Schedules of Controlled Substances: Placement of Butonitazene, Flunitazene, and Metodesnitazene Substances in Schedule I

Published date11 April 2024
Record Number2024-07694
Citation89 FR 25544
CourtDrug Enforcement Administration
SectionProposed rules
25544
Federal Register / Vol. 89, No. 71 / Thursday, April 11, 2024 / Proposed Rules
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA–900N]
Schedules of Controlled Substances:
Placement of Butonitazene,
Flunitazene, and Metodesnitazene
Substances in Schedule I
AGENCY
: Drug Enforcement
Administration, Department of Justice.
ACTION
: Notice of proposed rulemaking.
SUMMARY
: The Drug Enforcement
Administration proposes placing
butonitazene, flunitazene, and
metodesnitazene including their
isomers, esters, ethers, salts and salts of
isomers, esters and ethers in schedule I
of the Controlled Substances Act. 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 with, or possess), or propose to
handle these three specific controlled
substances.
DATES
: Comments must be submitted
electronically or postmarked on or
before May 13, 2024.
Interested persons may file a request
for a hearing or waiver of hearing
pursuant to 21 CFR 1308.44 and in
accordance with 21 CFR 1316.47 and/or
1316.49, as applicable. Requests for a
hearing, and waivers of an opportunity
for a hearing or to participate in a
hearing, must be received on or before
May 13, 2024.
ADDRESSES
: Interested persons may file
written comments on this proposal in
accordance with 21 CFR 1308.43(g). 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. To ensure
proper handling of comments, please
reference ‘‘Docket No. DEA–900N’’ on
all electronic and written
correspondence, including any
attachments.
Electronic comments: The Drug
Enforcement Administration (DEA)
encourages commenters to submit all
comments 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
https://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. 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 electronic submissions
are not necessary and are discouraged.
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: All requests for a
hearing and waivers of participation,
together with a written statement of
position on the matters of fact and law
asserted in the hearing, must be filed
with the DEA Administrator, who will
make the determination of whether a
hearing will be needed to address such
matters of fact and law in the
rulemaking. Such requests must be sent
to: Drug Enforcement Administration,
Attn: Administrator, 8701 Morrissette
Drive, Springfield, Virginia 22152. For
informational purposes, a courtesy copy
of 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.
Paperwork Reduction Act
Comments: All comments concerning
collections of information under the
Paperwork Reduction Act must be
submitted to the Office of Information
and Regulatory Affairs, OMB, Attention:
Desk Officer for DOJ, Washington, DC
20503. Please state that your comment
refers to Docket No. DEA–900N.
FOR FURTHER INFORMATION CONTACT
: Dr.
Terrence L. Boos, Drug and Chemical
Evaluation Section, Diversion Control
Division, Drug Enforcement
Administration; Telephone: (571) 362–
3249.
SUPPLEMENTARY INFORMATION
: In this
proposed rule, the Drug Enforcement
Administration (DEA) proposes to
permanently schedule the following
three controlled substances in schedule
I of the Controlled Substances Act
(CSA), including their isomers, esters,
ethers, salts, and salts of isomers, esters,
and ethers whenever the existence of
such isomers, esters, ethers, and salts is
possible within the specific chemical
designation:
butonitazene (2-(2-(4-
butoxybenzyl)-5-nitro-1H-benzimidazol-
1-yl)-N,N-diethylethan-1-amine),
flunitazene (N,N-diethyl-2-(2-(4-
fluorobenzyl)-5-nitro-1H-benzimidazol-
1-yl)ethan-1-amine),
metodesnitazene (N,N-diethyl-2-(2-
(4-methoxybenzyl)-1H-benzimidazol-1-
yl)ethan-1-amine).
Posting of Public Comments
All comments received in response to
this docket are considered part of the
public record. DEA will make comments
available for public inspection online at
https://www.regulations.gov, unless
reasonable cause is given. Such
information includes personal or
business identifiers (such as name,
address, state of federal identifiers, etc.)
voluntarily submitted by the
commenter.
Commenters submitting comments
which include personal identifying
information (PII), confidential, or
proprietary business information that
the commenter does not want made
publicly available should submit two
copies of the comment. One copy must
be marked ‘‘CONTAINS
CONFIDENTIAL INFORMATION’’ and
should clearly identify all PII or
business information the commenter
does not want to be made publicly
available, including any supplemental
materials. DEA will review this copy,
including the claimed PII and
confidential business information, in its
consideration of comments. The second
copy should be marked ‘‘TO BE
PUBLICLY POSTED’’ and must have all
claimed confidential PII and business
information already redacted. DEA will
post only the redacted comment on
https://www.regulations.gov for public
inspection. DEA generally will not
redact additional information contained
in the comment marked ‘‘TO BE
PUBLICLY POSTED.’’ The Freedom of
Information Act applies to all comments
received.
