Schedules of Controlled Substances: Placement of cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl Into Schedule I
| Published date | 30 January 2020 |
| Citation | 85 FR 5356 |
| Record Number | 2020-01681 |
| Section | Proposed rules |
| Court | Drug Enforcement Administration |
Federal Register, Volume 85 Issue 20 (Thursday, January 30, 2020)
[Federal Register Volume 85, Number 20 (Thursday, January 30, 2020)]
[Proposed Rules]
[Pages 5356-5361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-01681]
[[Page 5356]]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-565]
Schedules of Controlled Substances: Placement of cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl Into Schedule I
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Drug Enforcement Administration proposes placing
cyclopentyl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-
phenylcyclopentanecarboxamide), isobutyryl fentanyl (N-(1-
phenethylpiperidin-4-yl)-N-phenylisobutyramide), para-chloroisobutyryl
fentanyl (N-(4-chlorophenyl)-N-(1-phenethylpiperidin-4-
yl)isobutyramide), para-methoxybutyryl fentanyl (N-(4-methoxyphenyl)-N-
(1-phenethylpiperidin-4-yl)butyramide), and valeryl fentanyl (N-(1-
phenethylpiperidin-4-yl)-N-phenylpentanamide), 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, 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,
import, export, engage in research, conduct instructional activities or
chemical analysis, or possess), or propose to handle cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl.
DATES: Comments must be submitted electronically or postmarked on or
before March 2, 2020.
Interested persons may file a request for hearing or waiver of
hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR
1316.45 and/or 1316.47, as applicable. Requests for hearing and waivers
of an opportunity for a hearing or to participate in a hearing must be
received on or before March 2, 2020.
ADDRESSES: Interested persons may file written comments on this
proposal in accordance with 21 CFR 1308.43(g). 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. To ensure proper handling of comments, please reference
``Docket No. DEA-565'' on all electronic and written correspondence,
including any attachments.
Electronic comments: Drug Enforcement Administration
encourages that all comments be submitted electronically through the
Federal eRulemaking Portal which provides the ability to type short
comments directly into the comment field on the web page or to attach a
file for lengthier comments. Please go to http://www.regulations.gov
and follow the online instructions at that site for submitting
comments. Upon completion of your submission you will receive a Comment
Tracking Number for your comment. Please be aware that submitted
comments are not instantaneously available for public view on
Regulations.gov. If you have received a Comment Tracking Number, your
comment has been successfully submitted and there is no need to
resubmit the same comment.
Paper comments: Paper comments that duplicate the
electronic submission are not necessary. Should you wish to mail a
paper comment in lieu of an electronic comment, it should be sent via
regular or express mail to: Drug Enforcement Administration, Attn: DEA
Federal Register Representative/DRW, 8701 Morrissette Drive,
Springfield, Virginia 22152.
Hearing requests: All requests for hearing and waivers of
participation must be sent to: Drug Enforcement Administration, Attn:
Administrator, 8701 Morrissette Drive, Springfield, Virginia 22152. All
requests for hearing and waivers of participation should be sent to:
Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701
Morrissette Drive, Springfield, Virginia 22152; and (2) Drug
Enforcement Administration, Attn: DEA Federal Register Representative/
DRW, 8701 Morrissette Drive, Springfield, Virginia 22152.
FOR FURTHER INFORMATION CONTACT: Scott A. Brinks, Diversion Control
Division, Drug Enforcement Administration; Mailing Address: 8701
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
Please note that all comments received in response to this docket
are considered part of the public record. They will, unless reasonable
cause is given, be made available by the Drug Enforcement
Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying
information such as your name, address, etc. voluntarily submitted by
the commenter. The Freedom of Information Act (FOIA) applies to all
comments received. If you want to submit personal identifying
information (such as your name, address, etc.) as part of your comment,
but do not want it to be made publicly available, you must include the
phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of
your comment. You must also place all of the personal identifying
information you do not want made publicly available in the first
paragraph of your comment and identify what information you want
redacted.
If you want to submit confidential business information as part of
your comment, but do not want it to be made publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also prominently identify
confidential business information to be redacted within the comment.
Comments containing personal identifying information and
confidential business information identified as directed above will be
made publicly available in redacted form. If a comment has so much
confidential business information or personal identifying information
that it cannot be effectively redacted, all or part of that comment may
not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information
such as name, address, and phone number included in the text of your
electronic submission that is not identified as directed above as
confidential.
