Comments Invited

This AD is a final rule that involves requirements affecting flight safety, and we did not provide you with notice and an opportunity to provide your comments prior to it becoming effective. However, we invite you to participate in this rulemaking by submitting written comments, data, or views. We also invite comments relating to the economic, environmental, energy, or federalism impacts that resulted from adopting this AD. The most helpful comments reference a specific portion of the AD, explain the reason for any recommended change, and include supporting data. To ensure the docket does not contain duplicate comments, commenters should send only one copy of written comments, or if comments are filed electronically, commenters should submit them only one time. We will file in the docket all comments that we receive, as well as a report summarizing each substantive public contact with FAA personnel concerning this rulemaking during the comment period. We will consider all the comments we receive and may conduct additional rulemaking based on those comments.

We are adopting a new AD for the Enstrom Model F-28C, F-28C-2, F-28F, 280C, 280F, 280FX, TH-28, 480, and 480B helicopters with a trim relay, part-number (P/N) KUP14D55-472, M83536/10-015M, or M83536/10-024M. This AD does not apply to the specified helicopters with a reversible trim motor, P/N 28-16621 (Ford Motor Company C1AZ-14553A) or P/N AD1R-10 (Signal Electric). This AD requires modifying the lateral and longitudinal trim actuator assemblies by replacing the actuator and limit switch bracket to provide a positive stop for the trim actuator. In the event of a trim actuator runaway, the new bracket will stop the actuator, causing the circuit breaker to trip before any significant loss of control occurs. After the trim actuator assemblies are modified, this AD requires performing operational (ground) and flight tests to determine that the trim relay is working correctly. This AD was prompted by reports of 4 failures in the cyclic trim system in the field, 2 that occurred on the Enstrom Model 480B helicopter and 2 that occurred on the Enstrom Model F28 helicopter. These failures resulted in reduced controllability of the helicopter. We are issuing this AD to prevent failure of the cyclic trim system and subsequent loss of control of the helicopter.

We are issuing this AD because we evaluated all the relevant information and determined the unsafe condition described previously is likely to exist or develop in other products of the same type design.

We reviewed Enstrom Service Directive Bulletin (SDB) No. 0110, Revision 3, dated July 6, 2011 (SDB 0110), for Model F-28C, F-28C-2, F-28F, 280C, 280F, and 280FX helicopters; and Enstrom SDB No. T-039, Revision 3, dated July 6, 2011 (SDB T-039), for Model TH-28, 480, and 480B helicopters. SDB 0110 specifies, for helicopters with a trim relay, P/N KUP14D55-472, M83536/10-015M, or M83536/10-024M, procedures for modifying the lateral and longitudinal trim actuator assembly using the cyclic trim assembly kit (modification kit), P/N 28-01063-1, and specifies performing an operational check and flight test to determine the trim is operating correctly after the modification. SDB T-039 specifies, for helicopters with a trim relay, P/N M83536/10-024M, procedures for modifying the lateral and longitudinal trim actuator assembly using the modification kit, P/N 4230045-1, and specifies performing an operational check and flight test to determine the trim is operating correctly after the modification. The SDBs state that the modification kits contain the upgraded bracket.

This AD requires, within 5 hours time-in-service (TIS) or at the next annual or 100 hour time-in-service inspection, whichever occurs first, the following actions:

• For the Enstrom Model F-28C, F-28C-2, F-28F, 280C, 280F, and 280FX helicopters with a trim relay, P/N KUP14D55-472, M83536/10-015M, or M83536/10-024M, modify the lateral and longitudinal trim actuator assembly using the modification kit, P/N 28-01063-1.

• For the Enstrom Model TH-28, 480, and 480B helicopter with a trim relay, P/N M83536/10-024M, modify the lateral and longitudinal trim actuator assembly using the modification kit, P/N 4230045-1.

• For all affected helicopters, after accomplishing the modification of the lateral and longitudinal trim actuator assemblies and before further flight, perform an operational test and flight test to determine the trim is operating correctly.

The actions required by this AD are to be accomplished by following specified portions of the SDBs described previously.

The SDBs specify, before further flight, to insert a special addendum into the Emergency Procedures section of the Flight Manual, and this AD does not require this action.

We estimate that this AD will affect 207 helicopters of U.S. Registry. We estimate that operators may incur the following costs in order to comply with this AD. For Model 480, 480B, and TH-28, modifying the actuator assembly will require 4 work hours at a cost of $85 per hour and parts will cost $327; the cost per helicopter will be $667. For Model 280C, 280F, 280FX, F-28C, F-28C-2, and F-28F, modifying the actuator assembly will require 4 work hours at a cost of $85 per hour; parts will cost $383; and the cost per helicopter will be $723.

Providing an opportunity for public comments prior to adopting these AD requirements would delay implementing the safety actions needed to correct this known unsafe condition. Therefore, we find that the risk to the flying public justifies waiving notice and comment prior to the adoption of this rule because the required corrective actions must be accomplished within 5 hours time-in-service, a very short time period based on the average flight-hour utilization rate of these helicopters.

Since an unsafe condition exists that requires the immediate adoption of this AD, we determined that notice and opportunity for public comment before issuing this AD are impracticable and contrary to the public interest and that good cause exists for making this amendment effective in less than 30 days.

Title 49 of the United States Code specifies the FAA's authority to issue rules on aviation safety. Subtitle I, section 106, describes the authority of the FAA Administrator. “Subtitle VII: Aviation Programs,” describes in more detail the scope of the Agency's authority.