For easy reference, an electronic copy
of this document and supplemental
information to this proposed scheduling
action are available at https://
www.regulations.gov.
Request for Hearing or Appearance;
Waiver
Pursuant to 21 U.S.C. 811(a), this
action is a formal rulemaking ‘‘on the
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1
21 CFR 1308.41 through 1308.45; 21 CFR part
1316, subpart D.
2
21 CFR 1316.49.
3
21 CFR 1308.44(b), 1316.53.
4
21 U.S.C. 811(a).
5
See Schedules of Controlled Substances:
Temporary Placement of Butonitazene,
Etodesnitazene, Flunitazene, Metodesnitazene,
Metonitazene, N-Pyrrolidino etonitazene, and
Protonitazene in Schedule I, 87 FR 21556 (Apr. 12,
2022). The four additional benzimidazole-opioids
were etodesnitazene, metonitazene, N-pyrrolidino
etonitazene, and protonitazene. DEA pursued
separate scheduling actions for metonitazene, see
88 FR 56466 (Aug. 18, 2023) and for etodesnitazene,
N-pyrrolidino etonitazene, and protonitazene, to
remain as a schedule I substances under the CSA
in order to meet the United States’ obligations
under the United Nations Single Convention on
Narcotic Drugs, Mar. 30, 1961, 18 U.S.T. 1407, 520
U.N.T.S. 151 (Single Convention), as amended by
the 1972 Protocol.
6
The three other benzimidazole-opioids
(etodesnitazene, N-pyrrolidino etonitazene, and
protonitazene) will not be discussed further in this
proposed rule.
record after opportunity for a hearing.’’
Such proceedings are conducted
pursuant to the provisions of the
Administrative Procedure Act (APA), 5
U.S.C. 551–559.
1
Interested persons, as
defined in 21 CFR 1300.01(b), may file
requests for a hearing in conformity
with the requirements of 21 CFR
1308.44(a) and 1316.47(a), and such
requests must:
(1) state with particularity the interest
of the person in the proceeding;
(2) state with particularity the
objections or issues concerning which
the person desires to be heard; and
(3) state briefly the position of the
person with regarding to the objections
or issues.
Any interested person may file a
waiver of an opportunity for a hearing
or to participate in a hearing in
conformity with the requirements of 21
CFR 1308.44(c), together with a written
statement of position on the matters of
fact and law involved in any hearing.
2
All requests for a hearing and waivers
of participation, together with a written
statement of position on the matters of
fact and law involved in such hearing,
must be sent to DEA using the address
information provided above. The
decision whether a hearing will be
needed to address such matters of fact
and law in the rulemaking will be made
by the Administrator. If a hearing is
needed, DEA will publish a notice of
hearing on the proposed rulemaking in
the Federal Register.
3
Further, once the
Administrator determines a hearing is
needed to address such matters of fact
and law in rulemaking, she will then
designate an Administrative Law Judge
(ALJ) to preside over the hearing. The
ALJ’s functions shall commence upon
designation, as provided in 21 CFR
1316.52.
In accordance with 21 U.S.C. 811 and
812, the purpose of a hearing would be
to determine whether butonitazene,
flunitazene, and metodesnitazene meet
the statutory criteria for placement in
schedule I, as proposed in this rule.
Legal Authority
The 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, at the
request of the Secretary of Health and
Human Services (HHS), or on the
petition of any interested party.
4
This
proposed action is supported by a
recommendation from the Assistant
Secretary for Health of HHS (Assistant
Secretary for HHS or 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 these three
substances.
Background
On April 12, 2022, pursuant to 21
U.S.C. 811(h)(1), DEA published an
order in the Federal Register
temporarily placing butonitazene,
flunitazene, metodesnitazene, and four
additional benzimidazole-opioids in
schedule I of the Controlled Substances
Act (CSA) based upon a finding that
these substances pose an imminent
hazard to the public safety.
5
That
temporary order was effective upon the
date of publication. Under 21 U.S.C.
811(h)(2), the temporary scheduling of a
substance expires at the end of two
years from the date of issuance of the
scheduling order, except that DEA may
extend temporary scheduling of that
substance for up to one year during the
pendency of permanent scheduling
proceedings under 21 U.S.C. 811(a)(1)
with respect to the substance. Pursuant
to 21 U.S.C. 811(h)(2), the temporary
scheduling of butonitazene, flunitazene,
and metodesnitazene expires on April
12, 2024, unless extended. An extension
of the temporary order is being ordered
by the DEA Administrator in a separate
action, published elsewhere in this
issue of the Federal Register.
As described in the temporary order
published on April 12, 2022,
butonitazene, flunitazene, and
metodesnitazene belong to the class of
substances known as benzimidazole-
opioids and are synthetic opioids. The
Assistant Secretary for HHS has advised
DEA that there are no exemptions or
approvals in effect for butonitazene,
flunitazene, and metodesnitazene under
section 505 of the Federal Food, Drug
and Cosmetic Act, 21 U.S.C. 335.
