[Federal Register Volume 90, Number 197 (Wednesday, October 15, 2025)]
[Rules and Regulations]
[Pages 48259-48266]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-19542]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-1494]
Schedules of Controlled Substances: Temporary Placement of
Ethyleneoxynitazene, Methylenedioxynitazene, 5-Methyl Etodesnitazene,
N-Desethyl Etonitazene, N-Desethyl Protonitazene, N,N-Dimethylamino
Etonitazene, and N-Pyrrolidino Isotonitazene in Schedule I
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Temporary amendment; temporary scheduling order.
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SUMMARY: The Drug Enforcement Administration issues this temporary
order to schedule seven benzimidazole-opioids, as identified in this
order, in schedule I of the Controlled Substances Act. DEA bases this
action on a finding that placing these substances in schedule I is
necessary to avoid imminent hazard to public safety. This order imposes
the 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 these substances.
DATES: This temporary order is effective October 15, 2025, until
October 15, 2027. If this order is extended or made permanent, DEA will
publish a document in the Federal Register.
[[Page 48260]]
ADDRESSES: 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: The Drug Enforcement Administration (DEA)
issues a temporary scheduling order \1\ (in the form of a temporary
amendment) to add the following seven benzimidazole-opioid substances,
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, to schedule I under the Controlled
Substances Act (CSA):
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\1\ Though DEA has used the term ``final order'' with respect to
temporary scheduling orders in the past, this action adheres to the
statutory language of 21 U.S.C. 811(h), which refers to a
``temporary scheduling order.'' No substantive change is intended.
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2-(2-((2,3-dihydrobenzofuran-5-yl)methyl)-5-nitro-1H-
benzimidazol-1-yl)-N,N-diethylethan-1-amine (commonly known as,
ethyleneoxynitazene),
2-(2-(benzodioxol-5-ylmethyl)-5-nitro-1H-benzimidazol-1-
yl)-N,N-diethylethan-1-amine (commonly known as, methylenedioxynitazene
or 3',4'-methylenedioxynitazene),
2-(2-(4-ethoxybenzyl)-5-methyl-1H-benzimidazol-1-yl)-N,N-
diethylethan-1-amine (commonly known as, 5-methyl etodesnitazene),
2-(2-(4-ethoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)-N-
ethylethan-1-amine (commonly known as, N-desethyl etonitazene),
N-ethyl-2-(5-nitro-2-(4-propoxybenzyl)-1H-benzimidazol-1-
yl)ethan-1-amine (commonly known as, N-desethyl protonitazene),
2-(2-(4-ethoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)-N,N-
dimethylethan-1-amine (commonly known as, N,N-dimethylamino
etonitazene), and
2-(4-isopropoxybenzyl)-5-nitro-1-(2-(pyrrolidin-1-
yl)ethyl)-1H-benzimidazole (commonly known as, N-pyrrolidino
isotonitazene).
Legal Authority
Under 21 U.S.C. 811(h)(1), the CSA provides the Attorney General
(as delegated to the Administrator of DEA (Administrator) pursuant to
28 CFR 0.100) with the authority to temporarily place a substance in
schedule I of the CSA for two years without regard to the evaluation
requirements of 21 U.S.C. 811(b), if she finds that such action is
necessary to avoid an imminent hazard to the public safety.\2\ In
addition, if proceedings to control a substance are initiated under 21
U.S.C. 811(a)(1) while the substance is temporarily controlled under
section 811(h), the Attorney General may extend the temporary
scheduling for up to one year.\3\
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\2\ 21 U.S.C. 811(h)(1).
\3\ 21 U.S.C. 811(h)(2).
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Where the necessary findings are made, a substance may be
temporarily scheduled if it is not listed in any other schedule under
21 U.S.C. 812, or if there is no exemption or approval in effect for
the substance under section 505 of the Federal Food, Drug, and Cosmetic
Act, 21 U.S.C. 355.\4\
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\4\ 21 U.S.C. 811(h)(1); 21 CFR part 1308.
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Background
The CSA requires the Administrator to notify the Secretary of the
Department of Health and Human Services (HHS) of an intent to
temporarily place a substance in schedule I of the CSA (i.e., to issue
a temporary scheduling order).\5\ By letter dated April 15, 2025, the
then-Acting Administrator transmitted the required notice to place
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene in schedule I on a
temporary basis to the Acting Assistant Secretary for Health of HHS
(Assistant Secretary).\6\ On May 20, 2025, the Acting Assistant
Secretary responded to this notice and advised DEA that based on a
review by the Food and Drug Administration (FDA), there are currently
no investigational new drug applications (IND) or approved new drug
applications (NDA) for ethyleneoxynitazene, methylenedioxynitazene, 5-
methyl etodesnitazene, N-desethyl etonitazene, N-desethyl
protonitazene, N,N-dimethylamino etonitazene, and N-pyrrolidino
isotonitazene. The Acting Assistant Secretary also stated that HHS had
no objection to the temporary placement of these substances in schedule
I of the CSA. Ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene currently
are not listed in any schedule under the CSA, and no exemptions or
approvals under 21 U.S.C. 355 are in effect for these substances.
