Classification of Three Steroids as Schedule III Anabolic Steroids Under the Controlled Substances Act, 63603-63610 [E9-28572]

Agencies

• Drug Enforcement Administration
• Department of Justice

[Federal Register Volume 74, Number 232 (Friday, December 4, 2009)]
[Rules and Regulations]
[Pages 63603-63610]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E9-28572]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1300

[Docket No. DEA-285F]
RIN 1117-AB17


Classification of Three Steroids as Schedule III Anabolic 
Steroids Under the Controlled Substances Act

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

ACTION: Final rule.

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SUMMARY: With the issuance of this final rule, the Deputy Administrator 
of the Drug Enforcement Administration (DEA) classifies the following 
three steroids as ``anabolic steroids'' under the Controlled Substances 
Act (CSA): Boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione. 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: January 4, 2010.

FOR FURTHER INFORMATION CONTACT: Christine A. Sannerud, Ph.D., Chief, 
Drug and Chemical Evaluation Section, Drug Enforcement Administration, 
8701 Morrissette Drive, Springfield, VA 22152, (202) 307-7183.

SUPPLEMENTARY INFORMATION:

I. Background Information

    In a Notice of Proposed Rulemaking (NPRM) (73 FR 22294) published 
April 25, 2008, the DEA proposed the classification of three steroids 
as schedule III anabolic steroids under the CSA. These three steroids 
included boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione. With the publication of this Final Rule, DEA 
classifies these three steroids as schedule III anabolic steroids. 
Background information in support of this Final Rule is provided below.
    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 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 can be administratively 
classified as an anabolic steroid through the rulemaking process by 
adding the steroid to the regulatory definition of an anabolic steroid 
in 21 CFR 1300.01(b)(4).
    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 the criteria is considered an anabolic 
steroid and must be listed as a schedule III controlled substance. DEA 
finds that boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione meet this definition of anabolic steroid and is 
adding them to the list of anabolic steroids in 21 CFR 1300.01(b)(4).
    Anabolic steroids are a class of drugs with a basic steroid ring 
structure that produces anabolic and androgenic effects. The 
prototypical anabolic steroid is testosterone. Anabolic effects include 
promoting the growth of muscle. The androgenic effects consist of 
promoting the development of male secondary sexual characteristics such 
as facial hair, deepening of the voice, and thickening of the skin.
    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.,

[[Page 63604]]

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 
three substances that DEA is classifying as anabolic steroids under the 
definition set forth under 21 U.S.C. 802(41)(A). Moreover, DEA has not 
identified any chemical manufacturers currently using these substances 
as intermediates in their manufacturing process(es).
    Adverse effects are associated with the use or abuse of anabolic 
steroids. These effects depend on several factors (e.g., age, sex, 
anabolic steroid used, the amount used, and the duration of use). In 
early adolescence, the use of testosterone and other anabolic steroids 
that have estrogenic effects can cause premature closure of the growth 
plates in long bones resulting in a permanently stunted growth. In 
adolescent boys, anabolic steroid use can cause precocious sexual 
development. In both girls and women, anabolic steroid use induces 
permanent physical changes such as deepening of the voice, increased 
facial and body hair growth, and the lengthening of the clitoris. In 
men, anabolic steroid use can cause shrinkage of the testicles, 
decreased sperm count, and sterility. Gynecomastia (i.e., enlargement 
of the male breast tissue) can develop with the use of those anabolic 
steroids with estrogenic actions. In both men and women, anabolic 
steroid use can damage the liver and can cause high cholesterol levels, 
which may increase the risk of strokes and heart attacks. Furthermore, 
anabolic steroid use is purported to induce psychological effects such 
as aggression, increased feelings of hostility, and psychological 
dependence and addiction. Upon abrupt termination of long-term anabolic 
steroid use, a withdrawal syndrome may appear including severe 
depression.

