76760 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

1See § 500.82(b) (defining ‘‘marker residue’’ as 

the residue whose concentration is in a known 

relationship to the concentration of the residue of 

carcinogenic concern in the last tissue to deplete to 

the Sm and defining ‘‘Sm’’ as the concentration of 

a residue of carcinogenic concern in a specific 

edible tissue corresponding to no significant 

increase in the risk of cancer to the human 

consumer). 

2Consistent with FDA regulations, CVM treats 

unidentified residues of a carcinogenic drug as 

carcinogenic. See § 500.82(b) (defining ‘‘residue of 

carcinogenic concern’’ as all compounds in the total 

residue of a demonstrated carcinogen excluding any 

compounds judged by FDA not to present a 

carcinogenic risk). 

a presiding officer will be assigned, and 

a written notice of the time and place at 

which the hearing will commence will 

be issued as soon as practicable. 

This notice is issued under section 

512 of the FD&C Act and under the 

authority delegated to the Deputy 

Commissioner for Policy, Legislation, 

and International Affairs, Office of 

Policy, Legislation, and International 

Affairs. 

V. Environmental Impact 

The Agency has determined under 21 

CFR 25.33(g) that this action is of a type 

that does not individually or 

cumulatively have a significant impact 

on the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

VI. References 

The following references are on 

display in 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. Although FDA 

verified the website addresses in this 

document, please note that websites are 

subject to change over time. 

1. FDA, Freedom of Information Summary, 

NADA 041–061, MECADOX 10 

(carbadox) Type A medicated article, 

supplemental approval January 30, 1998. 

Available at https://

animaldrugsatfda.fda.gov/adafda/app/ 

search/public/document/downloadFoi/ 

308. 

2. Evaluations of the Joint Food and 

Agriculture Organization of the United 

Nations/World Health Organization 

Expert Committee on Food Additives 

(JECFA). Carbadox. 2021. Available at: 

https://apps.who.int/food-additivescontaminants-jecfa-database/Home/ 

Chemical/2176. 

3. Memorandum to File entitled ‘‘CVM 

Response to Phibro Animal Health 

Corporation’s September 18, 2020 

Comments on CVM’s July 20, 2020 

Proposed Order to Revoke the Regulatory 

Method for Carbadox’’ (January 6, 2022). 

4. Memorandum to File entitled ‘‘CVM 

review of comments on the Zhang article 

that Phibro references in the document 

submitted to the Part 15 Hearing docket 

under cover letter dated June 9, 2022, 

and entitled, ‘Phibro Animal Health 

Corporation’s Reply to the January 6, 

2022 ‘CVM Response to Phibro Animal 

Health Corporation’s September 18, 2020 

Comments on CVM’s July 20, 2020 

Proposed Order to Revoke the Regulatory 

Method for Carbadox.’ ’ ’’ (October 30, 

2023). 

5. Phibro Animal Health Corp.; Carbadox in 

Medicated Swine Feed; Revocation of 

Approved Method (November 7, 2023). 

6. ‘‘Determination of Carbadox as 

Quinoxaline-2-carboxylic Residues in 

Swine Liver and Muscle Tissues after 

Drug Withdrawal.’’ Available at https:// 

www.fda.gov/media/136267/download. 

Dated: November 1, 2023. 

Kimberlee Trzeciak, 

Deputy Commissioner for Policy, Legislation, 

and International Affairs. 

[FR Doc. 2023–24547 Filed 11–6–23; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2020–N–0955] 

Phibro Animal Health Corp.; Carbadox 

in Medicated Swine Feed; Revocation 

of Approved Method 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing a final 

order to revoke the approved method for 

detecting residues of carbadox, a 

carcinogenic new animal drug used in 

swine feed. An approved method is 

required by the Federal Food, Drug, and 

Cosmetic Act (FD&C Act), as 

implemented by regulation, to show that 

no residue of carcinogenic concern from 

a new animal drug persists in any edible 

tissue or in any food derived from 

treated animals. The approved method 

measures quinoxaline-2-carboxylic acid 

(QCA) as a marker residue to detect the 

presence of any residue of carcinogenic 

concern. QCA is a metabolite of 

carbadox that FDA has judged does not 

present a carcinogenic risk. FDA is 

revoking the approved method for 

carbadox based on its determination 

that the method is inadequate to 

monitor the residue of carcinogenic 

concern in compliance with FDA’s 

operational definition of no residue 

because there is no established 

relationship between the concentration 

of QCA residues as measured by the 

approved method and the concentration 

of the residue of carcinogenic concern. 

DATES: This order is effective November 

7, 2023. 

FOR FURTHER INFORMATION CONTACT: 

Diane Heinz, Center for Veterinary 

Medicine (HFV–6), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855, 240–402–5692. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

On July 20, 2020, FDA’s Center for 

Veterinary Medicine (CVM), the Center 

within FDA that reviews and approves 

new animal drug applications and 

supplemental applications, proposed to 

revoke the approved method for 

carbadox (Ref. 1), which measures QCA 

as the marker residue 1 to determine 

whether residues of carcinogenic 

concern 2 of carbadox are present (85 FR 

43853, July 20, 2020). QCA is a 

metabolite of carbadox that FDA has 

judged does not present a carcinogenic 

risk. The proposal to revoke the 

approved method was based on FDA’s 

determination that the method does not 

adequately monitor the residue of 

carcinogenic concern in compliance 

with FDA’s operational definition of no 

residue (§ 500.82(b) (21 CFR 

500.82(b)(defining ‘‘no residue’’; 

§ 500.84(c)(3) (21 CFR 500.84(c)(3))). 

That is because the sponsor has not 

established the relationship between the 

concentration of the marker residue 

QCA and the concentration of the 

residue of carcinogenic concern. 

On March 10, 2022, FDA held a 

public hearing under 21 CFR part 15, 

entitled, ‘‘Scientific Data and 

Information Related to the Residue of 

Carcinogenic Concern for the New 

Animal Drug Carbadox’’ to gather 

additional data and information. When 

FDA announced the hearing (87 FR 

2093, January 13, 2022; https://

www.fda.gov/animal-veterinary/ 

workshops-conferences-meetings/part15-public-hearing-scientific-data-andinformation-related-residuecarcinogenic-concern-new), we 

requested public comments and 

presentations at the public hearing, 

particularly: (1) on data to inform our 

knowledge of the residue of 

carcinogenic concern not summarized 

in the FOI Summary for the 1998 

supplemental approvals, including 

additional data regarding the fraction of 

noncarcinogenic residues in the total 

radiolabeled residues of carbadox; (2) 

for any given concentration of a marker 

residue, the corresponding 


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3See § 500.82(b) (defining target tissue as the 

edible tissue selected to monitor for residues in the 

target animals, including, where appropriate, milk 

or eggs). 

4See supra note 1 (defining ‘‘marker residue’’). 

5As discussed above, the Delaney Clause 

prohibits the use of carcinogenic animal drugs 

unless the DES Proviso applies (see section 

512(d)(1)(I) of the FD&C Act). The DES Proviso 

requires that, among other things, no residue of 

such drug will be found (by methods of 

examination prescribed or approved by the 

Secretary of HHS by regulations) in any edible 

portion of such animals after slaughter or in any 

food yielded by or derived from the living animals. 

FDA’s SOM regulations establish the process by 

which a carcinogenic new animal drug may satisfy 

the DES Proviso. The SOM regulations were 

amended in 2002 to revise the operational 

definition of the term ‘‘no residue.’’ Previously, 

FDA determined there was ‘‘no residue’’ in edible 

Continued 

concentration of the residue of 

carcinogenic concern; (3) on additional 

information related to the adequacy of 

the current approved method to 

measure QCA as a marker residue for 

the residue of carcinogenic concern for 

the new animal drug carbadox not 

already contained in Docket No. FDA– 

2020–N–0955, ‘‘Phibro Animal Health 

Corp.; Carbadox in Medicated Swine 

Feed; Revocation of Approved Method’’; 

(4) on any method, other than the 

current approved method, that 

demonstrates ‘‘no residue’’ for the new 

animal drug carbadox in conformance 

with 21 CFR part 500, subpart E; and (5) 

on detailed information on the conduct 

and quality of studies providing data to 

support the points above, including 

information on the extraction process 

and the stability of residues being 

analyzed. 

In addition to presentations from 

CVM and from the sponsor of the 

carbadox approved applications, several 

other stakeholders gave presentations. 

FDA also opened a docket (Docket No. 

FDA–2021–N–1326) to receive 

additional stakeholder comment on the 

topics listed above. After reviewing the 

comments to this docket (FDA–2020–N– 

0955), and presentations and the 

comments received in the docket for the 

public hearing (Docket No. FDA–2021– 

N–1326), FDA is now finalizing the 

order revoking the approved method for 

detecting residues of carbadox. 

Elsewhere in this issue of the Federal 

Register, FDA is publishing a notice of 

opportunity for hearing (NOOH) 

proposing to withdraw approval of all 

new animal drug applications for use of 

carbadox based on the lack of an 

approved method for measuring the 

residue of carcinogenic concern. An 

approved method for measuring the 

residue of carcinogenic concern that 

complies with part 500, subpart E (21 

CFR part 500, subpart E) is required by 

section 512(d)(1)(I) of the FD&C Act (21 

U.S.C. 360b(d)(1)(I)). 

