Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63603

because it would represent a substitution of or less depending on the individual’s Background information in support of current judgment for that of the prior height. this Final Rule is provided below. adjudicator that the annuitant’s impairment * * * * * On November 29, 1990, the President was medically disabling. The exception for signed into law the Anabolic error will not be applied retroactively under Appendix 1 to Part 220 [Removed and Control Act of 1990 (Title XIX of Pub. the conditions set out above unless the Reserved] conditions for reopening the prior decision L. 101–647), which became effective are met. ■ 17. Remove and reserve Appendix 1 February 27, 1991. This law established to Part 220. and regulated anabolic steroids as a * * * * * class of drugs under schedule III of the ■ 14. In § 220.180 revise paragraphs (b) Dated: November 20, 2009. CSA. As a result, a new anabolic and (c) to read as follows: For the Board. is not scheduled according to the § 220.180 Determining continuation or Beatrice Ezerski, procedures set out in 21 U.S.C. 811, but cessation of disability. Secretary to the Board. can be administratively classified as an through the rulemaking * * * * * [FR Doc. E9–28453 Filed 12–3–09; 8:45 am] process by adding the steroid to the (b) If the annuitant is not engaging in BILLING CODE 7905–01–P regulatory definition of an anabolic substantial gainful activity, does he or steroid in 21 CFR 1300.01(b)(4). she have an impairment or combination On October 22, 2004, the President of impairments which is medically DEPARTMENT OF JUSTICE signed into law the Anabolic Steroid disabling? If the annuitant’s Drug Enforcement Administration Control Act of 2004 (Pub. L. 108–358), impairment(s) is medically disabling, which became effective on January 20, his or her disability will be found to 2005. Section 2(a) of the Anabolic 21 CFR Part 1300 continue; Steroid Control Act of 2004 amended 21 (c) If the annuitant’s impairment(s) is [Docket No. DEA–285F] U.S.C. 802(41)(A) by replacing the not medically disabling, has there been existing definition of ‘‘anabolic steroid.’’ medical improvement as defined in RIN 1117–AB17 The Anabolic Steroid Control Act of § 220.177(a)? If there has been medical 2004 classifies a drug or hormonal Classification of Three Steroids as improvement as shown by a decrease in substance as an anabolic steroid if the Schedule III Anabolic Steroids Under medical severity, see step (d). If there following four criteria are met: (A) The has been no decrease in medical the Controlled Substances Act substance is chemically related to severity, then there has been no medical AGENCY: Drug Enforcement ; (B) the substance is improvement; (See step (e)); Administration (DEA), Department of pharmacologically related to * * * * * Justice. testosterone; (C) the substance is not an estrogen, progestin, or a corticosteroid; § 220.181 [Amended] ACTION: Final rule. and (D) the substance is not ■ 15. In § 220.181 amend paragraph (i) SUMMARY: With the issuance of this final (DHEA). Any by removing the word ‘‘not’’ and adding rule, the Deputy Administrator of the substance that meets the criteria is in its place the word ‘‘no’’. Drug Enforcement Administration considered an anabolic steroid and must ■ 16. In § 220.186(c) amend the (DEA) classifies the following three be listed as a schedule III controlled definition of ‘‘Permanent impairment, steroids as ‘‘anabolic steroids’’ under substance. DEA finds that , medical improvement not expected’’ by the Controlled Substances Act (CSA): , and 19-nor- removing the phrase ‘‘§ 220.178(c)(4)’’ Boldione, desoxymethyltestosterone, 4,9(10)-androstadienedione meet this and adding in its place the phrase and 19-nor-4,9(10)-androstadienedione. definition of anabolic steroid and is ‘‘§ 220.178(c)(3)’’ and revise paragraphs These steroids and their salts, esters, adding them to the list of anabolic (1) through (3) of the definition to read and ethers are schedule III controlled steroids in 21 CFR 1300.01(b)(4). as follows: substances subject to the regulatory Anabolic steroids are a class of drugs control provisions of the CSA. with a basic steroid ring structure that § 220.186 When and how often the Board produces anabolic and androgenic DATES: will conduct a continuing disability review. Effective Date: January 4, 2010. effects. The prototypical anabolic * * * * * FOR FURTHER INFORMATION CONTACT: steroid is testosterone. Anabolic effects (c) * * * Christine A. Sannerud, Ph.D., Chief, include promoting the growth of Permanent impairment medical Drug and Chemical Evaluation Section, muscle. The androgenic effects consist improvement not expected—*** Drug Enforcement Administration, 8701 of promoting the