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

    With the issuance of this Final Rule, DEA is classifying boldione, 
desoxymethyltestosterone, and 19-nor-4,9(10)-androstadienedione 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 a 
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. DEA discussed its evaluation of the 
chemical relationship of boldione, desoxymethyltestosterone, and 19-
nor-4,9(10)-androstadienedione in the NPRM published April 25, 2008 (73 
FR 22294). A Structure Activity Relationship (SAR) evaluation for each 
of the substances compared the chemical structure of the steroid to 
that of testosterone, as substances with a structure similar to that of 
testosterone are predicted to possess comparable pharmacological and 
biological activity.
    Boldione is also known by the following chemical name: Androsta-
1,4-diene-3,17-dione. DEA has determined that the chemical structure of 
boldione is chemically related to that of testosterone. The chemical 
structure of boldione differs from testosterone by only the following 
structural features: A ketone group at carbon 17 and a double bond 
between the carbon 1 and carbon 2. The human body would be expected to 
metabolize the ketone group at carbon 17 into a hydroxyl group that is 
present on testosterone (Payne and Hales, 2004; Peltoketo et al., 1999; 
Moghrabi and Andersson, 1998). Furthermore, the scientific literature 
reports that the additional double bond at carbon 1 in boldione does 
not significantly decrease the anabolic activity of the substance 
(Vida, 1969). Boldione is an anabolic steroid precursor, being 
metabolized by the body into boldenone (Galletti and Gardi, 1971; Kim 
et al., 2006), which is a schedule III anabolic steroid (21 U.S.C. 
802(41)(A)(vi)).
    Desoxymethyltestosterone (DMT) is also known by the following 
names: 17[alpha]-Methyl-5[alpha]-androst-2-en-17[beta]-ol; and madol. 
DEA has determined that the chemical structure of 
desoxymethyltestosterone is chemically related to testosterone. The 
chemical structure of desoxymethyltestosterone differs from 
testosterone by the following four structural features: The lack of a 
ketone group at the third carbon, a double bond between the second and 
third carbon, the lack of a double bond between the fourth and fifth 
carbon, and a methyl group at carbon 17. Each of these four chemical 
features is known through the scientific literature not to eliminate 
the anabolic and androgenic activity of the substance (Brueggemeir et 
al., 2002; Vida, 1969).
    19-Nor-4,9(10)-androstadienedione is also known by the following 
chemical names: 19-Norandrosta-4,9(10)-diene-3,17-dione; and estra-
4,9(10)-diene-3,17-dione. DEA has determined that the chemical 
structure of 19-nor-4,9(10)-androstadienedione is chemically related to 
testosterone. The chemical structure of 19-nor-4,9(10)-
androstadienedione differs from testosterone by the following three 
structural features: A ketone group at carbon 17, the absence of a 
methyl group at carbon 19, and a double-bond between carbon 9 and 
carbon 10. The human body would be expected to metabolize the ketone 
group at carbon 17 into a hydroxyl group like that present in 
testosterone (Payne and Hales, 2004; Peltoketo et al., 1999; Moghrabi 
and Andersson, 1998). Furthermore, the scientific literature reports 
that both the absence of the methyl group at carbon 19 and the 
additional double bond in 19-nor-4,9(10)-androstadienedione increase 
the anabolic activity of the substance (Vida, 1969).

(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, testicular 
atrophy assay, gonadotropin suppression 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 examining the effects of a 
steroid as compared to testosterone is to perform the testosterone 
sensitive assays, ventral prostate assay, seminal vesicle assay, and 
levator ani assay in rats. Certain male accessory organs (i.e., the 
ventral prostate, seminal vesicles, and levator ani muscle) 
specifically need 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 administered to rats following castration to maintain the 
normal weight and size of all three

[[Page 63605]]

