[Federal Register Volume 81, Number 207 (Wednesday, October 26, 2016)]
[Proposed Rules]
[Pages 74368-74372]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-25852]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. FDA-2015-N-1355]
RIN 0910-AH36


Use of Ozone-Depleting Substances

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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[[Page 74369]]

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to amend its regulation on uses of ozone-depleting substances 
(ODSs), including chlorofluorocarbons (CFCs), to remove the designation 
for certain products as ``essential uses'' under the Clean Air Act. 
Essential-use products are exempt from the ban by FDA on the use of 
CFCs and other ODS propellants in FDA-regulated products and from the 
ban by the Environmental Protection Agency (EPA) on the use of ODSs in 
pressurized dispensers. This action, if finalized, will remove the 
essential-use exemption for anesthetic drugs for topical use on 
accessible mucous membranes of humans where a cannula is used for 
application. FDA is proposing this action because these products are no 
longer being marketed in approved versions that contain ODSs and 
because alternative products that do not use ODSs are now available.

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

ADDRESSES: You may submit comments as follows:

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2015-N-1355 for ``Use of Ozone-Depleting Substances.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Daniel Orr, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 6246, Silver Spring, MD 20993, 240-402-0979, 
[email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Production of ODSs has been phased out worldwide under the terms of 
the Montreal Protocol on Substances that Deplete the Ozone Layer 
(Montreal Protocol) (September 16, 1987, S. Treaty Doc. No. 10, 100th 
Cong., 1st sess., 26 I.L.M. 1541 (1987)). In accordance with the 
provisions of the Montreal Protocol, under authority of Title VI of the 
Clean Air Act (section 601 et seq.), the manufacture of ODSs, including 
CFCs, in the United States was generally banned as of January 1, 1996. 
To receive permission to manufacture CFCs in the United States after 
the phase-out date, manufacturers must obtain an exemption from the 
phase-out requirements from the parties to the Montreal Protocol. 
Procedures for securing an essential-use exemption under the Montreal 
Protocol are described in a request by EPA for applications for 
exemptions (60 FR 54349, October 23, 1995).
    Firms that wished to use ODSs manufactured after the phase-out date 
in medical devices (as defined in section 601(8) of the Clean Air Act 
(42 U.S.C. 7671(8)) covered under section 610 of the Clean Air Act (42 
U.S.C. 7671i) must receive exemptions for essential uses under the 
Montreal Protocol. EPA regulations implementing the provisions of 
section 610 of the Clean Air Act contain a general ban on the use of 
ODSs in pressurized dispensers, such as metered-dose inhalers (MDIs) 
(40 CFR 82.64(c) and 82.66(d)). These EPA regulations exempt from the 
general ban ``medical devices'' that FDA considers essential and that 
are listed in Sec.  2.125(e) (21 CFR 2.125(e)). Section 601(8) of the 
Clean Air Act defines ``medical device'' as any device (as defined in 
the Federal Food, Drug & Cosmetic Act (the FD&C Act) (21 U.S.C. 321)), 
diagnostic product, drug (as defined in the FD&C Act), and drug 
delivery system, if such device, diagnostic product, drug, or drug 
delivery system uses a class I or class II ODS for which no safe and 
effective alternative has been developed (and, where necessary, has 
been approved by the Commissioner of Food and Drugs), and if such 
device, diagnostic product, drug, or drug delivery system has, after 
notice and opportunity for public comment, been

[[Page 74370]]

approved and determined to be essential by the Commissioner in 
consultation with the Administrator of EPA. Class I substances include 
CFCs, halons, carbon tetrachloride, methyl chloroform, methyl bromide, 
and other chemicals not relevant to this document (see 40 CFR part 82, 
appendix A to subpart A). Class II substances include 
hydrochlorofluorocarbons (see 40 CFR part 82, appendix B to subpart A).
    A drug, device, cosmetic, or food contained in an aerosol product 
or other pressurized dispenser that releases a CFC or other ODS 
propellant generally is not considered an essential use of the ODS 
under the Clean Air Act except as provided in Sec.  2.125(c) and (e). 
This prohibition is based on scientific research indicating that CFCs 
and other ODSs reduce the amount of ozone in the stratosphere and 
thereby increase the amount of ultraviolet radiation reaching the 
Earth. An increase in ultraviolet radiation will increase the incidence 
of skin cancer, and produce other adverse effects of unknown magnitude 
on humans, animals, and plants (80 FR 36937, June 29, 2015). Sections 
2.125(c) and (e) provide exemptions for essential uses of ODSs for 
certain products containing ODS propellants that FDA determines provide 
unique health benefits that would not be available without the use of 
an ODS.
    Faced with the statutorily mandated phase-out of the production of 
ODSs, drug manufacturers have developed alternatives to MDIs and other 
self-pressurized drug dosage forms that do not contain ODSs. Examples 
of these alternative dosage forms are MDIs that use non-ODSs as 
propellants and dry-powder inhalers. The availability of alternatives 
to ODSs means that certain drug products listed in Sec.  2.125(e) are 
no longer essential uses of ODSs. Therefore, due to lack of marketing 
of an approved product containing an ODS, and the availability of 
alternative products that do not contain an ODS, FDA is proposing to 
amend its regulations to remove the essential-use designation for 
anesthetic drugs for topical use on accessible mucous membranes of 
humans where a cannula is used for application (Sec.  
2.125(e)(4)(iii)).
    On June 29, 2015, FDA published a notice and request for comment 
concerning its tentative conclusion that anesthetic drugs for topical 
use on accessible mucous membranes of humans where a cannula is used 
for application no longer constitute an essential use under the Clean 
Air Act (June 2015 notice). FDA requested comment concerning its 
tentative finding that anesthetic drugs for topical use on accessible 
mucous membranes of humans where a cannula is used for application are 
no longer being sold in an approved ODS formulation. Under Sec.  
2.125(g)(1), an active moiety may no longer constitute an essential use 
(Sec.  2.125(e)) if it is no longer marketed in an approved ODS 
formulation. The failure to market indicates nonessentiality because 
the absence of a demand sufficient for even one company to market the 
product is highly indicative that the use is not essential.