We are issuing this rulemaking under the authority described in “Subtitle VII, Part A, Subpart III, Section 44701: General requirements.” Under that section, Congress charges the FAA with promoting safe flight of civil aircraft in air commerce by prescribing regulations for practices, methods, and procedures the Administrator finds necessary for safety in air commerce. This regulation is within the scope of that authority because it addresses an unsafe condition that is likely to exist or develop on products identified in this rulemaking action.

We determined that this AD will not have federalism implications under Executive Order 13132. This AD will not have a substantial direct effect on the States, on the relationship between the national Government and the States, or on the distribution of power and responsibilities among the various levels of government.

For the reasons discussed, I certify that this AD:

1. Is not a “significant regulatory action” under Executive Order 12866;

2. Is not a “significant rule” under DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979);

3. Will not affect intrastate aviation in Alaska to the extent that it justifies making a regulatory distinction; and

4. Will not have a significant economic impact, positive or negative, on a substantial number of small entities under the criteria of the Regulatory Flexibility Act.

We prepared an economic evaluation of the estimated costs to comply with this AD and placed it in the AD docket.

Accordingly, under the authority delegated to me by the Administrator, the FAA amends 14 CFR part 39 as follows:

We issued a supplemental notice of proposed rulemaking (NPRM) to amend 14 CFR part 39 to include an airworthiness directive (AD) that would apply to the specified products. The supplemental NPRM was published in the Federal Register on April 19, 2011 (76 FR 21815). The original NPRM was published in the Federal Register on April 28, 2008 (73 FR 22840). The supplemental NPRM proposed to require repetitive inspections, lubrications, and repetitive repairs/overhauls of the ball nut and ballscrew and attachment (Gimbal) fittings for the trim actuator of the horizontal stabilizer; various installation(s); and corrective actions if necessary; as applicable.

We gave the public the opportunity to participate in developing this AD. The following presents the comments received on the proposal and the FAA's response to each comment.

Boeing concurred with the content of the supplemental NPRM (76 FR 21815, April 19, 2011). Continental Airlines is complying with the actions and supported the supplemental NPRM.

US Airways and Southwest Airlines asked that the compliance time required by paragraph (g)(1) of the supplemental NPRM (76 FR 21815, April 19, 2011) be extended. US Airways stated that the compliance time for the modification is defined in Table 1 of paragraph 1.E., “Compliance” of Boeing Alert Service Bulletin 737-27A1278, Revision 1, dated January 7, 2010; that compliance time is within 24,000 flight hours since delivery or 24,000 flight hours since last overhaul, whichever comes first. US Airways added that this compliance time would put all airplanes having HSTAs with more than 24,000 flight hours since delivery immediately out of compliance. US Airways adds that this compliance time, coupled with the compliance time in the supplemental NPRM, would give operators only 12 months to modify all affected airplanes. US Airways noted that the compliance time specified in Table 1 of paragraph 1.E., “Compliance,” of Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010, specifies “whichever occurs later.” Southwest also stated that this compliance time would put its airplanes out of compliance because all its HSTAs have more than 24,000 flight hours since new.

Senem Sevinic stated that the compliance times given in the referenced service information seem quite complicated, and asked that we specify the compliance times in the supplemental NPRM (76 FR 21815, April 19, 2011).

We acknowledge the requests from US Airways and Southwest and provide the following information. We specified grace periods (i.e., compliance times after the effective date of the AD) in paragraph (g)(1)(ii) of the supplemental NPRM (76 FR 21815, April 19, 2011). However, we have extended the compliance time required by paragraph (g)(1)(ii)(C) of this AD to 24 months because this extension will provide an acceptable level of safety. We do not agree with the request to specify the compliance times in paragraph (g)(1)(i) of this AD; those compliance times adequately identify the time necessary to complete each task required by this AD. We have not changed the AD in this regard.

Delta asked that the “repair/overhaul” phrase specified in paragraph (g)(1)(ii)(B) of the supplemental NPRM (76 FR 21815, April 19, 2011) be changed to “overhaul” to match the language specified in Table 1 of paragraph 1.E., “Compliance,” of Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010. Delta stated that paragraph (g)(1)(ii)(B) of the supplemental NPRM can lead to uncertainty with respect to the necessary time to accomplish a repair. Delta noted that the compliance time for repair/overhaul required by this paragraph is “within 12 months of the effective date of this AD;” however, Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010, specifies repair prior to further flight if damage is found. Delta also noted that Table 1 of paragraph 1.E., “Compliance,” of that service bulletin does not include the word “repair” when referring to the overhaul actions, and adds that the only compliance time specified for the repair is “before further flight.”

We agree that some clarification is necessary. Therefore, we have changed the “repair/overhaul” phrase specified in the preamble and paragraphs (g), (g)(1), and (g)(1)(ii)(B) of this AD to specify “overhaul,” for the reasons provided by the commenter.

Delta and US Airways asked that paragraph (g)(1)(ii)(C) of the supplemental NPRM (76 FR 21815, April 19, 2011) be changed to clarify the phrase “for the installation” to identify the individual installation and its applicability, or, in the case of multiple installations, to identify each individual installation and its applicability. Delta stated that the installation could be a single installation or multiple installations, and noted that the phrase could be referring to the ball nut tube retainer installation. US Airways infers that we are identifying many references in the service information about removing certain parts and installing improved parts. US Airways suggested using the word “modification” since using “installation” could be confusing, and noted that “installation” could refer to installation of modifications or installation of the HSTA.