testosterone sensitive tissues (Biskind and Meyer, 1941; Dorfman and 
Dorfman, 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 tissues in castrated rats.
    Testicular Atrophy Assay: Administering testosterone to non-
castrated rats causes a decrease in serum levels of gonadotropins 
(i.e., luteinizing hormone [LH] and follicle stimulating hormone [FSH]) 
from normal levels. Gonadotropins are pituitary hormones that affect 
the size and function of the testes. The suppression of these 
gonadotropins by excess testosterone results in a significant decrease 
in the size and weight of the testes (Boris et al., 1970; McEuen et 
al., 1937; Moore and Price, 1938). Accordingly, a steroid with 
testosterone-like activity will also significantly diminish the size 
and weight of the testes.
    Gonadotropin Suppression Assay: The castration of rats causes a 
substantial increase in the serum levels of gonadotropins (i.e., LH and 
FSH) above normal levels due to the removal of the principal source of 
endogenous testosterone (Gay and Bogdanove, 1969; Swerdloff et al., 
1972, 1973; Swerdloff and Walsh, 1973). The administration of 
testosterone to castrated animals suppresses the increase in the serum 
levels of gonadotropins (Gay and Bogdanove, 1969; Swerdloff et al., 
1972; Swerdloff and Walsh, 1973; Verjans et al., 1974). The 
administration of anabolic steroids with testosterone-like activity 
will also prevent this increase in serum levels of LH and FSH.
    Androgen Receptor Binding and Efficacy Assay: Androgen receptor 
binding and efficacy assays are also used to demonstrate that the 
activity of a steroid is similar to that of testosterone. Testosterone 
produces its anabolic effects subsequent to binding to and activating 
the androgen receptor. Different cell-based assays can compare 
candidate steroids to testosterone for their ability to bind to and 
activate androgen receptors.
    There are several different types of assays used to establish 
androgen receptor binding and efficacy. In one assay, C3H10T1/2 stem 
cells express androgen receptors and are used to assess steroids for 
their ability to bind and activate the androgen receptor (Jasuja et 
al., 2005a,b; Singh et al., 2003). In these stem cells, the 
translocation of the androgen receptor to the nucleus of the cell in 
the presence of the ligand (e.g., testosterone or its active metabolite 
dihydroxytestosterone) confirms that the ligand bound to the androgen 
receptor and activated the downstream signaling cascade. When 
activated, the C3H10T1/2 stem cells differentiate into skeletal muscle 
cells as demonstrated by the increase in the expression of muscle 
specific proteins (i.e., myogenic determination transcription factor 
[MyoD] and myosin heavy chain [MHC]). Another assay uses human breast 
cancer cells genetically altered to contain a specific reporter gene 
(e.g., luciferase gene) regulated by androgen receptor activation 
(Hartig et al., 2002; Wilson et al., 2002). The expression of a 
bioluminescent protein (e.g., luciferase) signals both androgen 
receptor binding and activation.
    Results of the Androgenic and Anabolic Activity Assays: As 
discussed in the NPRM, in January 2006, DEA reviewed the published 
scientific literature for pharmacological data on the anabolic and 
androgenic activity of boldione, desoxymethyltestosterone, and 19-nor-
4,9(10)-androstadienedione using the assays described above. As 
discussed further below, there was sufficient information on the 
pharmacology of desoxymethyltestosterone in the reviewed scientific 
literature to determine that desoxymethyltestosterone is 
pharmacologically related to testosterone (i.e., produces biological 
effects similar to those of testosterone). However, the published 
literature contained insufficient pharmacological data to determine 
whether boldione and 19-nor-4,9(10)-androstadienedione were 
pharmacologically related to testosterone. Consequently, as discussed 
further below and in the NPRM, DEA sponsored pharmacological studies 
involving several different androgenic and anabolic activity assays to 
generate the data necessary to make this determination.
    Androgenic and anabolic activity assay results indicate that 
boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione have similar pharmacological activity as 
testosterone.
Boldione
    DEA sponsored a study \1\ by the Veteran's Administration Puget 
Sound Health Care System to determine the anabolic and androgenic 
effects of boldione in intact and castrated rats (Matsumoto and Marck, 
2006). The results of these studies were compared to the results of a 
study by the same laboratory using a similar protocol to characterize 
the androgenic and anabolic effects of testosterone (Marck et al., 
2003). Boldione administered to castrated male rats by silastic 
capsules implanted under the skin prevented atrophy of the ventral 
prostate, seminal vesicles, levator ani muscle, and the rise in serum 
gonadotropin (LH and FSH) associated with castration. Boldione 
administration also produced testicular atrophy in intact rats. Another 
DEA sponsored study \2\ at a laboratory at Boston University examined 
the ability of boldione to bind to the androgen receptor and to cause 
the differentiation of C3H10T1/2 stem cells into muscle cells (Bhasin, 
2005). All of these effects caused by boldione in C3H10T1/2 stem cells 
were comparable to those of testosterone as established in experiments 
using the same or similar methodology (Singh et al., 2003). 
Collectively, the evidence indicates that the pharmacology of boldione 
is similar to testosterone.
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    \1\ The study by the Veteran's Administration Puget Sound Health 
Care System may be found at https://www.regulations.gov in the 
electronic docket associated with this rulemaking.
    \2\ The study by Boston University may be found at https://www.regulations.gov in the electronic docket associated with this 
rulemaking.
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Desoxymethyltestosterone
    Desoxymethyltestosterone was administered subcutaneously, orally, 
or intramuscularly to castrated rats (Dorfman and Kincl, 1963; Kincl 
and Dorfman, 1964; Nutting et al., 1966). By all three routes of 
administration, desoxymethyltestosterone prevented the atrophy of 
ventral prostate, seminal vesicles, and levator ani muscle. 
Desoxymethyltestosterone also induced the expression of the 
bioluminescent protein luciferase in CAMA-1 breast cancer cells 
signaling androgen receptor binding and activation (Ayotte et al., 
2006). Collectively, the evidence indicates that the pharmacology of 
desoxymethyltestosterone is similar to testosterone.
19-Nor-4,9(10)-Androstadienedione
    As discussed in the NPRM, DEA sponsored a study \3\ by the 
Veteran's Administration Puget Sound Health Care System to determine 
the anabolic and androgenic effects of 19-nor-4,9(10)-
androstadienedione in intact and castrated rats (Matsumoto and Marck, 
2006). The results of these studies were compared to the results of a 
study by the same laboratory using a similar protocol to characterize 
the androgenic and anabolic effects of testosterone (Marck et al., 
2003). 19-Nor-4,9(10)-

