under the approved conditions of use results in residues of
carcinogenic concern in the edible tissues of the treated swine.

DATES: Phibro Animal Health Corp. may submit a request for a hearing by
May 12, 2016. Submit all data and analysis upon which the request for a
hearing relies by July 11, 2016.

ADDRESSES: The request for a hearing may be submitted by Phibro Animal
Health Corp. by either of the following methods:

Electronic Submission

     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments to submit your request
for hearing. Your request for a hearing submitted electronically,
including any attachments to the request for hearing, to http://www.regulations.gov will be posted to the docket unchanged.

Written/Paper Submission

     Mail/Hand delivery/Courier (for written/paper request for
a hearing): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Because your request for a hearing will be made public, you are
solely responsible for ensuring that your request does not include any
confidential information that you may not wish to be publicly posted,
such as confidential business information, e.g., a manufacturing
process. The request for a hearing must include the Docket No. FDA-
2016-N-0832 for ``Phibro Animal Health Corp.; Carbadox in Medicated
Swine Feed; Opportunity for Hearing.'' The request for a hearing will
be placed in the docket and publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
    Phibro Animal Health Corp. may submit all data and analysis upon
which the request for a hearing relies in the same manner as the
request for a hearing except as follows:
     Confidential Submissions--To submit any data and analyses
with confidential information that you do not wish to be made publicly
available, submit your data and analyses only as a written/paper
submission. You should submit two copies total of all data and
analysis. One copy will include the 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
any decisions on this matter. The second copy, which will have the
claimed confidential

information redacted/blacked out, will be available for public viewing
and posted on http://www.regulations.gov or available at the Division
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
Submit both copies to the Division of Dockets Management. Any
information marked as ``confidential'' will not be disclosed except in
accordance with 21 CFR 10.20 and other applicable disclosure law.
    Comments Submitted by Other Interested Parties: For all comments
submitted by other interested parties you may submit comments as
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of
Dockets Management, 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; Opportunity for Hearing.'' Received comments will be placed
in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at http://www.regulations.gov or at
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
     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 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 http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Vernon Toelle, Center for Veterinary
Medicine (HFV-230), 7519 Standish Pl., Rockville, MD 20855, 240-276-
9200.

SUPPLEMENTARY INFORMATION:

I. Approved NADAs for Use of Carbadox in Swine Feed

    Carbadox, a quinoxaline derivative, is a synthetic organic acid
antimicrobial. Currently, there are three approved NADAs for use of
carbadox in medicated swine feed, either by itself or in combination
with other approved new animal drugs. Phibro Animal Health Corp.
(Phibro), 65 Challenger Rd., Ridgefield Park, NJ 07660, is currently
the sponsor of all three approved NADAs.
    Carbadox is marketed as a Type A medicated article used to
manufacture complete Type C medicated feeds that are administered ad
libitum to swine. Carbadox is indicated for the control of dysentery
and bacterial enteritis, and for growth promotion. A tolerance of 30
parts per billion (ppb) \1\ has been established for residues of
quinoxaline-2-carboxylic acid (QCA), the marker residue, in liver of
swine (21 CFR 556.100).
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    \1\ For consistency and readability throughout this document,
concentrations are reported as parts per billion even though
original references may report some concentrations as parts per
trillion (ppt).
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    The following three NADAs are approved for the use of carbadox:
    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
for the following conditions of use:
     Carbadox at 10 to 25 grams per ton (g/ton) of feed for
increased rate of weight gain and improved feed efficiency; and
     Carbadox at 50 g/ton of feed for control of swine
dysentery (vibrionic dysentery, bloody scours, or hemorrhagic
dysentery); for 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))).
    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 for
the following conditions of use:
     Carbadox 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); for control of bacterial
swine enteritis (salmonellosis or necrotic enteritis caused by
Salmonella 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)).
    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 for the following
conditions of use:
     Carbadox 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)).

II. Basis for Withdrawal of Approval

    CVM is providing notice of an opportunity for a hearing (NOOH) on a
proposal to withdraw approval of the NADAs providing for use of
carbadox in medicated swine feeds. New evidence regarding carcinogenic
residues in edible tissues of swine treated with carbadox raises
serious questions about the human food safety of the drug. Grounds for
withdrawing carbadox are twofold. First, new evidence demonstrates that
the Delaney Clause in section 512(d) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 360b), which requires that no
residue of a carcinogenic drug can be found in any edible portion of
the animal after slaughter, applies because the Diethylstilbestrol
(DES) Proviso exception is no longer met (see, Section III.C). Second,
new evidence demonstrates that carbadox is not shown to be safe under
the General Safety Clause (section 512(e)(1)(B) of the FD&C Act).
    During the review of a supplemental application to NADA 041-061
approved in January 1998, CVM made the following conclusions about the
drug: (1) The parent compound carbadox is rapidly metabolized and
carcinogenic residues of the drug are not identifiable in any edible
tissues beyond 72 hours post dosing; (2) remaining unextracted residues
of carbadox are noncarcinogenic residues related to the noncarcinogenic
metabolite QCA; and (3) QCA is a reliable marker residue for carbadox
and its metabolites (Ref. 1).
    Since the evaluation of information submitted by the sponsor in
that supplemental application, CVM has become aware of new information
that calls into question the basis for its previous conclusions. As
described more fully in Section V., this includes new residue depletion
data presented to the Joint FAO/WHO Expert Committee on Food Additives
(JECFA) \2\ in 2003 that shows that when the marker residue QCA reaches
the approved tolerance of 30 ppb in liver, concentrations of the
carcinogen desoxycarbadox (DCBX) in the liver would be approximately 4
times higher than the concentration that would be considered safe (Ref.
2 at pp. 16-17). In addition, the new residue depletion data presented
to JECFA in 2003 call into question CVM's previously held conclusion
that the unextracted residues of carbadox at the withdrawal period are
noncarcinogenic compounds related to the QCA metabolite (Ref. 1). The
Agency treats the unidentified residues--metabolites of a carcinogenic
parent drug with demonstrated carcinogenic metabolites--as
carcinogenic. Therefore, the drug is not shown to be safe under the
General Safety Clause and the Delaney Clause applies to the drug,
because the DES Proviso exception is no longer met.
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    \2\ JECFA is an independent committee of international
scientific experts administered jointly by the United Nations Food
and Agriculture Organization (FAO) and the World Health Organization
(WHO) for the purpose of providing independent scientific advice to
the FAO, WHO, and member countries. It has been meeting since 1956
specifically to evaluate the safety of food additives, including the
animal drug residues in edible tissues. See http://www.codexalimentarius.org/scientific-basis-for-codex/jecfa/en/ and
http://www.who.int/foodsafety/areas_work/chemical-risks/jecfa/en/.
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    Continued approval of carbadox would expose humans to
concentrations of total residues of carcinogenic concern that are
approximately 30 times higher (for the approved 42-day withdrawal
period) or 11 times higher (for the approved 70-day withdrawal period)
than the 0.915 ppb concentration of total residues of carcinogenic
concern in liver that would be considered safe (Ref. 3 at p. 17, Table
8). Moreover, the sponsor has not identified an appropriate marker and
analytical method to assure that residues of carcinogenic concern are
below the level at which the residues present in the total human diet
present no significant increase in the risk of cancer to people (the
So).
    In addition to the new information presented to JECFA (Ref. 2),
publications by Boison, et al., in 2009 (Ref. 4) and Baars, et al., in
1990 (Ref. 5) that were recently provided to CVM by the sponsor call
into question the previous conclusion that QCA is an appropriate marker
and that all residues of carcinogenic concern deplete within 72 hours
after dosing.
    The new evidence from the 2003 JECFA report (Ref. 2) in conjunction
with the publications by Boison, et al., in 2009 (Ref. 4) and Baars, et
al., in 1991 (Ref. 6), erode the scientific justification for, and
validity of, conclusions previously made about the drug in 1998. Based
on this new information, evaluated together with the information
available at the time of the approvals, CVM has determined that the
drug is not shown to be safe under the General Safety Clause and that
the Delaney Clause applies to the drug, because the DES Proviso
exception is no longer met. Therefore, CVM proposes to withdraw
approval of all NADAs for new animal drugs containing carbadox.

III. Legal Context of the Proposed Action and Grounds for Withdrawal

A. The Determination of Safety in Section 512

    Carbadox, for each of its uses in swine, is a new animal drug as
defined in section 201(v) of the FD&C Act (21 U.S.C. 321(v)). As such,
under sections 301, 501, 512, 571, and 572 of the FD&C Act (21 U.S.C.
331, 351, 360b, 360ccc, 360ccc-1), the drug cannot be legally
introduced or delivered for introduction into interstate commerce in
the absence of an NADA approval, a conditional approval, or an animal
drug indexing. The requirements for approval of an NADA are set out in
section 512(d)(2)(A) of the FD&C Act. Section 512(b)(1)(A) of the FD&C
Act requires that a new animal drug must be shown to be safe and
effective for its intended uses. Section 201(u) of the FD&C Act
provides that ``safe'' as used in section 512 of the FD&C Act ``has
reference to the health of man or animal.'' The determination of safety
requires CVM to consider, among other relevant factors, ``the probable
consumption of such drug and any substance formed in or on food because
of the use of such drug . . .'' (section 512(d)(2)(A) of the FD&C Act).
Accordingly, CVM must consider not only safety of the new animal drug
to the target animal, but also the safety to humans of substances
formed in or on food as a result of the use of the new animal drug.