According to HHS, and also by DEA’s
findings in this proposed rule,
butonitazene, flunitazene, and
metodesnitazene have no known
accepted medical use. These substances
are not the subject of any approved new
drug application (NDA) or
investigational new drug application
(IND), and are not currently marketed as
approved drug products.
The Administrator, on her own
motion pursuant to 21 U.S.C. 811(a), is
initiating proceedings to permanently
schedule butonitazene, flunitazene, and
metodesnitazene. DEA gathered the
necessary data and reviewed the
available information regarding the
pharmacology, chemistry, trafficking,
actual abuse, pattern of abuse, and the
relative potential for abuse for these
substances. On July 13, 2022, in
accordance with 21 U.S.C. 811(b), the
Administrator then submitted a request
to the Assistant Secretary to provide
DEA with a scientific and medical
evaluation of available information and
a scheduling recommendation for six
benzimidazole substances.
On November 15, 2023, the Assistant
Secretary submitted HHS’s scientific
and medical evaluation and scheduling
recommendation for butonitazene,
flunitazene, metodesnitazene, and three
other benzimidazole-opioids and their
salts to the Administrator,
6
which
recommended placing butonitazene,
flunitazene, and metodesnitazene and
their salts in schedule I of the CSA. In
accordance with 21 U.S.C. 811(c), upon
receipt of the scientific and medical
evaluation and scheduling
recommendation from HHS, DEA
reviewed the documents and all other
relevant data, and conducted its own
eight-factor analysis of the abuse
potential of these three substances.
Proposed Determination to
Permanently Schedule Butonitazene,
Flunitazene, and Metodesnitazene
As discussed in the background
section, the Administrator is initiating
proceedings, pursuant to 21 U.S.C.
811(a), to permanently add
butonitazene, flunitazene, and
metodesnitazene to schedule I. DEA
reviewed the scientific and medical
evaluation and scheduling
recommendation received from HHS,
and all other relevant data, and it
conducted its own eight-factor analysis
of the abuse potential of these three
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7
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.
8
NFLIS-Drug represents an important resource in
monitoring illicit drug trafficking, including the
diversion of legally manufactured pharmaceuticals
into illegal markets. NFLIS-Drug is a comprehensive
information system that includes data from forensic
laboratories that handle the nation’s drug analysis
cases. NFLIS-Drug participation rate, defined as the
percentage of the national drug caseload
represented by laboratories that have joined NFLIS,
is currently 98.5 percent. NFLIS includes drug
chemistry results from completed analyses only.
NFLIS-Drug data was queried on November 21,
2023.
9
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 Schedules
of Controlled Substances: Placement of
Carisoprodol Into Schedule IV, 76 FR 77330, 77332
(Dec. 12, 2011).
10
DEA–VA Interagency Agreement. ‘‘In Vitro
Receptor and Transporter Assays for Abuse
Liability Testing for the DEA by the VA’’. Binding
and Functional Activity at Delta, Kappa and Mu
Opioid Receptors. 2020. Unpublished data.
11
DEA–VA Interagency Agreement. ‘‘In Vitro
Receptor and Transporter Assays for Abuse
Liability Testing for the DEA by the VA’’. Binding
and Functional Activity at Delta, Kappa and Mu
Opioid Receptors. 2021. Unpublished data.
12
Gatch MB. Evaluation of Abuse Potential of
Synthetic Opioids Using in Vivo Pharmacological
Studies. Test of analgesic effects alone and in
combination with naltrexone. Unpublished Data.
2022.
13
Paronis C. Evaluation of Synthetic Opioid
Substances using Analgesia and Drug
Discrimination Assays. Test of antinociceptive
effects. Unpublished Data. 2021a.
substances pursuant to 21 U.S.C. 811(c).
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 analyses are
available in their entirety under
‘‘Supporting Documents’’ of the public
docket for this proposed rule at https://
www.regulations.gov under Docket
Number ‘‘DEA–900N.’’
1. The Drug’s Actual or Relative
Potential for Abuse
In addition to considering the
information HHS provided in its
scientific and medical evaluation
document for butonitazene, flunitazene,
and metodesnitazene, DEA also
considered all other relevant data
regarding actual or relative potential for
abuse of these three substances. 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:
7
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 of the community; or
b. There is a significant diversion of the
drug or 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.
Both DEA and HHS eight-factor
analyses found that butonitazene,
flunitazene, and metodesnitazene have
pharmacological profiles similar to
those of the synthetic opioids
etonitazene and isotonitazene, which
are both schedule I controlled
substances and have high potential for
abuse. According to HHS, butonitazene,
flunitazene, and metodesnitazene have
no approved medical uses in the United
States, and they have been encountered
on the illicit drug market with adverse
outcomes on the public health and
safety. Because there are no Food and
Drug Administration (FDA)-approved or
FDA-exempted products for
butonitazene, flunitazene, and
metodesnitazene in the United States or
in any other country, a practitioner may
not legally prescribe them, and they
cannot be dispensed to an individual.
