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**PART 50—CLEARING REQUIREMENT**

Authority: 7 U.S.C. 2 as amended by Pub. L. 111–203, 124 Stat. 1376.

**§ 50.25 Clearing requirement compliance**

**schedule.**

(a) Definitions. For the purposes of this paragraph:

Active Fund means any private fund as defined in section 202(a) of the Investment Advisers Act of 1940, that is not a third-party subaccount and that executes 200 or more swaps per month based on a monthly average over the 12 months preceding the Commission issuing a clearing requirement determination under section 2(h)(2) of
the Act.

Category 1 Entity means a swap dealer, a security-based swap dealer; a major swap participant; a major security-based swap participant; or an
active fund.

Category 2 Entity means a commodity pool; a private fund as defined in section 202(a) of the
Investment Advisers Act of 1940 other than an active fund; or a person predominantly engaged in activities that are in the business of banking, or in
activities that are financial in nature as defined in section 4(k) of the Bank Holding Company Act of 1956, provided that, in each case, the entity is not a third-party subaccount.

Third-party Subaccount means an account that is managed by an investment manager that is independent
of and unaffiliated with the account’s beneficial owner or sponsor, and is responsible for the documentation necessary for the account’s beneficial owner to clear swaps.

(b) Upon issuing a clearing requirement determination under section 2(h)(2) of the Act, the Commission may determine, based on the group, category, type, or class of swaps subject to such determination, that the following schedule for compliance with the requirements of section 2(h)(1)(A) of the Act shall apply:

(1) A swap between a Category 1 Entity and another Category 1 Entity, or any other entity that desires to clear the transaction, must comply with the requirements of section 2(h)(1)(A) of the Act no later than ninety (90) days from the date of publication of such clearing requirement determination in the Federal Register

.

(2) A swap between a Category 2 Entity and a Category 1 Entity, another Category 2 Entity, or any other entity that desires to clear the transaction, must comply with the requirements of section 2(h)(1)(A) of the Act no later than one hundred and eighty (180) days from the date of publication of such clearing requirement determination in
the Federal Register

.

(3) All other swaps for which neither of the parties to the swap is eligible to claim the exception from the clearing requirement set forth in section 2(h)(7) of the Act and § 39.6, must comply with the requirements of section 2(h)(1)(A) of
the Act no later than two hundred and seventy (270) days from the date of publication of such clearing requirement determination in the Federal Register

.

(c) Nothing in this rule shall be construed to prohibit any person from voluntarily complying with the requirements of section 2(h)(1)(A) of the Act sooner than the implementation schedule provided under paragraph (b).

Issued in Washington, DC, on July 24, 2012, by the Commission.

Sauntia Warfield,
Assistant Secretary of the Commission.

Appendices to Swap Transaction Compliance and Implementation Schedule: Clearing Requirement under Section 2(h) of the CEA—Commission Voting Summary and Statements of

Commissioners

Note: The following appendices will not appear in the Code of Federal Regulations.

Appendix 1—Commission Voting Summary

On this matter, Chairman Gensler and Commissioners Sommers, Chilton, O’Malia and Wetjen voted in the affirmative; no Commissioner voted in the negative.

Appendix 1—Statement of Chairman Gary Gensler

I support the final rule to establish a schedule to phase in compliance with theclearing requirement provisions in the DoddFrank Wall Street Reform and Consumer

Protection Act.

The rule gives market participants an adequate amount of time to comply and helps facilitate an orderly transition to the new clearing requirements for the swaps market. The rule provides greater clarity to market participants regarding the timeframe for bringing their swaps into compliance with the clearing requirement.

[FR Doc. 2012–18383 Filed 7–27–12; 8:45 am]

**BILLING CODE 6351–01–P DEPARTMENT OF JUSTICE** 

**Drug Enforcement Administration**

**21 CFR Part 1300**

**[Docket No. DEA–341F]**

**RIN 1117–AB31**

**Classification of Two Steroids,**
**Prostanozol and**  **Methasterone, as**  **Schedule III Anabolic Steroids Under**
**the Controlled Substances Act**

**AGENCY :**  Drug Enforcement Administration (DEA), Department of Justice.

**ACTION :**  Final rule.

**SUMMARY :**  With the issuance of this Final Rule, the Administrator of the DEA classifies the following two
steroids as ‘‘anabolic steroids’’ under the Controlled Substances Act (CSA): prostanozol (17 b -hydroxy-5 aandrostano[3,2-c]pyrazole) and methasterone (2 a ,17 a-dimethyl-5 aandrostan-17 b -ol-3-one). These steroids and their salts, esters, and ethers are
Schedule III controlled substances subject to the regulatory control provisions of the CSA.

**DATES :**  Effective Date: August 29, 2012.

**FOR FURTHER INFORMATION CONTACT :**  Alan G. Santos, Associate Deputy Assistant Administrator, Office of Diversion Control, Drug Enforcement Administration; Mailing Address: 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 307–7165.

**SUPPLEMENTARY INFORMATION :** 
Legal Authority

The DEA implements and enforces Titles II and III of the Comprehensive Drug Abuse Prevention and Control Act of 1970, often referred to as the
Controlled Substances Act and the Controlled Substances Import and Export Act (21 U.S.C. 801–971), as amended (hereinafter, ‘‘CSA’’). The implementing regulations for these
statutes are found in Title 21 of the Code of Federal Regulations (CFR), parts 1300 to 1321. Under the CSA, controlled
substances are classified in one of five schedules based upon their potential for abuse, their currently accepted medical use, and the degree of dependence the substance may cause. 21 U.S.C. 812. The
initial schedules of controlled substances by statute are found at 21 U.S.C. 812(c) and the current list of scheduled substances is published at 21

CFR Part 1308.