development of male (1) Parkinsonian syndrome with Morrissette Drive, Springfield, VA secondary sexual characteristics such as significant rigidity, brady kinesia, or 22152, (202) 307–7183. facial hair, deepening of the voice, and tremor in two extremities, which, singly SUPPLEMENTARY INFORMATION: thickening of the skin. or in combination, result in sustained In the United States, only a small disturbance of gross and dexterous I. Background Information number of anabolic steroids are movements, or gait and station. In a Notice of Proposed Rulemaking approved for either human or veterinary (2) Amyotrophic lateral sclerosis, (NPRM) (73 FR 22294) published April use. Approved medical uses for anabolic based on documentation of a clinically 25, 2008, the DEA proposed the steroids include treatment of appropriate medical history, classification of three steroids as deficiency in hypogonadal males, neurological findings consistent with schedule III anabolic steroids under the adjunctive therapy to offset protein the diagnosis of ALS, and the results of CSA. These three steroids included catabolism associated with prolonged any electrophysiological and boldione, desoxymethyltestosterone, administration of corticosteroids, neuroimaging testing. and 19-nor-4,9(10)-androstadienedione. treatment of delayed puberty in boys, (3) Diffuse pulmonary fibrosis in an With the publication of this Final Rule, treatment of metastatic breast cancer in individual age 55 or older which DEA classifies these three steroids as women, and treatment of anemia reduces FEV1 to 1.45 to 2.05 (L, BTPS) schedule III anabolic steroids. associated with specific diseases (e.g.,

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00073 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES 63604 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations

anemia of chronic renal failure, testosterone; (C) the substance is not an names: 19-Norandrosta-4,9(10)-diene- Fanconi’s anemia, and acquired aplastic estrogen, progestin, or a corticosteroid; 3,17-dione; and estra-4,9(10)-diene-3,17- anemia). However, with the exception of and (D) the substance is not DHEA. dione. DEA has determined that the the treatment of male hypogonadism, chemical structure of 19-nor-4,9(10)- (A) Chemically Related to Testosterone anabolic steroids are not the first-line androstadienedione is chemically treatment due to the availability of other To classify a substance as an anabolic related to testosterone. The chemical preferred treatment options. DEA is not steroid, a substance must be chemically structure of 19-nor-4,9(10)- aware of any legitimate medical use or related to testosterone. DEA discussed androstadienedione differs from New Drug Applications (NDA) for the its evaluation of the chemical testosterone by the following three three substances that DEA is classifying relationship of boldione, structural features: A ketone group at as anabolic steroids under the definition desoxymethyltestosterone, and 19-nor- carbon 17, the absence of a methyl set forth under 21 U.S.C. 802(41)(A). 4,9(10)-androstadienedione in the group at carbon 19, and a double-bond Moreover, DEA has not identified any NPRM published April 25, 2008 (73 FR between carbon 9 and carbon 10. The chemical manufacturers currently using 22294). A Structure Activity human body would be expected to these substances as intermediates in Relationship (SAR) evaluation for each metabolize the ketone group at carbon their manufacturing process(es). of the substances compared the 17 into a hydroxyl group like that Adverse effects are associated with chemical structure of the steroid to that present in testosterone (Payne and the use or abuse of anabolic steroids. of testosterone, as substances with a Hales, 2004; Peltoketo et al., 1999; These effects depend on several factors structure similar to that of testosterone Moghrabi and Andersson, 1998). (e.g., age, sex, anabolic steroid used, the are predicted to possess comparable Furthermore, the scientific literature amount used, and the duration of use). pharmacological and biological activity. reports that both the absence of the In early adolescence, the use of Boldione is also known by the methyl group at carbon 19 and the testosterone and other anabolic steroids following chemical name: Androsta-1,4- additional double bond in 19-nor- that have estrogenic effects can cause diene-3,17-dione. DEA has determined 4,9(10)-androstadienedione increase the premature closure of the growth plates that the chemical structure of boldione anabolic activity of the substance (Vida, in long bones resulting in a permanently is chemically related to that of 1969). stunted growth. In adolescent boys, testosterone. The chemical structure of anabolic steroid use can cause boldione