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\5\ 21 U.S.C. 811(h)(4).
\6\ The Secretary of HHS has delegated to the Assistant
Secretary for Health of HHS the authority to make domestic drug
scheduling recommendations. See Comprehensive Drug Abuse Prevention
and Control Act of 1970, Public Law 91-513, As Amended; Delegation
of Authority, 58 FR 35460 (July 1, 1993).
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DEA has taken into consideration the Acting Assistant Secretary's
comments as required by 21 U.S.C. 811(h)(4). DEA has found the control
of ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene in schedule
I on a temporary basis is necessary to avoid an imminent hazard to the
public safety.
As required by 21 U.S.C. 811(h)(1)(A), DEA published a notice of
intent (NOI) to temporarily schedule ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene on June 26, 2025.\7\ That NOI discussed
findings from DEA's three-factor analysis dated June 2025, which DEA
made available on www.regulations.gov.
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\7\ Schedules of Controlled Substances: Temporary Placement of
Seven Benzimidazole Opioids in Schedule I, 90 FR 27268 (June 26,
2025).
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To find that temporarily placing a substance in schedule I of the
CSA is necessary to avoid an imminent hazard to the public safety, the
Administrator must consider three of the eight factors set forth in 21
U.S.C. 811(c): the substance's history and current pattern of abuse;
the scope, duration, and significance of abuse; and what, if any, risk
there is to the public health.\8\ Considerations of these factors
includes any information indicating actual abuse, diversion from
legitimate channels, and clandestine importation, manufacture, or
distribution of ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene.\9\
Substances meeting the statutory requirements for temporary scheduling
may only be placed in schedule I.\10\ Substances in schedule I have
high potential for abuse, no currently accepted medical use in
treatment in the United States, and a lack of accepted safety for use
under medical supervision.\11\
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\8\ 21 U.S.C. 811(h)(3).
\9\ 21 U.S.C. 811(h)(3).
\10\ 21 U.S.C. 811(h)(1).
\11\ 21 U.S.C. 812(b)(1).
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[[Page 48261]]
Seven Benzimidazole-Opioids: Ethyleneoxynitazene,
Methylenedioxynitazene, 5-Methyl Etodesnitazene, N-Desethyl
Etonitazene, N-Desethyl Protonitazene, N,N-Dimethylamino Etonitazene,
and N-Pyrrolidino Isotonitazene
The availability of synthetic opioids in the illicit drug market
continues to pose an imminent hazard to public safety. Adverse health
effects associated with the abuse of synthetic opioids and the
continued evolution and increased popularity of these substances have
been a serious concern in recent years. As the United States continues
to experience an unprecedented epidemic of opioid use and misuse, the
presence of new synthetic opioids with no approved medical use
exacerbates the epidemic. The trafficking and abuse of new synthetic
opioids are deadly new trends. The benzimidazole-opioids have a similar
pharmacological profile to fentanyl, morphine, and other mu-opioid
receptor agonists.
Beginning in 2019, this class of synthetic opioids known as
benzimidazole-opioids, commonly referred to as ``nitazenes,'' appeared
in the United States and have dominated the opioid recreational drug
market. Between August 2020 and July 2024, DEA has temporarily
controlled 10 benzimidazole-opioids because they posed a threat to
public safety.\12\ Recently, additional benzimidazole-opioids have been
identified within the rapidly expanding class of ``nitazene'' compounds
in the recreational drug market. Ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene etonitazene are some of the recently
encountered ``nitazene'' synthetic opioids identified in the illicit
drug market.
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\12\ 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); Schedules of Controlled
Substances: Temporary Placement of Isotonitazene in Schedule I, 85
FR 51342 (Aug. 20, 2020); Schedules of Controlled Substances:
Temporary Placement of N-Desethyl Isotonitazene and N-Piperidinyl
Etonitazene in Schedule I, 89 FR 60817 (Jul. 29, 2024).
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Benzimidazole-opioids have contributed to numerous fatalities. The
continued trafficking and identification of benzimidazole-opioids in
toxicology cases pose a significant threat to public health and safety.
