[Federal Register Volume 86, Number 51 (Thursday, March 18, 2021)]
[Proposed Rules]
[Pages 14707-14714]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-05589]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-806]


Schedules of Controlled Substances: Placement of Four Specific 
Fentanyl-Related Substances in Schedule I

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration proposes placing ethyl (1-
phenethylpiperidin-4-yl)(phenyl)carbamate (fentanyl carbamate), N-(2-
fluorophenyl)-N-(1-phenethylpiperidin-4-yl)acrylamide (ortho-
fluoroacryl fentanyl), N-(2-fluorophenyl)-N-(1-phenethylpiperidin-4-
yl)isobutyramide (ortho-fluoroisobutyryl fentanyl), and N-(4-
fluorophenyl)-N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide (para-
fluoro furanyl fentanyl), including their isomers, esters, ethers, 
salts, and salts of isomers, esters, and ethers, in schedule I of the 
Controlled Substances Act. These four specific substances fall within 
the definition of fentanyl-related substances set forth in the February 
6, 2018, temporary scheduling order. Through the Temporary 
Reauthorization and Study of the Emergency Scheduling of Fentanyl 
Analogues Act, which became law on February 6, 2020, Congress extended 
the temporary control of fentanyl-related substances until May 6, 2021. 
If finalized, this action would make permanent the existing regulatory 
controls and administrative, civil, and criminal sanctions applicable 
to schedule I controlled substances on persons who handle (manufacture, 
distribute, reverse distribute, import, export, engage in research, 
conduct instructional activities or chemical analysis, or possess), or 
propose to handle fentanyl carbamate, ortho-fluoroacryl fentanyl, 
ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl.

DATES: Comments must be submitted electronically or postmarked on or 
before April 19, 2021.
    Requests for hearing and waivers of an opportunity for a hearing or 
to participate in a hearing must be received on or before April 19, 
2021.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-806'' on all electronic and written correspondence, 
including any attachments.
     Electronic comments: Interested persons may file written 
comments on this proposal in accordance with 21 CFR 1308.43(g). The 
Drug Enforcement Administration (DEA) encourages that all comments be 
submitted electronically through the Federal eRulemaking Portal which 
provides the ability to type short comments directly into the comment 
field on the web page or to attach a file for lengthier comments. 
Please go to http://www.regulations.gov and follow the online 
instructions at that site for submitting comments. Upon completion of 
your submission you will receive a Comment Tracking Number for your 
comment. Please be aware that submitted comments are not 
instantaneously available for public view on Regulations.gov. If you 
have received a Comment Tracking Number, your comment has been 
successfully submitted and there is no need to resubmit the same 
comment. Commenters should be aware that the electronic Federal Docket 
Management System will not accept comments after 11:59 p.m. Eastern 
Time on the last day of the comment period.
     Paper comments: Paper comments that duplicate the 
electronic submission are not necessary. Should you wish to mail a 
paper comment in lieu of an electronic comment, it should be sent via 
regular or express mail to: Drug Enforcement Administration, Attn: DEA 
Federal Register Representative/DPW, 8701 Morrissette Drive, 
Springfield, Virginia 22152.
     Hearing requests: Interested persons may file a request 
for hearing or waiver of hearing pursuant to 21 CFR 1308.44 and in 
accordance with 21 CFR 1316.45 and/or 1316.47, as applicable. All 
requests for hearing and waivers of participation must be sent to: Drug 
Enforcement Administration, Attn: Administrator, 8701 Morrissette 
Drive, Springfield, Virginia 22152. All requests for hearing and 
waivers of participation should also be sent to: (1) Drug Enforcement 
Administration, Attn: Hearing Clerk/OALJ, 8701 Morrissette Drive, 
Springfield, Virginia 22152; and (2) Drug Enforcement Administration, 
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive, 
Springfield, Virginia 22152.

FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug and Chemical 
Evaluation Section, Diversion Control Division, Drug Enforcement 
Administration; Mailing Address: 8701 Morrissette Drive, Springfield, 
Virginia 22152; Telephone: (571) 362-3249.