However, these benzimidazole-opioids
substances are available for purchase
from legitimate chemical companies
because they can be used in scientific
research. There is no known diversion
from research activities for these
substances.
Because butonitazene, flunitazene,
and metodesnitazene are not formulated
or available for clinical use as approved
medicinal products, it is inferred that all
current use of these substances by
individuals are based on their own
initiative, rather than on the basis of
medical advice from a practitioner
licensed by law to administer such
drugs. According to drug seizure data
from 2020 and 2023 from the National
Forensic Laboratory Information System
(NFLIS-Drug)
8
database, which collects
drug identification results from drug
cases submitted to and analyzed by
Federal, State, and local forensic
laboratories, there have been a total of
130 reports for butonitazene,
flunitazene, or metodesnitazene.
Evidence from law enforcement
seizures
9
indicate that individuals are
taking these benzimidazole-opioids with
no accepted medical use, on their own
initiative rather than on the medical
advice of a licensed practitioner.
Individuals may be using these
benzimidazole-opioids on their own
initiative because of their opioidergic
effects similar to other schedule I or II
opioid substances. Consequently, law
enforcement encounters of
butonitazene, flunitazene, and
metodesnitazene demonstrate that these
substances are being abused, and thus
pose safety hazards to the health of
users or the community.
2. Scientific Evidence of the Drug’s
Pharmacological Effects, if Known
According to DEA and HHS, the
pharmacological activity of
butonitazene, flunitazene, and
metodesnitazene in humans is
unknown. Preclinical studies show that
these benzimidazole-opioids exhibit a
pharmacological profile similar to that
of morphine and fentanyl. As explained
in detail in both DEA and HHS eight-
factor analyses, data from binding
studies show that these substances,
similar to morphine and fentanyl,
selectively bound to mu-opioid
receptors.
10
In opioid receptor
functional assays, butonitazene,
flunitazene, and metodesnitazene,
similar to fentanyl and morphine, acted
as mu-opioid receptor agonists.
11
Further, data from preclinical studies
using rodents showed that butonitazene,
flunitazene, and metodesnitazene,
similar to morphine and fentanyl,
produced analgesic effects that can be
attenuated by an opioid antagonist pre-
treatment.
12 13
HHS concluded that,
similar to morphine and fentanyl,
butonitazene, flunitazene, and
metodesnitazene produced analgesic
effects via activation of mu-opioid
receptors.
Additionally, behavioral effects of
butonitazene, flunitazene, and
metodesnitazene were assessed using
the drug discrimination model. Drug
discrimination studies can be used to
determine whether a test drug produces
pharmacological effects (i.e.,
interoceptive stimulus effects) similar to
those produced by a known drug of
abuse. Drugs that produce stimulus
effects similar to known drugs of abuse
in animals are also likely to be abused
by humans. As explained in detail in
both DEA and HHS eight-factor
analyses, data from drug discrimination
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14
Gatch, M. Butonitazene: Test of substitution for
the discriminative stimulus effects of morphine
(15DDHQ21F00000340, 2021. Unpublished Data).
15
Paronis, C. Flunitazene: Test of morphine-like
discriminative stimulus effects
(15DDHQ20P00000709, 2021b. Unpublished Data).
16
Paronis, C. Metodesnitazene: Test of morphine-
like discriminative stimulus effects
(15DDHQ20P00000709, 2021c. Unpublished Data).
17
Hunger, A., Kebrle, J., Rossi, A., & Hoffmann,
K. [Synthesis of analgesically active benzimidazole
derivatives with basic substitutions]. Experientia,
1957 Oct 15;13(10), 400–401.
18
85 FR 51342 (Aug. 20, 2020).
19
87 FR 21556 (Apr. 12, 2022).
20
Department of Health and Human Services.
Basis for the Recommendation to Control
Butonitazene, Etodesnitazene, Flunitazene,
Metodesnitazene, N-Pyrrolidino Etonitazene, and
Protonitazene and Their Salts in Schedule I of the
Controlled Substances Act (November 2023).
21
Walton SE, Krotulski AJ, Logan BK. A Forward-
Thinking Approach to Addressing the New
Synthetic Opioid 2-Benzylbenzimidazole Nitazene
Analogs by Liquid Chromatography—Tandem
Quadrupole Mass Spectrometry (LC–QQQ–MS). J
Anal Toxicol. 2022 Mar 21;46(3):221–231.
