[Federal Register Volume 84, Number 133 (Thursday, July 11, 2019)]
[Rules and Regulations]
[Pages 32982-33002]
[FR Doc No: 2019-14098]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 500, 520, 522, 524, 526, 529, 556, and 558

[Docket No. FDA-2012-N-1067]
RIN 0910-AG17

New Animal Drugs; Updating Tolerances for Residues of New Animal
Drugs in Food

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; technical amendments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule to revise the animal drug regulations for
tolerances for residues of approved new animal drugs. This final rule
is necessary to standardize, simplify, and clarify the determination
standards of tolerances and provide definitions for key terms. This
final rule will enhance understanding of tolerance determination and
improve the overall readability of the relevant regulations.

DATES: This rule is effective September 9, 2019.

ADDRESSES: For access to the docket to read background documents or
comments received, go to https://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Dong Yan, Center for Veterinary
Medicine (HFV-151), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855,<PHONE_NUMBER>, email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose and Coverage of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits

II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. History and Scope of This Rulemaking
    B. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the 2012 Proposed Rule and 2016 Supplemental Proposed
Rule and FDA Response
    A. Introduction
    B. Comments on Scope
    C. Comments on Definition Section
    D. Comments on Analytical Method
    E. Comments on Subpart B, Listing of Tolerances for Residues of
Approved and Conditionally Approved New Animal Drugs
    F. Other Comments
VI. Effective/Compliance Date
VII. Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose and Coverage of the Final Rule

    This final rule revises the animal drug regulations regarding
tolerances for residues of approved and conditionally approved new
animal drugs in food. Specifically, we provide a revised scope and new
section for definitions of key terms FDA uses in the regulations.
Additionally, we explain the general considerations for using the
tolerance information to ensure the safety of veterinary drug use in
food-producing animals. Finally, we provide a uniform format for
listing tolerances in part 556 (21 CFR part 556), subpart B, by
removing obsolete or confusing terms and cross-referencing tolerances
to the approved conditions of use for that new animal drug.

B. Summary of the Major Provisions of the Final Rule

    This final rule standardizes and clarifies the standards for
determining, codifying, and updating tolerances, and provides a
definition section. Major provisions include:
     Establishing a new definitions section with the following
definitions in Sec.  556.3 (21 CFR 556.3):
    [cir] Acceptable daily intake;
    [cir] Acute reference dose;
    [cir] Edible tissues;
    [cir] Marker residue;
    [cir] Not required;
    [cir] Residue;
    [cir] Target tissue;
    [cir] Tolerance;
    [cir] Total residue;
    [cir] [mu]g/kg; and
    [cir] Zero.
     Revising the tolerance listings in subpart B to
standardize the format of listings and to add cross references to part
520, 522, 524, 526, 529, or 558 (21 CFR part 520, 522, 524, 526, 529,
or 558) that contain the approved or conditionally approved conditions
of use of the drug.

C. Legal Authority

    Our authority for issuing this final rule is provided by sections
512(b)(1)(G) and (H), (d)(1)(F), (d)(2), and (i), and 571(a)(2)(A) and
(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21
U.S.C. 360b(b)(1)(G) and (H), (d)(1)(F), (d)(2), and (i), and
360ccc(a)(2)(A) and (b)(1)). These provisions relate to the information
new animal drug and conditional new animal drug applicants provide with
respect to proposed tolerances, withdrawal periods, and practicable
methods, and the process by which FDA establishes and publishes
regulations setting tolerances for residues of approved and
conditionally approved new animal drugs. In addition, section 701(a) of
the FD&C Act (21 U.S.C. 371(a)) gives FDA general rulemaking authority
to issue regulations for the efficient enforcement of the FD&C Act.

D. Costs and Benefits

    This final rule will not impose compliance costs, other than
reading and understanding the final rule, on current or future sponsors
of any approved and conditionally approved new animal drugs. We
estimate those annualized costs to range from about $1,000 to about
$1,500.
    By providing a uniform format for listing tolerances, and removing
obsolete and confusing terms, this final rule may provide more clarity
to the listing of tolerances.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

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            Abbreviation                        What it means
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ARfD...............................  Acute reference dose.
ASDI...............................  Acceptable single-dose intake.
CFR................................  Code of Federal Regulations.
CVM................................  Center for Veterinary Medicine.
FDA................................  U.S. Food and Drug Administration.
FD&C Act...........................  Federal Food, Drug, and Cosmetic
                                      Act.
FSIS...............................  Food Safety and Inspection Service,
                                      United States Department of
                                      Agriculture.
GFI................................  Guidance for Industry.
VICH...............................  International Cooperation on
                                      Harmonisation of Technical
                                      Requirements for Registration of
                                      Veterinary Medicinal Products.
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III. Background

A. History and Scope of This Rulemaking

    We issued a proposed rule in the Federal Register of December 5,
2012 (77 FR 72254) (2012 proposed rule) to revise part 556 by
standardizing and simplifying the codification style, revising the
general considerations section, adding a scope section, and adding a
definition section to define key terms used in the part. The definition
section was proposed to include the terms used by FDA in the
determination of tolerances. We proposed a definition section because
some of the terms that had been used previously in part 556, subpart B
were never defined, and some terminology that had been used was
outdated or resulted in confusion to users of the part. We added a new
scope section and proposed a revision to the general considerations
section to provide additional information and clarification with
respect to the tolerances listed in proposed subpart B.
    We issued a supplemental notice of proposed rulemaking in the
Federal Register of October 28, 2016 (81 FR 74962) (2016 supplemental
proposed rule) to revise the proposed changes to part 556 to align with
and clarify our current thinking. We explained our current thinking
about analytical methods used to determine residue levels in tissues
for new animal drugs intended for use in food-producing animals. We
also explained that methods other than the ``regulatory method''
derived from the practicable method submitted by a sponsor as part of
the new animal drug application can be used to determine the quantity
of residue in edible tissues for surveillance and enforcement purposes.
We removed the definition previously proposed in 2012 for ``regulatory
method'' and an additional reference to the term to reserve the term
for use with carcinogenic compounds. We also revised the previously
proposed definitions for ``marker residue,'' ``tolerance,'' ``not
required,'' and ``zero.'' We also removed the previously proposed
definition for ``acceptable single-dose intake'' and added a proposed
definition for ``acute reference dose'' to be consistent with existing
international guidance.

B. General Overview of the Final Rule

    This final rule revises the animal drug regulations regarding
tolerances for residues of approved and conditionally approved new
animal drugs in food. We are finalizing most of the provisions proposed
in the 2012 proposed rule as revised by the 2016 supplemental proposed
rule. This final rule also reflects revisions FDA made after
considering all comments received. We have also made nonsubstantive
wording changes for clarity.

    This final rule amends part 556 by standardizing and simplifying
the codification style and adding definitions for key terms.
Specifically, we provide a revised scope and new section for
definitions of key terms FDA uses in the regulations. Additionally, we
explain the general considerations for using the tolerance information
to ensure the safety of veterinary drug use in food-producing animals.
Finally, we provide a uniform format for listing tolerances in subpart
B, by removing obsolete or confusing terms and cross-referencing
tolerances to the approved conditions of use for that new animal drug.

IV. Legal Authority

    We are issuing this final rule under sections 512(b)(1)(G) and (H),
(d)(1)(F), (d)(2), and (i), and 571(a)(2)(A) and (b)(1) of the FD&C
Act. These provisions relate to the information new animal drug and
conditional new animal drug applicants provide with respect to proposed
tolerances, withdrawal periods, and practicable methods, and the
process by which FDA establishes and publishes regulations establishing
tolerances for residues of approved and conditionally approved new
animal drugs. In addition, section 701(a) of the FD&C Act gives FDA
general rulemaking authority to issue regulations for the efficient
enforcement of the FD&C Act.

V. Comments on the 2012 Proposed Rule and 2016 Supplemental Proposed
Rule and FDA Response

A. Introduction

    We received comments on the 2012 proposed rule and 2016
supplemental proposed rule, each containing one or more comments on one
or more issues. We received comments from consumers, public health
organizations, and the pharmaceutical industry.
    We describe and respond to the comments in section V.B through E of
this document. We have numbered each comment to help distinguish
between different comments. We have grouped similar comments together
under the same number, and, in some cases, we have separated different
issues discussed in the same comment letter and designated them as
distinct comments for purposes of our responses. The number assigned to
each comment or comment topic is purely for organizational purposes and
does not signify the comment's value or importance or the order in
which comments were received.
    Some comments address issues that are outside of the scope of this
rule. We do not discuss such comments in this document.

B. Comments on Scope

    (Comment 1) One comment to the 2012 proposed rule asks FDA to
clarify whether the proposed regulations would apply to drug residues
in all foods (human and animal food), or only to human foods.
    (Response 1) The regulations apply only to foods intended for human
consumption. New Sec.  556.5(c) (21 CFR 556.5(c)) states in part ``. .
. the finding that the concentration of the marker residue in the
target tissue from a tested animal is at or below the tolerance
indicates that all edible tissues (excluding milk and eggs unless
otherwise indicated) from that tested animal are safe for human
consumption.''

C. Comments on Definition Section

    We received several comments regarding proposed definitions.
    (Comment 2) One comment to the 2012 proposed rule expresses concern
that the term ``edible tissues'' as defined in the proposed rule does
not include all parts of animals currently consumed as foods in the
United States, and thus, residues of drugs in these foods are not
included in the toxicological evaluation of new animal drugs. The
comment expresses the opinion that many other tissues are eaten by
humans and should be included in the toxicology evaluation and
tolerance assignments. The comment suggests that to ensure safety of
food for humans, the definition of edible tissue be equivalent to, and
broad enough to cover, any tissue that will become a component of the
food and not be limited to any specific set of tissues.
    (Response 2) We typically request residue data for muscle, which is
a highly consumed tissue; liver, kidney, and fat (skin with fat for
poultry), which are tissues where residues have a tendency to
accumulate; and milk, eggs, and honey, if applicable. The edible tissue
definition, which includes all the aforementioned edible products,
reflects our current thinking on how to address safety of residues in
food products derived from animals treated with new animal drugs.
    (Comment 3) One comment to the 2012 proposed rule suggests changes
to the proposed definition of ``not required'' with respect to
tolerances. In the 2012 proposed rule, we proposed that ``not
required,'' in reference to tolerances, means that at the time of
approval, the drug met one of the following conditions: (1) No
withdrawal period (i.e., zero withdrawal) was necessary for residues of
the drug to deplete to or below the concentrations considered to be
safe or an adequate withdrawal period was inherent in the proposed drug
use, and there was no concern about residues resulting from misuse or
overdosing; or (2) the drug qualified for a zero withdrawal period
because it was poorly absorbed or metabolized rapidly to such an extent
as to make selection of an analyte impractical or impossible. The
comment proposes that conditions (1) and (2) be replaced with: ``(1) no
withdrawal period (i.e., zero withdrawal) was necessary for residues of
the drug to deplete to or below the concentrations considered to be
safe, or (2) an adequate withdrawal period was inherent in the proposed
drug use, or (3) there was no concern about residues resulting from
misuse or overdosing, or (4) the drug was poorly absorbed or
metabolized rapidly to such an extent as to make selection of an
analyte impractical or impossible.''
    Additionally, a comment to the 2016 supplemental proposed rule asks
FDA to explain what revisions were made to the definition for ``not
required'' in reference to tolerance in the 2016 supplemental proposed
rule (81 FR 74962 at 74964), and FDA's current practice with regard to
the tolerance ``not required.''
    (Response 3) We disagree with the comment to the 2012 proposed rule
suggesting revisions because the revisions do not accurately reflect
the criteria we used in the past to determine that a tolerance is ``not
required.''
    In the past, we did not assign a tolerance for some drugs when
either of the conditions described under (1) or (2) in the 2012
proposed rule were met. However, currently and going forward, FDA
generally assigns and will assign a tolerance if a tolerance can be
established. There are some situations, however, under which it is not
possible to establish a tolerance. For example, a tolerance cannot be
established when FDA has determined that an Acceptable Daily Intake
(ADI) is not needed for the approval after considering the physical,
chemical, toxicological, and exposure characteristics of the drug
residues, or when the drug is poorly absorbed or metabolized rapidly so
as to make selection of an analyte impractical or impossible.
    In the 2016 supplemental proposed rule (81 FR 74962 at 74964), FDA
proposed to revise and clarify the definition for ``not required'' in
reference to tolerance by separately listing the conditions described
under (1) and (2) into two paragraphs, to make it clearer that if
either the described conditions under (1) or (2) were met at the time
of approval, a tolerance was