differs from testosterone by (B) Pharmacologically Related to precocious sexual development. In both only the following structural features: A Testosterone girls and women, anabolic steroid use ketone group at carbon 17 and a double A substance must also be induces permanent physical changes bond between the carbon 1 and carbon pharmacologically related to such as deepening of the voice, 2. The human body would be expected testosterone (i.e., produce similar increased facial and body hair growth, to metabolize the ketone group at carbon biological effects) to be classified as a and the lengthening of the clitoris. In 17 into a hydroxyl group that is present schedule III anabolic steroid. The men, anabolic steroid use can cause on testosterone (Payne and Hales, 2004; pharmacology of a steroid, as related to shrinkage of the testicles, decreased Peltoketo et al., 1999; Moghrabi and testosterone, can be established by sperm count, and sterility. Andersson, 1998). Furthermore, the performing one or more of the following Gynecomastia (i.e., enlargement of the scientific literature reports that the androgenic and anabolic activity assays: male breast tissue) can develop with the additional double bond at carbon 1 in Ventral assay, seminal vesicle use of those anabolic steroids with boldione does not significantly decrease assay, levator ani assay, testicular estrogenic actions. In both men and the anabolic activity of the substance atrophy assay, gonadotropin women, anabolic steroid use can (Vida, 1969). Boldione is an anabolic suppression assay, and androgen damage the liver and can cause high steroid precursor, being metabolized by receptor binding and efficacy assays. cholesterol levels, which may increase the body into (Galletti and These assays are described below. the risk of strokes and heart attacks. Gardi, 1971; Kim et al., 2006), which is Ventral Prostate Assay, Seminal Furthermore, anabolic steroid use is a schedule III anabolic steroid (21 U.S.C. Vesicle Assay, and Levator Ani Assay: purported to induce psychological 802(41)(A)(vi)). The classic scientific procedure for effects such as aggression, increased Desoxymethyltestosterone (DMT) is examining the effects of a steroid as feelings of hostility, and psychological also known by the following names: compared to testosterone is to perform dependence and addiction. Upon abrupt 17a-Methyl-5a-androst-2-en-17b-ol; and the testosterone sensitive assays, ventral termination of long-term anabolic madol. DEA has determined that the prostate assay, seminal vesicle assay, steroid use, a withdrawal syndrome may chemical structure of and levator ani assay in rats. Certain appear including severe depression. desoxymethyltestosterone is chemically male accessory organs (i.e., the ventral related to testosterone. The chemical prostate, seminal vesicles, and levator II. Evaluation of Statutory Factors for structure of desoxymethyltestosterone ani muscle) specifically need Classification as an Anabolic Steroid differs from testosterone by the testosterone to grow and remain With the issuance of this Final Rule, following four structural features: The healthy. Upon the removal of the testes DEA is classifying boldione, lack of a ketone group at the third (i.e., castration), the primary desoxymethyltestosterone, and 19-nor- carbon, a double bond between the endogenous source of testosterone is 4,9(10)-androstadienedione as anabolic second and third carbon, the lack of a eliminated causing the atrophy of the steroids under the definition set forth double bond between the fourth and ventral prostate, seminal vesicles, and under 21 U.S.C. 802(41)(A). As noted fifth carbon, and a methyl group at levator ani muscle (Eisenberg et al., previously, a drug or hormonal carbon 17. Each of these four chemical 1949; Nelson et al., 1940; Scow, 1952; substance is classified as an anabolic features is known through the scientific Wainman and Shipounoff, 1941). steroid by meeting the following four literature not to eliminate the anabolic Numerous scientific studies have definitional requirements: (A) The and androgenic activity of the substance demonstrated the ability of exogenous substance is chemically related to (Brueggemeir et al., 2002; Vida, 1969). testosterone administered to rats testosterone; (B) the substance is 19-Nor-4,9(10)-androstadienedione is following castration to maintain the pharmacologically related to also known by the following chemical normal weight and size of all three

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00074 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63605

