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here you go:
Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63603
because it would represent a substitution of
current judgment for that of the prior
adjudicator that the annuitant’s impairment
was medically disabling. The exception for
error will not be applied retroactively under
the conditions set out above unless the
conditions for reopening the prior decision
are met.
* * * * *
■ 14. In § 220.180 revise paragraphs (b)
and (c) to read as follows:
§ 220.180 Determining continuation or
cessation of disability.
* * * * *
(b) If the annuitant is not engaging in
substantial gainful activity, does he or
she have an impairment or combination
of impairments which is medically
disabling? If the annuitant’s
impairment(s) is medically disabling,
his or her disability will be found to
continue;
(c) If the annuitant’s impairment(s) is
not medically disabling, has there been
medical improvement as defined in
§ 220.177(a)? If there has been medical
improvement as shown by a decrease in
medical severity, see step (d). If there
has been no decrease in medical
severity, then there has been no medical
improvement; (See step (e));
* * * * *
§ 220.181 [Amended]
■ 15. In § 220.181 amend paragraph (i)
by removing the word ‘‘not’’ and adding
in its place the word ‘‘no’’.
■ 16. In § 220.186(c) amend the
definition of ‘‘Permanent impairment,
medical improvement not expected’’ by
removing the phrase ‘‘§ 220.178(c)(4)’’
and adding in its place the phrase
‘‘§ 220.178(c)(3)’’ and revise paragraphs
(1) through (3) of the definition to read
as follows:
§ 220.186 When and how often the Board
will conduct a continuing disability review.
* * * * *
(c) * * *
Permanent impairment medical
improvement not expected—* * *
(1) Parkinsonian syndrome with
significant rigidity, brady kinesia, or
tremor in two extremities, which, singly
or in combination, result in sustained
disturbance of gross and dexterous
movements, or gait and station.
(2) Amyotrophic lateral sclerosis,
based on documentation of a clinically
appropriate medical history,
neurological findings consistent with
the diagnosis of ALS, and the results of
any electrophysiological and
neuroimaging testing.
(3) Diffuse pulmonary fibrosis in an
individual age 55 or older which
reduces FEV1 to 1.45 to 2.05 (L, BTPS)
or less depending on the individual’s
height.
* * * * *
Appendix 1 to Part 220 [Removed and
Reserved]
■ 17. Remove and reserve Appendix 1
to Part 220.
Dated: November 20, 2009.
For the Board.
Beatrice Ezerski,
Secretary to the Board.
[FR Doc. E9–28453 Filed 12–3–09; 8:45 am]
BILLING CODE 7905–01–P
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.
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.,
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63604 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
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:
17a-Methyl-5a-androst-2-en-17b-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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63605
1 The study by the Veteran’s Administration
Puget Sound Health Care System may be found at
http://www.regulations.gov in the electronic docket
associated with this rulemaking.
2 The study by Boston University may be found
at http://www.regulations.gov in the electronic
docket associated with this rulemaking.
3 The study by the Veteran’s Administration
Puget Sound Health Care System may be found at
http://www.regulations.gov in the electronic docket
associated with this rulemaking.
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 noncastrated
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.
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)-
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63606 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
4 The study by Boston University may be found
at http://www.regulations.gov in the electronic
docket associated with this rulemaking.
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.
(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., 17b-alkyl
group) (Williams and Stancel, 1996), or
corticosteroidal activity (e.g., 17-ketone
group or 11b-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 17bhydroxyl,
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 17b-hydroxysteroid
dehydrogenase is known to be
responsible for catalyzing the
conversion of the 17-ketone group to a
17b-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 17b-hydroxyl
group, thereby producing boldenone
and 19-nor-4,9(10)-androstadiene-3-one-
17b-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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 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
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63608 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
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
http://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 thirtyone
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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 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 nonhumans.
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 foreignbased
companies in domestic and
export markets.
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. Section 1300.01 is amended in
paragraph (b)(4) by:
■ A. Redesignating paragraphs
(b)(4)(xiii) through (b)(4)(lx) as
(b)(4)(xiv) through (b)(4)(lxi),
■ B. Adding a new paragraph
(b)(4)(xiii),
■ C. Further redesignating newly
designated paragraphs (b)(4)(xvii)
through (b)(4)(lxi) as (b)(4)(xviii)
through (b)(4)(lxii),
■ D. Adding new paragraph (b)(4)(xvii),
■ E. Further redesignating newly
designated paragraphs (b)(4)(xlvii)
through (b)(4)(lxii) as (b)(4)(xlviii)
through (b)(4)(lxiii), and
■ F. Adding new paragraph (b)(4)(xlvii)
to read as follows:
§ 1300.01 Definitions relating to controlled
substances.