An electronic copy of this document and supplemental information to
this proposed rule are available at http://www.regulations.gov for easy
reference.
Request for Hearing or Waiver of Participation in a Hearing
Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking
``on the record after opportunity for a hearing.'' Such proceedings are
conducted pursuant to the provisions of the Administrative Procedure
Act (APA), 5 U.S.C. 551-559. (21 CFR 1308.41-1308.45; 21 CFR part 1316,
subpart D). Such requests or notices must conform to the requirements
of 21 CFR 1308.44(a) or (b), and 1316.47 or 1316.48, as applicable, and
include a
[[Page 5357]]
statement of the person's interests in the proposed scheduling action,
whether the person is adversely affected or aggrieved, and the
objections or issues, if any, concerning which the person desires to be
heard at a hearing. Any waiver must conform to the requirements of 21
CFR 1308.44(c) and may include a written statement regarding the
interested person's position on the matters of fact and law involved in
any hearing.
Legal Authority
The Controlled Substances Act (CSA) provides that proceedings for
the issuance, amendment, or repeal of the scheduling of any drug or
other substance may be initiated by the Attorney General (1) on his own
motion; (2) at the request of the Secretary of the Department of Health
and Human Services (HHS),\1\ or (3) on the petition of any interested
party. 21 U.S.C. 811(a). This proposed action is supported by a
recommendation from the Assistant Secretary for Health of the HHS
(Assistant Secretary) and an evaluation of all other relevant data by
the 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 cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl.
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\1\ As discussed in a memorandum of understanding entered into
by the Food and Drug Administration (FDA) and the National Institute
on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS
in carrying out the Secretary's scheduling responsibilities under
the CSA, with the concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. The
Secretary of the HHS has delegated to the Assistant Secretary for
Health of the HHS the authority to make domestic drug scheduling
recommendations. 58 FR 35460, July 1, 1993.
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Background
On February 1, 2018, DEA published an order in the Federal Register
amending 21 CFR 1308.11(h) to temporarily place cyclopentyl fentanyl
(N-(1-phenethylpiperidin-4-yl)-N-phenylcyclopentanecarboxamide),
isobutyryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-
phenylisobutyramide), para-chloroisobutyryl fentanyl (N-(4-
chlorophenyl)-N-(1-phenethylpiperidin-4-yl)isobutyramide), para-
methoxybutyryl fentanyl (N-(4-methoxyphenyl)-N-(1-phenethylpiperidin-4-
yl)butyramide), and valeryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-
phenylpentanamide), along with two other substances,\2\ in schedule I
of the CSA pursuant to the temporary scheduling provisions of 21 U.S.C.
811(h). 83 FR 4580. That temporary scheduling order was effective on
the date of publication, and was based on findings by the former Acting
Administrator of DEA (Acting Administrator) that the temporary
scheduling of these seven substances was necessary to avoid an imminent
hazard to public safety pursuant to 21 U.S.C. 811(h)(1). Section
201(h)(2) of the CSA, 21 U.S.C. 811(h)(2), requires that the temporary
control of these substances expire two years from the effective date of
the scheduling order, which was February 1, 2018. However, the CSA also
provides that during the pendency of proceedings under 21 U.S.C.
811(a)(1) with respect to the substance, the temporary scheduling of
that substance could be extended for up to one year. Proceedings for
the scheduling of a substance under 21 U.S.C. 811(a) may be initiated
by the Attorney General (delegated to the Administrator of the DEA
pursuant to 28 CFR 0.100) on his own motion, at the request of the
Secretary of HHS,\3\ or on the petition of any interested party. An
extension of the existing temporary order is being ordered by the
Acting Administrator in a separate action, and is published elsewhere
in this issue of the Federal Register.
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\2\ Those two other substances, ocfentanil (N-(2-fluorophenyl)-
2-methoxy-N-(phenethylpiperidin-4-yl)acetamide) and para-
fluorobutyryl fentanyl (N-(4-fluorophenyl)-N-(1-phenethylpiperidin-
4-yl)butyramide, were subsequently permanently placed in schedule I
on November 29, 2018 (83 FR 61320) and October 25, 2019 (84 FR
57327), respectively, pursuant to 21 U.S.C. 811(d)(1).
