
[Federal Register Volume 81, Number 209 (Friday, October 28, 2016)]
[Proposed Rules]
[Pages 74962-74966]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-26043]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 514 and 556

[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: Proposed rule; supplemental notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or we) is proposing to 
amend our 2012 document entitled ``New Animal Drugs; Updating 
Tolerances for Residues of New Animal Drugs in Food.'' The document 
proposed to revise the animal drug regulations regarding tolerances for 
residues of approved and conditionally approved new animal drugs in 
food by standardizing, simplifying, and clarifying the determination 
standards and codification style. We also proposed to add definitions 
for key terms. We are taking this action to more clearly explain our 
current thinking about certain provisions of the 2012 document based on 
comments from stakeholders, and to more accurately reflect the 
rationale FDA relied on in the past to approve certain new animal drugs 
without a tolerance. We are reopening the comment period only with 
respect to the specific issues identified in this supplemental proposed 
rule.

DATES: Submit either electronic or written comments on this proposed 
rule by December 27, 2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

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

Written/Paper Submission

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2012-N-1067 for this proposed rulemaking. Received comments will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at http://www.regulations.gov or at 
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Dong Yan, Center for Veterinary 
Medicine (HFV-151), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 240-402-0825, dong.yan@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

[[Page 74963]]

Table of Contents

Executive Summary
    Purpose and Coverage of the Supplemental Notice of Proposed 
Rulemaking
    Summary of the Major Provisions of the Supplemental Notice of 
Proposed Rulemaking
I. Background
    A. Introduction
    B. Comments to the 2012 Proposed Rule for Updating Tolerances 
for Residues of New Animal Drugs in Food
II. Proposed Revisions to Subpart A--General Provisions
    A. Analytical Method
    B. Proposed Revisions to Definitions (Proposed Sec.  556.3)
    C. Proposed Revisions to General Considerations (Proposed Sec.  
556.5)
III. Proposed Conforming Change to 21 CFR Part 514
IV. Legal Authority
V. Economic Analysis of Impacts
VI. Paperwork Reduction Act of 1995
VII. Analysis of Environmental Impact
VIII. Federalism
IX. References

Executive Summary

Purpose and Coverage of the Supplemental Notice of Proposed Rulemaking

    We previously proposed to revise the animal drug regulations 
regarding tolerances for residues of approved and conditionally 
approved new animal drugs in food. In addition to proposing to 
standardize, simplify, and clarify the standards of determination and 
codification style for tolerances, we proposed a new definition 
section. In this document, we are proposing to revise or remove some of 
the previously proposed definitions, taking into account comments we 
received that have led us to clarify our current thinking, and to more 
accurately reflect the rationale FDA relied on in the past to approve 
certain new animal drugs without a tolerance.

Summary of the Major Provisions of the Supplemental Notice of Proposed 
Rulemaking

    The previously proposed rule (2012 proposed rule) did not 
adequately explain our current view that methods other than the 
``regulatory method'' derived from the 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. Therefore, we are removing the proposed definition for 
``regulatory method'' and are reserving the term for use with 
carcinogenic compounds. We are also removing the use of this term from 
proposed Sec.  556.5(d) (21 CFR 556.5(d)). We are proposing to revise 
portions of the 2012 proposed rule to better align the proposed rule 
with our current thinking and practice that an analytical method other 
than the practicable method(s) submitted by the sponsor as part of the 
new animal drug application 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. However, as described in section II.C, we are not 
proposing similar changes to the regulations concerning carcinogenic 
compounds because our current interpretation of the relevant provisions 
in the Federal Food, Drug, and Cosmetic Act (the FD&C Act) is that, 
unlike for non-carcinogenic compounds, the regulatory method prescribed 
in the approval of the new animal drug must be used for surveillance 
and enforcement purposes for carcinogenic compounds.
    We are also revising the proposed definitions for ``marker 
residue'', ``tolerance'', ``not required'', and ``zero''. We are 
removing the definition for ``acceptable single-dose intake'' and 
adding a definition for ``acute reference dose''.