II. Background 

A. Regulation of Carcinogenic New 

Animal Drugs 

The Delaney Clause of the FD&C Act 

generally prohibits the approval of 

carcinogenic animal drugs unless the 

‘‘Diethylstilbestrol (DES) Proviso’’ 

applies. See section 512(d)(1)(I) of the 

FD&C Act. Under the DES Proviso 

exception, a carcinogenic new animal 

drug may be approved if, among other 

things, no residue of such drug will be 

found by methods of examination 

prescribed or approved by the Secretary 

of Health and Human Services (HHS) by 

regulations in any edible portion of such 

animals after slaughter or in any food 

yielded by or derived from the living 

animals. 

As part of a new animal drug 

application (NADA), the sponsor must 

include a description of practicable 

methods for determining the quantity, if 

any, of the new animal drug in or on 

food and any substance formed in or on 

food because of its use, and the 

proposed tolerance or withdrawal 

period or other use restrictions to ensure 

that the proposed use of this drug will 

be safe (§ 514.1(b)(7) (21 CFR 

514.1(b)(7))). Carcinogenic drugs, such 

as carbadox, must also meet the 

requirements in part 500, subpart E 

(§ 514.1(b)(7)(ii)). These regulations, 

known as the sensitivity of the method 

(SOM) regulations, set out the 

requirements to demonstrate that no 

residues of the drug will be found by an 

approved method in any edible tissues 

of or in any foods obtained from the 

animal, as required to comply with the 

DES Proviso. 

Specifically, the SOM regulations 

require FDA to determine if any animal 

drug or any of its metabolites is a 

carcinogen (§ 500.84(a)). For the drug 

and each metabolite that FDA decides 

should be regulated as a carcinogen, 

FDA calculates, based on submitted 

assays, the concentration of the test 

compound in the total diet of the test 

animal that corresponds to a maximum 

lifetime risk of cancer in the test animal 

of 1 in 1 million (§ 500.84(c)(1)). FDA 

designates the lowest concentration (i.e., 

the concentration of the most potent 

carcinogen) thus calculated as the So

(§ 500.84(c)(1)). The So corresponds to a 

concentration of residue of carcinogenic 

concern in the total human diet that 

represents no significant increase in the 

risk of cancer to people (§ 500.82(b)). 

Because FDA relies on the So from the 

most potent carcinogen, this approach 

ensures that use of the drug does not 

present a significant increase in the risk 

of cancer when considering all residues 

in edible tissues. 

Because the total human diet is not 

derived only from food-producing 

animals, the SOM regulations make 

adjustments for human food intake of 

edible tissues and determine the 

concentration of residue of carcinogenic 

concern in a specific edible tissue (such 

as muscle, liver, kidney, milk, or eggs) 

that corresponds to no significant 

increase in the risk of cancer to the 

human consumer. FDA assumes for 

purposes of these regulations that this 

value will correspond to the 

concentration of residues in a specific 

edible tissue that corresponds to a 

maximum lifetime risk of cancer in the 

test animals of 1 in 1 million. This value 

is designated as the Sm (§§ 500.82(b) and 

500.84(c)(1)). By limiting the 

concentration of residue of carcinogenic 

concern to a value at or below the Sm, 

consumers can eat a specific edible 

tissue every day for an entire lifetime 

with no significant increase in the risk 

of cancer. 

Based on data submitted by a sponsor, 

FDA selects a target tissue 3 and a 

marker residue 4 and designates the 

concentration of the marker residue that 

the method must be able to detect in the 

target tissue (§ 500.86(a) through (c) (21 

CFR 500.86(a) through (c))). This value, 

termed the Rm, is the concentration of a 

marker residue in the target tissue when 

the residue of carcinogenic concern is 

equal to Sm (500.82(b)). When the 

marker residue is at or below the Rm, the 

residue of carcinogenic concern in the 

human diet does not exceed So

(§ 500.86(c)). This regulation ensures 

that when the marker residue is no 

longer detectable, the residue of 

carcinogenic concern does not exceed 

Sm in any of the edible tissues 

(§§ 500.82(b) and 500.86(c)). For any 

given drug, there may be several 

different compounds to consider for use 

as a marker residue. The Rm would be 

different depending upon the 

compound selected as the marker 

residue. 

A sponsor must submit a method that 

is able to detect the marker residue at or 

below the Rm (§§ 500.88(b) (21 CFR 

500.88(b)) and 500.84(c)(2)). There may 

be multiple methods available to detect 

a particular marker residue; however, 

under the SOM regulations, a method 

must be able to confirm the identity of 

the marker residue in the target tissue at 

a minimum concentration 

corresponding to the Rm. The Limit of 

Detection (LOD) for the method must be 

less than or equal to the Rm

(§ 500.84(c)(2)). FDA will determine the 

LOD from the submitted analytical 

method validation data (§ 500.88(b)).5 If 


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tissues when the concentration of the marker 

residue was at or below Rm. However, in 1995, the 

Department of Justice (DOJ)’s Office of Legal 

Counsel determined that FDA’s interpretation was 

not legally supportable. Specifically, it opined that, 

if a method detected residue (even if the 

concentration of that residue fell below the Rm) the 

DES Proviso requirement for ‘‘no residue’’ was not 

satisfied. Accordingly, in 2002, FDA revised the 

definition of ‘‘no residue’’ to mean when the 

concentration of the marker residue is below the 

LOD of the method, meaning nondetectable by the 

method (67 FR 78174; see also DOJ, Mem. Op. for 

the Assistant Administrator & Gen. Counsel EPA & 

Gen. Counsel DHHS (October 13, 1995), https://

www.justice.gov/d9/olc/opinions/1995/10/31/opolc-v019-p0247_0.pdf). 

a method is not developed that can 

detect the marker residue at or below 

the Rm, the requirements of the SOM 

regulations are not satisfied, and FDA 

cannot approve the drug (see 21 U.S.C. 

360b(d)(1)(I); § 500.88). 

B. History of Carbadox Approvals 

Currently, there are three approved 

NADAs for use of carbadox in 

medicated swine feed, either alone or in 

combination with other approved new 

animal drugs. Carbadox, a quinoxaline 

derivative, is a synthetic antimicrobial 

used to manufacture medicated feeds 

that are administered ad libitum 

(available at all times) to swine. Phibro 

Animal Health Corp. (Phibro), 

GlenPointe Centre East, 3d Floor, 300 

Frank W. Burr Blvd., Suite 21, Teaneck, 

NJ 07666, is currently the sponsor of all 

three approved NADAs. 

1. NADA 041–061 

NADA 041–061, originally approved 

in 1972 (37 FR 20683, October 3, 1972), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article to 

manufacture single-ingredient Type C 

medicated swine feeds at the rate of 10 

to 25 grams per ton (g/ton) of feed for 

increased rate of weight gain and 

improved feed efficiency; and at 50 g/ 

ton of feed for control of swine 

dysentery (vibrionic dysentery, bloody 

scours, or hemorrhagic dysentery), 

control of bacterial swine enteritis 

(salmonellosis or necrotic enteritis 

caused by Salmonella choleraesuis), and 

for increased rate of weight gain and 

improved feed efficiency. 

In January 1998, CVM approved a 

supplemental application to NADA 

041–061, which included the approved 

method (Ref. 2). However, this method 

was not published in the Federal 

Register as required in § 500.88, and the 

method that had been published for the 

1972 approval was removed from the 

Code of Federal Regulations. 

Nevertheless, since the January 1998 

approval of the supplemental NADA, 

CVM and the sponsor have treated the 

method approved as part of the 1998 

supplemental application as the method 

of examination prescribed or approved 

by the Secretary of HHS by regulations 

for purposes of applying section 

512(d)(1)(I) of the FD&C Act, the 

Delaney Clause, to carbadox. 

In October 1998, CVM approved an 

additional supplemental NADA for 

NADA 041–061, changing the 

withdrawal period for carbadox 

medicated feeds from 70 days to 42 

days. This supplemental NADA was 

approved based on the previous 

approval of a tolerance of 30 parts per 

billion (ppb) for QCA as the marker 

residue and a residue depletion study 

using the approved method that showed 

residues of QCA in liver depleted below 

30 ppb by 42 days (Ref. 3). 

2. NADA 092–955 

NADA 092–955, originally approved 

in 1975 (40 FR 45164, October 1, 1975), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article 

with BANMINTH (pyrantel tartrate) 

Type A medicated article to 

manufacture two-way, combination 

drug Type C medicated swine feeds at 

50 g/ton of feed plus pyrantel tartrate at 

96 g/ton of feed for control of swine 

dysentery (vibrionic dysentery, bloody 

scours, or hemorrhagic dysentery), 

control of bacterial swine enteritis 

(salmonellosis or necrotic enteritis 

caused by S. choleraesuis), as an aid in 

the prevention of migration and 

establishment of large roundworm 

(Ascaris suum) infections, and as an aid 

in the prevention of establishment of 

nodular worm (Oesophagostomum) 

infections. The withdrawal period for 

the use of this drug combination is 70 

days (§ 558.115(d)(3)(ii) (21 CFR 

558.115(d)(3)(ii))). 