``not required.'' In addition, under (1), the phrase ``and there was a
rapid depletion of residues'' was added before the phrase ``so there
was no concern about residues resulting from misuse or overdosing'' to
explain the reason (i.e., rapid depletion of residues) for no concern
about residues resulting from misuse or overdosing.
    We received no further comment on the revised proposed definition
and are finalizing as proposed in the 2016 supplemental proposed rule.
    (Comment 4) A few comments to the 2012 proposed rule recommend that
FDA be consistent with the terms and definitions used by international
organizations, such as the International Cooperation on Harmonisation
of Technical Requirements for Registration of Veterinary Medicinal
Products (VICH). Specifically, they recommend that FDA use the VICH
definition for Acute Reference Dose (ARfD) to replace the FDA-proposed
definition for Acceptable Single-Dose Intake (ASDI). One comment states
that FDA should use the VICH term to avoid the confusion of having two
terms that mean virtually the same thing, while another comment also
recommends that we include the phrase ``microgram ([mu]g) or milligram
(mg)/kg of body weight'' in the definition for ARfD, as defined in the
relevant VICH guideline background information for the definition of
ARfD.
    (Response 4) We agree with the comment suggesting FDA replace the
proposed definition of ASDI with the VICH definition of ARfD. In the
2016 supplemental proposed rule (81 FR 74962 at 74964 and 74965), we
proposed to harmonize with the VICH by removing the definition of
``acceptable single-dose intake (ASDI)'' and adding the definition of
``acute reference dose (ARfD),'' referenced in our draft guidance for
industry ((GFI) #232 (VICH GL54)) entitled ``Studies to Evaluate the
Safety of Residues of Veterinary Drugs in Human Food: General Approach
to Establish an Acute Reference Dose (ARfD)'' (80 FR 31041, June 1,
2015), which has since been finalized (Ref. 1 and 82 FR 40010, August
23, 2017). We proposed ARfD to be defined as ``an estimate of the
amount of residues expressed on a body weight basis that can be
ingested in a period of 24 hours or less without adverse effects or
harm to the health of the human consumer.'' We disagree that the phrase
``microgram ([mu]g) or milligram (mg)/kg of body weight'' should be
included in the definition for ARfD, because the VICH definition for
ARfD is not limited to being reported as ``microgram ([mu]g) or
milligram (mg)/kg of body weight'' (GFI #232 (VICH GL54)). We received
no further comment on these proposed revisions and are finalizing as
proposed in the 2016 supplemental proposed rule.
    (Comment 5) One comment to the 2012 proposed rule recommends that
FDA use the term ``point of departure'' (POD) instead of ``no observed
effect level (NOEL)'' for calculation of the ADI.
    (Response 5) The ADI definition in the 2012 proposed rule stated
that an ADI is calculated by dividing the NOEL (from the most
appropriate toxicological study) by a safety factor. We agree with the
comment that the term ``POD,'' or threshold, is more appropriate than
the term ``NOEL'' for calculation of the ADI, because the term ``POD''
is more inclusive and reflects FDA's current and past practice for the
derivation of an ADI.
    However, since the publication of the 2012 proposed rule, GFI #232
(VICH GL54) has been published, which includes a different definition
for ADI than the one included in the 2012 proposed rule. There are no
fundamental scientific differences between the ADI definition from the
2012 proposed rule and the ADI definition found in GFI #232 (VICH
GL54). As a result, we are amending the ADI definition and using the
ADI definition from GFI #232 (VICH GL54) in this final rule, to be
consistent with the VICH definition for ADI.
    Unlike the ADI definition in the 2012 proposed rule, the ADI
definition found in GFI #232 (VICH GL54) and adopted here does not
include a calculation for an ADI and therefore does not use the term
NOEL or POD. We note, however, that we use the term POD in the
description for calculation of an ADI in the revision of guidance GFI
#3 entitled ``General Principles for Evaluating the Human Food Safety
of New Animal Drugs Used in Food-Producing Animals'' (Ref. 2 and 83 FR
27333, June 12, 2018).
    (Comment 6) One comment to the 2012 proposed rule requests
clarification on the proposed definition for ``regulatory method'' and
on the use of the term in proposed Sec.  556.5(d), which stated that
FDA requires that a drug sponsor develop a regulatory method to measure
drug residues in edible tissues of approved target species. This
comment notes that a regulatory method has historically been used to
refer to the ``required determinative and confirmatory procedures for
regulatory surveillance of residue concentrations in meat products
entering the food supply for comparison to the tolerance post-
commercialization of the product.'' The comment also states the context
of the proposed rule appears to be the method(s) used to collect data
to support the setting of the tolerances preapproval. The comment asks
if the proposed rule implies that tolerances may be established using
analytical procedures other than the determinative procedure. In
addition, the comment states it should be clarified if regulatory
method is referring to method(s) used preapproval for setting the
tolerance versus a finite method(s) used for determining post-
commercialization residue to compare to the tolerance. Additionally,
another comment to the 2016 supplemental proposed rule suggests that,
instead of removing the term ``regulatory method'' from the definitions
listed in part 556, FDA keep this term and add the term ``carcinogenic
compounds'' to the definitions and specify that a regulatory method is
only required for carcinogenic compounds.
    (Response 6) We realized that, in the 2012 proposed rule, the term
``regulatory method'' proposed in Sec.  556.3 and used in proposed
Sec.  556.5(d) caused some confusion; thus, the 2016 supplemental
proposed rule explains our current thinking about the term and its use
(81 FR 74962 at 74963). We explained in the 2016 supplemental proposed
rule that an analytical method other than the practicable method, which
is described in Sec.  514.1(b)(7) (21 CFR 514.1(b)(7)), can be used for
surveillance and enforcement purposes for non-carcinogenic compounds,
as long as the performance criteria of that method are comparable to
those of the practicable method submitted by the sponsor as part of the
new animal drug application. Such an analytical method other than the
practicable method can be used for surveillance and enforcement
purposes for non-carcinogenic compounds, so long as the performance
criteria (e.g., sensitivity, specificity, accuracy, and precision) of
that method are comparable to those of the practicable method submitted
by the sponsor as part of the new animal drug application. In addition,
we proposed a revision to the definition of ``zero'' in proposed Sec.
556.3, in reference to tolerances, by deleting ``when using a method of
detection prescribed or approved by FDA'' from the definition, because
an analytical method other than the practicable method can be used for
surveillance and enforcement purposes for non-carcinogenic compounds.
In the 2016 supplemental proposed rule we proposed to revise Sec.
556.5(d) to align with our current thinking and to remove the term
``regulatory method'' from this provision because we are reserving this

term for use with carcinogenic compounds (part 500, subpart E (21 CFR
part 500, subpart E)). Further, the regulations under part 556 are
dedicated to tolerances for non-carcinogenic compounds approved for use
in food-producing animals, while those under part 500, subpart E,
entitled ``Regulation of Carcinogenic Compounds Used in Food-Producing
Animals,'' are dedicated to carcinogenic compounds for use in food-
producing animals. FDA's intention is to clearly separate the purpose
of these two parts in Title 21 of the Code of Federal Regulations and,
therefore, does not agree with the recommendation. We are finalizing as
proposed in the 2016 supplemental proposed rule and removing the term
``regulatory method'' from part 556.
    (Comment 7) We received two comments to the 2016 supplemental
proposed rule regarding the proposed changes in the tolerance
definition. The comments express concern that by replacing the term
``target tissue'' with ``edible tissue'' in the definition, the focus
about using target tissue to indicate safety of other edible tissues
from treated animals is likely to be lost.
    (Response 7) FDA's revised definition reflects the fact that we can
establish tolerances for both target and non-target tissue. We intend
to continue to use the target tissue tolerance to indicate safety of
all of the edible tissue (excluding milk and eggs, unless otherwise
specified) from treated animals.
    (Comment 8) One comment to the 2016 supplemental proposed rule asks
us to explain how FDA will interpret the revised definition for
``zero'' in proposed Sec.  556.3, which reads, ``zero, in reference to
tolerances in this part, means any residues detected in the tissue
renders it unsafe.'' The comment states that ``zero'' is defined by the
sensitivity of the testing methodology and asks what would happen if
the ``testing method increases their sensitivity level that it will be
chasing zero?'' The comment asks FDA to explain how this will influence
zero tolerance and ``updating new withdrawal times'' and how this new
information will be communicated to the industry. The comment also
recommends that in the proposed definition for ``zero,'' the word
``tissue'' be replaced with ``edible tissue,'' to be consistent
throughout the document.
    (Response 8) We agree with the comment that ``zero'' is defined by
the sensitivity of the testing methodology. As explained in the
preamble of the 2012 proposed rule (77 FR 72254 at 72256), in approving
certain animal drugs in the past, FDA assigned a ``zero'' tolerance,
with ``zero'' meaning that no residues could be detected using the
``approved analytical method.'' Often, the analytical method chosen to
determine ``zero'' represented the limit of analytical method
technology at the time of the evaluation. However, we recognize that
equipment, reagents, and methodology change over time and the
analytical method (practicable method) submitted by the sponsor in
support of drug approval may become obsolete. Therefore, we explained
in the 2016 supplemental proposed rule (81 FR 74962 at 74964) that an
analytical method other than the practicable method can be used for
surveillance and enforcement purposes for non-carcinogenic compounds.
Such an analytical method should have the same capability as the
practicable method to determine the quantity of the drug residues such
that the tolerance, withdrawal period, or other use restrictions
continue to ensure that the use of the drug will be safe. Therefore,
the assigned withdrawal periods will not need to be changed.
    In response to the last part of the comment that we replace
``tissue'' with ``edible tissue'' in the definitions section, we agree
and finalize the codified as the comment suggested.
    (Comment 9) A comment to the 2016 supplemental proposed rule
observes that new terms such as ``practicable method,'' ``analytical
method,'' ``edible tissue,'' and ``acute reference dose'' were used to
replace ``regulatory method,'' ``target tissue,'' and ``acute single
dose intake''; however, these new terms are not present in FDA's draft
revised GFI #3 (81 FR 47397, July 21, 2016) (since finalized), and the
inconsistency will lead to confusion between the regulation and
guidance.
    (Response 9) We interpret the term, ``acute single dose intake,''
in the comment to mean ``acceptable single-dose intake.'' We disagree
with the comment that the terms, ``practicable method,'' ``analytical
method,'' ``edible tissue,'' and ``acute reference dose'' are not
present in the guidance. Although revised GFI #3 does not have a
definition section or glossary, all of these terms are used in the
guidance. We do not believe there is any inconsistency in how these
terms are used and therefore do not believe that will lead to confusion
between the regulation and the guidance.
    (Comment 10) One comment to the 2016 supplemental proposed rule
observes that many of the revised terms proposed for part 556 remain as
currently defined in 21 CFR 500.80. The comment expresses concern that
the existence of different definitions will lead to confusion.
    (Response 10) The regulations under part 500, including those terms
listed under 21 CFR 500.82, implement the Diethylstilbestrol (DES)
Proviso to the Delaney Clause in section 512(d)(1)(I) of the FD&C Act
(21 U.S.C. 360b(d)(1)(I)), which allows cancer-causing compounds to be
used in food-producing animals if, among other conditions, no residue
of such drug will be found in any edible portion of such animal after
slaughter or in any food yielded by or derived from the living animals.
Because there are different requirements for approving a new animal
drug under these provisions than those for approving non-carcinogenic
new animal drugs for use in food-producing animals, a different
definition is needed for the term ``marker residue'' depending on
whether the new animal drug is a carcinogenic compound or a non-
carcinogenic compound. The definitions of ``residue'' and ``target
tissue,'' although slightly different in wording, have the same meaning
in both parts 500 and 556, and we do not believe this will lead to
confusion.
    (Comment 11) One comment to the 2016 supplemental proposed rule
asks FDA to explain the differentiation of residue method requirements
for carcinogenic and non-carcinogenic compounds.
    (Response 11) Section 512(d)(1)(I) of the FD&C Act provides that an
animal drug will not be approved if, among other reasons, the drug is a
carcinogen, unless the Secretary of Health and Human Services finds
that, under the conditions of use specified in proposed labeling and
reasonably certain to be followed in practice, that no residue of such
drug will be found (by methods of examination prescribed or approved by
the Secretary by regulations) in any edible portion of such animals
after slaughter or in any food yielded by or derived from the living
animals. Thus, the FD&C Act requires the use of the approved regulatory
method as promulgated in regulation to show ``no residues'' of
carcinogens; however, there is no such requirement to use an approved
regulatory method for measuring residues of non-carcinogenic compounds
for post-approval residue surveillance and enforcement. Therefore, an
analytical method other than the practicable method (Sec.  514.1(b)(7))
can be used for residue surveillance and enforcement purpose for non-
carcinogenic compounds.