22
Metodesnitazene_092221_
ToxicologyAnalyticalReport.pdf (cfsre.org).
studies demonstrate that butonitazene,
14
flunitazene,
15
and metodesnitazene
16
have stimulus properties that are similar
to both morphine and fentanyl,
schedule II drugs. Taken together, data
from preclinical studies demonstrate
that butonitazene, flunitazene, and
metodesnitazene share similarities in
their pharmacological effects and
mechanism of action to the schedule II
opioid drugs morphine and fentanyl.
3. The State of Current Scientific
Knowledge Regarding the Drug or Other
Substance
Butonitazene, flunitazene, and
metodesnitazene belong to the 2-
benzylbenzimidazole structural class.
The chemical structures of these 2-
benzylbenzimidazoles contain a
benzimidazole ring and a benzyl group
at the benzimidazole 2-position. These
benzimidazole-opioids are structurally
related to several schedule I substances,
including etonitazene. There are no
FDA-approved marketing applications
for drug products containing
butonitazene, flunitazene, and
metodesnitazene for any therapeutic
indication in the United States or
medical use in any other country.
Further, there are no well-controlled
clinical studies that have demonstrated
the safety or efficacy for these
substances. According to HHS, FDA
concluded that butonitazene,
flunitazene, and metodesnitazene have
no currently accepted medical use in
the United States. Similarly, DEA
concludes that butonitazene,
flunitazene, and metodesnitazene have
no currently accepted medical use
according to established DEA procedure
and case law.
4. Its History and Current Pattern of
Abuse
In the late 1950s, the Swiss chemical
company CIBA Aktiengesellschaft
synthesized a group of benzimidazole
derivatives with analgesic properties;
17
however, the research did not lead to
any medically approved analgesic
products. These benzimidazole
derivatives include schedule I
substances, such as the synthetic
opioids clonitazene, etonitazene, and
isotonitazene. In 2019, isotonitazene
emerged on the illicit drug market and
was involved in numerous fatal
overdose events; in August 2020, it was
temporarily controlled as a schedule I
substance under the CSA.
18
Subsequently, additional six
benzimidazole-opioids emerged on the
illicit opioid drug market. In April 2022,
DEA temporarily controlled these six
benzimidazole-opioids as schedule I
substances due, in part, to their
involvement in numerous postmortem
and toxicology cases.
19
Law
enforcement agencies have encountered
butonitazene, flunitazene, and
metodesnitazene in several solid (e.g.,
powder, rock, and tablet) forms. These
substances are not approved for medical
use anywhere in the world.
According to HHS, there are no FDA-
approved drug products for
butonitazene, flunitazene, and
metodesnitazene in the United States.
20
The appearance of these benzimidazole-
opioids on the illicit drug market is
similar to other synthetic opioids that
are trafficked for their psychoactive
effects. These three benzimidazole-
opioid substances are likely to be
abused in the same manner as schedule
I opioids, such as etonitazene,
isotonitazene, and heroin. These
substances have been identified as
powders or tablets, typically of
unknown purity or concentration.
Between 2020 and 2021, butonitazene,
flunitazene, and metodesnitazene
emerged on the illicit synthetic drug
market as evidenced by their
identification in forensic drug seizures
and in biological samples. Based on
NFLIS-Drug data, law enforcement
encounters of butonitazene, flunitazene,
and metodesnitazene often included
mixtures. Substances found in
combination with some of these
benzimidazole-opioids include other
substances of abuse, such as heroin,
fentanyl, fentanyl analogues, designer
benzodiazepines, and cocaine.
5. The Scope, Duration, and
Significance of Abuse
Butonitazene, flunitazene, and
metodesnitazene, similar to schedule I
substances, such as etonitazene and
isotonitazene, are synthetic opioids, and
evidence suggests they are abused for
their opioidergic effects. The abuse of
these benzimidazole-opioids, similar to
other synthetic opioids, has resulted in
their identification in toxicology, post-
mortem cases, and law enforcement
encounters. Data from the toxicology
analysis showed that butonitazene has
been positively identified in three
postmortem cases, flunitazene in four
post mortem cases,
21
and
metodesnitazene in one case.
22
Data from law enforcement suggest
that butonitazene, flunitazene, and
metodesnitazene are being abused in the
United States as recreational drugs. The
law enforcement encounters of these
benzimidazole-opioids, as reported to
NFLIS-Drug, included 130 exhibits
since 2020. NFLIS-Drug registered 66
encounters of butonitazene from 7
states, 60 encounters of flunitazene from
11 states, and 4 encounters of
metodesnitazene from 3 states. Of the 66
reports involving butonitazene, fentanyl
was co-identified in 24 cases.
Flunitazene was commonly co-
identified with metonitazene (n = 30) in
fifty percent of the cases.
Metodesnitazene was co-reported with
diphenhydramine (n = 2), fentanyl (n =
2), and heroin (n = 2).
The identification of these
benzimidazole-opioids in forensic and
toxicology cases suggests they may be
presented as a substitute for heroin or
fentanyl and likely abused in the same
manner as either of those substances.