3. NADA 141–211 

NADA 141–211, originally approved 

in 2004 (69 FR 51173, August 18, 2004), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article 

with TERRAMYCIN 50, TERRAMYCIN 

100, or TERRAMYCIN 200 

(oxytetracycline) Type A medicated 

articles to manufacture two-way, 

combination drug Type C medicated 

swine feeds at 10 to 25 g/ton of feed 

plus oxytetracycline at levels in feed to 

deliver 10 mg carbadox per pound of 

body weight for treatment of bacterial 

enteritis caused by Escherichia coli and 

S. choleraesuis susceptible to 

oxytetracycline, for treatment of 

bacterial pneumonia caused by 

Pasteurella multocida susceptible to 

oxytetracycline, and for increased rate 

of weight gain and improved feed 

efficiency. The withdrawal period for 

the use of this animal drug combination 

is 42 days (§ 558.115(d)(4); 

§ 558.450(e)(3)(iii) (21 CFR 

558.450(e)(3)(iii)). 

C. Statutory Authority To Issue Order 

Under 5 U.S.C. 554(e) (section 5(d) of 

the Administrative Procedure Act 

(APA)), an agency, in its sound 

discretion, may issue a declaratory order 

to terminate a controversy or remove 

uncertainty. The APA defines ‘‘order’’ 

as the whole or a part of a final 

disposition, whether affirmative, 

negative, injunctive, or declaratory in 

form, of an agency in a matter other than 

rulemaking but including licensing (5 

U.S.C. 551(6)). The APA defines 

‘‘adjudication’’ as agency process for the 

formulation of an order (5 U.S.C. 

551(7)). FDA’s regulations, consistent 

with the APA, define ‘‘order’’ to mean 

the final Agency disposition, other than 

the issuance of a regulation, in a 

proceeding concerning any matter 

(§ 10.3(a) (21 CFR 10.3(a)). Our 

regulations also define ‘‘proceeding and 

administrative proceeding’’ to mean any 

undertaking to issue, amend, or revoke 

a regulation or order, or to take or not 

to take any other form of administrative 

action, under the laws administered by 

FDA (§ 10.3(a)). Moreover, our 

regulations establish that the 

Commissioner of Food and Drugs may 

initiate an administrative proceeding to 

issue, amend, or revoke an order 

(§ 10.25(b) (21 CFR 10.25(b)). 

On our own initiative, FDA is issuing 

a 5 U.S.C. 554(e) declaratory order to 

remove uncertainty regarding the 

approved method for carbadox that 

measures QCA as a marker residue. An 

order is the most appropriate procedure 

to revoke the approved method because 

there is no rule to amend. The approved 

method is not currently published in the 

Federal Register, contrary to § 500.88, 

and the method that had been published 

for the 1972 approval was removed from 

the Code of Federal Regulations in 1998 

and is no longer the approved method. 

The FD&C Act does not provide the 

procedure we must use to determine 

whether an approved method of 

examination that was never published 

in the Code of Federal Regulations 

satisfies the regulatory requirements of 

part 500, subpart E. Thus, we are 

choosing to issue a declaratory order to 

remove uncertainty. 

III. Discussion 

When CVM approved the 

supplemental NADA for carbadox in 

January 1998, it did not require the 

sponsor to provide data establishing a 

known relationship between the 

concentration of the marker residue 

(QCA) and the concentration of the 


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6Pfizer, Inc. was the sponsor for carbadox until 

2001. The current sponsor is Phibro. 

7These regulations require the sponsor to submit 

data that allows FDA to designate an Rm (the 

concentration of the marker residue in the target 

tissue at which the residue of carcinogenic concern 

in the diet of people represents no significant 

increase in the risk of cancer to people) based on 

a known relationship between the marker residue 

and the residue of carcinogenic concern. In 

addition, the sponsor must provide a method that 

can detect the marker residue at or below the Rm. 

Under § 500.86, the necessary steps to meet the 

operational definition of ‘‘no residue’’ for carbadox 

are: (1) measure the depletion of the residue of 

carcinogenic concern until its concentration is at or 

below the Sm (0.915 ppb) in liver; (2) measure the 

depletion of the marker residue until the 

concentration of the residue of carcinogenic 

concern is at or below the Sm; (3) use the 

information in (1) and (2) to establish an Rm; and, 

(4) according to the regulations as they existed in 

1998, develop a method that could detect the 

marker residue of the drug, as long as the marker 

residue would only be detected at or below the Rm

under the proposed conditions of use. According to 

the current regulations, step (4) requires the 

development of a method that complies with the 

operational definition of no residue (the method’s 

LOD is less than or equal to the Rm and the marker 

residue depletes to a concentration that cannot be 

detected by the method). 

residue of carcinogenic concern 

(§ 500.86). At that time, CVM did not 

believe that such information was 

necessary because of previous 

conclusions that it had made about the 

persistence of carcinogenic residue in 

the edible tissues of animals 

administered carbadox. CVM’s 

understanding, at that time, was that 

carcinogenic residues, including 

desoxycarbadox (DCBX), a known 

carcinogenic metabolite of carbadox, 

depleted quickly (within 72 hours) 

while QCA residues depleted more 

slowly. However, results from 

subsequent studies led CVM to 

reexamine the conclusions it made in 

1998 and conclude, based on data from 

these studies, that it is necessary to 

establish a known relationship between 

the marker residue and the residue of 

carcinogenic concern, as required by 

regulation. 

FDA is revoking the approved method 

for carbadox that measures QCA as the 

marker residue because it is inadequate 

to monitor the residue of carcinogenic 

concern. The approved method cannot 

adequately monitor residue of 

carcinogenic concern because CVM is 

not aware of any data to establish a 

relationship between QCA and the 

residue of carcinogenic concern. That 

means that determining the 

concentration of QCA in animal tissue 

does not allow CVM to determine 

whether the residue of carcinogenic 

concern remains in the edible tissue. 

Thus, the approved method does not 

comply with part 500, subpart E, and 

therefore does not satisfy the statutory 

requirement of section 512(d)(1)(I) of the 

FD&C Act. 

A. CVM’s Conclusions in the January 

1998 Approval 

In reviewing information for the 

supplemental NADA for carbadox in 

January 1998, CVM relied on studies 

conducted by the sponsor 6 and 

academic researchers (Ref. 2) to 

establish an So and an Sm for the most 

potent of the carcinogenic compounds. 

As part of the supplemental NADA, the 

sponsor submitted toxicology studies, 

including carcinogenicity bioassays 

with carbadox, DCBX, and hydrazine 

(another carcinogenic metabolite of 

carbadox). These studies indicated that 

DCBX was the most potent of the three 

identified carcinogenic residues of 

carbadox. Based on the carcinogenicity 

of DCBX, CVM calculated an So of 0.061 

ppb for residue of carcinogenic concern 

for carbadox in the total diet. CVM 

calculated an Sm value for the residue of 

carcinogenic concern in muscle at 0.305 

ppb, in liver at 0.915 ppb, and in kidney 

and fat at 1.830 ppb. Because liver 

residues persist the longest, CVM 

assigned it as the target tissue. 

Therefore, 0.915 ppb is the Sm value for 

the residue of carcinogenic concern for 

carbadox and liver is the target tissue 

(Ref. 2). 

Based on information submitted as 

part of the supplemental NADA 

approved in January 1998, CVM made 

conclusions about how long 

carcinogenic residues persist in the 

edible tissues of swine after treatment 

with carbadox and about the 

appropriate marker residue to select to 

monitor carbadox use. As stated in the 

FOI Summary for the January 1998 

approval of the supplemental NADA, 

CVM concluded that the data: 

[S]how that carbadox, desoxycarbadox and 

hydrazine do not persist in edible tissue as 

detectable residues beyond 72 hours. The 

agency’s evaluation of these data, and the 

new information provided by the sponsor, 

demonstrate that following administration, 

parent carbadox is rapidly metabolized; that 

the metabolism of carbadox is similar among 

species; that the in vivo metabolism of the 

compounds of carcinogenic concern is also 

rapid and irreversible such that the resulting 

metabolic products cannot regenerate 

compounds of carcinogenic concern; that the 

unextractable residues are related to 

noncarcinogenic compounds, quinoxaline-2- 

carboxylic acid (QCA) and quinoxaline-2- 

carboxaldehyde; and that QCA is the only 

residue detectable in the edible tissues 

beyond 72 hours post dosing. Thus, the 

agency concludes that the unextractable 

bound residue is not of carcinogenic concern 

and that QCA is a reliable marker residue for 

carbadox. 

CVM made the following conclusions 

during the review of the supplemental 

NADA for carbadox approved in January 

1998: 

1. Carcinogenic residues do not 

persist in animal tissue beyond 72 hours 

postdosing. 

2. Extractable QCA is the only residue 

detectable in edible tissues 72 hours 

postdosing. 

3. Unextractable residues are 

noncarcinogenic residues related to 

QCA. 

4. QCA is a reliable marker residue for 

carbadox and its metabolites. 

5. No residue of carcinogenic concern, 

even below the So, is detectable by any 

method after 72-hours postdosing. 

Because of the conclusions made at 

that time, CVM did not require the 

sponsor to submit data to meet the 

requirements of the part 500, subpart E, 

regulations 7 despite the fact that 

carbadox is a carcinogen. CVM instead 

established a tolerance of 30 ppb for 

QCA and granted the supplemental 

approval for carbadox. 