On November 29, 1990, the President signed into law the Anabolic Steroids Control Act of 1990 (Title XIX of Pub. L. 101–647), which became effective


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February 27, 1991. This law established and regulated anabolic steroids as a class of drugs under Schedule III of the CSA. As a result, a new anabolic steroid is not scheduled according to the procedures set out in 21 U.S.C. 811, but is administratively classified as an anabolic steroid through the rulemaking process if it meets the regulatory
definition of an anabolic steroid in 21

CFR 1300.01.

On October 22, 2004, the President signed into law the Anabolic Steroid Control Act of 2004 (Pub. L. 108–358), which became effective on January 20, 2005. Section 2(a) of the Anabolic
Steroid Control Act of 2004 amended 21 U.S.C. 802(41)(A) by replacing the existing definition of ‘‘anabolic steroid.’’
The Anabolic Steroid Control Act of 2004 classifies a drug or hormonal
substance as an anabolic steroid if the following four criteria are met: (A) The substance is chemically related to testosterone; (B) the substance is pharmacologically related to testosterone; (C) the substance is not an estrogen, progestin, or a corticosteroid; and (D) the substance is not dehydroepiandrosterone (DHEA). Any
substance that meets these criteria is
considered an anabolic steroid and must
be listed as a Schedule III controlled
substance.

Background

In a Notice of Proposed Rulemaking (NPRM) published on November 23, 2011 (76 FR 72355), DEA proposed
classification of two steroids as
Schedule III anabolic steroids under the
CSA: Prostanozol and methasterone. DEA believes that prostanozol (17 b

hydroxy-5 a-androstano[3,2-c]pyrazole) and methasterone (2 a ,17 a-dimethyl-5 aandrostan-17 b -ol-3-one) meet this
definition of anabolic steroid.

Anabolic steroids are a class of drugs structurally related to the endogenous
hormone testosterone that exert androgenic (masculinizing) as well as anabolic (body building) effects. These effects are mediated primarily through binding of the anabolic steroid to the androgen receptor in target tissues (Evans, 2004). Anabolic effects include promotion of protein synthesis in skeletal muscle and bone, while the androgenic effects are characterized by the development of male secondary
sexual characteristics such as hair growth, deepening of the voice, glandular activity, thickening of the skin, and central nervous system effects (Kicman, 2008). Anabolic efficacy is characterized by positive nitrogen balance and protein metabolism, resulting in increases in protein synthesis and lean body mass (Evans, 2004). These effects often come at a cost to the healthy individual who experiences clear physical and psychological complications (Trenton and Currier, 2005; Brower, 2002; Hall et al., 2005).

In the United States, only a small
number of anabolic steroids are approved for either human or veterinary use. Approved medical uses for anabolic steroids include treatment of androgen deficiency in hypogonadal males, adjunctive therapy to offset protein catabolism associated with prolonged administration of corticosteroids, treatment of delayed puberty in boys,
treatment of metastatic breast cancer in women, and treatment of anemia associated with specific diseases (e.g., anemia of chronic renal failure, Fanconi’s anemia, and acquired aplastic anemia). However, with the exception of the treatment of male hypogonadism,
anabolic steroids are not the first-line treatment due to the availability of other preferred treatment options. DEA is not aware of any legitimate medical use or New Drug Applications (NDA) for the two substances that DEA is proposing to classify by this NPRM as anabolic
steroids under the definition set forth under 21 U.S.C. 802(41)(A). Moreover, DEA has been unable to identify any chemical manufacturers currently using
these substances as intermediates in their manufacturing processes.

Adverse health effects are associated
with abuse of anabolic steroids and depend on several factors (e.g., age, sex, anabolic steroid used, the amount used, and the duration of use) (Hall and Hall, 2005; Quaglio et al., 2009). These include cardiovascular, dermatological, behavioral, hepatic, and gender specific
endocrine side effects. Anabolic steroids have direct and indirect impact on the developing adolescent brain and behavior (Sato et al., 2008). Furthermore, adolescent abuse of anabolic steroids may result in stunted growth due to premature closure of the growth plates in long bones.

In adolescent boys, anabolic steroid abuse can cause precocious sexual development. In both girls and women,
anabolic steroid abuse induces permanent physical changes such as deepening of the voice, increased facial and body hair growth, menstrual irregularities, and clitoral hypertrophy. In men, anabolic steroid abuse can cause testicular atrophy, decreased sperm count, and sterility. Gynecomastia (i.e., enlargement of the male breast tissue) can develop with the
abuse of those anabolic steroids with estrogenic actions. In both men and women, anabolic steroid abuse can damage the liver and may result in high cholesterol levels, which may increase
the risk of strokes and cardiovascular heart attacks. Furthermore, anabolic steroid abuse is purported to induce psychological effects such as aggression, increased feelings of hostility, and psychological dependence and addiction (Brower, 2002; Kanayama et al., 2008).

Upon abrupt termination of long-term anabolic steroid abuse, a withdrawal syndrome may appear including severe depression. Additionally, polysubstance abuse is routinely associated with anabolic steroid abuse, where ancillary drugs, including recreational and prescription drugs, are abused in response to unwanted side effects (Hall et al., 2005; Parkinson et al., 2005; Skarberg et al., 2009).

