Federal Register / Vol. 77, No. 4 / Friday, January 6, 2012 / Rules and Regulations 735 

(i) Parts Installation 

As of the effective date of this AD, no 

person may install a ballscrew assembly in 

the drive mechanism of the HSTA on any 

airplane, unless it has been inspected and 

modified, as applicable, in accordance with 

paragraph (g) of this AD. 

(j) Alternative Methods of Compliance 

(AMOCs) 

The Manager, Seattle Aircraft Certification 

Office (ACO), FAA, has the authority to 

approve AMOCs for this AD, if requested 

using the procedures found in 14 CFR 39.19. 

In accordance with 14 CFR 39.19, send your 

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appropriate. If sending information directly 

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attention of the person identified in the 

Related Information section of this AD. 

Information may be emailed to: 9-ANMSeattle-ACO-AMOC-Requests@faa.gov. 

(1) Before using any approved AMOC, 

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(2) An AMOC that provides an acceptable 

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been authorized by the Manager, Seattle ACO 

to make those findings. For a repair method 

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ANM–130S, FAA, Seattle Aircraft 

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(l) Material Incorporated by Reference 

(1) You must use the following service 

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Director of the Federal Register approved the 

incorporation by reference (IBR) of the 

following service information under 5 U.S.C. 

552(a) and 1 CFR part 51: 

(i) Boeing Alert Service Bulletin 737– 

27A1278, Revision 1, dated January 7, 2010. 

(ii) Boeing Alert Service Bulletin 737– 

27A1277, Revision 2, dated January 8, 2010. 

(2) For Boeing service information 

identified in this AD, contact Boeing 

Commercial Airplanes, Attention: Data & 

Services Management, P.O. Box 3707, MC 

2H–65, Seattle, Washington 98124–2207; 

telephone (206) 544–5000, extension 1; fax 

(206) 766–5680; email: 

me.boecom@boeing.com; Internet: https:// 

www.myboeingfleet.com. 

(3) You may review copies of the service 

information at the FAA, Transport Airplane 

Directorate, 1601 Lind Avenue SW., Renton, 

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6030, or go to http://www.archives.gov/ 

federal_register/code_of_federal_regulations/ 

ibr_locations.html. 

Issued in Renton, Washington, on 

December 14, 2011. 

Michael Kaszycki, 

Acting Manager, Transport Airplane 

Directorate, Aircraft Certification Service. 

[FR Doc. 2011–33351 Filed 1–5–12; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 530 

[Docket No. FDA–2008–N–0326] 

New Animal Drugs; Cephalosporin 

Drugs; Extralabel Animal Drug Use; 

Order of Prohibition 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency) is 

issuing an order prohibiting certain 

extralabel uses of cephalosporin 

antimicrobial drugs in certain foodproducing animals. We are issuing this 

order based on evidence that certain 

extralabel uses of these drugs in these 

animals will likely cause an adverse 

event in humans and, therefore, present 

a risk to the public health. 

DATES: This rule becomes effective April 

5, 2012. Submit either electronic or 

written comments on this document by 

March 6, 2012. 

ADDRESSES: You may submit comments, 

identified by Docket No. FDA–2008–N– 

0326, by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Fax: (301) 827–6870. 

• Mail/Hand delivery/Courier (For 

paper, disk, or CD–ROM submissions): 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

Instructions: All submissions received 

must include the Agency name and 

Docket No. FDA–2008–N–0326 for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.regulations.gov, including any 

personal information provided. For 

additional information on submitting 

comments, see the ‘‘Comments’’ heading 

of the SUPPLEMENTARY INFORMATION

section of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http:// 

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: Eric 

Nelson, Center for Veterinary Medicine 

(HFV–230), Food and Drug 

Administration, 7519 Standish Pl., 

Rockville, MD 20855, (240) 276–9201, 

email: eric.nelson@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. History 

In the Federal Register of July 3, 2008 

(73 FR 38110), FDA published an order 

prohibiting the extralabel use of 

cephalosporin antimicrobial drugs in 

food-producing animals, with a 60-day 

comment period and a 90-day effective 

date for the final order. The order, 

which was to take effect as a final rule 

on October 1, 2008, would have resulted 

in a change to part 530 (21 CFR part 

530) in § 530.41 to list cephalosporins as 

prohibited from extralabel use in foodproducing animals as provided for in 

§ 530.25(f). 


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In response to publication of this 

order, the Agency received requests for 

a 60-day extension of the comment 

period. The requests conveyed concern 

that the original 60-day comment period 

would not allow the requesters 

sufficient time to examine the available 

evidence, consider the impact of the 

order, and provide constructive 

comment. 

FDA considered the requests and, in 

the Federal Register of August 18, 2008 

(73 FR 48127), extended the comment 

period for the order for 60 days, until 

November 1, 2008. Accordingly, FDA 

also delayed the effective date of the 

final rule 60 days, until November 30, 

2008. 

The Agency received many 

substantive comments on the July 3, 

2008, order of prohibition. Therefore, to 

allow more time to fully consider the 

comments, FDA decided to revoke the 

order so that it would not take effect 

November 30, 2008. Accordingly, in the 

Federal Register of November 26, 2008 

(73 FR 71923), FDA withdrew the final 

rule and indicated that if, after 

considering the comments and other 

relevant information the Agency 

decided to issue another order of 

prohibition addressing this matter, FDA 

would follow the procedures in § 530.25 

that provide for a public comment 

period prior to implementing the new 

order. 

B. Comments on the July 3, 2008, Order 

of Prohibition 

The Agency received comments from 

approximately 170 organizations and 

individuals on the July 3, 2008, order of 

prohibition. Comments were received 

from a trade organization representing 

new animal drug manufacturers, several 

trade organizations representing food 

animal producers, several professional 

associations representing veterinarians, 

a consumer protection organization, 

several new animal drug manufacturers, 

and many individuals including food 

animal veterinarians, farmers, and 

ranchers. Only two of the commenters 

supported the July 3, 2008, order of 

prohibition as written. All others felt 

that the prohibition should be revised in 

some manner before enactment or that 

it was unnecessary and should not be 

enacted in any form. These comments 

can be summarized into two general 

categories: 

(1) The scope of the order was too 

broad in that it unnecessarily prohibited 

certain extralabel uses that do not 

significantly contribute to the problem 

of cephalosporin resistance. Many of 

these commenters were concerned about 

the unintended negative consequences 

on animal health that would result from 

such action; and 

(2) FDA failed to meet the legal 

standard for issuing a prohibition order. 

Some of these comments alleged that 

FDA appeared to have applied the 

‘‘precautionary principle’’ rather than 

basing its decision on sound scientific 

evidence. 

Although FDA does not agree with 

comments alleging that the Agency did 

not meet the legal standard for issuing 

an order of prohibition, the Agency does 

agree with comments that the scope of 

the original order of prohibition could 

have been more targeted. After 

considering the comments and 

information submitted in response to 

the July 2008 order of prohibition, FDA 

has re-examined the basis for the 

original order. Based on this reexamination, FDA has determined that 

there is sufficient basis for prohibiting 

certain extralabel uses of cephalosporin 

drugs in food-producing major animal 

species. Specifically, as explained in 

detail later in this document, FDA is 

prohibiting the extralabel use of 

cephalosporin antimicrobial drugs (not 

including cephapirin) in cattle, swine, 

chickens, and turkeys: (1) For disease 

prevention purposes; (2) at unapproved 

doses, frequencies, durations, or routes 

of administration; and (3) if the drug is 

not approved for that species and 

production class. 

Thus, with the exception of extralabel 

uses of cephapirin, the final effect of 

this order will be to prohibit many 

extralabel uses of cephalosporin drugs 

in food-producing major animal species 

(cattle, swine, chickens, and turkeys) 

including: 

(1) Use for disease prevention 

purposes; 

(2) Use at unapproved dose levels, 

frequencies, durations, or routes of 

administration (e.g., Biobullets in cattle 

and injection or dipping of poultry 

eggs); and 

(3) Use of products not approved in 

the major food species (e.g., use of 

human or companion animal 

cephalosporin drugs). 

The extralabel uses that are not 

prohibited by this order include: 

(1) Use of approved cephapirin 

products in food-producing animals; 

(2) Use to treat or control an extralabel 

disease indication as long as such use 

adheres to a labeled dosage regimen 

(i.e., dose, route, frequency, and 

duration of administration) approved for 

that species and production class; and 

(3) Use in food-producing minor 

species. 

The Agency is prohibiting these 

extralabel uses in food-producing major 

species because we believe such uses in 

these animals will likely cause an 

adverse event in humans and, therefore, 

present a risk to the public health. FDA 

may further restrict extralabel use of 

cephalosporin antimicrobial drugs in 

animals in the future if it has evidence 

that demonstrates that such use has 

caused or likely will cause an adverse 

event. 

II. Basis for Prohibiting the Extralabel 

Use of Cephalosporins With Certain 

Exceptions 

A. AMDUCA and Cephalosporins 

The Animal Medicinal Drug Use 

Clarification Act of 1994 (AMDUCA) 

(Public Law 103–396) was signed into 

law October 22, 1994. It amended the 

Federal Food, Drug, and Cosmetic Act 

(the FD&C Act) to permit licensed 

veterinarians to prescribe extralabel 

uses of approved human and animal 

drugs in animals. In the Federal 

Register of November 7, 1996 (61 FR 

57732), FDA published the 

implementing regulations (codified at 

part 530) for AMDUCA that include, 

among other things, a definition for the 

term ‘‘extralabel use’’ as well as 

provisions for prohibiting extralabel 

uses. 