The misuse of synthetic opioids has led to devastating consequences
including death. Preclinical pharmacology data demonstrate that
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene have pharmacological
profiles similar to those of the potent benzimidazole-opioids
etonitazene, metonitazene, and protonitazene, schedule I opioid
substances. Thus, it is expected that these seven substances will have
similar harmful effects in humans. Methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, and
N-pyrrolidino isotonitazene have been positively identified in at least
37 toxicology cases. As the United States continues to experience a
high number of opioid-involved overdoses and mortalities, the
introduction of new designer opioids further exacerbates the current
opioid epidemic.
Available data and information for ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene, summarized below, indicate that these
substances have high potentials for abuse, no currently accepted
medical uses in treatment in the United States,\13\ and a lack of
accepted safety for use under medical supervision. DEA's three-factor
analysis is available in its entirety under ``Supporting and Related
Material'' of the public docket for this action at www.regulations.gov
under Docket Number DEA-1494.
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\13\ When finding schedule I placement on a temporary basis is
necessary to avoid imminent hazard to the public, 21 U.S.C. 811(h)
does not require DEA to consider whether the substance has a
currently accepted medical use in treatment in the United States.
Nonetheless, there is no evidence suggesting that
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene,
N,N-dimethylamino etonitazene, and N-pyrrolidino isotonitazene have
a currently accepted medical use in treatment in the United States.
To determine whether a drug or other substance has a currently
accepted medical use, DEA has traditionally applied a five-part test
to a drug or substance that has not been approved by the FDA: (1)
The drug's chemistry must be known and reproducible; (2) there must
be adequate safety studies; (3) there must be adequate and well-
controlled studies proving efficacy; (4) the drug must be accepted
by qualified experts; and (5) the scientific evidence must be widely
available. See 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). DEA applied the traditional five-part test
and concluded the test was not satisfied. In a recent published
letter in a different context, HHS applied an additional two-part
test to determine currently accepted medical use for substances that
do not satisfy the five-part test: (1) whether there exists
widespread, current experience with medical use of the substance by
licensed health care providers operating in accordance with
implemented jurisdiction-authorized programs, where medical use is
recognized by entities that regulate the practice of medicine, and,
if so, (2) whether there exists some credible scientific support for
at least one of the medical conditions for which part (1) is
satisfied. On April 11, 2024, the Department of Justice's Office of
Legal Counsel (OLC) issued an opinion, which, among other things,
concluded that HHS's two-part test would be sufficient to establish
that a drug has a currently accepted medical use. Office of Legal
Counsel, Memorandum for Merrick B. Garland Attorney General Re:
Questions Related to the Potential Rescheduling of Marijuana at 3
(April 11, 2024). For purposes of this temporary order, there is no
evidence that health care providers have widespread experience with
medical use of these seven substances or that the use of these
substances is recognized by entities that regulate the practice of
medicine, so the two-part test also is not satisfied. By letter
dated May 20, 2025, DEA has been advised by HHS that there are
currently no approved new drug applications or investigational new
drug applications for seven benzimidazole-opioids. Additionally, HHS
communicated no objections to the temporary placement of these
substances into schedule I of the CSA.
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Factor 4. History and Current Pattern of Abuse
Benzimidazole-opioids were originally synthesized and studied for
their analgesic properties in the 1950s by the pharmaceutical research
laboratories of the Swiss chemical company Chemical Industries Basel.
The research produced a group of structurally unique benzimidazole
derivatives with analgesic properties; however, the research effort did
not produce any medically approved analgesic products. Since 2019,
there has been an emergence of benzimidazole-opioid compounds on the
illicit drug market, which have been positively identified in numerous
cases of fatal overdose events. These benzimidazole-opioid derivatives
include schedule I substances, such as synthetic opioids clonitazene,
etonitazene, and isotonitazene.
Recently, ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene have emerged
in the illicit drug market. Law enforcement officers have encountered
these seven substances in solid forms (e.g., powder and tablets) and
are often mixed with other illicit drugs. Commonly, benzimidazole-
opioids are co-detected with designer benzodiazepines, a combination
that poses significant risk to users. These substances are not approved
pharmaceutical products, and they are not approved for medical use
anywhere in the world. In a letter to DEA dated May 20, 2025, the
Acting Assistant
[[Page 48262]]
Secretary stated that there are no FDA-approved NDAs or INDs for
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene in the United States;
hence, there are no legitimate channels for these substances as
marketed drug products.