D. Comments on Analytical Method

    We received eight comments regarding the statement in the 2016
supplemental proposed rule that an

analytical method other than the practicable method can be used for
post-approval residue surveillance and enforcement (81 FR 74962 at
74964).
    (Comment 12) One comment recommends that FDA modify the proposed
revision to Sec.  556.5 General Considerations by removing the phrase
``FDA uses the practicable method to determine the quantity of the drug
residues that can safely remain in edible tissue (i.e., the tolerance)
. . .'' from the provision. The comment states that the quantity of
drug residues that can safely remain in the edible tissues is based on
the safe concentration derived from the ADI. In addition, the comment
states that ``while the practicable method may be utilized to determine
the ratio of the marker residue to the total drug residues, the work
typically precedes the finalization of the official marker residue
method.''
    (Response 12) FDA does not agree that the phrase should be removed
from the sentence under Sec.  556.5 General Considerations and is
finalizing as proposed. In proposed Sec.  556.5(d) of the 2016
supplemental proposed rule, we said that we require a drug sponsor to
submit a practicable method as part of their new animal drug
application. We use the practicable method to determine the quantity of
the drug residues that can safely remain in edible tissues (i.e., the
tolerance), the withdrawal period, and any other use restrictions
necessary to ensure that the proposed use of the drug will be safe. We
think that it is clear that the phrase refers to establishment of a
tolerance, which is based not only on the safe concentration derived
from the ADI, but also on the marker residue or other residues measured
by the practicable method.
    (Comment 13) Two comments to the 2016 proposed rule express
concerns that, with the implementation of the rule, an analytical
method other than the practicable method may be used for post-approval
residue surveillance and compliance when that other analytical method
is not actually equivalent to the practicable method. The comments
advocate for proper validation of the analytical method before its use
for residue surveillance and compliance. One of the comments asks FDA
to clarify the terms ``performance criteria'' and ``comparable'' used
in the 2016 supplemental proposed rule as they relate to the
requirements that an analytical method other than the practicable
method must meet before it can be used for residue surveillance and
enforcement. It recommends that FDA add a definition for the term
``performance criteria'' and provisions in the final rule to ensure
that the original marker residue to total residue ratio is achieved
with the analytical method.
    (Response 13) FDA establishes tolerances using the practicable
method (defined at Sec.  514.1(b)(7)) submitted by a sponsor as part of
the new animal drug application. The practicable method is used to
collect data for tolerance assignment. After the drug product is
approved, FDA makes the practicable method available for monitoring
drug residues in the food supply. In the 2016 supplemental proposed
rule, we stated that as technologies have evolved, many of the older
methods have become obsolete. In addition, there is an increased
reliance on multiresidue methods in the monitoring of the food supply.
We also stated that an analytical method other than the practicable
method can be used for residue surveillance and enforcement purposes
for non-carcinogenic compounds, as long as the performance criteria
(e.g., sensitivity, specificity, accuracy, and precision) of the
analytical method are comparable to those of the practicable method.
FDA considers the performance criteria of the two methods to be
``comparable'' if the analytical method has been shown, through
appropriate validation, to have the same capability as the practicable
method to determine the quantity of the drug residues remaining in
edible tissues of treated animals so that the tolerance, withdrawal
period, or other use restrictions continue to ensure that the use of
the drug will be safe. The proposal included sensitivity, specificity,
accuracy, and precision as examples of the performance criteria. As a
result, we do not believe additional definitions are necessary.
    (Comment 14) One comment to the 2016 supplemental proposed rule
asks FDA to clarify how the Food Safety and Inspection Service, United
States Department of Agriculture (FSIS) (USDA) methods will be viewed
by FDA and whether this supplemental proposed rule is ``intended to
indicate that any multi-residue method (MRM), independent of version,
can be used, and the version changes have no impact on the data.''
    (Response 14) We interpret that the comment is asking whether the
supplemental proposed rule is intended to indicate that any
multiresidue method (MRM), independent of version, can be used for
surveillance and enforcement purposes. The supplemental proposed rule
is intended to indicate, as explained above, that an analytical method
other than the practicable method can be used for surveillance and
enforcement purposes for non-carcinogenic compounds, as long as the
performance criteria (e.g., sensitivity, specificity, accuracy, and
precision) of that method are comparable to those of the practicable
method submitted by the sponsor as part of the new animal drug
application.
    (Comment 15) One comment suggests that ``the availability of
advanced methods that improve upon the practicable method necessarily
means that the tolerance, withdrawal period, and the need for use
restrictions of many drugs must be reassessed using the best available
technologies.''
    (Response 15) The 2016 supplemental proposed rule stated that an
analytical method other than the practicable method can be used for
post-approval residue surveillance and enforcement, which allows the
use of evolving analytical technologies while maintaining the
tolerance, withdrawal period, and other restrictions as part of the
conditions of the approval. The practicable method is used to collect
data for tolerance assignment. A different method may be used for
surveillance and enforcement purposes as long as it has the same
capability as the practicable method to measure residues to ensure the
established tolerance is not exceeded. If an analytical method has the
same capability as the practicable method to determine the quantity of
the same marker residue in the same tissue, then the tolerance,
withdrawal period, or other use restrictions for the approved drug will
continue to ensure that the use of the drug will be safe.
    (Comment 16) One comment suggests that, in the cases where the
performance criteria of a new analytical method and a practicable
method are not comparable, FDA consider implementing a strategy to
correct the tolerance based on the recovery of the marker residue
observed when the new analytical method is used, with the goal of
ensuring that the use of the approved drug is safe while avoiding the
need for new studies to update the marker to total residue ratio.
    (Response 16) FDA does not think that it is necessary to change the
tolerance based on the recovery of the marker residue observed with a
new analytical method. The point of using an analytical method with
comparable performance criteria as the practicable method is to allow
newer more useful methods to be used for surveillance and enforcement
purposes, as long as the newer method has the same capability as the
practicable method to determine the quantity of the drug residues so
that the tolerance, withdrawal period, or other use restrictions
continue to ensure

that the use of the drug will be safe. Such a policy ensures a safe
food supply and allows regulatory agencies to take advantages of
scientific advances in analytical methodology.
    (Comment 17) One comment to the 2016 supplemental proposed rule
asks that, if FSIS MRMs are used prior to an active pharmaceutical
ingredient (API) being approved, can the FSIS methods be used [to
support a new animal drug approval] with or without modification [vis-
[agrave]-vis version changes]; if the data FSIS generated for
validation can be submitted to Center for Veterinary Medicine (CVM);
and if a sponsor can submit a request for FSIS to provide all data on
their API.
    (Response 17) FDA encourages drug sponsors to take advantage of
available information from government laboratories and industry for the
development of an analytical method to support a new animal drug
approval. The modification of a method already validated in a
government laboratory may allow for a scaled down interlaboratory
method trial process during the drug application review period.
Although FDA does not object to a sponsor requesting information from
FSIS, we defer to USDA on whether, how, and under what conditions such
information is made available.
    (Comment 18) A comment asks FDA to encourage sponsors to utilize
the same analytical methods as those used by USDA FSIS for creation of
the approved analytical method, because of the many associated
benefits.
    (Response 18) Although, in theory, we agree that submitting a
practicable method that is in use by USDA FSIS may be beneficial, we
note that continued use of such a method by USDA FSIS is not
guaranteed, and as newer technologies become available and relied on,
the same need to use an analytical method other than the practicable
method for monitoring the food supply may appear after approval of the
new animal drug application. We also note that the USDA FSIS MRMs,
which are used for screening purposes, may or may not be appropriate to
use to establish a tolerance, withdrawal period, and other conditions
of safe use, which is the purpose behind requiring submission of a
practicable method as part of the new animal drug application.
Therefore, as long as a method meets the requirements of Sec.
514.1(b)(7) for the sponsor of a new animal drug application to submit
a practicable method, FDA declines the commenter's request to encourage
sponsors to use USDA FSIS methods to meet those requirements. We
encourage drug sponsors to reference FDA's relevant GFI documents for
the method performance recommendations. We further encourage drug
sponsors to use a method that is in line with the recommendations in
the relevant GFIs, regardless of the method's origin.

E. Comments on Subpart B, Listing of Tolerances for Residues of
Approved and Conditionally Approved New Animal Drugs

    (Comment 19) We received two comments to the 2012 proposed rule
about the removal of safe concentrations from part 556. One comment
agrees with our decision and states this will reduce the potential for
confusion. A second comment expresses concern that, for some drugs for
which FDA historically listed only ADI and safe concentrations,
removing the listing of safe concentrations will lead to the loss of
valuable toxicological information about the drugs. The comment cites
fenprostalene as an example. The comment asks that FDA keep pertinent
toxicological information for these drugs for which tolerances are not
required.
    (Response 19) We agree with the comment that removing safe
concentrations from part 556 will reduce the potential for confusion.
We disagree with the comment that toxicological information about a
drug is lost when listings of safe concentrations for that drug are
removed, so long as the ADI for that drug is listed. Toxicological
information for the residue of a drug is determined through
toxicological evaluations and reflected by the assigned ADI. Safe
concentrations for an edible tissue are calculated from the ADI using a
formula in which the only variable is the ADI (safe concentration = ADI
x Human Body Weight/Food Consumption Value) (see GFI #3 ``General
Principles for Evaluating the Human Food Safety of New Animal Drugs
Used in Food-Producing Animals'' Ref. 2 and 83 FR 27333). When there is
an ADI assigned for the residue of a drug, the ADI is listed under that
drug's name in part 556, together with any tolerances (if tolerances
are established). Therefore, after removing safe concentrations from
the listings, toxicological information about the drug is still
reflected by the ADI. Listing of the ADI alone in part 556 provides
sufficient toxicological information for the drug. We note that the
safe concentrations remain available through the Freedom of Information
Drug Summaries, available on the CVM website at https://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ucm2006466.htm.
Additionally, safe concentrations can be calculated with the ADI in
part 556 using the formula described above.
    (Comment 20) One comment to the 2012 proposed rule questions why
FDA's ``safe level of residue'' for the same drug is different in
different food products. The commenter is concerned that FDA's decision
is not based on science, but ``on rule of law.'' The comment uses
carbendazim in orange juice as an example.
    (Response 20) The comment uses the example of carbendazim in orange
juice; however, because the proposed rule addresses tolerances for
residues of drugs in edible tissues of treated animals, we assume the
commenter is asking why the tolerance for the same drug may be
different in different edible tissues from a treated animal.
    FDA assigns one ADI to reflect the quantity of the drug residues
that humans can safely consume on a daily basis. The ADI is based on
the toxicological, microbiological, or pharmacological properties of
the drug and represents the total amount of residues that humans can
safely consume on a daily basis from the different food sources of the
residue (i.e., food derived from the food-producing animal species for
which the drug is approved).
    FDA assigns a tolerance based on not only the ADI, but also the
ratio of the marker residue to total residue in the specific edible
tissue, which can potentially differ as a function of pharmacokinetic
properties of the drug in the food-producing animal species for which
the drug is approved. The marker residue is the residue whose
concentration is in a known relationship to the concentration of total
residue in an edible tissue. In addition, the tolerance also takes into
account the amount of the edible tissue that is consumed. Therefore,
different tolerances, rather than a single tolerance, are often needed
and assigned for different edible tissues of the same food-producing
animal species, or for the same edible tissue from different food-
producing animal species, to ensure that daily human consumption of the
total drug residue in the edible tissues will not exceed the ADI.
    (Comment 21) One comment to the 2016 supplemental proposed rule
asks FDA to clarify the regulatory/enforcement use of available
surveillance residue methods for non-target tissues in a species of
livestock where a tolerance has not been established for that tissue
but has been established for another tissue.
    (Response 21) When CVM establishes a tolerance for a specific
edible tissue as part of a new animal drug approval,