Section 530.3 states that extralabel 

use means actual use or intended use of 

a drug in an animal in a manner that is 

not in accordance with the approved 

labeling. This includes, but is not 

limited to: 

(1) Use in species not listed in the 

labeling; 

(2) Use for indications (disease or 

other conditions) not listed in the 

labeling; 

(3) Use at dose levels, frequencies, or 

routes of administration other than 

those stated in the labeling; and 

(4) Deviation from the labeled 

withdrawal time based on these 

different uses. 

The sections in FDA’s implementing 

regulations governing the prohibition of 

extralabel use of drugs in animals 

include §§ 530.21, 530.25, and 530.30. 

These sections describe the basis for 

issuing an order prohibiting an 

extralabel drug use in animals and the 

procedure to be followed in issuing 

such an order. FDA may issue a 

prohibition order if it finds that 

extralabel use of a drug in animals 

presents a risk to the public health. 

Under § 530.3(e), this means that FDA 

has evidence demonstrating that the use 

of the drug has caused, or likely will 

cause, an adverse event. Furthermore, as 

discussed in section III.B of this 

document, the regulations permit a 

prohibition order to be either a general 

ban on the extralabel use of the drug or 


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Federal Register / Vol. 77, No. 4 / Friday, January 6, 2012 / Rules and Regulations 737 

class of drugs, or a ban limited to one 

or more of the uses described in the 

definition of extralabel use cited 

previously. 

Section 530.25 provides for a public 

comment period of not less than 60 

days. It also provides that the order of 

prohibition become effective 90 days 

after the date of publication, unless FDA 

revokes or modifies the order, or 

extends the period of public comment. 

The list of drugs prohibited from 

extralabel use is found in § 530.41. 

At this time, FDA is concerned that 

certain extralabel uses of cephalosporins 

in food-producing major species are 

likely to lead to the emergence and 

dissemination of cephalosporinresistant strains of foodborne bacterial 

pathogens. If these drug-resistant 

bacterial strains infect humans, it is 

likely that cephalosporins will no longer 

be effective for treating disease in those 

people. The Agency is particularly 

concerned about the extralabel use of 

cephalosporin drugs that are not 

approved for use in food-producing 

major species because very little is 

known about their microbiological or 

toxicological effects when used in foodproducing animals. Therefore, FDA is 

issuing an order prohibiting, with 

limited exceptions, the extralabel use of 

cephalosporins in food-producing major 

species because, as discussed in this 

document, the Agency has determined 

that such extralabel use likely will cause 

an adverse event and, therefore, 

presents a risk to the public health. 

B. Importance of Cephalosporins in 

Veterinary and Human Medicine 

Cephalosporins are members of the 

beta-lactam (b-lactam) class of 

antimicrobials. Members of the 

cephalosporin class have a b-lactam ring 

fused to a sulfur-containing ringexpanded system (Ref. 1). These 

antimicrobials work by targeting 

synthesis of the bacterial cell wall, 

resulting in increased permeability and 

eventual hydrolysis of the cell. 

Introduced into clinical use in 1964, 

cephalosporins are widely used 

antimicrobial agents in human 

medicine. Beta-lactams make up 40 

percent of total prescriptions in the 

outpatient setting, and cephalosporins 

contribute 14 percent of the total 

outpatient antibiotic prescriptions. This 

use accounts for over 50 million 

prescriptions per year (Ref. 2). In the 

inpatient setting, cephalosporins are 

most commonly used to treat 

pneumonia. Older cephalosporins are 

widely used as therapy for skin and soft 

tissue infections caused by 

Staphylococcus aureus and 

Streptococcus pyogenes, as well as 

treatment of upper respiratory tract 

infections, intra-abdominal infections, 

pelvic inflammatory disease, and 

diabetic foot infections. Approved 

indications for newer cephalosporins 

include the treatment of lower 

respiratory tract infections, acute 

bacterial otitis media, skin and skin 

structure infections, urinary tract 

infections (complicated and 

uncomplicated), uncomplicated 

gonorrhea, pneumonia (moderate to 

severe), empiric therapy for febrile 

neutropenic patients, complicated intraabdominal infections, pelvic 

inflammatory disease, septicemia, bone 

and joint infections, meningitis, and 

surgical prophylaxis. Indicated 

pathogens include, but are not limited 

to, Acinetobacter calcoaceticus, 

Bacteroides fragilis, Enterobacter 

agglomerans, Escherichia coli, 

Haemophilus influenzae (including blactamase producing strains), Klebsiella 

oxytoca, Klebsiella pneumoniae, 

Moraxella catarrhalis, Morganella 

morganii, Proteus mirabilis, 

Pseudomonas aeruginosa, Serratia 

marcescens, Staphylococcus aureus, 

Streptococcus pneumoniae, and 

Streptococcus pyogenes (Ref. 3). Newer 

cephalosporins (for example, third 

generation cephalosporins such as 

ceftriaxone) are used in the hospital 

setting to treat seriously ill patients with 

life-threatening disease, many of which 

are due to organisms that reside in the 

gastrointestinal tract. These newer 

cephalosporins are the antibiotics of 

choice in the treatment of serious 

Salmonella and Shigella infections, 

particularly in children where 

fluoroquinolones may be avoided due to 

potential for toxicity (Ref. 4). 

Two cephalosporin drugs are 

currently approved for use in foodproducing animal species: Ceftiofur and 

cephapirin. Injectable ceftiofur products 

are approved for the treatment and 

control of certain diseases, including: 

(1) The treatment of respiratory disease 

in cattle, swine, sheep, and goats; (2) the 

treatment of acute bovine interdigital 

necrobacillosis (foot rot) and acute 

bovine metritis; (3) the control of bovine 

respiratory disease; and (4) the control 

of early mortality associated with E. coli 

infections in day-old chicks and poults. 

In addition, ceftiofur is approved as an 

intramammary infusion for the 

treatment of clinical mastitis in lactating 

dairy cattle associated with coagulasenegative staphylococci, Streptococcus 

dysgalactiae, and E. coli. Cephapirin is 

only approved as an intramammary 

infusion for the treatment of lactating 

cows having bovine mastitis caused by 

susceptible strains of Streptococcus 

agalactiae and Staphylococcus aureus. 

C. Mechanism of Cephalosporin 

Resistance 

In general, there are three major 

mechanisms by which bacteria become 

resistant to antimicrobial agents: 

(1) Alteration of the antimicrobial target, 

(2) efflux of the antimicrobial or changes 

in permeability of the bacterial cell, and 

(3) inactivation of the antimicrobial 

agent itself. Gram-negative bacterial 

resistance to cephalosporins occurs 

mainly through inactivation of the 

cephalosporin by b-lactamases. These 

enzymes can be both innate and 

acquired (Ref. 5). 

Among bacteria of human health 

concern, the two most important classes 

of b-lactamase enzymes are the AmpC 

cephalosporinases and the extendedspectrum b-lactamases (ESBL). CMY–2 

(a type of AmpC) enzymes are found on 

the chromosome of most 

Enterobacteriaceae, and are also 

currently found on promiscuous 

plasmids in Salmonella, E. coli, and 

other members of the 

Enterobacteriaceae. These enzymes 

provide resistance to first, second, and 

third generation cephalosporins. CMY– 

2 is currently the predominant blactamase associated with Salmonella 

collected from animals and humans in 

the United States displaying resistance 

to ceftiofur and decreased susceptibility 

or resistance to ceftriaxone (Refs. 6–8), 

both third generation cephalosporins. 

‘‘Fourth generation’’ cephalosporins 

are active in vitro against bacteria 

producing AmpC type b-lactamases, but 

there is some disagreement as to the 

clinical significance of that activity. 

Recently, three E. coli producing variant 

CMY–2 b-lactamases were isolated from 

patients in Pennsylvania. Two of the 

three patients from whom these isolates 

were obtained had undergone treatment 

with cefepime, a fourth generation 

cephalosporin, within the 2 months 

preceding isolation of the organisms. 

These isolates were shown to have 

reduced susceptibility to fourth 

generation cephalosporins, suggesting 

that CMY–2 has the potential to evolve 

to provide resistance to fourth 

generation cephalosporins when 

exposed to selective pressure (Ref. 9). 

ESBLs present in bacteria of human 

health concern include members of the 

TEM, SHV, and CTX–M families. These 

enzymes are plasmid-mediated and 

have the potential to provide resistance 

to all cephalosporins. Different ESBLs 

hydrolyze different cephalosporins at 

different efficiencies and rates, thus 

leading to varying patterns of in vitro 

susceptibility. In 2010, the CLSI revised 


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the cephalosporin resistance 

breakpoints to more accurately reflect in 

vivo susceptibility. Prior to this time, a 

particular ESBL strain that might not 

raise the minimum inhibitory 

concentration (MIC) for a given 

cephalosporin to a level above the 

breakpoint for resistance would 

commonly prove to be resistant in vivo 

(Ref. 5). Therefore, there were specific 

guidelines for screening bacterial 

isolates for the presence of ESBLs when 

MICs fell in the susceptible range. Any 

bacterial isolate which produced either 

an AmpC enzyme or an ESBL was 

reported to clinicians as resistant to all 

cephalosporins even though 

susceptibility testing may have shown 

in vitro susceptibility to some of the 

cephalosporins (Ref. 10). 

In a review of the CTX–M family of 

ESBLs, Livermore, et al. (Ref. 11) noted 

that until the late 1990s, European 

surveys found the TEM and SHV 

families of ESBLs almost exclusively. 