Reports of detection of benzimidazole-opioids in forensic casework
are on the rise. The appearance of benzimidazole-opioids on the illicit
drug market is similar to other designer opioid drugs trafficked for
their psychoactive effects. In 2023 and 2024, ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene emerged on the illicit synthetic drug
market as evidenced by their identification in forensic drug seizures
and in biological samples.\14\ According to the National Forensic
Laboratory Information System (NFLIS-Drug) and DEA STARLiMS databases,
law enforcement encounters of ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene have been identified in powder or
tablet forms.
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\14\ Gao, G., Yang, S., Wang, X., Xiang, P., Ma, L., Yan, F., &
Shi, Y. (2025). UHPLC-MS/MS-based analysis of 17 nitazenes in human
hair for practical forensic casework with simultaneous separation of
6 groups of isomers. Journal of pharmaceutical and biomedical
analysis, 257, 116707.
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Factor 5. Scope, Duration and Significance of Abuse
Ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene, similar to
etonitazene, metonitazene, and protonitazene (schedule I substances),
have been described as potent synthetic opioids, and evidence suggests
they are abused for their opioidergic effects (see Factor 6). The abuse
of these benzimidazole-opioids, similar to other synthetic opioids, has
resulted in serious adverse health effects. According to the center for
forensic science research education (CFSRE) monograph reports published
between November 2023 and December 2024, some of these benzimidazole-
opioids have been co-identified with designer benzodiazepines,
fentanyl, heroin, or other benzimidazole-opioids.\15\ Data from law
enforcement suggest that ethyleneoxynitazene, methylenedioxynitazene,
5-methyl etodesnitazene, N-desethyl etonitazene, N-desethyl
protonitazene, N-pyrrolidino isotonitazene, and N,N-dimethylamino
etonitazene are being abused in the United States as recreational
drugs.\16\ Since 2023, there have been 184 exhibits reported to the
National Forensic Laboratory Information System (NFLIS-Drug) \17\
database pertaining to the trafficking, distribution, and abuse of
these substances.\18\ NFLIS registered 14 encounters of
ethyleneoxynitazene from 5 states; 19 encounters of
methylenedioxynitazene from 5 states; four encounters of 5-methyl
etodesnitazene from 1 state, 114 encounters of N-desethyl etonitazene
from 14 states; 9 encounters of N-desethyl protonitazene from 6 states;
12 encounters of N,N-dimethylamino etonitazene from 4 states; and 12
encounters of N-pyrrolidino isotonitazene from 9 states. According to
data from DEA STARLiMS \19\ database, there have been 66
identifications of 6 of these substances.\20\ There have been 7
identifications of ethyleneoxynitazene; 2 identifications of
methylenedioxynitazene; 24 identifications of N-desethyl etonitazene; 7
identifications of N-desethyl protonitazene; 4 identifications of N-
pyrrolidino isotonitazene; and 22 identifications of N,N-dimethylamino
etonitazene in drug seizures.
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\15\ Monographs, N-Desethyl etonitazene (Nov. 30, 2023),
available at www.cfsre.org/images/monographs/N-Desethyl-Etonitazene-New-Drug-Monograph-NPS-Discovery-113023.pdf; Monographs, 5Mmethyl
etodesnitazene (Aug. 26, 2024), available at www.cfsre.org/images/monographs/5-Methyl-Etodesnitazene-New-Drug-Monograph-NPS-Discovery.pdf; Monographs, Methylenedioxynitazene (Aug. 29, 2024),
available at www.cfsre.org/images/monographs/Methylenedioxynitazene-New-Drug-Monograph-NPS-Discovery.pdf; Monographs--N-Pyrrolidino
isotonitazene (Dec. 20, 2024), available at www.cfsre.org/images/monographs/N-Pyrrolidino-Isotonitazene-New-Drug-Monograph-NPS-Discovery.pdf.
\16\ While law enforcement data are 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).
\17\ DEA's National Forensic Laboratory Information System
(NFLIS) is a comprehensive information system that collects
scientifically verified data on drug items and cases submitted to
and analyzed by participating federal, state, and local forensic
drug laboratories within the United States. NFLIS-Drug, a component
of NFLIS, includes drug chemistry results from completed analyses
only. While NFLIS data are 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).
\18\ NFLIS-Drug was queried on May 12, 2025.
\19\ On October 1, 2014, DEA implemented STARLiMS (a web-based,
commercial laboratory information management system) to replace the
System to Retrieve Information from Drug Evidence (STRIDE) as its
laboratory drug evidence data system of record. Accessed June 25,
2025.
\20\ There is duplication of records between NFLIS and STARLiMS.