testosterone sensitive tissues (Biskind dihydroxytestosterone) confirms that to the results of a study by the same and Meyer, 1941; Dorfman and the ligand bound to the androgen laboratory using a similar protocol to Dorfman, 1963; Kincl and Dorfman, receptor and activated the downstream characterize the androgenic and 1964; Nelson et al., 1940; Scow, 1952; signaling cascade. When activated, the anabolic effects of testosterone (Marck et Wainman and Shipounoff, 1941). Thus, C3H10T1/2 stem cells differentiate into al., 2003). Boldione administered to a steroid with testosterone-like activity skeletal muscle cells as demonstrated by castrated male rats by silastic capsules will also prevent the atrophy of these the increase in the expression of muscle implanted under the skin prevented three testosterone-dependent tissues in specific proteins (i.e., myogenic atrophy of the ventral prostate, seminal castrated rats. determination transcription factor vesicles, levator ani muscle, and the rise Testicular Atrophy Assay: [MyoD] and myosin heavy chain in serum gonadotropin (LH and FSH) Administering testosterone to non- [MHC]). Another assay uses human associated with castration. Boldione castrated rats causes a decrease in serum breast cancer cells genetically altered to administration also produced testicular levels of gonadotropins (i.e., luteinizing contain a specific reporter gene (e.g., atrophy in intact rats. Another DEA hormone [LH] and follicle stimulating luciferase gene) regulated by androgen sponsored study 2 at a laboratory at hormone [FSH]) from normal levels. receptor activation (Hartig et al., 2002; Boston University examined the ability Gonadotropins are pituitary hormones Wilson et al., 2002). The expression of of boldione to bind to the androgen that affect the size and function of the a bioluminescent protein (e.g., receptor and to cause the differentiation testes. The suppression of these luciferase) signals both androgen of C3H10T1/2 stem cells into muscle gonadotropins by excess testosterone receptor binding and activation. cells (Bhasin, 2005). All of these effects results in a significant decrease in the Results of the Androgenic and caused by boldione in C3H10T1/2 stem size and weight of the testes (Boris et al., Anabolic Activity Assays: As discussed cells were comparable to those of 1970; McEuen et al., 1937; Moore and in the NPRM, in January 2006, DEA testosterone as established in Price, 1938). Accordingly, a steroid with reviewed the published scientific experiments using the same or similar testosterone-like activity will also literature for pharmacological data on methodology (Singh et al., 2003). significantly diminish the size and the anabolic and androgenic activity of Collectively, the evidence indicates that weight of the testes. boldione, desoxymethyltestosterone, the pharmacology of boldione is similar Gonadotropin Suppression Assay: and 19-nor-4,9(10)-androstadienedione to testosterone. The castration of rats causes a using the assays described above. As Desoxymethyltestosterone substantial increase in the serum levels discussed further below, there was of gonadotropins (i.e., LH and FSH) sufficient information on the Desoxymethyltestosterone was above normal levels due to the removal pharmacology of administered subcutaneously, orally, or of the principal source of endogenous desoxymethyltestosterone in the intramuscularly to castrated rats testosterone (Gay and Bogdanove, 1969; reviewed scientific literature to (Dorfman and Kincl, 1963; Kincl and Swerdloff et al., 1972, 1973; Swerdloff determine that Dorfman, 1964; Nutting et al., 1966). By and Walsh, 1973). The administration of desoxymethyltestosterone is all three routes of administration, testosterone to castrated animals pharmacologically related to desoxymethyltestosterone prevented the suppresses the increase in the serum testosterone (i.e., produces biological atrophy of ventral prostate, seminal levels of gonadotropins (Gay and effects similar to those of testosterone). vesicles, and levator ani muscle. Bogdanove, 1969; Swerdloff et al., 1972; However, the published literature Desoxymethyltestosterone also induced Swerdloff and Walsh, 1973; Verjans et contained insufficient pharmacological the expression of the bioluminescent al., 1974). The administration of data to determine whether boldione and protein luciferase in CAMA–1 breast anabolic steroids with testosterone-like 19-nor-4,9(10)-androstadienedione were cancer cells signaling activity will also prevent this increase binding and activation (Ayotte et al., in serum levels of LH and FSH. pharmacologically related to testosterone. Consequently, as discussed 2006). Collectively, the evidence Androgen Receptor Binding and indicates that the pharmacology of Efficacy Assay: Androgen receptor further below and in the NPRM, DEA sponsored pharmacological studies desoxymethyltestosterone is similar to binding and efficacy assays are also