A review of the scientific literature finds adverse health effects including liver toxicity with renal failure reported in conjunction with methasterone abuse (Shah et al., 2008; Jasiurkowski et al., 2006; Singh et al., 2009; Nasr and Ahmad, 2008; and Krishnan et al., 2009). In March 2006, the U.S. Food and Drug Administration (FDA) issued a Warning Letter in response to adverse
health effects associated with the product Superdrol (methasterone). In July 2009, FDA issued a warning regarding bodybuilding products containing steroid or steroid-like substances. In this warning, a product containing the THP ether derivative of prostanozol was named in conjunction with other products presenting safety

concerns. Evaluation of Statutory Factors for
Classification as an Anabolic Steroid

With the issuance of this Final Rule, DEA classifies prostanozol (17 b

hydroxy-5 a-androstano[3,2-c]pyrazole) and methasterone (2 a ,17 a-dimethyl-5 aandrostan-17 b -ol-3-one) as anabolic
steroids under the definition set forth under 21 U.S.C. 802(41)(A). As noted previously, a drug or hormonal
substance is classified as an anabolic steroid by meeting the following four definitional requirements: (A) The substance is chemically related to testosterone; (B) the substance is pharmacologically related to testosterone; (C) the substance is not an estrogen, progestin, or corticosteroid; and (D) the substance is not DHEA.

(A) Chemically Related to Testosterone

To classify a substance as an anabolic steroid, a substance must be chemically
related to testosterone. A structure activity relationship (SAR) evaluation for each substance compared the
chemical structure of the steroid to that
of testosterone. Substances with a


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structure similar to that of testosterone are predicted to possess comparable pharmacological and biological activity.

Prostanozol is also known by the following name: 17 b -hydroxy-5 aandrostano[3,2-c]pyrazole. DEA
determined that the chemical structure of prostanozol is similar to testosterone, differing by only the attachment of a pyrazole ring at carbon 2 (C2) and carbon 3 (C3) positions of the androstane skeleton, replacing the C3- keto group and the lack of a double bond between carbon 4 (C4) and carbon 5 (C5) positions. Similar modifications
to testosterone’s chemical structure have been documented and, in general, they have been found to be well tolerated, displaying both anabolic and androgenic activity (Fragkaki et al., 2009; Vida, 1969). Clinton and coworkers, in their synthesis of prostanozol, described the modification as a fusion of a pyrazole ring to the
androstane steroidal nucleus at C2 and C3 (Clinton et al., 1961). Further analysis finds the chemical structure of prostanozol to be very similar to the
anabolic steroid stanozolol. The two structures differ only about a 17 amethyl group (alpha methyl group attached to carbon 17).

Methasterone is known by the following chemical names: 2 a ,17 adimethyl-5 a-androstan-17 b -ol-3-one;

2 a ,17 a-dimethyl-17 b -hydroxy-5 aandrostan-3-one; 17 a-methyldrostanolone; methasteron; methyldrostanolone; 2 a ,17 adimethyldihydrotestosterone; and

2 a ,17 a-dimethyl-etiocholan-17 b -ol-3-
one. DEA has determined that the
chemical structure of methasterone is chemically related to testosterone. The
chemical structure of methasterone differs from testosterone by the following three chemical groups: An alpha methyl group at carbon 17 (C17), an alpha methyl group at C2, and the lack of a double bond between spanning
C4 and C5. Removal of the C4–C5 double bond (A-ring) and methylation at the C2 and C17 positions has been shown to increase anabolic activity (Zaffroni, 1960; Fragkaki et al., 2009). Furthermore, methyl group substitution at the C2 and C17 has been reported to impair aromatization, thus, prolonging the anabolic effect (Fragkaki et al., 2009).

(B) Pharmacologically Related to

Testosterone

A substance must also be pharmacologically related to testosterone (i.e., produce similar biological effects) to be classified as a
Schedule III anabolic steroid. The pharmacology of a steroid, as related to testosterone, can be established by performing one or more of the following androgenic and anabolic activity assays: ventral prostate assay, seminal vesicle assay, levator ani assay, and androgen receptor binding and efficacy assays. These assays are described below.

Ventral Prostate Assay, Seminal Vesicle Assay, and Levator Ani Assay: The classic scientific procedure for evaluating androgenic (masculinizing) and anabolic (muscularizing) effects of a steroid is the ventral prostate assay, seminal vesicle assay, and levator ani assay. This testing paradigm allows for the direct comparison to testosterone. Select male accessory tissues (i.e., the ventral prostate, seminal vesicles, and levator ani muscle) are testosterone sensitive, specifically requiring testosterone to grow and remain healthy. Upon the removal of the testes (i.e., castration), the primary endogenous source of testosterone is eliminated causing the atrophy of the ventral prostate, seminal vesicles, and levator ani muscle (Eisenberg et al., 1949; Nelson et al., 1940; Scow, 1952; Wainman and Shipounoff, 1941).
Numerous scientific studies have demonstrated the ability of exogenous testosterone or a pharmacologically
similar steroid administered to rats following castration to maintain the normal weight and size of all three testosterone sensitive organs (Biskind and Meyer, 1941; Dorfman and Dorfman, 1963; Dorfman and Kincl, 1963; Kincl and Dorfman, 1964; Nelson et al., 1940; Scow, 1952; Wainman and Shipounoff, 1941). Thus, a steroid with testosterone-like activity will also prevent the atrophy of these three testosterone-dependent organs in
castrated rats.

Castrated male rats are administered the steroid for a number of days, then
the rats are euthanized and the previously described tissues are excised and weighed. Tissue weights from the three animal test groups are compared, castrated animals alone, castrated animals receiving the steroid, and healthy intact animals (control), to assess anabolic and androgenic activity. A reduction in tissue weights relative to the control group suggests a lack of androgenic and/or anabolic activity. An increase in tissue weights relative to the castrated rats receiving no steroid suggests an androgenic and/or anabolic
effect.