CVM provides, for surveillance and enforcement purpose, an analytical
method that has been evaluated in an interlaboratory study for assay of
the residue in the specific edible tissue. A tolerance assigned for a
residue in a specific edible tissue or tissues as listed in part 556,
subpart B applies only to the specific tissue or tissues.
    (Comment 22) A comment to the 2012 proposed rule expresses concern
that, as testing abilities improve over time, ``smaller and smaller''
levels of detection are attained. The end result could be ``that there
will be no food naturally produced that will be totally free of
detectable residues.'' The comment also observes that the proposed rule
establishes that approved drugs meet established tolerance levels, but
that there are drugs that are approved for use in food-producing
animals that have no published tolerance levels. The comment asks where
FDA stands on this, i.e., when a drug is approved, but no tolerance
exists for a particular tissue. The comment also questions why some new
animal drugs for use in food-producing animals have been approved
without a tolerance even though residues are able to be detected at
very low concentrations as analytical methods improve.
    (Response 22) The detection limit for the analytical methods is not
a basis to determine if a tolerance needs to be assigned or if a
tolerance is not required for approval of a new animal drug. However,
in the past, during the new animal drug approval process FDA determined
that a tolerance was not required for some drugs. As we explained in
the 2016 supplemental proposed rule, ``not required'' means: (1) No
withdrawal period was necessary for residues of the drug to deplete to
or below the concentrations considered to be safe, or an adequate
withdrawal period was inherent in the proposed drug use, and there was
a rapid depletion of residues, so there was no concern about residues
resulting from misuse or overdosing; or (2) No withdrawal period was
necessary because the drug was poorly absorbed or metabolized rapidly
so as to make selection of an analyte impractical (81 FR 74962 at
74966). Currently, FDA's general practice is to establish a tolerance
for all new animal drugs we approve. However, as discussed earlier, FDA
recognizes that there are some situations for which it is not possible
to establish a tolerance. For example, a tolerance cannot be
established when FDA has determined that an ADI is not needed for the
approval after considering the physical, chemical, toxicological, and
exposure characteristics of the drug residues, or when the drug is
poorly absorbed or metabolized rapidly so as to make selection of an
analyte impractical or impossible. Under both circumstances, FDA
requires that drug sponsors provide toxicology and residue information
to ensure that the approved use is safe even though a tolerance is not
assigned.
    (Comment 23) A comment to the 2012 proposed rule recommends that
the regulation should also include tolerances for residues of ``new as
well as old drugs,'' as old and/or forgotten drugs may have new or
undiscovered impacts in human health, especially those drugs used in
different countries from which the United States receives imported
animal-derived food.
    (Response 23) ``New animal drug'' is a term defined by section
201(v) of the FD&C Act (21 U.S.C. 321(v)). With very limited
exceptions, drugs intended for use for animals meet the definition of
``new animal drug.'' Since 1968, FDA has had a specific statutory
requirement under section 512(i) of the FD&C Act to codify any
tolerance established as a consequence of the approval of a new animal
drug application (NADA). Subpart B in part 556 was created to satisfy
this requirement; it is a listing of tolerances assigned for ``new
animal drugs'' approved or conditionally approved for use in food-
producing animals in the United States. Tolerances for substances
administered to food-producing animals as food additives prior to 1968
were added to this listing as appropriate if these substances became
the subject of an approved NADA.
    When approval of an NADA is withdrawn, section 512(i) of the FD&C
Act requires that the Agency revoke the regulations that were published
following the approval. That revocation includes the regulation for any
tolerance listed in part 556; thus, the tolerance is removed for any
drug for which approval has been withdrawn.
    Regarding importation of animal-derived food, in addition to
establishing tolerances for approved new animal drugs, FDA also has
authority to establish import tolerances for new animal drugs not
approved in the United States, but used lawfully in another country, to
ensure that food imported into the United States is safe (section
512(a)(6) of the FD&C Act).
    (Comment 24) A comment to the 2012 proposed rule agrees with FDA's
proposal to delete salt designations and safe concentrations from the
tolerance listings in part 556, subpart B. However, the comment
suggests that it is not necessary to delete the word ``uncooked'' from
the individual listings for tolerances in subpart B.
    (Response 24) Section 556.5, General Considerations clarifies that,
``All tolerances refer to the concentrations of the marker residue, or
other residue indicated for monitoring, permitted in uncooked
tissues.'' Therefore, the word ``uncooked'' is not necessary in the
listing of tolerances, so we are finalizing as proposed.

F. Other Comments

    (Comment 25) One comment to the 2012 proposed rule expresses
concern that an unintended consequence of this rule is that it would
have the effect of acting as a ``non-tariff trade barrier as it does
not conform and is contradictory to the practices of our trading
partners.''
    (Response 25) We recognize the importance of harmonizing
international food safety standards to facilitate trade. We also
recognize that sometimes, because of our requirement to meet applicable
U.S. statutes and regulations governing food safety, our tolerances are
sometimes not harmonized with international food safety standards.
    FDA participates in the trilateral (European Union, Japan, United
States) VICH to harmonize the technical requirements for veterinary
product registration. This harmonization develops common guidelines,
including the development of data to support an ADI and tolerance for a
particular drug. FDA also participates in The Codex Committee on
Residues of Veterinary Drugs in Foods, which determines priorities for
the consideration of residues of veterinary drugs in foods and
recommends maximum residue limits (MRLs) for veterinary drugs to The
Codex Alimentarius Commission of the Food and Agriculture Organization
and the World Health Organization of the United Nations.\1\ 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 the food trade. Again,
although FDA recognizes the value in harmonizing requirements and
standards, we are required to follow U.S. law with respect to our
standard setting activities.
---------------------------------------------------------------------------

    \1\ See http://www.fao.org/fao-who-codexalimentarius/committees/committee/en/?committee=CCRVDF.
---------------------------------------------------------------------------

VI. Effective/Compliance Date

    The rule is effective September 9, 2019.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this final rule is not a significant regulatory action as
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because this final rule would not impose compliance costs on
current or future sponsors of any approved or conditionally approved
new animal drugs, and because we did not receive any comments
pertaining to this same assertion in the 2016 supplemental proposed
rule, we certify that the final rule will not have a significant
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $150
million, using the most current (2017) Implicit Price Deflator for the
Gross Domestic Product. This final rule would not result in an
expenditure in any year that meets or exceeds this amount.
    All entities affected by this final rule will incur the one-time
cost for reading and understanding this rule. We use the time required
to complete this activity to estimate the burden of this activity. To
understand this rule, affected entities will read the preamble and
codified, which together contain almost 16,800 words. If those
reviewing the rule read at the average adult reading speed of
approximately 200 words to 250 words per minute, the time to read and
understand the regulation is about 67 to 84 minutes per person. There
are currently 41 sponsors with approved applications for new animal
drugs for use in food-producing animals that will read the final rule.
We also estimate that approximately one sponsor per year will submit a
first-time application for approval of a new animal drug for use in a
food-producing animal. Thus, we estimate that about 51 firms would need
to read and understand this rule over the next 10 years.
    To value the time for complying with reading and understanding the
rule, we use wages calculated from the Bureau of Labor Statistics'
national industry-specific occupational employment and wage estimates
for the pharmaceutical and medical manufacturing industry (Ref.
3).2 3 We use the average of the $71.06 hourly wage of
management occupations (occupation code 11-0000) and the $79.52 hourly
wage of legal occupations. We double this average hourly wage to
account for benefits and overhead, yielding an average hourly labor
cost of $150.58. We estimate the cost for the one person to read and
understand the rule ranges from $169 to $211. The total costs for
reading and understanding the rule over 10 years range from around
$8,600 to around $10,800.
---------------------------------------------------------------------------

    \2\ May 2017 National Industry-Specific Occupational Employment
and Wage Estimates for the North American Industry Classification
System (NAICS) 325400--Pharmaceutical and Medicine Manufacturing. We
use estimates from NAICS 325400 because detailed estimates for NAICS
325412 are not available. Please see http://www.bls.gov/oes/.
    \3\ This wage is slightly higher than that of management
occupations for NAICS 622110--General Medical and Surgical
Hospitals, but this difference does not significantly impact of the
cost of the final rule.
---------------------------------------------------------------------------

    In table 1, FDA provides the Regulatory Information Service Center
and Office of Information and Regulatory Affairs Consolidated
Information Center accounting information.

                                                  Table 1--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                                                                ---------------------------------------
                           Category                              Primary        Low          High                                  Period       Notes
                                                                 estimate     estimate     estimate       Year       Discount     covered
                                                                                dollars      rate (%)     (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/year......................  ...........  ...........  ...........  ...........            7
                                                                                3
                                                              ------------------------------------------------------------------------------------------
    Annualized Quantified....................................  ...........  ...........  ...........  ...........            7
                                                                                3
                                                              ------------------------------------------------------------------------------------------
    Qualitative..............................................  Standardizing and simplifying the
                                                               determination standards and
                                                               codification style regarding
                                                               tolerances should provide more
                                                               clarity for industry members.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized $millions/year......................      $0.0011      $0.0010      $0.0013         2017            7           10
                                                                   $0.0010      $0.0009      $0.0011         2017            3           10
                                                              ------------------------------------------------------------------------------------------
    Annualized Quantified....................................  ...........  ...........  ...........  ...........            7
                                                                                3
                                                              ------------------------------------------------------------------------------------------
    Qualitative..............................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:

    Federal Annualized Monetized $millions/year..............  ...........  ...........  ...........  ...........            7
                                                                                3
                                                              ------------------------------------------------------------------------------------------
    From/To..................................................  From:
                                                               To:
                                                              ------------------------------------------------------------------------------------------
    Other Annualized Monetized $millions/year................  ...........  ...........  ...........  ...........            7
                                                                                3
                                                              ------------------------------------------------------------------------------------------
    From/To..................................................  From:
                                                               To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: No Effect........................................................................................................
    Small Business: The final rule will not have a significant impact on a substantial number of small entities that manufacture new animal drugs for
     use in food-producing animals......................................................................................................................
    Wages: No effect....................................................................................................................................
    Growth: No effect...................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Table 2 presents a summary of the costs, cost savings, and net
costs of the final rule. We estimate that the final rule has net costs
with present values that range from about $11,000 to $17,000, well
below the de minimis cost threshold for Executive Order 13771.

                                                      Table 2--Executive Order 13771 Summary Table
                                               [In $ millions 2016 dollars, over a perpetual time horizon]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Lower bound     Upper bound                     Lower bound     Upper bound
                                                           Primary (7%)        (7%)            (7%)        Primary (3%)        (3%)            (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs..................................           $.011           $.009           $.012           $.014           $.013           $.016
Present Value of Cost Savings...........................               0               0               0               0               0               0
Present Value of Net Costs..............................            .011            .009            .012            .014            .013            .016
Annualized Costs........................................          0.0007          0.0007          0.0008          0.0004          0.0004          0.0005
Annualized Cost Savings.................................               0               0               0               0               0               0
Annualized Net Costs....................................          0.0007          0.0007          0.0008          0.0004          0.0004          0.0005
--------------------------------------------------------------------------------------------------------------------------------------------------------

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(i) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

IX. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.

X. Federalism

    We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. We have determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we conclude that the rule
does not contain policies that have federalism implications as defined
in the Executive Order and, consequently, a federalism summary impact
statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set
forth in Executive Order 13175. We have determined that the rule does
not contain policies that have substantial direct effects on one or
more Indian Tribes, on the relationship between the Federal Government
and Indian Tribes, or on the distribution of power and responsibilities
between the Federal Government and Indian Tribes. Accordingly, we
conclude that the rule does not contain policies that have tribal
implications as defined in the Executive Order and, consequently, a
tribal summary impact statement is not required.

XII. References

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

    1. FDA, Guidance for Industry #232, ``Studies to Evaluate the
Safety of Residues of Veterinary Drugs in Human Food: General
Approach to Establish an Acute Reference Dose (ARfD), VICH GL54,''
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM448430.pdf,
August 2017.
    2. FDA, Guidance for Industry #3, ``General Principles for
Evaluating the Human Food Safety of New Animal Drugs Used In Food-
Producing Animals,'' https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052180.pdf,
June 2018.
    3. Bureau of Labor Statistics, United States Department of
Labor, May 2017 National Industry-Specific Occupational Employment
and Wage Estimates for the North American Industry Classification
System (NAICS) 325400--Pharmaceutical and Medicine

Manufacturing. Available at http://www.bls.gov/oes/.

List of Subjects

21 CFR Part 500

    Animal drugs, Animal feeds, Cancer, Labeling, Packaging and
containers, Polychlorinated biphenyls (PCBs).

21 CFR Parts 520, 522, 524, 526, and 529

    Animal drugs.

21 CFR Part 556

    Animal drugs, Foods.

21 CFR Part 558

    Animal drugs, Animal feeds.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR
chapter I, subchapter E, is amended as follows:

PART 500--GENERAL

0
1. The authority citation for part 500 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353,
360b, 371, 379e.

0
2. Amend Sec.  500.82, in paragraph (b), by alphabetically adding a
definition for ``No residue'' to read as follows:

Sec.  500.82  Definitions.

* * * * *
    (b) * * *
    No residue means the marker residue is below the limit of detection
using the approved regulatory method. The ``no residue'' designation
applies only to compounds of carcinogenic concern.
* * * * *

PART 520--ORAL DOSAGE FORM NEW ANIMAL DRUGS

0
3. The authority citation for part 520 continues to read as follows:

    Authority:  21 U.S.C. 360b.

0
4. In Sec.  520.462, redesignate paragraph (c) as paragraph (d) and add
new paragraph (c) to read as follows:

Sec.  520.462  Clorsulon drench.

* * * * *
    (c) Related tolerances. See Sec.  556.163 of this chapter.
* * * * *

0
5. In Sec.  520.1840, add paragraph (c) to read as follows:

Sec.  520.1840  Poloxalene.

* * * * *
    (c) Related tolerances. See Sec.  556.517 of this chapter.
* * * * *

0
6. In Sec.  520.2325b, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  520.2325b  Sulfaquinoxaline drench.