We agree that clarification is necessary for the reasons provided by the commenters. Therefore, in paragraph (g)(1)(ii)(C) of this AD we have changed the phrase “For the installation(s)” to “For the modification(s).” In addition, we have changed “installation(s)” to “modification(s)” in the Summary section and paragraphs (g) and (g)(1) of this AD.

Southwest asked that the work instructions in the MPD task cards be expanded to match the procedures for the detailed inspections specified in the service information specified in paragraph (g) of the supplemental NPRM (76 FR 21815, April 19, 2011). Southwest added that this would allow for one set of instructions to accomplish the inspections and would eliminate the human error factor involved with more than one set of inspection requirements since the task cards do not match the service information. Senem Sevinic asked that a note be added to the supplemental NPRM that specifies which MPD tasks meet which steps in Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010, because it is difficult to follow both the steps in this service information and the MPD tasks.

We disagree with adding a note to this AD. The actions required by this AD, and referred to in Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010, address a specific safety issue. Accomplishing the tasks in the MPD task cards does not satisfy the actions specified in this service information; however, accomplishing the actions specified in this service information does satisfy certain MPD tasks. Because the MPD is a Boeing document and is not maintained by the FAA, operators may request any change to a task related to an MRB item through the Industry Steering Committee, which would ensure that approved changes are made to the applicable MPD task. We have not changed the AD in this regard.

US Airways asked that we clarify the requirements in paragraph (i) of the supplemental NPRM (76 FR 21815, April 19, 2011) (the parts installation paragraph). US Airways reiterated the language used in this paragraph and asked if an operator may install a serviceable unit (i.e., inspected and lubricated) after the effective date of the AD, or if we are requiring only replacement units that are inspected and lubricated, and have zero time since overhaul and post-modification.

We infer that the commenter is asking if unmodified ballscrew assemblies may be used on replacement HSTAs, provided that they are inspected and lubricated as required. For clarification, the ballscrew assembly in the drive mechanism of the HSTA may not be installed unless it has been inspected, and modified, as applicable, to ensure that HSTAs used as replacements are not exposed to the unsafe condition addressed in this AD. No change to the AD is necessary in this regard.

Boeing Alert Service Bulletin 737-27A1278, Revision 1, dated January 7, 2010; and Boeing Alert Service Bulletin 737-27A1277, Revision 2, dated January 8, 2010; refer to accomplishing certain actions as given in certain component maintenance manuals (CMMs). This AD includes a new Note 1 (and renumbers subsequent notes) identifying those CMMs as additional sources of guidance. The note also clarifies a typographical error in Boeing Alert Service Bulletin 737-27A1278, Revision 1, dated January 7, 2010, which referred to “CMM 27-45-12,” and should have referred to “CMM 27-45-11” as an additional source of guidance.

We reviewed the relevant data, considered the comments received, and determined that air safety and the public interest require adopting the AD with the changes described previously. We also determined that these changes will not increase the economic burden on any operator or increase the scope of the AD.

We estimate that this AD affects 1,641 airplanes of U.S. registry. The following table provides the estimated costs for U.S. operators to comply with this AD.

The number of work hours, as indicated above, is presented as if the accomplishment of the actions in this AD is to be conducted as new “stand alone” actions. However, in actual practice, the lubrications, detailed inspections, and overhauls are currently being done as part of normal airplane maintenance. The repair (if necessary) can be done coincidentally or in combination with the normally scheduled HSTA and ballscrew overhaul. Therefore, the actual number of necessary additional work hours will be minimal in many instances. Additionally, any costs associated with special airplane scheduling will be minimal.

We estimate the following costs to do any necessary repairs/replacements that would be required based on the results of the inspection. We have no way of determining the number of aircraft that might need these repairs/replacements:

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 food-producing animals as provided for in § 530.25(f).

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.

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 re-examination, 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.

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 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 cephalosporin-resistant 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 food-producing 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.

Cephalosporins are members of the beta-lactam (β-lactam) class of antimicrobials. Members of the cephalosporin class have a β-lactam ring fused to a sulfur-containing ring-expanded 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 intra-abdominal 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 β-lactamase 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 food-producing 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 coagulase-negative 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.

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 β-lactamases. These enzymes can be both innate and acquired (Ref. 5).

Among bacteria of human health concern, the two most important classes of β-lactamase enzymes are the AmpC cephalosporinases and the extended-spectrum β-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 β-lactamase 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 β-lactamases, but there is some disagreement as to the clinical significance of that activity. Recently, three E. coli producing variant CMY-2 β-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 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 cephalosporin-resistant 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, amoxicillin-clavulanate, 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).

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 β-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 β-lactamases (Ref. 6), which confer cephalosporin resistance and are transmissible between enteric bacteria. Acquired resistance to β-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 non-Typhi 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 β-lactams, 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 (Ref. 27) and supports the finding that cephalosporin use in food-producing animals is likely contributing to an increase in cephalosporin-resistant human pathogens.

The U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) conducts both ante-mortem 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 post-mortem 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 crystalline-free 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 extended-spectrum β-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 dairy products, as well as dairy farm contact, represents important risk factors for human S. Newport MDR-AmpC 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.

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.

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.

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 veterinary-client-patient-relationship provisions of AMDUCA and 21 CFR part 530.

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 food-producing 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.

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.

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 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.

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 life-threatening 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 food-producing 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 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.

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 food-producing 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 food-producing 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.

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 food-producing 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.

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.

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 food-producing 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.

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.

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 food-producing 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.

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 .

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:

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).