* * * * *
(b) * * *
(4) * * *
(xiii) boldione (androsta-1,4-diene-
3,17-dione)
* * * * *
(xvii) desoxymethyltestosterone (17amethyl-
5a-androst-2-en-17b-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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estrogens and 17beta-hydroxy-1,4-
androstadien-3-one. Journal of Steroid
Biochemistry, 14: 1115–1125.
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.
Moghrabi, N. and Andersson, S. (1998).
17Beta-Hydroxysteroid dehydrogenases:
Physiological roles in health and disease.
Trends in Endocrinology and
Metabolism, 9(7): 265–270.
Moore, C.R. and Price, D. (1938). Some
effects of testosterone and testosteronepropionate
in the rat. The Anatominal
Record, 71(1): 59–78.
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.
Nutting, E.F., Klimstra, P.D., and Counsell,
R.E. (1966). Anabolic-androgenic activity
of A-ring modified androstane
derivatives. Part I: A comparison of
parenteral activity. ACTA
Endocrinologica, 53: 627–634.
Payne A.H. and Hales D.B. (2004). Overview
of steroidogenic enzymes in the pathway
from cholesterol to active steroid
hormones. Endocrine Reviews, 25(6):
947–970.
Peltoketo, H., Luu-The, V., Simard, J. and
Adamski, J. (1999). 17Beta-
Hydroxysteroid dehydrogenase (HSD)/
17-ketosteroid reductase (KSR) family;
nomenclature and main characteristics of
the 17HSD/KSR enzymes. Journal of
Molecular Endocrinology, 23: 1–11.
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.
Singh, R., Artaza, J.N., Taylor, W.E.,
Gonzalez-Cadavid, N.F., and Bhasin, S.
(2003). Androgens stimulate myogenic
differentiation and inhibit adipogenesis
in C3H10T1/2 pluripotent cells through
an androgen receptor-mediated pathway.
Endocrinology, 144(11): 5081–5088.
Swerdloff, R.S., Grover, P.K., Jacobs, H.S.,
and Bain, J. (1973). Search for a
substance which selectively inhibits
FSH—Effects of steroids and
prostaglandins on serum FSH and LH
levels. Steroids, 21(5): 703–722.
Swerdloff, R.S. and Walsh, P.C. (1973).
Testosterone and oestradiol suppression
of LH and FSH in adult male rats:
Duration of castration, duration of
treatment and combined treatment.
ACTA Endocrinologica, 73: 11–21.
Swerdloff, R.S., Walsh, P.C., and Odell, W.D.
(1972). Control of LH and FSH secretion
in the male: Evidence that aromatization
of androgens to estradiol is not required
for inhibition of gonadotropin secretion.
Steroids, 20(1): 13–22.
Verjans, H.L., Eik-Nes, K.B., Aafjes, J.H., Vels,
F.J.M., and van der Molen, H.J. (1974).
Effects of testosterone propionate,
5alpha-dihydrotestosterone propionate
and oestradiol benzoate on serum levels
of LH and FSH in the castrated adult
male rat. ACTA Endocrinologica, 77:
643–654.
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.
[FR Doc. E9–28572 Filed 12–3–09; 8:45 am]
BILLING CODE 4410–09–P
DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 117
[Docket No. USCG–2009–0968]
RIN 1625–AA09
Drawbridge Operation Regulation;
Automated and Remotely Operated
Bridges
AGENCY: Coast Guard, DHS.
ACTION: Final rule.
SUMMARY: The Commander, Ninth Coast
Guard District, is identifying all
remotely operated or automated
drawbridges in his area of responsibility
in subpart B of this part. This rule
identifies all the remotely operated or
automated drawbridges in this district
that currently open on signal to
navigation. This rule does not revise the
operating schedule or conditions for any
of the identified drawbridges.
DATES: This rule is effective December
15, 2009.