    ``Safe,'' in the context of human food safety, means a ``reasonable
certainty of no harm.'' The definition is derived from language in H.
Rep. No. 85-2284, at 4-5 (1958), defining the term ``safe'' as it
appears in section 409 of the FD&C Act, which governs food additives
(21 U.S.C. 348). Until passage of the Animal Drug Amendments of 1968
(Pub. L. 90-399) (the 1968 amendments), substances formed in or on food
due to the use of animal drugs in food-producing animals were regulated
under the food additive provisions in section 409 of the FD&C Act. The
1968 amendments consolidated all of the existing statutory authorities
related to animal drugs into section 512 of the FD&C Act, and the
legislative history shows that the consolidation in no way changed the
authorities with respect to the regulation of new animal drugs (S. Rep.
No. 90-1308, at 1 (1968)). During the new animal drug application
review process, CVM has consistently applied the ``reasonable certainty
of no harm'' standard in determining the safety of substances formed in
or on food as a result of the use of a new animal drug in a food-
producing animal.
    In order to determine whether a new animal drug meets this
standard, section 512(b)(1)(G)-(H) of the FD&C Act requires that
whenever a drug may result in residues of the drug or its metabolites
in food, an application must include not only full reports of
investigations to show that the use of the drug is safe, but also a
description of practicable methods for monitoring food to assure that
there are no unsafe residues in human food attributable to the drug
use, and a demonstration that the conditions of use are adequate to
assure there are no unsafe residues.
    In sum, under section 512(d)(2) of the FD&C Act, the Agency is
required, in the evaluation of the supporting safety data, among other
things, to consider:
     The probable consumption of such drug and of any substance
formed in or on food because of the use of such drug (i.e., probable
human consumption of residues including the parent drug and its
metabolites);
     The cumulative effect on man or animal of such drug,
taking into account any chemically or pharmacologically related
substance, i.e., toxicological effects of the compounds comprising the
residues; and
     Safety factors which, in the opinion of experts qualified
by scientific training and experience to evaluate the safety of such
drugs, are appropriate for the use of animal experimentation data
(i.e., establishing ``safe'' levels of residues using appropriate
safety factors to extrapolate animal data on cumulative effects to
humans).
    When establishing the human food safety of a noncarcinogenic new
animal drug used in food-producing animals, CVM establishes a no
observed effect level (NOEL) for the residues of that drug in edible
tissues--namely, the highest dose of the drug that does not produce the
most sensitive treatment-related toxic endpoint in test animals (Ref.
7). From the NOEL, CVM uses safety factors to calculate an acceptable
daily intake, and consumption factors to calculate the safe
concentration of residues in a particular edible tissue (Ref. 7 at p.
15; section 512(b)(1)(H) of the FD&C Act).
    Carbadox is both a genotoxic \3\ and mutagenic carcinogen in
animals. In the case of a genotoxic carcinogenic drug, establishing the
human food safety of the compound via a NOEL is not feasible, therefore
human food safety of carcinogenic compounds is ordinarily evaluated by
using linear, low-dose extrapolation to evaluate the maximum
concentration of total residues of carcinogenic concern that can be
present in the total human diet without a significant increase in the
risk of cancer to the human consumer (section 512(d)(1)(I) of the FD&C
Act; 21 CFR 500.82 and 500.84). In both cases, the safe residue level
of the drug is determined through an evaluation of the relevant data
relating to the three factors listed above; viz., the probable
consumption of the drug residue and its cumulative effect as determined
through all relevant safety factors (section 512(d)(2) of the FD&C
Act).
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    \3\ Genotoxic refers to chemicals that react with DNA or
chromosomes to cause damage. When the damage is not repaired and the
effect is a heritable change (cell to cell or parent to offspring),
it is also termed mutagenic. Thus not all genotoxic chemicals are
mutagenic, but all mutagenic chemicals are genotoxic. Uncorrected
mutagenesis is thought to be a key step in the development of
cancer. ``Mechanisms of Toxicity,'' in Casarett & Doull's
Toxicology: The Basic Science of Poisons, edited by Klassen, C.D.,
8th Ed., pp. 49-123, 2013.
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B. Grounds for Withdrawal Under the FD&C Act

    Section 512(e)(1)(B) of the FD&C Act provides grounds for
withdrawal of approval of an NADA if new evidence not contained in an
approved application or not available to the Secretary of Health and
Human Services until after such application was approved, or tests by
new methods, or tests by methods not deemed reasonably applicable when
such application was approved, evaluated together with the evidence
available to the Secretary when the application was approved, shows
that such drug is not shown to be safe for use under the conditions of
use upon the basis of which the application was approved or that
subparagraph (I) of paragraph (1) of subsection (d) applies to such
drug. The Secretary of Health and Human Services has delegated this
authority to the Commissioner of Food and Drugs. See FDA Staff Manual
Guide 1410.10 (April 11, 2014).
    In other words, grounds for withdrawal exist where new evidence
shows either that the Delaney Clause applies to the drug
(``subparagraph (I) of paragraph (1) of subsection (d)'') or that the
drug is not shown to be safe under the approved conditions of use (the
General Safety Clause). As explained further, new evidence demonstrates
that carbadox meets both grounds for withdrawal.
    In a proceeding to withdraw the approval of an NADA, the sponsor
has the burden of proof to demonstrate that the product is safe and
therefore that the NADA approval should remain in effect (21 CFR
12.87(d): (``At a hearing involving issuing, amending, or revoking a
regulation or order relating to the safety or effectiveness of a drug .
. . the participant who is contending that the product is safe or
effective or both and who is . . . contesting withdrawal of approval
has the burden of proof in establishing safety or effectiveness or both
and thus the right to approval.''); (see also Rhone-Poulenc, Inc. v.
FDA, 636 F.2d 750, 752 (D.C. Cir. 1980); Hess & Clark v. FDA, 495 F.2d
975, 992 (D.C. Cir. 1974)). Nevertheless, CVM bears an initial burden
of showing that new evidence regarding the new animal drug raises
serious questions about the safety of the new animal drug. See Rhone-
Poulenc, 636 F.2d at 752. Once CVM has satisfied the initial burden,
the burden shifts to the sponsor to establish the safety of the drug:

    In the Hess & Clark case we held that the ``new evidence''
requirement of the safety clause ``plainly places on the [CVM] an
initial burden to adduce the `new evidence' and what that evidence
`shows'. Only when the [CVM] has met this initial burden of coming
forward with the new evidence is there a burden on the manufacturer
to show that the drug is safe.'' Rhone-Poulenc, 636 F.2d at 752
(quoting Hess & Clark, 495 F.2d at 992).

    To meet its initial burden of proof to withdraw approval of a new
animal drug that is ``not shown to be safe,'' CVM must provide ``a
reasonable basis from which serious questions about the ultimate safety
of [the drug] and the residues that may result from its use may be
inferred.'' See Diethylstilbestrol: Withdrawal of Approval of New
Animal Drug Applications; Commissioner's Decision (44 FR 54852 at
54861,

September 21, 1979) (hereinafter DES Commissioner Decision) (quoting
Proposal to Withdraw Approval of New Animal Drug Applications for
Diethylstilbestrol, ALJ Initial Decision, Docket No. FDA-1976-N-0028
(formerly 76N-0002), I.D. at 8 (September 21, 1978)), aff'd Rhone-
Poulenc, 636 F.2d 750; see also Nitrofurans Commissioner Decision (56
FR 41902 at 41902, August 23, 1991). Serious questions can be raised
where the evidence is not conclusive but merely suggestive of an
adverse effect. See DES Commissioner Decision.

C. Withdrawal Under the Delaney Clause and the DES Proviso

    Section 512(e)(1)(B) of the FD&C Act provides grounds for
withdrawal of approval of an NADA if new evidence, tests by new
methods, or tests by methods not deemed reasonably applicable when such
application was approved, evaluated together with the evidence
available when the application was approved shows that the Delaney
Clause, section 512(d)(1)(I) of the FD&C Act, applies to the drug.
Under the Delaney Clause, the Secretary may not approve a new animal
drug application if ``such drug induces cancer when ingested by man or
animal or, after tests which are appropriate for the evaluation of the
safety of such drug, induces cancer in man or animal'' (section 512
(d)(1)(I) of the FD&C Act). An exception to this general rule, referred
to as the DES Proviso, allows for the approval of a carcinogenic new
animal drug where FDA 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)(i)-(ii) of the FD&C Act).
    FDA has issued implementing regulations that set 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
yielded from the animal (21 CFR part 500, subpart E). These
regulations, referred to as the sensitivity of the method regulations
(SOM regulations), describe how FDA determines whether the regulatory
method proposed by a sponsor to detect no residues of the carcinogenic
drug is sufficiently sensitive to ensure that residues of carcinogenic
concern in edible tissues will not exceed concentrations that represent
no significant increase in the risk of cancer to humans.
    Pursuant to these regulations, CVM determines for each drug and
each drug metabolite (on the basis of the results of chronic bioassays
and other information) whether the drug or any of its metabolites
should be regulated as a carcinogen (Sec.  500.84(a)). For the drug and
each metabolite determined to be carcinogenic, CVM calculates, based
upon 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 value 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). Residue of carcinogenic concern includes all
compounds in the total residue of a demonstrated carcinogen excluding
any compound judged by CVM not to present a carcinogenic risk (Sec.
500.82(b)). The total residues of carcinogenic concern (the drug and
all of its metabolites less metabolites shown to be noncarcinogenic)
are regulated based on the most potent carcinogenic residue (Sec.
500.84(c)(1)). 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.
    Because the total 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 residues of
carcinogenic concern in a specific edible tissue 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 test animals
of 1 in 1 million. This value is termed the Sm (Sec. Sec.
500.82(b) and 500.84(c)(1)).
    Based upon residue depletion 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 (a residue whose
concentration is in a known relationship to the concentration of the
residues of carcinogenic concern in the last tissue to deplete to the
Sm) and designates the concentration of the marker residue
that the regulatory method must be capable of detecting in the target
tissue (Sec.  500.86(a)-(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, such that
the absence of the marker residue in the target tissue above
Rm can be taken as confirmation that the residue of
carcinogenic concern does not exceed Sm in each of the
edible tissues (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 diet of people does not exceed So (Sec.
500.86(c)).
    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 LOD [Limit of Detection for the regulatory
method] must be less than or equal to Rm.'')). 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. The DES Proviso and FDA's
implementing regulations are satisfied where no marker residue is
detectable using the approved regulatory method under the proposed
conditions of use of the drug, including the proposed preslaughter
withdrawal period (Sec.  500.84(c)(3)).
    As stated above, pursuant to section 512(e)(1)(B) of the FD&C Act,
the Secretary shall, after due notice and an opportunity for a hearing,
withdraw approval of an NADA if the Secretary finds that new evidence,
tests by new methods, or tests by methods not deemed reasonably
applicable when such application was approved, evaluated together with
the evidence available when the application was approved shows that the
Delaney Clause applies to the drug. Evidence that the Delaney Clause
applies to a drug exists where the drug has previously been determined
to be a carcinogen and the new evidence shows CVM's prior establishment
of an analytical method and residue tolerance under the DES proviso
exception to the Delaney Clause is inadequate. An analytical method is
inadequate where new evidence demonstrates that the method does not
accurately detect the marker residue or where new evidence demonstrates
that not all residues of carcinogenic concern have depleted at the
approved tolerance level of the marker residue (see, e.g., Rhone-
Poulenc, 636 F.2d at 752-53.)
    In establishing that grounds for withdrawal of approval exist under
this clause, CVM carries an initial burden to demonstrate that the new
animal drug and/or any of its metabolites induces cancer when ingested
by man or animals. Proposal to Withdraw New Animal Drug Applications
for Furazolidone (NF-180) and Nitrofurazone (NF-7), ALJ Decision, FDA
Docket No. FDA-1976-N-0511, at 73 (formerly 76N-0172; November 12,