* * * * *
    (c) Related tolerances. See Sec.  556.685 of this chapter.
* * * * *

0
7. In Sec.  520.2640, revise paragraph (c) to read as follows:

Sec.  520.2640  Tylosin.

* * * * *
    (c) Related tolerances. See Sec.  556.746 of this chapter.
* * * * *

PART 522--IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS

0
8. The authority citation for part 522 continues to read as follows:

    Authority: 21 U.S.C. 360b.

0
9. In Sec.  522.150, redesignate paragraph (c) as paragraph (d) and add
new paragraph (c) to read as follows:

Sec.  522.150  Azaperone.

* * * * *
    (c) Related tolerances. See Sec.  556.68 of this chapter.
* * * * *

0
10. In Sec.  522.468, add paragraph (c) to read as follows:

Sec.  522.468  Colistimethate sodium powder for injection.

* * * * *
    (c) Related tolerances. See Sec.  556.167 of this chapter.
* * * * *

0
11. In Sec.  522.770, revise paragraph (c) to read as follows:

Sec.  522.770  Doramectin.

* * * * *
    (c) Related tolerances. See Sec.  556.222 of this chapter.
* * * * *

0
12. In Sec.  522.850, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  522.850  Estradiol valerate and norgestomet in combination.

* * * * *
    (c) Related tolerances. See Sec.  556.240 of this chapter.
* * * * *

0
13. In Sec.  522.1077, redesignate paragraphs (c) and (d) as paragraphs
(d) and (e) and add new paragraph (c) to read as follows:

Sec.  522.1077  Gonadorelin.

* * * * *
    (c) Related tolerances. See Sec.  556.304 of this chapter.
* * * * *

0
14. In Sec.  522.1079, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  522.1079  Serum gonadotropin and chorionic gonadotropin.

* * * * *
    (c) Related tolerances. See Sec.  556.304 of this chapter.
* * * * *

0
15. In Sec.  522.1192, add paragraph (c) to read as follows:

Sec.  522.1192  Ivermectin.

* * * * *
    (c) Related tolerances. See Sec.  556.344 of this chapter.
* * * * *

0
16. In Sec.  522.1242, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  522.1242  Levamisole.

* * * * *
    (c) Related tolerances. See Sec.  556.350 of this chapter.
* * * * *

0
17. In Sec.  522.1662a, add paragraph (l) to read as follows:

Sec.  522.1662a  Oxytetracycline hydrochloride injection.

* * * * *
    (l) For related tolerances see Sec.  556.500 of this chapter.

0
18. In Sec.  522.2120, redesignate paragraphs (c) and (d) as paragraphs
(d) and (e) and add new paragraph (c) to read as follows:

Sec.  522.2120  Spectinomycin dihydrochloride injection.

* * * * *
    (c) Related tolerances. See Sec.  556.600 of this chapter.
* * * * *

0
19. In Sec.  522.2477, add paragraph (c) to read as follows:

Sec.  522.2477  Trenbolone acetate and estradiol.

* * * * *
    (c) Related tolerances. See Sec. Sec.  556.240 and 556.739 of this
chapter.
* * * * *

0
20. In Sec.  522.2640, revise paragraph (c) to read as follows:

Sec.  522.2640  Tylosin.

* * * * *
    (c) Related tolerances. See Sec.  556.746 of this chapter.
* * * * *

PART 524--OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS

0
21. The authority citation for part 524 continues to read as follows:

    Authority: 21 U.S.C. 360b.

Sec.  524.770  [Amended]

0
22. In Sec.  524.770, in paragraph (c), remove ``Sec.  556.225'' and in
its place add ``Sec.  556.222''.

0
23. In Sec.  524.920, revise paragraph (c) to read as follows:

Sec.  524.920  Fenthion.

* * * * *
    (c) Related tolerances. See Sec.  556.280 of this chapter.
* * * * *

0
24. In Sec.  524.1044e, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  524.1044e  Gentamicin spray.

* * * * *
    (c) Related tolerances. See Sec.  556.300 of this chapter.
* * * * *

0
25. In Sec.  524.1600b, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  524.1600b  Nystatin, neomycin, thiostrepton, and triamcinolone
ophthalmic ointment.

* * * * *
    (c) Related tolerances. See Sec. Sec.  556.430 and 556.470 of this
chapter.
* * * * *

PART 526--INTRAMAMMARY DOSAGE FORM NEW ANIMAL DRUGS

0
26. The authority citation for part 526 continues to read as follows:

    Authority:  21 U.S.C. 360b.

0
27. In Sec.  526.820, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  526.820  Erythromycin.

* * * * *
    (c) Related tolerances. See Sec.  556.230 of this chapter.
* * * * *

0
28. In Sec.  526.1696d, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  526.1696d  Penicillin G procaine-novobiocin for intramammary
infusion.

* * * * *
    (c) Related tolerances. See Sec. Sec.  556.460 and 556.510 of this
chapter.
* * * * *

PART 529--CERTAIN OTHER DOSAGE FORM NEW ANIMAL DRUGS

0
29. The authority citation for part 529 continues to read as follows:

    Authority: 21 U.S.C. 360b.

0
30. In Sec.  529.400, redesignate paragraph (c) as paragraph (d) and
add new paragraph (c) to read as follows:

Sec.  529.400  Chlorhexidine tablets and suspension.

* * * * *
    (c) Related tolerances. See Sec.  556.120 of this chapter.
* * * * *

0
31. Revise part 556 to read as follows:

PART 556--TOLERANCES FOR RESIDUES OF NEW ANIMAL DRUGS IN FOOD

Subpart A--General Provisions
Sec.
556.1 Scope.
556.3 Definitions.
556.5 General considerations.
Subpart B--Specific Tolerances for Residues of Approved and
Conditionally Approved New Animal Drugs
Sec.
556.34 Albendazole.
556.36 Altrenogest.
556.38 Amoxicillin.
556.40 Ampicillin.
556.50 Amprolium.
556.52 Apramycin.
556.60 Avilamycin.
556.68 Azaperone.
556.70 Bacitracin.
556.75 Bambermycins.
556.100 Carbadox.
556.110 Carbomycin.
556.113 Ceftiofur.
556.115 Cephapirin.
556.118 Chloramine-T.
556.120 Chlorhexidine.
556.150 Chlortetracycline.
556.160 Clopidol.
556.163 Clorsulon.
556.165 Cloxacillin.
556.167 Colistimethate.
556.168 Coumaphos.
556.169 Danofloxacin.
556.170 Decoquinate.
556.180 Dichlorvos.
556.185 Diclazuril.
556.200 Dihydrostreptomycin.
556.222 Doramectin.
556.224 Efrotomycin.
556.226 Enrofloxacin.
556.227 Eprinomectin.
556.230 Erythromycin.
556.240 Estradiol and related esters.
556.260 Ethopabate.
556.273 Famphur.
556.275 Fenbendazole.
556.277 Fenprostalene.
556.280 Fenthion.
556.283 Florfenicol.
556.286 Flunixin.
556.292 Gamithromycin.
556.300 Gentamicin.
556.304 Gonadotropin.
556.308 Halofuginone.
556.310 Haloxon.
556.330 Hygromycin B.
556.344 Ivermectin.
556.346 Laidlomycin.
556.347 Lasalocid.
556.350 Levamisole.
556.360 Lincomycin.
556.370 Lubabegron.
556.375 Maduramicin.
556.380 Melengestrol.
556.410 Metoserpate.
556.420 Monensin.
556.425 Morantel.
556.426 Moxidectin.
556.428 Narasin.
556.430 Neomycin.
556.445 Nicarbazin.
556.460 Novobiocin.
556.470 Nystatin.
556.490 Ormetoprim.
556.495 Oxfendazole.
556.500 Oxytetracycline.
556.510 Penicillin.
556.513 Piperazine.
556.515 Pirlimycin.
556.517 Poloxalene.
556.540 Progesterone.
556.560 Pyrantel.
556.570 Ractopamine.
556.580 Robenidine.
556.592 Salinomycin.
556.597 Semduramicin.
556.600 Spectinomycin.
556.610 Streptomycin.
556.620 Sulfabromomethazine.
556.625 Sulfachloropyrazine.
556.630 Sulfachlorpyridazine.
556.640 Sulfadimethoxine.
556.650 Sulfaethoxypyridazine.
556.660 Sulfamerazine.
556.670 Sulfamethazine.
556.685 Sulfaquinoxaline.
556.700 Sulfomyxin.
556.710 Testosterone.
556.720 Tetracycline.
556.730 Thiabendazole.
556.732 Tiamulin.
556.733 Tildipirosin.
556.735 Tilmicosin.
556.739 Trenbolone.
556.741 Tripelennamine.
556.745 Tulathromycin.
556.746 Tylosin.
556.748 Tylvalosin.
556.750 Virginiamycin.
556.760 Zeranol.
556.765 Zilpaterol.
556.770 Zoalene.

    Authority:  21 U.S.C. 342, 360b, 371.

Subpart A--General Provisions

Sec.  556.1  Scope.

    (a) The Federal Food, Drug, and Cosmetic Act requires an applicant
seeking approval or conditional approval of a new animal drug to submit
a proposed tolerance as part of its new animal drug application when
such a tolerance is needed to assure that the proposed use of the new
animal drug will be safe (see sections 512(b)(1)(H)

and 571(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act). FDA
assigns tolerances for animal drugs used in food-producing animals as
part of the application approval process. Tolerances for approved and
conditionally approved new animal drugs are codified in subpart B of
this part.
    (b) Compounds that have been found to be carcinogenic are regulated
under subpart E of part 500 of this chapter.

Sec.  556.3  Definitions.

    As used in this part:
    Acceptable daily intake (ADI) means the daily intake which, during
up to an entire life of a human, appears to be without adverse effects
or harm to the health of the consumer. The ADI most often will be set
on the basis of the drug's toxicological, microbiological, or
pharmacological properties. It is usually expressed in micrograms or
milligrams of the chemical per kilogram of body weight per day.
    Acute reference dose (ARfD) means an estimate of the amount of
residues expressed on a body weight basis that can be ingested in a
period of 24 hours or less without adverse effects or harm to the
health of the human consumer.
    Edible tissues means muscle, liver, kidney, fat, skin with fat in
natural proportions, whole eggs, whole milk, and honey.
    Marker residue means the residue whose concentration is in a known
relationship to the concentration of total residue in an edible tissue.
    mg/kg means milligrams per kilogram.
    Not required, in reference to tolerances in this part, means that
at the time of approval:
    (1) No withdrawal period was necessary for residues of the drug to
deplete to or below the concentrations considered to be safe, or an
adequate withdrawal period was inherent in the proposed drug use, and
there was a rapid depletion of residues, so there was no concern about
residues resulting from misuse or overdosing; or
    (2) No withdrawal period was necessary because the drug was poorly
absorbed or metabolized rapidly so as to make selection of an analyte
impractical or impossible.
    ppb means parts per billion (equivalent to nanograms per gram (ng/
g) or [mu]g/kg).
    ppm means parts per million (equivalent to micrograms per gram
([mu]g/g) or mg/kg).
    ppt means parts per trillion (equivalent to picograms per gram (pg/
g) or nanograms per kilogram (ng/kg)).
    Residue means any compound present in edible tissues that results
from the use of a drug, and includes the drug, its metabolites, and any
other substance formed in or on food because of the drug's use.
    Target tissue means the edible tissue selected to monitor for
residues in the target animals.
    Tolerance means the maximum concentration of a marker residue, or
other residue indicated for monitoring, that can legally remain in a
specific edible tissue of a treated animal.
    Total residue means the aggregate of all compounds that results
from the use of an animal drug, including the drug, its metabolites,
and any other substances formed in or on food because of such drug use.
    [mu]g/kg means microgram per kilogram.
    Zero, in reference to tolerances in this part, means any residues
detected in the edible tissue renders it unsafe.

Sec.  556.5  General considerations.

    (a) The tolerances listed in subpart B of this part pertain only to
the species and production classes of the animal for which the drug use
has been approved or conditionally approved. Approved and conditionally
approved conditions of use in parts 516, 520, 522, 524, 526, 529, and
558 of this chapter, including the species and production classes of
animals, are referenced in each tolerance section in subpart B of this
part.
    (b) All tolerances refer to the concentrations of a marker residue,
or other residue indicated for monitoring, permitted in uncooked
tissues.
    (c) After a tolerance is listed, the finding that the concentration
of the marker residue in the target tissue from a tested animal is at
or below the tolerance indicates that all edible tissues (excluding
milk and eggs unless otherwise indicated) from that tested animal are
safe for human consumption. If a listed tolerance is not expressly
linked to a target tissue, then the tolerance is specific only for the
named edible tissue and inferences cannot be made about the safety of
the other edible tissues from the tested animal.
    (d) FDA requires that a drug sponsor submit a practicable method as
part of their new animal drug application. FDA uses the practicable
method to determine the quantity of the drug residues that can safely
remain in edible tissues (i.e., the tolerance), the withdrawal period,
and any other use restrictions necessary to ensure that the proposed
use of the drug will be safe.