Androgen Receptor Binding and Efficacy Assay: Anabolic steroids bind with the androgen receptor to exert their biological effect. Affinity for the receptor is evaluated in the receptor binding assay, while the transactivation (functional) assay provides additional information as to both affinity and ability to activate the receptor. Receptor binding and transactivation studies are valuable tools in evaluating pharmacological activity and drawing comparisons to other substances. A steroid displaying affinity for the androgen receptor and properties of being an agonist in transactivation
studies is determined to be pharmacologically similar to

testosterone.

Studies used to evaluate anabolic steroids are the androgen receptor binding assay and the androgen receptortransactivation assay. Both are wellestablished and provide significant utility in evaluating steroids for affinity to their biological target and the modulation of activity. The androgen receptor binding assay provides specific detail as to the affinity of a steroid for the androgen receptor (biological target of anabolic steroids). To assess further whether the steroid is capable of activating the androgen receptor, the androgen receptor transactivation assay evaluates the binding of a steroid to the androgen receptor and subsequent interaction with DNA. In this study, transcription of a reporter gene provides information as to a steroid’s ability to modulate a biological event. This activity measurement provides information as to the potency of a steroid to bind to a receptor and either initiate or inhibit the transcription of the reporter gene. The androgen receptor binding assay and androgen receptor transactivation assay are highly valuable tools in assessing the potential activity of a steroid and comparing the activity to testosterone.

Results of the Androgenic and Anabolic Activity Assays: DEA reviewed the published scientific literature, and pharmacological studies were
undertaken to collect additional information on prostanozol and
methasterone in several different androgenic and anabolic activity assays. Findings from these studies indicate that in addition to being structurally similar to testosterone, prostanozol and
methasterone have similar pharmacological activity as testosterone.

Prostanozol

The chemical synthesis and anabolic and androgenic effects of prostanozol (17 b -hydroxy-5 a-androstano[3,2- c]pyrazole) were published in 1961 (Clinton et al., 1961). Clinton and
coworkers evaluated the anabolic activity by means of nitrogen balance and androgenic activity based on weight changes of the ventral prostrate of prostanozol upon subcutaneous
administration to rats with the reference


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1 The study by Bioqual, Inc., Rockville, MD, may
be found at http://www.regulations.gov in the electronic docket associated with this rulemaking. standard testosterone propionate. The potency ratio of anabolic activity to androgenic activity for prostanozol was reported to be eight (Clinton et al., 1961). In another study, prostanozol was reported to have approximately the same relative binding affinity for human sex steroid binding protein as testosterone (Cunningham et al., 1981).

To build on these findings, a pharmacological study 1 was conducted to evaluate the anabolic and androgenic effects of prostanozol in castrated male rats. Results were compared to testosterone by a similar protocol. Administration of prostanozol to castrated male rats by subcutaneous injection prevented the atrophy (loss in weight) of the ventral prostate, seminal vesicles, and levator ani muscle. 1 These

testosterone sensitive tissues experienced increases in weight comparable to testosterone in castrated male rats. Results from this study support that prostanozol possesses both androgenic and anabolic activity.
Additional studies were conducted to further assess prostanozol’s anabolic effect. In a competitive binding assay, prostanozol was found to possess affinity for the androgen receptor comparable to testosterone. 1 In the androgen receptor transactivation assay, prostanozol displayed increased activity
relative to testosterone. 1 Effects elicited by prostanozol in this transactivation assay were consistent and comparable to those of testosterone. Taken together, data from in vitro and in vivo assays indicate the pharmacology of prostanozol to be similar to testosterone.

Methasterone

The synthesis of methasterone (2 a ,17 a-dimethyl-5 a-androstan-17 b -ol3-one) was reported in 1956 and the anabolic activity in 1959 (Ringold and Rosenkranz, 1956; Ringold et al., 1959). Methasterone was described as a potent anabolic agent exhibiting weak androgenic activity in the castrated male rat (Ringold et al., 1959). Zaffaroni and coworkers reported methasterone possessed one-fifth the androgenic activity and four times the anabolic activity of the anabolic steroid methyltestosterone, when administered orally to the experimental animal (Zaffaroni et al. , 1960).

Additional pharmacological studies
were undertaken to further evaluate the androgenic and anabolic effects of
methasterone. 1 Methasterone was administered subcutaneously and orally to castrated male rats. By both routes of administration, methasterone prevented the atrophy (loss in weight) of ventral prostate, seminal vesicles, and levator ani muscle. Tissue weight increases for
the castrated methasterone-treated animals were comparable to the
castrated rats treated with testosterone and methyltestosterone. These results were consistent with earlier findings
that methasterone is anabolic and androgenic (Zaffaroni, 1960; Ringold et al., 1959). Functional assays were also
undertaken to further evaluate
methasterone. 1 Methasterone displayed affinity for the androgen receptor comparable to testosterone in a competitive binding assay. 1 In the androgen receptor transactivation assay, methasterone displayed increased activity relative to testosterone. 1 Effects elicited by methasterone in the androgen transactivation assay were consistent and comparable to those of testosterone. Collectively, in vivo and in
vitro results indicate that the pharmacology of methasterone is similar

to testosterone.
(C) Not Estrogens, Progestins, and
Corticosteroids

DEA has determined that prostanozol
and methasterone are unrelated to estrogens, progestins, and
corticosteroids. DEA evaluated the SAR
for each of the substances. The chemical
structure of each substance was compared to that of estrogens, progestins, and corticosteroids, since
chemical structure can be related to its pharmacological and biological activity.
DEA found that these two substances lack the necessary chemical structures to impart significant estrogenic activity (e.g., aromatic A ring) (Duax et al., 1988; Jordan et al., 1985; Williams and Stancel, 1996), progestational activity (e.g., 17 b -alkyl group) (Williams and Stancel, 1996), or corticosteroidal activity (e.g., 17 b -ketone group or 11 b

hydroxyl group) (Miller et al., 2002). Furthermore, methasterone was reported to display anti-estrogenic activity in mouse assay to assess estrogen stimulated uterine growth (Dorfman et al., 1961). To assess the estrogenic, progestational, and corticosteroid activity of prostanozol and methasterone, these substances were evaluated in receptor binding and functional transactivation assays.
Prostanozol and methasterone showed low binding affinity for the estrogen, progesterone, and glucocorticoid receptors. Furthermore, these steroids displayed low to no transactivation mediated by the estrogen receptors, progesterone receptors, or glucocorticoid receptors. Therefore, based on these data, prostanozol and methasterone are not estrogens, progestins, or corticosteroids and these anabolic steroids are not exempt from
control on this basis.