1986) (hereinafter ALJ Decision, November 12, 1986). Once CVM has
satisfied its initial burden, the sponsor bears the burden of showing
that the drug satisfies the DES Proviso exception to the Delaney Clause
and FDA's implementing regulations. ALJ Decision, November 12, 1986, at
73. (``Since furazolidone is also being challenged under the Delaney
Clause, an additional issue . . . is whether new evidence put forth by
the Center shows that furazolidone and/or its metabolites induces
cancer when ingested by man or animal. If this burden is met, the
sponsors must show [that the drug satisfies the DES proviso and FDA's
implementing regulations]''); see also 21 CFR 500.92(b) (providing that
for those compounds that FDA determines have been shown to induce
cancer when ingested by man or animals, Sec. Sec.  500.82 through
500.90 apply).
    In this case, CVM had previously determined, in the approval and
supplemental approvals of new animal drugs containing carbadox, that
carbadox and its metabolites, including DCBX, induce cancer in animals,
but that the drug could be approved under the DES Proviso exception to
the Delaney Clause. See Section IV. However, new evidence raises
questions about whether the drug is properly approved under the DES
Proviso to the Delaney Clause and FDA's implementing regulations. See
Criteria and Procedures for Evaluating Assays for Carcinogenic Residues
(44 FR 17070 at 17104, March 20, 1979) (reproposal of rules revoked in
accordance with court order). (``[The FD&C Act] defines the new
evidence that the Commissioner can consider in determining whether a
previously approved compound is safe. [Proper analytical methods
establishing residue levels] are necessary to show that a sponsored
compound is safe under the FD&C Act. For that reason, the absence of
data satisfying the [criteria in 512(e)(1)(B) of the FD&C Act], in
conjunction with the evidence already available about a compound,
clearly can support the withdrawal of approval of an application.'').
In particular, new evidence indicating that an approved regulatory
method can no longer be relied upon is sufficient to satisfy the
Agency's burden to support withdrawal of approval under section
512(e)(1)(B) of the FD&C Act and the Delaney Clause:

    In the case of an approved NADA for a carcinogenic compound, if
FDA determines based on new information that the approved analytical
method for detecting residues is inadequate . . . FDA could withdraw
the approval on the basis of the Delaney Clause. Faced with evidence
that an approved method was inadequate, FDA could not make a finding
that ``no residue'' of the sponsored compound would be found in the
edible products of treated animals. The DES Proviso cannot begin to
operate without that finding, and, accordingly, the Delaney Clause
would preclude continued approval. See Sponsored Compounds in Food
Producing Animals; Criteria and Procedures for Evaluating Safety of
Carcinogenic Residues; Proposed Rule (50 FR 45530 at 45550, October
31, 1985); \4\ see DES Commissioners' Decision (44 FR 54852 at
54859, September 21, 1979).
---------------------------------------------------------------------------

    \4\ Under FDA's regulations implementing the Delaney Clause for
animal drugs, part 500, subpart E, a carcinogenic drug may not be
approved if the regulatory method to test for the compound is not
sufficiently sensitive. Sec. Sec.  500.84(c)(2) and 500.88(b). A
carcinogenic drug will be withdrawn if new evidence shows that an
approved regulatory method is not sufficiently sensitive.

    In this case, new evidence raises serious questions both about the
acceptability of the current method in determining levels of known
carcinogenic residues of carbadox, and, further, demonstrates that
previously unidentified carcinogenic metabolites exist that are
entirely unaccounted for in current approved testing methodology.
Because the current analytic method is inadequate to identify the level
of known carcinogens and does not identify the residue level of
unidentified metabolites of carcinogenic concern, the current method
and tolerance are inadequate to satisfy the DES Proviso.

D. Withdrawal Under the General Safety Clause

    The General Safety Clause in section 512(e) of the FD&C Act
provides grounds for withdrawal of approval of an NADA if new evidence,
tests by new methods, or tests by methods not deemed reasonably
applicable when such application was approved, evaluated together with
the evidence available when the application was approved shows that the
drug is ``not shown to be safe for use under the conditions of use upon
the basis of which the application was approved'' (section 512(e)(1)(B)
of the FD&C Act). CVM has the initial burden to present new evidence
that raises serious questions about the safety of the drug. Only upon
that showing is there a burden on the manufacturer to demonstrate that
the drug is safe. See Rhone-Poulenc, 636 F.2d at 752-53; Hess & Clark,
495 F.2d 975, 992 (D.C. Cir. 1974).
    When evaluating a drug for withdrawal under the General Safety
Clause, for CVM to satisfy its initial burden that new evidence raises
serious human food safety questions, it must demonstrate a relationship
between the drug residues found in edible tissues and risk to human
health.

    [Without using] the Delaney Clause, it is not enough for the
Commissioner merely to show that animal carcasses contain residues
and that [the drug] is a carcinogen. Instead, the FDA must show that
two different issues are resolved in its favor before it can shift
to petitioners the burden of showing safety: (1) whether the
detected residues are related to the use of [the drug]; (2) if so,
whether the residues, because of their composition, and in the
amounts present in the tissue, present some potential hazard to the
public health. See Hess & Clark, 495 F.2d at 992 (D.C. Cir. 1974).

    Applying this test, the D.C. Circuit Court of Appeals has held that
new evidence of drug residues in edible tissues in conjunction with
evidence that any drug residues of the drug in question present safety
concerns is sufficient to satisfy CVM's burden of raising serious
questions regarding the safety of the drug. See Rhone-Poulenc, 636 F.2d
at 752-53. CVM, acknowledging the Hess & Clark standard and its
subsequent application, has withdrawn approval of a new animal drug
under the General Safety Clause where new evidence showed that: (1) The
new animal drug was carcinogenic; (2) some drug metabolites were
mutagenic; and (3) residues left in edible tissues at the withdrawal
time were unidentified. See Nitrofurans Commissioners' Decision, 56 FR
41902 at 41910, August 23, 1991 (``Since the nature of these residues
and their toxicity were not evaluated, they cannot be regarded as safe
. . . Contrary to the sponsors' assertions, the evidence fails to
demonstrate that furazolidone's metabolites pose no health risk to the
human consumers. Given all the other evidence in the record
demonstrating that furazolidone is a carcinogen and that its
metabolites are mutagens, I find that, contrary to the sponsors'
assertions, the metabolites of furazolidone pose a potential health
risk to human consumers.'') see also DES Commissioners' Decision, 44 FR
54852 at 54868 (explaining that, ``[w]here new evidence shows that use
of the drug results in residues of unidentified substances,'' CVM must
decide whether, despite this lack of knowledge, ``the drug may be
considered to be 'shown to be safe[,]' '' as the General Safety Clause
requires). In other words, because residues of a mutagenic carcinogen
are presumptively carcinogenic, and therefore presumptively unsafe,
where new evidence demonstrates that unidentified residues of a
mutagenic carcinogen remain at the time of withdrawal, the drug meets
the standard set forth in Hess & Clark.

    Applying the Hess & Clark standard here, the new evidence regarding
carbadox clearly meets both prongs of that test. New evidence
demonstrates that previously unidentified mutagenic residues of
carbadox, a known carcinogen, remain present well after the established
withdrawal period. As discussed further in Section V.D., because
carbadox is a mutagenic carcinogen and QCA is the only known quantified
noncarcinogenic residue of carbadox, all other residues are of
carcinogenic concern. The new evidence demonstrates that the total
residues of carcinogenic concern at the established 42-day withdrawal
period are much higher than previously thought because the residues are
no longer shown to be residues related to a noncarcinogenic compound,
QCA, as previously believed. See, infra, Section V.D. Thus, the new
evidence demonstrates that: (1) The unidentified residues are related
to the use of carbadox and (2) the residues pose a potential hazard to
public health because of the amount present and because they are
residues of carcinogenic concern.

IV. Regulation of Residues of Carbadox

A. 1972 and 1975 Approvals

    Carbadox is a carcinogen and was approved as a new animal drug
pursuant to the DES Proviso exception to the Delaney Clause. At the
time of the initial approval of carbadox in 1972, CVM (then the Bureau
of Veterinary Medicine) recognized that carbadox is a carcinogen and
therefore required that no residues of carbadox or its metabolite QCA
be found in uncooked edible tissues of swine at the time of slaughter,
as determined by the approved method of analysis. See 37 FR 20683,
October 3, 1972, as amended by 37 FR 23906, November 10, 1972. This
approval occurred prior to FDA's 1987 initial issue of regulations
implementing the DES Proviso and therefore did not involve the
development of a regulatory method sensitive enough to detect a marker
residue that corresponded to a lifetime risk of cancer to test animals
of 1 in 1 million (as described in Section III.C).
    In this initial approval, based upon the submission of studies
showing the depletion of carbadox residues in edible tissues, CVM
determined that ``[a]ll tissues except the liver [were] free of all
residues'' of unchanged carbadox at 24 hours after withdrawal of
treatment and that unchanged carbadox ``ha[d] disappeared from the
liver after 24 hours'' (Ref. 8). CVM also determined from submitted
studies that the carcinogenic parent drug was undetectable in liver at
24 hours (Id.). CVM further determined that a ``restriction of use in
the labeling provides a withdrawal period long enough [70 days] to
assure no hazard to humans consuming residues in meat. In proper use
there would be virtually no residues'' of carbadox in tissues at
slaughter (Ref. 9). The conclusions CVM made in 1972 regarding the
rapid depletion of carcinogenic residues were later independently
corroborated by a 1990 evaluation of carbadox by JECFA (Ref. 10 at p.
30).
    Labeled use restrictions, as the drug was approved in 1972,
included an upper weight limit of 75 pounds body weight and a
prohibition on mixing into complete feeds containing less than 15
percent crude protein, thus limiting the drug's use to young pigs.
These use restrictions provided assurances that the 70-day withdrawal
period would likely be followed in practice (Ref. 11).
    Similarly in 1975, FDA approved NADA 092-955 for the use of
carbadox with pyrantel tartrate in Type C medicated swine feed (40 FR
45164, October 1, 1975). At that time, CVM reviewed drug residue
studies of carbadox and pyrantel tartrate used in combination. The
studies showed that, at 45 and 60 days withdrawal, concentrations of
residues of carbadox in all tissues tested were undetectable using the
previously approved analytical method with a 30 ppb limit of detection
(Ref. 12 at p. 2).