B. The Approved Method That Measures 

QCA as the Marker Residue for 

Carbadox Is Inadequate 

Under section 512(d)(1)(I) of the 

FD&C Act, carcinogenic new animal 

drugs, such as carbadox, must have a 

method of detection, prescribed or 

approved by regulation, to ensure that 

no residue of carcinogenic concern 

persists in any edible portion of the 

treated animals after slaughter or in any 

food derived from treated animals. FDA 

has implemented this statutory 

requirement through its SOM 

regulations in part 500, subpart E, 

which require that each carcinogenic 

new animal drug have a marker residue 

with a known relationship to the 

residue of carcinogenic concern. This 

relationship is necessary to establish a 

concentration of the marker residue (the 

Rm) that ensures any residue of 

carcinogenic concern in a specific 

edible tissue is below the level 

corresponding to maximum lifetime risk 

of cancer in the test animal of 1 in 1 

million (the Sm), based on calculations 

that consider the entire human diet (the 

So). The approved method must have a 

limit of detection less than or equal to 

the Rm. 

Although CVM approved the method 

for carbadox as part of the supplemental 

NADA in January 1998 and designated 

the Sm and So, it did not require the 

sponsor to provide data showing the 

relationship between QCA and the 

residue of carcinogenic concern and 

therefore could not designate an Rm. Nor 

did CVM require the sponsor to identify 


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8For more information about Codex, see https:// 

www.fao.org/fao-who-codexalimentarius/ 

committees/cac/about/en/. 

9CVM issued a Notice of Opportunity for Hearing 

(NOOH) on a proposal to withdraw approval of the 

carbadox containing NADAs on April 12, 2016. [81 

FR 21559; (Correction published on April 21, 2016 

(81 FR 23499), to correct the telephone number for 

the individual to be contacted for further 

information. The address for Phibro Animal Health 

Corp. was also corrected.)] Phibro submitted data 

from the 2008 study in its Request for a Hearing in 

response to the NOOH. [https://

www.regulations.gov/document/FDA-2016-N-0832- 

0029] Phibro also submitted to that same docket 

reports from additional studies in July 2016. CVM 

withdrew the 2016 NOOH on July 20, 2020 (85 FR 

43852). 

a method with a limit of detection less 

than or equal to the Rm. Without an Rm

and an appropriate method for detecting 

the marker residue (i.e., a method 

sensitive enough to detect residues at or 

below the Rm), it is impossible to 

determine that the residue of 

carcinogenic concern falls below the Sm. 

Accordingly, based on information 

currently available to CVM, it is 

impossible to use the approved method 

or any other method to ensure 

compliance with the operational 

definition of no residue. 

Furthermore, based on studies 

conducted since 1998, CVM reevaluated 

the conclusions that originally led it to 

determine that assignment of a tolerance 

of 30 ppb for QCA in swine liver would 

ensure that the residue of carcinogenic 

concern would remain at or below its 

respective So in all edible tissues (Refs. 

4–6). Based on a review of these data, 

CVM concluded that: (1) carcinogenic 

residues persist in animal tissue more 

than 72 hours postdosing and (2) QCA 

is not the only residue detectable in 

animal tissue after 72 hours postdosing. 

For the 2003 Joint Food and 

Agriculture Organization (FAO)/World 

Health Organization (WHO) Expert 

Committee on Food Additives (JECFA) 

meeting, the sponsor provided data in 

which it reported that DCBX is 

measurable quantitatively (specific 

concentration measured) at 15 days 

postdosing (the last sampling timepoint 

in the study) (Refs. 4 and 5). Based on 

those studies, which showed the 

persistence of genotoxic, carcinogenic 

residues, JECFA recommended 

withdrawal of the previously 

established Codex Alimentarius 

Commission 8 (Codex) Maximum 

Residue Limit (MRL). Codex 

subsequently agreed because the 

amount of residues of carbadox in 

human food that would have no adverse 

health effects in consumers could not be 

determined. Following that meeting, the 

Codex Committee on Residues of 

Veterinary Drugs in Foods withdrew the 

MRL for carbadox (Ref. 7). Carbadox has 

been removed from the market in many 

foreign jurisdictions, including the 

European Union (Ref. 8), Canada (Ref. 

9), and Australia (Ref. 10). 

In 2005, the sponsor provided CVM 

with summary reports for the studies 

evaluated by the 2003 JECFA. CVM 

responded later that year, informing the 

sponsor that: (1) because the summaries 

indicated that carcinogenic residues 

persist longer than previously known 

and there is no established relationship 

between QCA and the residue of 

carcinogenic concern, CVM was 

concerned that the use of the 30 ppb 

tolerance for QCA and the use of QCA 

generally as a marker residue may not 

be appropriate and (2) accordingly, the 

sponsor would need to submit existing 

or new studies to address the 

relationship of QCA at 30 ppb and the 

residue of carcinogenic concern. CVM 

also told the sponsor that, if it was 

determined that QCA is not appropriate 

as the marker residue, the sponsor 

would need to conduct additional 

metabolism and residue depletion 

studies to identify an appropriate 

marker residue and tolerance in order to 

maintain the carbadox approvals. 

Between 2005 and 2011, CVM 

continued to meet with the sponsor and 

to review various submissions from the 

sponsor, including but not limited to a 

study the sponsor conducted in 2008 to 

2009 and submitted in 2009 (hereinafter 

‘‘the 2008 study’’). None of the 

submissions, however, contained 

reports of studies that were designed to 

generate the needed information. 

Therefore, in 2011, pursuant to section 

512(l)(1) of the FD&C Act, FDA ordered 

the sponsor to provide FDA with all 

data, studies, analyses, reviews, reports, 

or other scientific evaluations in its 

possession related to the persistence of 

DCBX in edible tissues, the 

appropriateness of QCA as an analyte 

for residue monitoring and for 

establishing a withdrawal time for the 

use of carbadox in pigs, and whether an 

analytical method for monitoring 

carbadox-related carcinogenic residues 

in edible tissues can be developed that 

would comply with part 500, subpart E. 

The sponsor responded with, among 

other submissions, the complete study 

reports for the studies evaluated by the 

2003 JECFA. CVM reviewed the reports 

and determined that the data show 

qualitatively (specific concentration not 

measured) that carbadox and DCBX are 

present in liver tissue samples at 48 

hours and at 15 days withdrawal, 

respectively. For samples exposed to 

enzymes to mimic human digestion, 

CVM concluded that the mass 

spectrometry chromatograms and the 

reported DCBX concentration data 

provide qualitative confirmation of the 

presence of DCBX at 15 days 

withdrawal. These reports show that the 

known carcinogenic residues (DCBX) 

persist beyond 72 hours and that QCA 

is not the only residue detectable after 

72 hours. 

In response to CVM’s proposal to 

withdraw approval of the carbadox 

containing new animal drug 

applications in 2016,9 the sponsor 

submitted reports from six studies 

(hereinafter ‘‘the 2016 studies’’). These 

studies, some of which began in 2012, 

were initiated without agreement from 

CVM that they would provide the 

necessary data to address CVM’s 

concerns (specifically, data to 

demonstrate that the approved method 

was adequate to measure the residue of 

carcinogenic concern in compliance 

with FDA’s SOM regulations, or that an 

alternative method to do so was 

available). 

Finally, the sponsor and others 

submitted presentations, documents, 

and information in response to the 2020 

proposed order, at the March 10, 2022, 

public hearing, and/or to the docket for 

the public hearing. CVM reviewed the 

presentations, documents, and 

information, and determined that they 

were not sufficient to establish a 

relationship between QCA and the 

residue of carcinogenic concern, which 

includes carbadox and DCBX. 

Additionally, there were no data to 

establish the residue level of QCA at 

which the residue of carcinogenic 

concern in the diet of people represents 

no significant increase in the risk of 

cancer to people. Without these data, 

CVM cannot establish the Rm and the 

sponsor cannot demonstrate ‘‘no 

residue’’ of carcinogenic concern as 

required by the SOM regulations in part 

500, subpart E, which implement the 

FD&C Act at 21 U.S.C. 360b(d)(1)(I). 

In sum, based on review of data 

submitted following the 1998 approval 

of the method, CVM concludes that: (1) 

carcinogenic residues persist in animal 

tissue more than 72 hours postdosing 

and (2) QCA is not the only residue 

detectable in animal tissue after 72 

hours postdosing. CVM also concludes 

that data and information submitted 

since 1998, including to this docket and 

to Docket No. FDA–2021–N–1326 by the 

sponsor and others, do not provide 

information needed to establish the 

relationship between QCA and the 

residue of carcinogenic concern. 

Without knowing this relationship and 

without a method for measuring a 

marker residue with a limit of detection 


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10According to the 1998 FOI Summary, QCA and 

methyl carbazate are noncarcinogenic metabolites 

of carbadox (Ref. 2). The sponsor provided 

quantitative measurements for QCA, but not for 

methyl carbazate. 

at or below the Rm, the approved 

method is inadequate for monitoring 

compliance with FDA’s operational 

definition of no residue (see 

§ 500.84(c)(3)). Accordingly, the 

approved method for carbadox does not 

satisfy the statutory or regulatory 

requirements and is being revoked. 