[[Page 63606]]

androstadienedione administered to castrated male rats by silastic 
capsules implanted under the skin prevented the atrophy of the ventral 
prostate, seminal vesicles, levator ani muscle, and the rise in serum 
gonadotropins (LH and FSH) associated with castration. Another DEA 
sponsored study at a laboratory at Boston University \4\ examined the 
ability of 19-nor-4,9(10)-androstadienedione to bind to the androgen 
receptor and to cause the differentiation of C3H10T1/2 stem cells into 
muscle cells (Bhasin, 2005). 19-Nor-4,9(10)-androstadienedione induced 
the translocation of the androgen receptor to the nucleus of the 
C3H10T1/2 stem cells, demonstrating binding affinity and efficacy for 
the androgen receptor. All of these effects caused by 19-nor-4,9(10)-
androstadienedione in C3H10T1/2 stem cells were comparable to those of 
testosterone as established in experiments using the same or similar 
methodology (Singh et al., 2003). Collectively, the evidence indicates 
that the pharmacology of 19-nor-4,9(10)-androstadienedione is similar 
to testosterone.
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    \3\ The study by the Veteran's Administration Puget Sound Health 
Care System may be found at https://www.regulations.gov in the 
electronic docket associated with this rulemaking.
    \4\ The study by Boston University may be found at https://www.regulations.gov in the electronic docket associated with this 
rulemaking.
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(C) Not Estrogens, Progestins, and Corticosteroids

    As discussed in the NPRM, DEA has determined that boldione, 
desoxymethyltestosterone, and 19-nor-4,9(10)-androstadienedione 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 because the chemical structure can be related to its 
pharmacological and biological activity. DEA found that the three 
substances lacked 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[beta]-alkyl group) (Williams and Stancel, 1996), or 
corticosteroidal activity (e.g., 17-ketone group or 11[beta]-hydroxyl 
group) (Miller et al., 2002).

(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)). Boldione, 
desoxymethyltestosterone, and 19-nor-4,9(10)-androstadienedione are not 
dehydroepiandrosterone and are therefore not exempted from control on 
this basis.