In the final rule (FR Doc. 2011-33104) published on December 27, 2011 (76 FR 80744-80747), make the following correction:

You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are not limited to:

• Crop production (NAICS code 111);

• Animal production (NAICS code 112);

• Food manufacturing (NAICS code 311);

• Pesticide manufacturing (NAICS code 32532).

This listing is not intended to be exhaustive, but, rather, provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist readers in determining whether this action might apply to certain entities. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT .

You may access a frequently updated electronic version of 40 CFR part 180 through the Government Printing Office's e-CFR site at http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl. To access the harmonized test guidelines referenced in this document electronically, please go to http://www.epa.gov/ocspp and select “Test Methods and Guidelines.”

Under FFDCA section 408(g), 21 U.S.C. 346a(g), any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2010-0944 in the subject line on the first page of your submission. All objections and requests for a hearing must be in writing, and must be received by the Hearing Clerk on or before March 6, 2012. Addresses for mail and hand delivery of objections and hearing requests are provided in 40 CFR 178.25(b).

In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR part 178, please submit a copy of the filing that does not contain any CBI for inclusion in the public docket. Information not marked confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA without prior notice. Submit a copy of your non-CBI objection or hearing request, identified by docket ID number EPA-HQ-OPP-2010-0944, by one of the following methods:

• Federal eRulemaking Portal: http://www.regulations.gov. Follow the on-line instructions for submitting comments.

• Mail: Office of Pesticide Programs (OPP) Regulatory Public Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania Avenue NW., Washington, DC 20460-0001.

• Delivery: OPP Regulatory Public Docket (7502P), Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr. Arlington, VA. Deliveries are only accepted during the Docket Facility's normal hours of operation (8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays). Special arrangements should be made for deliveries of boxed information. The Docket Facility telephone number is (703) 305-5805.

In the Federal Register of February 4, 2011 (76 FR 6465) (FRL-8858-7), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 0F7760) by Certis USA LLC, 9145 Guilford Road, Suite 175, Columbia, MD 21046. The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of Bacillus subtilis variant amyloliquefaciens strain D747 (now recognized as Bacillus amyloliquefaciens strain D747). This notice referenced a summary of the petition prepared by the petitioner, Certis USA LLC, which is available in the docket, http://www.regulations.gov. Comments were received on the notice of filing. EPA's response to these comments is discussed in Unit VII.C.

Based upon review of the data supporting the petition, EPA has modified the nomenclature of the active ingredient, which was recently reclassified as Bacillus amyloliquefaciens strain D747 (Refs. 1, 2, and 3). The reason for this change is explained in Unit III. A.

Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is “safe.” Section 408(c)(2)(A)(ii) of FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.” This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Pursuant to section 408(c)(2)(B) of FFDCA, in establishing or maintaining in effect an exemption from the requirement of a tolerance, EPA must take into account the factors set forth in section 408(b)(2)(C) of FFDCA, which require EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. * * *” Additionally, section 408(b)(2)(D) of FFDCA requires that the Agency consider “available information concerning the cumulative effects of [a particular pesticide's] * * * residues and other substances that have a common mechanism of toxicity.”

EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, EPA determines the toxicity of pesticides. Second, EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings.

Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the available scientific data and other relevant information in support of this action and considered its validity, completeness, and reliability, and the relationship of this information to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.

Bacillus amyloliquefaciens strain D747 was previously identified as Bacillus subtilis variant amyloliquefaciens strain D747 in the petition submitted to exempt the bacterium from the requirement of a tolerance when used as a microbial pesticide in or on all food commodities. Bacillus subtilis and Bacillus amyloliquefaciens were considered subtypes or variants of the same species. Now, however, Bacillus amyloliquefaciens is taxonomically designated as a separate species. The taxonomic designation used in this final rule is correct.

Certis USA, LLC, has proposed to register Bacillus amyloliquefaciens strain D747 for control of fungi and bacteria in greenhouses, nurseries, and shadehouses, and on outdoor agricultural crops, ornamentals, and turfgrass. Bacillus amyloliquefaciens strain D747 is the active ingredient in the two end-use products (EP) CX-9030 (EPA File Symbol 70051-RNI) and CX-9032 (EPA File Symbol 70051-RNT).

All mammalian toxicology data requirements supporting the petition to exempt from the requirement of a tolerance residues of Bacillus amyloliquefaciens strain D747 in or on all food commodities have been fulfilled with acceptable studies. The acute oral, injection and pulmonary toxicity/pathogenicity studies show that Bacillus amyloliquefaciens strain D747 is not toxic, infective, or pathogenic at the doses tested.

1. Acute oral toxicity/pathogenicity (Office of Chemical Safety and Pollution Prevention (OCSPP) Guideline 885.3050; Master Record Identification Number (MRID) No. 481657-04). Bacillus amyloliquefaciens strain D747 was administered once orally to 14 rats of both sexes (5-weeks old) at a single dosage of 10 8 colony-forming units (CFU) per animal. No deaths occurred, and no abnormalities (clinical signs, body weight) were observed, during the study or at necropsy. The test microbe was detected at 10 3 −10 5 CFU/g in feces 1 day after administration of the test material, but was not detected on day 14. The examination for internal persistence did not detect the test microbe in any organs or tissues, such as the kidney, brain, liver, lung, spleen, stomach, small intestine (duodenum), large intestine (cecum), mesenteric lymph nodes, or blood, throughout the experimental period. Fecal clearance occurred by day 14, and no viable organisms were recovered from blood or other organs or tissues. The results of this acceptable study demonstrated that Bacillus amyloliquefaciens strain D747 was not infective, pathogenic, or toxic to rats when orally dosed with 1.0 × 10 8 CFU/animal.