                   Table of Abbreviations and Acronyms
------------------------------------------------------------------------
             Abbreviation/acronym                    What it means
------------------------------------------------------------------------
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.
JECFA........................................  World Health Organization/
                                                Food and Agriculture
                                                Organization of the
                                                United Nations Joint
                                                Expert Committee on Food
                                                Additives.
VICH.........................................  International Cooperation
                                                on Harmonisation of
                                                Technical Requirements
                                                for Registration of
                                                Veterinary Medicinal
                                                Products.
------------------------------------------------------------------------

I. Background

A. Introduction

    In the Federal Register of December 5, 2012 (77 FR 72254), we 
issued a document to revise part 556 (21 CFR 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. Some of the terms had been used previously in part 556, but 
never defined, and some terminology that had been used was outdated or 
resulted in confusion to users of the part. We proposed a general 
considerations section (proposed Sec.  556.5) to provide additional 
information and clarification for the tolerances listed in proposed 
subpart B. We are issuing this supplemental notice of proposed 
rulemaking to revise the proposed changes to part 556 to align with our 
current thinking.

B. Comments to the 2012 Proposed Rule for Updating Tolerances for 
Residues of New Animal Drugs in Food

    We received several stakeholder comments to the proposed rule 
including a comment that 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 proposal appears to be the 
method(s) used to collect data to support the setting of the tolerances 
preapproval. The comment also asks if the proposal implies that 
tolerances may be established using

[[Page 74964]]

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.
    We realize that the term ``regulatory method'' proposed in Sec.  
556.3 and used in proposed Sec.  556.5(d) has caused some confusion. As 
a result of the comments, we are taking this opportunity to better 
explain our current thinking about analytical methods used to determine 
residue levels in tissues for new animal drugs intended for use in 
food-producing animals.

II. Proposed Revisions to Subpart A--General Provisions

A. Analytical Method

    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. Such an analytical method would need to 
have 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. However, as described in section II.C, for carcinogenic 
compounds, the regulatory method prescribed in the approval of the new 
animal drug must be used for surveillance and enforcement purposes for 
carcinogenic compounds (see 21 CFR part 500, subpart E).
    FDA establishes tolerances using the practicable method submitted 
by a sponsor as part of the new animal drug application as required by 
section 512(b)(1)(G) of the FD&C Act (21 U.S.C. 360b(b)(1)(G)). The 
practicable method has to meet certain performance criteria, including 
evaluation of accuracy, precision, and sensitivity. We use the 
practicable method submitted by the sponsor as part of the new animal 
drug application 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, and make these use 
restrictions part of the conditions of approval. These conditions of 
use are designed to ensure that the proposed use of the drug will be 
safe Sec.  514.1(b)(7) (21 CFR 514.1(b)(7)). In the past, the 
practicable method was often used for determining the quantity of 
residue in edible tissue when monitoring the food supply. However, 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 (i.e., methods that 
analyze for a number of different drug residues at the same time). As a 
result, we are clarifying that an analytical method other than the 
practicable method can be used for surveillance and enforcement 
purposes for non-carcinogenic compounds, provided it meets the same 
performance criteria as the practicable method to determine the 
quantity of the relevant drug residues. Therefore, we are proposing to 
revise some of the definitions in proposed Sec.  556.3 of the 2012 
proposed rule as well as revise some of the language under ``General 
Considerations'' in proposed Sec.  556.5, to more accurately reflect 
our current thinking.