\3\ Because the Secretary of HHS has delegated to the Assistant
Secretary the authority to make domestic drug scheduling
recommendations, for purposes of this proposed rulemaking, all
subsequent references to ``Secretary'' have been replaced with
``Assistant Secretary.''
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The Acting Administrator, on his own motion pursuant to 21 U.S.C.
811(a), is initiating proceedings under 21 U.S.C. 811(a)(1) to
permanently schedule cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl. DEA has gathered 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 November 5, 2018, the Acting Administrator submitted a
request to the Assistant Secretary to provide DEA with a scientific and
medical evaluation of available information and a scheduling
recommendation for cyclopropyl fentanyl, para-fluorobutyryl fentanyl,
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl, in
accordance with 21 U.S.C. 811(b) and (c).
In a letter dated September 6, 2019, DEA notified HHS that it no
longer needed scientific and medical evaluations for cyclopropyl
fentanyl and para-fluorobutyryl fentanyl. Subsequently, DEA permanently
placed these two substances in schedule I of the CSA on October 25,
2019, pursuant to 21 U.S.C. 811(d)(1). (84 FR 57323).
On November 12, 2019, the Assistant Secretary submitted HHS's
scientific and medical evaluation and scheduling recommendation \4\ for
cyclopropyl fentanyl and para-fluorobutyryl fentanyl, cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl to the Acting
Administrator. Upon receipt of the scientific and medical evaluation
and scheduling recommendation from the HHS, in accordance with 21
U.S.C. 811(c), the DEA reviewed the documents and all other relevant
data, and conducted its own eight-factor analysis of the abuse
potential of cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl.
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\4\ Although HHS provided information on cyclopropyl fentanyl
and para-fluorobutyryl fentanyl, these two substances will not be
discussed in this notice of proposed rulemaking because they are
already permanently controlled.
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Proposed Determination to Permanently Schedule Cyclopentyl fentanyl,
Isobutyryl fentanyl, para-Chloroisobutyryl fentanyl, para-
Methoxybutyryl fentanyl, and Valeryl fentanyl
As discussed in the background section, the Acting Administrator is
initiating proceedings, pursuant to 21 U.S.C. 811(a)(1), to add
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl
permanently to schedule I. DEA has reviewed the scientific and medical
evaluation and scheduling recommendation received from HHS, and all
other relevant data and conducted its own eight-factor analysis of the
abuse potential of these five substances pursuant to 21 U.S.C. 811(c).
Included below is a brief summary of each factor as analyzed by the HHS
and the DEA, and as considered by the DEA in its proposed scheduling
action. Please note that both DEA 8-Factor and HHS 8-Factor analysis
and the Assistant
[[Page 5358]]
Secretary's November 12, 2019, letter are available in their entirety
under the tab ``Supporting Documents'' of the public docket for this
action at http://www.regulations.gov under Docket Number ``DEA-565.''
1. The Drug's Actual or Relative Potential for Abuse: The term
``abuse'' is not defined in the CSA. However, the legislative history
of the CSA suggests DEA consider the following criteria when
determining whether a particular drug or substance has a potential for
abuse:\5\
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\5\ 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.
(a) There is evidence that individuals are taking the drug or
drugs containing such a substance in amounts sufficient to create a
hazard to their health or to the safety of other individuals or to
the community; or
(b) There is significant diversion of the drug or drugs
containing such a substance from legitimate drug channels; or
(c) Individuals are taking the drug or drugs containing such a
substance on their own initiative rather than on the basis of
medical advice from a practitioner licensed by law to administer
such drugs in the course of his professional practice; or
(d) The drug or drugs containing such a substance are new drugs
so related in their action to a drug or drugs already listed as
having a potential for abuse to make it likely that the drug will
have the same potentiality for abuse as such drugs, thus making it
reasonable to assume that there may be significant diversions from
legitimate channels, significant use contrary to or without medical
advice, or that it has a substantial capability of creating hazards
to the health of the user or to the safety of the community.
The abuse potential of cyclopentyl fentanyl, isobutyryl fentanyl,
para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and
valeryl fentanyl is associated with its pharmacological similarity to
other schedule I and II mu-opioid receptor agonist substances which
have a high potential for abuse. Similar to morphine, fentanyl and
several schedule I opioid substances that are structurally related to
fentanyl, cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl have been shown to bind and act as mu-opioid receptor
agonists.
Cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl have no
approved medical use in the United States and have been encountered on
the illicit drug market. The use of cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
and valeryl fentanyl has been associated with adverse outcomes to
include intoxications for para-chloroisobutyryl fentanyl and para-
methoxybutyryl fentanyl. Because these five substances are not Food and
Drug Administration (FDA) approved drug products, a practitioner may
not legally prescribe them, and these substances cannot be dispensed to
an individual. Therefore, the use of cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
and valeryl fentanyl is without medical advice, and accordingly, leads
to the conclusion that these five substances are abused for their
opioid-like properties. There are no legitimate channels for these five
substances to be marketed as FDA-approved drug products but they are
available for purchase from legitimate chemical companies to be used in
scientific research. However, despite the limited legitimate use of
these substances, reports from public health and law enforcement
indicate that cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl are being abused and taken in amounts sufficient to create a
hazard to an individual's health. Data from forensic databases can be
used as an indicator of illicit activity with drugs and abuse \6\
within the United States. According to drug seizure data from STRIDE
and STARLiMS \7\ and the National Forensic Laboratory Information
System (NFLIS),\8\ cyclopentyl fentanyl, isobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl are being encountered in
the United States. Although there have been no law enforcement
encounters for para-chloroisobutyryl fentanyl thus far, this substance
poses the same qualitative public health risks as heroin, fentanyl, and
other opioid analgesic substances.
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\6\ While law enforcement data is not direct evidence of abuse,
it can lead to an inference that a drug has been diverted and
abused. See 76 FR 77330, 77332, Dec. 12, 2011.
\7\ October 1, 2014, the 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. DEA laboratory data
submitted after September 30, 2014, are reposited in STARLiMS.
STRIDE/STARLiMS data were queried on 11/20/2019.
\8\ NFLIS is a DEA program and a national forensic laboratory
reporting system that systematically collects results from drug
chemistry analyses conducted by state and local forensic
laboratories in the United States. The NFLIS database also contains
Federal data from U.S. Customs and Border Protection (CBP). NFLIS
only includes drug chemistry results from completed analyses. NFLIS
data were queried 11/20/2019. NFLIS is still reporting data from
2018-2019 due to normal lag time in reporting.
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2. Scientific Evidence of the Drug's Pharmacological Effects, if
Known: Cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl are
pharmacologically similar to other schedule I and schedule II mu-opioid
receptor agonist substances. Non-clinical and clinical studies
conducted on abuse potential of mu-opioid receptor agonists such as
morphine and fentanyl indicate that these substances share
discriminative stimulus effects and have reinforcing properties.
Similar to schedule I and II opioid analgesics, cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl bind to and activate the
mu-opioid receptor. Additionally, behavioral studies in animals
demonstrate that similar to fentanyl and morphine, cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl produce analgesic
effects. Pre-treatment with naltrexone, an opioid antagonist,
attenuated analgesic effects of cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
valeryl fentanyl, fentanyl, and morphine. Thus, it is concluded from in
vitro and in vivo pharmacological studies that effects of cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl are similar to that of
fentanyl and morphine and mediated by mu-opioid receptor agonism.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance: Cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl are synthetic opioids in the 4-anilidopiperidine structural
class which includes fentanyl. These five substances differ in chemical
structure from fentanyl by modification at the acyl group. Fentanyl is
substituted with an ethyl group at this position. Modifications of this
group include cycloalkyl groups (cyclopentyl fentanyl), branched alkyl
groups (isobutyryl fentanyl and para-chloroisobutyryl fentanyl), or
other linear alkyl groups by adding one methylene group to give a
propyl group (para-methoxybutyryl fentanyl) or two
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methylene groups to give a butyl group (valeryl fentanyl). In addition
to modification of the acyl group, para-methoxybutyryl fentanyl and
para-chloroisobutyryl fentanyl are substituted at the para-position of
the N-phenyl ring with a methoxy group or a chlorine atom,
respectively. No study has been undertaken to evaluate the efficacy,
toxicology, and safety of cyclopentyl fentanyl, isobutyryl fentanyl,
para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, or
valeryl fentanyl in humans. It can be inferred from medical examiner
reports and data obtained from animal studies that these five
substances have sufficient distribution to the brain to produce
depressant effects similar to that of mu-opioid receptor agonists.
There are no FDA-approved marketing applications for drug products
containing cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, or valeryl
fentanyl for any therapeutic indication in the United States. Moreover,
there are no clinical studies or petitioners which have claimed an
accepted medical use in the United States for these substances.