B. 1986 Citizen Petition

    On May 9, 1986, the Center for Science in the Public Interest
submitted a citizen petition requesting that FDA withdraw approval of
new animal drug applications for ipronidazole, dimetridazole, and
carbadox (Ref. 13). The petition asserted that FDA must withdraw the
approval of carbadox because carbadox and its metabolites DCBX and
hydrazine were found to be carcinogenic, and the approved test method
for carbadox residues is ``unsuitable'' (Ref. 13 at p. 20). The
asserted unsuitability of the approved test method was based upon the
fact that only a small portion of total residues had been positively
identified and that the analytical method for carbadox residues was not
sensitive enough to ensure that all residues had depleted.
    FDA responded to the 1986 citizen petition in 1995 after a review
of new residue depletion data submitted by (the then sponsor) Pfizer as
well as data previously submitted to the Agency as part of the carbadox
NADAs. Based upon this review, FDA denied the petition as it related to
carbadox because it determined that ``if used according to label
directions, residues of carbadox remaining in edible tissues of swine
do not pose a human food safety risk to consumers'' (Ref. 14 at p. 2).
FDA based this safety determination on the following findings:

    1. At 70 days withdrawal, the drug-related residue in swine
liver measured 13 ppb. 2. Ten percent of the drug-related residue
was extractable and identified to be a noncarcinogenic metabolite,
quinoxaline-2-carboxylic acid. 3. The remaining 90% of the drug-
related residue was unextractable or bound residues. 4. The bound
residues were related to quinoxaline-2-carbodoxaldehyde and
quinoxaline-2-carboxylic acid, both of which are of no carcinogenic
concern. (Ref. 14 at p. 1).

C. Approval of 1998 Supplemental NADAs

    In 1998, FDA approved two supplemental applications to NADA 041-
061. The first supplement, approved in January 1998, assigned the
noncarcinogenic metabolite QCA as the marker residue and set a
tolerance of 30 ppb QCA in swine liver (Ref. 1).
    Toxicology studies, including carcinogenicity bioassays with
carbadox, DCBX (a primary metabolite of carbadox), and hydrazine were
submitted as part of that supplemental application (Ref. 1 at pp. 1-5).
The studies demonstrated the carcinogenicity of carbadox, DCBX, and
hydrazine, and indicated that DCBX was the most potent of the three
carcinogenic compounds (id.). Consequently, based on DCBX, CVM
calculated an So of 0.061 ppb for total residues of
carcinogenic concern for carbadox in the total diet (Ref. 1 at p. 5).
CVM calculated an Sm value for total residues of
carcinogenic concern in muscle at 0.305 ppb, in liver at 0.915 ppb, and
in kidney and fat at 1.830 ppb (Ref. 1 at pp. 8-9).
    The SOM regulations, as they existed in 1998, directed CVM to
establish an Rm for carcinogenic compounds used in food-
producing animals. CVM did not establish an Rm because CVM
concluded the parent carbadox was rapidly metabolized, carcinogenic
residues were not detectable beyond 72 hours post dosing, and
unextracted residues \5\ were

related to noncarcinogenic QCA and not of carcinogenic concern. Because
the noncarcinogen QCA was the only detectable metabolite persisting
beyond 72 hours post dosing, CVM assigned it as the marker residue
(id.).
---------------------------------------------------------------------------

    \5\ Unextracted residues are residues of the drug that are not
released when tissues are exposed to mild aqueous or organic
extraction conditions. Guidance on analysis of unextracted total
radiolabeled residue is provided in ``Guidance for Industry: General
Principles for Evaluating the Safety of Compounds Used in Food-
Producing Animals (GFI #3),'' 2006. Unextracted or bound residues
can be either: (1) Endogenous components resulting from fragments of
the radiolabeled compound being incorporated into naturally
occurring molecules such as amino or nucleic acids or (2) covalently
bound residues. Covalently bound residues are considered to be of
toxicological concern and their availability for absorption into the
human gastrointestinal tract is considered during an evaluation of
human food safety. Residues incorporated into endogenous molecules
are not considered bioavailable or to be of toxicological concern.
However, CVM has determined that establishing a potentially
carcinogenic compound is bound and not of carcinogenic concern can
be complicated by the possibility of gastrointestinal binding and
gastrointestinal carcinogenesis and consequently can involve a more
comprehensive assessment of the bound compounds as described in GFI
#3. Note that while CVM has recognized that carbadox residues have
not been fully extracted and characterized, CVM has not made an
assessment that the compounds are not carcinogenic because they are
bound to endogenous molecules (Ref. 15 at pp. 3-4). Moreover,
residue studies presented to JECFA in 2003 suggest that carcinogenic
residues that had not been extracted when exposed to organic
extraction were released by simulated digestive enzymes (Ref. 2 at
pp. 7-8, Table 5).
---------------------------------------------------------------------------

    At the time it approved the supplement in January 1998, CVM said:

    The sponsor and academic researchers have conducted numerous
studies evaluating the fate of carbadox in animals. These residue
depletion data are summarized in FAO Food and Nutrition Paper 41/3
(Food and Agriculture Organization (FAO) of the United Nations,
1991) and 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 quinoxaline-2-carboxylic acid
[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 carbadox. (Ref. 1 at p. 9).

    CVM established a tolerance of 30 ppb for residues of QCA in liver,
the tissue in which residues persist for the longest time. CVM
concluded that the concentration of residues of carcinogenic concern in
edible tissues was below the Sm when the concentration of
QCA in liver had depleted to 30 ppb.\6\
---------------------------------------------------------------------------

    \6\ The SOM regulations, as they existed in 1998, permitted
approval of a regulatory 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. See
Sec.  500.86(c) (1998).

    Under FDA's operational definition of ``no residue,'' a residue
of carcinogenic concern, so long as it does not exceed the
So, may be detectable by an approved method. The residue
data show that carbadox, desoxycarbadox and hydrazine do not persist
in edible tissue as detectable residues beyond 72 hours. The in vivo
metabolism of the compounds of carcinogenic concern is irreversible.
Therefore, in this case, no residue of carcinogenic concern, even
below the So, is detectable by any method. The
unextracted residues are related to a noncarcinogenic compound,
quinoxaline-2-carboxylic acid (QCA), and extractable QCA is the only
residue detectable in the edible tissues 72 hours postdosing. Thus,
the agency concludes that QCA is a reliable marker residue for
carbadox and its metabolites.
    From these data, FDA has selected liver as the target tissue and
quinoxaline-2-carboxylic acid (QCA) as the marker residue. FDA has
determined that when QCA, the marker, is at or below 30 ppb in the
target tissue, liver, that no residue of carcinogenic concern, above
the So, is detectable in each of the edible tissues by
any method.
    The sponsor has submitted a regulatory method capable of
measuring QCA at and below 30 ppb in the target tissue. (Ref. 1 at
p. 14).

    As part of their application supporting the January 1998
supplemental approval, the sponsor submitted a regulatory method for
residues of QCA in swine liver. The regulatory method relies on a gas
chromatograph assay with electron capture detection and has a limit of
quantification of 5 ppb (Ref. 1 at p. 13), a 6-fold improvement of the
sensitivity from the previously approved regulatory method (Ref 1.)
    In October 1998, FDA approved an additional supplement to NADA 041-
061 changing the withdrawal period for carbadox medicated feeds from 70
days to 42 days. The supplement was approved based upon the previous
approval of a tolerance of 30 ppb for QCA and a residue depletion study
that showed that residues of QCA in liver depleted below 30 ppb by 42
days (Ref. 16).
    To summarize, in 1998, when FDA approved supplements to NADA 041-
061 establishing a drug tolerance and shortening the withdrawal period,
the evidence before CVM indicated:
     A 0.915 ppb concentration of total residues of
carcinogenic concern in liver is the concentration that represents no
significant increase in the risk of cancer to people--total residues of
carcinogenic concern in liver above 0.915 ppb under the drug's approved
conditions of use are unsafe. Such residues would preclude continued
approval because the drug would not be shown to be safe and because the
exception to the Delaney Clause would not apply (Ref. 1 at pp. 8-9, 10,
14).
     The parent compound carbadox is rapidly metabolized and
carcinogenic residues of the drug are not identifiable in any edible
tissues beyond 72 hours post dosing (Ref. 1 at p. 9).
     Remaining unextracted residues of carbadox are
noncarcinogenic residues related to the noncarcinogenic metabolite QCA
(Ref. 1 at pp. 9, 14).
     QCA is a reliable marker residue for carbadox and its
metabolites; that is, measuring QCA residues in swine liver is a valid
method for demonstrating the absence of residues of carcinogenic
concern in edible tissues (id.).
    Based upon these conclusions, CVM found that under the conditions
of use the drug did not result in unsafe residues of carcinogenic
concern in edible tissues and that the use of carbadox, as approved in
the NADA supplements, satisfied the DES Proviso exception to the
Delaney Clause prohibition on carcinogenic animal drugs (id.).