CTX–M enzymes were recorded rarely, 

although large outbreaks caused by 

Salmonella serovar Typhimurium with 

CTX–M–4 and CTX–M–5 were reported 

in Latvia, Russia, and Belarus in the 

mid-1990s. However, CTX–M enzymes 

are now the predominant ESBLs in 

many European countries, and E. coli 

has joined Klebsiella pneumoniae as a 

major host. CTX–M enzymes are 

supplanting TEM and SHV in East Asia 

as well as in Europe. Only in the United 

States do TEM and SHV still 

predominate, although CTX–M enzymes 

are now rising in prevalence (Refs. 12– 

19). Once mobilized, CTX–M enzymes 

can be hosted by many different genetic 

elements, but are most often found on 

large multi-drug resistance plasmids. 

Therefore, FDA is concerned that if 

CTM–X becomes prevalent in the 

United States, as has occurred in other 

countries, cephalosporin resistance may 

escalate. 

Serious infections caused by 

cephalosporin-resistant bacteria may be 

empirically treated with ineffective 

antibacterial regimens, significantly 

increasing the likelihood of death. 

Urinary tract infections caused by 

community-acquired cephalosporinresistant E. coli may be associated with 

bloodstream infections, and these 

infections may also be resistant to most 

or all antibiotics commonly used to treat 

such infections. Empirical treatment of 

such infections is often with a 

fluoroquinolone, amoxicillinclavulanate, or a cephalosporin; 

however, these E. coli are likely to be 

resistant to all of these agents, making 

treatment of these infections more 

difficult (Ref. 11). 

D. Cephalosporin-Resistant Zoonotic 

Foodborne Bacteria 

In regard to antimicrobial drug use in 

animals, the Agency considers the most 

significant risk to the public health 

associated with antimicrobial resistance 

to be human exposure to food 

containing antimicrobial-resistant 

bacteria resulting from the exposure of 

food-producing animals to 

antimicrobials, including 

cephalosporins. Resistance to certain 

cephalosporins is of particular public 

health concern in light of the evidence 

of cross-resistance among drugs in the 

cephalosporin class. Importantly, 

resistance to ceftiofur compromises the 

efficacy of ceftriaxone, a first-line 

therapy for treating salmonellosis in 

humans. A recent review of b-lactam 

resistance in bacteria of animal origin 

states that an emerging issue of concern 

is the increase in reports of CMY–2 and 

CTX–M b-lactamases (Ref. 6), which 

confer cephalosporin resistance and are 

transmissible between enteric bacteria. 

Acquired resistance to b-lactams in 

animal and human isolates has been 

observed in surveillance programs such 

as the U.S. National Antimicrobial 

Resistance Monitoring System (NARMS) 

and the Canadian Integrated Program for 

Antimicrobial Resistance Surveillance 

(CIPARS). 

Because food-producing animals are a 

known source of resistant Salmonella 

infections in humans (Ref. 20), the 

NARMS program has monitored 

ceftiofur resistance among Salmonella 

isolates from food-producing animals at 

slaughter since 1997. In 1997, no 

Salmonella isolates from cattle or swine 

were resistant to ceftiofur, while 

ceftiofur resistance among isolates from 

chickens and turkeys was 0.5 percent 

and 3.7 percent, respectively. By 2009, 

the prevalence of ceftiofur resistance 

among Salmonella slaughter isolates 

increased to 14.5 percent for cattle, 4.2 

percent for swine, 12.7 percent for 

chickens, and 12.4 percent for turkeys 

(Ref. 21). 

Among food animal Salmonella 

isolates in NARMS, ceftiofur resistance 

has been identified in more than 20 

different serotypes, and it has increased 

substantially in several serotypes 

commonly found in humans (Ref. 22). 

Ceftiofur resistance among all 

Salmonella Typhimurium isolates from 

chickens was 0.0 percent in 1997 and 

33.3 percent in 2009. Among all 

Salmonella Typhimurium isolates from 

cattle, ceftiofur resistance was 3.0 

percent in 1998 and 27.8 percent in 

2009. Ceftiofur resistance rose from 12.5 

percent in 1998 to 58.8 percent in 2009 

among Salmonella Newport isolates 

from cattle. There was no ceftiofur 

resistance among Salmonella Heidelberg 

isolates from poultry in 1997, but 

resistance rose to 17.6 percent in 

chicken isolates and 33.3 percent in 

turkey isolates in 2009 (Refs. 22, 23). 

The NARMS program has also 

monitored ceftiofur resistance among 

Salmonella isolates from humans since 

1996. Ceftiofur resistance among nonTyphi Salmonella isolates from humans 

rose from 0.2 percent in 1996 to 3.4 

percent in 2009. Resistance to ceftiofur 

also rose in several Salmonella 

serotypes commonly isolated from 

humans. In 1996, ceftiofur resistance 

among Salmonella isolates from humans 

was 0.0 percent, 0.0 percent, and 1.4 

percent for serotypes Typhimurium, 

Newport, and Heidelberg, respectively. 

In 2009, ceftiofur resistance among 

isolates from these serotypes was 6.5 

percent, 6.4 percent, and 20.9 percent, 

respectively (Refs. 23, 24). 

The CIPARS program revealed an 

increase in Quebec of resistance to 

cephalosporins among Salmonella 

Heidelberg isolates from humans 

reaching a level of 36 percent of isolates 

in 2004. This increase was accompanied 

temporally by an increase in ceftiofur 

resistance in Salmonella Heidelberg 

isolates from retail chicken, which rose 

to 62 percent in 2004. Hatcheries in 

Quebec voluntarily stopped the use of 

ceftiofur in eggs and day-old chicks in 

February 2005. This action was 

followed temporally by a dramatic 

decline in the prevalence of ceftiofur 

resistance in Salmonella Heidelberg 

isolates from humans and retail chicken 

in Quebec, which by 2008 had declined 

to 12 percent and 18 percent, 

respectively. These trends in 

Salmonella Heidelberg were 

accompanied by similar trends in 

ceftiofur resistance in E. coli isolates 

from retail chicken (Ref. 25). 

Ceftiofur is not used in human 

medicine in the United States, but after 

the 2010 CLSI change in the 

cephalosporin breakpoint, resistance to 

this agent largely coincides with 

resistance to ceftriaxone, a third 

generation cephalosporin that is a 

critically important antimicrobial 

approved for use in humans (Ref. 23). 

As discussed earlier, this resistance trait 

conferred by the CMY–2 enzyme. CMY– 

2 provides resistance to first, second, 

and third generation cephalosporins. In 

addition to conferring ceftiofur and 

ceftriaxone resistance, CMY–2 also 

imparts resistance to several other blactams, including ampicillin and 

amoxicillin/clavulanate (Ref. 26). The 

prevalence and spread of CMY–2 is 

reflected in the surveillance data on 

ceftriaxone and ceftiofur susceptibility 


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(Ref. 27) and supports the finding that 

cephalosporin use in food-producing 

animals is likely contributing to an 

increase in cephalosporin-resistant 

human pathogens. 

E. Extralabel Uses of Greatest Concern 

1. Dairy Cattle 

The U.S. Department of Agriculture 

(USDA) Food Safety and Inspection 

Service (FSIS) conducts both antemortem and post-mortem inspection of 

livestock and poultry presented for 

slaughter at each official establishment. 

As part of ante-mortem inspection, FSIS 

personnel inspect animals to determine 

whether they exhibit behaviors or 

conditions that are indicative of illegal 

chemical use. If such behaviors or 

symptoms are exhibited, the animals are 

tagged and further examined at postmortem inspection. During post-mortem 

inspection, FSIS veterinarians examine 

carcasses and their organs to determine 

whether the animals they came from 

had pathological diseases or other 

conditions that could have warranted 

the use of drugs or other chemicals and 

whether there are any indications of 

illegal chemical use. In addition, FSIS 

conducts laboratory analysis of sample 

tissues that have been taken from 

carcasses that have pathologies or other 

conditions indicative of chemical use to 

determine whether they contain 

violative chemical residues. FSIS 

transmits to FDA information about the 

violative chemical residue found, 

including the name of the official 

establishment where the livestock or 

poultry was presented for slaughter. 

During the 1-year period ending June 

25, 2009, FSIS reported 113 instances of 

violative ceftiofur residues in dairy 

cows and an additional 22 instances of 

violative ceftiofur residues in other 

food-producing animals, including beef 

cattle and veal calves. The FSIS reports 

include quantitative drug residue levels 

for each violation. In most instances, the 

violative residue levels of ceftiofur 

detected in dairy cows were 

significantly above the allowable 

tolerance of 0.4 ppm (kidney) in tested 

tissues and are summarized as follows: 

• Up to 2x above the tolerance = 12 

violations 

• Between 2x and 5x above the 

tolerance = 17 violations 

• Between 5x and 10x above the 

tolerance = 16 violations 

• Between 10x and 20x above the 

tolerance = 30 violations 

• Over 20x above the tolerance = 38 

violations 

An examination of 25 recent 

inspections of farms responsible for 

violative ceftiofur residues identified a 

number of factors that resulted in the 

misuse of ceftiofur animal drug 

products. These factors include, but 

were not limited to, the following: (1) 

Poor or nonexistent animal treatment 

records for adequately monitoring 

treated animals; (2) inadequate animal 

identification systems for monitoring 

treated animals; (3) animal owners’ lack 

of knowledge regarding withdrawal 

times associated with the animal drug 

product; (4) the animal drug product 

was administered by a route not 

included in the approved labeling; (5) 

the animal drug product was 

administered at a dose higher than 

stated in the approved labeling; and (6) 

the animal drug product was 

administered to a type of animal (e.g., 

veal calves) not listed in the approved 

labeling. Most of the violations involved 

culled dairy cows. More than half of the 

violations involved ceftiofur residue 

levels more than 10 times the 

established tolerance level. 

