[Federal Register Volume 84, Number 41 (Friday, March 1, 2019)]
[Notices]
[Pages 7070-7082]
[FR Doc No: 2019-03663]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-0671]

International Drug Scheduling; Convention on Psychotropic
Substances; Single Convention on Narcotic Drugs; World Health
Organization; Scheduling Recommendations; Cyclopropyl Fentanyl;
Methoxyacetyl Fentanyl; Ortho-Fluorofentanyl; Para-Fluorobutyrfentanyl;
N-Ethylnorpentylone; and Four Additional Substances; Request for
Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of comment.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is providing interested
persons with the opportunity to submit written comments concerning
recommendations by the World Health Organization (WHO) to impose
international manufacturing and distributing restrictions, under
international treaties, on certain drug substances. The comments
received in response to this notice will be considered in preparing the
United States' position on these proposals for a meeting of the United
Nations Commission on Narcotic Drugs (CND) in Vienna, Austria, in March
18-22, 2019. This notice is issued under the Controlled Substances Act
(CSA).

DATES: Submit either electronic or written comments by March 14, 2019.

The short time period for the submission of comments is needed to
ensure that the Department of Health and Human Services (HHS) may, in a
timely fashion, carry out the required action and be responsive to the
United Nations.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before March 14, 2019. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of March 14, 2019. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2019-N-0671 for ``International Drug Scheduling; Convention on
Psychotropic Substances; Single Convention on Narcotic Drugs; World
Health Organization; Scheduling Recommendations; Cyclopropyl Fentanyl;
Methoxyacetyl Fentanyl; Ortho-Fluorofentanyl; Para-Fluorobutyrfentanyl;
N-Ethylnorpentylone; ADB-FUBINACA; FUB-AMB(MMB-FUBINACA_AMB-FUBINACA);
ADB-CHMINACA; CUMYL-4CN-BINACA; Request for Comments.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: http://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug
Evaluation and Research, Controlled Substance Staff, Food and Drug
Administration, 10903 New Hampshire Ave. Bldg. 51, Rm. 5150, Silver
Spring, MD 20993-0002,<PHONE_NUMBER><EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic
Substances (Psychotropic Convention). Section 201(d)(2)(B) of the CSA
(21 U.S.C. 811(d)(2)(B)) provides that when the United States is
notified under Article 2 of the Psychotropic Convention that the CND
proposes to decide whether to add a drug or other substance to one of
the schedules of the Psychotropic Convention, transfer a drug or
substance from one schedule to another, or delete it from the
schedules, the Secretary of State must transmit notice of such
information to the Secretary of HHS. The Secretary of HHS must then
publish a summary of such information in the Federal Register and
provide opportunity for interested persons to submit comments. The
Secretary of HHS must then evaluate the proposal and furnish a
recommendation to the Secretary of State that shall be binding on the
representative of the United States in discussions and negotiations
relating to the proposal.
    As detailed in the following paragraphs, the Secretary of State has
received notification from the Secretary-General of the United Nations
(the Secretary-General) regarding five substances to be considered for
control under the Psychotropic Convention. This notification reflects
the recommendation from the 41st WHO Expert Committee for Drug
Dependence (ECDD), which met in November 2018. In the Federal Register
of October 10, 2018 (83 FR 50938), FDA announced the WHO ECDD review
and invited interested persons to submit information for WHO's
consideration.
    The full text of the notification from the Secretary-General is
provided in section II of this document. Section 201(d)(2)(B) of the
CSA requires the Secretary of HHS, after receiving a notification
proposing scheduling, to publish a notice in the Federal Register to
provide the opportunity for interested persons to submit information
and comments on the proposed scheduling action.

    The United States is also a party to the 1961 Single Convention on
Narcotic Drugs (1961 Single Convention). The Secretary of State has
received a notification from the Secretary-General regarding four
substances to be considered for control under this convention. The CSA
does not require HHS to publish a summary of such information in the
Federal Register. Nevertheless, to provide interested and affected
persons an opportunity to submit comments regarding the WHO
recommendations for narcotic drugs, the notification regarding these
substances is also included in this Federal Register notice. The
comments will be shared with other relevant agencies to assist the
Secretary of State in formulating the position of the United States on
the control of these substances. The HHS recommendations are not
binding on the representative of the United States in discussions and
negotiations relating to the proposal regarding control of substances
under the 1961 Single Convention.

II. United Nations Notification

    The formal notification from the United Nations that identifies the
drug substances and explains the basis for the recommendations is
reproduced as follows (non-relevant text removed):

Reference: NAR/CL.2/2019
    WHO/ECDD41; 1961C-Art.3, 1971C-Art.2 CU
    2019/35/DTA/SGB (A)

    The Secretary-General of the United Nations presents his
compliments to the Secretary of State of the United States of America
and has the honour to inform the Government that on 28 January 2019, he
received a notification from the Director-General of the World Health
Organization (WHO), pursuant to article 3, paragraphs 1 and 3 of the
Single Convention on Narcotic Drugs of 1961 as amended by the 1972
Protocol (1961 Convention), and article 2, paragraphs 1 and 4 of the
Convention on Psychotropic Substances of 1971 (1971 Convention) with
the following recommendations regarding ten New Psychoactive Substances
(NPS):
    Substances recommended to be added to Schedule I of the 1961
Convention:
    --Parafluorobutyrylfentanyl
    chemical name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
    --Ortho-fluorofentanyl
    chemical name: N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide
    --Methoxyacetyl fentanyl
    chemical name: 2-methoxy-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]acetamide
    --Cyclopropylfentanyl
    chemical name: N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]cyclopropanecarboxamide
    Substances recommended to be added to Schedule II of the 1971
Convention:
    --ADB-FUBINACA
    chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide
    --FUB-AMB (MMB-FUBINACA, AMB-FUBINACA)
    chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-
indazole-3-carbonyl{time} amino)-3-methylbutanoate
    --CUMYL-4CN-BINACA
    chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-
indazole-3-carboxamide
    --ADB-CHMINACA (MAB-CHMINACA)
    chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide
    --N-Ethylnorpentylone (ephylone)
    chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)pentan-1-
one
    In the letter from the Director-General of the World Health
Organization to the Secretary-General, reference is also made to the
recommendation by the forty-first meeting of the WHO Expert Committee
on Drug Dependence (ECDD) to keep the following New Psychoactive
Substance under surveillance:
    --Paramethoxybutyrylfentanyl
    chemical name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
    In addition, in the letter from the Director-General of the World
Health Organization to the Secretary-General, reference is made to the
recommendations by the forty-first meeting of the WHO ECDD to keep the
following two pain-relieving medicines under surveillance:
    --Pregabalin
    chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid
    --Tramadol
    chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-
(3methoxyphenyl)cyclohexan-1-ol
    In accordance with the provisions of article 3, paragraph 2 of the
1961 Convention and article 2, paragraph 2 of the 1971 Convention, the
Secretary-General hereby transmits the notification as annex I to the
present note. In connection with the notification, WHO has also
submitted the relevant extract from the report of the forty-first
meeting of the WHO ECDD which is hereby transmitted as annex II. For
time reasons, this notification and its annexes I and II are
transmitted in English only. The notification will be transmitted in
French and Spanish as soon as it becomes available.
    Also in accordance with the same provisions, the notification from
WHO will be brought to the attention of the sixty-second session of the
Commission on Narcotic Drugs (from 14 to 22 March 2019) in document E/
CN.7/2019/8 which will be made available on the website of the 62nd
session of the CND:
    http://www.unodc.org/unodc/en/commissions/CND/session/62_Session_2019/session-62-of-the-commission-on-narcotic-drugs.html.
    In order to assist the Commission in reaching a decision, it would
be appreciated if the Government could communicate any comments it
considers relevant to the possible scheduling of New Psychoactive
Substances recommended by WHO to be placed under international control
under the 1961 Convention, namely:
    --Parafluorobutyrylfentanyl; Ortho-fluorofentanyl; Methoxyacetyl
fentanyl; Cyclopropylfentanyl
    as well as any economic, social, legal, administrative or other
factors that it considers relevant to the possible scheduling of New
Psychoactive Substances recommended by WHO to be placed under
international control under the 1971 Convention, namely:
    --ADB-FUBINACA, FUB-AMB (MMB-FUBINACA, AMB-FUBINACA), CUMYL-4CN-
BINACA, ADB-CHMINACA (MAB-CHMINACA), N-Ethylnorpentylone (ephylone).
    Communications should be sent to the Executive Director of the
United Nations Office on Drugs and Crime, c/o Secretary, Commission on
Narcotic Drugs, P.O. Box 500, 1400 Vienna, Austria, email<EMAIL_ADDRESS>(fax: +43-1-26060-5885), at the latest by 28 February 2019.