The population likely to be harmed by
these benzimidazole-opioids appears to
be the same as that harmed by other
opioid substances, such as heroin,
tramadol, fentanyl, and other synthetic
opioid substances. This is evidenced by
the types of other drugs co-identified in
biological samples and law enforcement
encounters. Law enforcement and
toxicology reports demonstrate that
butonitazene, flunitazene, and
metodesnitazene are being abused, and
that their use can produce serious
adverse events that can lead to death.
Because users of butonitazene,
flunitazene, and metodesnitazene are
likely to obtain these substances
through unregulated sources, the
identity, purity, and quantity of these
substances are uncertain and likely to be
inconsistent, thus posing significant
adverse health risks to the end user.
Individuals who initiate use of one or
more of these benzimidazole-opioids are
likely to be at risk of developing a
substance use disorder, fatal or non-fatal
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23
21 U.S.C. 812(b).
24
HHS and DEA both applied a five-part test for
currently accepted medical use as part of this
scheduling action. Under that test, with respect to
a drug that has not been approved by the Food and
Drug Administration, 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. Marijuana Scheduling
Petition; Denial of Petition; Remand, 57 FR 10499
(Mar. 26, 1992), pet. for rev. denied, Alliance for
Cannabis Therapeutics v. Drug Enforcement
Admin., 15 F.3d 1131, 1135 (D.C. Cir. 1994).
25
21 U.S.C. 812(b)(1).
overdose, similar to that of other opioid
analgesics (e.g., fentanyl, morphine,
etc.).
6. What, if Any, Risk There Is to the
Public Health
The increase in opioid overdose
deaths in the United States has been
exacerbated recently by the availability
of potent synthetic opioids on the illicit
drug market. It is well established that
substances that act as mu-opioid
receptor agonists have a high potential
for abuse and addiction and can induce
dose-dependent respiratory depression.
As with any mu-opioid receptor agonist,
the potential health and safety risks for
users of butonitazene, flunitazene, and
metodesnitazene are high. Consistently,
these three benzimidazole-opioids have
been positively identified in toxicology
cases. The public health risks associated
with the abuse of mu-opioid receptor
agonists are well established.
The introduction of synthetic opioids,
such as butonitazene, flunitazene, and
metodesnitazene, into the illicit drug
market may serve as a portal to
problematic opioid use for those seeking
these opioids. Evidence from toxicology
reports show that poly-substance abuse
remains common in fatalities associated
with the abuse of some of these
benzimidazole-opioids.
7. Its Psychic or Physiological
Dependence Liability
Butonitazene, flunitazene, and
metodesnitazene have pharmacological
effects similar to those of schedule I
benzimidazole-opioids such as
clonitazene, etonitazene, and
isotonitazene. According to HHS,
analgesic studies conducted on these
benzimidazole-opioids show that they
produce effects similar to that of either
morphine or fentanyl, both schedule II
narcotic drugs. Although there are no
clinical studies that have evaluated the
dependence potential of these
substances, they are mu-opioid receptor
agonists, and it is well known that the
discontinuation of the use of mu-opioid
receptor agonists, such as fentanyl and
morphine, causes withdrawal symptoms
indicative of physical dependence. The
similarities in the pharmacological
profile and pattern of abuse of these
benzimidazole-opioids, heroin, and
fentanyl are indicative of their similar
potential to have psychic and
physiological dependence liability.
8. Whether the Substance Is an
Immediate Precursor of a Substance
Already Controlled Under the CSA
Butonitazene, flunitazene, and
metodesnitazene are not immediate
precursors of a substance controlled
under the CSA, as defined by 21 U.S.C.
802(23).
Conclusion:
After considering the scientific and
medical evaluation and accompanying
scheduling recommendation of HHS,
and DEA’s own eight-factor analysis,
DEA finds that these facts and all
relevant data constitute substantial
evidence of potential for abuse of
butonitazene, flunitazene, and
metodesnitazene. As such, DEA
proposes to permanently schedule these
three benzimidazole-opioids as
schedule I controlled substances under
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.
23
After
consideration of the analysis and
recommendation of the Assistant
Secretary for HHS and review of all
other available data, the Administrator
of DEA, pursuant to 21 U.S.C. 811(a)
and 812(b)(1), finds that:
(1) Butonitazene, flunitazene, and
metodesnitazene have a high potential
for abuse. Butonitazene, flunitazene,
and metodesnitazene, similar to
etonitazene and fentanyl, are mu-opioid
receptor agonists. These three
benzimidazole-opioids 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 are considered as
having a high potential for abuse (e.g.
morphine and fentanyl). Data obtained
from drug discrimination studies
indicate that butonitazene, flunitazene,
and metodesnitazene fully substituted
for the discriminative stimulus effects of
morphine.