Based on investigations conducted by 

FDA, the majority of residue violations 

were the result of poor recordkeeping 

and other management practices. 

Among the provisions required for 

extralabel drug use in animals under 21 

CFR part 530, the client (the owner of 

the animal or animals or other caretaker) 

must agree to follow the instructions of 

the veterinarian, the veterinarian must 

institute procedures to assure that the 

identity of the treated animal or animals 

is carefully maintained, and the 

veterinarian must take appropriate 

measures to assure that assigned 

timeframes for withdrawal are met and 

no illegal drug residues occur in any 

food-producing animal subjected to 

extralabel treatment. 

Adhering to the ELU requirements is 

particularly important for extralabel 

drug use in dairy cattle because 

treatment often occurs in sick adult 

dairy cows close to the time of potential 

slaughter and introduction into the food 

supply. Evidence of this practice is the 

fact that 67 percent of all tissue residue 

violations reported by FSIS at slaughter 

are attributed to adult dairy cattle. In 

comparison, antimicrobial drug 

treatment in swine and beef cattle more 

often occurs earlier in the life of the 

animal, typically at some transition 

point that is well before slaughter. This 

aspect of dairy husbandry is not only a 

concern regarding violative drug 

residues, it is also a concern in the 

context of antimicrobial resistance. 

Recent evidence suggests that 

administration of ceftiofur crystallinefree acid (CCFA) in cattle will cause a 

transient increase in the population of 

ceftiofur-resistant isolates in gut bacteria 

that lasts approximately two weeks 

before a return to more normal 

susceptibility patterns (Ref. 28). Because 

of this, the Agency is concerned that 

improper extralabel use of ceftiofur in 

culled dairy cows just prior to slaughter 

could result in increased levels of 

cephalosporin resistance in carcass 

bacteria. 

Ceftiofur use in dairy herds has been 

shown to increase herd prevalence of 

ceftriaxone resistant E. coli over that in 

herds without ceftiofur use. Herds 

reporting ceftiofur use were 25 times 

more likely to have cows from which 

ceftriaxone resistant E. coli were 

isolated than those that did not use 

ceftiofur (Ref. 29). In addition, a 

ceftiofur-resistant fecal E. coli isolate 

expressing CTX-M-type extendedspectrum b-lactamase was recovered 

from a sick dairy calf that was treated 

in an extralabel manner for diarrhea 

with ceftiofur (Ref 17). Escherichia coli 

are considered good indicators of the 

selective pressure imposed by 

antimicrobial use in food-producing 

animals and, as such, may reflect what 

might occur in Salmonella spp. under 

the same conditions (Ref. 30). 

Salmonella Newport has been shown to 

be the predominant serotype among 

cases of clinical salmonellosis in dairy 

cattle, followed by S. Typhimurium, 

including the S. Typhimurium variant, 

4,5,12:i:- (Refs. 31, 32). Over 68 percent 

of all isolates were resistant to five or 

more antimicrobials in these studies. In 

one study, 97 percent of S. Newport 

isolates were multi-drug resistant 

(MDR), exhibiting an MDR-AmpC 

phenotype (Ref. 31). The proportion of 

multi-drug resistance was significantly 

higher (p < 0.0001) among S. Newport 

and S. Typhimurium, both serotypes of 

human importance, than among all 

other serotypes. MDR-AmpC S. Newport 

resistant to third generation 

cephalosporins has also been shown to 

persist in the dairy environment and 

can be shed from individual cows for up 

to 190 days (Ref. 33). Studies have also 

shown that recent antimicrobial 

treatment, including ceftiofur, can 

increase the probability of isolating 

Salmonella in calves, heifers, and cows 

(Refs. 34, 35). 

It is estimated that just over one 

million cases of human salmonellosis 

occur every year in the United States 

(Ref 36). Salmonella serovars 

Typhimurium and Newport are often 

multi-drug resistant and appear to be 

associated with more severe human 

disease than other serovars (Refs. 37, 

38). These infections can lead to 

treatment failures, greater 

hospitalization or death rates, and 

higher costs than infections with 

susceptible strains. Consumption of 


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dairy products, as well as dairy farm 

contact, represents important risk 

factors for human S. Newport MDRAmpC infection (Ref. 39). Additionally, 

a number of outbreaks of S. Newport 

MDR-AmpC have been linked to dairy 

product consumption (Refs. 40, 41). 

NARMS data indicate that in 2006, 42.6 

percent of diagnostic Salmonella 

isolates from cattle were ceftiofur 

resistant. S. Typhimurium and S. 

Newport were the second and third 

most frequently isolated serovars from 

human infections in that year, and S. 

Newport was the third most frequently 

isolated serovar from cattle. Thirty-four 

percent of S. Newport isolated from 

humans and 32 percent of S. Newport 

isolated from cattle were resistant to 

ceftiofur, making this serovar the 

leading source of ceftiofur-resistant 

isolates for both hosts. 

2. Poultry 

FDA conducted inspections at U.S. 

poultry hatcheries in 2001 and 

examined records relating to the 

hatcheries’ antimicrobial use during the 

30-day period prior to inspection. FDA 

found that six of the eight hatcheries 

inspected that used ceftiofur during that 

period were doing so in an extralabel 

manner (Ref. 42). For example, ceftiofur 

was being administered at unapproved 

dosing levels or via unapproved 

methods of administration. In 

particular, ceftiofur was being 

administered via egg injection, rather 

than by the approved method of 

administering the drug to day-old 

chicks. The Agency is concerned that 

this extralabel use, particularly when 

employed in conjunction with 

automated technology, could result in 

levels of cephalosporin exposure in 

food-producing animals that are 

significantly higher than exposure levels 

from the approved uses. As a result, 

FDA believes human exposure to food 

containing cephalosporin-resistant 

bacteria would be significantly higher as 

well. Therefore, considering the large 

amount of food produced by the poultry 

industry each year, the Agency believes 

such extralabel use presents a risk to the 

public health. 

3. Other Extralabel Uses That Increase 

Drug Exposure 

One of the goals of this order of 

prohibition is to reduce the amount of 

cephalosporins used in food-producing 

animals for uses that have not been 

evaluated for safety and approved by 

FDA. This is particularly important for 

uses that result in significant increases 

in cephalosporin drug exposure such as 

the injection of chick eggs previously 

noted. Other extralabel uses that 

significantly increase drug exposure 

include certain deviations from an 

approved dosage regimen. This would 

include higher doses and longer 

durations of administration than 

approved and extralabel routes of 

administration that facilitate mass 

dosing of large numbers of animals, 

such as through drinking water. A 

similar concern is the use of a 

cephalosporin drugs to prevent an 

extralabel disease or condition, 

particularly when such use involves 

entire flocks or herds of animals. FDA 

believes that exposing large numbers of 

animals to cephalosporin drugs when 

such use has been neither evaluated nor 

approved by FDA presents a risk to the 

public health. 

4. Biobullets 

The Agency received 35 comments on 

the July 3, 2008, order of prohibition 

that documented the extralabel use of 

ceftiofur in a compounded new animal 

drug product known as Biobullets. 

According to the manufacturer’s Web 

site, Biobullets deliver a solid pellet of 

ceftiofur sodium (NADA 140–338) 

encased in a biodegradable bullet 

propelled by an air rifle into the muscle 

of cattle. Such use clearly represents an 

extralabel use because ceftiofur sodium 

is only approved for injection in liquid 

form by hypodermic needle. Since the 

rate and extent of dissolution and 

distribution of ceftiofur sodium in solid 

form delivered as an implant has not 

been established, the microbiological 

and toxicological profile of this 

extralabel use is unknown; thus, the 

safety of human food derived from 

animals treated in this manner is also 

unknown. Furthermore, based on these 

comments, and on past regulatory 

actions regarding Biobullets (Ref. 43), 

FDA continues to have concerns that the 

manufacture, distribution, and use of 

this product may violate the 

compounding and valid veterinaryclient-patient-relationship provisions of 

AMDUCA and 21 CFR part 530. 

5. Human Cephalosporins 

Another concern is the extralabel use 

in food-producing animals of 

cephalosporin drugs that are only 

approved for use in humans. The use of 

these human drug products in foodproducing animals presents a risk to 

public health because, like Biobullets, 

the microbiological and toxicological 

profile of this extralabel use is 

unknown; thus, the safety of human 

food derived from animals treated with 

these drugs is also unknown. Also, since 

none of these drugs are approved for use 

in food-producing animals, there are no 

approved labels to guide the use of these 

drugs regarding, for example, dosing 

regimen or withdrawal period. 

FDA has evidence of the extralabel 

use of human cephalosporins 

(cephalexin) by veterinarians for the 

treatment of cattle. This evidence was 

obtained during inspections of farms 

and veterinary hospitals by FDA 

investigators. Furthermore, one of the 

comments on the July 3, 2008, order of 

prohibition reported that cephalosporin 

drugs that are either being researched or 

approved for human use are being 

administered to food-producing 

animals, including via drinking water. 