1 February 2019

His Excellency

Mr. Michael Pompeo

Secretary of State of the United States of America
Annex I
Letter addressed to the Secretary-General of the United Nations from
the Director-General of the World Health Organization, dated 24 January
2019
    ``The forty-first meeting of the WHO Expert Committee on Drug
Dependence (ECDD) convened from 12 to 16 November 2018 at WHO
headquarters in Geneva. The objective of this meeting was to carry out
an in-depth evaluation of psychoactive substances in order to determine
whether the World Health

Organization (WHO) should recommend if these substances should be
placed under international control or if their level of control should
be changed.
    The forty-first WHO ECDD reviewed ten New Psychoactive Substances
(NPS), five of which are synthetic opioids and two pain-relieving
medicines; pregabalin and tramadol. The ECDD scheduling recommendations
for these substances are detailed below.
    In addition, the forty-first WHO ECDD critically reviewed cannabis
and cannabis-related substances. The recommendations regarding cannabis
and cannabis-related substances are communicated to you through a
separate letter under the same date as this letter.
    With reference to Article 3, paragraphs 1 and 3 of the Single
Convention on Narcotic Drugs (1961), as amended by the 1972 Protocol,
and Article 2, paragraphs 1 and 4 of the Convention on Psychotropic
Substances (1971), I am pleased to submit recommendations of the forty-
first meeting of the ECDD regarding NPS and two pain-relieving
medicines, tramadol and pregabalin, as follows:

New Psychoactive Substances

    To be added to Schedule I of the Single Convention on Narcotic
Drugs (1961):

--Parafluorobutyrylfentanyl
chemical name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
--Ortho-fluorofentanyl
chemical name: N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide
--Methoxyacetyl fentanyl
chemical name: 2-methoxy-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]acetamide
--Cyclopropylfentanyl
chemical name: N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]cyclopropanecarboxamide

    To be added to Schedule II of the Convention on Psychotropic
Substances (1971):

--ADB-FUBINACA
chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide
--FUB-AMB (MMB-FUBINACA, AMB-FUBINACA)
chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H- indazole-
3-carbonyl{time} amino)-3-methylbutanoate
--CUMYL-4CN-BINACA
chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H- indazole-3-
carboxamide
--ADB-CHMINACA (MAB-CHMINACA)
chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide
--N-Ethylnorpentylone (ephylone)
chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)pentan-1-one

    To be kept under surveillance:

--Paramethoxybutyrylfentanyl
chemical name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide

Medicines

    To be kept under surveillance:

--Pregabalin
chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid
--Tramadol
chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-
(3methoxyphenyl)cyclohexan-1-ol

    The assessments and findings on which they are based are set out in
detail in the forty-first report of the WHO Expert Committee on Drug
Dependence. An extract of the report is attached in Annex II of this
letter.
    I am very pleased with the ongoing collaboration between WHO, the
United Nations Office on Drugs and Crime (UNODC) and the International
Narcotics Control Board (INCB), and in particular, how this
collaboration has benefited the work of the WHO Expert Committee on
Drug Dependence (including through the participation of UNODC and INCB
in the forty-first meeting of the ECDD), and more generally, the
implementation of the operational recommendations of the United Nations
General Assembly Special Session (UNGASS) 2016.

[signed]
Annex II
Extract from the Report of the 41st Expert Committee on Drug
Dependence: Fentanyl analogues, synthetic cannabinoids, cathinones, and
medicines: pregabalin and tramadol

1. Fentanyl Analogues

1.1 Para-fluoro-butyrylfentanyl

Substance identification
    Para-fluoro-butyrylfentanyl (N-(4-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) is a synthetic analogue of the
opioid analgesic fentanyl. Samples obtained from seizures and from
other collections suggest that para-fluoro-butyrylfentanyl appears in
powder, tablet, nasal spray and vaping form.
WHO review history
    Para-fluoro-butyrylfentanyl has not been previously pre-reviewed or
critically reviewed by the WHO Expert Committee on Drug Dependence
(ECDD) [the Committee]. A direct critical review was proposed based on
information brought to WHO's attention that para-fluoro-butyrylfentanyl
poses serious risk to public health and has no recognised therapeutic
use.
Similarity to known substances and effects on the central nervous
system
    Para-fluoro-butyrylfentanyl binds to [mu]-opioid receptors with
high selectivity over [kappa]- and [delta]-opioid receptors and has
been shown to act as a partial agonist at the [mu]-opioid receptor. In
animals, it produces typical opioid effects including analgesia, with a
potency between that of morphine and fentanyl. In cases of non-fatal
intoxication in humans, para-fluoro-butyrylfentanyl has produced signs
and symptoms such as disorientation, slurred speech, unsteady gait,
hypotension and pupil constriction that are consistent with an opioid
mechanism of action.
    Para-fluoro-butyrylfentanyl can be readily converted to its isomer
p-fluoro-isobutyrylfentanyl (N-(4-fluorophenyl)-2-methyl-N-[1-(2-
phenylethyl)piperidin-4-yl]propanamide), which is an opioid listed in
Schedule I of the 1961 Single Convention on Narcotic Drugs.
Dependence potential
    There are no studies of the dependence potential of this substance
in humans or laboratory animals. However, based on its mechanism of
action, para-fluoro-butyrylfentanyl would be expected to produce
dependence similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    There are no controlled studies of the abuse potential of para-
fluoro-butyrylfentanyl and there is very little information on the
extent of abuse. The substance has been detected in biological samples
obtained from cases of fatal and non-fatal intoxication. Fatalities
have been reported in some countries where the compound has been
identified in biological fluids in combination with other drugs,
including cases where death has been attributed to the effects of para-
fluoro-butyrylfentanyl.
Therapeutic applications/usefulness
    Para-fluoro-butyrylfentanyl is not known to have any therapeutic
uses.
Recommendation
    Para-fluoro-butyrylfentanyl is an opioid receptor agonist that has
significant potential for dependence and

likelihood of abuse. The limited available evidence indicates that it
has typical opioid adverse effects that include the potential for death
due to respiratory depression. Para-fluoro-butyrylfentanyl has caused
substantial harm and has no therapeutic usefulness. As it is liable to
similar abuse and produces similar ill-effects as many other opioids
placed in Schedule I of the 1961 Single Convention on Narcotic Drugs:
     Recommendation 1.1: The Committee recommended that Para-
fluoro-butyryl fentanyl (N-(4-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) be added to Schedule I of the
1961 Single Convention on Narcotic Drugs.

1.2 Para-methoxy-butyryl fentanyl

Substance identification
    Para-methoxy-butyrylfentanyl (N-(4-methoxyphenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) is a synthetic analogue of the
opioid analgesic fentanyl. Samples obtained from seizures and from
other collections suggest that para-methoxy-butyrylfentanyl occurs in
powder, tablet, and nasal spray forms.
WHO review history
    Para-methoxy-butyrylfentanyl has not been previously pre-reviewed
or critically reviewed by the WHO ECDD. A critical review was proposed
based on information brought to WHO's attention that para-methoxy-
butyrylfentanyl poses serious risk to public health and has no
recognised therapeutic use.
Similarity to known substances and effects on the central nervous
system
    Para-methoxy-butyrylfentanyl binds to [mu]-opioid receptors with
high selectivity over [kappa]- and [delta]-opioid receptors and has
been shown to act as a partial agonist at the [mu]-opioid receptor. In
animals, it produces typical opioid effects, including analgesia, and
in some tests it has a potency higher than morphine and close to that
of fentanyl.
    Reported clinical features of intoxication in which para-methoxy-
butyrylfentanyl is involved included the typical opioid effects of
reduced level of consciousness, respiratory depression and pupil
constriction. In some cases, treatment with the opioid antagonist
naloxone was shown to reverse the drug-induced respiratory depression.
While this is consistent with an opioid mechanism of action, it should
be noted that in all such cases at least one other opioid was present.
Dependence potential
    There are no studies of the dependence potential of this substance
in humans or laboratory animals. However, based on its mechanism of
action, Para-methoxy-butyrylfentanyl would be expected to produce
dependence similar to other opioid drugs.
Abuse potential and/or evidence of likelihood of abuse
    There are no controlled studies of the abuse potential of Para-
methoxy-butyrylfentanyl and very little information on the extent of
abuse. Para-methoxy-butyrylfentanyl has been detected in biological
samples obtained from a limited number of acute intoxication cases.
Reported clinical features are consistent with opioid effects and
including respiratory depression. However, in all of the documented
cases of severe adverse events associated with use of para-methoxy-
butyrylfentanyl, other fentanyl derivatives were detected and hence the
role of para-methoxy-butyrylfentanyl is not clear.
Therapeutic applications/usefulness
    Para-methoxy-butyrylfentanyl is not known to have any therapeutic
uses.
Recommendation
    The limited available information indicates that para-methoxy-
butyrylfentanyl is an opioid drug, and an analogue of the opioid
analgesic fentanyl. There is evidence of its use in a limited number of
countries with few reports of intoxication and no reports of deaths. In
the intoxication cases, the role of para-methoxy-butyrylfentanyl was
not clear due to the presence of other opioids. It has no therapeutic
usefulness. At this time, there is little evidence of the impact of
para-methoxy-butyrylfentanyl in causing substantial harm that would
warrant its placement under international control.
     Recommendation 1.2: The Committee recommended that para-
methoxy-butyrylfentanyl (N-(4-methoxyphenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) be kept under surveillance by
the WHO Secretariat.