2. Acute pulmonary toxicity/pathogenicity (OCSPP Guideline 885.3150; MRID No.481657-06). Twenty male and female rats were given a single dose of 1.0 × 10 7 spores Bacillus amyloliquefaciens strain D747 via a tracheal route of administration. No mortalities or clinical effects were observed in the test animals throughout the duration of the study. Clearance of the test material was steady, although residual viable cells remained in the lungs and trachea at the end of the 60 day study. This result was typical of spore forming bacteria because bacterial spores take longer to be cleared by healthy immune systems than the vegetative form of bacteria. This acceptable study demonstrated that Bacillus amyloliquefaciens strain D747 was not toxic and/or pathogenic to rats when dosed intratracheally at 1.0 × 10 7 (CFU)/animal.

3. Acute injection toxicity/pathogenicity (intravenous)—rat (OCSPP Guideline 885.3200; MRID No. 481657-05). An acceptable acute injection toxicity and pathogenicity study demonstrated that Bacillus amyloliquefaciens strain D747 was not toxic, infective, or pathogenic to rats that were injected with approximately 1.0 × 10 7 CFU/animal.

4. Bacillus amyloliquefaciens strain D747 was administered intravenously to groups of 17 male and female rats at a dose of 1.0 × 10 7 spores per animal. There were no mortalities, no clinical effects from intravenous administration, and steady weight gain of treated rats throughout the study duration. Clearance was steady though residual viable cells remained in the liver and spleen at day 60 on study termination, typical of spore forming bacteria administered to rats. There was no evidence of an increase in viable counts over time that would be indicative of a chronic infection. Since a pattern of clearance was shown, it is assumed that the remaining viable cells were spores that take longer to be cleared by healthy immune systems.

5. Acute dermal toxicity (OCSPP Guideline 870.1200; MRID No. 481657-08). An acceptable 14-day acute dermal toxicity study demonstrated that that the CX-9030 product, which contains Bacillus amyloliquefaciens strain D747, was not toxic in rats dosed at 5,050 mg/kg. [median lethal dose, (LD 50 ) > 5,050 mg/kg. EPA Toxicity Category IV.]

6. Acute dermal irritation (OCSPP Guideline 870.2500; MRID No.: 481655-11). An acceptable dermal irritation study demonstrated that no evidence of irritation occurred from dermal administration of 500 mg of CX-9030 to rabbits during the 4-hour exposure and the 72-hour observation period. The dermal irritation score for Bacillus amyloliquefaciens strain D747 CX-9030 was 0.00 (EPA Toxicity Category IV).

7. Acute dermal irritation (OCSPP Guideline 870.2500; MRID No.: 481655-06). A second acceptable dermal irritation study also demonstrated that CX-9032 product containing Bacillus amyloliquefaciens strain D747 was non-irritating. No evidence of irritation was observed for 72 hours following the 4 hour dermal administration of 0.5 mL undiluted CX-9032 to the shaved skin rabbits. The dermal irritation score for Bacillus amyloliquefaciens strain D747 CX-9032 was 0.00 (EPA Toxicity Category IV).

In examining aggregate exposure, section 408 of FFDCA directs EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

Dietary exposure to this microbial pesticide may occur, but the complete absence of any acute oral toxicity, infectivity, and/or pathogenicity effects, as discussed in Unit III.B., supports the conclusion that this active ingredient is not toxic at high exposure levels, and, therefore, establishment of a tolerance exemption for residues of Bacillus amyloliquefaciens strain D747 is appropriate.

1. Food. Based on the results from the toxicity studies presented in Unit III.B., no toxicity, infectivity, pathogenicity or other adverse effects from dietary exposure to Bacillus amyloliquefaciens strain D747 from the proposed pesticidal uses of Bacillus amyloliquefaciens strain D747 are expected. Bacillus species, including Bacillus amyloliquefaciens, are commonly found in agricultural settings, and occur naturally on fresh produce with no known adverse effects. The Manual of Clinical Microbiology (9th edition) mentions that dried food, such as spices, milk powder, and grains, often contains large amounts of Bacillus spores (Ref. 3). Bacillus amyloliquefaciens is not known to produce mammalian toxins, and no foodborne illnesses associated with Bacillus amyloliquefaciens have been reported.

2. Drinking water exposure. Bacillus amyloliquefaciens is naturally present in soils (Ref. 2); therefore, Bacillus amyloliquefaciens may occur in surface water and possibly groundwater. According to the World Health Organization , Bacillus species are often detected in drinking water even after going through acceptable water treatment processes, largely because the spores are resistant to these disinfection processes (Ref. 4). Should this microbial pesticide be present, no adverse effects are expected from exposure to Bacillus amyloliquefaciens through drinking water, based on the results of toxicity studies described in Unit III.B.

The use sites for these products include residential gardens, as well as agricultural sites. Based on the results of the acute toxicity tests described in Unit III.B., the Agency believes that the potential aggregate, non-occupational risks from exposure to Bacillus amyloliquefaciens strain D747, when used as a microbial pesticide, are negligible.

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information concerning the cumulative effects of [a particular pesticide's] * * * residues and other substances that have a common mechanism of toxicity.”

EPA has not found the microbial active ingredient to share a common mechanism of toxicity with any other substances, and Bacillus amyloliquefaciens strain D747 does not appear to produce any toxic metabolites. For the purposes of this tolerance action, therefore, EPA has assumed that Bacillus amyloliquefaciens strain D747 does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's Web site at http://www.epa.gov/pesticides/cumulative.