B. Proposed Revisions to Definitions (Proposed Sec.  556.3)

    In the 2012 proposed rule, we included a section of definitions 
(proposed Sec.  556.3). We propose to revise four of the definitions, 
remove two definitions, and add a new definition in proposed Sec.  
556.3.
    In the definition of ``marker residue'', we propose to delete 
``selected for assay by the regulatory method'' because we are 
reserving the term ``regulatory method'' for use with carcinogenic 
compounds (see part 500, subpart E). Also, we propose to delete the 
explanatory text that follows the first sentence of the definition 
because an explanation of how the tolerance is used is not needed in 
this definition. In addition, we are removing the term ``target 
tissue'' in the definition and replacing it with ``an edible tissue''.
    In the definition of ``not required'', we propose to more 
accurately reflect the rationale FDA relied on in the past to approve 
certain new animal drugs without a tolerance. Currently, our general 
practice is to establish a tolerance for all new animal drugs we 
approve.
    In the definition of ``tolerance'', we propose to delete the 
explanatory text that follows the first sentence of the definition 
because an explanation of how the tolerance is used is not needed in 
this definition.
    In the definition of ``zero'', we propose to delete ``when using a 
method of detection prescribed or approved by FDA'' because, as 
discussed previously, an analytical method other than the practicable 
method can be used for surveillance and enforcement purposes for non-
carcinogenic compounds. The additional proposed revisions to this 
definition are intended to clarify the meaning of the term ``zero'' as 
used in part 556 so that ``zero'' means any residues detected in the 
tissue renders it unsafe.
    We propose to remove the definition of ``acceptable single-dose 
intake (ASDI)''. See discussion for ``acute reference dose (ARfD)'' 
further in this section for the explanation.
    We propose to remove the definition of ``regulatory method'' 
because we are reserving the term ``regulatory method'' for use with 
carcinogenic compounds, consistent with our current interpretation of 
the FD&C Act (see part 500, subpart E).
    We propose to add the definition of ``acute reference dose (ARfD)'' 
to mean ``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.'' 
ARfD would be used in place of ASDI wherever this term is currently 
used in the tolerances listed in subpart B of part 556.
    In the 2012 proposed rule, we explained that sometimes the concept 
of an ASDI was used to calculate tolerances. We proposed to define the 
ASDI as ``the amount of total residue that may safely be consumed in a 
single meal. The ASDI may be used to derive the tolerance for residue 
of a drug at the injection site where the drug is administered 
according to the label.'' The definition of the ASDI was based on the 
U.S. Environmental Protection Agency definition of ARfD and chosen, in 
part, to provide additional clarity for the veterinary drug health 
based guidance value. Since that time, the use of the term ARfD has 
been more broadly applied by scientific and regulatory authorities, as 
further discussed in this section.
    The United States is an active member of the Codex Alimentarius and 
the Codex Committee for Residues of Veterinary Drugs in Food, which 
rely on the World Health Organization/Food and Agriculture Organization 
of the United Nations Joint Expert Committee on Food Additives (JECFA) 
for scientific advice. The JECFA uses the guidance Environmental Health 
Criteria (EHC) 240, Principles and Methods for the Risk Assessment of 
Chemicals in Food in its evaluations (Ref. 1). This guidance defines 
and discusses the term ARfD. More importantly for FDA, the

[[Page 74965]]

International Cooperation on Harmonisation of Technical Requirements 
for Registration of Veterinary Medicinal Products (VICH) has also 
developed guidelines that discuss the ARfD. The United States is a 
member of VICH and adopts finalized VICH guidelines for technical 
requirements for new animal drug approvals in the United States. On 
June 1, 2015 (80 FR 31041), we announced a draft guidance (Guidance for 
Industry #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)'', in which the term ``acute 
reference dose (ARfD)'' is used to describe the same concept as the 
2012 proposed definition of ASDI (Ref. 2). There are no fundamental 
differences between the meaning of ASDI and ARfD.
    We consider it appropriate to propose using the VICH definition of 
ARfD to replace the 2012 proposed definition of ASDI. The ARfD may be 
used in the same manner as the ASDI, which is to derive the tolerance 
for residues of a drug at an injection site where the drug is 
administered according to the label, or to derive the tolerance for 
residues of a drug in other edible tissues as a result of concern for 
the acute toxicity of the residues of the veterinary drug.

C. Proposed Revisions to General Considerations (Proposed Sec.  556.5)

    We propose to revise proposed Sec.  556.5(d) to align with our 
current thinking. In addition, we propose to remove the term 
``regulatory method'' from this provision because we are reserving this 
term for use with carcinogenic compounds (part 500, subpart E).
    Although the proposed revisions would clarify that an analytical 
method other than the practicable method may be used for surveillance 
and enforcement purposes for residue levels of non-carcinogenic animal 
drugs, with regard to approved carcinogenic compounds, our current 
interpretation of the relevant provisions of the FD&C Act is that it 
requires that a regulatory method be prescribed for such a compound and 
used for surveillance and enforcement purposes. Under the Delaney 
Clause, section 512(d)(1)(I) of the FD&C Act, FDA cannot approve an 
application for a new animal drug if it is found to induce cancer when 
ingested by humans or animals. An exception to this provision, referred 
to as the DES (diethylstilbestrol) Proviso, allows for the approval of 
a carcinogenic compound if FDA finds that, under the approved 
conditions of use, the drug will not adversely affect treated animals 
and no residue of the drug will be found (by methods of examination 
prescribed or approved by the Secretary by regulations) (emphasis 
added) in any food for human consumption derived from the treated 
animals (see section 512(d)(1)(I)(i) and (ii) of the FD&C Act). FDA has 
issued regulations defining the operational definition of no residue 
and regulatory method for purposes of measuring carcinogenic compounds 
(21 CFR 500.82 and 500.88).