1.3 Ortho-fluorofentanyl

Substance identification
    Ortho-fluorofentanyl (N-(2-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]propanamide) is a synthetic analogue of the
opioid analgesic fentanyl. It has two positional isomers (para-
fluorofentanyl and meta-fluorofentanyl).
WHO review history
    Ortho-fluorofentanyl has not been previously pre-reviewed or
critically reviewed by the WHO ECDD. A direct critical review was
proposed based on information brought to WHO's attention that ortho-
fluorofentanyl poses a serious risk to public health and has no
recognised therapeutic use.
Similarity to known substances and effects on the central nervous
system
    Receptor binding data show that ortho-fluorofentanyl binds to [mu]-
opioid receptors with high selectivity over [kappa]- and [delta]-opioid
receptors. There were no preclinical or clinical studies available in
the scientific literature. However, the clinical features present in
non-fatal intoxication cases include characteristic opioid effects such
as loss of consciousness, pupil constriction and respiratory
depression. The effects of ortho-fluorofentanyl are responsive to the
administration of the opioid antagonist naloxone, further confirming
its opioid agonist mechanism of action.
Dependence potential
    There are no studies of the dependence potential of ortho-
fluorofentanyl in humans or laboratory animals. However, based on its
mechanism of action, it would be expected to produce dependence similar
to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    There are no available preclinical or clinical studies to assess
the abuse liability of ortho-fluorofentanyl. There is evidence of use
from several countries, including seizures in Europe and the United
States. A number of confirmed fatalities associated with the compound
have been reported. Ortho-fluorofentanyl is being sold as heroin or an
adulterant in heroin. A number of fatalities have been associated with
this substance (1 in Europe and 16 in the United States since 2016). As
a consequence of ortho-fluorofentanyl cross-reacting with standard
fentanyl immunoassays, it is possible that deaths due to ortho-
fluorofentanyl have been attributed to fentanyl and hence the number of
recorded ortho-fluorofentanyl deaths may be an underestimate. Several
countries in different parts of the world have controlled ortho-
fluorofentanyl.
Therapeutic applications/usefulness
    Ortho-fluorofentanyl is not known to have any therapeutic uses.

Recommendation
    Ortho-fluorofentanyl is an opioid receptor agonist that has
potential for dependence and likelihood of abuse. The limited available
evidence indicates that it has typical opioid adverse effects that
include the potential for death due to respiratory depression. Ortho-
fluorofentanyl has caused substantial harm and has no therapeutic
usefulness. As it is liable to similar abuse and produces similar ill-
effects as many other opioids placed in Schedule I of the 1961 Single
Convention on Narcotic Drugs:
     Recommendation 1.3: The Committee recommended that ortho-
fluorofentanyl (N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide) be added to Schedule I of the 1961 Single Convention on
Narcotic Drugs.

1.4 Methoxyacetylfentanyl

Substance identification
    Methoxyacetylfentanyl (2-methoxy-N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl] acetamide) is a synthetic analogue of the
opioid fentanyl. Samples obtained from seizures and from other
collections suggest that methoxyacetylfentanyl has appeared in powders,
liquids, and tablets.
WHO review history
    Methoxyacetylfentanyl has not been previously pre-reviewed or
critically reviewed by the WHO ECDD. A critical review was proposed
based on information brought to WHO's attention that
methoxyacetylfentanyl poses serious risk to public health and has no
recognised therapeutic use.
Similarity to known substances and effects on the central nervous
system
    Methoxyacetylfentanyl binds to [mu]-opioid receptors with high
selectivity over [kappa]- and [delta]-opioid receptors and has been
shown to act as an agonist at the [mu]-opioid receptor. In animals, it
produces analgesia with a potency higher than morphine and close to
that of fentanyl. The analgesia was blocked by the opioid antagonist
naltrexone, confirming its opioid mechanism of action.
    In people using methoxyacetylfentanyl the most serious acute health
risk is respiratory depression, which in overdose can lead to
respiratory arrest and death. This is consistent with its opioid
mechanism of action.
Dependence potential
    There are no studies of the dependence potential of this substance
in humans or laboratory animals. However, based on its mechanism of
action, methoxyacetylfentanyl would be expected to produce dependence
similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    In the animal drug discrimination model of subjective drug effects,
methoxyacetylfentanyl produced effects similar to those of morphine. It
also decreased activity levels and both the discriminative and rate-
decreasing effects were blocked by the opioid antagonist naltrexone.
Based on its receptor action and these effects in animal models, it
would be expected that methoxyacetylfentanyl would be subject to abuse
in a manner comparable to other opioids.
    There is evidence that methoxyacetyl- fentanyl has been used by
injection and by nasal insufflation of powder. A large number of
seizures of this substance have been reported in Europe and the United
States. A number of deaths have been reported in Europe and the United
States in which methoxyacetylfentanyl was detected in post-mortem
samples. While other drugs were present in most of these cases,
methoxyacetylfentanyl was deemed the cause of death or a major
contributor to death in a significant proportion of these. Several
countries have controlled methoxyacetylfentanyl in their national
legislation.
Therapeutic applications/usefulness
    Methoxyacetylfentanyl is not known to have any therapeutic uses.
    The committee considered that methoxyacetylfentanyl is a substance
with high abuse liability and dependence potential. It is an opioid
agonist that is more potent than morphine and its use has contributed
to a large number of deaths in different regions. It has no therapeutic
usefulness and it poses a significant risk to public health. The
Committee considered that the evidence of its abuse warrants placement
under international control.
    Recommendation 1.4: The Committee recommended that
methoxyacetylfentanyl (2-methoxy-N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl] acetamide) be added to Schedule I of the
Single Convention on Narcotic Drugs of 1961.

1.5 Cyclopropylfentanyl

Substance identification
    Cyclopropylfentanyl ((N-phenyl-N-1-(2-phenylethyl)-4-piperidyl)
cyclopropanecarboxamide) is a synthetic analogue of the opioid
fentanyl. Samples obtained from seizures and from other collections
suggest that cyclopropylfentanyl has appeared in powders, liquids, and
tablets.
WHO review history
    Cyclopropylfentanyl has not been previously pre-reviewed or
critically reviewed by the WHO ECDD. A critical review was proposed
based on information brought to WHO's attention that
cyclopropylfentanyl poses a serious risk to public health and has no
recognised therapeutic use.
Similarity to known substances and effects on the central nervous
system
    Cyclopropylfentanyl binds selectively to the [mu] opioid receptors
compared to [delta] and [kappa] opioid receptors. There is no further
information on the actions and effects of cyclopropylfentanyl from
controlled studies. Based on its role in numerous deaths, as described
below, it is reasonable to consider that cyclopropylfentanyl acts as a
[mu] opioid receptor agonist similar to morphine and fentanyl.
Dependence potential
    There are no preclinical or clinical studies published in the
scientific literature concerning dependence on cyclopropylfentanyl.
However, based on its mechanism of action, cyclopropylfentanyl would be
expected to produce dependence similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    A large number of seizures of cyclopropylfentanyl have been
reported from countries in different regions. In some countries, this
substance has been among the most common fentanyl analogues detected in
post-mortem samples. In almost all of these deaths, cyclopropylfentanyl
was determined to either have caused or contributed to death, even in
presence of other substances.
Therapeutic applications/usefulness
    Cyclopropylfentanyl is not known to have any therapeutic uses.
Recommendation
    The available evidence indicates that cyclopropylfentanyl has
opioid actions and effects. It has been extensively trafficked and has
been used by several different routes of administration. Its use has
been associated with a large number of documented deaths, and for most
of these it has been the principal cause of death. Cyclopropylfentanyl
has

no known therapeutic use and has been associated with substantial harm.
     Recommendation 1.5: The Committee recommended that
cyclopropylfentanyl (N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]cyclopropanecarboxamide) be added to Schedule I of the 1961 Single
Convention on Narcotic Drugs.