SUPPLEMENTARY INFORMATION:

[[Page 14708]]

Posting of Public Comments

    Please note that all comments received in response to this docket 
are considered part of the public record. They will, unless reasonable 
cause is given, be made available by the Drug Enforcement 
Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying 
information (such as your name, address, etc.) voluntarily submitted by 
the commenter. The Freedom of Information Act applies to all comments 
received. If you want to submit personal identifying information (such 
as your name, address, etc.) as part of your comment, but do not want 
it to be made publicly available, you must include the phrase 
``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of your 
comment. You must also place all of the personal identifying 
information you do not want made publicly available in the first 
paragraph of your comment and identify what information you want 
redacted.
    If you want to submit confidential business information as part of 
your comment, but do not want it to be made publicly available, you 
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the 
first paragraph of your comment. You must also prominently identify 
confidential business information to be redacted within the comment.
    Comments containing personal identifying information and 
confidential business information identified as directed above will be 
made publicly available in redacted form. If a comment has so much 
confidential business information or personal identifying information 
that it cannot be effectively redacted, all or part of that comment may 
not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information 
(such as name, address, and phone number) included in the text of your 
electronic submission that is not identified as directed above as 
confidential.
    An electronic copy of this document and supplemental information to 
this proposed rule are available at http://www.regulations.gov for easy 
reference.

Request for Hearing or Waiver of Participation in a Hearing

    Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking 
``on the record after opportunity for a hearing.'' Such proceedings are 
conducted pursuant to the provisions of the Administrative Procedure 
Act, 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316, 
subpart D. Interested persons may file requests for hearing or notices 
of intent to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(a) or (b), and include a statement of 
interest in the proceeding and the objections or issues, if any, 
concerning which the person desires to be heard. Any interested person 
may file a waiver of an opportunity for a hearing or to participate in 
a hearing together with a written statement regarding the interested 
person's position on the matters of fact and law involved in any 
hearing as set forth in 21 CFR 1308.44(c).
    All requests for a hearing and waivers of participation must be 
sent to DEA using the address information provided above.

Legal Authority

    The Controlled Substances Act (CSA) provides that proceedings for 
the issuance, amendment, or repeal of the scheduling of any drug or 
other substance may be initiated by the Attorney General (delegated to 
the Administrator of DEA pursuant to 28 CFR 0.100) on his own motion. 
21 U.S.C. 811(a). This proposed action is supported by a recommendation 
from the Acting Assistant Secretary for Health of U.S. Department of 
Health and Human Services (HHS) (Acting Assistant Secretary) and an 
evaluation of all other relevant data by DEA. If finalized, this action 
would make permanent the existing temporary regulatory controls and 
administrative, civil, and criminal sanctions of schedule I controlled 
substances on any person who handles or proposes to handle fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl.

Background

    On February 6, 2018, pursuant to 21 U.S.C. 811(h)(1), the then-
Acting Administrator of DEA published an order in the Federal Register 
(83 FR 5188) temporarily placing fentanyl-related substances, as 
defined in that order, in schedule I of the CSA upon finding that these 
substances pose an imminent hazard to the public safety. As discussed 
below in Factor 3, the four substances named in this proposed rule 
(fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl) meet the 
existing definition of fentanyl-related substances as they are not 
otherwise controlled in any other schedule (i.e., not included under 
another Administration Controlled Substance Code Number) and are 
structurally related to fentanyl by one or more of the five 
modifications listed under the definition.
    That temporary order was effective upon the date of publication. 
Pursuant to 21 U.S.C. 811(h)(2), the temporary control of fentanyl-
related substances, a class of substances as defined in the order, as 
well as the four specific substances already covered by that order, was 
set to expire on February 6, 2020. However, as explained in DEA's April 
10, 2020, correcting amendment (85 FR 20155), Congress overrode and 
extended that expiration date until May 6, 2021, by enacting on 
February 6, 2020 the Temporary Reauthorization and Study of the 
Emergency Scheduling of Fentanyl Analogues Act (Pub. L. 116-114, sec. 
2, 134 Stat. 103). By operation of law, the temporary control of 
fentanyl-related substances, which includes these four covered 
substances, will remain in effect until May 6, 2021, unless DEA 
permanently places them in schedule I prior to May 6, 2021. As 
discussed in the above Legal Authority section, proceedings under 21 
U.S.C. 811(a) may be initiated by the Administrator of DEA on his own 
motion.
    The Acting Administrator, on his own motion, is initiating 
proceedings to permanently schedule the following four fentanyl-related 
substances: Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-
fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl. DEA 
gathered the available information regarding the pharmacology, 
chemistry, trafficking, actual abuse, pattern of abuse, and the 
relative potential for abuse for 16 fentanyl-related substances (the 
four that are the subject of this proposed rule as well as 12 other 
fentanyl-related substances \1\). On April 3, and October 2, 2019, the 
then-Acting Administrator submitted this data to the Assistant 
Secretary for Health of HHS, and requested that HHS provide DEA with a 
scientific and medical evaluation and a scheduling recommendation for 
these 16 fentanyl-related substances, in accordance with 21 U.S.C. 
811(b) and (c). On July 2, 2020, HHS provided DEA with a scientific and 
medical evaluation and scheduling recommendation for 11