(D) Not Dehydroepiandrosterone

Dehydroepiandrosterone, also known as DHEA, is exempt from control as an anabolic steroid by definition (21 U.S.C. 802(41)(A)). Prostanozol and
methasterone are not dehydroepiandrosterone and therefore, are not exempt from control on this
basis.

Comments Received

On November 23, 2011, DEA published a NPRM (76 FR 72355) to classify prostanozol and methasterone
as Schedule III anabolic steroids. The proposed rule provided an opportunity for all interested persons to submit their comments on or before January 23, 2012. In response to the request, DEA
received three comments.

Comment: One commenter disagreed that anabolic steroids, and in particular those encountered in dietary supplements, should be placed in
Schedule III of the CSA. He indicated that classifying these substances as
Schedule III anabolic steroids wouldforce the public to procure other, nonregulated and unsafe substitutes from illicit sources in the future, and that DEA should employ an alternate method of regulation.

DEA Response: DEA disagrees with
this comment. As stated in the NPRM and this Final Rule, these substances
were found to be similar in structure and pharmacology to testosterone through substantive scientific evaluation and investigation. Further, the United States Food and Drug Administration has issued multiple warnings regarding dietary supplements, especially concerning contamination through novel synthetic steroids that do not qualify as dietary ingredients.

Regarding the commenter’s request for alternative regulation of these substances. DEA regulates the manufacture, importation, export, distribution, and sale of controlled substances for medical, scientific, or other legitimate uses pursuant to the
CSA. These substances have not been approved as safe for human consumption and, despite the
commenter’s unsubstantiated and factually inaccurate claims of their benefits, should neither be consumed nor should other unapproved substances ever be sought from any source, illicit or otherwise.

The additional remarks this commenter made regarding a perceived


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disparity between men and women in access to hormonal products, and other perceived problems with the regulation of substances by the government, are not germane to this rulemaking.

Comment: Two separate commenters agreed placement of these two
substances under the CSA was appropriate as provided per the
Anabolic Steroid Control Act of 2004.

DEA Response: DEA appreciates the support for this rulemaking. As discussed above, prostanozol and
methasterone are similar in structure and pharmacology to testosterone and are not approved for human consumption. DEA believes their placement into Schedule III as anabolic steroids will provide the appropriate safeguards to limit their availability to and prevent their abuse by the public.

Conclusion

After evaluation of the statutory
factors above and consideration of the comments to the NPRM, DEA concludes that prostanozol and methasterone meet
the CSA definition of ‘‘anabolic steroid’’ because each substance is: (A) Chemically related to testosterone; (B) pharmacologically related to testosterone; (C) not an estrogen, progestin, or a corticosteroid; and (D) not DHEA (21 U.S.C. 802(41)). Once a
substance is determined to be an anabolic steroid, DEA has no discretion regarding the placement of these
substances into Schedule III of the CSA.

Impact of Classification as Anabolic
Steroids

With the publication of this Final Rule, DEA classifies prostanozol (17 b

hydroxy-5 a-androstano[3,2-c]pyrazole) and methasterone (2 a ,17 a-dimethyl-5 aandrostan-17 b -ol-3-one) as Schedule III anabolic steroids subject to the CSA. Any person who manufactures, distributes, dispenses, imports, or exports prostanozol or methasterone, or who engages in research or conducts instructional activities with respect to these two substances, will be required to obtain a Schedule III registration in
accordance with the CSA and its implementing regulations.

As of the effective date of this Final Rule, the manufacture, import, export, distribution, or sale of prostanozol or methasterone, except by DEA registrants, is a violation of the CSA that may result in imprisonment and fines (see, e.g., 21 U.S.C. 841 and 960). Possession of these two steroids, unless legally obtained, is also subject to criminal penalties pursuant to 21 U.S.C.

844.

Manufacturers and importers of these two substances will be required to register with DEA and will be permitted to distribute these substances only to other DEA registrants. Only persons registered as dispensers will be allowed to dispense these substances to end users. The CSA defines a practitioner as ‘‘a physician, dentist, veterinarian, scientific investigator, pharmacy, hospital, or other person licensed, registered, or otherwise permitted, by the United States or the jurisdiction in which he practices or does research, to distribute, dispense, conduct research with respect to, administer, or use in teaching or chemical analysis, a
controlled substance in the course of professional practice or research.’’ 21 U.S.C. 802(21). At present, there are no approved medical uses for these two
substances. Until a manufacturer applies to the FDA and gains approval for products containing these substances, no person may dispense them in response to a prescription.