(2) Butonitazene, flunitazene, and
metodesnitazene have no currently
accepted medical use in the United
States. There are no FDA-approved drug
products for butonitazene, flunitazene,
and metodesnitazene in the United
States. There are no known therapeutic
applications for these benzimidazole-
opioids and DEA is not aware of any
currently accepted medical uses for
these substances in the United States.
24
(3) There is a lack of accepted safety
for use of butonitazene, flunitazene, and
metodesnitazene under medical
supervision. Because these substances
have no FDA-approved medical use and
have not been investigated as new
drugs, their safety for use under medical
supervision is not determined.
Based on these findings, the
Administrator of DEA concludes that
butonitazene, flunitazene, and
metodesnitazene, including their
isomers, esters, ethers, salts, and salts of
isomers, esters, and ethers whenever the
existence of such isomers, esters, ethers,
and salts is possible within the specific
chemical designation, warrant
continued control in schedule I of the
CSA.
25
Requirements for Handling
Butonitazene, Flunitazene, and
Metodesnitazene
As discussed above, these three
substances are currently subject to a
temporary scheduling order, which
added them to schedule I. If this rule is
finalized as proposed, butonitazene,
flunitazene, and metodesnitazene would
be subject, on a permanent basis, to the
CSA’s schedule I regulatory controls
and administrative, civil, and criminal
sanctions applicable to the manufacture,
distribution, reverse distribution,
dispensing, importation, exportation,
engagement in research, and conduct of
instructional activities or chemical
analysis with, and possession of
schedule I substances, including the
following:
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)
butonitazene, flunitazene, and
metodesnitazene must 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. Security.
Butonitazene, flunitazene, and
metodesnitazene are subject to schedule
I security requirements and must be
handled and stored pursuant to 21
U.S.C. 821, 823, and 871(b), and in
accordance with 21 CFR 1301.71
through 1301.76. Non-practitioners
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26
44 U.S.C. 3501–3521.
handling these three substances also
must comply with the screening
requirements of 21 CFR 1301.90 through
1301.93.
3. Labeling and Packaging. All labels
and labeling for commercial containers
of butonitazene, flunitazene, and
metodesnitazene must comply 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 butonitazene, flunitazene,
and metodesnitazene 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 butonitazene,
flunitazene, and metodesnitazene 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 butonitazene, flunitazene,
and metodesnitazene) 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 must maintain records and
submit reports with respect to
butonitazene, flunitazene, and
metodesnitazene, pursuant to 21 U.S.C.
827, 832(a), and 958(e), and in
accordance with 21 CFR 1301.74(b) and
(c) and 1301.76(b) and 21 CFR parts
1304, 1312, and 1317. Manufacturers
and distributors would be required to
submit reports regarding butonitazene,
flunitazene, and metodesnitazene to the
Automation of Reports and
Consolidated Order System pursuant to
21 U.S.C. 827, and in accordance with
21 CFR parts 1304 and 1312.
7. Order Forms. Every DEA registrant
who distributes butonitazene,
flunitazene, and metodesnitazene must
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
butonitazene, flunitazene, and
metodesnitazene must comply with 21
U.S.C. 952, 953, 957, and 958, and in
accordance with 21 CFR part 1312.
9. Liability. Any activity involving
butonitazene, flunitazene, and
metodesnitazene not authorized by, or
in violation of, the CSA or its
implementing regulations is unlawful,
and may subject the person to
administrative, civil, and/or criminal
sanctions.
Regulatory Analyses
Executive Orders 12866 (Regulatory
Planning and Review), 13563
(Improving Regulation and Regulatory
Review), and 14094 (Modernizing
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
Management and Budget (OMB)
pursuant to section 3(d)(1) of Executive
Order (E.O.) 12866 and the principles
reaffirmed in E.O. 13563. E.O. 14094
modernizes the regulatory review
process to advance policies that
promote the public interest and address
national priorities.
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 Administrator, in accordance
with the Regulatory Flexibility Act, 5
U.S.C. 601–612, has reviewed this rule
and, by approving it, certifies that it will
not have a significant economic impact
on a substantial number of small
entities.
On April 12, 2022, DEA published an
order to temporarily place seven
benzimidazole-opioids 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
butonitazene, flunitazene, and
metodesnitazene have already
established and implemented systems
and processes required to handle these
substances.
There are currently 45 registrations
authorized to specifically handle
butonitazene, flunitazene, or
metodesnitazene, as well as 1,239
registered analytical labs and 861
researchers that are authorized to
handle schedule I controlled substances
generally. These 45 registrations
represent 31 entities. A review of the 45
registrations indicates that all entities
that currently handle butonitazene,
flunitazene, and metodesnitazene also
handle other schedule I controlled
substances and have established and
implemented (or maintained) systems
and processes required to handle these
substances. Therefore, DEA anticipates
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
affected small entity. Therefore, DEA
has concluded that this proposed rule
will not have a significant 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 $100,000,000 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 proposed rule would not impose
a new collection or modify an existing
collection of information under the
Paperwork Reduction Act of 1995.