Subpart B--Specific Tolerances for Residues of Approved and
Conditionally Approved New Animal Drugs

Sec.  556.34  Albendazole.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
albendazole is 5 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for albendazole 2-aminosulfone
(marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 0.2 ppm.
    (ii) Muscle: 0.05 ppm.
    (2) Sheep. (i) Liver (target tissue): 0.25 ppm.
    (ii) Muscle: 0.05 ppm.
    (3) Goat. (i) Liver (target tissue): 0.25 ppm.
    (ii) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.38a and 520.38b
of this chapter.

Sec.  556.36  Altrenogest.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
altrenogest is 0.04 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for altrenogest (marker residue)
are:
    (1) Swine. (i) Liver (target tissue): 4 ppb.
    (ii) Muscle: 1 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  520.48 of this chapter.

Sec.  556.38  Amoxicillin.

    (a) [Reserved]
    (b) Tolerances. The tolerance for amoxicillin is:
    (1) Cattle. Edible tissues: 0.01 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.88d, 522.88, and
526.88 of this chapter.

Sec.  556.40  Ampicillin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for ampicillin are:
    (1) Cattle. Edible tissues: 0.01 ppm.
    (2) Swine. Edible tissues: 0.01 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.90e, 520.90f,
522.90a, and 522.90b of this chapter.

Sec.  556.50  Amprolium.

    (a) [Reserved]
    (b) Tolerances. The tolerances for amprolium are:
    (1) Cattle. (i) Liver, kidney, and muscle: 0.5 ppm.
    (ii) Fat: 2.0 ppm.
    (2) Chickens and turkeys. (i) Liver and kidney: 1 ppm.
    (ii) Muscle: 0.5 ppm.
    (iii) Eggs:
    (A) Egg yolks: 8 ppm.
    (B) Whole eggs: 4 ppm.

    (3) Pheasants. (i) Liver: 1 ppm.
    (ii) Muscle: 0.5 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.100, 558.55, and
558.58 of this chapter.

Sec.  556.52  Apramycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
apramycin is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for apramycin (marker residue) is:
    (1) Swine. Kidney (target tissue): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.110 and 558.59 of
this chapter.

Sec.  556.60  Avilamycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
avilamycin is 1.1 mg/kg of body weight per day.
    (b) Tolerances. The tolerances for avilamycin are:
    (1) Chickens. Edible tissues (excluding eggs): Not required.
    (2) Swine. Edible tissues: Not required.
    (c) Related conditions of use. See Sec.  558.68 of this chapter.

Sec.  556.68  Azaperone.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
azaperone is 0.63 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for azaperone is:
    (1) Swine. Edible tissues: Not required.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.150 of this chapter.

Sec.  556.70  Bacitracin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
bacitracin is 0.05 mg/kg of body weight per day.
    (b) Tolerances. The tolerances for bacitracin are:
    (1) Cattle. Edible tissues: 0.5 ppm.
    (2) Chickens, turkeys, pheasants, quail. Edible tissues: 0.5 ppm.
    (3) Swine. Edible tissues: 0.5 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.154a, 520.154c,
558.76, and 558.78 of this chapter.

Sec.  556.75  Bambermycins.

    (a) [Reserved]
    (b) Tolerances. The tolerances for bambermycins are:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): Not
required.
    (3) Swine. Edible tissues: Not required.
    (c) Related conditions of use. See Sec.  558.95 of this chapter.

Sec.  556.100  Carbadox.

    (a) [Reserved]
    (b) Tolerances. The tolerance for quinoxaline-2-carboxylic acid
(marker residue) is:
    (1) Swine. Liver (target tissue): 30 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.115 of this chapter.

Sec.  556.110  Carbomycin.

    (a) [Reserved]
    (b) Tolerances. The tolerance for carbomycin is:
    (1) Chickens. Edible tissues (excluding eggs): Zero.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  520.1660a of this chapter.

Sec.  556.113  Ceftiofur.

    (a) Acceptable daily intake and acute reference dose--(1)
Acceptable daily intake (ADI). The ADI for total residue of ceftiofur
is 30 [mu]g/kg of body weight per day.
    (2) Acute reference dose (ARfD). The ARfD for total residue of
ceftiofur is 0.830 mg/kg of body weight.
    (b) Tolerances. The tolerances for desfuroylceftiofur (marker
residue) are:
    (1) Cattle. (i) Kidney (target tissue): 0.4 ppm.
    (ii) Liver: 2 ppm.
    (iii) Muscle: 1 ppm.
    (iv) Milk: 0.1 ppm.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): Not
required.
    (3) Goats. (i) Kidney (target tissue): 8 ppm.
    (ii) Liver: 2 ppm.
    (iii) Muscle: 1 ppm.
    (iv) Milk: 0.1 ppm.
    (4) Sheep. Edible tissues (excluding milk): Not required.
    (5) Swine. (i) Kidney (target tissue): 0.25 ppm.
    (ii) Liver: 3 ppm.
    (iii) Muscle: 2 ppm.
    (c) Related conditions of use. See Sec. Sec.  522.313a, 522.313b,
522.313c, and 526.313 of this chapter.

Sec.  556.115  Cephapirin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for cephapirin are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: 0.02 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  526.363 and 526.365
of this chapter.

Sec.  556.118  Chloramine-T.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
chloramine-T is 5 [micro]g/kg of body weight per day.
    (b) Tolerances. The tolerance for para-toluenesulfonamide (marker
residue) is:
    (1) Fish. Muscle/skin (target tissue): 0.9 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  529.382 of this chapter.

Sec.  556.120  Chlorhexidine.

    (a) [Reserved]
    (b) Tolerances. The tolerance for chlorhexidine is:
    (1) Cattle. Edible tissues (excluding milk): Zero.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  529.400 of this chapter.

Sec.  556.150  Chlortetracycline.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
tetracyclines including chlortetracycline, oxytetracycline, and
tetracycline is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for the sum of tetracycline residues
are:
    (1) Cattle. (i) Liver: 6 ppm.
    (ii) Kidney and fat: 12 ppm.
    (iii) Muscle: 2 ppm.
    (2) Chickens, turkeys, and ducks. (i) Liver: 6 ppm.
    (ii) Kidney and fat: 12 ppm.
    (iii) Muscle: 2 ppm.
    (iv) Eggs: 0.4 ppm for chlortetracycline only.
    (3) Sheep. (i) Liver: 6 ppm.
    (ii) Kidney and fat: 12 ppm.
    (iii) Muscle: 2 ppm.
    (4) Swine. (i) Liver: 6 ppm.
    (ii) Kidney and fat: 12 ppm.
    (iii) Muscle: 2 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.441, 520.443,
520.445, 558.128, and 558.140 of this chapter.

Sec.  556.160  Clopidol.

    (a) [Reserved]
    (b) Tolerances. The tolerances for clopidol are:
    (1) Chickens and turkeys. (i) Liver and kidney: 15 ppm.
    (ii) Muscle: 5 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.175 of this chapter.

Sec.  556.163  Clorsulon.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
clorsulon is 8 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for clorsulon (marker residue) are:
    (1) Cattle. (i) Kidney (target tissue): 1.0 ppm.
    (ii) Muscle: 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.462 and 522.1193
of this chapter.

Sec.  556.165  Cloxacillin.

    (a) [Reserved]
    (b) Tolerances. The tolerance for cloxacillin is:
    (1) Cattle. Edible tissues: 0.01 ppm.

    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  526.464a, 526.464b,
and 526.464c of this chapter.

Sec.  556.167  Colistimethate.

    (a) [Reserved]
    (b) Tolerances. The tolerance for colistimethate is:
    (1) Chickens. Edible tissues (excluding eggs): Not required.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.468 of this chapter.

Sec.  556.168  Coumaphos.

    (a) [Reserved]
    (b) Tolerances. The tolerances for coumaphos (measured as coumaphos
and its oxygen analog, O,O-diethyl O-3-chloro-4-methyl-2-oxo-2 H-1-
benzopyran-7-yl phosphate) are:
    (1) Cattle. (i) Edible tissues (excluding milk): 1 ppm.
    (ii) Milk fat: 0.5 ppm.
    (2) Chickens. (i) Edible tissues (excluding eggs): 1 ppm.
    (ii) Eggs: 0.1 ppm.
    (c) Related conditions of use. See Sec.  558.185 of this chapter.

Sec.  556.169  Danofloxacin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
danofloxacin is 2.4 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for danofloxacin (marker residue)
are:
    (1) Cattle. (i) Liver (target tissue): 0.2 ppm.
    (ii) Muscle: 0.2 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.522 of this chapter.

Sec.  556.170  Decoquinate.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
decoquinate is 75 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for decoquinate are:
    (1) Cattle. (i) Muscle: 1 ppm.
    (ii) Other edible tissues (excluding milk): 2 ppm.
    (2) Chickens. (i) Muscle: 1 ppm.
    (ii) Other edible tissues (excluding eggs): 2 ppm.
    (3) Goats. (i) Muscle: 1 ppm.
    (ii) Other edible tissues (excluding milk): 2 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.543 and 558.195
of this chapter.

Sec.  556.180  Dichlorvos.

    (a) [Reserved]
    (b) Tolerances. The tolerance for dichlorvos is:
    (1) Swine. Edible tissues: 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.596 and 558.205
of this chapter.

Sec.  556.185  Diclazuril.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
diclazuril is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for diclazuril are:
    (1) Chickens and turkeys. (i) Liver: 3 ppm.
    (ii) Muscle: 0.5 ppm.
    (iii) Skin/fat: 1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.198 of this chapter.

Sec.  556.200  Dihydrostreptomycin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for dihydrostreptomycin are:
    (1) Cattle. (i) Kidney: 2.0 ppm.
    (ii) Other edible tissues (excluding milk): 0.5 ppm.
    (iii) Milk: 0.125 ppm.
    (2) Swine. (i) Kidney: 2.0 ppm.
    (ii) Other edible tissues: 0.5 ppm.
    (c) Related conditions of use. See Sec. Sec.  522.650, 526.1696b,
and 526.1696c of this chapter.

Sec.  556.222  Doramectin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
doramectin is 0.75 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for doramectin (marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 100 ppb.
    (ii) Muscle: 30 ppb.
    (2) Swine. Liver (target tissue): 160 ppb.
    (c) Related conditions of use. See Sec. Sec.  522.770 and 524.770
of this chapter.

Sec.  556.224  Efrotomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
efrotomycin is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for efrotomycin is:
    (1) Swine. Edible tissues: Not required.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.235 of this chapter.

Sec.  556.226  Enrofloxacin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
enrofloxacin is 3 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for enrofloxacin are:
    (1) Cattle. Liver (target tissue): 0.1 ppm desethylene
ciprofloxacin (marker residue).
    (2) Swine. Liver (target tissue): 0.5 ppm enrofloxacin (marker
residue).
    (c) Related conditions of use. See Sec.  522.812 of this chapter.

Sec.  556.227  Eprinomectin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
eprinomectin is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for eprinomectin B1a
(marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 1.5 ppm.
    (ii) Muscle: 100 ppb.
    (iii) Milk: 12 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  522.814 and 524.814
of this chapter.

Sec.  556.230  Erythromycin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for erythromycin are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: Zero.
    (2) Chickens and turkeys. (i) Edible tissues (excluding eggs):
0.125 ppm.
    (ii) Eggs: 0.025 ppm.
    (3) Swine. Edible tissues: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.823, 522.820,
526.820, and 558.248 of this chapter.

Sec.  556.240  Estradiol and related esters.

    (a) [Reserved]
    (b) Residues. Residues of estradiol are not permitted in excess of
the following increments above the concentrations of estradiol
naturally present in untreated animals:
    (1) Cattle. (i) Muscle: 120 ppt.
    (ii) Fat: 480 ppt.
    (iii) Kidney: 360 ppt.
    (iv) Liver: 240 ppt.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  522.840, 522.842,
522.850, 522.1940, 522.2477, and 522.2478 of this chapter.

Sec.  556.260  Ethopabate.

    (a) [Reserved]
    (b) Tolerances. The tolerances for ethopabate, measured as
metaphenetidine, are:
    (1) Chickens. (i) Liver: 1.5 ppm.
    (ii) Kidney: 1.5 ppm.
    (iii) Muscle: 0.5 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.58 of this chapter.

Sec.  556.273  Famphur.

    (a) [Reserved]
    (b) Tolerances. The tolerance for famphur including its oxygen
analog is:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.1242g, 524.900,
and 558.254 of this chapter.