III. Comments Received

    On April 25, 2008, DEA published a NPRM (73 FR 22294) proposing to 
classify boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione as schedule III anabolic steroids. The proposed rule 
provided an opportunity for all interested persons to submit their 
comments on or before June 24, 2008. In response to the NPRM, DEA 
received one comment from a consulting firm that described itself as 
``[assisting] dietary supplement companies in understanding 
governmental regulations while facilitating their growth.'' These 
comments are summarized and responded to below.
    Desoxymethyltestosterone: The commenter indicated that the 
scientific literature cited in the NPRM pertaining to 
desoxymethyltestosterone was sufficient to meet the four criteria that 
must be satisfied for DEA to designate the steroid as a schedule III 
anabolic steroid. DEA agrees with this conclusion. Therefore, DEA is 
placing desoxymethyltestosterone into schedule III as an anabolic 
steroid as proposed.
    Chemical relationship of boldione and 19-nor-4,9(10)-
androstadienedione to testosterone: The commenter claimed that DEA 
failed to show that boldione and 19-nor-4,9(10)-androstadienedione are 
chemically related to testosterone. The commenter claimed that both 
steroids were distinctly different from testosterone in that each lacks 
the 17[beta]-hydroxyl, which is present in testosterone. The commenter 
noted that DEA did not provide any authority for the claim made that 
``the human body would be expected to metabolize the ketone group at 
carbon 17 into a hydroxyl group that is present on testosterone.''
    DEA Response: DEA disagrees with this comment. The presence of the 
ketone group at carbon 17 in boldione and 19-nor-4,9(10)-
androstadienedione is consistent with both steroids being chemically 
related to testosterone, which has a hydroxyl group instead of a ketone 
group at carbon 17. The enzyme 17[beta]-hydroxysteroid dehydrogenase is 
known to be responsible for catalyzing the conversion of the 17-ketone 
group to a 17[beta]-hydroxyl group in steroids such as androgens and 
estrogens. This enzyme, in various isoenzymatic forms, has been 
documented in many body tissues in humans and various animal species 
(Payne and Hales, 2004; Peltoketo et al., 1999; Moghrabi and Andersson, 
1998; Melewich et al., 1981). Considering the wide distribution of this 
enzyme in tissues of humans and animals, it is expected that this 
enzyme would convert the 17-ketone group found in boldione and 19-nor-
4,9(10)-androstadienedione to the 17[beta]-hydroxyl group, thereby 
producing boldenone and 19-nor-4,9(10)-androstadiene-3-one-17[beta]-ol. 
Direct evidence that this conversion takes place comes from two studies 
showing that boldione is converted to boldenone, a schedule III 
anabolic steroid, in the human body (Galletti and Gardi, 1971; Kim et 
al., 2006). Therefore, the presence of the ketone group at carbon 17 in 
boldione and 19-nor-4,9(10)-androstadienedione is consistent with both 
steroids being chemically related to testosterone.
    DEA-sponsored studies regarding pharmacological relationship: The 
commenter claimed that the two studies sponsored by DEA were 
insufficient to justify determining whether boldione and 19-nor-
4,9(10)-androstadienedione are pharmacologically related to 
testosterone.
    DEA Response: DEA disagrees with this statement. The study using 
C3H10T1/2 cells demonstrates the ability of both steroids to act like 
testosterone in binding and activation of the androgen receptor 
resulting in protein synthesis and myotube formation. The second study 
reveals the ability of the steroids to act like testosterone in 
reversing the effects of castration of the rat on the size of selected 
androgen-selective organs (ventral prostate, seminal vesicles, levator 
ani muscle). This particular assay has been used in hundreds of studies 
within the scientific and industrial community to evaluate steroids for 
anabolic and androgenic activity similar to that found for testosterone 
(Vida, 1969). In addition, the effects of these two steroids on LH and 
FSH levels and testicular size in intact rats is also consistent with 
producing pharmacological effects similar to those of testosterone. 
Collectively, both studies demonstrate that boldione and 19-nor-
4,9(10)-androstadienedione are pharmacologically similar to 
testosterone.
    DEA-sponsored study at Boston University: The commenter claimed 
that the pharmacological analysis of boldione and 19-nor-4,9(10)-
androstadienedione for androgenic activity using C3H10T1/2 stem cells 
did not show a pharmacological relationship. According to the 
commenter, this failure was due to: (1) Failure to obtain a random 
sample of C3H10T1/2 cells; (2) erroneously assuming that mere binding 
to an