IV. Comments Received on the 

Proposed Order and Public Hearing 

A. Comments Submitted by the Sponsor 

The sponsor of the carbadox NADAs 

submitted information to the docket of 

the proposed order, presented 

information at the public hearing, and 

submitted information to the docket for 

that hearing. CVM’s scientific review of 

the sponsor’s submitted data, analysis, 

and comments prior to the hearing is 

discussed below and in ‘‘CVM Response 

to Phibro Animal Health Corporation’s 

September 18, 2020 Comments on 

CVM’s July 20, 2020 Proposed Order to 

Revoke the Regulatory Method for 

Carbadox’’ (January 6, 2022), which was 

posted to the public docket before the 

hearing (Ref. 6). Information submitted 

during or after the hearing is discussed 

below and in ‘‘CVM’s review of 

documents Phibro submitted to Docket 

No. FDA–2021–N–1326 and 

presentation at the March 10, 2022 Part 

15 Hearing’’ (October 30, 2023) (Ref. 11), 

and ‘‘CVM review of comments on the 

Zhang Article that Phibro references in 

the document submitted to the Part 15 

Hearing docket under cover letter dated 

June 9, 2022, and entitled, ‘Phibro 

Animal Health Corporation’s Reply to 

the January 6, 2022 ‘‘CVM Response to 

Phibro Animal Health Corporation’s 

September 18, 2020 Comments on 

CVM’s July 20, 2020 Proposed Order to 

Revoke the Regulatory Method for 

Carbadox’’ ’ ’’ (October 30, 2023) (Ref. 

12). CVM’s review of the sponsor’s 

procedural and policy objections is 

reflected below and in the denials of the 

sponsor’s citizen petition (Docket No. 

FDA–2020–P–2312) and petition for 

stay of action (Docket No. FDA–2020–P– 

2313), available at https://

www.regulations.gov. 

In the sponsor’s comments and oral 

presentation, it argued that QCA is an 

adequate marker residue and defended 

the approved method, which measures 

QCA. The comments defended the use 

of the 30 ppb QCA tolerance and 42-day 

withdrawal period as sufficient to 

protect human and animal safety. The 

sponsor alternatively suggested use of 

the U.S. Department of Agriculture Food 

Safety and Inspection Service (FSIS) 

method to measure QCA. The sponsor 

also proposed that DCBX could be used 

as a marker residue. For measuring 

DCBX, the sponsor proposed the 

Canadian Food inspection Agency 

(CFIA) method. The sponsor also 

suggested that other unnamed methods 

were available. Finally, the sponsor 

argued that a final order was not the 

appropriate process to revoke an 

approved method and that an NOOH is 

required instead. 

Comment on use of QCA as a marker 

residue. The sponsor states that an Rm

can be calculated for QCA based on the 

available data and submitted an expert 

opinion about the Rm for QCA. By 

analyzing QCA and DCBX 

concentrations, the sponsor’s expert 

states that the Rm for QCA is either 

28.49 ppb (using the 2008 study data 

and the approved method) or 28.61 ppb 

(using the data submitted for the 1998 

supplemental approval and the 

approved method). The sponsor also 

asserted that even if DCBX residues 

persist longer than previously known, 

no residue of carcinogenic concern 

persists beyond the current 42-day 

withdrawal period. The sponsor stated 

that either the approved method or FSIS 

method could be used to measure QCA. 

Response to use of QCA as a marker 

residue. After reviewing the sponsor’s 

studies submitted to the 2003 JECFA, 

the 2008 study, the 2016 studies, and 

other comments and analyses provided 

by the sponsor, CVM concludes that it 

lacks the data to establish an Rm for 

QCA or any other marker residue. The 

sponsor’s expert opinion estimated the 

concentration of QCA when DCBX is 

0.915 ppb (the Sm for the residue of 

carcinogenic concern in liver for 

carbadox). This analysis relied solely on 

residues of DCBX instead of considering 

the residue of carcinogenic concern. 

DCBX is only one metabolite of 

carbadox and therefore just one 

component of the residue of 

carcinogenic concern, which includes 

all compounds in the total residue of a 

demonstrated carcinogen excluding any 

compounds judged by FDA not to 

present a carcinogenic risk (§ 500.82). 

Because QCA and another metabolite, 

methyl carbazate, are the only 

compounds of carbadox that FDA has 

judged to not present a carcinogenic 

risk, the residue of carcinogenic concern 

for carbadox includes all carbadox 

residues except for QCA and methyl 

carbazate. The sponsor did not provide 

an Rm for the marker residue QCA that 

accounted for the residue of 

carcinogenic concern, nor is CVM able 

to calculate one based on the data 

available. Without an Rm, CVM cannot 

determine if the approved method, FSIS 

method, or any other method that 

measures QCA as the marker residue is 

sufficiently sensitive to satisfy the 

regulatory and statutory requirements. 

Contrary to the sponsor’s assertion 

that the residue of carcinogenic concern 

does not persist beyond the 42-day 

withdrawal period, data quantifying the 

residue of carcinogenic concern for 

carbadox from the 1998 supplemental 

approval indicates that a marker residue 

would exceed the Rm (the concentration 

associated with no increase in risk to 

the human consumer) more than 70 

days post-dosing. The data submitted 

for the 1998 supplemental approval 

showed that the total radiolabeled 

residues have a concentration of 13.3 

ppb at 70 days post-dosing, the last 

timepoint in the study. After removing 

the 9.9 percent QCA residues detected 

at 70 days,10 the remaining residue has 

a concentration of 11.98 ppb. This 

concentration far exceeds the Sm value 

of 0.915 ppb for carbadox and therefore 

these data cannot be used to calculate 

an Rm. At most, these data indicate that 

a marker residue would not reach the 

Rm until more than 70 days post-dosing, 

well past the current 42-day withdrawal 

period. 

The sponsor’s 2008 study and 2016 

studies did not provide the information 

to determine the residue of carcinogenic 

concern. The sponsor’s 2008 study does 

not provide information on the residue 

of carcinogenic concern because it 

measured only QCA and DCBX, not 

total residues of carbadox. In addition, 

CVM concluded that the data from that 

study cannot be considered quantitative 

because of poor method performance. 

Likewise, the sponsor’s 2016 studies do 

not provide quantitative data on the 

residue of carcinogenic concern. 

Additionally, although the sponsor 

attempted to separate the residues and 

measure the presence of each compound 

individually, it failed to demonstrate 

that the analytical procedures used did 

not cause carcinogenic compounds to 

degrade to noncarcinogenic compounds. 

CVM’s review of the method 

performance issues and analytical flaws 

in the sponsor’s studies is discussed in 

greater detail in Refs. 6 and 11. 

CVM also reviewed the information 

provided by the sponsor during the 

public hearing and to the docket 

following the hearing and concluded 

that such information does not allow 

CVM to determine an Rm for the 

approved method. The new information 

concerns the procedures, analysis, and 

documentation for the 2016 studies; 

however, none of the new information 


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provides the data necessary to calculate 

an Rm because the studies were not 

designed to generate the quantitative 

data necessary to make these 

calculations. CVM’s review of the new 

information is discussed in greater 

detail in Ref. 11. 

Comment on use of DCBX as a marker 

residue. The sponsor proposed the use 

of DCBX as a marker residue and 

suggested the CFIA method for detecting 

DCBX. According to an expert opinion 

submitted by the sponsor, DCBX 

depletes to a concentration of 0.915 ppb 

at approximately 23 days post-dosing 

and depletes to the 0.015 ppb detection 

limit for the CFIA method at 75 days 

post-dosing. 

Response to use of DCBX as a marker 

residue. Because DCBX is only part of 

the residue of carcinogenic concern, the 

sponsor’s expert opinion and analysis 

are insufficient to ensure compliance 

with the SOM regulations. The residue 

of carcinogenic concern for carbadox 

includes all carbadox residues 

excluding residues judged by FDA not 

to present a carcinogenic risk 

(§ 500.82(b)). For carbadox, only the 

compounds QCA and methyl carbazate 

have been judged by FDA to be 

noncarcinogenic. All other compounds 

cannot be excluded from the residue of 

carcinogenic concern. At most, the 

expert’s opinion indicates that the 

concentration of the residue of 

carcinogenic concern would reach the 

Sm at some point after 23 days (since 

DCBX is only part of the residue of 

carcinogenic concern) and that 

detectable residues of a carcinogenic 

new animal drug are present at 75 days 

post-dosing, which is 33 days longer 

than the current withdrawal period and 

72 days longer than was known in 1998. 

This information is insufficient to 

determine an Rm for DCBX as a marker 

residue. Without an Rm, CVM cannot 

determine if the CFIA method or any 

other method to measure DCBX is 

sufficiently sensitive to satisfy the 

regulatory and statutory requirements 

(§ 500.88(b)). 

Comment on carbadox metabolism. 

During the public hearing, the sponsor 

stated that the metabolism for carbadox 

is well-known and asserted that 

carbadox depletes to DCBX, which in 

turn depletes to the noncarcinogenic 

QCA. The sponsor addressed an April 

2022 study (Ref. 13) about the 

metabolism and residue depletion of 

carbadox and asserted that compounds 

other than DCBX and QCA are 

intermediates that are present ‘‘only 

fleetingly.’’ The sponsor also stated 

during the public hearing that it would 

be willing to conduct additional studies. 

Response on carbadox metabolism. 

CVM reviewed the sponsor’s comments 

regarding a study published in April 

2022 that describes metabolism and 

residue depletion of carbadox (Ref. 12). 

The study identified eight different 

metabolites of carbadox (DCBX, QCA, 

and six others) and proposed two 

different metabolic pathways for the 

degradation of carbadox. The study 

contradicts the sponsor’s claim that 

DCBX represents the entirety of the 

residue of carcinogenic concern. 