D. Approval of the 2004 Feed Use Combination

    In 2004, FDA approved a combination drug medicated feed containing
carbadox and oxytetracycline under NADA 141-211 (Ref. 17). In
accordance with section 512(d)(4)(A) of the FD&C Act, approval of a
combination new animal drug, where the underlying new animal drugs have
previously been separately approved for particular uses and conditions
of use for which they are intended for use in the combination, will not
be refused on human food safety grounds unless the application fails to
establish that: (1) None of the animal drugs used in combination, at
the longest withdrawal period for any of the drugs in the combination,
exceeds its established tolerance or (2) none of the drugs in the
combination interferes with the method of analysis for any of the other
drugs in the combination (section 512(d)(4)(A)(i)-(ii) of the FD&C
Act). In other words, in order to approve a combination new animal drug
for a drug product that contains two previously approved new animal
drugs, no new information needs to be supplied to establish the safety
of either drug. Instead, the application need only demonstrate that use
of the drugs in combination will not result in violative

residues of any component drug or in drug assay interference.
    Both carbadox and oxytetracycline had been previously and
separately approved by FDA for the same conditions of use proposed for
their use in combination. See 21 CFR 558.450 (Oxytetracycline); Sec.
558.115 (Carbadox). The sponsor, Phibro, provided tissue residue
depletion data demonstrating that QCA residues did not exceed the
tolerance of 30 ppb when carbadox was administered in conjunction with
oxytetracycline to swine (Ref. 17). A pharmacokinetic study comparing
blood levels of oxytetracycline when administered alone and when
administered in conjunction with carbadox satisfied the need to
demonstrate that residues of oxytetracycline would not exceed the
oxytetracycline tolerance at 42 days (id.).
    The sponsor further provided data demonstrating noninterference of
oxytetracycline with the method of analysis of QCA in liver (id.).
Having made the required human food safety demonstrations for
combination animal drugs, there was no basis to refuse approval of the
product on human food safety grounds. The combination new animal drug
was subsequently approved (id.).

V. New Information Regarding Carcinogenic Residues in Edible Tissues

    Three sources provide new information regarding carcinogenic
residues in edible tissues: Data submitted to the 2003 JECFA and the
subsequent JECFA report (Ref. 2) and two publications in the peer-
reviewed literature (Refs. 4 and 6).
    JECFA is an internationally recognized expert body, providing the
scientific evaluations that become the basis for international food
standards established by the Codex Alimentarius Commission and
supporting international treaties such as the Sanitary Phytosanitary
Agreement. JECFA experts are chosen based on expertise, reputation,
assurance of lack of conflict of interest, and familiarity with the
subject of that particular evaluation.
    In addition, pursuant to section 512(l)(1) of the FD&C Act,\7\ FDA
ordered Phibro to provide it with the same data provided to the 2003
JECFA. CVM evaluated the submitted data and found that it raised
questions regarding the safety of food resulting from swine treated
with carbadox. Confidence in the information evaluated by the 2003
JECFA that is the basis for CVM's concern about carbadox was increased
by the independent findings reported in the two publications discussed
further.
---------------------------------------------------------------------------

    \7\ An order issued pursuant to section 512(l) of the FD&C Act,
requires a sponsor to submit such data and information as FDA may
find necessary to determine or facilitate a determination whether
grounds to withdraw approval of an NADA under section 512(e) of the
FD&C Act exist.
---------------------------------------------------------------------------

A. New Information Provided to JECFA

    In 2003, at the request of the Codex Committee on Residues of
Veterinary Drugs in Foods (CCRVDF), JECFA reevaluated the recommended
Maximum Residue Limits (MRLs) for carbadox that were based upon a 1990
JECFA evaluation of the new animal drug (Ref. 2). CCRVDF, which
includes CVM as a participant, determines priorities for the
consideration of residues of veterinary drugs in foods and recommends
MRLs for veterinary drugs to the Codex Alimentarius Commission of the
Food and Agriculture Organization and the World Health Organization of
the United Nations. The Codex Alimentarius Commission develops
harmonized international food standards, guidelines, and codes of
practice to protect the health of the consumers and ensure fair
practices in food trade (see footnote 2).
    Based on studies submitted to JECFA that 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. JECFA recommended that the Codex MRLs be
withdrawn. CCRVDF concurred with JECFA's recommendation and proposed to
the Commission that the MRLs be withdrawn. The Commission subsequently
agreed and withdrew the Codex MRLs for carbadox (Ref. 18 at p. 120).
    As part of the JECFA reevaluation process, Phibro presented two new
residue studies to JECFA in 2003. Only one of these studies involved
measurement of the depletion of carcinogenic metabolites of carbadox in
edible tissues. In that study, animals were fed for 14 days at the
approved dose of 55 ppm carbadox in feed (Ref. 2 at pp. 6-10). Animals
were euthanized at various time points between 0 hours and 15 days post
treatment, and samples of swine muscle, liver, skin, and fat were
collected (Ref. 2 at pp. 7-8, Table 5).
    Prior to analysis for residues, some of the tissue samples were
exposed to human digestive enzymes \8\ (Ref. 2 at p. 7). This in vitro
model of bioavailability was designed to mimic effects of gastric fluid
and intestinal fluid incubation in human stomach and small intestine to
evaluate whether residues potentially could be released in the human
gastrointestinal tract. To allow comparison, some tissue samples were
left untreated while other tissue samples were incubated in simulated
gastric fluid (with pepsin) or in simulated intestinal fluid (with
pancreatin). Residues of carbadox, DCBX, and QCA were measured in the
untreated tissues, in tissues that were incubated with enzymes, and in
the supernatant of those tissues that were incubated with enzymes
(id.).
---------------------------------------------------------------------------

    \8\ The use of enzymic preparations to characterize residues is
described in section <IP_ADDRESS>.2 of CVM Guidance for Industry (GFI)
#205 VICH GL 46, ``Studies to Evaluate the Metabolism and Residue
Kinetics of Veterinary Drugs in Food-Producing Animals: Metabolism
Study to Determine the Quantity and Identify the Nature of Residues
(MRK),'' Sept. 15, 2011 (Ref. 19).
---------------------------------------------------------------------------

    Residues of carbadox, DCBX, and QCA were measured by liquid
chromatography-atmospheric pressure chemical ionization tandem mass
spectrometry (LC/APCI-MS/MS). The tissue samples that were not
incubated with enzymes were extracted with acetonitrile prior to
analysis. The tissue samples that were incubated with enzymes were
extracted with ethyl acetate prior to analysis. Supernatants of the
enzyme digestion were analyzed directly without extraction. The limits
of quantification for LC/APCI-MS/MS were 0.050 ppb for carbadox
residues and 0.030 ppb for DCBX residues (id.). The detection
capabilities of this methodology were greatly enhanced compared to the
previous method for carbadox and DCBX (i.e., the method used for the
previous analytical work had a detection limit of 2 ppb) (Ref. 20).
    The study presented to JECFA showed that residue concentrations of
carbadox and DCBX were higher and persisted for a longer period post
dosing in liver than in the other sampled tissues. In liver without
treatment with simulated digestive fluids, carbadox was detectable
(0.050 ppb) as long as 48 hours post dosing and DCBX was detectable
(0.138 ppb) at the last sampling time point, which was 15 days post
treatment (Ref. 2 at pp. 7-8, Table 5). Treatment of tissues with
simulated digestive fluids resulted in measurement of significantly
higher concentrations of DCBX. ``Pretreatment of the samples with
digestive fluids increased the amounts of carcinogenic residues found
in all tissues. In liver the concentration of . . .[DCBX] increased by
more than fourfold when the samples were treated with intestinal fluid,
and large quantities were present 15 days after withdrawal . . .''
(Ref. 2 at p. 17).

    In particular, the study showed that concentrations of
approximately 35 ppb of DCBX at 0 hours post dosing and approximately
2.7 ppb of DCBX at 15 days post dosing were measured in liver treated
with pancreatin (Ref. 2 at p. 8, Table 5). The significantly increased
residues found in liver after treatment with intestinal enzymes show
that enzymatic treatment was able to release carcinogenic residues that
were not extractable by organic solvents, such as those used in tissue
residue studies to support the original and supplemental approval of
NADAs for use of carbadox.
    JECFA evaluated the percent recoveries of the analytes. Percent
recovery is a measurement of accuracy of the analytical procedure and
expresses the closeness of agreement between the true value of the
analyte concentration and the mean value obtained by applying the
analytical procedure (Ref. 21). JECFA reported that when carbadox,
DCBX, and QCA were incubated for 4 hours with digestive enzymes,
carbadox and DCBX were unstable (percent recovery decreased) in the
samples treated with pepsin, but were stable in pancreatin (Ref. 2 at
p. 16). JECFA also reported that the recoveries of the analytes from
the liver samples were generally variable and decreased to low levels
when digestive enzymes were used prior to extraction (Ref. 2 at pp. 17-
18).
    After evaluating the residue study, JECFA concluded that the poor
recoveries obtained with the enzyme experiments ``showed that the true
concentrations of the carcinogenic metabolites in tissues cannot yet be
estimated with certainty, since an unknown portion of the releasable
residue [of carbadox and DCBX] is destroyed during incubation [of liver
tissues] with the [digestive] enzymes'' (Ref. 2 at p. 18). JECFA
therefore concluded that the measured values of DCBX and carbadox
``represent[ed] a lower estimate of the total present in the tissue''
(id.).
    Presented with data demonstrating both the depletion of QCA and
depletion of the carcinogenic residue DCBX, JECFA established a
relationship between the concentrations of QCA and DCBX in liver (Ref.
2 at p. 14). The statistical analysis of the data showed a linear
relationship between the logarithms of the concentrations of QCA and
DCBX (Ref. 2 at pp. 14, 18). This relationship allowed JECFA to use
regression analysis to assess the concentrations of DCBX when QCA
depleted to 30 ppb in liver (the Codex MRL and FDA approved tolerance
for carbadox). JECFA determined that ``[a]t the MRL [of 30 ppb] for QCA
in liver, the average concentrations of the carcinogenic residue
desoxy-carbadox in liver estimated by regression analysis were about 4
[ppb]'' (Ref. 2 at pp. 14, 16-17). JECFA recognized that ``tolerance
limits for the concentration of desoxycarbadox were several times
higher owing to the wide variation of the data'' and thereby concluded
that ``QCA is not a suitable marker for monitoring carcinogenic
metabolites of carbadox in liver . . . and QCA does not ensure the
absence of carcinogenic residues'' (Ref. 2 at p. 17).
    In contrast to the previous findings of JECFA, these new data show
that carcinogenic residues, in particular DCBX, are present in edible
tissues for a significant time during the depletion of parent carbadox
(Ref. 2 at p. 18). Moreover, the study shows that treatment with
simulated digestive enzymes releases higher levels of the carcinogenic
residues DCBX than were recovered using organic extractions in the
study. These higher concentrations provide evidence that the carbadox
residues that were not extractable or identified in previous studies
submitted to the Agency could include carcinogenic residues of carbadox
that are releasable with enzymatic treatment of tissues. This evidence
calls into question the Agency's previous conclusions that all
unextracted and unidentified residues were noncarcinogenic residues
related to QCA.
    After reviewing the new residue data, and considering the
previously evaluated genotoxicity and carcinogenicity data, JECFA
recommended withdrawal of the previously established Codex MRLs (Ref. 2
at p. 18). Codex subsequently agreed and withdrew the MRLs for carbadox
(Ref. 18 at p. 120).
    In summary, the studies considered by JECFA during its 2003 review
of the drug indicated that:
     Residues of the carcinogenic metabolite of carbadox, DCBX,
were measured in edible tissues for 15 days, which was the last
sampling time point. DCBX was measured in swine liver after treatment
with simulated digestive enzymes at concentrations as high as 2.69 ppb
at 15 days post treatment (Ref. 2 at p. 8, Table 5).
     Analysis of measured concentrations of QCA and DCBX in
liver indicated that approximately 4 ppb of DCBX would be present in
the liver of treated animals when QCA reached the Codex MRL and the FDA
tolerance of 30 ppb in liver (Ref. 2 at pp. 14, 17). This concentration
of DCBX alone is more than 4 times higher than the concentration of
total residues of carcinogenic concern in liver that would present no
significant increase in the risk of cancer to people.
     Residues of carbadox previously unextracted from edible
tissues could be released by gastric and intestinal fluids that mimic
the human digestive process (Ref. 2 at p. 16). The enzymatic treatment
used in the study significantly increased the recoveries of
concentrations of DCBX and carbadox from edible tissues, thereby
indicating that some portion of the previously unextracted and
unidentified total residues is composed of carcinogenic compounds.