2. Synthetic cannabinoids

2.1 ADB-FUBINACA

Substance identification
    ADB-FUBINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide) is encountered as a
powder, in solution or sprayed on herbal material that mimics the
appearance of cannabis. It is sold as herbal incense or branded
products with a variety of different names.
WHO review history
    ADB-FUBINACA has not been previously pre-reviewed or critically
reviewed by the WHO Expert Committee on Drug Dependence (ECDD). A
critical review was proposed based on information brought to WHO's
attention that ADB-FUBINACA poses serious risk to public health and has
no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    ADB-FUBINACA is similar to other synthetic cannabinoid receptor
agonists that are currently scheduled under the Convention on
Psychotropic Substances of 1971. It binds to both the CB1
and CB2 cannabinoid receptors with full agonist activity as
demonstrated by in vitro studies. The efficacy and potency of ADB-
FUBINACA is substantially greater when compared to [Delta]\9\-THC.
Reported clinical features of intoxication include confusion,
agitation, somnolence, hypertension and tachycardia, similar to other
synthetic cannabinoid receptor agonists.
Dependence potential
    No controlled experimental studies examining the dependence
potential of ADB-FUBINACA in humans or animals were available. However,
based on its central nervous system action as a full CB1
agonist, ADB-FUBINACA would be expected to produce dependence in a
manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    ADB-FUBINACA is sold and used as a substitute for cannabis. It is
invariably smoked or vaped (i.e. using an e-cigarette) but due to the
nature of synthetic cannabinoid products (whereby drug components are
introduced onto herbal material), users are unaware of which synthetic
cannabinoid may be contained within such products. Evidence from case
reports in which ADB-FUBINACA has been detected in biological samples
has demonstrated that use of this substance has contributed to severe
adverse reactions in humans including death. However, it was also noted
that other substances, including other synthetic cannabinoids, were
also present in the urine or blood following non-fatal and fatal
intoxications and/or in the product used. Evidence of use has been
reported in Europe, the United States and Asia. In recognition of its
abuse and associated harm, ADB-FUBINACA has been placed under national
control in a number of countries in several different regions.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of ADB-
FUBINACA.
Recommendation
    ADB-FUBINACA is a synthetic cannabinoid receptor agonist that is
used by smoking plant material sprayed with the substance or inhaling
vapour after heating. Its mode of action suggests the potential for
dependence and likelihood of abuse. Its use has been associated with a
range of severe adverse effects including death. These effects are
similar to those produced by other synthetic cannabinoids which have a
mechanism of action the same as that of ADB-FUBINACA and which are
placed in Schedule II of the Convention on Psychotropic Substances of
1971. ADB-FUBINACA has no therapeutic usefulness.
     Recommendation 2.1: The Committee recommended that ADB-
FUBINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide) be added to Schedule II
of the Convention on Psychotropic Substances of 1971.

2.2 FUB-AMB

Substance identification
    FUB-AMB (chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-
1H-indazole-3- carbonyl{time} amino)-3-methylbutanoate) is a synthetic
cannabinoid that is also referred to as MMB-FUBINACA and AMB-FUBINACA.
FUB-AMB is encountered as a powder, in solution or sprayed on herbal
material that mimics the appearance of cannabis. It is sold as herbal
incense or branded products with a variety of different names.
WHO review history
    FUB-AMB has not been previously pre-reviewed or critically reviewed
by the WHO ECDD. A critical review was proposed based on information
brought to WHO's attention that FUB-AMB poses serious risk to public
health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    FUB-AMB is similar to other synthetic cannabinoid receptor agonists
that are currently scheduled under the Convention on Psychotropic
Substances of 1971. It binds to both the CB1 and
CB2 cannabinoid receptors with full agonist activity as
demonstrated by in vitro studies. The efficacy and potency of FUB-AMB
is substantially greater than [Delta] \9\-THC and it shares effects
with other synthetic cannabinoids including severe central nervous
system depression, resulting in slowed behaviour and speech.
Dependence potential
    No controlled experimental studies examining the dependence
potential of FUB-AMB in humans or animals were available. However,
based on its central nervous system action as a full CB1
agonist, FUB-AMB would be expected to produce dependence in a manner
similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist
activity, FUB-AMB produces complete dose-dependent substitution for the
discriminative stimulus effects of [Delta]\9\-THC in mice by various
routes of administration. This suggests that it has abuse potential at
least as great as that of [Delta]\9\-THC.
    Evidence of the use of FUB-AMB has been reported in Europe, the
United States and New Zealand. It is usually smoked or vaped (i.e.
using an e-cigarette) but due to the nature of synthetic cannabinoid
products (whereby drug components are introduced onto herbal material),
users are unaware of which synthetic cannabinoid may be contained
within such products.
    FUB-AMB use was confirmed in case reports of a mass intoxication in
the United States with the predominant symptom being severe central
nervous system depression, resulting in slowed behaviour and speech. It
was reported that in New Zealand there were at least

20 deaths related to the use of FUB-AMB. It was noted that the amounts
of FUB-AMB in confiscated products were 2 to 25 times greater than
those reported in the incidents in the United States.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of FUB-
AMB.
Recommendation
    FUB-AMB is a synthetic cannabinoid receptor agonist that is used by
smoking plant material sprayed with the substance or inhaling vapour
after heating. Its mode of action suggests the potential for dependence
and likelihood of abuse. Its use has been associated with a range of
severe adverse effects including a number of deaths. Its mechanism of
action and manner of use are similar to other synthetic cannabinoids
placed in Schedule II of the Convention on Psychotropic Substances of
1971. FUB-AMB has no therapeutic usefulness.
     Recommendation 2.2: The Committee recommended that FUB-AMB
(chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-
3-carbonyl{time} amino)-3-methylbutanoate) be added to Schedule II of
the Convention on Psychotropic Substances of 1971.

2.3 ADB-CHMINACA

Substance identification
    ADB-CHMINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)indazole-3-carboxamide) is a synthetic cannabinoid
that is also referred to as MAB-CHMINACA. ADB-CHMINACA is encountered
as a powder, in solution or sprayed on herbal material that mimics the
appearance of cannabis. It is sold as herbal incense or branded
products with a variety of different names.
WHO review history
    ADB-CHMINACA has not been previously pre-reviewed or critically
reviewed by the WHO ECDD. A critical review was proposed based on
information brought to WHO's attention that ADB-CHMINACA poses a
serious risk to public health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    ADB-CHMINACA is similar to other synthetic cannabinoid receptor
agonists that are currently scheduled under the Convention on
Psychotropic Substances of 1971. It binds to both the CB1
and CB2 cannabinoid receptors with full agonist activity as
demonstrated by in vitro studies. The efficacy and potency of ADB-
CHMINACA is substantially greater than [Delta]\9\-THC and it is among
the most potent synthetic cannabinoids studied to date. It shares a
profile of central nervous system mediated effects with other synthetic
cannabinoids. ADB-CHMINACA demonstrates decreased locomotor activity in
mice in a time and dose dependent fashion with a rapid onset of action
and long-lasting effects.
    Signs and symptoms of intoxication arising from use of ADB-CHMINACA
have included tachycardia, unresponsiveness, agitation, combativeness,
seizures, hyperemesis, slurred speech, delirium and sudden death. These
are consistent with the effects of other synthetic cannabinoids.
Dependence potential
    No controlled experimental studies examining the dependence
potential of ADB-CHMINACA in humans or animals were available. However,
based on its central nervous system action as a full CB1
agonist, ADB-CHMINACA would be expected to produce dependence in a
manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist
activity, ADB-CHMINACA fully substituted for [Delta]\9\-THC in drug
discrimination tests. This suggests that it has abuse potential at
least as great as that of [Delta]\9\-THC.
    Evidence of the use of ADB-CHMINACA has been reported in Europe,
the United States and Japan, including cases of driving under the
influence. It is invariably smoked or vaped (i.e. using an e-cigarette)
but due to the nature of synthetic cannabinoid products (whereby drug
components are introduced onto herbal material), users are unaware of
which synthetic cannabinoid may be contained within such products.
    ADB-CHMINACA use was analytically confirmed in case reports of
several drug-induced clusters of severe illness and death in the United
States. In Europe, 13 deaths with analytically confirmed use of ADB-
CHMINACA were reported between 2014 and 2016, and another death
occurred in Japan.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of ADB-
CHMINACA.
Recommendation
    ADB-CHMINACA is a synthetic cannabinoid receptor agonist that is
used by smoking plant material sprayed with the substance or inhaling
vapour after heating. It has effects that are similar to other
synthetic cannabinoid receptor agonists placed in Schedule II of the
Convention on Psychotropic Substances of 1971. Its mode of action
suggests the potential for dependence and likelihood of abuse. Its use
has resulted in numerous cases of severe intoxication and death. There
is evidence that ADB-CHMINACA has been associated with fatal and non-
fatal intoxications in a number of countries. The substance causes
substantial harm and has no therapeutic usefulness.
    Recommendation 2.3: The Committee recommended that ADB-CHMINACA
(chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide) be added to Schedule II
of the Convention on Psychotropic Substances of 1971.