Sec.  556.275  Fenbendazole.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
fenbendazole is 40 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for fenbendazole are:

    (1) Cattle. (i) Liver (target tissue): 0.8 ppm fenbendazole (marker
residue).
    (ii) Muscle: 0.4 ppm fenbendazole.
    (iii) Milk: 0.6 ppm fenbendazole sulfoxide.
    (2) Chickens. (i) Liver (target tissue): 5.2 ppm fenbendazole
sulfone (marker residue).
    (ii) Eggs: 1.8 ppm fenbendazole sulfone (marker residue).
    (3) Goats. (i) Liver (target tissue): 0.8 ppm fenbendazole (marker
residue).
    (ii) Muscle: 0.4 ppm fenbendazole.
    (4) Swine. (i) Liver (target tissue): 3.2 ppm fenbendazole (marker
residue).
    (ii) Muscle: 2 ppm fenbendazole.
    (5) Turkeys. (i) Liver (target tissue): 6 ppm fenbendazole sulfone
(marker residue).
    (ii) Muscle: 2 ppm fenbendazole sulfone.
    (c) Related conditions of use. See Sec. Sec.  520.905a, 520.905c,
520.905d, 520.905e, and 558.258 of this chapter.

Sec.  556.277  Fenprostalene.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
fenprostalene is 0.08 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for fenprostalene are:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) Swine. Edible tissues: Not required.
    (c) Related conditions of use. See Sec.  522.914 of this chapter.

Sec.  556.280  Fenthion.

    (a) [Reserved]
    (b) Tolerances. The tolerance for fenthion is:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  524.920 of this chapter.

Sec.  556.283  Florfenicol.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
florfenicol is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for florfenicol amine (marker
residue) are:
    (1) Cattle. (i) Liver (target tissue): 3.7 ppm.
    (ii) Muscle: 0.3 ppm.
    (2) Swine. (i) Liver (target tissue): 2.5 ppm.
    (ii) Muscle: 0.2 ppm.
    (3) Catfish. Muscle (target tissue): 1 ppm.
    (4) Freshwater-reared warmwater finfish (other than catfish) and
salmonids. Muscle/skin (target tissue): 1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.955, 522.955,
522.956, and 558.261 of this chapter.

Sec.  556.286  Flunixin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
flunixin is 0.72 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for flunixin are:
    (1) Cattle. (i) Liver (target tissue): 125 ppb flunixin free acid
(marker residue).
    (ii) Muscle: 25 ppb flunixin free acid.
    (iii) Milk: 2 ppb 5-hydroxy flunixin (marker residue).
    (2) Swine. (i) Liver (target tissue): 30 ppb flunixin free acid
(marker residue).
    (ii) Muscle: 25 ppb flunixin free acid.
    (c) Related conditions of use. See Sec. Sec.  522.956, 522.970,
522.1664, and 524.970 of this chapter.

Sec.  556.292  Gamithromycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
gamithromycin is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for gamithromycin (marker residue)
are:
    (1) Cattle. (i) Liver (target tissue): 500 ppb.
    (ii) Muscle: 150 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.1014 of this chapter.

Sec.  556.300  Gentamicin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
gentamicin is 60 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for gentamicin are:
    (1) Chickens and turkeys. Edible tissues (excluding eggs): 0.1 ppm.
    (2) Swine. (i) Liver: 0.3 ppm.
    (ii) Kidney (target tissue): 0.4 ppm gentamicin (marker residue).
    (iii) Fat: 0.4 ppm.
    (iv) Muscle: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  522.1044a, 520.1044b,
520.1044c, and 524.1044e of this chapter.

Sec.  556.304  Gonadotropin.

    (a) Acceptable daily intake (ADI). The ADI for residues of total
gonadotropins (human chorionic gonadotropin and pregnant mare serum
gonadotropin) is 42.25 International Units per kilogram of body weight
per day.
    (b) Tolerances. The tolerances for gonadotropin are:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) Fish. Edible tissues: Not required.
    (3) Swine. Edible tissues: Not required.
    (c) Related conditions of use. See Sec. Sec.  522.1077, 522.1079,
and 522.1081 of this chapter.

Sec.  556.308  Halofuginone.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
halofuginone hydrobromide is 0.7 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for halofuginone (marker residue)
are:
    (1) Chickens. Liver (target tissue): 0.16 ppm.
    (2) Turkeys. Liver (target tissue): 0.13 ppm.
    (c) Related conditions of use. See Sec.  558.265 of this chapter.

Sec.  556.310  Haloxon.

    (a) [Reserved]
    (b) Tolerances. The tolerance for haloxon is:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.1120a and
520.1120b of this chapter.

Sec.  556.330  Hygromycin B.

    (a) [Reserved]
    (b) Tolerances. The tolerances for hygromycin B are:
    (1) Chickens. Edible tissues: Zero.
    (2) Swine. Edible tissues: Zero.
    (c) Related conditions of use. See Sec.  558.274 of this chapter.

Sec.  556.344  Ivermectin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
ivermectin is 1 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for 22,23-dihydroavermectin
B1a (marker residue) are:
    (1) American bison. Liver (target tissue): 15 ppb.
    (2) Cattle. (i) Liver (target tissue): 100 ppb.
    (ii) Muscle: 10 ppb.
    (3) Reindeer. Liver (target tissue): 15 ppb.
    (4) Sheep. Liver (target tissue): 30 ppb.
    (5) Swine. (i) Liver (target tissue): 20 ppb.
    (ii) Muscle: 20 ppb.
    (c) Related conditions of use. See Sec. Sec.  520.1192, 520.1195,
520.1197, 522.1192, 522.1193, 524.1193, and 558.300 of this chapter.

Sec.  556.346  Laidlomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
laidlomycin is 7.5 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for laidlomycin (marker residue) is:
    (1) Cattle. Liver (target tissue): 0.2 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.305 of this chapter.

Sec.  556.347  Lasalocid.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
lasalocid is 10 [mu]g/kg of body weight per day.

    (b) Tolerances. The tolerances for lasalocid (marker residue) are:
    (1) Cattle. Liver (target tissue): 0.7 ppm.
    (2) Chickens. (i) Skin with adhering fat (target tissue): 1.2 ppm.
    (ii) Liver: 0.4 ppm.
    (3) Rabbits. Liver (target tissue): 0.7 ppm.
    (4) Sheep. Liver (target tissue): 1.0 ppm.
    (5) Turkeys. (i) Liver (target tissue): 0.4 ppm.
    (ii) Skin with adhering fat: 0.4 ppm.
    (c) Related conditions of use. See Sec.  558.311 of this chapter.

Sec.  556.350  Levamisole.

    (a) [Reserved]
    (b) Tolerances. The tolerances for levamisole are:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) Sheep. Edible tissues (excluding milk): 0.1 ppm.
    (3) Swine. Edible tissues: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.1242a, 520.1242b,
520.1242d, 520.1242e, 520.1242f, 520.1242g, 522.1242, and 524.1240 of
this chapter.

Sec.  556.360  Lincomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
lincomycin is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for lincomycin are:
    (1) Chickens. Edible tissues (excluding eggs): Not required.
    (2) Swine. (i) Liver: 0.6 ppm.
    (ii) Muscle: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.1263c, 522.1260,
and 558.325 of this chapter.

Sec.  556.370  Lubabegron.

    (a) Acceptable daily intake (ADI). The ADI for total residues of
lubabegron is 3 micrograms per kilogram of body weight per day.
    (b) Tolerances. The tolerance for lubabegron (marker residue) is:
    (1) Cattle. Liver (target tissue): 10 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.330 of this chapter.

Sec.  556.375  Maduramicin.

    (a) [Reserved]
    (b) Tolerances. The tolerance for maduramicin (marker residue) is:
    (1) Chickens. Fat (target tissue): 0.38 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.340 of this chapter.

Sec.  556.380  Melengestrol.

    (a) [Reserved]
    (b) Tolerances. The tolerance for melengestrol is:
    (1) Cattle. Fat: 25 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.342 of this chapter.

Sec.  556.410  Metoserpate.

    (a) [Reserved]
    (b) Tolerances. The tolerance for metoserpate is:
    (1) Chickens. Edible tissues (excluding eggs): 0.02 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  520.1422 of this chapter.

Sec.  556.420  Monensin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
monensin is 12.5 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for monensin are:
    (1) Cattle. (i) Liver: 0.10 ppm.
    (ii) Muscle, kidney, and fat: 0.05 ppm.
    (iii) Milk: Not required.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): Not
required.
    (3) Goats. Edible tissues (excluding milk): 0.05 ppm.
    (4) Quail. Edible tissues (excluding eggs): Not required.
    (c) Related conditions of use. See Sec.  558.355 of this chapter.

Sec.  556.425  Morantel.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
morantel tartrate is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for N-methyl-1,3-propanediamine
(marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 0.7 ppm.
    (ii) Milk: Not required.
    (2) Goats. (i) Liver (target tissue): 0.7 ppm.
    (ii) Milk: Not required.
    (c) Related conditions of use. See Sec. Sec.  520.1450a, 520.1450b,
520.1450c, and 558.360 of this chapter.

Sec.  556.426  Moxidectin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
moxidectin is 4 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for moxidectin (marker residue) are:
    (1) Cattle. (i) Fat (target tissue): 900 ppb.
    (ii) Liver: 200 ppb.
    (iii) Muscle: 50 ppb.
    (iv) Milk: 40 ppb.
    (2) Sheep. (i) Fat (target tissue): 900 ppb.
    (ii) Liver: 200 ppb.
    (iii) Muscle: 50 ppb.
    (c) Related conditions of use. See Sec. Sec.  520.1454, 522.1450,
and 524.1450 of this chapter.

Sec.  556.428  Narasin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
narasin is 5 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for narasin (marker residue) is:
    (1) Chickens. Abdominal fat (target tissue): 480 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  558.363 and 558.364
of this chapter.

Sec.  556.430  Neomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
neomycin is 6 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for neomycin are:
    (1) Cattle. (i) Kidney (target tissue): 7.2 ppm.
    (ii) Liver: 3.6 ppm.
    (iii) Muscle: 1.2 ppm.
    (iv) Fat: 7.2 ppm.
    (v) Milk: 0.15 ppm.
    (2) Sheep and goats. (i) Kidney (target tissue): 7.2 ppm.
    (ii) Liver: 3.6 ppm.
    (iii) Muscle: 1.2 ppm.
    (iv) Fat: 7.2 ppm.
    (v) Milk: 0.15 ppm.
    (3) Swine. (i) Kidney (target tissue): 7.2 ppm.
    (ii) Liver: 3.6 ppm.
    (iii) Muscle: 1.2 ppm.
    (iv) Fat: 7.2 ppm.
    (4) Turkeys. (i) Skin with adhering fat: 7.2 ppm.
    (ii) Liver: 3.6 ppm.
    (iii) Muscle: 1.2 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.1484, 524.1600b,
558.365, and 558.455 of this chapter.

Sec.  556.445  Nicarbazin.

    (a) Acceptable daily intake (ADI). The ADI for total residues of
nicarbazin (4,4'-dinitrocarbanilide and 2-hydroxy-4,6-
dimethylpyrimidine) is 200 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for 4,4'-dinitrocarbanilide (marker
residue) is:
    (1) Chickens. Liver (target tissue): 52 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  558.364 and 558.366
of this chapter.

Sec.  556.460  Novobiocin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for novobiocin are:
    (1) Cattle. (i) Edible tissues (excluding milk): 1 ppm.
    (ii) Milk: 0.1 ppm.
    (2) Chickens, turkeys, and ducks. Edible tissues (excluding eggs):
1 ppm.
    (c) Related conditions of use. See Sec. Sec.  526.1590, 526.1696d,
and 558.415 of this chapter.

Sec.  556.470  Nystatin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for nystatin are:
    (1) Cattle. Edible tissues (excluding milk): Zero.
    (2) Chickens and turkeys. Edible tissues: Zero.
    (c) Related conditions of use. See Sec. Sec.  524.1600b and 558.430
of this chapter.

Sec.  556.490  Ormetoprim.

    (a) [Reserved]
    (b) Tolerances. The tolerances for ormetoprim are:
    (1) Chickens, turkeys, ducks, and chukar partridges. Edible tissues
(excluding eggs): 0.1 ppm.
    (2) Salmonids and catfish. Edible tissues: 0.1 ppm.
    (c) Related conditions of use. See Sec.  558.575 of this chapter.

Sec.  556.495  Oxfendazole.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
oxfendazole is 7 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for fenbendazole (marker residue) is:
    (1) Cattle. Liver (target tissue): 0.8 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.1629 and 520.1630
of this chapter.

Sec.  556.500  Oxytetracycline.