[[Page 14709]]

of the 12 \2\ other fentanyl-related substances (none of which included 
the four substances named in this proposed rule). In October 2020 and 
March 2021, DEA issued two scheduling actions for these 11 substances, 
with one action permanently controlling one of the 11 substances, and 
another action proposing the continued control of 10 substances.\3\
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    \1\ 2'-fluoro ortho-fluorofentanyl, 4'-methyl acetyl fentanyl, 
[beta]'-phenyl fentanyl, [beta]-methyl fentanyl, benzodioxole 
fentanyl, crotonyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-
methyl acetylfentanyl, ortho-methyl methoxyacetylfentanyl, para-
methylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl.
    \2\ HHS' scientific and medical evaluation for benzodioxole 
fentanyl is ongoing. DEA will not further discuss this substance in 
this proposed rule.
    \3\ On October 2, 2020, DEA issued a final order (85 FR 62215) 
for crotonyl fentanyl and maintained its placement in schedule I, 
using DEA's authority under 21 U.S.C. 811(d)(1), to meet obligations 
under the 1961 Single Convention on Narcotic Drugs, March 30, 1961, 
18 U.S.T. 1407, 570 U.N.T.S. 151, as amended. On March 3, 2021, DEA 
issued a general notice of proposed rulemaking (86 FR 12296) to 
permanently control 2'-fluoro ortho-fluorofentanyl, 4'-methyl acetyl 
fentanyl, [beta]-methyl fentanyl, [beta]'-phenyl fentanyl, ortho-
fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl 
methoxyacetyl fentanyl, para-methylfentanyl, phenyl fentanyl, and 
thiofuranyl fentanyl in schedule I.
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    On March 2, 2021, the Acting Assistant Secretary submitted to the 
Acting Administrator, HHS's scientific and medical evaluation and 
scheduling recommendation for the four fentanyl-related substances 
named in this proposed rule. Upon receipt of the scientific and medical 
evaluation and scheduling recommendation from HHS, DEA reviewed these 
documents and all other relevant data, and conducted its own eight-
factor analysis of the abuse potential of the four substances in 
accordance with 21 U.S.C. 811(c).

Proposed Determination to Permanently Schedule Fentanyl Carbamate, 
ortho-Fluoroacryl Fentanyl, ortho-Fluoro Isobutyryl Fentanyl, and para-
Fluoro Furanyl Fentanyl

    As discussed in the background section, the Acting Administrator is 
initiating proceedings to permanently add fentanyl carbamate, ortho-
fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro 
furanyl fentanyl to schedule I. DEA has reviewed the scientific and 
medical evaluation and scheduling recommendation from HHS, and all 
other relevant data, and conducted its own eight-factor analysis of the 
abuse potential of these four substances. Included below is a brief 
summary of each factor as analyzed by HHS and DEA, and as considered by 
DEA in its proposed scheduling action. Please note that both the DEA 
and HHS 8-Factor analyses and the Acting Assistant Secretary's March 2, 
2021, letter are available in their entirety under the tab ``Supporting 
Documents'' of the public docket for this action at http://www.regulations.gov under Docket Number ``DEA-806.''
    1. The Drug's Actual or Relative Potential for Abuse: The term 
``abuse'' is not defined in the CSA. However, the legislative history 
of the CSA suggests that DEA consider the following criteria when 
determining whether a particular drug or substance has a potential for 
abuse: \4\
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    \4\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); reprinted in 1970 
U.S.C.C.A.N. 4566, 4603.
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    (a) There is evidence that individuals are taking the drug or drugs 
containing such a substance in amounts sufficient to create a hazard to 
their health or to the safety of other individuals or to the community; 
or
    (b) There is significant diversion of the drug or drugs containing 
such a substance from legitimate drug channels; or
    (c) Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice; or
    (d) The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having a 
potential for abuse to make it likely that the drug will have the same 
potentiality for abuse as such drugs, thus making it reasonable to 
assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the health 
of the user or to the safety of the community.
    The abuse potential of fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl is associated with their pharmacological similarity to other 
schedule I (acetyl fentanyl and furanyl fentanyl) and II mu-opioid 
receptor agonist substances, which have a high potential for abuse. 
Similar to schedule II substances morphine and fentanyl, these four 
fentanyl-related substances have been shown to bind and act as mu-
opioid receptor agonists.
    These four substances have no approved medical use in the United 
States and have been encountered on the illicit drug market. The use of 
some fentanyl-related substances has been associated with adverse 
health outcomes, including death. The appearance of several substances 
structurally related to fentanyl in the illicit drug market has 
resulted in a significant increase in drug overdose deaths in the 
United States. According to the Centers for Disease Control and 
Prevention (CDC) overdose death data for 2019, there continues to be an 
increase in the number of deaths related to synthetic opioids. Opioids 
were involved in about 71 percent of all drug-involved overdose deaths 
in 2019. Further, CDC reports demonstrate that the increase in 
synthetic opioid overdose deaths are largely attributed to an increase 
in the supply of illicitly manufactured fentanyl and substances 
structurally related to fentanyl. Because fentanyl carbamate, ortho-
fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro 
furanyl fentanyl are not Food and Drug Administration (FDA)-approved 
drug products, a practitioner may not legally prescribe them, and these 
substances cannot be dispensed to an individual. Therefore, the use of 
fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl is without medical advice, 
and accordingly leads to the conclusion that these four substances are 
abused for their opioidergic properties.
    There are no legitimate drug channels for fentanyl carbamate, 
ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-
fluoro furanyl fentanyl as marketed FDA-approved drug products, but 
these substances are available for purchase from legitimate chemical 
companies for research purposes. However, despite the limited 
legitimate research use of these four substances, reports from public 
health and law enforcement data indicate that all four substances are 
being abused and taken in amounts sufficient to create a hazard to an 
individual's health. Data from forensic databases can be used as an 
indicator of illicit activity with drugs and abuse \5\ within the 
United States. According to the National Forensic Laboratory 
Information System (NFLIS),\6\ which collects and analyzes drug 
exhibits submitted to Federal, State, and local forensic laboratories, 
there were 187 total reports of these substances between 2017 and 2020 
(queried on February 22, 2021).