26
Also, this proposed rule would not
impose new or modify existing
recordkeeping or reporting requirements
on state or local governments,
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individuals, businesses, or
organizations. However, this proposed
rule would require compliance with the
following existing OMB collections:
1117–0003, 1117–0004, 1117–0006,
1117–0008, 1117–0009, 1117–0010,
1117–0012, 1117–0014, 1117–0021,
1117–0023, 1117–0029, and 1117–0056.
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.
Signing Authority
This document of the Drug
Enforcement Administration was signed
on April 5, 2024, by Administrator
Anne Milgram. That document with the
original signature and date is
maintained by DEA. For administrative
purposes only, and in compliance with
requirements of the Office of the Federal
Register, the undersigned DEA Federal
Register Liaison Officer has been
authorized to sign and submit the
document in electronic format for
publication, as an official document of
DEA. This administrative process in no
way alters the legal effect of this
document upon publication in the
Federal Register.
Scott Brinks,
Federal Register Liaison Officer, Drug
Enforcement Administration.
For the reasons set out above, DEA
proposes to amend 21 CFR part 1308 as
follows:
PART 1308—SCHEDULES OF
CONTROLLED SUBSTANCES
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.
2. In § 1308.11:
a. Redesignate paragraphs (b)(62)
through (107) as paragraphs (b)(66)
through (110);
b. Redesignate paragraphs (b)(44)
through (62) as paragraphs (b)(46)
through (64);
c. Redesignate paragraphs (b)(24)
through (43) as paragraphs (b)(25)
through (44);
d. Add new paragraphs (b)(24), (45),
and (65); and
e. Remove and reserve paragraphs
(h)(50), (52), and (53).
The additions to read as follows:
§ 1308.11 Schedule I.
* * * * *
(b) * * *
*******
(24) Butonitazene (2-(2-(4-butoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)-N,N-diethylethan-1-amine) ....................................................... 9751
*******
(45) Flunitazene (N,N-diethyl-2-(2-(4-fluorobenzyl)-5-nitro-1H-benzimidazol-1-yl)ethan-1-amine) ........................................................... 9756
*******
(65) Metodesnitazene (N,N-diethyl-2-(2-(4-methoxybenzyl)-1H-benzimidazol-1-yl)ethan-1-amine) ........................................................... 9764
* * * * *
[FR Doc. 2024–07694 Filed 4–10–24; 8:45 am]
BILLING CODE 4410–09–P
DEPARTMENT OF THE TREASURY
Internal Revenue Service
26 CFR Part 1
[REG–100908–23]
RIN 1545–BQ62
Increased Credit or Deduction
Amounts for Satisfying Certain
Prevailing Wage and Registered
Apprenticeship Requirements;
Correction
AGENCY
: Internal Revenue Service (IRS),
Treasury.
ACTION
: Notice of proposed rulemaking;
correction.
SUMMARY
: This document corrects a
notice of proposed rulemaking (REG–
100908–23) published in the Federal
Register on August 30, 2023, containing
proposed regulations regarding
increased credit or deduction amounts
available for taxpayers satisfying
prevailing wage and registered
apprenticeship (collectively, PWA)
requirements established by the
Inflation Reduction Act of 2022 (IRA).
DATES
: Written or electronic comments
were to be received by October 30, 2023.
ADDRESSES
: Commenters were strongly
encouraged to submit public comments
electronically.
FOR FURTHER INFORMATION CONTACT
:
Concerning the proposed regulations,
the Office of Associate Chief Counsel
(Passthroughs & Special Industries) at
(202) 317–6853 (not a toll-free number);
concerning submissions of comments or
the public hearing, Vivian Hayes, (202)
317–6901 (not toll-free number) or by
email to publichearings@irs.gov
(preferred).
SUPPLEMENTARY INFORMATION
:
Background
The notice of proposed rulemaking
(REG–100908–23) that is the subject of
this correction is under sections 30C,
45, 45L, 45Q, 45U, 45V, 45Y, 45Z, 48C,
48E, and 179D of the Code.
Need for Correction
As published, the notice of proposed
rulemaking (REG–100980–23) contains
an error that needs to be corrected.
Correction of Publication
Accordingly, the notice of proposed
rulemaking (REG–100908–23) that is the
subject of FR Doc. 2023–18514,
published on August 30, 2023, is
corrected on page 60018, in the first
column, by correcting the fifth line of
the heading to read ‘‘1545–BQ62’’.
Oluwafunmilayo A. Taylor,
Section Chief, Publications and Regulations
Section, Associate Chief Counsel, (Procedure
and Administration).
[FR Doc. 2024–07723 Filed 4–10–24; 8:45 am]
BILLING CODE 4830–01–P
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