III. Proposed Conforming Change to 21 CFR Part 514

    We are proposing a conforming change to the language in the 
introductory text of Sec.  514.1(b)(7) by removing the term 
``regulatory'' in the last sentence to reflect the fact that we are 
reserving this term for use with carcinogenic compounds. (See 
discussion in section II.C.)

IV. Legal Authority

    Our authority for issuing this proposed rule is provided by 
sections 512(b)(1)(G) and (H), 512(d)(1)(F), 512(d)(2), 512(i), 
571(a)(2)(A), and 571(b)(1) of the FD&C Act (21 U.S.C. 360b(b)(1)(G) 
and (H), 360b(d)(1)(F), 360(d)(2), 360b(i), 360ccc(a)(2)(A), and 
360ccc(b)(1)). These provisions relate to the information new animal 
drug and conditional approval 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.

V. Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, 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). We 
believe that this proposed 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 proposed rule would not impose compliance costs 
on the current or future sponsors of any approved and conditionally 
approved new animal drugs, we proposed to certify that the proposed 
rule would 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 proposing ``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 $146 million, using the most current (2015) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

VI. Paperwork Reduction Act of 1995

    We tentatively conclude that this proposed 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.

VII. Analysis of Environmental Impact

    The Agency has 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.

VIII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the proposed 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 proposed 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.

IX. References

    The following references are on display in the Division of Dockets

[[Page 74966]]

Management (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 http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. International Programme on Chemical Safety, ``Environmental 
Health Criteria 240, Principals and Methods for the Risk Assessment 
of Chemicals in Food,'' 2009. (http://www.who.int/foodsafety/publications/chemical-food/en/). Accessed on February 11, 2016.
2. FDA, ``Draft 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), 
June 2015. Accessed on February 11, 2016.

List of Subjects

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 556

    Animal drugs, Foods.

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

PART 514--NEW ANIMAL DRUG APPLICATIONS

0
1. The authority citation for part 514 continues to read as follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 
360ccc, 371, 379e, 381.


Sec.  514.1  [Amended]

0
2. In Sec.  514.1(b)(7) introductory text, remove the word 
``regulatory'' from the last sentence.

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

0
3. The authority citation for part 556, as proposed to be revised on 
December 5, 2012 (77 FR 72254), continues to read as follows:

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

0
4. Amend Sec.  556.3, as proposed to be added on December 5, 2012 (77 
FR 72254), as follows:
0
a. Remove the definition of ``Acceptable single-dose intake'';
0
b. Add, in alphabetical order, a definition for ``Acute reference 
dose'';
0
c. Revise the definitions for ``Marker residue'' and ``Not required'';
0
d. Remove the definition of ``Regulatory method''; and
0
e. Revise the definitions for ``Tolerance'' and ``Zero''.
    The revisions and additions read as follows:


Sec.  556.3  Definitions.

* * * * *
    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.
* * * * *
    Marker residue means the residue whose concentration is in a known 
relationship to the concentration of total residue in an edible tissue.
* * * * *
    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.
* * * * *
    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.
* * * * *
    Zero, in reference to tolerances in this part, means any residues 
detected in the tissue renders it unsafe.
0
5. Amend Sec.  556.5, as proposed to be added on December 5, 2012 (77 
FR 72254), by revising paragraph (d) to read as follows:


Sec.  556.5  General considerations.

* * * * *
    (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.

    Dated: October 21, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-26043 Filed 10-27-16; 8:45 am]
 BILLING CODE 4164-01-P