4. Its History and Current Pattern of Abuse: Cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl have recently been
encountered by law enforcement and/or public health officials in the
United States or elsewhere. Evidence suggests that the pattern of abuse
of these five substances parallels that of prescription opioid
analgesics. The first reports of cyclopentyl fentanyl and valeryl
fentanyl in the United States were in 2015. Para-methoxybutyryl
fentanyl followed in 2016 and isobutyryl fentanyl was first reported in
2017. While there are no drug seizure reports for para-chloroisobutyryl
fentanyl, one intoxication was associated with this substance in
Sweden.
5. The Scope, Duration, and Significance of Abuse: Cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl, similar to other
substances structurally related to fentanyl, are often used as
recreational drugs. The recreational use of these substances continues
to be of significant concern in the United States. These substances are
distributed to users often with unpredictable outcomes. Currently, the
United States is in the midst of an illicit opioid abuse epidemic.
NFLIS and STARLiMS data indicate that law enforcement encounters
for isobutyryl fentanyl and valeryl fentanyl have increased over the
years, with valeryl fentanyl nearly doubling from 2018 to 2019.
Cyclopentyl fentanyl was found in three exhibits in 2017 and para-
methoxybutyryl fentanyl was found in one exhibit in 2016; these two
substances haven't been reported since. para-Chloroisobutyryl fentanyl
has not been found in any drug seizure reports. DEA notes that the data
from pharmacological testing of cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
and valeryl fentanyl are consistent with those of other opioids such as
fentanyl and other related opioid agonists. Thus, it can be inferred
that the abuse potential of these substances is similar to mu-opioid
receptor agonists such as fentanyl and morphine.
6. What, if Any, Risk There is to the Public Health: Available
evidence on the overall public health risks associated with cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl can be measured by
hospitalization or fatalities associated with the use of such
substances. Other countries have identified fatal and non-fatal
intoxications from toxicological samples for para-methoxybutyryl
fentanyl and para-chloroisobutyryl fentanyl. Abusers of these
substances may not know the origin, identity, or purity of these
substances, thus posing significant adverse health risks when compared
to abuse of pharmaceutical preparations of opioid analgesics, such as
morphine and oxycodone. The abuse of cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
and valeryl fentanyl leads to the same qualitative public health risks
as heroin, fentanyl and other opioid analgesic substances. Taken
together, evidence posits that individuals experimenting with
substances with unknown potency are at high risk of adverse health
outcomes.
7. Its Psychic or Physiological Dependence Liability: There are no
pre-clinical or clinical studies that have evaluated the psychic or
physiologic dependence of cyclopentyl fentanyl, isobutyryl fentanyl,
para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and
valeryl fentanyl. Several studies have shown that due to fentanyl's
short duration of action, more frequent dosing is often required that
can lead to a fast induction of tolerance, dependence and opiate
withdrawal syndrome. Opioid withdrawal includes nausea and vomiting,
depression, agitation, anxiety, craving, sweats, hypertension,
diarrhea, and fever. These five substances act as agonists at the mu-
opioid receptors and exhibit a full and dose-dependent substitution for
the discriminative stimulus effects produced by morphine. Thus, the
pharmacological similarity and pattern of abuse of cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl to fentanyl are
indicative of their potential to possess a psychic and physiological
dependence liability similar to that of other mu-opioid receptor
agonist substances, such as heroin and fentanyl.
8. Whether the Substance is an Immediate Precursor of a Substance
Already Controlled Under the CSA: Cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
and valeryl fentanyl are not immediate precursors of any controlled
substance of the CSA as defined by 21 U.S.C. 802(23).
Conclusion: After considering the scientific and medical evaluation
conducted by the HHS, the HHS's recommendation, and the DEA's own
eight-factor analysis, the DEA finds that the facts and all relevant
data constitute substantial evidence of the potential for abuse of
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl. As such,
DEA hereby proposes to permanently schedule cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl as schedule I controlled
substances under the CSA.
Proposed Determination of Appropriate SSchedule
The CSA establishes five schedules of controlled substances known
as schedules I, II, III, IV, and V. The CSA also outlines the findings
required to place a drug or other substance in any particular schedule.