2.4 CUMYL-4CN-BINACA

Substance identification
    CUMYL-4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-
phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a synthetic
cannabinoid. It is encountered as a powder, in solution or sprayed on
herbal material that mimics the appearance of cannabis. It is sold as
herbal incense or branded products with a variety of different names.
WHO review history
    CUMYL-4CN-BINACA has not been previously pre-reviewed or critically
reviewed by the WHO ECDD. A critical review was proposed based on
information brought to WHO's attention that CUMYL-4CN-BINACA poses
serious risk to public health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    CUMYL-4CN-BINACA is similar to other synthetic cannabinoid receptor
agonists that are currently scheduled under the Convention on
Psychotropic Substances of 1971. It binds to both the CB1
and CB2 cannabinoid receptors with full agonist activity as
demonstrated by in vitro studies. The efficacy and potency of CUMYL-
4CN-BINACA is substantially greater than [Delta]\9\-THC and it shares a
profile of central nervous system mediated effects with other synthetic
cannabinoids. Data have shown that it produced hypothermia in mice in
common with other CB1 cannabinoid receptor agonists.

Dependence potential
    No controlled experimental studies examining the dependence
potential of CUMYL-4CN-BINACA in humans or animals were available.
However, based on its central nervous system action as a full
CB1 agonist, CUMYL-4CN-BINACA would be expected to produce
dependence in a manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist
activity, CUMYL-4CN-BINACA fully substituted for [Delta]\9\-THC in drug
discrimination tests. This suggests that it has abuse potential at
least as great as that of [Delta]\9\-THC.
    Evidence of the use of CUMYL-4CN-BINACA has been currently reported
only from Europe but this may be due to under-reporting including
through lack of detection in other countries. In Europe, CUMYL-4CN-
BINACA has been among the most frequently seized synthetic
cannabinoids. It is invariably smoked or vaped (i.e. using an e-
cigarette) but due to the nature of synthetic cannabinoid products
(whereby drug components are introduced onto herbal material), users
are unaware of which synthetic cannabinoid may be contained within such
products.
    A number of non-fatal intoxications involving CUMYL-4CN-BINACA have
been reported. CUMYL-4CN-BINACA has been analytically confirmed as
being present in 11 fatalities and 5 non-fatal intoxications in Europe.
In 2 deaths, CUMYL-4CN-BINACA was the only drug present.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of
CUMYL-4CN-BINACA.
Recommendation
    CUMYL-4CN-BINACA is a synthetic cannabinoid receptor agonist that
is used by smoking plant material sprayed with the substance or
inhaling vapour after heating and is sold under a variety of brand
names. It has effects that are similar to other synthetic cannabinoid
receptor agonists placed in Schedule II of the Convention on
Psychotropic Substances of 1971. Its mode of action suggests the
potential for dependence and likelihood of abuse. There is evidence
that CUMYL-4CN-BINACA has been associated with fatal and non-fatal
intoxications in a number of countries. The substance causes
substantial harm and has no therapeutic usefulness.
     Recommendation 2.4: The Committee recommended that CUMYL-
4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-
indazole-3-carboxamide) be added to Schedule II of the Convention on
Psychotropic Substances of 1971.

3. Cathinone

3.1 N-ethylnorpentylone

Substance identification
    N-Ethylnorpentylone (chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-
(ethylamino)pentan-1-one) is a ring-substituted synthetic cathinone
analogue that originally emerged in the 1960s during pharmaceutical
drug development efforts. It is also known as ephylone and incorrectly
referred to as N-ethylpentylone. In its pure form, N-Ethylnorpentylone
exists as a racemic mixture in form of a powder or crystalline solid.
However, the substance is usually available as a capsule, powered
tablet, pill and powder often sold as ``Ecstasy'' or MDMA. N-
Ethylnorpentylone is also available in its own right and is advertised
for sale by internet retailers.
WHO review history
    N-Ethylnorpentylone has not been previously pre-reviewed or
critically reviewed by the WHO Expert Committee on Drug Dependence
(ECDD). A critical review was proposed based on information brought to
WHO's attention that N-Ethylnorpentylone poses serious risk to public
health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    The information currently available suggests that N-
Ethylnorpentylone is a psychomotor stimulant. N-Ethylnorpentylone users
exhibit psychomotor stimulant effects including agitation, paranoia,
tachycardia and sweating which are consistent with other substituted
cathinone and central nervous system stimulant drugs. Not all reported
adverse effects could be causally linked to N-Ethylnorpentylone alone,
but there are indications that the observed effects are consistent with
those seen with other psychomotor stimulants, with some instances
involving cardiac arrest.
    Its molecular mechanism of action is similar to the synthetic
cathinones MDPV and [alpha]-PVP which are both listed in Schedule II of
the Convention on Psychotropic Substances of 1971. In vitro
investigations showed that N-Ethylnorpentylone inhibited the reuptake
of dopamine, noradrenaline and, to a lesser extent, serotonin, which is
consistent with closely related other substituted cathinones with known
abuse liability and with cocaine.
    There is no specific information available to indicate that N-
Ethylnorpentylone may be converted into a substance currently
controlled under the U.N. Conventions.
Dependence potential
    No controlled experimental studies examining the dependence
potential of N-Ethylnorpentylone in humans or animals were available.
However, based on its action in the central nervous system, it would be
expected that N-Ethylnorpentylone would have the capacity to produce a
state of dependence similar to that of other stimulants such as the
ones listed in Schedule II of the Convention on Psychotropic Drugs of
1971.
Actual abuse and/or evidence of likelihood of abuse
    In rodent drug discrimination studies, N-Ethylnorpentylone fully
substituted for methamphetamine and cocaine, and it was also shown to
increase activity levels, suggesting it has potential for abuse similar
to other psychomotor stimulants.
    N-Ethylnorpentylone has been detected in biological fluids
collected from a number of cases involving adverse effects including
deaths. It is frequently used in combination with other drugs. Users
may be unaware of the additional risks of harm associated with the
consumption of N-Ethylnorpentylone either alone or in combination with
other drugs. Users may also be unaware of the exact dose or compound
being ingested.
    A number of countries in various regions have reported use or
detection of this compound in either seized materials or biological
samples of individuals, including in cases of driving under the
influence of drugs. Increased seizures of N-Ethylnorpentylone were
reported by the United States over the last 2 years. N-
Ethylnorpentylone has been detected in biological fluids collected from
fatal and non-fatal cases of intoxication with a total of 125
toxicological reports associated with N-Ethynorpentylone between 2016
and 2018 having been documented.
    The current available data therefore suggest that N-
Ethylnorpentylone is liable to abuse.
Therapeutic applications/usefulness
    N-Ethylnorpentylone is not known to have any therapeutic uses.

Recommendation
    N-Ethylnorpentylone is a synthetic cathinone with effects that are
similar to other synthetic cathinones listed as Schedule II substances
in the Convention on Psychotropic Substances of 1971. Its mode of
action and effects are consistent with those of other central nervous
system stimulants such as cocaine, indicating that it has significant
potential for dependence and likelihood of abuse. There is evidence of
use of N-Ethylnorpentylone in a number of countries in various regions
and this use has resulted in fatal and non-fatal intoxications. The
substance causes substantial harm and has no therapeutic usefulness.
Accordingly:
     Recommendation 3.1: The Committee recommended that N-
Ethylnorpentylone (chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-
(ethylamino)pentan-1-one) be added to Schedule II of the 1971
Convention on Psychotropic Substances.