[[Page 14710]]

Consequently, the positive identification of the four fentanyl-related 
substances in law enforcement encounters indicates that these 
substances are being abused, and thus pose safety hazards to the health 
of users.
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    \5\ While law enforcement data is not direct evidence of abuse, 
it can lead to an inference that a drug has been diverted and 
abused. See 76 FR 77330, 77332, Dec. 12, 2011.
    \6\ NFLIS is a DEA program and a national forensic laboratory 
reporting system that systematically collects results from drug 
chemistry analyses conducted by state and local forensic 
laboratories in the United States. The NFLIS database also contains 
Federal data from U.S. Customs and Border Protection. NFLIS only 
includes drug chemistry results from completed analyses.
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    2. Scientific Evidence of the Drug's Pharmacological Effects, if 
Known: Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl are 
pharmacologically similar to other schedule I and schedule II mu-opioid 
receptor agonist substances. The abuse potential (assessed by drug 
discriminative studies) of fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl show that these substances share discriminative stimulus 
effects similar to fentanyl and morphine. Similar to schedule I and II 
opioid analgesics, these four substances bind to and activate the mu-
opioid receptor. Additionally, behavioral studies in animals 
demonstrate these four substances produce analgesic effects similar to 
fentanyl and morphine. Pre-treatment with naltrexone, an opioid 
antagonist, attenuated analgesic effect of these four substances, as 
well as fentanyl and morphine. These data indicate that the four 
substances are mu-opioid receptor agonists with effects on the central 
nervous system. Data from drug discrimination studies showed that these 
four substances share discriminative stimulus effects similar to those 
of morphine. Thus, it is concluded from in vitro and in vivo 
pharmacological studies that the effects of the four substances are 
similar to that of fentanyl and morphine and are mediated by mu-opioid 
receptor agonism.
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance: Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-
fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl are 
synthetic opioids of the 4-anilidopiperidine structural class, which 
includes fentanyl. As defined in the February 6, 2018, temporary order, 
fentanyl-related substances include any substance not otherwise 
controlled in any schedule (i.e., not included under any other 
Administration Controlled Substance Code Number) that is structurally 
related to fentanyl by one or more of the following modifications:
    (A) Replacement of the phenyl portion of the phenethyl group by any 
monocycle, whether or not further substituted in or on the monocycle;
    (B) Substitution in or on the phenethyl group with alkyl, alkenyl, 
alkoxyl, hydroxyl, halo, haloalkyl, amino or nitro groups;
    (C) Substitution in or on the piperidine ring with alkyl, alkenyl, 
alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino or nitro 
groups;
    (D) Replacement of the aniline ring with any aromatic monocycle 
whether or not further substituted in or on the aromatic monocycle; 
and/or
    (E) Replacement of the N-propionyl group by another acyl group.
    [GRAPHIC] [TIFF OMITTED] TP18MR21.000
    