[[Page 63607]]

androgen receptor and translocation to the nucleus is sufficient to 
show androgenic activity; and (3) the lower potency of boldione and 19-
nor-4,9(10)-androstadienedione compared to dihydrotestosterone in the 
assay.
    DEA Response: DEA disagrees with these comments. First, to conduct 
the study it was necessary, as provided in the protocol, to identify 
batches of C3H10T1/2 cells that had the potential to differentiate into 
myogenic cells when exposed to anabolic steroids. This was done and 
verified using the schedule III anabolic steroid dihydrotestosterone as 
a positive control. Second, this study did not simply examine androgen 
receptor binding and subsequent translocation of the bound receptor to 
the nucleus. Instead, with respect to boldione, 19-nor-4,9(10)-
androstadienedione, and dihydrotestosterone, the study also 
demonstrated that this binding and translocation to the nucleus lead to 
the commitment of these cells to form muscle cells as evidenced by 
selected protein expression and the creation of myotubes. These various 
effects have previously been induced by exposure of C3H10T1/2 cells to 
the schedule III anabolic steroids testosterone, androstenedione, and 
tetrahydrogestrinone (Singh et al., 2003; Jasuja et al., 2005a,b). The 
fact that boldione and 19-nor-4,9(10)-androstadienedione were less 
potent than dihydrotestosterone at producing these effects does not 
preclude using this information to support the pharmacological 
similarity of these steroids to testosterone. It simply means that a 
higher dose of the two steroids is required to produce the effects.
    DEA-sponsored study by the Veteran's Administration Puget Sound 
Health Care System: The commenter also asserted that DEA failed to show 
in the rat study that boldione and 19-nor-4,9(10)-androstadienedione 
produced androgenic and anabolic effects, thereby failing to show a 
pharmacological relationship to testosterone. The commenter indicated 
that this conclusion was based on the limited weight gain or lack of 
weight gain found in animals given these steroids compared to control 
animals not exposed to the steroids. Additionally, the commenter noted 
as evidence for a failure to demonstrate androgenic activity the 
statement in the study report that read ``[t]he direct androgenic and 
anabolic activity of 1,4-androstadien-3,17-dione in sham operated rats 
is less clear.''
    DEA Response: DEA disagrees with this comment. DEA believes that 
using this assay, both steroids were found to produce pharmacological 
effects like that of testosterone. Although body weight was recorded in 
the study, it was not used as an endpoint for determining anabolic or 
androgenic effects. This was due to the fact that the regulation of 
body weight is complex, involving, among other factors, food intake, 
changes in fat mass, and changes in lean body mass. Instead, the 
androgenic and anabolic effects of both steroids were demonstrated by 
their ability to reverse the effects of castration of male rats on the 
size of the ventral prostate, seminal vesicles, and levator ani muscle, 
all three being androgen sensitive tissues. As discussed in the NPRM, 
numerous scientific studies have shown that exogenous testosterone 
administered to castrated rats can reverse the effects of castration on 
the ventral prostate, seminal vesicles, and levator ani muscle (Biskind 
and Meyer, 1941; Dorfman and Dorfman, 1963; Kincl and Dorfman, 1964; 
Nelson et al., 1940; Scow, 1952; and Wainman and Shipounoff, 1941). 
This particular assay has been used extensively over the years by the 
scientific community, including the pharmaceutical industry, to 
evaluate steroids for anabolic and androgenic activity (Vida, 1969). 
The authors of the DEA sponsored study specifically conclude that ``In 
summary, we found that, 1,4-androstadien-3,17-dione (A0100) and 4,9-
estradien-3,17-dione (E0160) demonstrated both androgenic activity, as 
evidenced by stimulation of the androgenic tissues (prostate and 
seminal vesicles) and anabolic activity, as evidenced by stimulation of 
the levator ani muscle growth in castrated male rats.''
    In regard to androgenic activity comment, the commenter did not 
provide the full statement from the report which reads: ``The direct 
androgenic and anabolic activity of 1,4-androstadien-3,17-dione in sham 
operated rats is less clear because of the measured increases in serum 
T levels that could mediate the androgenic and anabolic activities of 
1,4-androstadien-3,17-dione.'' This statement in the report mentioned 
the possibility that the pharmacological effects (reduction in LH and 
FSH levels and testes size) of 1,4-androstadien-3,17-dione could result 
indirectly by metabolism to an active steroid such as testosterone. As 
noted in the report, it was not possible to determine whether or not 
1,4-androstadien-3,17-dione actually metabolized to testosterone or 
some other substance that cross reacted in the testosterone assay. 
Regardless of whether 1,4-androstadien-3,17-dione acts directly or 
serves as a prodrug, it still produced pharmacological effects similar 
to that of testosterone when administered to rats.
    DEA has evaluated the comment received and finds that it does not 
provide any justification to dispute the determination that boldione, 
desoxymethyltestosterone and 19-nor-4,9(10)-androstadienedione are 
anabolic steroids.