Although the sponsor states that the six 

non-QCA, non-DCBX carbadox residues 

identified in the April 2022 study are 

present ‘‘only fleetingly,’’ the method 

used in that study was not capable of 

detecting carbadox metabolites below 20 

ppb, a concentration far greater than the 

Sm. Further, FDA regulations prohibit us 

from excluding compounds from the 

residue of carcinogenic concern until 

they have been judged to be 

noncarcinogenic. Only compounds 

known to be noncarcinogenic can be 

subtracted from the total residues for the 

determination of residue of carcinogenic 

concern. Although the 2022 study adds 

to our knowledge about previously 

unidentified carbadox residues, it does 

not provide total residue data that could 

be used to calculate the residue of 

carcinogenic concern or to determine a 

relationship between a marker residue 

and the residue of carcinogenic concern 

for establishment of an Rm. Finally, 

although the sponsor stated that it 

would be willing to conduct additional 

studies, it has not submitted additional 

studies to date. 

Comment on process to revoke the 

method. The sponsor also argued that 

CVM cannot lawfully revoke an 

approved method using a final order 

under the FD&C Act and its 

implementing regulations, agency 

precedent, the Administrative 

Procedure Act, and the Due Process 

Clause of the U.S. Constitution and 

must rely instead on an NOOH and an 

evidentiary hearing before an impartial 

adjudicator to address the adequacy of 

the approved method. Alternatively, the 

sponsor asserted that revocation of the 

method requires rulemaking under the 

APA instead of a declaratory order. The 

sponsor also argued that it is arbitrary 

and capricious to revoke an approved 

method without establishing an 

alternative method and that a public 

hearing is not a substitute for a formal 

evidentiary hearing. 

Response on process to revoke the 

method. It is appropriate under the 

FD&C Act and its regulations, agency 

precedent, the Administrative 

Procedure Act, and the Due Process 

Clause of the U.S. Constitution to 

address the adequacy of the approved 

method through a declaratory order as a 

threshold matter before proceeding to an 

NOOH on withdrawal of the drug’s 

approval. Although the FD&C Act 

requires an opportunity for a hearing 

prior to withdrawing an animal drug 

approval (which FDA is providing by 

issuing an NOOH and considering any 

request for hearing it receives), the 

FD&C Act does not require a specific 

procedure to determine whether a 

particular method of examination 

satisfies the statutory and regulatory 

requirements, nor does it address the 

situation when an agency did not follow 

a regulatory requirement to publish that 

method in the Federal Register. A 

declaratory order is an appropriate 

process under the FD&C Act and APA 

to determine whether a statutory 

exclusion applies. See Weinberger v. 

Hynson, Westcott & Dunning, Inc., 412 

U.S. 609, 626 (1973) (holding that FDA 

could issue a declaratory order to 

terminate controversy and remove 

uncertainty regarding whether a new 

drug and ‘‘me-too’’ drugs were exempt 

from providing efficacy data). 

In Weinberger, the Supreme Court 

agreed with FDA’s conclusion that 

efficacy data was required for a class of 

drugs but held that a hearing was 

necessary before withdrawal because 

the drug sponsor had submitted 

substantial evidence of efficacy in line 

with FDA’s regulatory requirements for 

well-controlled studies. Id. at 622–23. 

Here, FDA concludes that the approved 

method, which relies on a tolerance of 

30 ppb for QCA, does not comply with 

the statute and implementing 

regulations because there is no Rm for 

the marker residue QCA and no 

determination that the approved method 

is sufficiently sensitive to detect the 

marker residue at or below the Rm.

Unlike the situation in Weinberger, 

where the drug sponsor submitted 

efficacy data in line with the regulatory 

and statutory requirements, the drug 

sponsor does not assert here that the 

current tolerance of 30 ppb for QCA has 

a known relationship with the residue 

of carcinogenic concern and therefore 

has not submitted evidence that the 

approved method satisfies the statutory 

and regulatory requirements. Instead, 

the drug sponsor’s expert states that the 

Rm for QCA is either 28.49 ppb (using 

the 2008 data and the approved method) 

or 28.61 ppb (using the data submitted 

for the 1998 supplemental approval and 

the approved method) based on a 

calculation that estimates 

concentrations of QCA when the 

estimated concentration of DCBX is 

0.915 ppb. DCBX is not the only 


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11As discussed above, DCBX is not the only 

residue of carcinogenic concern and we have 

concerns regarding the quality of data from the 2008 

study. 

12While, subsequent to the 1974 DES decisions, 

FDA proceeded to a hearing on the withdrawal of 

DES without revoking the method first, FDA relied 

on both the general safety clause and the Delaney 

Clause as the basis for withdrawal and, upon 

subsequent challenge, the D.C. Circuit declined to 

address FDA’s application of, or procedure 

regarding, the Delaney Clause. Rhone-Poulenc, Inc., 

Hess & Clark Division v. FDA, 636 F.2d 750, 751– 

52 & n.2 (D.C. Cir. 1980). 

carcinogenic residue that must be 

considered when determining an Rm, so 

the sponsor’s calculations do not 

account for the entire residue of 

carcinogenic concern. However, even if 

we were to assume that DCBX is the 

only carcinogenic residue present, the 

sponsor’s assertion essentially admits 

that its own expert does not think the 

current tolerance satisfies the regulatory 

requirements because the current 

tolerance of 30 ppb is more than 28.49 

ppb or 28.61 ppb (the Rm identified by 

the sponsor’s expert). 

Currently, edible tissues may enter 

the food supply if they contain a 

concentration of QCA at or below 30 

ppb. According to the expert’s 

calculation, when QCA is more than 

28.49 ppb or 28.61 ppb, edible tissues 

would still contain carcinogenic DCBX 

above 0.915 ppb, the level that 

corresponds to no significant increase in 

the risk of cancer to the human 

consumer. If we accept the expert’s 

calculations as true,11 edible tissues 

with a QCA concentration of 29 ppb, for 

example, could contain carcinogenic 

residues above 0.915 ppb, yet those 

edible tissues could enter the food 

supply because the QCA tolerance 

would be satisfied. The sponsor argues 

that the current 42-day withdrawal 

period provides an additional margin of 

safety sufficient to meet the statutory 

and regulatory requirements because the 

sponsor’s expert estimates that DCBX 

depletes to 0.915 ppb at 23 days, 19 

days before the end of the withdrawal 

period. However, edible tissues are 

analyzed for residue concentrations; the 

length of time since the animal was 

treated is not measurable from tissue 

analysis. Thus, safety is assured by 

measuring the concentration of a marker 

residue that tracks the residue of 

carcinogenic concern in edible tissues to 

determine whether the concentration is 

below or above the Rm. Regardless of the 

length of the withdrawal period, the ‘‘no 

residue’’ requirement cannot be met if 

the marker residue is above the Rm. 

Even if we accepted the sponsor’s 

calculations as true, a tolerance of 30 

ppb for QCA would not be at or below 

the Rm (calculated by the sponsor’s 

expert as 28.49 ppb or 28.61 ppb) in 

edible tissues of treated swine. Thus, 

even the sponsor’s own expert opinion 

supports FDA’s conclusion that the 

approved method does not satisfy the 

statutory and regulatory requirements. 

CVM spent a decade (2005 to 2015) in 

discussions with the sponsor regarding 

the data necessary to identify an 

adequate method and did, and 

continues to, invite the sponsor to 

provide that data. At this time, as 

discussed above, the sponsor has not 

submitted that data. 

The method revocation and 

withdrawal of NADA approvals are not 

so intertwined as to require a hearing on 

revocation under the statute or FDA’s 

regulations. While a sponsor may have 

an opportunity at a hearing held on 

either NADA approvability or NADA 

withdrawal to show whether there is an 

approvable method to meet the DES 

Proviso, the FD&C Act does not require 

an opportunity for a hearing on the 

interlocutory revocation of an approved 

method. 21 U.S.C. 360b(c)(1) and 

(e)(1)(B). Furthermore, CVM’s decision 

to revoke the method separately from 

(and before) taking action on the NADA 

is consistent with D.C. Circuit opinions 

regarding the DES withdrawal 

proceedings, which declined to apply 

the Delaney Clause when there were 

currently approved methods that did 

not result in detectable levels of residue. 

In Hess & Clark, Division of Rhodia, Inc. 

v. FDA, 495 F.2d 975 (D.C. Cir. 1974), 

and its companion case, Chemetron 

Corp. v. U.S. Dep’t of Health, Educ. & 

Welfare, 495 F.2d 995 (D.C. Cir. 1974), 

the court overturned FDA’s withdrawal 

of approvals of DES because it held that 

the NOOH preceding the withdrawals 

did not adequately provide notice and a 

meaningful opportunity to respond to 

test results that FDA claimed supported 

withdrawal. Hess & Clark, 495 F.2d at 

983; Chemetron, 495 F.2d at 999. 