    According to the February 6, 2018, temporary scheduling order, the 
existence of a substance with any one, or any combination, of above-
mentioned modifications (see Figure 1) would meet the structural 
requirements of the definition of fentanyl-related substances. The 
present four substances fall within the definition of fentanyl-related 
substances by the following modifications:
    1. Fentanyl carbamate: Replacement of the N-propionyl group by 
another acyl group (meets definition for modification E);
    2. ortho-fluoroacryl fentanyl: Substitution on the aniline ring and 
replacement of the N-propionyl group with another acyl group (meets 
definition for modifications D and E);
    3. ortho-fluoro isobutyryl fentanyl: Substitution on the aniline 
ring and replacement of the N-propionyl group with another acyl group 
(meets definition for modifications D and E);
    4. para-fluoro furanyl fentanyl: Substitution on the aniline ring 
and replacement of the N-propionyl group with another acyl group (meets 
definition for modifications D and E).
    No study has been undertaken to evaluate the efficacy, toxicology, 
and safety of the four substances in humans. It can be inferred from 
data obtained from animal studies that these four substances have 
sufficient distribution to the brain to produce depressant effects 
similar to that of other mu-opioid receptor agonists such as fentanyl. 
Data from in vitro receptor binding studies show that these four 
substances, similar to fentanyl, display high selectivity for the mu-
opioid receptor over other opioid receptor subtypes.

[[Page 14711]]

    There are no FDA-approved marketing applications for a drug product 
containing fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl for any 
therapeutic indication in the United States. Moreover, there are no 
clinical studies or petitions which have claimed an accepted medical 
use in the United States for these four substances.
    4. Its History and Current Pattern of Abuse: Fentanyl carbamate, 
ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-
fluoro furanyl fentanyl, like other substances structurally related to 
fentanyl, are disguised as a ``legal'' alternative to fentanyl. Between 
2017 and 2020, law enforcement officials in the United States 
encountered these four substances.
    5. The Scope, Duration, and Significance of Abuse: Fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl, similar to other substances 
structurally related to fentanyl, are often used as recreational drugs. 
The recreational use of these four substances and other fentanyl-
related substances continues to be of significant concern as the United 
States currently is in the midst of an opioid epidemic. These 
substances are distributed to users, often with unpredictable outcomes. 
Because users of these fentanyl-related substances and their associated 
drug products are likely to obtain these substances through unregulated 
sources, the identity, purity, and quantity are uncertain and 
inconsistent, thus posing significant adverse health risks to abusers. 
Evidence that these four substances are being abused and trafficked is 
confirmed by law enforcement encounters. NFLIS contained 187 reports of 
fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl from Federal, State, and 
local forensic laboratories between 2017 and 2020.
    6. What, if Any, Risk There Is to the Public Health: The increase 
in opioid overdose deaths in the United States has been exacerbated by 
the availability of potent synthetic opioids such as fentanyl and 
structurally related substances in the illicit drug market. These 
substances have a history of being trafficked as replacements for 
heroin and other synthetic opioids. Increasingly, law enforcement has 
encountered fentanyl and substances structurally related to fentanyl in 
counterfeit prescription opioids, heroin, and other street drugs such 
as cocaine, methamphetamine, and synthetic cannabinoids. Fentanyl is a 
potent synthetic opioid that is primarily prescribed for acute and 
chronic pain and is approximately 100 times more potent than morphine. 
As such, fentanyl has a high risk of abuse, dependence, and overdose 
that can lead to death. Because fentanyl-related substances, as defined 
in the February 6, 2018, temporary order, have similar chemical 
structure to fentanyl, these substances are expected to have similar 
biological effects. In in vitro and in vivo studies, fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl produced pharmacological 
effects similar to fentanyl. Thus, these four substances pose the same 
qualitative public health risks as heroin, fentanyl, and other mu-
opioid receptor agonists.
    According to a CDC report, from 2013 to 2019, deaths involving 
synthetic opioids other than methadone increased by 1,040 percent from 
3,105 to 36,359. The increase in the number of opioid-related deaths 
was primarily driven by illicitly manufactured fentanyl.\7\ According 
to CDC 2019 data, there were 70,630 drug overdose fatalities; of those, 
49,860 (approximately 71 percent) involved an opioid. The use of some 
fentanyl-related substances has been associated with adverse health 
outcomes, including death.
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    \7\ If evidence of prescription or illicit use was not 
available, fentanyl was categorized as illicitly-manufactured 
fentanyl (``IMF'') because the vast majority of fentanyl overdose 
deaths involve IMF. Gladden RM, O'Donnell J, Mattson CL, Seth P. 
Changes in Opioid-Involved Overdose Deaths by Opioid Type and 
Presence of Benzodiazepines, Cocaine, and Methamphetamine--25 
States, July-December 2017 to January-June 2018. MMWR Morb Mortal 
Wkly Rep. 30; 68(34):737-744.
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    7. Its Psychic or Physiological Dependence Liability: There are no 
pre-clinical and clinical studies that have evaluated the dependence 
potential of fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-
fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl. These 
four substances are mu-opioid receptor agonists, and discontinuation of 
the use of mu-opioid receptor agonists such as fentanyl and morphine is 
known to cause withdrawal indicative of physical dependence. Opioid 
withdrawal includes nausea and vomiting, depression, agitation, 
anxiety, craving, sweats, hypertension, diarrhea, and fever.
    8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under the CSA: Fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl are not considered immediate precursors of any controlled 
substance of the CSA as defined by 21 U.S.C. 802(23).
    Conclusion: After considering the scientific and medical evaluation 
conducted by HHS, HHS's scheduling recommendation, and DEA's own eight-
factor analysis, DEA finds that the facts and all relevant data 
constitute substantial evidence of the potential for abuse of fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl. As such, DEA hereby 
proposes to permanently schedule fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl in schedule I of the CSA.