III. Response to Comments 

A. Revised Scope of the Order 

Many of the comments received on 

the July 3, 2008, order of prohibition 

said the scope of the original order was 

too broad in that it unnecessarily 

prohibited certain extralabel uses that 

do not significantly contribute to the 

development of antimicrobial 

resistance. 

As is recognized for the use of 

antimicrobial drugs in general, the use 

of cephalosporins provides selection 

pressure that favors expansion of 

resistant variants of bacteria. Given the 

importance of the cephalosporin class of 

drugs for treating disease in humans, 

FDA believes that preserving the 

effectiveness of such drugs is critical. 

Therefore, as stated in the July 2008 

order of prohibition, FDA believes that 

it is necessary to take action to limit the 

extent to which extralabel use of 

cephalosporins in food-producing 

animals may be contributing to the 

emergence and dissemination of 

resistant variants. However, as noted 

earlier, FDA also agrees with many of 

the comments received on the July 3, 

2008, order of prohibition that said the 

scope of the original order was too 

broad in that it unnecessarily prohibited 

certain extralabel uses that are not likely 

to cause an adverse event and present a 

risk to the public health. As discussed 

below, based on the comments and 

additional information submitted in 

response to the July 3 order, the Agency 

has reconsidered its position on the 

following three specific areas: extralabel 

use of cephapirin, extralabel use for 

unapproved indications, and extralabel 

use in food-producing minor species. 

1. Cephapirin 

FDA considered the possibility of 

limiting the order of prohibition to 

certain generations of cephalosporins, or 

to certain individual cephalosporin 

drugs. FDA recognized that not all 

cephalosporin drugs necessarily posed 

the same level of risk. But given the 


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potential for confusion regarding the 

classification of individual 

cephalosporin drugs into various 

generations, FDA concluded in the July 

3, 2008, final rule, that it would be 

problematic to define the scope of the 

prohibition based on cephalosporin 

‘‘generation.’’ Although FDA continues 

to believe that a ‘‘generation-based’’ 

prohibition would be problematic, the 

Agency has given further consideration 

to excluding certain cephalosporin 

drugs from the order of prohibition. 

Therefore, based on the comments 

received on the July 3, 2008, order of 

prohibition, the Agency now believes 

that it is not necessary to prohibit the 

extralabel use of approved cephapirin 

drug products in food-producing 

animals. 

Several factors contribute to 

cephapirin drug products being of a 

lesser concern for promoting 

antimicrobial resistance in bacteria of 

significant public health concern. First, 

there are currently no cephapirin drug 

products approved for use in humans 

and, since cephapirin has such a narrow 

spectrum of activity compared to newer 

cephalosporins like ceftiofur, it is less 

likely to cause cross-resistance to drugs 

in other cephalosporin classes (Refs. 26, 

28). Furthermore, target organisms for 

approved uses of cephapirin include 

those not normally considered to cause 

serious human infections through the 

foodborne route. 

Second, cephapirin is currently only 

approved for use in food-producing 

animals as intramammary infusion drug 

products for dairy cattle. These products 

are formulated and dispensed in a 

manner that limits their suitability for 

other uses or routes of administration, 

thus restricting their potential for 

extralabel use significantly. 

Therefore, because the impact of 

cephapirin on antimicrobial resistance 

among bacteria of public health concern 

is substantially less than other, newer 

cephalosporins, and its unique dosage 

form restricts the extent of its extralabel 

use significantly, the Agency believes 

that it is appropriate to exclude 

cephapirin drug products from the 

prohibition order. 

2. Extralabel Indications for Use 

People often think of extralabel use 

only in terms of unapproved indications 

for use, that is, diseases or conditions 

not included in the approved labeling. 

However, as noted earlier, the definition 

of ‘‘extralabel use’’ includes several 

aspects of drug use not described in the 

approved labeling including, but not 

limited to: 

(1) Use in species not listed in the 

labeling; 

(2) Use for indications (disease or 

other conditions) not listed in the 

labeling; 

(3) Use at dose levels, frequencies, or 

routes of administration other than 

those stated in the labeling; and 

(4) Deviation from the labeled 

withdrawal time based on these 

different uses. 

For example, if a veterinarian uses a 

drug for an approved therapeutic 

indication, but administers it at twice 

the labeled dose, such use would 

represent an extralabel use. 

Alternatively, if a veterinarian uses a 

drug for an approved therapeutic 

indication, and administers the drug at 

the approved dosage regimen for that 

indication, but there is a failure to 

observe the labeled withdrawal time 

before the treated animal is sent to 

slaughter, such use would also represent 

an extralabel use. It is important to 

understand that there are many ways to 

use an approved drug in an extralabel 

fashion. 

As noted earlier, a prohibition order 

can be either a general ban on all 

extralabel use of a drug or class of drugs, 

or a lesser ban limited to one or more 

of the individual extralabel uses. Many 

commenters were concerned that a 

blanket prohibition of all extralabel use 

of cephalosporins would have a 

negative impact on animal health and 

welfare because, by prohibiting all 

extralabel use, therapeutic use for 

unapproved indications would also be 

prohibited, thereby eliminating effective 

treatment options for many lifethreatening diseases for which there are 

limited or no approved therapies. 

However, while the vast majority of the 

comments objected to a blanket 

prohibition, few expressed an objection 

to prohibiting extralabel dosage 

regimens. Only those comments 

regarding intramammary use of 

cephalosporins expressed a need for 

extralabel dosage regimens. In fact, 

several comments explicitly suggested 

FDA narrow the order to only allow 

extralabel use for unapproved 

therapeutic indications, but still 

prohibit most other extralabel use, 

including modifications to approved 

dosage regimens. 

An important tenet of the Agency’s 

microbial food safety assessment for 

antimicrobial drugs in food-producing 

animals is its focus on conditions of use. 

When the microbial food safety hazard 

associated with the use of an 

antimicrobial drug in food-producing 

animals is evaluated as part of the new 

animal drug approval process, the 

evaluation takes into consideration the 

proposed conditions of use, including: 

(1) Dosage regimen (dose level, 

frequency of administration, duration, 

and route of administration), and 

(2) Indications for use (purpose of 

treatment, species, class or age of the 

target animal, and the number of 

animals likely to be treated). 

As such, it is the approved conditions 

of use that help mitigate antimicrobial 

resistance risks associated with a 

particular drug’s use by controlling the 

overall drug exposure in treated 

animals. Although all aspects of the 

conditions of use contribute to some 

extent to drug exposure, FDA believes, 

after re-examining the basis for this 

order of prohibition, that extralabel uses 

of cephalosporins that involve 

modifications of the approved dosage 

regimen are likely to pose the greatest 

risk of increasing the extent to which 

animals are exposed to the drug. Such 

extralabel uses allow for greater 

exposure of individual animals through 

modification of dose levels, duration of 

administration, and/or frequency of 

administration. Furthermore, using the 

drug by unapproved routes of 

administration (e.g., via drinking water) 

can also increase exposure levels by 

facilitating administration of the drug to 

a significantly larger number of animals. 

It is in this context that FDA 

concluded that extralabel uses that 

conform to the approved dosage 

regimen, but involve use for 

unapproved therapeutic indications, 

pose a significantly lower risk with 

respect to increasing overall drug 

exposure than uses at unapproved dose 

levels, unapproved duration and/or 

frequency of administration, or 

unapproved routes of administration. 

Accordingly, the Agency also concluded 

that an exception to the order of 

prohibition could be made on this basis. 

However, FDA also took into account 

the extralabel uses of cephalosporin 

drugs in food-producing animals of 

greatest concern (see discussion in 

section II.E of this document regarding 

prevention use) and concluded that this 

exception to the prohibition should only 

be for the treatment and control of 

disease. 

Therefore, the Agency thinks it is 

appropriate to narrow the scope of the 

prohibition order somewhat by only 

allowing extralabel use in foodproducing major species for treatment or 

control of unapproved disease 

indications, but continuing to prohibit 

most other extralabel use in these 

species including unapproved dosage 

regimens and use to prevent extralabel 

disease indications. 

For the reasons described previously, 

FDA does not at this time believe that 

extralabel use in food-producing major 


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species to treat or control an 

unapproved disease indication presents 

a risk to the public health as long as the 

drug is used at a labeled dose, 

frequency, duration, and route of 

administration approved for that species 

and production class. 

3. Food-Producing Minor Species 

In accordance with the act, minor 

species means animals other than cattle, 

swine, chickens, turkeys, horses, dogs, 

cats, and humans. Many comments 

requested that food-producing minor 

species, particularly small ruminants, be 

excluded from the order of prohibition. 

Most of these comments cited the 

limited availability of approved animal 

drug products for these species and 

several comments also noted that small 

ruminants represent only very limited 

uses of cephalosporin drug products 

compared to cattle, swine, and poultry. 

Based on these comments, the Agency 

reconsidered the decision to include 

food-producing minor species in the 

prohibition on the extralabel use of 

cephalosporin drugs in food-producing 

animals. 

As noted earlier, in regard to the use 

of antimicrobial drugs in animals, the 

Agency considers the most significant 

risk to the public health associated with 

antimicrobial resistance to be human 

exposure to food containing 

antimicrobial-resistant bacteria resulting 

from the exposure of food-producing 

animals to antimicrobials. However, 

when considering the foodborne 

pathway, the potential for human 

exposure to antimicrobial-resistant 

pathogens is significantly less for food 

derived from minor species than it is for 

food derived from the food-producing 

major species. The exposure potential is 

less in part because the amount of food 

derived from cattle, swine, and poultry 

is much greater than the amount of food 

derived from sheep, goats, and 

aquaculture, the minor species from 

which the most food is derived. 