FFDCA section 408(b)(2)(C) provides that EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the Food Quality Protection Act Safety Factor. In applying this provision, EPA either retains the default value of 10X or uses a different safety factor when reliable data available to EPA support the choice of a different factor.

Based on the acute toxicity and pathogenicity data/information summarized in Unit III, EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to the residues of Bacillus amyloliquefaciens strain D747. Such exposure includes all anticipated dietary exposures and all other exposures for which there is reliable information. EPA has arrived at this conclusion because, considered collectively, the data and other information (e.g., lack of toxicity noted for oral, dermal, and inhalation routes of exposure) available on Bacillus amyloliquefaciens strain D747 do not demonstrate toxic, pathogenic, and/or infective potential to sensitive populations from exposure to this microbial pest control agent. There are no threshold effects of concern and, as a result, the provision requiring an additional margin of safety is not necessary.

An analytical method is not required for enforcement purposes since the Agency is establishing an exemption from the requirement of a tolerance without any numerical limitation.

In making its tolerance decisions, EPA seeks to harmonize U.S. tolerances with international standards whenever possible, consistent with U.S. food safety standards and agricultural practices. EPA considers the international maximum residue limits (MRLs) established by the Codex Alimentarius Commission (Codex), as required by FFDCA section 408(b)(4). The Codex Alimentarius is a joint U.N. Food and Agriculture Organization/World Health Organization food standards program, and it is recognized as an international food safety standards-setting organization in trade agreements to which the United States is a party. EPA may establish a tolerance that is different from a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain the reasons for departing from the Codex level.

The Codex has not established a MRL for Bacillus amyloliquefaciens strain D747.

Two comments were submitted. An anonymous comment was submitted expressing opposition to granting an exemption from the requirement of a tolerance to the applicant. (EPA-HQ-OPP-2010-0012-0019). The commenter submitted a number of comments in the same communication that suggested that this and other active ingredients should not be granted exemptions. The commenter expressed concern about toxic chemical residues on produce and on earth, and suggested that the “Dept. of Health” should analyze the health effects of toxic chemicals. In the United States, EPA is responsible for regulating pesticides under FIFRA and the FQPA, and has analyzed the toxicity of this microbial active ingredient. As described in Unit III.B., the results of the acute oral, injection and pulmonary toxicity/pathogenicity studies demonstrated that Bacillus amyloliquefaciens strain D747 is not toxic, infective or pathogenic at the doses tested.

Another commenter also expressed opposition to granting a tolerance or an exemption from the requirement of a tolerance for this and other chemicals that were listed in the same registration notice. (EPA-HQ-OPP-2010-0905-0003). This commenter stated that the food supply must be rigorously tested, that studies must be subjected to independent peer review, and that only long term studies can provide data on the health impact to these chemicals. Consistent with section 408(b)(2)(D) of FFDCA, the testing data that were provided and evaluated by EPA for Bacillus amyloliquefaciens strain D747, as described in Unit III.B., support granting this exemption.

Therefore, an exemption is established for residues of Bacillus amyloliquefaciens strain D747.

This final rule establishes an exemption from the requirement of a tolerance under section 408(d) of FFDCA in response to a petition submitted to the Agency. The Office of Management and Budget (OMB) has exempted these types of actions from review under Executive Order 12866, entitled Regulatory Planning and Review (58 FR 51735, October 4, 1993). Because this final rule has been exempted from review under Executive Order 12866, this final rule is not subject to Executive Order 13211, entitled Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, May 22, 2001) or Executive Order 13045, entitled Protection of Children from Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 1997). This final rule does not contain any information collections subject to OMB approval under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq., nor does it require any special considerations under Executive Order 12898, entitled Federal Actions To Address Environmental Justice in Minority Populations and Low-Income Populations (59 FR 7629, February 16, 1994).

Since tolerances and exemptions that are established on the basis of a petition under section 408(d) of FFDCA, such as the tolerance in this final rule, do not require the issuance of a proposed rule, the requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq. ) do not apply.

This final rule directly regulates growers, food processors, food handlers, and food retailers, not States or tribes, nor does this action alter the relationships or distribution of power and responsibilities established by Congress in the preemption provisions of section 408(n)(4) of FFDCA. As such, the Agency has determined that this action will not have a substantial direct effect on States or tribal governments, on the relationship between the national government and the States or tribal governments, or on the distribution of power and responsibilities among the various levels of government or between the Federal Government and Indian tribes. Thus, the Agency has determined that Executive Order 13132, entitled Federalism (64 FR 43255, August 10, 1999) and Executive Order 13175, entitled Consultation and Coordination with Indian Tribal Governments (65 FR 67249, November 9, 2000) do not apply to this final rule. In addition, this final rule does not impose any enforceable duty or contain any unfunded mandate as described under Title II of the Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4).

This action does not involve any technical standards that would require Agency consideration of voluntary consensus standards pursuant to section 12(d) of the National Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272 note).

The Congressional Review Act, 5 U.S.C. 801 et seq., generally provides that before a rule may take effect, the agency promulgating the rule must submit a rule report to each House of the Congress and to the Comptroller General of the United States. EPA will submit a report containing this rule and other required information to the U.S. Senate, the U.S. House of Representatives, and the Comptroller General of the United States prior to publication of this final rule in the Federal Register . This final rule is not a “major rule” as defined by 5 U.S.C. 804(2).