B. Additional New Evidence

    Following the reports of the 2003 JECFA reevaluation of carbadox,
CVM requested that Phibro also provide the carcinogenic residue
depletion study to CVM. In 2005, in response to CVM's request for
information, Phibro submitted a summary of the carcinogenic residue
depletion study previously provided to JECFA. Upon review of the
summary data, CVM asked Phibro to submit existing studies or provide
new and complete studies that address the relationship of QCA at 30 ppb
and carbadox and DCBX residues, and about the use of QCA as the marker
residue for surveillance purposes. In 2006, CVM asked for and received
from Phibro a timeline for submission of complete information that
addresses concerns about the relationship of QCA at 30 ppb and carbadox
and DCBX residues, and about the use of QCA as the marker residue for
surveillance purposes. Between 2006 and 2011, interactions between CVM
and Phibro continued, with protocols submitted and reviewed, method
validation reports submitted and reviewed, informal communications by
email, and informal discussions by telephone. The focus of the
interactions was development and validation of methods to measure QCA
and DCBX in a tissue residue depletion study. Despite the continued
interaction between Phibro and CVM, Phibro has not submitted the
requested information.
    In 2011, pursuant to section 512(l)(1) of the FD&C Act, FDA ordered
Phibro to provide all information in its possession with respect to:
(1) The persistence of DCBX in edible tissues; (2) the appropriateness
of QCA as an analyte for residue monitoring and for establishing a
withdrawal time for the use of carbadox in pigs; and (3) whether an
analytical method for monitoring carbadox-related carcinogenic residues
in edible tissues can be developed that would comply with part 500,
subpart E.

    In response to the 2011 FDA order, Phibro provided CVM with the
full study report and appendices, previously provided to JECFA in 2003.
    CVM has independently evaluated the data from the Phibro study of
depletion of carcinogenic residues reviewed by JECFA in 2003, and in
particular has reviewed the JECFA conclusion that when QCA reaches 30
ppb in liver, residues of DCBX in liver are ``estimated by regression
analysis to be about 4 [ppb]'' (Ref. 2 at p. 18). CVM's statistical
analysis of the residue concentrations of DCBX in liver treated with
pancreatin (a simulated intestinal fluid) shows that concentrations of
DCBX in liver, when QCA reaches the 30 ppb approved tolerance, would
average 4 ppb and, based on the data in the JECFA report, could
reasonably range from 1.4 ppb to 11 ppb, using a 95 percent prediction
range. Based upon this analysis, DCBX alone--leaving aside additional,
unidentified residues of carcinogenic concern--significantly exceeds
the approved Sm when QCA, the approved marker residue,
reaches the approved tolerance. The new evidence from the 2003 JECFA
re-evaluation of carbadox, along with studies that were later submitted
to CVM, undermine the human food safety conclusions that CVM had
previously reached when considering the approval of the new animal drug
applications for carbadox for its various uses. CVM has engaged with
Phibro to evaluate the carbadox-associated safety concerns raised by
the new evidence and repeatedly has asked Phibro to submit information
that would address these safety concerns. Information provided by
Phibro in response to these requests has not resolved CVM's human food
safety concerns.
1. Boison, et al., 2009
    In addition, a 2009 publication calls into question conclusions
made by CVM when it approved the NADAs and supplemental NADAs for
carbadox (Ref. 4). Boison, et al., 2009, demonstrates the availability
of a sensitive analytical method for DCBX, and provides information
from which serious questions about the safety of carbadox can be
inferred, specifically whether DCBX may be present in edible tissues of
treated swine above the Sm even when the marker residue
(QCA) concentration is below the tolerance of 30 ppb (id.).
    Boison, et al., report: (1) QCA is not a suitable marker for the
regulation of carbadox because while QCA is very stable under
temperature conditions above 60 [deg]C (i.e., 105 [deg]C), DCBX is not
(Ref. 4 at p. 133); (2) the existence of an analytical method capable
of detecting DCBX below the Sm for porcine muscle and liver
(Ref. 4 at p. 132, Table 5); and (3) detection of DCBX at a
concentration greater than 0.050 ppb in the diaphragm (but not the
liver) of 2 of 6 hogs fed carbadox, while QCA was not detected in the
liver of those same hogs at a limit of quantitation (LOQ) of 0.500 ppb
(Ref. 4 at pp. 132-33). The findings of Boison, et al., are significant
for two reasons: (1) QCA appears not to be a reliable marker residue
and (2) DCBX is reported to be sensitive to the processing temperature
used in the analytical method.
2. Baars, et al., 1991
    In 2012, in response to FDA's 2011 order under section 512(l) of
the FD&C Act, Phibro sent CVM a letter citing Baars, et al., 1990 (Ref.
5), an abstract of a study not previously provided. CVM obtained the
study report Baars, et al., 1991 (Ref. 6), which reports an analytical
method with a limit of detection of 1 ppb that detects the presence of
DCBX in edible tissues for greater than 72 hours after removal of feed
containing carbadox. Specifically, Baars, et al., 1991, demonstrated
the presence of DCBX for up to 7 days (~168 hours) in the kidney and 14
days (~336 hours) in the liver of swine fed carbadox (Ref. 5 at p. 3,
Fig. 3; Ref. 6 at p. 290, Fig. 2). This observation called into
question CVM's previous conclusion that all residues of carcinogenic
concern deplete within 72 hours.

C. New Evidence Calls Into Question Prior CVM Conclusions That Were the
Basis of the 1998 Supplemental Approval

    CVM's prior conclusion that QCA is a reliable marker residue for
carbadox and its metabolites was predicated on several underlying
conclusions (Ref. 1 at pp. 13-14). These underlying conclusions are
reviewed below in light of the new evidence presented above.
    1. Previous Conclusion 1: The residue data show that carbadox,
DCBX, and hydrazine do not persist in edible tissues as detectable
residues beyond 72 hours.\9\
---------------------------------------------------------------------------

    \9\ This underlying conclusion is described in the January 30,
1998, summary basis of approval under the Freedom of Information Act
(FOI Summary) for NADA 041-061 (Ref. 1 at p. 9) and in the report of
the 1990 JECFA meeting (Ref. 10 at p. 30).
---------------------------------------------------------------------------

    Since the time CVM made this previous conclusion, we have become
aware of information that undermines the previous conclusion that
carbadox and its carcinogenic metabolites do not persist in edible
tissues beyond 72 hours. JECFA, in 2003, reviewed a study detecting
DCBX in livers of swine up to 15 days after cessation of carbadox
exposure. The study JECFA reviewed was limited to 15 days. The data
presented to JECFA in 2003 provide new scientific evidence that DCBX
persists in edible tissues of swine as a detectable residue beyond 72
hours (Ref. 2).
    Further, Baars, et al., 1991, reports detecting DCBX in liver up to
Day 14 after cessation of exposure to carbadox using an analytical
method with a detection limit of 1 ppb (Ref. 6). Baars, et al., 1991,
provides new scientific evidence that DCBX persists as a detectable
residue in edible tissues of swine for greater than 72 hours.
    Scientific evidence from JECFA's 2003 evaluation of submitted
information and Baars, et al., 1991, demonstrate that DCBX, one residue
of carcinogenic concern for carbadox, persists in edible tissues of
swine beyond 72 hours. All of this evidence was first received by CVM
after the 1998 approval of the supplemental application to NADA 041-
061. Based on this new scientific evidence, the previous conclusion
that DCBX does not persist in edible tissues of swine as a detectable
residue beyond 72 hours is no longer justified.
    2. Previous Conclusion 2: The unextracted residues are related to a
noncarcinogenic compound, QCA, and extractable QCA is the only residue
detectable in the edible tissues of swine 72 hours post dosing.\10\
---------------------------------------------------------------------------

    \10\ This underlying conclusion is described in the January 30,
1998, summary basis of approval under the Freedom of Information Act
(FOI Summary) for NADA 041-061 (Ref. 1 at p. 9) and in the report of
the 1990 JECFA meeting (Ref. 10 at p. 30).
---------------------------------------------------------------------------

    At the time of the 1998 supplemental approval, CVM concluded that
that unextracted residues were related to the noncarcinogenic compound,
QCA, and that extractable QCA was the only residue detectable in the
edible tissues after 72 hours post dosing. However, CVM is now aware of
reports of extraction of residues being enhanced by pepsin or
pancreatin digestion prior to organic extraction, making non-QCA
residues previously thought to be unextractable currently extractable
(Ref. 2). JECFA reports that some residues of carbadox previously
identified as unextractable can now be extracted (id.). DCBX was found
in the newly extractable residues. This scientific evidence
demonstrates that some residues previously found to be unextractable
are extractable and that the unextractable residues are not all related
to QCA.
    As discussed above, residues of DCBX, a residue of carcinogenic
concern, have been detected in edible tissues longer than 72 hours post
dosing