Proposed Determination of Appropriate Schedule

    The CSA establishes five schedules of controlled substances known 
as schedules I, II, III, IV, and V. The CSA also outlines the findings 
required to place a drug or other substance in any particular schedule. 
21 U.S.C. 812(b). After consideration of the analysis and 
recommendation of the Acting Assistant Secretary for Health of HHS and 
review of all other available data, the Acting Administrator of DEA, 
pursuant to 21 U.S.C. 811(a) and 21 U.S.C. 812(b)(1), finds that:
    (1) Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl have a high 
potential for abuse.
    According to HHS, fentanyl carbamate, ortho-fluoroacryl fentanyl, 
ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl, 
similar to fentanyl, are mu-opioid receptor agonists. These substances 
have analgesic effects, and these effects are mediated by mu-opioid 
receptor agonism. HHS states that substances that produce mu-opioid 
receptor agonist effects in the central nervous system (e.g., morphine 
and fentanyl) are considered as having a high potential for abuse. Data 
obtained from drug discrimination studies indicate that fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl fully substituted for the 
discriminative stimulus effects of morphine.
    (2) Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl have no currently 
accepted medical use in treatment in the United States.

[[Page 14712]]

    According to HHS, there are no FDA-approved new drug applications 
for fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl in the United 
States. There are no known therapeutic applications for these fentanyl-
related substances and thus they have no currently accepted medical use 
in the United States.\8\
---------------------------------------------------------------------------

    \8\ Although there is no evidence suggesting that fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl have a currently accepted 
medical use in treatment in the United States, it bears noting that 
a drug cannot be found to have such medical use unless DEA concludes 
that it satisfies a five-part test. Specifically, with respect to a 
drug that has not been approved by FDA, to have a currently accepted 
medical use in treatment in the United States, all of the following 
must be demonstrated:
     i. The drug's chemistry must be known and reproducible;
     ii. there must be adequate safety studies;
     iii. there must be adequate and well-controlled studies proving 
efficacy;
     iv. the drug must be accepted by qualified experts; and
     v. the scientific evidence must be widely available.
    57 FR 10499 (1992), pet. for rev. denied, Alliance for Cannabis 
Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994).
---------------------------------------------------------------------------

    (3) There is a lack of accepted safety for use of fentanyl 
carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl under medical supervision.
    Because fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-
fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl have no 
FDA-approved medical use and have not been thoroughly investigated as 
new drugs, their safety for use under medical supervision is 
undetermined. Thus, there is a lack of accepted safety for use of 
fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl 
fentanyl, and para-fluoro furanyl fentanyl under medical supervision.
    Based on these findings, the Acting Administrator of DEA concludes 
that fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl, including their 
isomers, esters, ethers, salts, and salts of isomers, esters, and 
ethers, warrant continued control in schedule I of the CSA. 21 U.S.C. 
812(b)(1).
    Requirements for Handling fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl.
    If this rule is finalized as proposed, fentanyl carbamate, ortho-
fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro 
furanyl fentanyl would continue \9\ to be subject to the CSA's schedule 
I regulatory controls and administrative, civil, and criminal sanctions 
applicable to the manufacture, distribution, reverse distribution, 
dispensing, importation, exportation, research, and conduct of 
instructional activities, including the following:
---------------------------------------------------------------------------