IV. Conclusion and Impact of Final Rule

Conclusion

    Therefore, based on the above, DEA concludes that boldione, 
desoxymethyltestosterone, and 19-nor-4,9(10)-androstadienedione 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)(A)). All anabolic steroids are 
classified as schedule III controlled substances (21 U.S.C. 812(e) 
schedule III). Once a substance is determined to be an anabolic 
steroid, DEA has no discretion regarding the scheduling of these 
substances. As discussed further below, upon the effective date of this 
Final Rule all requirements pertaining to controlled substances in 
schedule III pertain to these three substances.

Impact of Classifying These Substances as Anabolic Steroids

    The classification of boldione, desoxymethyltestosterone, and 19-
nor-4,9(10)-androstadienedione as schedule III anabolic steroids makes 
these three substances subject to CSA requirements. Any person who 
manufactures, distributes, dispenses, imports, or exports boldione, 
desoxymethyltestosterone, or 19-nor-4,9(10)-androstadienedione, or who 
engages in research or conducts instructional activities with respect 
to these three substances, must obtain a schedule III registration in 
accordance with the CSA and its implementing regulations.
    As of January 4, 2010, manufacture, import, export, distribution, 
or sale of boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-
androstadienedione, except by DEA registrants, is a violation of the 
CSA that may result in imprisonment and fines (21 U.S.C. 841 and 960). 
Possession of these three steroids, unless legally obtained, is also 
subject to criminal penalties (21 U.S.C. 844).
    In addition, under the CSA, these three substances may be imported 
only

[[Page 63608]]

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. An 
individual who purchases any of these substances directly from foreign 
companies and has them shipped to the U.S. is considered to be 
importing even if the steroids are intended for personal use. Illegal 
importation of these substances is a violation of the CSA that may 
result in imprisonment and fines (21 U.S.C. 960).

Requirements for Handling Substances Defined as Anabolic Steroids

    Effective January 4, 2010, boldione, desoxymethyltestosterone, and 
19-nor-4,9(10)-androstadienedione are subject to CSA regulatory 
controls and 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, must be registered to conduct 
such activities with schedule III controlled substances in accordance 
with 21 CFR part 1301.
    Security. Substances defined as anabolic steroids are subject to 
schedule III-V security requirements and must 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 which are 
distributed on or after January 4, 2010, shall comply with 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 
is required to keep an inventory of all stocks of the substances on 
hand pursuant to 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 shall conduct an inventory of all stocks of the 
substances on hand at the time of registration.
    Records. All registrants are required to keep records pursuant to 
21 CFR 1304.03, 1304.04, 1304.05, 1304.21, 1304.22, 1304.23.
    Prescriptions. All prescriptions for these schedule III substances 
or for products containing these schedule III substances are required 
to be issued pursuant to 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, 
are limited to five refills within six months of the date of issuance 
of the prescription.
    Importation and Exportation. All importation and exportation of any 
substance defined as an anabolic steroid must be in compliance with 21 
CFR part 1312.
    Criminal Liability. Any activity with any substance defined as an 
anabolic steroid not authorized by, or in violation of, the Controlled 
Substances Act or the Controlled Substances Import and Export Act 
occurring on or after January 4, 2010 is unlawful.

Disposal of Anabolic Steroids

    Persons who possess substances 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. DEA Diversion 
field offices will provide the person with instructions regarding the 
disposal. A list of local DEA Diversion field offices may be found at 
https://www.deadiversion.usdoj.gov.