Additionally, these two substances may only be imported for medical, scientific, or other legitimate uses (21 U.S.C. 952(b)) under an import declaration filed with DEA (21 CFR 1312.18). Importation of these substances will be illegal unless the person importing these substances is registered with DEA as an importer or researcher and files the required declaration for each shipment. Any individual who purchases either of these substances directly from foreign companies and has them shipped to the
United States will be considered to be importing even if the steroids are intended for personal use. Illegal importation of these substances will be a violation of the CSA that may result in imprisonment and fines pursuant to

21 U.S.C. 960.

Requirements for Handling Substances
Defined as Anabolic Steroids

As of the effective date of this Final Rule, prostanozol and methasterone are subject to CSA regulatory controls and the administrative, civil, and criminal sanctions applicable to the manufacture, distribution, dispensing, importation, and exportation of a Schedule III controlled substance, including the following:

Registration. Any person who manufactures, distributes, dispenses, imports, exports, or engages in research
or conducts instructional activities with
a substance defined as an anabolic steroid, or who desires to engage in such activities, will be required to be registered to conduct such activities
with Schedule III controlled substances
in accordance with 21 CFR Part 1301.

Security. Substances defined as anabolic steroids will be subject to Schedule III security requirements and will be required to be manufactured, distributed, and stored in accordance with 21 CFR 1301.71, 1301.72(b), (c), and (d), 1301.73, 1301.74, 1301.75(b) and (c), 1301.76 and 1301.77.

Labeling and Packaging. All labels and labeling for commercial containers
of substances defined as anabolic steroids will be required to comply with the requirements of 21 CFR 1302.03–

1302.07.

Inventory. Every registrant required to keep records and who possesses any quantity of any substance defined as an anabolic steroid will be required to keep an inventory of all stocks of the substances on hand pursuant to 21 U.S.C. 827 and 21 CFR 1304.03, 1304.04 and 1304.11. Every registrant who desires registration in Schedule III for any substance defined as an anabolic steroid will be required to conduct an inventory of all stocks of the substances on hand at the time of registration.

Records. All registrants will be required to keep records, as generally provided in 21 U.S.C. 827(a) and specifically pursuant to 21 CFR 1304.03, 1304.04, 1304.05, 1304.21, 1304.22, and

1304.23.

Prescriptions. All prescriptions for
these Schedule III substances or for products containing these Schedule III substances, if approved in the future by FDA, will be required to be issued pursuant to 21 U.S.C. 829(b) and 21 CFR
1306.03–1306.06 and 1306.21–1306.27. All prescriptions for these Schedule III compounds or for products containing these Schedule III substances, if authorized for refilling, will be limited
to five refills within six months of the date of issuance of the prescription. Controlled substance dispensing via the Internet will have to comply with 21 U.S.C. 829(e).

Importation and Exportation. All importation and exportation of any
substance defined as an anabolic steroid will be required to be in compliance with 21 U.S.C. 952(b), 953(e), and 21

CFR Part 1312.

Disposal. Persons who possess
substances that become classified as
anabolic steroids and who wish to dispose of them rather than becoming registered to handle them should
contact their local DEA Diversion field office for assistance in disposing of these substances legally pursuant to 21
CFR 1307.21. The DEA Diversion field office will provide the person with instructions regarding the disposal. A
list of local DEA Diversion field offices may be found at http:// www.deadiversion.usdoj.gov.

Criminal Liability. Any activity with any substance defined as an anabolic


### 44461 Federal Register / Vol. 77, No. 146 / Monday, July 30, 2012 / Rules and Regulations

steroid not authorized by, or in violation of, the Controlled Substances Act or the Controlled Substances Import and Export Act will be unlawful.

Regulatory Analyses

Regulatory Flexibility Act

The Administrator hereby certifies that this rulemaking has been drafted in accordance with the Regulatory Flexibility Act (5 U.S.C. 601–612). This regulation will not have a significant economic impact on a substantial
number of small entities. As of March 2010, DEA had identified approximately 75 dietary supplements that were currently or had been promoted for building muscle and increasing strength that purported to contain prostanozol or methasterone. Thirteen dietary supplements were purported to contain prostanozol and 62 dietary supplements were purported to contain methasterone. These dietary supplements are marketed and sold over
the Internet.

The manufacturers and distributors of dietary supplements purported to contain prostanozol and methasterone also sell a variety of other dietary supplements. DEA has identified a
substantial number of Internet distributors that sell these dietary supplements. However, these distributors also sell a variety of other nutritional products. Without information on the percentage of revenues derived from these dietary supplements, DEA is not able to determine the economic impact of the removal of these dietary supplements
alone on the business of the firms.
These steroids have been the focus of warning letters issued by the FDA. However, products continue to be marketed despite these warnings. DEA has not been able to identify any
chemical manufacturers that are currently using these substances as intermediates in their manufacturing process(es). As of March 2010, DEA had
identified 13 chemical manufacturers
and distributors that sell at least one of
the two steroids. Most of these companies are located in China and sell a variety of other anabolic steroids. DEA notes that, as the vast majority of entities handling these substances are Internet based, it is virtually impossible to accurately quantify the number of persons handling these substances at any given time. DEA has not identified any company based in the United States
that manufactures or distributes these substances. DEA notes, upon placement into Schedule III, these substances may be used for analytical purposes. These companies are registered with DEA and are already in compliance with the CSA and DEA implementing regulations regarding the handling of Schedule III
substances.

Executive Orders 12866 and 13563

This rulemaking has been drafted in accordance with the principles of Executive Order 12866, 1(b), as reaffirmed by Executive Order 13563. This rule is not a significant regulatory action but has been reviewed by the Office of Management and Budget. As discussed above, the effect of this rule will be to remove products containing
these substances from the over-thecounter marketplace. DEA has no basis for estimating the size of the market for these products. DEA notes, however, that virtually all of the substances are imported. According to U.S. International Trade Commission data, the import value of all anabolic steroids in 2009 was $5.9 million. These two
substances would be a subset of those imports. The total market for products containing these substances, therefore, is probably quite small. Moreover, DEA believes that the importation of these two substances is for illegitimate

purposes.