    \9\ Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro 
isobutyryl fentanyl, and para-fluoro furanyl fentanyl, are covered 
by the February 6, 2018, temporary scheduling order, and are 
currently subject to schedule I controls on a temporary basis, 
pursuant to 21 U.S.C. 811(h). 83 FR 5188.
---------------------------------------------------------------------------

    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses), or who desires to handle, fentanyl carbamate, ortho-
fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro 
furanyl fentanyl is required to be registered with DEA to conduct such 
activities pursuant to 21 U.S.C. 822, 823, 957, and 958, and in 
accordance with 21 CFR parts 1301 and 1312.
    2. Security. Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-
fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl are 
subject to schedule I security requirements and must be handled and 
stored pursuant to 21 U.S.C. 821, 823, and in accordance with 21 CFR 
1301.71-1301.76. Non-practitioners handling fentanyl carbamate, ortho-
fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro 
furanyl fentanyl also must comply with the employee screening 
requirements of 21 CFR 1301.90 -1301.93.
    3. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of fentanyl carbamate, ortho-fluoroacryl 
fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl 
fentanyl must be in compliance with 21 U.S.C. 825 and 958(e), and be in 
accordance with 21 CFR part 1302.
    4. Quota. Only registered manufacturers are permitted to 
manufacture fentanyl carbamate, ortho fluoroacryl fentanyl, ortho-
fluoroisobutyryl fentanyl, and para-fluoro furanyl fentanyl in 
accordance with a quota assigned pursuant to 21 U.S.C. 826 and in 
accordance with 21 CFR part 1303.
    5. Inventory. Any person registered with DEA to handle fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl must have an initial inventory of all 
stocks of controlled substances (including these substances) on hand on 
the date the registrant first engages in the handling of controlled 
substances pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 
CFR 1304.03, 1304.04, and 1304.11.
    After the initial inventory, every DEA registrant must take a new 
inventory of all stocks of controlled substances (including fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl) on hand every two years pursuant to 
21 U.S.C. 827 and 958, and in accordance with 21 CFR 1304.03, 1304.04, 
and 1304.11.
    6. Records and Reports. Every DEA registrant is required to 
maintain records and submit reports with respect to fentanyl carbamate, 
ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, and para-
fluoro furanyl fentanyl, pursuant to 21 U.S.C. 827 and 958(e), and in 
accordance with 21 CFR 1301.74(b) and (c) and parts 1304, 1312, and 
1317.
    7. Order Forms. Every DEA registrant who distributes fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl is required to comply with the order 
form requirements, pursuant to 21 U.S.C. 828 and 21 CFR part 1305.
    8. Importation and Exportation. All importation and exportation of 
fentanyl carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl 
fentanyl, and para-fluoro furanyl fentanyl must be in compliance with 
21 U.S.C. 952, 953, 957, and 958, and in accordance with 21 CFR part 
1312.
    9. Liability. Any activity involving fentanyl carbamate, ortho 
fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, and para-fluoro 
furanyl fentanyl not authorized by, or in violation of, the CSA or its 
implementing regulations is unlawful, and could subject the person to 
administrative, civil, and/or criminal sanctions.

Regulatory Analyses

Executive Orders 12866 (Regulatory Planning and Review) and 13563 
(Improving Regulation and Regulatory Review)

    In accordance with 21 U.S.C. 811(a), this proposed scheduling 
action is subject to formal rulemaking procedures done ``on the record 
after opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for 
scheduling a drug or other substance. Such actions are exempt from 
review by the Office of

[[Page 14713]]

Management and Budget (OMB) pursuant to section 3(d)(1) of Executive 
Order (E.O.) 12866 and the principles reaffirmed in E.O. 13563.

Executive Order 12988, Civil Justice Reform

    This proposed regulation meets the applicable standards set forth 
in sections 3(a) and 3(b)(2) of E.O. 12988 to eliminate drafting errors 
and ambiguity, minimize litigation, provide a clear legal standard for 
affected conduct, and promote simplification and burden reduction.

Executive Order 13132, Federalism

    This proposed rulemaking does not have federalism implications 
warranting the application of E.O. 13132. The proposed rule does not 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or the distribution of 
power and responsibilities among the various levels of government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This proposed rule does not have tribal implications warranting the 
application of E.O. 13175. It does not have substantial direct effects 
on one or more Indian tribes, on the relationship between the Federal 
Government and Indian tribes, or on the distribution of power and 
responsibilities between the Federal Government and Indian tribes.