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Because abusers of these substances are likely to obtain these
substances through unregulated sources, the identity, purity, and
quantity of these substances are uncertain and inconsistent, thus
posing significant adverse health risks to the end user. The misuse and
use of opioids have been demonstrated and are well-characterized.
Individuals who initiate use (i.e., use a drug for the first time) of
these benzimidazole-opioids are likely to be at risk of developing
substance use disorder, an overdose event, or death, similar to that of
other opioid analgesics (e.g., fentanyl and morphine). The population
likely to abuse these benzimidazole-opioids appears to be the same as
those misusing prescription opioid analgesics, fentanyl, and other
synthetic drugs. 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
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene are being illicitly
distributed and abused.
Factor 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. Data obtained from pre-clinical
studies demonstrate that ethyleneoxynitazene, methylenedioxynitazene,
5-methyl etodesnitazene, N-desethyl etonitazene, N-desethyl
protonitazene, N,N-dimethylamino etonitazene, and N-pyrrolidino
isotonitazene exhibit pharmacological profiles similar to that of
etonitazene, metonitazene, protonitazene, and other mu-opioid receptor
agonists.\21\ It is well established that substances that act as mu-
opioid receptor agonists have a high potential
[[Page 48263]]
for addiction and can induce dose-dependent respiratory depression.
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\21\ 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. 2022 2024.
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Consistent with any mu-opioid receptor agonist, the potential
health and safety risks for users of these seven substances are high.
Data obtained from trend reports published by CFSRE, which reports on
novel psychoactive substances (NPS) opioid positivity in cases and
samples types from recreational drug use, medicolegal death
investigations, clinical intoxications, and/or driving under the
influence of drugs investigations, showed that in 2024, 5-methyl
etodesnitazene was identified in 6 toxicology cases;
methylenedioxynitazene was identified in 4 toxicology cases; N-desethyl
etonitazene was identified in 11 cases; N-desethyl protonitazene was
identified as a metabolite of protonitazene in 11 cases and as a parent
compound in 7 cases; and N-pyrrolidino isotonitazene was identified in
1 case.\22\ A study conducted to develop an analytical method for
identifying nitazenes in human hair detected the presence of N,N-
dimethylamino etonitazene in two biological samples obtained from
individuals suspected of smoking tobacco products containing
nitazenes.\23\
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\22\ NPS Opioids--2024 Q1-Q4 reports, available at
www.cfsre.org/nps-discovery/trend-reports/nps-opioids/report/49?trend_type_id=2.
\23\ Gao, G., Yang, S., Wang, X., Xiang, P., Ma, L., Yan, F., &
Shi, Y. (2025). UHPLC-MS/MS-based analysis of 17 nitazenes in human
hair for practical forensic casework with simultaneous separation of
6 groups of isomers. Journal of pharmaceutical and biomedical
analysis, 257, 116707.
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The public health risks attendant to the use of mu-opioid receptor
agonists are well established and have resulted in large numbers of
drug treatment admissions, emergency department visits, and fatal
overdoses. The introduction of potent synthetic opioids, such as
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene, into the illicit market
may serve as a portal to problematic opioid use for those seeking these
powerful opioids. The United States is currently experiencing an opioid
epidemic, and the presence of synthetic opioids on the illicit drug
market further exacerbates the problem. The trafficking and abuse of
new synthetic opioids are deadly trends which pose imminent hazard to
the public safety. Adverse health effects associated with the use of
synthetic opioids and the continued evolution and increased popularity
of these substances has been a serious concern in recent years.
Because of the pharmacological similarities of ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene to other schedule I opioids such as
etonitazene and protonitazene, the use of these substances presents
high risk of abuse and may negatively affect users and communities. The
positive identification of these substances in toxicology and forensic
cases demonstrates that the use of these substances is of serious
concern to public safety. Thus, ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene pose imminent hazard to public safety.
Finding of Necessity of Schedule I Placement To Avoid Imminent Hazard
to Public Safety
In accordance with 21 U.S.C. 811(h)(3), based on the available data
and information summarized above, the uncontrolled manufacture,
distribution, reverse distribution, importation, exportation, conduct
of research and chemical analysis, possession, and abuse of
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene pose imminent hazards to
public safety. DEA is not aware of any currently accepted medical uses
for these substances in the United States. A substance meeting the
statutory requirements for temporary scheduling, found in 21 U.S.C.
811(h)(1), may only be placed in schedule I. Substances in schedule I
must have a high potential for abuse, no currently accepted medical use
in treatment in the United States, and a lack of accepted safety for
use under medical supervision. Available data and information for
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene indicate that these
substances meet the three statutory criteria.