Regulatory Certifications

Regulatory Flexibility Act
    The Deputy 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 August 2008, 
DEA identified 61 dietary supplements promoted for building muscle and 
increasing strength that are purported to contain boldione, 
desoxymethyltestosterone, or 19-nor-4,9(10)-androstadienedione. Seven 
dietary supplements purport to contain boldione; twenty-three dietary 
supplements purport to contain desoxymethyltestosterone; and thirty-one 
dietary supplements purport to contain 19-nor-4,9(10)-
androstadienedione. All 61 dietary supplements are marketed and sold on 
the Internet.
    The manufacturers and distributors of the 61 identified dietary 
supplements purported to contain boldione, desoxymethyltestosterone, or 
19-nor-4,9(10)-androstadienedione 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. DEA did 
not receive any information regarding the percentage of revenues 
derived from these dietary supplements. DEA did not receive any 
comments regarding legitimate uses of these three substances. DEA has 
not identified any chemical manufacturers that are currently using 
these substances as intermediates in their manufacturing process(es).
    As of August 2008, DEA identified 32 chemical manufacturers and 
distributors that sell at least one of the three substances. Most of 
the companies are located in China and sell a variety of 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. 
Further, DEA has no information regarding the percentage of revenue 
these substances constitute for each handler.
    DEA has identified five companies based in the U.S. that are DEA 
registrants that manufacture and/or distribute at least one of these 
substances as reference products for testing laboratories. 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 Order 12866
    The Deputy Administrator hereby certifies that this rulemaking has 
been drafted in accordance with Executive Order 12866 section 1(b). It 
has been determined that this rule is a significant regulatory action. 
Therefore, this action has been reviewed by the Office of Management 
and Budget.
    As discussed above, the effect of this rule removes products 
containing these substances from the over-the-counter 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 for the first eleven months of 2008 was $2.1 
million. These three substances are

[[Page 63609]]

a subset of those imports. The value of anabolic steroid imports for 
the first eleven months of 2008 declined by 28.1 percent over the 
comparable period in 2007; the quantity imported during the first 
eleven months decreased by 60.1 percent over the comparable period in 
2007. The total market for these products containing these substances, 
therefore, is probably quite small. Moreover, DEA believes that the 
importation of these three 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 will 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 bars the importation, exportation, and sale of 
these three 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.
Paperwork Reduction Act
    This rule regulates three anabolic steroids, which are neither 
approved for medical use in humans nor approved for administration to 
cattle or other non-humans. Only chemical manufacturers who may use 
these substances as chemical intermediates for the synthesis of other 
steroids are required to register with DEA under the CSA. However, DEA 
has not identified any chemical manufacturers that are currently using 
these substances as intermediates in their manufacturing process(es). 
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 
$120,000,000 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.
Congressional Review Act
    This rule is not a major rule as defined by Section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act). This rule will not result in an annual 
effect on the economy of $100,000,000 or more; a major increase in cost 
or prices; or significant adverse effects on competition, employment, 
investment, productivity, innovation, or on the ability of United 
States-based companies to compete with foreign-based companies in 
domestic and export markets.

List of Subjects in 21 CFR Part 1300

    Chemicals, Drug traffic control.


0
For the reasons set out above, 21 CFR Part 1300 is amended as follows:

PART 1300--DEFINITIONS

0
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).


0
2. Section 1300.01 is amended in paragraph (b)(4) by:
0
A. Redesignating paragraphs (b)(4)(xiii) through (b)(4)(lx) as 
(b)(4)(xiv) through (b)(4)(lxi),
0
B. Adding a new paragraph (b)(4)(xiii),
0
C. Further redesignating newly designated paragraphs (b)(4)(xvii) 
through (b)(4)(lxi) as (b)(4)(xviii) through (b)(4)(lxii),
0
D. Adding new paragraph (b)(4)(xvii),
0
E. Further redesignating newly designated paragraphs (b)(4)(xlvii) 
through (b)(4)(lxii) as (b)(4)(xlviii) through (b)(4)(lxiii), and
0
F. Adding new paragraph (b)(4)(xlvii) to read as follows:


Sec.  1300.01  Definitions relating to controlled substances.

* * * * *
    (b) * * *
    (4) * * *
    (xiii) boldione (androsta-1,4-diene-3,17-dione)
* * * * *
    (xvii) desoxymethyltestosterone (17[alpha]-methyl-5[alpha]-androst-
2-en-17[beta]-ol) (a.k.a., madol)
* * * * *
    (xlvii) 19-nor-4,9(10)-androstadienedione (estra-4,9(10)-diene-
3,17-dione)
* * * * *

    Dated: November 20, 2009.
Michele M. Leonhart,
Deputy Administrator.

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[FR Doc. E9-28572 Filed 12-3-09; 8:45 am]
BILLING CODE 4410-09-P