Regulatory Flexibility Act

    The Acting Administrator, in accordance with the Regulatory 
Flexibility Act, 5 U.S.C. 601-602, has reviewed this proposed rule and 
by approving it, certifies that it will not have a significant economic 
impact on a substantial number of small entities. On February 6, 2018, 
DEA published an order to temporarily place fentanyl-related 
substances, as defined in the order, in schedule I of the CSA pursuant 
to the temporary scheduling provisions of 21 U.S.C. 811(h). DEA 
estimates that all entities handling or planning to handle fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl have already established and 
implemented the systems and processes required to handle these 
substances which meet the definition of fentanyl-related substances.
    There are currently 90 unique registrations authorized to 
specifically handle the fentanyl-related substances as a class, which 
include fentanyl carbamate, ortho fluoroacryl fentanyl, ortho-
fluoroisobutyryl fentanyl, and para-fluoro furanyl fentanyl, as well as 
a number of registered analytical labs that are authorized to handle 
schedule I controlled substances generally. Some of these entities are 
likely to be large entities. However, since DEA does not have 
information of registrant size and the majority of DEA registrants are 
small entities or are employed by small entities, DEA estimates a 
maximum of 79 entities are small entities. Therefore, DEA 
conservatively estimates as many as 79 small entities are affected by 
this proposed rule.
    A review of the 90 registrations indicates that all entities that 
currently handle fentanyl-related substances, including fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl, also handle other schedule I 
controlled substances, and have established and implemented (or 
maintain) the systems and processes required to handle fentanyl 
carbamate, ortho fluoroacryl fentanyl, ortho-fluoroisobutyryl fentanyl, 
and para-fluoro furanyl fentanyl. Therefore, DEA anticipates that this 
proposed rule will impose minimal or no economic impact on any affected 
entities; and thus, will not have a significant economic impact on any 
of the 79 affected small entities. Therefore, DEA has concluded that 
this proposed rule will not have a significant effect economic impact 
on a substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined and certifies that this 
action would not result in 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 million or more (adjusted annually 
for inflation) in any 1 year . . . .'' Therefore, neither a Small 
Government Agency Plan nor any other action is required under UMRA of 
1995.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information under 
the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-3521. This action 
would not impose recordkeeping or reporting requirements on State or 
local governments, individuals, businesses, or organizations. An agency 
may not conduct or sponsor, and a person is not required to respond to, 
a collection of information unless it displays a currently valid OMB 
control number.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

    For the reasons set out above, DEA proposes to amend 21 CFR part 
1308 as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

    Authority:  21 U.S.C. 811, 812, 871(b), 956(b), unless otherwise 
noted.

0
2. In Sec.  1308.11:
0
a. Redesignate paragraphs (b)(70), (71), and (75) as paragraphs 
(b)(74), (75), and (76), respectively.
0
b. Add paragraph (b)(73);
0
c. Redesignate paragraphs (b)(64) through (69) as paragraphs (b)(67) 
through (72);
0
d. Add new paragraph (b)(66);
0
e. Redesignate paragraphs (b)(61) through (63) as paragraphs (b)(63) 
through (65);
0
f. Add new paragraph (b)(62);
0
g. Redesignate paragraphs (b)(39) through (60) as paragraphs (b)(40) 
through (61); and
0
h. Add new paragraph (b)(39).
    The additions read as follows:


Sec.  1308.11   Schedule I.

* * * * *
    (b) * * *

(39) Fentanyl carbamate (ethyl (1-phenethylpiperidin-4-             9851
 yl)(phenyl)carbamate)........................................
 
                              * * * * * * *
(62) ortho-Fluoroacryl fentanyl (N-(2-fluorophenyl)-N-(1-           9852
 phenethylpiperidin-4-yl)acrylamide)..........................
 
                              * * * * * * *
(66) ortho-Fluoroisobutyryl fentanyl (N-(2-fluorophenyl)-N-(1-      9853
 phenethylpiperidin-4-yl)isobutyramide).......................
 
                              * * * * * * *
(73) para-Fluoro furanyl fentanyl (N-(4-fluorophenyl)-N-(1-         9854
 phenethylpiperidin-4-yl)furan-2-carboxamide).................
 


[[Page 14714]]

* * * * *

D. Christopher Evans,
Acting Administrator.
[FR Doc. 2021-05589 Filed 3-17-21; 8:45 am]
BILLING CODE 4410-09-P