Furthermore, the amount of food 

derived from any of the other foodproducing minor species, such as deer, 

bison, elk, rabbit, duck, goose, quail, 

pheasant, partridge, pigeon, ostrich, or 

emu is considerably less than the 

amount of food derived from sheep, 

goats, and aquaculture. In addition, 

cephalosporins are approved for use in 

sheep and goats, thereby reducing the 

potential for extralabel use in these 

species, and there is little or no practical 

use for cephalosporin drugs in 

aquaculture. 

Therefore, for the reasons described 

previously, FDA does not at this time 

believe that extralabel use in foodproducing minor species presents a risk 

to the public health. 

Please note that all the provisions of 

AMDUCA remain applicable to the 

exceptions noted above. This includes 

provisions making it unlawful for the 

permitted extralabel use of a 

cephalosporin drug to result in a residue 

above an established tolerance or safe 

level. See 21 U.S.C. 360b(a)(4)(B) and 

FDA regulations at 21 CFR 530.11. 

B. Legal Standard 

Several comments questioned the 

legal standard applied by FDA in 

implementing the order of prohibition. 

Some comments referred to the 

Agency’s approach as involving the 

‘‘precautionary principle,’’ an apparent 

reference to a principle used in the 

European Union in some environmental 

and regulatory decision-making. Two 

comments suggested that, in order to 

support an order of prohibition, it 

would be necessary for FDA to 

demonstrate ‘‘either a demonstrative 

negative impact on human health or an 

imminent danger to human health.’’ 

Some comments suggested that FDA 

must perform a risk assessment that 

would characterize the hazard, evaluate 

the risk, and ascertain the impact of any 

risk management recommendations 

associated with the order. 

One comment suggested that a link 

between the use of cephalosporins in 

the treatment of animals and the 

development of bacterial resistance in 

humans would not meet the criterion of 

the AMDUCA implementing regulation 

that the extralabel use of cephalosporins 

has caused or will likely cause an 

adverse event. That comment appears to 

make a technical argument that an 

adverse event in the context of the 

regulation can only be an adverse event 

in animals, as opposed to humans. (The 

commenter acknowledged that the lack 

of drug efficacy when used for a labeled 

pathogen in target animals would be 

considered an adverse event.) 

AMDUCA was enacted in 1994, and 

its provisions became effective upon 

FDA’s issuance of final regulations 

implementing those provisions in 1996. 

Prior to the passage of AMDUCA, 

Federal law prohibited the use of a new 

animal drug in a manner other than in 

accordance with the approved label 

directions, i.e., extralabel use. 

Recognizing the reality that 

veterinarians are often confronted with 

situations in which there are no 

approved drugs for the species of animal 

that they are treating, or for particular 

diseases or conditions afflicting those 

animals, Congress enacted AMDUCA to 

allow licensed veterinarians to prescribe 

extralabel uses of approved animal 

drugs and approved human drugs for 

animals without violating the law. 

The provisions of AMDUCA relating 

to extralabel use in animals of approved 

new animal drugs and approved human 

drugs, sections 512(a)(4) and 512(a)(5) of 

the FD&C Act, respectively, provide that 

such extralabel use must be in 

compliance with conditions specified in 

implementing regulations promulgated 

by FDA. (21 U.S.C. 360b(a)(4) and 

360b(a)(5)). Section 512(a)(4) further 

provides that if FDA finds, after 

extending an opportunity for public 

comment, that the extralabel use of a 

new animal drug ‘‘presents a risk to the 

public health * * * [FDA] may, by 

order, prohibit any such use.’’ (Section 

512(a)(4)(D) (21 U.S.C. 360b(a)(4)(D)). 

Although the express language 

relating to prohibiting extralabel use 

appears in the provisions of AMDUCA 

that deal with extralabel use of 

approved new animal drugs, in its 

implementing regulations at part 530, 

FDA has interpreted the statute as 

applying the same standard to extralabel 

use of approved human drugs in foodproducing animals. FDA’s 

implementing regulations state that a 

prohibition may occur if FDA 

determines that ‘‘[t]he extralabel use of 

the drug or class of drugs presents a risk 

to the public health.’’ 21 CFR 

530.21(a)(2). See also 21 CFR 

530.25(a)(2). The regulations permit a 

prohibition to be either a general ban on 

the extralabel use of the drug or class of 

drugs, or a ban limited to particular 

species, indications for use, dosage 

forms, routes of administration, or a 

combination of those factors. 21 CFR 

530.21(b). 

The regulations further define the 

phrase ‘‘use of a drug presents a risk to 

the public health’’ to mean that ‘‘FDA 

has evidence that demonstrates that the 

use of the drug has caused or likely will 

cause an adverse event.’’ 21 CFR 

530.3(e). FDA has thus, by regulation, 

imposed upon itself the requirement 

that it have some evidence that 

demonstrates either that a drug has 

caused an adverse event or that it likely 

will cause an adverse event. FDA 

believes that, when the issue is, as with 

cephalosporins, a question of the 

development of antibacterial resistance 

in animals that may affect human 

health, an order of prohibition may be 

based on evidence that such 

development of antibacterial 

resistance—which could lead to serious 

adverse events in humans—is ‘‘likely’’ 

as a result of the extralabel animal drug 

use. The regulation is clear that there 

need not be evidence that such an event 

has actually occurred. 


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FDA rejects the apparent suggestion of 

one commenter, noted above, that an 

order of prohibition cannot be based on 

an adverse event in humans. Such a 

reading would be squarely inconsistent 

with the statutory provisions 

authorizing FDA to ban extralabel uses 

that present a risk to the public health. 

FDA addressed this issue in the 

preamble to the final AMDUCA 

implementing regulations, clarifying 

that ‘‘[t]he agency did not intend for the 

term ‘adverse event’ to be interpreted as 

related only to animal ‘adverse drug 

reactions.’ ’’ (61 FR 57732 at 57737, 

November 7, 1996). Also, as made clear 

by the preamble, ‘‘* * * the primary 

focus will be on human health.’’ (61 FR 

at 57732 at 57737). 

FDA also rejects the assertion by some 

commenters that FDA relied on the 

‘‘precautionary principle.’’ As 

previously noted, the standard in the 

regulation does require the existence of 

evidence. In the preamble to the final 

rule, FDA addressed the question of 

what type of evidence would be 

necessary by saying that the risk 

determinations that would lead to 

prohibition of an extralabel use 

‘‘typically will involve documented 

scientific information. However, the 

Agency believes that it is not limited to 

making risk determinations based solely 

on documented scientific information, 

but may use other suitable information 

as appropriate.’’ (61 FR 57732 and 

57738; November 7, 1996). In other 

sections of this preamble, FDA provides 

a detailed description of the evidence 

supporting its conclusion that the 

extralabel use that is being prohibited 

by this revised order does in fact present 

a risk to the public health, including a 

likelihood that the use would, if not 

prohibited, ultimately lead to adverse 

events in humans resulting from the 

development of resistance to antibiotic 

drugs needed to treat human infections. 

IV. Conclusions 

Based on information regarding 

cephalosporin resistance as discussed 

previously, FDA continues to believe, as 

it did in July of 2008, that it is likely 

that the extralabel use of cephalosporins 

in certain food-producing animal 

species is contributing to the emergence 

of cephalosporin-resistant zoonotic 

foodborne bacteria. Therefore, FDA has 

determined in accordance with the 

relevant provisions of 21 CFR part 530 

that, with some exceptions, such 

extralabel use likely will cause an 

adverse event and, as such, presents a 

risk to the public health. As also noted 

earlier, FDA agrees with many of the 

comments received on the July 3, 2008, 

order of prohibition that said the scope 

of the original order was too broad and, 

in response, has narrowed the scope of 

this order accordingly. Specifically, this 

order prohibits all extralabel use of 

cephalosporin drugs in food-producing 

animals except for the following uses, 

provided they comply with AMDUCA 

and FDA’s regulations implementing 

AMDUCA at 21 CFR part 530: 

(1) Cephapirin: Extralabel uses of 

approved cephapirin products are 

excluded from the prohibition. 

(2) Extralabel Indications for Use: 

Extralabel uses to treat or control an 

extralabel disease indication in foodproducing major species when used at 

a labeled dose, frequency, duration, and 

route of administration approved for 

that species and production class, are 

excluded from the prohibition. 

(3) Food-Producing Minor Species: 

Extralabel uses in food-producing minor 

species are excluded from the 

prohibition. 

To restate in more practical terms, 

after this order becomes effective, the 

following extralabel use restrictions will 

apply to all cephalosporin drug 

products, except approved cephapirin 

products, when used in food-producing 

animals: 

Major Species: Extralabel use of a 

cephalosporin drug product is permitted 

in food-producing major species to treat 

or control an extralabel disease 

indication, but only when it is approved 

and labeled for use in that particular 

species and production class, and only 

when the product is administered at 

dose levels, frequencies, durations, and 

routes of administration stated on the 

approved labeling for that particular 

species and production class. However, 

extralabel use for disease prevention 

purposes is prohibited. 

Minor Species: All extralabel use of a 

cephalosporin drug product is permitted 

in food-producing minor species 

provided such use complies with the 

requirements of AMDUCA and 21 CFR 

part 530. 

V. Comments 

FDA is providing 60 days from the 

date of this publication for the public to 

comment on this document. For the 

effective date of the order, see the DATES

section of this document, unless the 

Agency revokes or modifies the order, or 

extends the comment period. Interested 

persons may submit to the Division of 

Dockets Management (see ADDRESSES) 

either electronic or written comments 

regarding this document. It is only 

necessary to send one set of comments. 