As required by 21 U.S.C. 811(h)(4), the then-Acting Administrator
transmitted to the Acting Assistant Secretary, via letter dated April
15, 2025, notice of DEA's intent to place ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene in schedule I on a temporary basis. By
letter dated May 20, 2025, the Acting Assistant Secretary had no
objection to the temporary placement of these substances in schedule I.
DEA subsequently published this NOI in the Federal Register on June 26,
2025.\24\
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\24\ Schedules of Controlled Substances: Temporary Placement of
Seven Benzimidazole-Opioids in Schedule I, 90 FR 27268 (June 26,
2025).
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Conclusion
In accordance with 21 U.S.C. 811(h)(1) and (3), the Administrator
considered available data and information, herein set forth the grounds
for his determination that it is necessary to temporarily schedule
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene in schedule I of the CSA,
and finds that placement of these substances in schedule I is necessary
to avoid an imminent hazard to the public safety.
The temporary placement of ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene in schedule I of the CSA will take
effect on the date the order is published in the Federal Register and
will remain in effect for two years, with a possible extension of one
year, pending completion of the regular (permanent) scheduling
process.\25\
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\25\ 21 U.S.C. 811(h)(1) and (2).
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The CSA sets forth specific criteria for scheduling drugs or other
substances. Regular scheduling actions in accordance with 21 U.S.C.
811(a) are subject to formal rulemaking procedures ``on the record
after opportunity for a hearing'' conducted pursuant to the provisions
of 5 U.S.C. 556 and 557.\26\ The permanent scheduling process of formal
rulemaking affords interested parties appropriate process and the
government any additional relevant information needed to make a
determination. Final decisions that conclude the permanent scheduling
process of formal rulemaking are subject to judicial review.\27\
Temporary
[[Page 48264]]
scheduling orders are not subject to judicial review.\28\
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\26\ 21 U.S.C. 811.
\27\ 21 U.S.C. 877.
\28\ 21 U.S.C. 811(h)(6).
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Requirements for Handling
Upon the effective date of this temporary order,
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene will be subject to the
regulatory controls and administrative, civil, and criminal sanctions
applicable to the manufacture, distribution, reverse distribution,
importation, exportation, possession of, and engagement in research and
conduct of instructional activities or chemical analysis with, schedule
I controlled substances, including but not limited to the following:
1. Registration. Any person who handles (possesses, manufactures,
distributes, reverse distributes, imports, exports, engages in
research, or conducts instructional activities or chemical analysis
with) or desires to handle, ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene 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, as of October 15, 2025. Any
person who currently handles ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene and is not registered with DEA must
submit an application for registration and may not continue to handle
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene as of October 15, 2025,
unless DEA has approved that application for registration pursuant to
21 U.S.C. 822, 823, 957, and 958, and in accordance with 21 CFR parts
1301 and 1312. Retail sales of schedule I controlled substances to the
general public are not allowed under the CSA. Possession of any
quantity of these substances in a manner not authorized by the CSA on
or after October 15, 2025 is unlawful, and those in possession of any
quantity of these substances may be subject to prosecution pursuant to
the CSA.
2. Disposal of stocks. Any person who does not desire or is unable
to obtain a schedule I registration to handle ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene must surrender all currently held
quantities of these seven substances.
3. Security. Ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene are subject
to schedule I security requirements and must be handled in accordance
with 21 CFR 1301.71-1301.93, as of October 15, 2025.
4. Labeling and Packaging. All labels, labeling, and packaging for
commercial containers of ethyleneoxynitazene, methylenedioxynitazene,
5-methyl etodesnitazene, N-desethyl etonitazene, N-desethyl
protonitazene, N,N-dimethylamino etonitazene, and N-pyrrolidino
isotonitazene must comply with 21 U.S.C. 825 and 958(e) and 21 CFR part
1302. Current DEA registrants will have 30 calendar days from October
15, 2025 to comply with all labeling and packaging requirements.
5. Inventory. Every DEA registrant who possesses any quantity of
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene on the effective date of
this order must take an inventory of all stocks of these substances on
hand pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR
1304.03, 1304.04, and 1304.11. Current DEA registrants will have 30
calendar days from the effective date of this order to comply with all
inventory requirements. After the initial inventory, every DEA
registrant must take an inventory of all controlled substances
(including ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene) on hand on
a biennial basis pursuant to 21 U.S.C. 827 and 958 and in accordance
with 21 CFR 1304.03, 1304.04, and 1304.11.