The benefit of controlling these
substances is to remove from the marketplace substances that have dangerous side effects and no legitimate
medical use in treatment in the United States. As discussed in detail above, these substances can produce serious
health effects in adolescents and adults.
If medical uses for these substances are developed and approved, the drugs
would be available as Schedule III controlled substances in response to a prescription issued by a medical professional for a legitimate medical purpose. Until that time, however, this action will bar the importation, exportation, and sale of these two substances except for legitimate
research or industrial uses.

Executive Order 12988

This regulation meets the applicable standards set forth in Sections 3(a) and 3(b)(2) of Executive Order 12988 Civil Justice Reform.

Executive Order 13132

This rulemaking does not preempt or modify any provision of State law; nor does it impose enforcement responsibilities on any State; nor does it diminish the power of any State to enforce its own laws. Accordingly, this rulemaking does not have federalism implications warranting the application
of Executive Order 13132. Executive Order 13175

This rule will not have tribal implications and will not impose substantial direct compliance costs on Indian tribal governments.

Paperwork Reduction Act

This rule regulates two anabolic steroids, which are neither approved for medical use in humans nor approved for
administration to cattle or other nonhumans. Only chemical manufacturers who may use these substances as chemical intermediates for the synthesis of other steroids would be required to register with DEA under the CSA. However, DEA has not been able to identify any chemical manufacturers that are currently using these substances as intermediates in their manufacturing processes. Thus DEA does not expect this rule to impose any additional paperwork burden on the regulated industry.

Unfunded Mandates Reform Act of 1995

This rule will not result in the expenditure by state, local, and tribal governments, in the aggregate, or by the private sector, of $136,000,000 or more (adjusted for inflation) in any one year, and will not significantly or uniquely affect small governments. Therefore, no actions were deemed necessary under the provisions of the Unfunded Mandates Reform Act of 1995, 2 U.S.C.

1532.

List of Subjects in 21 CFR Part 1300

Chemicals, Drug traffic control.
For the reasons set out above, 21 CFR part 1300 is amended as follows:

**PART 1300—DEFINITIONS**

■ 1. The authority citation for part 1300
continues to read as follows:

Authority: 21 U.S.C. 802, 821, 829, 871(b), 951, 958(f).

■ 2. In § 1300.01, the definition of
Anabolic steroid under paragraph (b) is amended by:

■ A. Redesignating paragraphs (32) through (63) as (33) through (64),

■ B. Adding a new paragraph (32),

■ C. Further redesignating newly designated paragraphs (58) through (64) as (59) through (65), and

■ D. Adding new paragraph (58).

The additions read as follows:

**§ 1300.01 Definitions relating to controlled**
**substances.**

* * * * *

(b) * * * Anabolic steroid * * * (32) Methasterone (2 a ,17 a-dimethyl5 a-androstan-17 b -ol-3-one)

* * * * *


### 44462 Federal Register / Vol. 77, No. 146 / Monday, July 30, 2012 / Rules and Regulations

(58) Prostanozol (17 b -hydroxy-5 aandrostano[3,2-c]pyrazole)

* * * * *

Dated: July 13, 2012.
Michele M. Leonhart,

Administrator.

Note: The following appendix will not appear in the Code of Federal Regulations.

List of References

Biskind, G.R. and Meyer, M.A. (1941). The comparative androgenic potency of testosterone, methyltestosterone and testosterone propionate administered in pellet form. Endocrinology, 28 (2): 217–

221. Brower, K.J. (2002). Anabolic steroid abuse and dependence. Current Psychiatry Reports, 4: 377–387. Clinton, R.O., Manson, A.J., Stonner, F.W., Neumann, H.C., Christiansen, R.G., Clarke, R.L., Ackerman, J.H., Page, D.F., Dean, J.W., Dickinson, W.B., and Carabateas, C. (1961). Steroidal[3,2- c]pyrazoles. II. Androstanes, 19–
Norandrostanes and their Unsaturated Analogs. Journal of the American Chemical Society, 83: 1478–1491. Cunningham, G.R., Tindall, D.J., Lobl, T.J., Campbell, J.A., and Means, A.R. (1981). Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP). Steroids, 38 (3):

243–262. Dorfman, R.I. and Dorfman, A.S. (1963). The assay of subcutaneously injected androgens in the castrated rat. ACTA Endocrinologica, 42: 245–253. Dorfman, R.I. and Kincl, F.A. (1963). Relative potency of various steroids in an anabolic-androgenic assay using the
castrated rat. Endocrinology, 72: 259–

266. Dorfman, R.I., Kincl, F.A., and Ringold, H.J. (1961). Anti-estrogen assay of neutral steroids administered by subcutaneous injection. Endocrinology, 68: 17–24. Duax, W.L., Griffin, J.F., Weeks, C.M., and Wawrzak, Z. (1988). The mechanism of action of steroid antagonists: insights from crystallographic studies. Journal of Steroid Biochemistry and Molecular Biology, 31: 481–492. Eisenberg, E., Gordan, G.S. and Elliott, H.W. (1949). Testosterone and tissue respiration of the castrate male rat with possible test for myotrophic activity. Endocrinology, 45 (2): 113–119. Evans, N.A. (2004). Current concepts in anabolic-androgenic steroids. The American Journal of Sports Medicine,

32 (2): 534–542. Fragkaki, A.G., Angelis, Y.S., Koupparis, M., Tsantili-Kakoulidou, A., Kokotos, G., Georgakopoulos, C. (2009). Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied
modifications in the steroidal structure. Steroids, 74: 172–197. Hall, R.C.W and Hall, R.C.W. (2005). Abuse of supraphysiological doses of anabolic steroids. Southern Medical Journal,