II. Comment on the June 2015 Notice and FDA Response

    FDA received one comment concerning its tentative finding that 
anesthetic drugs for topical use on accessible mucous membranes of 
humans where a cannula is used for application are no longer marketed 
in an approved ODS formulation and, therefore, no longer constitute an 
essential use (see June 2015 notice). On August 21, 2015, Cetylite 
Industries, Inc. (Cetylite) submitted a comment stating that ``FDA's 
belief that no products are marketed under this exemption is 
incorrect'' (Comment 1). According to the comment, Cetylite 
manufactures Cetacaine Spray (CETACAINE), a topical anesthetic spray 
with an active ingredient combination of benzocaine, tetracaine HCl, 
and butamben that uses a blend of CFCs as the propellant under the 
essential-use exemption found in Sec.  2.125(e)(4)(iii). However, 
CETACAINE is not an approved drug product and does not qualify as an 
essential use under Sec.  2.125(e)(4)(iii). As described in Sec.  
2.125(c), an aerosol drug product or other pressurized dispenser that 
releases an ODS is an essential use of the ODS under the Clean Air Act 
only if it is listed in Sec.  2.125(e) and if an investigational 
application or an approved marketing application is in effect.
    Cetylite states that CETACAINE has been marketed continuously since 
the mid-1950s under a request for a Drug Efficacy Study Implementation 
(DESI) review that was submitted in 1976. FDA published a DESI notice 
(DESI 8076 (Docket No. 75N-0203) in the Federal Register of December 9, 
1975 (40 FR 57379)) in which the Agency offered an opportunity for a 
hearing on a proposal to withdraw approval of a combination drug 
product containing two of the three ingredients contained in CETACAINE. 
In response to this DESI notice, Cetylite requested a hearing regarding 
the effectiveness of CETACAINE. While FDA's review of the product's 
effectiveness has been pending, Cetylite has been marketing CETACAINE 
without an approved new drug application.
    In 1979, based on a citizen petition submitted by Cetylite 
regarding its CETACAINE product, FDA proposed that anesthetic drugs for 
topical use on accessible mucous membranes of humans where a cannula is 
used for application were essential uses of ODSs (44 FR 33114, June 8, 
1979) (1979 Proposed Rule). In the preamble to the 1979 Proposed Rule, 
FDA noted that its tentative finding as to CETACAINE's essentiality 
under Sec.  2.125 was ``conditional'' on the product being found 
effective. Similarly, in the preamble to the Final Rule amending Sec.  
2.125, FDA stated that ``the determination in this document that 
CETACAINE Aerosol is an essential use of a chlorofluorocarbon is also 
conditional'' on a finding that CETACAINE is effective for the use 
described in Sec.  2.125(e)(4)(iii) (45 FR 22902, April 4, 1980).
    To date, FDA has not made a finding that CETACAINE is effective for 
the use described in Sec.  2.125(e)(4)(iii). There is no 
investigational new drug application or approved marketing application 
in effect for the ODS formulation of CETACAINE, as required for a 
finding of essentiality under Sec.  2.125(c). Accordingly, CETACAINE 
does not meet the conditions to qualify as an essential use of ODSs 
under Sec.  2.125(e)(4)(iii), and FDA believes that its proposed 
finding that anesthetic drugs for topical use on accessible mucous 
membranes of humans where a cannula is used for application are no 
longer marketed in an approved ODS formulation remains correct. 
Moreover, alternative products for the same use that do not use ODSs, 
such as lidocaine, are now available, further suggesting that 
anesthetic drugs for topical use are no longer an essential use of 
ODSs. In addition, a recently completed laboratory study demonstrated 
that lidocaine may be a safer alternative to benzocaine (Ref. 1). The 
study found that benzocaine was substantially more likely than 
lidocaine to form methemoglobin, the cause of the serious blood 
disorder called methemoglobinemia.

III. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563

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direct us to assess all costs and benefits of available regulatory 
alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). We have developed a comprehensive 
Economic Analysis of Impacts that assesses the impacts of the proposed 
rule. We believe that this proposed rule is not a significant 
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. We propose to certify that the proposed rule will 
not have a significant economic impact on a substantial number of small 
entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $146 million, using the most current (2015) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

B. Need for the Regulation

    This rule is necessary to comply with the Montreal Protocol under 
authority of Title VI of the Clean Air Act (section 601 et seq.), which 
banned the manufacture of ODSs, including CFCs, to reduce the depletion 
of the ozone layer in the United States as of January 1, 1996. EPA 
regulations exempted from the ban medical devices, diagnostic products, 
drugs, and drug delivery systems that FDA considered essential and that 
are listed in Sec.  2.125(e) when they use a class I or class II ODS 
for which no safe and effective alternative has been developed.
    Anesthetic drugs for topical use on accessible mucous membranes of 
humans where a cannula is used for application are not available in the 
product market in an approved ODS formulation. Because the product is 
not marketed under an investigational new drug (IND), new drug 
application (NDA), or abbreviated new drug application (ANDA) and 
alternative products for the same use that do not use ODSs, such as 
lidocaine, are now available, the product is nonessential under Sec.  
2.125(g)(1). With the adoption of this rule, any potential 
manufacturers of these anesthetic drugs will have notice about their 
requirements to comply with the ban of products from containing ODSs.

C. Costs and Benefits

1. Number of Affected Entities
    There are no affected entities covered by this rule because there 
are no current manufacturers of approved products that would qualify as 
``essential'' products under the current regulation.
2. Costs
    ODS-containing anesthetic products for topical use on accessible 
mucous membranes of humans where a cannula is used for application are 
not marketed under an IND, NDA, or ANDA and would not qualify as 
``essential'' products under the current regulation; consequently, 
removal of the exemption for such drugs would not present the public, 
consumers, insurers, or producers with any costs.
3. Health Benefits
    The proposed rule would implement the requirements of the Clean Air 
Act that ban the use of products containing ODSs that no longer meet 
the requirements for essential use. The benefits stem from preventing 
the ODSs that would have been emitted by potential market entrants. The 
social benefits of the proposed rule derive from greater compliance 
with the Clean Air Act. Because there will not be any change in 
exposure and any resulting risk from the proposed rule, there will not 
be any direct public health benefits.

D. Economic Summary

    The proposed rule, if finalized, will remove the essential-use 
exemption for anesthetic drugs for topical use on accessible mucous 
membranes of humans where a cannula is used for application. The 
primary public health benefit from adoption of the proposed rule is to 
reduce the depletion of the ozone layer to decrease human exposure to 
ultraviolet radiation. Because anesthetic drugs for topical use are not 
currently sold in the market in an approved form, there would be no 
health benefit or social cost for removing the exemption for such 
products from the ban.

IV. Regulatory Flexibility Analysis

    FDA has examined the economic implications of the proposed rule as 
required by the Regulatory Flexibility Act. If a rule will have a 
significant economic impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires Agencies to analyze regulatory 
options that would lessen the economic effect of the rule on small 
entities. We propose to certify that this proposed rule will not have a 
significant economic impact on a substantial number of small entities. 
This analysis, together with other relevant sections of this document, 
serves as the proposed regulatory flexibility analysis.

V. Analysis of Environmental Impacts

    We have determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no 
collection of information. Therefore, clearance by the Office of 
Management and Budget under the Paperwork Reduction Act of 1995 is not 
required.

VII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
this proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we conclude that the rule does not contain policies that have 
federalism implications as defined in the Executive Order and, 
consequently, a federalism summary impact statement is not required.

VIII. Reference

    The following reference is on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; it are also 
available electronically at http://www.regulations.gov.

1. Hartman, N. R., J. J. Mao, H. Zhou, et al., ``More Methemoglobin 
is Produced by Benzocaine Treatment Than Lidocaine Treatment in 
Human In Vitro Systems.'' Regulatory Toxicology and Pharmacology, 
70:182-188, 2014.

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List of Subjects

In 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Drugs, Foods.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, we propose 
that 21 CFR part 2 be amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

0
1. The authority citation for part 2 continues to read as follows:

    Authority: 15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342, 
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42 
U.S.C. 7671 et seq.


Sec.  2.125  [Amended]

0
2. In Sec.  2.125, remove and reserve paragraph (e)(4)(iii).

    Dated: October 20, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-25852 Filed 10-25-16; 8:45 am]
 BILLING CODE 4164-01-P