ADDRESSES: Comments and material
received from the public as well as
documents mentioned in this preamble
as being available in the docket, are part
of docket USCG–2009–0968 and are
available online by going to http://
www.regulations.gov, inserting USCG–
2009–0968 in the ‘‘Keyword’’ box, and
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63603
because it would represent a substitution of
current judgment for that of the prior
adjudicator that the annuitant’s impairment
was medically disabling. The exception for
error will not be applied retroactively under
the conditions set out above unless the
conditions for reopening the prior decision
are met.
* * * * *
■ 14. In § 220.180 revise paragraphs (b)
and (c) to read as follows:
§ 220.180 Determining continuation or
cessation of disability.
* * * * *
(b) If the annuitant is not engaging in
substantial gainful activity, does he or
she have an impairment or combination
of impairments which is medically
disabling? If the annuitant’s
impairment(s) is medically disabling,
his or her disability will be found to
continue;
(c) If the annuitant’s impairment(s) is
not medically disabling, has there been
medical improvement as defined in
§ 220.177(a)? If there has been medical
improvement as shown by a decrease in
medical severity, see step (d). If there
has been no decrease in medical
severity, then there has been no medical
improvement; (See step (e));
* * * * *
§ 220.181 [Amended]
■ 15. In § 220.181 amend paragraph (i)
by removing the word ‘‘not’’ and adding
in its place the word ‘‘no’’.
■ 16. In § 220.186(c) amend the
definition of ‘‘Permanent impairment,
medical improvement not expected’’ by
removing the phrase ‘‘§ 220.178(c)(4)’’
and adding in its place the phrase
‘‘§ 220.178(c)(3)’’ and revise paragraphs
(1) through (3) of the definition to read
as follows:
§ 220.186 When and how often the Board
will conduct a continuing disability review.
* * * * *
(c) * * *
Permanent impairment medical
improvement not expected—* * *
(1) Parkinsonian syndrome with
significant rigidity, brady kinesia, or
tremor in two extremities, which, singly
or in combination, result in sustained
disturbance of gross and dexterous
movements, or gait and station.
(2) Amyotrophic lateral sclerosis,
based on documentation of a clinically
appropriate medical history,
neurological findings consistent with
the diagnosis of ALS, and the results of
any electrophysiological and
neuroimaging testing.
(3) Diffuse pulmonary fibrosis in an
individual age 55 or older which
reduces FEV1 to 1.45 to 2.05 (L, BTPS)
or less depending on the individual’s
height.
* * * * *
Appendix 1 to Part 220 [Removed and
Reserved]
■ 17. Remove and reserve Appendix 1
to Part 220.
Dated: November 20, 2009.
For the Board.
Beatrice Ezerski,
Secretary to the Board.
[FR Doc. E9–28453 Filed 12–3–09; 8:45 am]
BILLING CODE 7905–01–P
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.
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.,
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63604 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
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:
17a-Methyl-5a-androst-2-en-17b-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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63605
1 The study by the Veteran’s Administration
Puget Sound Health Care System may be found at
http://www.regulations.gov in the electronic docket
associated with this rulemaking.
2 The study by Boston University may be found
at http://www.regulations.gov in the electronic
docket associated with this rulemaking.
3 The study by the Veteran’s Administration
Puget Sound Health Care System may be found at
http://www.regulations.gov in the electronic docket
associated with this rulemaking.
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 noncastrated
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.
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)-
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63606 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
4 The study by Boston University may be found
at http://www.regulations.gov in the electronic
docket associated with this rulemaking.
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.
(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., 17b-alkyl
group) (Williams and Stancel, 1996), or
corticosteroidal activity (e.g., 17-ketone
group or 11b-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 17bhydroxyl,
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 17b-hydroxysteroid
dehydrogenase is known to be
responsible for catalyzing the
conversion of the 17-ketone group to a
17b-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 17b-hydroxyl
group, thereby producing boldenone
and 19-nor-4,9(10)-androstadiene-3-one-
17b-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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 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
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63608 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations
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
http://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 thirtyone
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
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Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 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 nonhumans.
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 foreignbased
companies in domestic and
export markets.