Notably, the test results were from a 

method that the U.S. Department of 

Agriculture (USDA) utilized that was 

different from the approved methods for 

DES. In discussing the USDA method, 

the court stated that ‘‘the Delaney 

Clause is plainly inapplicable’’ where 

‘‘the only method by which residues 

have been detected is [an unapproved 

method].’’ Hess & Clark, 495 F.2d at 

991; see also Chemetron, 495 F.2d at 

999 (‘‘The ‘DES’ exception to the 

Delaney Clause . . . continues effective 

unless the agency detects residues in a 

slaughtered animal while using an 

approved test method. And the residues 

detected by [USDA] were not found by 

an ‘approved method.’ ’’). Under this 

logic, the Delaney Clause will only 

apply after the approved method has 

been revoked or residue is found by the 

approved method. Consistent with these 

cases (the only court cases that address 

the applicability of the Delaney Clause 

when there is still an approved method), 

CVM is addressing the adequacy of the 

approved method for carbadox before 

relying on the Delaney Clause to take 

action to withdraw the NADAs.12 FDA’s 

decision to revoke the approved method 

relies on the information submitted to 

date by the drug sponsor. This 

revocation does not prevent the drug 

sponsor from providing new or 

additional data to establish an Rm for a 

marker residue in accordance with the 

statute and regulations. 

On the two previous occasions when 

FDA withdrew approval for 

carcinogenic animal drugs (DES and a 

class of drugs called ‘‘nitrofurans’’), 

FDA relied on both the Delaney Clause 

and the general safety clause, so these 

prior situations differ significantly from 

a withdrawal based solely on the 

Delaney Clause. Furthermore, both sets 

of withdrawal proceedings began before 

FDA finalized the SOM regulations in 

1987 and therefore provide no guidance 

on the appropriate process to determine 

whether a method complies with the 

SOM regulations. The SOM regulations 

(which implement the DES Proviso) are 

a rule of general applicability because 

they set forth the general requirements 

for all regulatory methods for 

carcinogenic new animal drugs; by 

contrast, this final order revoking the 

method is appropriate as a declaratory 

order because it determines whether one 

specific method satisfies these general 

requirements. Notably, FDA does not 

approve regulatory methods through 

notice-and-comment rulemaking under 

the APA. See 76 FR 72617, November 

25, 2011 (publishing regulatory method 

to detect residues of carcinogen without 

notice-and-comment rulemaking). 

Because notice-and-comment 

rulemaking is not required to publish a 

regulatory method, it is not required to 

revoke a regulatory method. See Perez v. 

Mortg. Bankers Ass’n, 575 U.S. 92, 101 

(2015). 

CVM provided notice of the proposed 

order and a meaningful opportunity to 

be heard. The drug sponsor and other 

interested parties had an opportunity to 

provide comments and other 

information. The public hearing served 

as an additional opportunity for the 

sponsor and the public to comment on 

this matter. The sponsor presented 

orally and submitted additional 

comments to the public hearing docket. 

In addition, the sponsor remains able to 

market carbadox lawfully, so the 


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76768 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

sponsor has not been deprived of a 

property right. 

CVM, as the component of FDA 

charged with applying the Delaney 

Clause and DES Proviso, is 

appropriately advising on this order and 

its involvement does not infect any 

subsequent proceedings with any bias. 

Elsewhere in this issue of the Federal 

Register, FDA is publishing an NOOH 

and, pursuant to FDA regulations, were 

the sponsor to request a hearing, the 

adjudicator of that request would be 

affiliated with FDA’s Office of the 

Commissioner and would have had no 

previous role in the proceedings to date. 

Comment on policy considerations. 

The sponsor asserts that revoking the 

approved method for carbadox and the 

resulting withdrawal of carbadox, if it 

were to occur, would be poor policy 

because carbadox supports animal 

health and serves the public interest in 

preventing antimicrobial resistance and 

because the swine industry and U.S. 

economy would face significant costs 

following revocation of the method and/ 

or withdrawal of approval of the 

NADAs. The sponsor also asserts that 

carbadox is safe in that it has been used 

for over 50 years and has not been 

linked to a single instance of cancer in 

pigs or humans. 

Response to comment on policy 

considerations. These comments are not 

relevant to whether the approved 

method meets our regulatory 

requirements and is adequate to monitor 

the residue of carcinogenic concern in 

compliance with FDA’s operational 

definition of no residue or provide 

information needed to establish the 

relationship of QCA to the residue of 

carcinogenic concern. Without an 

adequate method, the drug cannot meet 

the DES Proviso in section 512(d)(1)(I) 

of the FD&C Act that permits the 

approval of carcinogenic animal drugs 

under certain conditions. The 

carcinogenicity studies of carbadox 

provided clear evidence that carbadox 

caused cancer in mice and rats under 

laboratory conditions; therefore, the 

Delaney Clause applies because ‘‘such 

drug induces cancer when ingested by 

man or animal.’’ 21 U.S.C. 360b(d)(1)(I). 

CVM considered the sponsor’s other 

comments and concluded that they were 

not relevant to determining whether the 

approved method, the CFIA method, the 

FSIS method, or any other method 

complies with the regulatory and 

statutory requirements. The comments 

are discussed in greater detail in CVM’s 

memoranda regarding carbadox (Refs. 6, 

11, and 12) and denials of the sponsor’s 

citizen petition (Docket No. FDA–2020– 

P–2312) and petition for stay of action 

(Docket No. FDA–2020–P–2313). Based 

on the available evidence, there 

currently is no analytical method for 

which CVM can conclude that the SOM 

regulations are met, nor has the sponsor 

provided the data to establish an Rm for 

any marker residue. Without this 

information, CVM is unable to conclude 

that there is no residue of carcinogenic 

concern in swine treated with carbadox. 

B. Comments Submitted by Other 

Stakeholders 

The non-sponsor comments submitted 

to this docket and to Docket No. FDA– 

2021–N–1326, and non-sponsor 

presentations at the part 15 hearing, 

generally concerned the need for 

carbadox for animal health and 

projected economic losses to the swine 

industry from a decrease in animal 

health; the increase in the use of 

medically important antimicrobials if 

carbadox were no longer available; 

human food safety and environmental 

safety; and requests for FDA to work 

with the sponsor to develop and 

approve an adequate method. However, 

none of the non-sponsor comments 

contained any data or information 

demonstrating that the approved 

method meets our regulatory 

requirements and is adequate to monitor 

the residue of carcinogenic concern in 

compliance with FDA’s operational 

definition of no residue or that a 

different method meets the 

requirements. 

Comments on animal health and 

projected economic losses to the swine 

industry. FDA received several 

comments stating that carbadox is the 

only effective option for stopping swine 

dysentery and that alternatives 

(including vaccines) either do not exist 

or do not work as well. Several 

comments indicated that removing 

carbadox from the market would lead to 

animal suffering and death, and several 

cited a survey of veterinarians 

conducted in 2016 and again in 2020 

that estimates the removal of carbadox 

would result annually in sickness for 

53.5 million otherwise healthy pigs and 

cost the nation’s hog industry $5.3 

billion over the next decade. Other 

comments noted that the approved uses 

of carbadox are limited to growth 

promotion, the control of swine 

dysentery, and control of salmonellosis 

caused by Salmonella choleraesuis. A 

comment stated that swine dysentery 

and S. choleraesuis are rare in U.S. 

swine herds and can be managed 

without antibiotics, pointing to 

countries that have banned the use of 

carbadox. 

Comments on antimicrobial 

resistance. Some comments stated that 

the only alternatives to carbadox that 

could be used to treat swine dysentery 

are medically important antibiotics for 

humans, such as aminoglycosides, and 

that removing carbadox is contrary to 

FDA’s strategy with respect to 

antimicrobial resistance. We also 

received comments stating that research 

has shown that the use of carbadox in 

swine increases gene transfer, creating 

its own resistance problems. 

Comments on human food safety and 

environmental safety issues. We 

received several comments defending 

the human food safety of swine 

administered carbadox. One comment 

pointed out that Salmonella is zoonotic 

and could result in food safety issues if 

not controlled and that there is an 

expectation that Salmonella and 

Brachyspira would make their way into 

slaughterhouses, potentially resulting in 

lower meat quality and increased 

contamination if carbadox is no longer 

available. We also received comments 

that asserted that the use of carbadox 

creates dangerous residues in food 

products and results in residues of 

carbadox and its metabolites in surface 

waters in states with large numbers of 

pig-producing facilities, and that 

carbadox poses allergen and 

genotoxicity hazards to the farm and 

feed mill workers who handle products 

containing the drug. 

Response to comments on animal 

health, industry economic losses, 

antimicrobial resistance, and human 

food safety. These comments are not 

relevant to whether the approved 

method meets our regulatory 

requirements and is adequate to monitor 

the residue of carcinogenic concern in 

compliance with FDA’s operational 

definition of no residue or provide 

information needed to establish the 

relationship of QCA or any other marker 

residue to the residue of carcinogenic 

concern. Without an adequate method, 

the drug cannot meet the provisions of 

section 512(d)(1)(I) of the FD&C Act. 

Comments on process to develop a 

new method. Several comments 

requested that FDA work with the 

sponsor to develop and approve a new 

method. Comments also presented the 

view that FDA did not provide the 

sponsor of carbadox with a clear path 

forward and that FDA diverged from its 

established process, urging that FDA 

work with the sponsor or publish an 

NOOH regarding the adequacy of the 

approved method. 

Response to comments on process to 

develop a new method. Before 

publishing the proposed order, CVM 

worked with the sponsor for many years 

(from 2005 to 2015), during which time 

it described the steps needed to be 

completed to obtain the necessary data 


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Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 76769 

to establish an Rm. CVM has repeatedly 

requested data from the sponsor to 

establish the relationship between QCA 

and the residue of carcinogenic concern. 