It is no longer necessary to send two 

copies of mailed comments. Identify 

comments with the docket number 

found in brackets in the heading of this 

document. Received comments may be 

seen in the Division of Dockets 

Management between 9 a.m. and 4 p.m., 

Monday through Friday. 

VI. Order of Prohibition 

Therefore, I hereby issue the 

following order under 21 CFR 530.21 

and 530.25. FDA finds that certain 

extralabel use of the cephalosporin class 

of antimicrobial drugs in foodproducing animals likely will cause an 

adverse event, which constitutes a 

finding that extralabel use of these drugs 

presents a risk to the public health. 

Therefore, the Agency is prohibiting the 

extralabel use of the cephalosporin class 

of antimicrobial drugs as follows: 

Cephalosporins (not including 

cephapirin) are prohibited from 

extralabel use in cattle, swine, chickens, 

or turkeys as follows: (1) For disease 

prevention purposes; (2) at unapproved 

doses, frequencies, durations, or routes 

of administration; and (3) if the drug is 

not approved for that species and 

production class. 

VII. References 

The following references have been 

placed on display in the Dockets 

Management Branch (see ADDRESSES). 

You may view them between 9 a.m. and 

4 p.m., Monday through Friday. FDA 

has verified the Web site addresses, but 

FDA is not responsible for any 

subsequent changes to the Web site after 

this document publishes in the Federal 

Register. 

1. Livermore, D.M. and L.D. Williams. bLactams: Mode of Action and 

Mechanisms of Resistance. In Antibiotics 

in Laboratory Medicine; Victor Lorian 

(ed.); Williams & Wilkins, Baltimore, pp. 

502–578, 1991. 

2. John H. Powers, M.D., Transcript—Official 

Meeting of the Veterinary Medicine 

Advisory Committee, New Drug 

Microbial Safety Review Under 

Guidance #152, http://www.fda.gov/

AdvisoryCommittees/Committees

MeetingMaterials/VeterinaryMedicine

AdvisoryCommittee/ucm126971.htm 

(accessed January 6, 2011), September 

25, 2006. 

3. U.S. Food and Drug Administration, 

MAXIPIME (cefepime hydrochloride) for 

Injection, NDA 50–679/S–021, http://

www.accessdata.fda.gov/drugsatfda_

docs/label/2007/050679s028lbl.pdf 

(accessed January 6, 2011). 

4. Biedenbach, D.J. et al. Analysis of 

Salmonella spp. with resistance to 

extended-spectrum cephalosporins and 

fluoroquinolones isolated in North 

America and Latin America: report from 

the SENTRY Antimicrobial Surveillance 

Program (1997–2004). Diagnostic 

Microbiology and Infectious Disease 

54:13–21, 2006. 

5. Livermore, D.M. Beta-Lactamases in 

Laboratory and Clinical Resistance. 


pmangrum on DSK3VPTVN1PROD with RULES
744 Federal Register / Vol. 77, No. 4 / Friday, January 6, 2012 / Rules and Regulations 

Clinical Microbiology Review 8:557–584, 

1995. 

6. Li, X.Z. et al. b-Lactam Resistance and blactamases in Bacteria of Animal Origin. 

Veterinary Microbiology 121:197–214, 

2007. 

7. Centers for Disease Control and Prevention 

(CDC), National Antimicrobial 

Resistance Monitoring System for Enteric 

Bacteria (NARMS): Human Isolates Final 

Report, 2008. Atlanta, Georgia: U.S. 

Department of Health and Human 

Services, CDC, 2010. 

8. Glenn, L.M. et al. Analysis of 

Antimicrobial Resistance Genes Detected 

in Multidrug-Resistant Salmonella 

enterica Serovar Typhimurium Isolated 

from Food Animals. Microbial Drug 

Resistance 17:407–418, 2011. 

9. Doi, Y. et al. Reduced Susceptibility to 

Cefepime among Escherichia coli 

Clinical Isolates Producing Novel 

Variants of CMY–2 b-Lactamase. 

Antimicrobial Agents and Chemotherapy 

53:3159–3161, 2009. 

10. Clinical and Laboratory Standards 

Institute, Performance Standards for 

Antimicrobial Susceptibility Testing: 

Sixteenth Informational Supplement, 

M100–S16, Wayne, PA, USA: CLSI, 

2006. 

11. Livermore, D.M. et al. CTX–M: Changing 

the Face of ESBLs in Europe. J. 

Antimicrobial Chemotherapy 59:165– 

174, 2007. 

12. Lewis, J.S. et al. First Report of the 

Emergence of CTX–M-Type ExtendedSpectrum +-Lactamases (ESBLs) as the 

Predominant ESBL Isolated in a U.S. 

Health Care System. Antimicrobial 

Agents and Chemotherapy 51:4015– 

4021, 2007. 

13. Castanheira, M. et al. Rapid Emergence of 

blaCTX–M Among Enterobacteriaceae in 

U.S. Medical Centers: Molecular 

Evaluation From the MYSTIC Program 

(2007). Microbial Drug Resistance 

14:211–216, 2008. 

14. Sjo ̈lund-Karlsson, M. et al. Human 

Salmonella Infection Yielding CTX–M bLactamase, United States. Emerging 

Infectious Diseases 14:1957–1959, 2008. 

15. McGettigan, SE. et al. Prevalence of CTX– 

M b-Lactamases in Philadelphia, 

Pennsylvania. Journal of Clinical 

Microbiology 47:2970–2974, 2009. 

16. Sjo ̈lund-Karlsson, M. et al. Salmonella 

Isolates with Decreased Susceptibility to 

Extended-Spectrum Cephalosporins in 

the United States. Foodborne Pathogens 

and Disease 7:1503–1509, 2010. 

17. Wittum, T.E. et al. CTX–M-Type 

Extended-Spectrum +-Lactamases 

Present in Escherichia coli from the 

Feces of Cattle in Ohio, United States. 

Foodborne Pathogens and Disease 

7:1575–1579, 2010. 

18. Naseer, U. and A. Sundsfjord. The CTX– 

M Conundrum: Dissemination of 

Plasmids and Escherichia coli Clones. 

Microbial Drug Resistance 17:83–97, 

2011. 

19. Sjo ̈lund-Karlsson, M. et al. CTX–Mproducing Non-Typhi Salmonella spp. 

Isolated from Humans, United States. 

Emerging Infectious Diseases 17:97–99, 

2011. 

20. M<lbak, K. Spread of Resistant Bacteria 

and Resistance Genes from Animal to 

Humans—The Public Health 

Consequence. Journal of Veterinary 

Medicine B51:364–369, 2004. 

21. USDA, ‘‘National Antimicrobial 

Resistance Monitoring System for Enteric 

Bacteria (NARMS): Animal Arm Annual 

Report, 2009,’’ Athens, Georgia, U.S. 

Department of Agriculture, USDA, 2011. 

22. FDA, ‘‘National Antimicrobial Resistance 

Monitoring System-Enteric Bacteria 

(NARMS): 2009 Executive Report,’’ 

Rockville, MD, U.S. Department of 

Health and Human Services, Food and 

Drug Administration, 2011. 

23. FDA, ‘‘National Antimicrobial Resistance 

Monitoring System-Enteric Bacteria 

(NARMS): 2007 Executive Report,’’ 

Rockville, MD, U.S. Department of 

Health and Human Services, FDA, 2010. 

24. CDC, ‘‘National Antimicrobial Resistance 

Monitoring System for Enteric Bacteria 

(NARMS): Human Isolates Final Report, 

2009,’’ Atlanta, Georgia, U.S. Department 

of Health and Human Services, CDC, 

2011. 

25. Dutil, L. et al. Ceftiofur resistance in 

Salmonella enterica serovar Heidelberg 

in chicken meat and humans, Canada. 

Emerging Infectious Diseases 16:1, 2010. 

26. Zhao, S. et al. Beta-Lactam Resistance in 

Salmonella Isolated From Retail Meats in 

the United States: National 

Antimicrobial Resistance Monitoring 

System (NARMS): 2002–2006. Applied 

and Environmental Microbiology Oct. 23, 

2009. 

27. Zhao, S. et al. Identification and 

expression of cephamycinase blaCMY 

genes in Escherichia coli and Salmonella 

isolates from food animals and ground 

meat. Antimicrobial Agents and 

Chemotherapy 45:3647–50, 2001. 

28. Lowrance, T.C. et al. Changes in 

antimicrobial susceptibility in a 

population of Escherichia coli isolated 

from feedlot cattle administered ceftiofur 

crystalline-free acid. American Journal of 

Veterinary Research 68:501–507, 2007. 

29. Tragesser, L.A. et al. Association between 

ceftiofur use and isolation of Escherichia 

coli with reduced susceptibility to 

ceftriaxone from fecal samples of dairy 

cows. American Journal of Veterinary 

Research 67:1696–1700, 2006. 

30. van den Bogaard, A.E. and E.E. 

Stobberingh. Epidemiology of resistance 

to antibiotics. Links between animals 

and humans. International Journal of 

Antimicrobial Agents 14:327–335, 2000. 

31. Cummings, K.J. et al. The incidence of 

salmonellosis among dairy herds in the 

northeastern United States. Journal of 

Dairy Science 92:3766–3774, 2009. 

32. Cummings, K.J. et al. The duration of 

fecal Salmonella shedding following 

clinical disease among dairy cattle in the 

northeastern USA. Preventive Veterinary 

Medicine 92:134–139, 2009. 