6. Records. All DEA registrants must maintain records with respect
to ethyleneoxynitazene, methylenedioxynitazene, 5-methyl
etodesnitazene, N-desethyl etonitazene, N-desethyl protonitazene, N,N-
dimethylamino etonitazene, and N-pyrrolidino isotonitazene pursuant to
21 U.S.C. 827 and 958(e) and in accordance with 21 CFR parts 1304,
1312, and 1317, and section 1307.11. Current DEA registrants authorized
to handle these seven substances shall have 30 calendar days from the
effective date of this order to comply with all recordkeeping
requirements.
7. Reports. All DEA registrants must submit reports with respect to
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene pursuant to 21 U.S.C. 827
and in accordance with 21 CFR parts 1304, 1312, and 1317, and sections
1301.74(c) and 1301.76(b), as of October 15, 2025. Manufacturers and
distributors must also submit reports regarding these seven substances
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.
8. Order Forms. All DEA registrants who distribute
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene must comply with order
form requirements pursuant to 21 U.S.C. 828 and in accordance with 21
CFR part 1305 as of October 15, 2025.
9. Importation and Exportation. All importation and exportation of
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene must be in compliance with
21 U.S.C. 952, 953, 957, and 958, and in accordance with 21 CFR part
1312 as of October 15, 2025.
10. Quota. Only DEA-registered manufacturers may manufacture
ethyleneoxynitazene, methylenedioxynitazene, 5-methyl etodesnitazene,
N-desethyl etonitazene, N-desethyl protonitazene, N,N-dimethylamino
etonitazene, and N-pyrrolidino isotonitazene in accordance with a quota
assigned pursuant to 21 U.S.C. 826 and in accordance with 21 CFR part
1303, as of October 15, 2025.
11. Liability. Any activity involving ethyleneoxynitazene,
methylenedioxynitazene, 5-methyl etodesnitazene, N-desethyl
etonitazene, N-desethyl protonitazene, N,N-dimethylamino etonitazene,
and N-pyrrolidino isotonitazene not authorized by or in violation of
the CSA, occurring as of October 15, 2025, is unlawful, and
[[Page 48265]]
may subject the person to administrative, civil, and/or criminal
sanctions.
Regulatory Analyses
The CSA provides for expedited temporary scheduling actions where
necessary to avoid an imminent hazard to public safety. Under 21 U.S.C.
811(h)(1), the Administrator, as delegated by the Attorney General,
may, by order, temporarily place substances in schedule I. Such orders
may not be issued before the expiration of 30 days from: (1) the
publication of a notice in the Federal Register of the intent to issue
such order and the grounds upon which such order is to be issued, and
(2) the date that notice of the proposed temporary scheduling order is
transmitted to the Assistant Secretary, as delegated by the Secretary
of HHS.\29\
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\29\ 21 U.S.C. 811(h)(1).
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Inasmuch as section 811(h) directs that temporary scheduling
actions be issued by order (as distinct from a rule) and sets forth the
procedures by which such orders are to be issued, DEA believes the
notice-and-comment requirements of section 553 of the Administrative
Procedure Act (APA), 5 U.S.C. 553, which are applicable to rulemaking,
do not apply to this temporary scheduling order. The APA expressly
differentiates between orders and rules, as it defines an ``order'' to
mean a ``final disposition, whether affirmative, negative, injunctive,
or declaratory in form, of an agency in a matter other than rule
making.'' \30\ (Emphasis added). This contrasts with permanent
scheduling actions, which are subject to formal rulemaking procedures
done ``on the record after opportunity for a hearing,'' and final
decisions that conclude the scheduling process and are subject to
judicial review. 21 U.S.C. 811(a) and 877. The specific language chosen
by Congress indicates its intent that DEA issue orders instead of
proceeding by rulemaking when temporarily scheduling substances. Given
that Congress specifically requires the Administrator (as delegated by
the Attorney General) to follow rulemaking procedures for other kinds
of scheduling actions, see 21 U.S.C. 811(a), it is noteworthy that, in
section 811(h)(1), Congress authorized the issuance of temporary
scheduling actions by order rather than by rule.
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\30\ 5 U.S.C. 551(6).
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Even assuming that this action is subject to section 553 of the
APA, the Acting Administrator finds that there is good cause to forgo
its notice-and-comment requirements pursuant to 5 U.S.C. 553(b)(B), as
any further delays in the process for issuing temporary scheduling
orders would be impracticable and contrary to the public interest given
the manifest urgency to avoid an imminent hazard to public safety.