During this time, the sponsor chose not 

to submit protocols for our review under 

CVM’s generally available protocol 

review process, except for one study 

protocol submitted in 2006. That study 

would have been conducted under 

FDA’s Good Laboratory Practices and 

would have provided preliminary 

information about residue depletion 

(although not the data necessary to 

establish an Rm), but the sponsor did not 

submit a report from this study and it 

does not appear this study was ever 

conducted. 

These decade-long communications, 

along with the clear requirements of the 

regulatory text, provided the sponsor 

with notice of what is needed to meet 

the statutory requirements as well as 

ample time to carry out the necessary 

studies. To date, CVM has not received 

data demonstrating the approved 

method is adequate to measure the 

residue of carcinogenic concern in 

compliance with the requirements of 

FDA regulations or that an alternative 

analytical method would meet such 

requirements. 

CVM, too, has made the swine 

industry and general public aware of its 

concerns with the adequacy of the 

approved method for carbadox. Its 

concern was discussed in the 2016 

NOOH, the 2020 Proposed Order, and 

during the subsequent public hearing. 

Indeed, members of the industry and the 

general public submitted comments to 

the dockets and made oral presentations 

at the public hearing. While we take 

seriously the concept that the sponsor, 

veterinarians, swine producers, and 

consumers have relied on the existence 

of the approved method for carbadox for 

the last 25 years (and the prior approved 

method for more than two decades 

before that) in the form of monetary and 

physical resource allocation decisions 

(including inventory decisions on the 

part of the industry), decisions about 

animal health, and consumer spending 

and costs, they have received notice of, 

and an opportunity to comment on, 

CVM’s concerns and proposed actions. 

Additionally, were the sponsor to 

request a hearing in response to the 

NOOH and point to new or additional 

data to support the approved method or 

another approvable method, it may 

follow that a hearing is granted on that 

basis and/or that the carbadox NADAs 

are not withdrawn for that or any other 

applicable reason. Those considerations 

together with the considerations 

discussed throughout this order— 

including that the larger purpose of an 

approved method is to protect against 

the presence of residue of carcinogenic 

concern in animal tissues consumed by 

the public—outweigh any such reliance 

interests. 

V. Conclusion and Order 

Although CVM previously determined 

that carbadox and its metabolites, 

including DCBX, induce cancer in 

animals, in the January 1998 approval of 

the supplemental NADA for carbadox, 

CVM determined that no such residues 

of the drug would be found in edible 

tissues after the preslaughter 

withdrawal period by the approved 

method. The failure to establish an Rm

(which depends on knowing the 

relationship between a marker residue 

and the residue of carcinogenic concern) 

during the 1998 process, coupled with 

analysis of new information showing 

that carcinogenic residues persist longer 

than previously known, means that the 

approved method does not meet the 

requirements of the FD&C Act and the 

SOM regulations and is inadequate to 

monitor carbadox residues in 

compliance with FDA’s operational 

definition of no residue. The new 

information available since the approval 

of the January 1998 supplemental 

NADA reinforces the importance of 

having an approved method that 

complies with the SOM regulations. 

Nothing submitted to this docket or 

presented at the public hearing or 

submitted to Docket No. FDA–2021–N– 

1326 demonstrates that the approved 

method is adequate to monitor the 

residue of carcinogenic concern in 

compliance with FDA’s operational 

definition of ‘‘no residue.’’ No new 

information was submitted or presented 

that establishes the relationship 

between QCA and the residue of 

carcinogenic concern. Such a 

relationship must be known in order for 

the method to determine that there is no 

residue of carcinogenic concern. In 

addition, no information was submitted 

or presented that demonstrates an 

alternative method is adequate to 

monitor the residue of carcinogenic 

concern in compliance with FDA’s 

regulations. 

Therefore, FDA is revoking the 

approved method. 

VI. 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, and are available electronically 

at https://www.regulations.gov. 

Although FDA verified the website 

addresses in this document, please note 

that websites are subject to change over 

time. 

1. ‘‘Determination of Carbadox as 

Quinoxaline-2-Carboxylic Residues in 

Swine Liver and Muscle Tissues after 

Drug Withdrawal.’’ Available at https:// 

www.fda.gov/media/136267/download. 

2. FDA, Freedom of Information (FOI) 

Summary, NADA 041–061, MECADOX 

10 (carbadox) Type A medicated article, 

supplemental approval January 30, 1998. 

Available at https://

animaldrugsatfda.fda.gov/adafda/app/ 

search/public/document/downloadFoi/ 

308. 

3. FDA, FOI Summary, NADA 041–061, 

MECADOX 10 (carbadox) Type A 

medicated article, supplemental 

approval October 5, 1998. Available at 

https://animaldrugsatfda.fda.gov/ 

adafda/app/search/public/document/ 

downloadFoi/1673. 

4. Sua ́rez, A.F. and Arnold, D., Addendum to 

the carbadox monograph prepared by the 

36th meeting of the Committee and 

published in the FAO Food and 

Nutrition Paper 41/3, Rome 1991, http:// 

www.fao.org/fileadmin/user_upload/ 

vetdrug/docs/41-15-carbadox.pdf. 

5. Evaluations of the Joint FAO/WHO Expert 

Committee on Food Additives (JECFA). 

Carbadox, https://apps.who.int/foodadditives-contaminants-jecfa-database/ 

chemical.aspx?chemID=2176. 

6. Memorandum to File entitled, ‘‘CVM 

Response to Phibro Animal Health 

Corporation’s September 18, 2020 

Comments on CVM’s July 20, 2020 

Proposed Order to Revoke the Regulatory 

Method for Carbadox’’ (January 6, 2022). 

7. Report from Codex Alimentarius 

International Food Standards FAO/WHO 

‘‘Maximum Residue Limits (MRLs) and 

Risk Management Recommendations 

(RMRs) for Residues of Veterinary Drugs 

in Foods, CX/MRL 2–2021,’’ Carbadox, 

page 47, https://www.fao.org/fao-whocodexalimentarius/sh-proxy/en/ 

?lnk=1&url=https://workspace.fao.org/ 

sites/codex/Standards/CXM+2/MRL

2e.pdf. 

8. WHO FOOD ADDITIVES SERIES: 51 

CARBADOX (addendum), ‘‘Toxicological 

Evaluation of Certain Veterinary Drug 

Residues in Food,’’ prepared by the 

Sixtieth Meeting of the Joint FAO/WHO 

Expert Committee on Food Additives 

(JECFA), WHO, Geneva, 2003, https://

iris.who.int/bitstream/handle/10665/ 

42800/924166051X.pdf?sequence=1. 

9. Health Canada, Drug and health products, 

Veterinary drugs, ‘‘List of Maximum 

Residue Limits (MRLs) for Veterinary 

Drugs in Foods,’’ https://

www.canada.ca/en/health-canada/ 

services/drugs-health-products/ 

veterinary-drugs/maximum-residuelimits-mrls/list-maximum-residue-limitsmrls-veterinary-drugs-foods.html (not 

listing carbadox as an approved 

veterinary drug in food). 

10. Australian Pesticides and Veterinary 

Medicines Authority, ‘‘Substances Not 

Permitted for Use on Food-Producing 

Animals in Australia,’’ https://

apvma.gov.au/node/11626. 


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76770 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

1 ‘‘Other eligible entities’’ that participate in the 

NPDB are defined in the provisions of Title IV, 

Section 1921, Section 1128E, and implementing 

regulations. In addition, a few federal agencies also 

participate with the NPDB through federal 

memorandums of understanding. Eligible entities 

are responsible for complying with all reporting 

and/or querying requirements that apply; some 

entities may qualify as more than one type of 

eligible entity. Each eligible entity must certify its 

eligibility in order to report to the NPDB, query the 

NPDB, or both. Information from the NPDB is 

available only to those entities specified as eligible 

in the statutes and regulations. Not all entities have 

the same reporting requirements or level of query 

access. 

11. Memorandum to File entitled, ‘‘CVM’s 

review of documents Phibro submitted to 

Docket No. FDA–2021–N–1326 and 

presentation at the March 10, 2022 Part 

15 Hearing’’ (October 30, 2023). 

12. Memorandum to File entitled, ‘‘CVM 

review of comments on the Zhang 

Article that Phibro references in the 

document submitted to the Part 15 

Hearing docket under cover letter dated 

June 9, 2022, and entitled, ‘Phibro 

Animal Health Corporation’s Reply to 

the January 6, 2022 ‘‘CVM Response to 

Phibro Animal Health Corporation’s 

September 18, 2020 Comments on CVM’s 

July 20, 2020 Proposed Order to Revoke 

the Regulatory Method for Carbadox’’ ’ ’’ 

(October 30, 2023). 

13. Zhang, J., W. Qu, Z. Wang, and Y. Pan, 

‘‘Metabolism and Tissue Depletion of 

Carbadox in Swine, Broilers, and Rats,’’ 

ACS Agricultural Science & Technology 

2022 2(3), 477–485. Abstract is available 

at https://pubs.acs.org/doi/abs/10.1021/ 

acsagscitech.1c00260. 

Dated: November 1, 2023. 

Kimberlee Trzeciak, 

Deputy Commissioner for Policy, Legislation, 

and International Affairs. 

[FR Doc. 2023–24548 Filed 11–6–23; 8:45 am] 

BILLING CODE 4164–01–P 

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