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. Section 1300.01 is amended in
paragraph (b)(4) by:
■ A. Redesignating paragraphs
(b)(4)(xiii) through (b)(4)(lx) as
(b)(4)(xiv) through (b)(4)(lxi),
■ B. Adding a new paragraph
(b)(4)(xiii),
■ C. Further redesignating newly
designated paragraphs (b)(4)(xvii)
through (b)(4)(lxi) as (b)(4)(xviii)
through (b)(4)(lxii),
■ D. Adding new paragraph (b)(4)(xvii),
■ E. Further redesignating newly
designated paragraphs (b)(4)(xlvii)
through (b)(4)(lxii) as (b)(4)(xlviii)
through (b)(4)(lxiii), and
■ F. Adding new paragraph (b)(4)(xlvii)
to read as follows:
§ 1300.01 Definitions relating to controlled
substances.
* * * * *
(b) * * *
(4) * * *
(xiii) boldione (androsta-1,4-diene-
3,17-dione)
* * * * *
(xvii) desoxymethyltestosterone (17amethyl-
5a-androst-2-en-17b-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.
List of References
Ayotte, C., Goudreault, D., Gauthier, J.,
Ayotte, P., Larochelle, C., and Poirier, D.
(2006). Characterization of chemical and
hormonal properties of new steroid
related to doping of athletes. Presented at
the Cologne Workshop on Dope
Analysis, June 2006.
Bhasin, S. (2005). [Pharmacological analysis
of boldione and 19-nor-4,9(10)-
androstadienedione for androgenic
activity using C3H10T1/2 stem cells].
Unpublished report.
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.
Boris, A., Stevenson, R.H., and Trmal,- T.
(1970). Comparative androgenic,
myotrophic and antigonadotrophic
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[FR Doc. E9–28572 Filed 12–3–09; 8:45 am]
BILLING CODE 4410–09–P
DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 117
[Docket No. USCG–2009–0968]
RIN 1625–AA09
Drawbridge Operation Regulation;
Automated and Remotely Operated
Bridges
AGENCY: Coast Guard, DHS.
ACTION: Final rule.
SUMMARY: The Commander, Ninth Coast
Guard District, is identifying all
remotely operated or automated
drawbridges in his area of responsibility
in subpart B of this part. This rule
identifies all the remotely operated or
automated drawbridges in this district
that currently open on signal to
navigation. This rule does not revise the
operating schedule or conditions for any
of the identified drawbridges.
DATES: This rule is effective December
15, 2009.
ADDRESSES: Comments and material
received from the public as well as
documents mentioned in this preamble
as being available in the docket, are part
of docket USCG–2009–0968 and are
available online by going to http://
www.regulations.gov, inserting USCG–
2009–0968 in the ‘‘Keyword’’ box, and
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Just ordered a couple of phs from various stores. Even they know the deal from the FDA coz they have a comment in some of their homepages saying that all phs are no longer for sale after Jan 4 2010, as soon as Jan 1st. First come first serve, getting while you still can type of deal. Man! Where will all the bodybuilders, lifters, athletes and people who know how to use them correctly go to?????:crying:
imported_Skyling35
New member
Boldione, desoxymethyltestosterone,
and 19-nor-4,9(10)-androstadienedione.
These are the 3 being banned correct. The critera for deciding wether an item is an anabolic steroid or not are hazy.
I think im missing something and will look like an idiot. I dont see superdrol and phera etc listed. I see the trens in the 19 Nor, and 1-4ad with the boldione, but what is this desoxymethyltestosterone. Is that the one that covers the superdrol and etc.
and 19-nor-4,9(10)-androstadienedione.
These are the 3 being banned correct. The critera for deciding wether an item is an anabolic steroid or not are hazy.
I think im missing something and will look like an idiot. I dont see superdrol and phera etc listed. I see the trens in the 19 Nor, and 1-4ad with the boldione, but what is this desoxymethyltestosterone. Is that the one that covers the superdrol and etc.
N
Needtogetaas
Guest
Bro I lifted that shit. HAd I known sooner I would have lifted it the second it happen. Next time come str8 to me when that happens man.
N
Needtogetaas
Guest
yes
imported_Skyling35
New member
Last I heard no one is quite sure yet on 1-t
well other than PH/ PS because those are superior!!
I loved amp02 when I used it last year, and N2KTS is def awesome for noticable affects, lol
plus the 2 of them combined is a freak show! lol
The burner is a close 2nd. Also a fan on clen, but the jitters are a bit too much for the first few days! lol
I loved amp02 when I used it last year, and N2KTS is def awesome for noticable affects, lol
plus the 2 of them combined is a freak show! lol
The burner is a close 2nd. Also a fan on clen, but the jitters are a bit too much for the first few days! lol