4. Medicines

4.1 Pregabalin

Substance identification
    Chemically, pregabalin is (3S)-3-(aminomethyl)-5-methylhexanoic
acid.
WHO review history
    Pregabalin was previewed by the 39th ECDD in November 2017.
Similarity to known substances/effects on the central nervous system
    Pregabalin is an inhibitor of alpha-2-delta subunit containing
voltage-gated calcium channels (VGCCs). Through this mechanism it
decreases the release of neurotransmitters such as glutamate,
noradrenaline and substance P. It has been suggested that pregabalin
exerts its therapeutic effects by reducing the neuronal activation of
hyper-excited neurons while leaving normal activation unaffected. The
mechanism(s) by which pregabalin produces euphoric effects or induces
physical dependence is unknown.
    Despite being a chemical analogue of the neurotransmitter gamma
aminobutyric acid (GABA), pregabalin does not influence GABA activity
via either GABA receptors or benzodiazepine receptors. However,
pregabalin has been found to produce effects that are similar to those
produced by controlled substances, such as benzodiazepines, that
increase GABA activity.
Dependence potential
    Tolerance has been shown to develop to the effects of pregabalin,
particularly the euphoric effects. A number of published reports have
described physical dependence associated with pregabalin use in humans.
The withdrawal symptoms that occur following abrupt discontinuation of
pregabalin include insomnia, nausea, headache, anxiety, sweating, and
diarrhoea. Current evidence suggests that the incidence and severity of
withdrawal symptoms may be dose-related and hence those taking doses
above the normal therapeutic range are most at risk of withdrawal. At
therapeutic doses, withdrawal may be minimized by gradual dose
tapering.
Actual abuse and/or evidence of likelihood to produce abuse
    While some preclinical research using self-administration and
conditioned place preference models has shown reinforcing effects of
pregabalin, taken as a whole, the results from such research are
contradictory and inconclusive.
    In clinical trials, patients have reported euphoria, although
tolerance develops rapidly to this effect. Human laboratory research is
very limited and only a relatively low dose of pregabalin has been
tested in a general population sample; the results indicated low abuse
liability. However, a higher dose of pregabalin administered to users
of alcohol or sedative/hypnotic drugs was rated similar to diazepam,
indicative of abuse liability.
    Pregabalin is more likely to be abused by individuals who are using
other psychoactive drugs (especially opioids) with significant
potential of adverse effects among these subpopulations. The adverse
effects of pregabalin include dizziness, blurred vision, impaired
coordination, impaired attention, somnolence, confusion and impaired
thinking. Other reported harms associated with non-medical use of
pregabalin include suicidal ideation and impaired driving. Users of
pregabalin in a number of countries have sought treatment for
dependence on the drug. Whilst pregabalin has been cited as the main
cause of death in over 30 documented overdose fatalities, there are
very few cases of fatal intoxications resulting from pregabalin use
alone and the vast majority of instances involve other central nervous
system depressants such as opioids and benzodiazepines.
    There is only limited information regarding the scope and magnitude
of the illicit trade in pregabalin, but there is evidence of illicit
marketing through online pharmacies.
    Pregabalin is under national control in many countries across
different regions of the world.
Therapeutic applications/usefulness
    Pregabalin is used for the treatment of neuropathic pain, including
painful diabetic peripheral neuropathy and postherpetic neuralgia,
fibromyalgia, anxiety and the adjunctive treatment of partial seizures.
The exact indications for which pregabalin has received approval vary
across countries. Pregabalin has also been used for conditions such as
substance use disorders, alcohol withdrawal syndrome, restless legs
syndrome and migraine.
Recommendation
    The Committee noted that there has been increasing concern in many
countries regarding the abuse of pregabalin. A number of cases of
dependence have been reported and there are increasing reports of
adverse effects. While these problems are concentrated in certain drug
using populations, there is presently limited data on the extent of the
problems related to pregabalin abuse in the general population. The
Committee also noted that pregabalin has approved therapeutic uses for
a range of medical conditions, including some for which there are few
therapeutic options. Given the limitations in the available information
regarding the abuse of pregabalin:
     Recommendation 4.1: The Committee recommended that
pregabalin (chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid)
should not be scheduled but be kept under surveillance by the WHO
Secretariat.

4.2 Tramadol

Substance identification
    Tramadol (chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-(3-
methoxyphenyl)cyclohexan-1-ol) is a white, bitter, crystalline and
odourless powder soluble in water and ethanol. Tramadol is marketed as
the hydrochloride salt and is available in a variety of pharmaceutical
formulations for oral (tablets, capsules), sublingual (drops),
intranasal, rectal (suppositories), intravenous, subcutaneous, and
intramuscular administration. It is also available in combination with
acetaminophen (paracetamol). Preparations of tramadol are available as
immediate- and extended-release formulations.
WHO review history
    Tramadol has been considered for critical review by the ECDD five
times: in 1992, 2000, 2002, 2006 and 2014. Tramadol was pre-reviewed at
the 39th

ECDD meeting in November 2017 and it was recommended that tramadol be
subject to a critical review at a subsequent ECDD meeting. The
Committee requested the WHO Secretariat to collect additional data for
the critical review, including information on the extent of problems
associated with tramadol misuse in countries. Also, the Committee asked
for information on the medical use of tramadol including the extent to
which low income countries, and aid and relief agencies, use and
possibly rely on tramadol for provision of analgesia. In response to
these requests, the WHO Secretariat collected data from Member States
and relief agencies on the extent of medical use of tramadol, its
misuse and on the level of control implemented in countries.
Similarity to known substances/effects on the central nervous system
    Tramadol is a weak opioid analgesic that produces opioid-like
effects primarily due to its metabolite, O-desmethyltramadol (M1). The
analgesic effect of tramadol is also believed to involve its actions on
noradrenergic and serotonergic receptor systems. The adverse effects of
tramadol are consistent with its dual opioid and non-opioid mechanisms
of action and they include dizziness, nausea, constipation and
headache. In overdose, symptoms such as lethargy, nausea, agitation,
hostility, aggression, tachycardia, hypertension and other cardiac
complications, renal complications, seizures, respiratory depression
and coma have been reported. Serotonin syndrome (a group of symptoms
associated with high concentrations of the neurotransmitter serotonin
that include elevated body temperature, agitation, confusion, enhanced
reflexes, and tremor and might result in seizures and respiratory
arrest) is a potential complication of the use of tramadol in
combination with other serotonergic drugs. Tramadol has been detected
in a number of deaths. It is often present along with other drugs,
including opioids, benzodiazepines and antidepressants, but fatalities
have also been reported due to tramadol alone.
Dependence potential
    Evidence suggests that the development of physical dependence to
tramadol is dose-related, and administration of supra-therapeutic doses
leads to a similar dependence profile to morphine and other opioids
such as oxycodone and methadone. There are reports of considerable
number of people with tramadol dependence seeking help. Withdrawal
symptoms include those typical of opioids such as pain, sweating,
diarrhoea and insomnia as well as symptoms not normally seen with
opioids and related to noradrenergic and serotonergic activity, such as
hallucinations, paranoia, confusion and sensory abnormalities. Low dose
tramadol use over extended periods is associated with a lower risk of
dependence.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its opioid mechanism of action, human brain imaging
has shown that tramadol activates brain reward pathways associated with
abuse. While reports from people administered tramadol in controlled
settings have shown that it is identified as opioid-like and tramadol
has reinforcing effects in experienced opioid users, these effects may
be weaker than those produced by opioids such as morphine and may be
partially offset by unpleasant effects of tramadol such as sweating,
tremor, agitation, anxiety and insomnia.
    Abuse, dependence and overdose from tramadol have emerged as
serious public health concerns in countries across several regions.
Epidemiological studies in the past have reported a lower tendency for
tramadol misuse when compared to other opioids, but more recent
information indicates a growing number of people abusing tramadol,
particularly in a number of Middle Eastern and African countries. The
sources of tramadol include diverted medicines as well as falsified
medicines containing high doses of tramadol. Seizures of illicitly
trafficked tramadol, particularly in African countries, have risen
dramatically in recent years.
    The oral route of administration has been the predominant mode of
tramadol abuse as it results in a greater opioid effect compared to
other routes. It is unlikely that tramadol will be injected to any
significant extent. Abuse of tramadol is likely to be influenced by
genetic factors such that some people will experience a much stronger
opioid effect following tramadol administration compared to others. The
genotype associated with a stronger opioid effect following tramadol
administration occurs at different rates in populations across
different parts of the world.
    Many countries have placed tramadol under national control.
Therapeutic applications/usefulness
    Tramadol is used to treat both acute and chronic pain of moderate
to severe intensity. The conditions for which tramadol has been used
include osteoarthritis, neuropathic pain, chronic low back pain, cancer
pain and postoperative pain. It has also been used for treatment of
restless leg syndrome and opioid withdrawal management. As is the case
with abuse potential, the analgesic efficacy and the nature of adverse
effects experienced are strongly influenced by genetic factors.
Systematic reviews have reported that the ability of tramadol to
control chronic pain such as cancer pain is less than optimal, and its
use is associated with a relatively high prevalence of adverse effects.
    Tramadol is listed on the national essential medicines lists of
many countries across diverse regions, but it is not listed on the WHO
Lists of Essential Medicines.
    As an opioid analgesic available in generic forms which is not
under international control, tramadol is widely used in many countries
where access to other opioids for the management of pain is limited. It
is also used extensively by international aid organisations in
emergency and crisis situations for the same reasons.
Recommendations
    The Committee was concerned by the increasing evidence for tramadol
abuse in a number of countries in diverse regions, in particular the
widespread abuse of tramadol in many low to middle income countries.
Equally concerning was the clear lack of alternative analgesics for
moderate to severe pain for which tramadol is used. The Committee was
strongly of the view that the extent of abuse and evidence of public
health risks associated with tramadol warranted consideration of
scheduling, but the Committee recommended that tramadol not be
scheduled at this time in order that access to this medication not be
adversely impacted, especially in countries where tramadol may be the
only available opioid analgesic or in crisis situations where there is
very limited or no access at all to other opioids.
    The Committee also strongly urged the WHO and its partners to
address, as a high priority, the grossly inadequate access and
availability of opioid pain medication in low income countries. WHO and
its partners are also strongly encouraged to update and disseminate WHO
pain management guidelines and to support both country-specific
capacity building needs and prevention and treatment initiatives in
order to address the tramadol crisis in low income countries. The
Committee also recommended that WHO and its partners support countries
in strengthening their regulatory capacity

and mechanisms for preventing the supply and use of falsified and
substandard tramadol.
    Recommendation 4.2: The Committee recommended that the WHO
Secretariat continues to keep tramadol under surveillance, collect
information on the extent of problems associated with tramadol misuse
in countries and on its medical use, and that it be considered for
review at a subsequent meeting.