(21 U.S.C. 812(b)). After consideration of the analysis and
recommendation of the Assistant Secretary for HHS and review of all
other available data, the Acting Administrator of the DEA, pursuant to
21 U.S.C. 811(a) and 21 U.S.C. 812(b)(1), finds that:
1. Cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl have a
high potential for abuse as indicated either by law enforcement data,
intoxications reported by scientific literature, or
[[Page 5360]]
pharmacological testing of these substances;
2. Cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl have no
currently accepted medical use in treatment in the United States; \9\
and
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\9\ Although there is no evidence suggesting that cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl have a currently
accepted medical use in treatment in the United States, it bears
noting that a drug cannot be found to have such medical use unless
DEA concludes that it satisfies a five-part test. Specifically, with
respect to a drug that has not been approved by the FDA, to have a
currently accepted medical use in treatment in the United States,
all of the following must be demonstrated:
i. The drug's chemistry must be known and reproducible;
ii. there must be adequate safety studies;
iii. there must be adequate and well-controlled studies proving
efficacy;
iv. the drug must be accepted by qualified experts; and
v. the scientific evidence must be widely available.
57 FR 10499 (1992).
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3. There is a lack of accepted safety for use of cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl under medical
supervision.
Based on these findings, Acting Administrator of DEA concludes that
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl, 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, warrant continued control in schedule I of the CSA. (21
U.S.C. 812(b)(1)).
Requirements for Handling cyclopentyl fentanyl, isobutyryl fentanyl,
para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and
valeryl fentanyl
If this rule is finalized as proposed, cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl would continue \10\ to be
subject to the CSA's schedule I regulatory controls and administrative,
civil, and criminal sanctions applicable to the manufacture,
distribution, dispensing, importing, exporting, research, and conduct
of instructional activities, including the following:
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\10\ Cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl are currently subject to schedule I controls on a temporary
basis, pursuant to 21 U.S.C. 811(h). 83 FR 4580, February 1, 2018.
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1. Registration. Any person who handles, manufactures, distributes,
dispenses, imports, exports, engages in research, or conducts
instructional activities or chemical analysis with, or possesses
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl, or who
desires to handle cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl, is required to be registered with the DEA to conduct such
activities pursuant to 21 U.S.C. 822, 823, 957, and 958, and in
accordance with 21 CFR parts 1301 and 1312.
2. Security. Cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl are subject to schedule I security requirements and must be
handled and stored pursuant to 21 U.S.C. 821, 823, and in accordance
with 21 CFR 1301.71-1301.93.
3. Labeling and Packaging. All labels and labeling for commercial
containers of cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl must be in compliance with 21 U.S.C. 825 and 958(e), and be in
accordance with 21 CFR part 1302.
4. Quota. Only registered manufacturers are permitted to
manufacture cyclopentyl fentanyl, isobutyryl fentanyl, para-
chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl, and valeryl
fentanyl in accordance with a quota assigned pursuant to 21 U.S.C. 826
and in accordance with 21 CFR part 1303.
5. Inventory. Any person registered with DEA to handle cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl must have an initial
inventory of all stocks of controlled substances including these
substances on hand on the date the registrant first engages in the
handling of controlled substances pursuant to 21 U.S.C. 827 and 958,
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
After the initial inventory, every DEA registrant must take a new
inventory of all stocks of controlled substances (including cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl) on hand every two years
pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR
1304.03, 1304.04, and 1304.11.
6. Records and Reports. Every DEA registrant is required to
maintain records and submit reports with respect to cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl, pursuant to 21 U.S.C.
827 and 958(e), and in accordance with 21 CFR parts 1304 and 1312.
7. Order Forms. Every DEA registrant who distributes cyclopentyl
fentanyl, isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl is required to comply
with the order form requirements, pursuant to 21 U.S.C. 828, and 21 CFR
part 1305.
8. Importation and Exportation. All importation and exportation of
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl must be in
compliance with 21 U.S.C. 952, 953, 957, and 958, and in accordance
with 21 CFR part 1312.
9. Liability. Any activity involving cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl not authorized by, or in
violation of, the CSA or its implementing regulations is unlawful, and
could subject the person to administrative, civil, and/or criminal
sanctions.
Regulatory Analyses
Executive Orders 12866, 13563, and 13771, Regulatory Planning and
Review, Improving Regulation and Regulatory Review, and Reducing
Regulation and Controlling Regulatory Costs
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 12866 and the principles reaffirmed in
Executive Order 13563.
This proposed rule does not meet the definition of an Executive
Order 13771 regulatory action, and the repeal and cost offset
requirements of Executive Order 13771 have not been triggered. OMB has
previously determined that formal rulemaking actions concerning the
scheduling of controlled substances, such as this rule, are not
significant
[[Page 5361]]
regulatory actions under Section 3(f) of Executive Order 12866.
Executive Order 12988, Civil Justice Reform
This proposed regulation meets the applicable standards set forth
in sections 3(a) and 3(b)(2) of Executive Order 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 Executive Order 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 Executive Order 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 (RFA), 5 U.S.C. 601-602, has reviewed this proposed rule and by
approving it, certifies that it will not have a significant economic
impact on a substantial number of small entities. On February 1, 2018,
the DEA published an order to temporarily place cyclopentyl fentanyl,
isobutyryl fentanyl, para-chloroisobutyryl fentanyl, para-
methoxybutyryl fentanyl, and valeryl fentanyl 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
cyclopentyl fentanyl, isobutyryl fentanyl, para-chloroisobutyryl
fentanyl, para-methoxybutyryl fentanyl, and valeryl fentanyl have
already established and implemented the systems and processes required
to handle these substances.
There are currently 34 registrations authorized to handle one or
more of the following substances: Cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
or valeryl fentanyl, as well as a number of registered analytical labs
that are authorized to handle schedule I controlled substances
generally. These 34 registrations represent 26 entities, of which 8 are
small entities. Therefore, DEA estimates 8 small entities are affected
by this proposed rule. A review of the 34 registrations indicates that
all entities that currently handle cyclopentyl fentanyl, isobutyryl
fentanyl, para-chloroisobutyryl fentanyl, para-methoxybutyryl fentanyl,
or valeryl fentanyl also handle other schedule I controlled substances
and have established and implemented (or maintain) the systems and
processes required to handle these substances. Therefore, the DEA
anticipates that this proposed rule will impose minimal or no economic
impact on any affected entities; and thus, will not have a significant
economic impact on any of the eight affected small entities. 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 action does not impose a new collection of information under
the Paperwork Reduction Act of 1995. (44 U.S.C. 3501-3521). This action
would not impose recordkeeping or reporting requirements on State or
local governments, individuals, businesses, or organizations. An agency
may not conduct or sponsor, and a person is not required to respond to,
a collection of information unless it displays a currently valid OMB
control number.
List of Subjects in 21 CFR Part 1308
Administrative practice and procedure, drug traffic control,
reporting and recordkeeping requirements.
For the reasons set out above, DEA proposes to amend 21 CFR part
1308 as follows:
PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES
0
1. The authority citation for 21 CFR part 1308 continues to read as
follows:
Authority: 21 U.S.C. 811, 812, 871(b), 956(b), unless otherwise
noted.
0
2. In Sec. 1308.11:
0
a. Redesignate paragraphs (b)(56) through (70) as (b)(60) through (74);
0
b. Redesignate paragraphs (b)(54) and (55) as (b)(57) and (58);
0
c. Redesignate paragraphs (b)(39) through (53) as (b)(41) through (55);
0
d. Redesignate paragraphs (b)(22) through (38) as (b)(23) through (39);
0
e. Add new paragraphs (b)(22), (40), (56), (59), and (75); and
0
f. Remove and reserve paragraphs (h)(23), and (h)(25) through (28).
The additions read as follows:
Sec. 1308.11 Schedule I.
* * * * *
(b) * * *
(22) Cyclopentyl fentanyl (N-(1-phenethylpiperidin-4-yl)-N- (9847)
phenylcyclopentanecarboxamide)...............................
* * * * *
(40) Isobutyryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N- (9827)
phenylisobutyramide).........................................
* * * * *
(56) para-Chloroisobutyryl fentanyl (N-(4-chlorophenyl)-N-(1- (9826)
phenethylpiperidin-4-yl)isobutyramide........................
* * * * *
(59) para-Methoxybutyryl fentanyl (N-(4-methoxyphenyl)-N-(1- (9837)
phenethylpiperidin-4-yl)butyramide)..........................
* * * * *
(75) Valeryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N- (9804)
phenylpentanamide)...........................................
* * * * *
Dated: January 23, 2020.
Uttam Dhillon,
Acting Administrator.
[FR Doc. 2020-01681 Filed 1-29-20; 8:45 am]
BILLING CODE 4410-09-P