98 (5): 550–555. Hall, R.C.W, Hall, R.C.W., and Chapman, M.J. (2005). Psychiatric complications of
anabolic steroid abuse. Psychosomatics,

46 (4): 285–290. Hartig, P.C., Bobseine, K.L., Britt, B.H., Cardon, M.C., Lambright, C.R., Wilson, V.S., and Gray, L.E. (2002). Development of two androgen receptor assays using
adenoviral transduction of MMTV–Luc reporter and/or hAR for endocrine screening. Toxicological Sciences, 66:

82–90. Jasiurkowski, B., Raj, J., Wisinger, D., Carlson, R., Zou, L., and Nadir, A. (2006). Cholestatic jaundice and IgA nephropathy induced by OTC muscle building agent superdrol. American Journal of Gastroenterology, 101 (11):

2659–2662. Jordan, V.C., Mittal, S., Gosden, B., Koch, R.,and Lieberman, M.E. (1985). Structureactivity relationships of estrogen. Environmental Health Perspectives, 61:

97–110. Kanayama, G., Hudson, J.I., and Pope, H.G. (2008). Long-term psychiatric andmedical consequences of anabolicandrogenic steroid abuse: a looming public health concern? Drug and Alcohol Dependence, 98: 1–12. Kicman, A.T. (2008). Pharmacology of
anabolic steroids. British Journal of Pharmacology, 154: 502–521. Kincl, F.A. and Dorfman, R.I. (1964). Anabolic-androgenic potency of various steroids in a castrated rat assay. Steroids,

3: 109–122. Krishnan, P.V., Feng, Z–Z., Gordon, S.C. (2009). Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements. Journal of Clinical Gastroenterology, 43 (7): 672–675. Miller, D.D., Brueggemeier, R.W., and Dalton, J.T. (2002). Adrenocorticoids. In D.A. Williams and T.L. Lemke (Eds.) Foye’s Principle of Medicinal Chemistry (5th ed.). Philadelphia, Lippincott Williams
and Wilkins. Nasr, J. and Ahmad, J. (2009). Severe
cholestasis and renal failure associated with the use of the designer steroid superdrol (methasteron): a case report
and literature review. Digestive Diseases and Science, 54: 1144–46. Nelson, D., Greene, R.R. and Wells, J.A. (1940). Variations in the effectiveness of percutaneously applied androgens in the

rat. Endocrinology, 26: 651–655. Parkinson, A.B. and Evans, N.A. (2005). Anabolic androgenic steroids: a survey of

500 users. Medicine & Science in Sports & Exercise, 644–651. Quaglio, G., Fornasiero, A., Mezzelani, P., Moreschini, S., Lugoboni, F., and Lechi, A. (2009). Anabolic steroids: dependence and complications of chronic use. Internal and Emergency Medicine, 4:

289–296. Ringold, H.J., Batres, E., Halpern, O., and Necoechea, E. (1959). Steroids. CV. 2–Methyl and 2-hydroxymethyleneandrostane derivatives. Journal of the American Chemical Society, 81: 427–

432. Ringold, H.J. and Rosenkranz, G. (1956). Steroids. LXXXIII. Synthesis of 2-methyl and 2,2-dimethyl hormone analogs. Journal of Organic Chemistry, 21: 1333–

1335. Sato, S.M., Schulz, K.M., Sisk, C.L., and Wood, R.I. (2008). Adolescents and androgens, receptors, and rewards. Hormones and Behavior, 53: 647–658. Scow, R.O. (1952). Effect of testosterone on

muscle and other tissues and on carcass composition in hypophysectomized, thyroidectomized, and gonadectomized

male rats. Endocrinology, 51: 42–51. Skarberg, K., Nyberg, F., and Engstrom, I. (2009). Multisubstance use as a feature of addiction to anabolic-androgenic

steroids. European Addiction Research,

15: 99–106. Shah, N.L., Zacharias, I., Khettry, U., Afdhal, N., and Gordon, F.D. (2008).

Methasteron-associated cholestic liver injury: clinicopathologic findings in 5

cases. Clinical Gastroenterology and Hepatology, 6 (2): 255–258. Singh, V., Rudraraju, M., Carey, E.J., Byrne, T.J., Vargas, H.E., Williams, J.E., Balan, V., and Douglas, D.D. (2009). Severehepatotoxicity caused by a methasteroncontaining, performance-enhancing supplement. Journal of Clinical Gastroenterology, 43 (3): 287. Trenton, A.J. and Currier, G.W. (2005).

Behavioural manifestations of anabolic

steroid use. CNS Drugs, 19 (7): 571–595. Vida, J.A. (1969). Androgens and Anabolic Agents: Chemistry and Pharmacology.

New York: Academic Press. Wainman, P. and Shipounoff, G.C. (1941).

The effects of castration and testosterone propionate on the striated perineal

musculature in the rat. Endocrinology,

29 (6): 975–978. Williams, C.L. and Stancel, G.M. (1996). Estrogens and Progestins. In J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A. Goodman Gilman (Eds.) Goodman and Gilman’s The Pharmacological Basis of Therapeutics (9th ed.). New York: McGraw-Hill, 1411–

1440. Wilson, V.S., Bobseine, K., Lambright, C.R., and Gray, L.E. (2002). A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists. Toxicological Sciences, 66: 69–81. Zaffaroni, A. (1960). The effect of alkyl- and electronegative-group substitution on steroidal hormone activity. Acta Endrocrinologica, 34 (2 Suppla): S139–

S145.

[FR Doc. 2012–18495 Filed 7–27–12; 8:45 am]

**BILLING CODE 4410–09–P**