Therefore, 40 CFR chapter I is amended as follows:

The GSA Office of the Inspector General (OIG) conducted an audit of GSA's information and information technology systems to verify that GSA has met the requirements of the Federal Information Security Management Act of 2002 (FISMA). The OIG made a recommendation to strengthen the security requirements in contracts and orders for information technology supplies, services and systems. GSA agreed with the OIG recommendation and published an interim rule in the Federal Register at 76 FR 34886 on June 15, 2011, with a request for comments. As a result, this final rule implements the interim rule with only minor changes.

The changes to GSAR Parts 539 and 552 will remain as implemented by the interim rule.

The final rule contains the following changes to GSAR Parts 501 and 552:

Two public comments from one respondent were received in response to the interim rule.

1. Comment: The first comment recommended that a specific reference to Federal Information Processing Standards (FIPS) 199 and 200 should be referenced within GSAR Part 539.

Response: Within GSAR section 539.7001(d) and GSAR clause 552.239-71(b), there is a reference and link to the “CIO IT Security Procedural Guide 09-48, “Security Language for Information Technology Acquisitions Efforts.” ” This document contains security requirements for protecting the government's data and systems; this includes the requirements of FIPS 199 and 200. Therefore, the paragraph is not changed.

2. Comment: Suggested minor changes to 552.239-71(k). The suggestion changed the language to read as follows: “* * * Access shall be provided to the extent required, in the Government's judgment, to conduct an inspection, evaluation, investigation or audit * * *”.

Response: The language in 552.239-71(k) will be changed to reflect the proposed change.

Executive Orders 12866 and 13563 direct agencies to assess all costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety effects, distributive impacts, and equity). Executive Order 13563 emphasizes the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules, and of promoting flexibility. This is a significant regulatory action and, therefore, was subject to review under Section 6(b) of Executive Order 12866, Regulatory Planning and Review, dated September 30, 1993. This rule is not a major rule under 5 U.S.C. 804.

This final rule may have a significant economic impact on a substantial number of small entities within the meaning of the Regulatory Flexibility Act, 5 U.S.C. 601 et seq., because the rule requires contractors, within 30 days after contract award to submit an IT Security Plan to the contracting officer and contracting officer's representative that describes the processes and procedures that will be followed to ensure appropriate security of IT resources that are developed, processed, or used under the contract. The rule will also require that contractors submit written proof of IT security authorization six months after award, and verify that the IT Security Plan remains valid annually. Where this information is not already available, this may mean small businesses will need to become familiar with the requirements, research the requirements, develop the documents, submit the information, and create the infrastructure to track, monitor and report compliance with the requirements. However, GSA expects that the impact will be minimal, because the clause includes requirements that IT service contractors should be familiar with through other agency clauses, existing GSA IT security requirements, and Federal laws and guidance. Small businesses are active providers of IT services.

The Regulatory Secretariat has submitted a copy of the Final Regulatory Flexibility Analysis (FRFA) to the Chief Counsel for Advocacy of the Small Business Administration. A copy of the FRFA may be obtained from the Regulatory Secretariat.

The analysis is summarized as follows:

The Paperwork Reduction Act (44 U.S.C. chapter 35) applies. The rule contains information collection requirements. OMB has cleared this information collection requirement under OMB Control Number 3090-0294, titled: Implementation of Information Technology Security Provision.

Section 501.106, OMB Approval under the Paperwork Reduction Act, the chart will be revised to include the OMB approval of the collection requirement from 552.239-71, Security Requirements for Unclassified Information Technology Resources. The collection request was defined in the interim rule; however no OMB control number was available at time of the interim rule publication. The information collection request was posted in the Federal Register at 76 FR 781010, December 15, 2011, and is currently requesting comments. Any comments received will be addressed in a subsequent Federal Register document.

Accordingly, the interim rule amending 48 CFR parts 539 and 552, which was published in the Federal Register at 76 FR 34886 on June 15, 2011, is adopted as final with the following changes and part 501 is amended as follows:

Pursuant to 5 U.S.C. 552(a) and 1 CFR Part 51, when NHTSA wishes to incorporate the standards and practices of other standardizing bodies into its FMVSSs, it may incorporate those materials by reference instead of reproducing them verbatim in the FMVSS. It must, however, obtain the approval of the Director of the Federal Register for each such incorporation. This final rule updates and consolidates all of the references to the many standards and practices that are incorporated by reference into the FMVSSs in Part 571. Although this part already contains a section devoted to materials incorporated by reference, § 571.5, Matter Incorporated by Reference, the list is incomplete in that section and has not been updated regularly. Instead, in many cases, materials have been incorporated piecemeal into individual FMVSSs throughout Part 571.

This final rule moves those scattered references into the centralized list and moves the individual “incorporation by reference” paragraphs contained in some of the sections of Part 571 into § 571.5 so that all of the incorporations appear in one location in that part. Additionally, we are revising other paragraphs in the sections of Part 571 in order to include citations to § 571.5 when incorporated materials are referenced and to correct grammatical errors. This rule does not substantively alter or remove from Part 571 any of the existing incorporations by reference, except for those publications that are only referenced in the obsolete standard and provisions that, as discussed below, are being removed from the CFR. However, this rule does make minor textual changes to the citations to the publications incorporated by reference.

Specifically, this rule standardizes the format used to reference the various materials incorporated by reference and makes minor corrections to reflect the accurate titles of these materials. Additionally this rule incorporates the most recently reapproved versions of several ASTM International standards. 1 These versions are identical to the versions of the standards currently incorporated by reference. This rule also amends the title of the American Association of Textile Chemists and Colorists (AATCC) “Geometric Gray Scale,” referenced in FMVSS Nos. 209 and 213, to its current title, “Gray Scale for Evaluating Change in Color.”  2 These amendments do not alter the substance of any of the sections of Part 571 nor do they alter the requirements of the FMVSSs contained therein.