III. Discussion

    Although WHO has made specific scheduling recommendations for each
of the drug substances, the CND is not obliged to follow the WHO
recommendations. Options available to the CND for substances considered
for control under the Psychotropic Convention include the following:
(1) Accept the WHO recommendations; (2) accept the recommendations to
control, but control the drug substance in a schedule other than that
recommended; or (3) reject the recommendations entirely.
    ADB-FUBINACA (chemical name: N-[1-(aminocarbonyl)-2,2-
dimethylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide)
is an indazole-based synthetic cannabinoid that is a potent, full
agonist at CB1 receptors. This substance functionally
(biologically) mimics the effects of the structurally unrelated delta-
9-tetrahydrocannabinol (THC), a Schedule I substance, and the main
psychoactive chemical constituent in the cannabis (marijuana) plant.
Synthetic cannabinoids have been marketed under the guise of ``herbal
incense,'' and promoted by drug traffickers as legal alternatives to
marijuana. ADB-FUBINACA use has been associated with serious adverse
events including death in the United States. There are no commercial or
approved medical uses for ADB-FUBINACA. On April 10, 2017, ADB-FUBINACA
was temporarily controlled as a Schedule I substance under the CSA. As
such, additional permanent controls will be necessary to fulfill U.S.
obligations if ADB-FUBINACA is controlled under Schedule II of the 1971
Convention on Psychotropic Substances.
    FUB-AMB (other names: MMB-FUBINACA; AMB-FUBINACA; chemical name:
methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-
methylbutanoate) is an indazole-based synthetic cannabinoid that is a
potent full agonist at CB1 receptors. This substance
functionally (biologically) mimics the effects of the structurally
unrelated THC, a Schedule I substance, and the main psychoactive
chemical constituent in marijuana. Synthetic cannabinoids have been
marketed under the guise of ``herbal incense,'' and promoted by drug
traffickers as legal alternatives to marijuana. FUB-AMB use has been
associated with serious adverse events including death in the United
States. There are no commercial or approved medical uses for FUB-AMB.
On November 3, 2017, FUB-AMB was temporarily controlled as a Schedule I
substance under the CSA. As such, additional permanent controls will be
necessary to fulfill U.S. obligations if FUB-AMB is controlled under
Schedule II of the 1971 Convention on Psychotropic Substances.
    ADB-CHMINACA (other name: MAB-CHMINACA; chemical name: N-(1-amino-
3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indole-3-
carboxamide) is an indazole-based synthetic cannabinoid that is a
potent full agonist at CB1 receptors. This substance
functionally (biologically) mimics the effects of the structurally THC,
a Schedule I substance, and the main psychoactive chemical constituent
in marijuana. Synthetic cannabinoids have been marketed under the guise
of ``herbal incense,'' and promoted by drug traffickers as legal
alternatives to marijuana. ADB-CHMINACA use has been associated with
serious adverse events including death in the United States. There are
no commercial or approved medical uses for ADB-CHMINACA. On January 29,
2019, ADB-CHMINACA was permanently controlled as a Schedule I substance
under the CSA. As such, additional permanent controls will not be
necessary to fulfill U.S. obligations if ADB-CHMINACA is controlled
under Schedule II of the 1971 Convention on Psychotropic Substances.
    CUMYL-4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-
phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a clandestinely
produced indazole-3-carboxamide based synthetic cannabinoid that has
been sold online and used to mimic the biological effects of THC, the
main psychoactive chemical constituent in marijuana. Synthetic
cannabinoids have been marketed under the guise of ``herbal incense,''
and promoted by drug traffickers as legal alternatives to marijuana.
Hospital, scientific publications and law enforcement reports show that
CUMYL-4CN-BUTINACA is abused for its psychoactive properties. CUMYL-
4CN-BUTINACA has been associated with serious adverse events in the
United States, in addition to multiple deaths in Europe. CUMYL-4CN-
BUTINACA has no commercial or medical uses. On July 10, 2018, CUMYL-
4CN-BUTINACA was temporarily controlled as a Schedule I substance under
the CSA. As such, additional permanent controls will be necessary to
fulfill U.S. obligations if CUMYL-4CN-BUTINACA is controlled under
Schedule II of the 1971 Convention on Psychotropic Substances.
    Cyclopropyl fentanyl is a synthetic opioid that has a
pharmacological profile similar to other Schedule I and II controlled
opioid substances such as acetyl fentanyl, fentanyl, and other related
[micro]-opioid receptor agonist substances. This clandestinely produced
analog of fentanyl is associated with adverse events typically
associated with opioid use such as respiratory depression, anxiety,
constipation, tiredness, hallucinations, and withdrawal. Cyclopropyl
fentanyl has been associated with numerous fatalities. At least 115
confirmed overdose deaths involving cyclopropyl fentanyl abuse have
been reported in the United States. Cyclopropyl fentanyl has no
commercial or currently accepted medical uses in the United States. On
January 4, 2018, cyclopropyl fentanyl was temporarily placed into
Schedule I of the CSA. As such, additional permanent controls will be
necessary to fulfill U.S. obligations if Cyclopropyl fentanyl is
controlled under Schedule I of the 1961 Single Convention.
    Methoxyacetyl fentanyl has a pharmacological profile similar to
other Schedule I and II opioid substances such as acetyl fentanyl,
fentanyl, and other related [micro]-opioid receptor agonist substances.
Evidence suggests that the pattern of abuse of fentanyl analogues,
including methoxyacetyl fentanyl is similar to heroin and prescription
opioid analgesics. Law enforcement and public health reports
demonstrate that methoxyacetyl fentanyl is being illicitly distributed
and abused. The Drug Enforcement Administration (DEA) is aware of at
least two overdose deaths associated with the abuse of methoxyacetyl
fentanyl in the United States. Methoxyacetyl fentanyl has no currently
accepted medical use in treatment in the United States. On October 26,
2017, methoxyacetyl fentanyl was temporarily placed into Schedule I of
the CSA. As such, additional permanent controls will be necessary to
fulfill U.S. obligations if methoxyacetyl fentanyl is controlled under
Schedule I of the 1961 Single Convention.
    Para-fluorobutyrfentanyl shares pharmacological profile with other
Schedule I (e.g. butyryl fentanyl) and II

(e.g., fentanyl) opioid substances. Para-fluorobutyrfentanyl has no
currently accepted medical use in treatment in the United States. The
abuse of para-fluorobutyrfentanyl carries public health risks similar
to that of heroin, fentanyl, and prescription opioid analgesics. On
February 1, 2018, para-fluorobutyrfentanyl was temporarily placed into
Schedule I of the CSA. As such, additional permanent controls will be
necessary to fulfill U.S. obligations if Para-fluorobutyrfentanyl is
controlled under Schedule I of the 1961 Single Convention.
    Ortho-fluorofentanyl has a pharmacological profile similar to
fentanyl and other related [micro]-opioid receptor agonist. Ortho-
fluorofentanyl has no currently accepted medical use in treatment in
the United States. Ortho-fluorofentanyl has been encountered by law
enforcement and public health officials. The DEA has received reports
for at least 13 confirmed overdose deaths involving ortho-
fluorofentanyl abuse in the United States. On October 26, 2017, ortho-
fluorofentanyl was temporarily placed into Schedule I of the CSA. As
such, additional permanent controls will be necessary to fulfill U.S.
obligations if Ortho-fluorofentanyl is controlled under Schedule I of
the 1961 Single Convention.
    N-ethylnorpentylone (other name: N-ethylpentylone) is a synthetic
cathinone with stimulant and psychoactive properties similar to
cathinone, a Schedule I substance. N-Ethylpentylone abuse has been
associated with adverse health effects leading to emergency department
admissions, and deaths. N-Ethylpentylone has no currently accepted
medical use in treatment in the United States. On August 31, 2018, N-
ethylnorpentylone was temporarily controlled as a Schedule I substance
under the CSA. As such, additional permanent controls will be necessary
to fulfill U.S. obligations if N-ethylnorpentylone is controlled under
Schedule II of the 1971 Convention on Psychotropic Substances.
    FDA, on behalf of the Secretary of HHS, invites interested persons
to submit comments on the notifications from the United Nations
concerning these drug substances. FDA, in cooperation with the National
Institute on Drug Abuse, will consider the comments on behalf of HHS in
evaluating the WHO scheduling recommendations. Then, under section
201(d)(2)(B) of the CSA, HHS will recommend to the Secretary of State
what position the United States should take when voting on the
recommendations for control of substances under the Psychotropic
Convention at the CND meeting in March 2019.
    Comments regarding the WHO recommendations for control of
Cyclopropyl fentanyl; Methoxyacetyl fentanyl; Ortho-fluorofentanyl;
Para-fluorobutyrfentanyl; under the 1961 Single Convention will also be
forwarded to the relevant Agencies for consideration in developing the
U.S. position regarding narcotic substances at the CND meeting.

    Dated: February 25, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-03663 Filed 2-28-19; 8:45 am]
BILLING CODE 4164-01-P


0;left:384pt;top:119pt;width:24pt;height: 1pt;background-color:#9d9793;"><span style="position:a


[Federal Register Volume 88, Number 151 (Tuesday, August 8, 2023)]
[Notices]
[Pages 53483-53484]
[FR Doc No: 2023-16873]

=======================================================================
-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OAR-2007-0269; FRL 11000-01-OAR]

Proposed Information Collection Request; Comment Request;
Transportation Conformity Determinations for Federally Funded and
Approved Transportation Plans, Programs and Projects, EPA ICR No.
2130.07, OMB Control No. 2060-0561

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Environmental Protection Agency (EPA) is planning to
submit an information collection request (ICR), ``Transportation
Conformity Determinations for Federally Funded and Approved
Transportation Plans, Programs, and Projects'' (EPA ICR No. 2130.07,
OMB Control No. 2060-0561), to the Office of Management and Budget
(OMB) for review and approval in accordance with the Paperwork
Reduction Act. Before doing so, EPA is soliciting public comments on
specific aspects of the proposed information collection as described
below. This is a proposed extension of the ICR, which is currently
approved through February 29, 2024.

DATES: Comments must be submitted on or before October 10, 2023.

ADDRESSES: Submit your comments, referencing Docket ID No. EPA-HQ-OAR-
2007-0269 online using www.regulations.gov (our preferred method) or by
mail to: EPA Docket Center, Environmental Protection Agency, Mail Code
28221T, 1200 Pennsylvania Ave. NW, Washington, DC 20460. EPA's policy
is that all comments received will be included in the public docket
without change including any personal information provided, unless the
comment includes profanity, threats, information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute.

FOR FURTHER INFORMATION CONTACT: Aaron Letterly, Office of
Transportation and Air Quality, Environmental Protection Agency, 2000
Traverwood Drive, Ann Arbor, MI 48105; telephone number:<PHONE_NUMBER>;
email address: [email protected].

SUPPLEMENTARY INFORMATION: Supporting documents which explain in detail
the information that EPA will be collecting are available in the public
docket for this ICR. The docket can be viewed online at
www.regulations.gov or in person at the EPA Docket Center, WJC West,
Room 3334, 1301 Constitution Ave. NW, Washington, DC. The telephone
number for the Docket Center is<PHONE_NUMBER>. For additional
information about EPA's public docket, visit https://www.epa.gov/dockets.
    Pursuant to section 3506(c)(2)(A) of the PRA, EPA is soliciting
comments and information to enable it to: (i) evaluate whether the
proposed collection of information is necessary for the proper
performance of the functions of the Agency, including whether the
information will have practical utility; (ii) evaluate the accuracy of
the Agency's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (iii) enhance the quality, utility, and clarity of the
information to be collected; and (iv) minimize the burden of the
collection of information on those who are to respond, including
through the use of appropriate automated electronic, mechanical, or
other technological collection techniques or other forms of information
technology, e.g., permitting electronic submission of responses. EPA
will consider the comments received and amend the ICR as appropriate.
The final ICR package will then be submitted to OMB for review and
approval. At that time, EPA will issue another Federal Register notice
to announce the submission of the ICR to OMB and the opportunity to
submit additional comments to OMB.
    Abstract: Transportation conformity is required under Clean Air Act
section 176(c) (42 U.S.C. 7506(c)) to ensure that federally supported
transportation activities are consistent with (``conform to'') the
purpose of the state air quality implementation plan (SIP).
Transportation activities include transportation plans, transportation
improvement programs (TIPs), and federally funded or approved highway
or transit projects. Conformity to the purpose of the SIP means that
transportation activities will not cause

or contribute to new air quality violations, worsen existing
violations, or delay timely attainment of the relevant national ambient
air quality standards (NAAQS or ``standards'') or interim milestones.
    Transportation conformity applies under EPA's conformity
regulations at 40 CFR part 93, subpart A, to areas that are designated
nonattainment, and those redesignated to attainment after 1990
(``maintenance areas'' with plans developed under Clean Air Act section
175A) for the following transportation-related criteria pollutants:
ozone, particulate matter (PM2.5 and PM10),
carbon monoxide (CO), and nitrogen dioxide (NO2). EPA
published the original transportation conformity rule on November 24,
1993 (58 FR 62188), and subsequently published several revisions. EPA
develops the conformity regulations in coordination with the Federal
Highway Administration (FHWA) and Federal Transit Administration (FTA).
    Transportation conformity determinations are required before
federal approval or funding is given to certain types of transportation
planning documents as well as non-exempt highway and transit
projects.\1\
---------------------------------------------------------------------------

    \1\ Some projects are exempt from all or certain conformity
requirements; see 40 CFR 93.126, 93.127, and 93.128.
---------------------------------------------------------------------------

    EPA considered the following in renewing the existing ICR:
     Burden estimates for transportation conformity
determinations (including both regional and project-level) in current
nonattainment and maintenance areas for the ozone, PM2.5,
PM10, and CO NAAQS; \2\
---------------------------------------------------------------------------

    \2\ Currently there are no NO2 nonattainment or
maintenance areas that are required to make transportation
conformity determinations.
---------------------------------------------------------------------------

     Federal burden associated with EPA's adequacy review
process for submitted SIP motor vehicle emissions budgets that are to
be used in conformity determinations;
     Efficiencies in areas making conformity determinations for
multiple NAAQS;
     Differences in conformity resource needs in large and
small metropolitan areas and isolated rural areas;
     Infrequency of conformity determinations in isolated rural
areas;
     Reduced burden from certain areas no longer determining
conformity for the 1997 annual PM2.5 NAAQS due to
revocation; \3\
---------------------------------------------------------------------------

    \3\ See 81 FR 58010 (published on August 24, 2016 and effective
October 24, 2016) for a description of this revocation and
implications for transportation conformity.
---------------------------------------------------------------------------

     Reduced burden from areas completing 20 years of
maintenance for PM10, NO2 and CO NAAQS, at which
time transportation conformity is no longer required; and,
     The limited conformity requirements that apply in the 1997
ozone NAAQS areas that were not designated nonattainment for a later
ozone NAAQS.
    This ICR does not include burden associated with the general
development of transportation planning and air quality planning
documents for meeting other federal requirements.
    Form Numbers: None.
    Respondents/affected entities: Entities potentially affected by
this action are metropolitan planning organizations (MPOs), state
departments of transportation, local transit agencies, and state and
local air quality agencies. Federal agencies potentially affected by
this action include FHWA, FTA, and EPA.
    Respondent's obligation to respond: Mandatory pursuant to Clean Air
Act section 176(c) (42 U.S.C. 7506(c)) and 40 CFR and Part 93 Subpart
A.
    Estimated number of respondents: EPA estimates that 102 MPOs will
be subject to transportation conformity requirements during the period
covered by this ICR and that EPA Regional Offices, FHWA, and FTA will
be involved in interagency consultation, and review of MPO
transportation-related conformity determinations during this process.
EPA also estimates that similar consultation will occur for project-
level conformity determinations in isolated rural areas. In addition,
there are 46 MPOs that determine conformity only for the 1997 ozone
NAAQS that are also accounted for, but their conformity-related
requirements are estimated to be limited and less burdensome due to the
circumstances with that NAAQS.
    Frequency of response: The information collections described in
this ICR must be completed before a transportation plan, TIP, or
project conformity determination is made. The Clean Air Act requires
conformity to be determined for transportation plans and TIPs every
four years. Conformity determinations on projects in metropolitan and
isolated rural areas are required on an as-needed basis.
    Total estimated burden: 42,481 hours (per year). Burden is defined
at 5 CFR 1320.3(b).
    Total estimated cost: $2,946,914 (per year), includes zero
annualized capital or operation and maintenance costs.
    Changes in Estimates: There is a decrease of 8,590 hours in the
total estimated respondent burden compared with the ICR currently
approved by OMB. This decrease is due to PM10,
NO2, and CO areas reaching the end of the 20-year
maintenance period, beyond which transportation conformity is not
required, as well as fewer transportation conformity determinations for
areas previously designated nonattainment or maintenance for the 1997
annual PM2.5 NAAQS and the 1997 ozone NAAQS. Additionally,
EPA updated its assumptions about the frequency of conformity
determinations in isolated rural areas, which reduced the number of
actions and resulting burden hours compared to previous ICRs.

Michael Moltzen,
Deputy Director, Transportation and Climate Division, Office of
Transportation and Air Quality, Office of Air and Radiation.
[FR Doc. 2023-16873 Filed 8-7-23; 8:45 am]
BILLING CODE 6560-50-P