Although DEA believes this temporary scheduling order is not
subject to the notice-and-comment requirements of section 553 of the
APA, DEA notes that in accordance with 21 U.S.C. 811(h)(4), the
Administrator took into consideration comments submitted by the Acting
Assistant Secretary in response to the notices that DEA transmitted to
the Acting Assistant Secretary pursuant to such subsection.
Further, DEA believes that this temporary scheduling action is not
a ``rule'' as defined by 5 U.S.C. 601(2), and, accordingly, is not
subject to the requirements of the Regulatory Flexibility Act (RFA).
The requirements for the preparation of an initial regulatory
flexibility analysis in 5 U.S.C. 603(a) are not applicable where, as
here, DEA is not required by section 553 of the APA or any other law to
publish a general notice of proposed rulemaking. Therefore, in this
instance, since DEA believes this temporary scheduling action is not a
``rule,'' it is not subject to the requirements of the RFA when issuing
this temporary action.
In accordance with the principles of Executive Orders (E.O.) 12866,
13563, and 14192, this action is not a significant regulatory action.
E.O. 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, if regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health, and safety effects;
distributive impacts; and equity). E.O. 13563 is supplemental to and
reaffirms the principles, structures, and definitions governing
regulatory review as established in E.O. 12866. E.O. 12866, sec. 3(f),
provides the definition of a ``significant regulatory action,''
requiring review by the Office of Management and Budget. Because this
is not a rulemaking action, this is not a significant regulatory action
as defined in Section 3(f) of E.O. 12866. DEA scheduling actions are
not subject to either E.O. 14192, Unleashing Prosperity Through
Deregulation, or E.O. 14294, Fighting Overcriminalization in Federal
Regulations.
This action will not have substantial direct effects on the states,
on the relationship between the national government and the states, or
on the distribution of power and responsibilities among the various
levels of government. Therefore, in accordance with E.O. 13132, it is
determined that this action does not have sufficient federalism
implications to warrant the preparation of a Federalism Assessment.
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 amends 21 CFR part 1308 as
follows:
PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES
0
1. The authority citation for 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, add paragraphs (h)(79) through (85) to read as
follows:
Sec. 1308.11 Schedule I.
* * * * *
(h) * * *
------------------------------------------------------------------------
------------------------------------------------------------------------
* * * * * * *
(79) 2-(2-((2,3-dihydrobenzofuran-5-yl)methyl)-5-nitro-1H- 9770
benzimidazol-1-yl)-N,N-diethylethan-1-amine, its isomers,
esters, ethers, salts, and salts of isomers, esters and ethers
(Other name: Ethyleneoxynitazene).............................
(80) 2-(2-(benzodioxol-5-ylmethyl)-5-nitro-1H-benzimidazol-1- 9766
yl)-N,N-diethylethan-1-amine, its isomers, esters, ethers,
salts, and salts of isomers, esters and ethers (Other names:
Methylenedioxynitazene; 3',4'-methylenedioxynitazene).........
(81) 2-(2-(4-ethoxybenzyl)-5-methyl-1H-benzimidazol-1-yl)-N,N- 9767
diethylethan-1-amine, its isomers, esters, ethers, salts, and
salts of isomers, esters and ethers (Other name: 5-methyl
etodesnitazene)...............................................
(82) 2-(2-(4-ethoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)-N- 9768
ethylethan-1-amine, its isomers, esters, ethers, salts, and
salts of isomers, esters and ethers (Other name: N-desethyl
etonitazene)..................................................
[[Page 48266]]
(83) N-ethyl-2-(5-nitro-2-(4-propoxybenzyl)-1H-benzimidazol-1- 9769
yl)ethan-1-amine its isomers, esters, ethers, salts, and salts
of isomers, esters and ethers (Other name: N-desethyl
protonitazene)................................................
(84) 2-(2-(4-ethoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)-N,N- 9771
dimethylethan-1-amine, its isomers, esters, ethers, salts, and
salts of isomers, esters and ethers (Other name: N,N-
dimethylamino etonitazene)....................................
(85) 2-(4-isopropoxybenzyl)-5-nitro-1-(2-(pyrrolidin-1- 9772
yl)ethyl)-1H-benzimidazole, its isomers, esters, ethers,
salts, and salts of isomers, esters and ethers (Other name: N-
pyrrolidino isotonitazene)....................................
------------------------------------------------------------------------
Signing Authority
This document of the Drug Enforcement Administration was signed on
October 9, 2025, by Administrator Terrance Cole. 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.
Heather Achbach,
Federal Register Liaison Officer, Drug Enforcement Administration.
[FR Doc. 2025-19542 Filed 10-14-25; 8:45 am]
BILLING CODE 4410-09-P