In addition to consolidating the list of materials incorporated by reference, this rule amends § 571.5 to include updated language regarding how the public may obtain copies of the incorporated materials, including new procedures for retrieving materials from the National Archives and Records Administration and a new format indicating the sections where incorporated materials are referenced. Today's document also updates the contact information for all sources of the incorporated materials, including phone numbers and Web sites, where possible, to assist members of the public in acquiring the incorporated materials.

As indicated in the DATES section above, the amendments to FMVSS No. 108 (§ 571.108) are not effective until December 1, 2012. The reason for this delay is that on December 4, 2007, NHTSA published a final rule amending FMVSS No. 108 (72 FR 68234). The purpose of the 2007 rule was to reorganize the standard and provide a more straightforward and logical presentation of the applicable regulatory requirements. In response to several petitions for reconsideration, the agency delayed the effective date of the 2007 rule until December 1, 2012 (73 FR 50730; 74 FR 58213). Accordingly, the technical amendments made to the amended version of FMVSS No. 108 by today's final rule are likewise not effective until December 1, 2012. Additionally, the agency notes that the updated table of incorporated materials created by this document in § 571.5 only includes the publications referenced by the amended version of FMVSS No. 108, and does not include all of the publications cited in the version of the standard currently in effect. However, this final rule does not substantively alter or remove any of the references to the incorporated materials in the version of FMVSS No. 108 currently in effect.

This final rule removes the text of one obsolete FMVSS, No. 208a (571.208a). FMVSS No. 208a only applies to vehicles manufactured between January 27, 2004, and August 31, 2004. Given the limited period of applicability of this FMVSS and the fact that those dates are well in the past, this standard is no longer needed in the text of the CFR. This final rule also removes references to FMVSS No. 208a contained in other FMVSSs.

Likewise, this final rule removes outdated provisions contained in other FMVSSs. These provisions are applicable to vehicles and equipment manufactured before dates that have already passed. Accordingly, like FMVSS No. 208a, these provisions are no longer needed in the text of the CFR.

Finally, this final rule makes two technical amendments to Part 571 to correct inaccurate references. First, the authority citation of Part 571 incorrectly cites 49 U.S.C. 30177. This section does not exist. The correct citation is 49 U.S.C. 30117. Second, paragraph S7.2.1 of FMVSS No. 202a incorrectly references paragraph S6.1 of that standard. Paragraph S7.2.1 describes the calculation of annual vehicle production for the purposes of the September 1, 2010, to September 1, 2011, phase-in of the rear seat requirements of the new standard. However, paragraph S7.2.1 references S6.1, which describes the percentage of vehicles manufactured between September 1, 2009, and September 1, 2010, that must comply with the new standard as opposed to the old standard. The correct reference is paragraph S7.1, which describes the percentage of vehicles manufactured between September 1, 2010, and September 1, 2011, that must comply with the rear seat requirements of the new standard.

Section 553 of the Administrative Procedure Act (5 U.S.C. 553) provides that when an agency, for good cause, finds that notice and public procedure are impracticable, unnecessary, or contrary to the public interest, the agency may issue a final rule without providing notice and an opportunity for public comment (5 U.S.C. 553(b)(B)). NHTSA has determined that there is good cause for making these technical amendments final without notice and an opportunity for public comment. These amendments consolidate the references to materials currently incorporated by reference in the individual sections of Part 571 and correct the syntax of the references to these publications within each section. The amendments also correct grammatical errors and incorrect references in Part 571. Finally, the amendments delete the text of one obsolete FMVSS as well as various obsolete provisions in other sections of Part 571. The amendments do not alter the substance of the amended sections nor do they alter the requirements of the FMVSSs contained therein. Accordingly, notice and public comment are unnecessary.

We are making the amendments effective 30 days after publication of this document, with the exception of the amendments to FMVSS No. 108, which are effective December 1, 2012. Given that the amendments do not make any substantive changes, we find good cause for making the amendments effective within this timeframe.

The agency has discussed the relevant requirements of Executive Order 12866, Executive Order 13563, DOT Regulatory Policies and Procedures, the National Environmental Policy Act, the Regulatory Flexibility Act, Executive Order 13132 (Federalism), Executive Order 12988 (Civil Justice Reform), the Unfunded Mandates Reform Act, the Paperwork Reduction Act, Executive Order 13045 (Protection of Children from Environmental Health and Safety Risks), the National Technology Transfer and Advancement Act, and Executive Order 13211 (Energy Effects), as applicable, in the underlying substantive rules establishing and amending the various sections of Part 571. Those discussions are not affected by these amendments.

The Department of Transportation assigns a regulation identifier number (RIN) to each regulatory action listed in the Unified Agenda of Federal Regulations. The Regulatory Information Service Center publishes the Unified Agenda in April and October of each year. You may use the RIN contained in the heading at the beginning of this document to find this action in the Unified Agenda.

Anyone is able to search the electronic form of all comments received into any of our dockets by the name of the individual submitting the comment (or signing the comment, if submitted on behalf of an association, business, labor union, etc.). You may review DOT's complete Privacy Act Statement in the Federal Register published on April 11, 2000 (Volume 65, Number 70; Pages 19477-78) or you may visit http://www.regulations.gov .

In consideration of the foregoing, NHTSA amends 49 CFR Part 571 as follows: