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Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Proposed Rules
2018, temporary order, fentanyl-related substances include any substance not otherwise controlled in any schedule i.e., not included under any other Administration Controlled Substance Code Number that is structurally related to fentanyl by one or more of the following modifications:

A Replacement of the phenyl portion of the phenethyl group by any monocycle, whether or not further substituted in or on the monocycle;
B substitution in or on the phenethyl group with alkyl, alkenyl, alkoxyl, hydroxyl, halo, haloalkyl, amino or nitro groups;
C substitution in or on the piperidine ring with alkyl, alkenyl,
alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino or nitro groups;
D replacement of the aniline ring with any aromatic monocycle whether or not further substituted in or on the aromatic monocycle; and/or E replacement of the N-propionyl group by another acyl group.

According to the February 6, 2018, temporary scheduling order, the existence of a substance with any one, or any combination, of above-mentioned modifications see Figure 1 would meet the structural requirements of the definition of fentanyl-related substances. The present 10 substances fall within the definition of fentanylrelated substances by the following modifications:
1. 2-Fluoro ortho-fluorofentanyl:
Substitution on the phenethyl group with a halo group and substitution on the aniline ring meets definition for modifications B and D;
2. 4-methyl acetyl fentanyl:
Substitution on the phenethyl group with an alkyl group and replacement of the N-propionyl group by another acyl group meets definition for modifications B and E;
3. b-methyl fentanyl: Substitution on the phenethyl group with an alkyl group meets definition for modification B;
4. b-phenyl fentanyl: Replacement of the N-propionyl group by another acyl group meets definition for modification E;
5. ortho-fluorobutyryl fentanyl:
Substitution on the aniline ring and replacement of the N-propionyl group
with another acyl group meets definition for modifications D and E;
6. ortho-methyl acetylfentanyl:
Substitution on the aniline ring and replacement of the N-propionyl group with another acyl group meets definition for modifications D and E;
7. ortho-methyl methoxyacetylfentanyl: Substitution on the aniline ring and replacement of the N-propionyl group with another acyl group meets definition for modifications D and E;
8. para-methylfentanyl: Substitution on the aniline ring meets definition for modification D;
9. phenyl fentanyl: Replacement of the N-propionyl group by another acyl group meets definition for modification E; and 10. thiofuranyl fentanyl: Replacement of the N-propionyl group by another acyl group meets definition for modification E.
No study has been undertaken to evaluate the efficacy, toxicology, and safety of the 10 substances in humans.
It can be inferred from data obtained from animal studies that these 10
substances have sufficient distribution to the brain to produce depressant effects similar to that of other mu-opioid
receptor agonists such as fentanyl. Data from in vitro receptor binding studies show that these 10 substances, similar to fentanyl, display high selectivity for the mu-opioid receptor over other opioid receptor subtypes.
There are no FDA-approved marketing applications for a drug product containing 2-fluoro orthofluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, orthomethyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl for any therapeutic indication in the United States.
Moreover, there are no clinical studies or petitions which have claimed an accepted medical use in the United States for these 10 substances.
4. Its History and Current Pattern of Abuse: 2-Fluoro ortho-fluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, orthofluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl, like other substances structurally related to fentanyl, are disguised as a legal
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