(Refs. 2, 5, and 6). The previous underlying conclusions that
unextracted residues are related to noncarcinogenic compound, QCA, and
extractable QCA is the only residue detectable in the edible tissues 72
hours post dosing is no longer justified based on new scientific
evidence.
    3. Previous Conclusion 3: No residue of carcinogenic concern even
below the S0, is detectable by any method beyond 72
hours.\11\
---------------------------------------------------------------------------

    \11\ This underlying conclusion is part of the basis of the
January 1998 supplemental approval (FOI Summary) (Ref. 1 at pp. 13-
14).
---------------------------------------------------------------------------

    Boison, et al., 2009, reports a method capable of detecting DCBX at
0.05 ppb, which is below the 0.061 ppb So and below the
Sm of 0.305 ppb in muscle, 0.915 ppb in liver, and 1.83 ppb
in kidney and fat. The method is also capable of measuring QCA at 0.500
ppb, below the current tolerance of 30 ppb (Ref. 4 at p. 132, Table 5).
Consequently, measurement of the relationship of QCA to at least one
residue of carcinogenic concern, DCBX, is now scientifically feasible
at the time the last tissue depletes to its Sm. In fact,
Boison, et al., 2009, reports the presence of DCBX at a concentration
greater than 0.050 ppb in the diaphragm (muscle) of 2 of 6 market-
weight hogs fed carbadox, when QCA was not detected, at a limit of
quantitation of 0.50 ppb, in the livers of those same hogs (Ref. 4 at
pp. 132-133). This evidence raises a serious question about whether QCA
at 30 ppb is an appropriate marker residue for carbadox residues of
carcinogenic concern. Based on this new scientific evidence, the
previous underlying conclusion that no residue of carcinogenic concern,
even below the SO, is detectable by any method beyond 72
hours is no longer justified.
    4. Previous Conclusion 4: QCA is a reliable marker residue for
carbadox and its metabolites.\12\
---------------------------------------------------------------------------

    \12\ This underlying conclusion is part of the basis of the
January 1998 supplemental approval (FOI Summary) (Ref. 1 at pp. 13-
14).
---------------------------------------------------------------------------

    In light of the new evidence presented above, the conclusion that
QCA is a reliable marker residue for carbadox and its metabolites is no
longer justified because: (1) Previous conclusions made by the Agency
are no longer scientifically justified and (2) the relationship of QCA
to a carbadox residue of carcinogenic concern, DCBX, in the last tissue
to deplete to its Sm is not known.

D. CVM's Reanalysis of the Human Health Risk From Previously Submitted
Residue Data

    CVM reevaluated the existing carbadox residue data as a result of
discussions that took place during meetings in 2011 with Phibro about
the composition of total residues of carbadox (Refs. 3 and 22). CVM
also reexamined the residue data submitted in support of the 1998 NADA
supplements in light of the new understanding from the 2003 JECFA
report that carcinogenic residues of carbadox persisted in edible
tissues for 15 days, which was the last sampling time point, and that
the previously unextractable residues are not necessarily
noncarcinogenic residues related to QCA (Ref. 2).
    Using data in the FOI Summary for the January 30, 1998,
supplemental approval, CVM reviewed information on total residue
concentrations (measured from total radioactivity present in tissue
from swine administered the radiolabeled drug), as well as the percent
of total residues represented by QCA--the only noncarcinogenic
metabolite of carbadox identified and quantified in the total residues
of carbadox (Ref. 1). CVM used the total residue data and the percent
of total residues represented by QCA to calculate the total residue of
carcinogenic concern present in liver. Under the SOM regulations,
``residues of carcinogenic concern'' in edible tissues are total
residues of a carcinogenic drug minus identified residues that are
judged by CVM to be noncarcinogenic (Sec.  500.82(b)). CVM previously
excluded the unextracted portions of total residues from carcinogenic
concern because it believed they were noncarcinogenic, QCA-related
residues. The data presented to JECFA in 2003 now refute that
conclusion, and CVM has no information, from Phibro or otherwise, that
identifies or measures noncarcinogenic residues other than QCA in total
residues of carbadox at the withdrawal period. As such, CVM now
identifies the total residue of carcinogenic concern by subtracting QCA
(identified residues that are confirmed to be noncarcinogenic) from
total residues of carbadox. Determining the concentration of residues
of carcinogenic concern present in the liver allowed CVM to compare
that value with the Sm established for residues of
carcinogenic concern in liver.
    CVM reviewed data regarding concentrations of total residues in
swine tissues following 5 days of feeding \14\C-carbadox contained in a
residue depletion study (the same study submitted to JECFA for its 1990
evaluation of carbadox (Ref. 10 at p. 31)) submitted by the sponsor in
support of the supplemental application to NADA 041-061 approved in
January 1998 (Ref. 1, Study No. 1525N-60-87-005). The study measured
concentrations of total residues of \14\C-carbadox and residues of QCA.
Using these data, the study reported QCA as a mean percentage of the
total residues of carbadox. QCA represented 24.4 percent of the total
residues at 30 days, 27.5 percent at 45 days, and 9.9 percent at 70
days post dosing (Ref. 1 at p. 13, Table 9).
    Table 1 presents total carbadox residues and total carbadox
residues minus the noncarcinogenic QCA. Column 1 lists the sampling
time point when swine were slaughtered following administration of the
last dose of carbadox. Column 2 presents mean total residues measured
in livers collected from swine slaughtered at each time point. Column 3
lists the mean QCA percentage of total residues at each time point.
Column 4 lists the calculated mean total residues of carcinogenic
concern based on a subtraction of QCA from the mean total residue
values in Column 2.

   Table 1--Mean Total Residues Measured as \14\C-Carbadox Equivalents, the Mean Percentage of Total Residues
Represented by QCA, and Mean Total Residue of Carcinogenic Concern in Liver of Swine (n=3 or 4) Following 5 Days
                                       of Feeding \14\C-Carbadox at 55 PPM
----------------------------------------------------------------------------------------------------------------
                                                                                Total residue
                                                                                of
                        Days post dosing                          Total residues    Percent QCA    carcinogenic
                                                                       (ppb)                       concern (ppb)
                                                                                \1\
----------------------------------------------------------------------------------------------------------------
30..............................................................            74.5            24.4            56.3
45..............................................................            20.0            27.5            14.5

70..............................................................            13.3             9.9           11.98
----------------------------------------------------------------------------------------------------------------
\1\ Values calculated by subtracting noncarcinogenic QCA portion from total residues.

    FDA first approved the use of carbadox in 1972 prior to the
issuance of the Agency's SOM regulations. CVM did not make a
calculation comparing total residues less QCA to the Sm in
approving the January 1998 NADA supplement because the data available
at the time indicated that DCBX was not detectable beyond 72 hours post
dosing (by the analytical method used at the time) and because CVM
believed all unextractable residues were noncarcinogenic residues
related to QCA (Ref. 1). No residue depletion data presented to the
Agency in original or supplemental NADAs showed that carcinogenic
residues persisted beyond 72 hours or that the unextractable residues
were carcinogenic. As a result, CVM did not, at that time, ask for data
regarding the composition of total residues beyond establishing QCA as
an appropriate marker residue. New evidence presented to JECFA in 2003
and reported by Boison, et al., 2009, and Baars, et al., 1991, calls
CVM's prior conclusions into question and places new significance on
the concentrations of total residues of carcinogenic concern for
carbadox (Refs. 2, 4, and 6).
    The individual data shown as mean values in Table 1 were used to
predict total residues of carcinogenic concern at the approved 42-day
withdrawal period for carbadox in NADAs 041-061 and 141-211, and the
approved 70-day withdrawal period for carbadox in NADA 092-955. CVM
analyzed the data using the logarithm of the dependent variable
(carbadox-equivalents in liver). The logarithmic transformation or
``exponential model'' is consistent with the published JECFA analyses
of carbadox and commonly observed elimination behavior of
pharmaceuticals (Ref. 22). Using this modeling procedure, the total
residues of carcinogenic concern at 42 days are estimated to be 27 ppb
with a 95 percent prediction interval of 9 ppb to 80 ppb (Ref. 3 at p.
17, Table 8). These predictions can be compared with the Sm
for swine liver of 0.915 ppb. The regression model predicts that swine
liver concentrations of total carcinogenic residues will be
significantly in excess of the Sm--approximately 30-fold (27
ppb / 0.915 ppb = 29.51) greater residues of carcinogenic concern than
the Sm at the approved 42-day withdrawal period for NADAs
041-061 and 141-211 (Ref. 3 at p. 16). Total residues of carcinogenic
concern at 70 days are estimated to be 10 ppb with a 95 percent
prediction interval of 3 ppb to 32 ppb (Ref. 3 at p. 17, Table 8). The
analysis predicts that swine liver concentrations of total carcinogenic
residues will be significantly in excess of the Sm--
approximately 11-fold greater residues of carcinogenic concern than the
Sm at the approved 70-day withdrawal period for NADA 092-
955.
    Approval of a carcinogenic new animal drug under the DES Proviso to
the Delaney Clause requires development of a sufficiently sensitive
regulatory method that detects no residues of carcinogenic concern in
the edible tissues of food-producing animals from the use of the animal
drug. New evidence raises serious questions about whether the currently
approved tolerance for uses of carbadox is adequate under the SOM
regulations, and raises serious questions about the continued approval
of the compound under the DES Proviso exception to the Delaney Clause
due to the lack of a sufficiently sensitive regulatory method.
    Carbadox is currently approved based upon CVM's previous conclusion
that unextractable residues were QCA related and noncarcinogenic. Given
this conclusion and the fact that no residues of carcinogenic compounds
were detectable by any method beyond 72 hours, CVM determined that QCA
was an acceptable marker residue and established the tolerance at 30
ppb. New evidence presented to JECFA in 2003 undermines the conclusion
that all unextractable residues at the withdrawal period are QCA
related. As a result, under FDA's SOM regulations, all unextractable
residues except for measured residues of QCA must be considered
residues of carcinogenic concern (Sec.  500.82(b)). Under CVM's
analysis (Table 1), concentrations of total residues of carcinogenic
concern in liver are approximately 30 times higher than the
Sm at the approved 42-day withdrawal period and 11 times
higher at the approved 70-day withdrawal period (Ref. 3 at pp. 16-17).
CVM would expect that total residues of carcinogenic concern would also
exceed the Sm when QCA reaches the approved tolerance of 30
ppb in liver. CVM can no longer conclude that when QCA is at or below
30 ppb, the residues of carcinogenic concern are present at or below a
concentration that would present no significant increase in the risk of
cancer to humans (Sec.  500.86(c)).
    The new evidence indicates that QCA is not an appropriate marker
residue for residues of carcinogenic concern and that QCA at 30 ppb in
swine liver is not an appropriate tolerance. The new evidence also
shows that the approved regulatory method for all approved carbadox
NADAs is inadequate under the SOM regulations (part 500, subpart E).
The inadequacy of the regulatory method is a basis for withdrawal of
approval of all carbadox NADAs under section 512(e)(1)(B) of the FD&C
Act. See Sponsored Compounds in Food-Producing Animals; Criteria and
Procedures for Evaluating the Safety of Carcinogenic Residues, Proposed
Rule, preamble to the proposed SOM regulations II (50 FR 45530 at
45550).
    Similarly, these findings demonstrate that carbadox is no longer
shown to be safe under the General Safety Clause because residues of
carcinogenic concern remain in swine tissue well past the established
withdrawal period. Under the General Safety Clause, drug residues must
be determined to be safe based on all available evidence. Where a drug
is a known mutagenic carcinogen and new evidence shows that
unidentified residues of carcinogenic concern are present at the
established withdrawal time, the drug is no longer shown to be safe.
See Section III.D.
    As stated previously, the new evidence presented to JECFA
undermines the previously held conclusion that all unextracted residues
are QCA related and noncarcinogenic. Because carbadox is a mutagenic
carcinogen, all otherwise unidentified