    (a) Acceptable daily intake (ADI). The ADI for total tetracycline
residues (chlortetracycline, oxytetracycline, and tetracycline) is 25
[mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for the sum of tetracycline residues
are:
    (1) Cattle. (i) Muscle: 2 ppm.
    (ii) Liver: 6 ppm.
    (iii) Fat and kidney: 12 ppm.
    (iv) Milk: 0.3 ppm.
    (2) Chickens and turkeys. (i) Muscle: 2 ppm.
    (ii) Liver: 6 ppm.
    (iii) Fat and kidney: 12 ppm.
    (3) Finfish. Muscle (with adhering skin when edible): 2 ppm.
    (4) Lobster. Muscle: 2 ppm.
    (5) Swine and sheep. (i) Muscle: 2 ppm.
    (ii) Liver: 6 ppm.
    (iii) Fat and kidney: 12 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.1660a, 520.1660c,
520.1660d, 522.1660a, 522.1660b, 522.1662a, 522.1664, 529.1660,
558.450, and 558.455 of this chapter.

Sec.  556.510  Penicillin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for penicillin are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.05 ppm.
    (ii) Milk: Zero.
    (2) Chickens. Edible tissues: Zero.
    (3) Pheasants and quail. Edible tissues: Zero.
    (4) Sheep and swine. Edible tissues: Zero.
    (5) Turkeys. Edible tissues (excluding eggs): 0.01 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.1696b, 522.1696a,
522.1696b, 526.1696a, 526.1696b, 526.1696c, and 526.1696d of this
chapter.

Sec.  556.513  Piperazine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for piperazine are:
    (1) Chickens and turkeys. Edible tissues (excluding eggs): 0.1 ppm.
    (2) Swine. Edible tissues: 0.1 ppm.
    (c) Related conditions of use. See Sec.  520.1807 of this chapter.

Sec.  556.515  Pirlimycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
pirlimycin is 0.01 mg/kg of body weight per day.
    (b) Tolerances. The tolerances for pirlimycin (marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 0.5 ppm.
    (ii) Muscle: 0.3 ppm.
    (iii) Milk: 0.4 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  526.1810 of this chapter.

Sec.  556.517  Poloxalene.

    (a) [Reserved]
    (b) Tolerances. The tolerance for poloxalene is:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.1840, 558.464,
and 558.465 of this chapter.

Sec.  556.540  Progesterone.

    (a) [Reserved]
    (b) Residues. Residues of progesterone are not permitted in excess
of the following increments above the concentrations of progesterone
naturally present in untreated animals:
    (1) Cattle and sheep. (i) Muscle: 5 ppb.
    (ii) Liver: 15 ppb.
    (iii) Kidney: 30 ppb.
    (iv) Fat: 30 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  522.1940 and 529.1940
of this chapter.

Sec.  556.560  Pyrantel.

    (a) [Reserved]
    (b) Tolerances. The tolerances for pyrantel are:
    (1) Swine. (i) Liver and kidney: 10 ppm.
    (ii) Muscle: 1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.2045 and 558.485
of this chapter.

Sec.  556.570  Ractopamine.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
ractopamine hydrochloride is 1.25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for ractopamine (marker residue)
are:
    (1) Cattle. (i) Liver (target tissue): 0.09 ppm.
    (ii) Muscle: 0.03 ppm.
    (2) Swine. (i) Liver (target tissue): 0.15 ppm.
    (ii) Muscle: 0.05 ppm.
    (3) Turkeys. (i) Liver (target tissue): 0.45 ppm.
    (ii) Muscle: 0.1 ppm.
    (c) Related conditions of use. See Sec.  558.500 of this chapter.

Sec.  556.580  Robenidine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for robenidine are:
    (1) Chickens. (i) Skin and fat: 0.2 ppm.
    (ii) Other edible tissues (excluding eggs): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.515 of this chapter.

Sec.  556.592  Salinomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
salinomycin is 5 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for salinomycin are:
    (1) Chickens. Edible tissues (excluding eggs): Not required.
    (2) Quail. Edible tissues (excluding eggs): Not required.
    (c) Related conditions of use. See Sec.  558.550 of this chapter.

Sec.  556.597  Semduramicin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
semduramicin is 3 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for semduramicin are:
    (1) Chickens. (i) Liver: 400 ppb.
    (ii) Muscle: 130 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.555 of this chapter.

Sec.  556.600  Spectinomycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
spectinomycin is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for spectinomycin are:
    (1) Cattle. (i) Kidney (target tissue): 4 ppm spectinomycin (marker
residue).

    (ii) Muscle: 0.25 ppm.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): 0.1 ppm.
    (3) Swine. Edible tissues: Not required.
    (c) Related conditions of use. See Sec. Sec.  520.1265, 520.2123b,
520.2123c, 522.2120, and 522.2121 of this chapter.

Sec.  556.610  Streptomycin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for streptomycin are:
    (1) Cattle and swine. (i) Kidney: 2.0 ppm.
    (ii) Other edible tissues (excluding milk): 0.5 ppm.
    (2) Chickens. (i) Kidney: 2.0 ppm.
    (ii) Other edible tissues (excluding eggs): 0.5 ppm.
    (c) Related conditions of use. See Sec.  520.2158 of this chapter.

Sec.  556.620  Sulfabromomethazine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfabromomethazine are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: 0.01 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  520.2170 of this chapter.

Sec.  556.625  Sulfachloropyrazine.

    (a) [Reserved]
    (b) Tolerances. The tolerance for sulfachloropyrazine is:
    (1) Chickens. Edible tissues (excluding eggs): Zero.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  520.2184 of this chapter.

Sec.  556.630  Sulfachlorpyridazine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfachlorpyridazine are:
    (1) Cattle and swine. Edible tissues (excluding milk): 0.1 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.2200 and 522.2200
of this chapter.

Sec.  556.640  Sulfadimethoxine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfadimethoxine are:
    (1) Catfish and salmonids. Edible tissues: 0.1 ppm.
    (2) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: 0.01 ppm.
    (3) Chickens, turkeys, ducks, and chukar partridges. Edible tissues
(excluding eggs): 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2220a, 520.2220d,
520.2220e, 522.2220, and 558.575 of this chapter.

Sec.  556.650  Sulfaethoxypyridazine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfaethoxypyridazine are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: Zero.
    (2) Swine. Edible tissues: Zero.
    (c) Related conditions of use. See Sec. Sec.  520.2240a, 520.2240b,
and 522.2240 of this chapter.

Sec.  556.660  Sulfamerazine.

    (a) [Reserved]
    (b) Tolerances. The tolerance for sulfamerazine is:
    (1) Trout. Edible tissues: Zero.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  558.582 of this chapter.

Sec.  556.670  Sulfamethazine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfamethazine are:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): 0.1 ppm.
    (3) Swine. Edible tissues: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2260a, 520.2260b,
520.2260c, 520.2261a, 520.2261b, 522.2260, 558.140, and 558.630 of this
chapter.

Sec.  556.685  Sulfaquinoxaline.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfaquinoxaline are:
    (1) Cattle. Edible tissues (excluding milk): 0.1 ppm.
    (2) Chickens and turkeys. Edible tissues (excluding eggs): 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2325a, 520.2325b,
and 558.586 of this chapter.

Sec.  556.700  Sulfomyxin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for sulfomyxin are:
    (1) Chickens and turkeys. Edible tissues (excluding eggs): Zero.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.2340 of this chapter.

Sec.  556.710  Testosterone.

    (a) [Reserved]
    (b) Residues. Residues of testosterone are not permitted in excess
of the following increments above the concentrations of testosterone
naturally present in untreated animals:
    (1) Cattle. (i) Fat: 2.6 ppb.
    (ii) Kidney: 1.9 ppb.
    (iii) Liver: 1.3 ppb.
    (iv) Muscle: 0.64 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.842 of this chapter.

Sec.  556.720  Tetracycline.

    (a) Acceptable daily intake (ADI). The ADI for total tetracycline
residues (chlortetracycline, oxytetracycline, and tetracycline) is 25
[mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for the sum of tetracycline residues
are:
    (1) Cattle and sheep. (i) Kidney and fat: 12 ppm.
    (ii) Liver: 6 ppm.
    (iii) Muscle: 2 ppm.
    (2) Chickens and turkeys. (i) Kidney and fat: 12 ppm.
    (ii) Liver: 6 ppm.
    (iii) Muscle: 2 ppm.
    (3) Swine. (i) Kidney and fat: 12 ppm.
    (ii) Liver: 6 ppm.
    (iii) Muscle: 2 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2345c and
520.2345d of this chapter.

Sec.  556.730  Thiabendazole.

    (a) [Reserved]
    (b) Tolerances. The tolerances for thiabendazole are:
    (1) Cattle. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: 0.05 ppm.
    (2) Swine. Edible tissues: 0.1 ppm.
    (3) Sheep and goats. (i) Edible tissues (excluding milk): 0.1 ppm.
    (ii) Milk: 0.05 ppm.
    (4) Pheasants. Edible tissues (excluding eggs): 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2380a, 520.2380b,
520.2380c, and 558.600 of this chapter.

Sec.  556.732  Tiamulin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
tiamulin is 25 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for 8-alpha-hydroxymutilin (marker
residue) is:
    (1) Swine. Liver (target tissue): 0.6 ppm.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  520.2455 and 558.612
of this chapter.

Sec.  556.733  Tildipirosin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
tildipirosin is 10 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for tildipirosin (the marker residue)
is:
    (1) Cattle. (i) Liver (the target tissue): 10 ppm.
    (ii) [Reserved]
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.2460 of this chapter.

Sec.  556.735  Tilmicosin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
tilmicosin is 25 [mu]g/kg of body weight per day.

    (b) Tolerances. The tolerances for tilmicosin (marker residue) are:
    (1) Cattle. (i) Liver (target tissue): 1.2 ppm.
    (ii) Muscle: 0.1 ppm.
    (2) Sheep. (i) Liver (target tissue): 1.2 ppm.
    (ii) Muscle: 0.1 ppm.
    (3) Swine. (i) Liver (target tissue): 7.5 ppm.
    (ii) Muscle: 0.1 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2471, 522.2471,
and 558.618 of this chapter.

Sec.  556.739  Trenbolone.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
trenbolone is 0.4 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerance for trenbolone is:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) [Reserved]
    (c) Related conditions of use. See Sec. Sec.  522.2476, 522.2477,
and 522.2478 of this chapter.

Sec.  556.741  Tripelennamine.

    (a) [Reserved]
    (b) Tolerances. The tolerances for tripelennamine are:
    (1) Cattle. (i) Edible tissues (excluding milk): 200 ppb.
    (ii) Milk: 20 ppb.
    (2) [Reserved]
    (c) Related conditions of use. See Sec.  522.2615 of this chapter.

Sec.  556.745  Tulathromycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
tulathromycin is 15 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for CP-60,300 (marker residue) are:
    (1) Cattle. Liver (target tissue): 5.5 ppm.
    (2) Swine. Kidney (target tissue): 15 ppm.
    (c) Related conditions of use. See Sec.  522.2630 of this chapter.

Sec.  556.746  Tylosin.

    (a) [Reserved]
    (b) Tolerances. The tolerances for tylosin are:
    (1) Cattle. (i) Liver, kidney, fat, and muscle: 0.2 ppm.
    (ii) Milk: 0.05 ppm.
    (2) Chickens and turkeys. (i) Liver, kidney, fat, and muscle: 0.2
ppm.
    (ii) Eggs: 0.2 ppm.
    (3) Swine. Liver, kidney, fat, and muscle: 0.2 ppm.
    (c) Related conditions of use. See Sec. Sec.  520.2640, 522.2640,
558.625, and 558.630 of this chapter.

Sec.  556.748  Tylvalosin.

    (a) Acceptable daily intake (ADI). The ADI for total residues of
tylvalosin is 47.7 [mu]g/kg of body weight per day.
    (b) Tolerances. A tolerance for tylvalosin in edible tissues of
swine is not required.
    (c) Related conditions of use. See Sec. Sec.  520.2645 and 558.633
of this chapter.

Sec.  556.750  Virginiamycin.

    (a) Acceptable daily intake (ADI). The ADI for total residue of
virginiamycin is 250 [mu]g/kg of body weight per day.
    (b) Tolerances. The tolerances for virginiamycin are:
    (1) Cattle. Edible tissues (excluding milk): Not required.
    (2) Chickens. Edible tissues (excluding eggs): Not required.
    (3) Swine. (i) Kidney, skin, and fat: 0.4 ppm.
    (ii) Liver: 0.3 ppm.
    (iii) Muscle: 0.1 ppm.
    (4) Turkeys. Edible tissues (excluding eggs): Not required.
    (c) Related conditions of use. See Sec.  558.635 of this chapter.

Sec.  556.760  Zeranol.

    (a) Acceptable daily intake (ADI). The ADI for total residue of