AGENCY:

Food and Drug Administration, HHS.

ACTION:

Final rule; technical amendments.

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, 240-402-0825, email: dong.yan@fda.hhs.gov.

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 § 556.3 (21 CFR 556.3):

○ Acceptable daily intake;

○ Acute reference dose;

○ Edible tissues;

○ Marker residue;

○ Not required;

○ Residue;

○ Target tissue;

○ Tolerance;

○ Total residue;

○ μg/kg; and

○ 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

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 § 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 (μg) 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 (μg) 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 (μg) 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 § 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 § 556.3 and used in proposed § 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 § 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 § 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 § 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 § 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 (§ 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 § 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 § 556.5 General Considerations and is finalizing as proposed. In proposed § 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 § 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-à-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 § 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 × 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.

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.

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

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.

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

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.

2. Amend § 500.82, in paragraph (b), by alphabetically adding a definition for “No residue” to read as follows:

PART 520—ORAL DOSAGE FORM NEW ANIMAL DRUGS

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

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

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

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

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

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

PART 522—IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PART 524—OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS

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

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

22. In § 524.770, in paragraph (c), remove “§ 556.225” and in its place add “§ 556.222”.

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

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

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

PART 526—INTRAMAMMARY DOSAGE FORM NEW ANIMAL DRUGS

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

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

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

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

PART 529—CERTAIN OTHER DOSAGE FORM NEW ANIMAL DRUGS

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

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

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

31. Revise part 556 to read as follows:

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

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

Subpart A—General Provisions

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

PART 558—NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS

32. The authority citation for part 558 continues to read as follows:

Authority: 21 U.S.C. 354, 360b, 360ccc, 360ccc-1, 371.

33. In § 558.68, in paragraph (c), remove “556.68” and in its place add “556.60”.

34. In § 558.95, add paragraph (c) to read as follows:

35. In § 558.185, revise paragraph (c) to read as follows:

36. In § 558.235, revise paragraph (a), redesignate paragraph (b) as paragraph (d), and add new paragraphs (b) and (c) to read as follows:

37. In § 558.464, revise paragraph (a), redesignate paragraph (b) as paragraph (d), and add new paragraphs (b) and (c) to read as follows:

38. In § 558.465, revise paragraph (a), redesignate paragraph (b) as paragraph (d), and add new paragraphs (b) and (c) to read as follows:

39. In § 558.625, in paragraph (c), remove “556.740” and in its place add “556.746”.

40. In § 558.630, in paragraph (c), remove “556.740” and in its place add “556.746”.

Footnotes