residues are treated as carcinogenic. No evidence has been presented to
CVM by Phibro or any other source to show that the unidentified
residues are noncarcinogenic or that the residues do not otherwise
present a threat to public health. As a result, carbadox is not shown
to be safe under the General Safety Clause.

VI. Notice of Opportunity for a Hearing

    New evidence regarding carcinogenic residues in edible tissues of
swine treated with carbadox raises serious questions about the human
food safety of the drug. Therefore, CVM is proposing to withdraw
approval of the three NADAs that provide for use of carbadox in swine
feed because new evidence demonstrates that the drug no longer meets
the DES Proviso exception to the Delaney Clause and because new
evidence demonstrates that carbadox is not shown to be safe under the
General Safety Clause.
    Therefore, notice is given to Phibro Animal Health Corp., 65
Challenger Rd., Ridgefield Park, NJ 07660, and to all other interested
persons, that the Director of CVM proposes to issue an order under
section 512(e) of the FD&C Act withdrawing approval of all NADAs
providing for use of carbadox in medicated swine feed.
    In accordance with section 512 of the FD&C Act and part 514 (21 CFR
part 514) and under the authority delegated to the Director of CVM,
Phibro Animal Health Corp., the sponsor, is hereby given an opportunity
for hearing to show why approval of NADAs 041-061, 092-955, and 141-211
should not be withdrawn.
    If the sponsor, Phibro Animal Health Corp., wishes to request a
hearing the sponsor must file: (1) On or before [see DATES], a written
notice of appearance and request for a hearing and (2) on or before
[see DATES], the data, information, and analyses relied on to
demonstrate that there is a genuine and substantial issue of fact to
justify a hearing as specified in Sec.  514.200. Any other interested
person may also submit comments on this notice (see, ADDRESSES).
Procedures and requirements governing this NOOH, a notice of appearance
and request for a hearing, submission of data, information, and
analyses to justify a hearing, other comments, and a grant of denial of
a hearing, are contained in Sec.  514.200 and 21 CFR part 12.
    The failure of a holder of an approval to file timely a written
appearance and request for hearing as required by Sec.  514.200
constitutes an election not to avail himself or herself of the
opportunity for a hearing and a waiver of any contentions concerning
the legal status of any such drug product, and the Director of CVM will
summarily enter a final order withdrawing the approvals. Any new animal
drug product marketed without an approved NADA is subject to regulatory
action at any time.
    A request for a hearing may not rest upon mere allegations of
denials, but must set forth specific facts showing that there is a
genuine and substantial issue of fact that requires a hearing. If it
conclusively appears from the face of the data, information, and
factual analyses in the request for hearing that there is no genuine
and substantial issue of fact that precludes the withdrawal of approval
of the applications, or when a request for hearing is not made in the
required format or with the required analyses, the Commissioner of Food
and Drugs will enter summary judgment against the person who requests a
hearing, making findings and conclusions, and denying a hearing.
    If a hearing is requested and is justified by the sponsor's
response to this NOOH, the issues will be defined, a presiding officer
will be assigned, and a written notice of the time and place at which
the hearing will commence will be issued as soon as practicable.
    This notice is issued under section 512 of the FD&C Act and under
the authority delegated to the Director of CVM.

VII. Environmental Impact

    The Agency has determined under 21 CFR 25.33(g) that this action is
of a type that does not individually or cumulatively have a significant
impact on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VIII. Paperwork Reduction Act of 1995

    The collections of information requirements for this document are
covered under OMB control numbers 0910-0032 and 0910-0184.

IX. References

    The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at http://www.regulations.gov. (FDA
has verified the Web site addresses, but FDA is not responsible for any
subsequent changes to the Web sites after this document publishes in
the Federal Register.)

1. FDA, Freedom of Information (FOI) Summary, NADA 041-061, MECADOX
10 (carbadox) Type A medicated article, supplemental approval
January 30, 1998. Available at http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM429999.pdf (accessed on March 19, 2016).
2. JECFA, Report on Carbadox, 2003. Available at ftp://ftp.fao.org/ag/agn/jecfa/vetdrug/41-15-carbadox.pdf (accessed on March 19,
2016).
3. FDA, Memorandum to the File, Claycamp, H.G., ``Preliminary Risk
Characterization: Cancer Risk Estimation from Carbadox Residues in
Pork from Swine Treated with Carbadox,'' December 16, 2014.
4. Boison, J.O., S.C. Lee, and R.G. Gedir, ``A Determinative and
Confirmatory Method for Residues of the Metabolites of Carbadox and
Olaquindox in Porcine Tissues,'' Analytica Chimica Acta, 637:128-
134, 2009.
5. Baars, A.J., L.A. van Ginkel, M.M.L. Aerts, et al., ``Kinetics of
Carbadox Residues in Pigs,'' In: Proceedings of the EuroResidue
Conference, Noorwijkerhout (Haagsma, N., A. Ruiter, and P.B. Czedik-
Eysenberg, eds., May 21-23, 1990.
6. Baars, A.J., L.P. Jager, T.J. Spierenberg, et al., ``Residues of
Carbadox Metabolites in Edible Pork Products,'' Archives of
Toxicology Supplement, 14:288-92, 1991.
7. FDA, CVM Guidance for Industry (GFI) #3, ``General Principles for
Evaluating the Safety of Compounds Used in Food-Producing Animals,''
July 25, 2006. Available at http://www.fda.gov/downloads/animalveterinary/guidancecomplianceenforcement/guidanceforindustry/ucm052180.pdf (accessed on March 19, 2016).
8. FDA, Memorandum to the File, from Director, Division of New
Animal Drugs to Director, Bureau of Veterinary Medicine regarding
NADA 41-061--Carbadox for Swine (September 22, 1972).
9. FDA, Memorandum to the File, S.H. Frazier, Jr., Division of
Toxicology, to Director, Bureau of Veterinary Medicine, regarding
Carbadox for Swine, August 27, 1970.
10. JECFA, Report on Carbadox, 1990. Available at ftp://ftp.fao.org/ag/agn/jecfa/vetdrug/41-3-carbadox.pdf (accessed on March 19, 2016).
11. FDA, Memorandum to the File, from Division of New Animal Drugs
to Director, Bureau of Veterinary Medicine, regarding NADA 41-061,
Carbadox for Swine (July 7, 1972).
12. FDA, Memorandum to the File, Approval of Original New Animal
Drug Application NADA 92-955 (July 29, 1975).
13. Citizen Petition, Center for Science in the Public Interest,
Docket No. FDA-1986-P-0299 (formerly 86P-0212), May 9, 1986.
14. FDA, Response to Citizen Petition, Center for Science in the
Public Interest, Docket No. FDA-1986-P-0299 (formerly 86P-0212), May
30, 1995.
15. FDA, Memorandum to the File, from Residue Evaluation Branch,
Division of Chemistry to Director, Division of

Chemistry, regarding Review of Carbadox Metabolism (September 7,
1994).
16. FDA, Freedom of Information (FOI) Summary, NADA 041-061, MECADOX
10 (carbadox) Type A medicated article, supplemental approval
October 5, 1998. Available at http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm064223.htm
(accessed on March 19, 2016).
17. FDA, Freedom of Information (FOI) Summary, NADA 141-211, MECADOX
10 (carbadox) and TERRAMYCIN 50, 100, or 200 (oxytetracycline) in
Type C medicated feed, original approval July 21, 2004. Available at
http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118005.pdf (accessed
on March 19, 2016).
18. Codex Alimentarius Commission, Twenty-Eighth Session,
Headquarters, Food and Agriculture Organization, Rome, Italy, 2005.
19. FDA, CVM Guidance for Industry (GFI) #205, VICH GL 46, ``Studies
to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs
in Food-Producing Animals: Metabolism Study to Determine the
Quantity and Identify the Nature of Residues (MRK),'' September 15,
2011. Available at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM207939.pdf
(accessed on March 19, 2016).
20. MacIntosh, A.I., G. Lauriault, and G.A. Neville, ``Liquid
Chromatographic Monitoring of the Depletion of Carbadox and its
Metabolite Desoxycarbadox in Swine Tissues,'' Journal--Association
of Official Analytical Chemists, 68:665-71, 1985.
21. FDA, CVM Guidance for Industry (GFI) #208, VICH GL 49, ``Studies
to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs
in Food-Producing Animals: Validation of Analytical Methods Used in
Residue Depletion Studies,'' September 15, 2011. Available at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM207942.pdf
(accessed on March 19, 2016).
22. FDA, Memorandum to the File, Claycamp, H. G., Verification and
Extension of the 2003 JECFA Carbadox Monograph Analyses, July 29,
2012.

    Dated: April 6, 2016.
Tracey Forfa,
Acting Director, Center for Veterinary Medicine.
[FR Doc. 2016-08327 Filed 4-8-16; 11:15 am]
 BILLING CODE 4164-01-P