33. Cobbold, R.N. et al. Long-term 

persistence of multi-drug-resistant 

Salmonella enterica serovar Newport in 

two dairy herds. Journal of the American 

Veterinary Medical Association 228:585– 

591, 2006. 

34. Warnick, L.D. et al. Effect of previous 

antimicrobial treatment on fecal 

shedding of Salmonella enterica subsp. 

enterica serogroup B in New York dairy 

herds with recent clinical salmonellosis. 

Preventive Veterinary Medicine 56:285– 

297, 2003. 

35. Berge, A.C., D.A. Moore, and W.M. 

Sischo. Prevalence and antimicrobial 

resistance patterns of Salmonella 

enterica in preweaned calves from 

dairies and calf ranches. American 

Journal of Veterinary Research 67:1580– 

1588, 2006. 

36. Scallan, E. et al. Foodborne Illness 

Acquired in the United States—Major 

Pathogens. Emerging Infectious Diseases 

January 2011. 

37. Varma, J.K. et al. Antimicrobial-resistant 

nontyphoidal Salmonella is associated 

with excess bloodstream infections and 

hospitalizations. Journal of Infectious 

Diseases 191:554–561, 2005. 

38. Varma, J.K. et al. Hospitalization and 

antimicrobial resistance in Salmonella 

outbreaks, 1984–2002. Emerging 

Infectious Diseases 11:943–946, 2005. 

39. Varma, J.K., et al. Highly Resistant 

Salmonella Newport-MDRAmpC 

Transmitted through the Domestic US 

Food Supply: A FoodNet Case-Control 

Study of Sporadic Salmonella Newport 

Infections, 2002–2003. Journal of 

Infectious Diseases 194:222–230, 2006. 

40. Centers for Disease Control and 

Prevention. Outbreak of multidrugresistant Salmonella Newport—United 

States, January-April 2002. Morbidity 

and Mortality Weekly Report 51:545– 

548, 2002. 

41. CDC, Outbreak of multidrug-resistant 

Salmonella enterica serotype Newport 

infections associated with consumption 

of unpasteurized Mexican-style aged 

cheese—Illinois, March 2006–April 

2007. Morbidity and Mortality Weekly 

Report 57:432–435, 2008. 

42. U.S. Food and Drug Administration, 

Center for Veterinary Medicine, 

unpublished report, Summary of Data 

From Hatchery Inspections Conducted 

September-October 2001, April 15, 2002. 

43. U.S. Food and Drug Administration, 

Dallas District, Warning Letter: The 

Veterinary Pharmacy, Inc. REF–2004– 

DAL–WL–29, August 6, 2004. http:// 

www.fda.gov/ICECI/ 

EnforcementActions/WarningLetters/ 

2004/ucm146544.htm (accessed January 

6, 2011). 

List of Subjects in 21 CFR Part 530 

Administrative practice and 

procedure, Advertising, Animal drugs, 

Labeling, Reporting and recordkeeping 

requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs and redelegated to 

the Director of the Center for Veterinary 

Medicine, 21 CFR part 530 is amended 

as follows: 


pmangrum on DSK3VPTVN1PROD with RULES
Federal Register / Vol. 77, No. 4 / Friday, January 6, 2012 / Rules and Regulations 745 

PART 530—EXTRALABEL DRUG USE 

IN ANIMALS 

■ 1. The authority citation for 21 CFR 

part 530 continues to read as follows: 

Authority: 15 U.S.C. 1453, 1454, 1455; 21 

U.S.C. 321, 331, 351, 352, 353, 355, 357, 

360b, 371, 379e. 

■ 2. In § 530.41, add paragraph (a)(13) to 

read as follows: 

§ 530.41 Drugs prohibited for extralabel 

use in animals. 

(a) * * * 

(13) Cephalosporins (not including 

cephapirin) in cattle, swine, chickens, 

or turkeys: 

(i) For disease prevention purposes; 

(ii) At unapproved doses, frequencies, 

durations, or routes of administration; 

or 

(iii) If the drug is not approved for 

that species and production class. 

* * * * * 

Dated: November 23, 2011. 

Bernadette Dunham, 

Director, Center for Veterinary Medicine. 

[FR Doc. 2012–35 Filed 1–4–12; 11:15 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF DEFENSE 

Office of the Secretary 

[DOD–2010–OS–0043; RIN 0790–AI62] 

32 CFR Part 222 

DoD Mandatory Declassification 

Review (MDR) Program; Correction 

AGENCY: Department of Defense. 

ACTION: Final rule; correction. 

SUMMARY: On December 27, 2011 (76 FR 

80744–80747), Department of Defense 

published a final rule titled DoD 

Mandatory Declassification Review 

(MDR) Program, which assigns 

responsibilities and provides 

procedures for members of the public to 

request a declassification review of 

information classified under the 

provisions of Executive Order 13526, or 

predecessor orders. This rule corrects a 

paragraph identification error in the 

regulations. 

DATES: This correction is effective 

January 26, 2012. 

FOR FURTHER INFORMATION CONTACT: 

Patricia Toppings, (571) 372–0485. 

SUPPLEMENTARY INFORMATION: On 

December 27, 2011, Department of 

Defense published a final rule titled 

DoD Mandatory Declassification Review 

(MDR) Program. Subsequent to the 

publication of that final rule, 

Department of Defense discovered that 

paragraph § 222.5(f) in the third column 

of page 80746 should have read 

§ 222.5(j). 

Correction 

In the final rule (FR Doc. 2011–33104) 

published on December 27, 2011 (76 FR 

80744–80747), make the following 

correction: 

§ 222.5 [Corrected] 

On page 80746, in § 222.5, in the third 

column, in the first line of the third 

paragraph, ‘‘(f) MDR Appeals.’’ should 

read ‘‘(j) MDR Appeals.’’. 

Dated: December 30, 2011. 

Aaron Siegel, 

Alternate OSD Federal Register Liaison 

Officer, Department of Defense. 

[FR Doc. 2011–33857 Filed 1–5–12; 8:45 am] 

BILLING CODE 5001–06–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 52 

[EPA–R09–OAR–2011–0547; FRL–9480–1] 

Revisions to the California State 

Implementation Plan, San Joaquin 

Valley Unified Air Pollution Control 

District (SJVUAPCD) 

Correction 

In rule document 2011–33660 

appearing on pages 214–217 in the issue 

of Wednesday, January 4, 2012, make 

the following corrections: 

(1) On page 214, in the second 

column, in the DATES section, in the 

second line, ‘‘February 3, 2011’’ should 

read ‘‘February 3, 2012’’. 

(2) On page 217, in the first column, 

in the last paragraph, in the fifth line, 

‘‘March 7, 2011’’ should read ‘‘March 5, 

2012’’. 

[FR Doc. C1–2011–33660 Filed 1–5–12; 8:45 am] 

BILLING CODE 1505–01–D 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 180 

[EPA–HQ–OPP–2010–0944; FRL–9330–4] 

Bacillus Amyloliquefaciens Strain 

D747; Exemption From the 

Requirement of a Tolerance 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Final rule. 

SUMMARY: This regulation establishes an 

exemption from the requirement of a 

tolerance for residues of the Bacillus 

amyloliquefaciens strain D747 (formerly 

known as Bacillus subtilis variant 

amyloliquefaciens strain D747) in or on 

all food commodities when used in 

accordance with good agricultural 

practices. Certis USA LLC submitted a 

petition to EPA under the Federal Food, 

Drug, and Cosmetic Act (FFDCA), 

requesting an exemption from the 

requirement of a tolerance. This 

regulation eliminates the need to 

establish a maximum permissible level 

for residues of Bacillus 

amyloliquefaciens strain D747 (formerly 

known as Bacillus subtilis variant 

amyloliquefaciens strain D747). 

DATES: This regulation is effective 

January 6, 2012. Objections and requests 

for hearings must be received on or 

before March 6, 2012, and must be filed 

in accordance with the instructions 

provided in 40 CFR part 178 (see also 

Unit I.C. of the SUPPLEMENTARY

INFORMATION). 

ADDRESSES: EPA has established a 

docket for this action under docket 

identification (ID) number EPA–HQ– 

OPP–2010–0944. All documents in the 

docket are listed in the docket index 

available at http://www.regulations.gov. 

Although listed in the index, some 

information is not publicly available, 

e.g., Confidential Business Information 

(CBI) or other information the disclosure 

of which is restricted by statute. Certain 

other material, such as copyrighted 

material, is not made available via the 

Internet and will be publicly available 

only in hard copy form. Publicly 

available docket materials are available 

in the electronic docket at http:// 

www.regulations.gov, or, if only 

available in hard copy, at the OPP 

Regulatory Public Docket in Rm. S– 

4400, One Potomac Yard (South Bldg.), 

2777 S. Crystal Dr., Arlington, VA. The 

Docket Facility is open from 8:30 a.m. 

to 4 p.m., Monday through Friday, 

excluding legal holidays. The Docket 

Facility telephone number is (703) 305– 

5805. 

FOR FURTHER INFORMATION CONTACT: 

Susanne Cerrelli, Biopesticides and 

Pollution Prevention Division (7511P), 

Office of Pesticide Programs, 

Environmental Protection Agency, 1200 

Pennsylvania Ave. NW., Washington, 

DC 20460–0001; telephone number: 

(703) 308–8077; email address: 

cerrelli.susanne@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

You may be potentially affected by 

this action if you are an agricultural 


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