testosterone. used to demonstrate that the activity of involving several different androgenic a steroid is similar to that of and anabolic activity assays to generate 19-Nor-4,9(10)-Androstadienedione testosterone. Testosterone produces its the data necessary to make this As discussed in the NPRM, DEA anabolic effects subsequent to binding determination. sponsored a study 3 by the Veteran’s to and activating the androgen receptor. Androgenic and anabolic activity Administration Puget Sound Health Different cell-based assays can compare assay results indicate that boldione, Care System to determine the anabolic candidate steroids to testosterone for desoxymethyltestosterone, and 19-nor- and androgenic effects of 19-nor-4,9(10)- their ability to bind to and activate 4,9(10)-androstadienedione have similar androstadienedione in intact and androgen receptors. pharmacological activity as testosterone. castrated rats (Matsumoto and Marck, There are several different types of Boldione 2006). The results of these studies were assays used to establish androgen compared to the results of a study by the DEA sponsored a study 1 receptor binding and efficacy. In one by the same laboratory using a similar protocol assay, C3H10T1/2 stem cells express Veteran’s Administration Puget Sound to characterize the androgenic and androgen receptors and are used to Health Care System to determine the anabolic effects of testosterone (Marck et assess steroids for their ability to bind anabolic and androgenic effects of al., 2003). 19-Nor-4,9(10)- and activate the androgen receptor boldione in intact and castrated rats (Jasuja et al., 2005a,b; Singh et al., (Matsumoto and Marck, 2006). The 2 The study by Boston University may be found 2003). In these stem cells, the results of these studies were compared at http://www.regulations.gov in the electronic translocation of the androgen receptor to docket associated with this rulemaking. 1 The study by the Veteran’s Administration 3 The study by the Veteran’s Administration the nucleus of the cell in the presence Puget Sound Health Care System may be found at Puget Sound Health Care System may be found at of the ligand (e.g., testosterone or its http://www.regulations.gov in the electronic docket http://www.regulations.gov in the electronic docket active metabolite associated with this rulemaking. associated with this rulemaking.

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00075 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES 63606 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations

androstadienedione administered to therefore not exempted from control on wide distribution of this enzyme in castrated male rats by silastic capsules this basis. tissues of humans and animals, it is implanted under the skin prevented the expected that this enzyme would III. Comments Received atrophy of the ventral prostate, seminal convert the 17-ketone group found in vesicles, levator ani muscle, and the rise On April 25, 2008, DEA published a boldione and 19-nor-4,9(10)- in serum gonadotropins (LH and FSH) NPRM (73 FR 22294) proposing to androstadienedione to the 17b-hydroxyl associated with castration. Another DEA classify boldione, group, thereby producing boldenone sponsored study at a laboratory at desoxymethyltestosterone, and 19-nor- and 19-nor-4,9(10)-androstadiene-3-one- Boston University 4 examined the ability 4,9(10)-androstadienedione as schedule 17b-ol. Direct evidence that this of 19-nor-4,9(10)-androstadienedione to III anabolic steroids. The proposed rule conversion takes place comes from two bind to the androgen receptor and to provided an opportunity for all studies showing that boldione is cause the differentiation of C3H10T1/2 interested persons to submit their converted to boldenone, a schedule III stem cells into muscle cells (Bhasin, comments on or before June 24, 2008. In anabolic steroid, in the human body 2005). 19-Nor-4,9(10)- response to the NPRM, DEA received (Galletti and Gardi, 1971; Kim et al., androstadienedione induced the one comment from a consulting firm 2006). Therefore, the presence of the translocation of the androgen receptor to that described itself as ‘‘[assisting] ketone group at carbon 17 in boldione the nucleus of the C3H10T1/2 stem dietary supplement companies in and 19-nor-4,9(10)-androstadienedione cells, demonstrating binding affinity understanding governmental regulations is consistent with both steroids being and efficacy for the androgen receptor. while facilitating their growth.’’ These chemically related to testosterone. All of these effects caused by 19-nor- comments are summarized and DEA-sponsored studies regarding 4,9(10)-androstadienedione in responded to below. pharmacological relationship: The Desoxymethyltestosterone: The C3H10T1/2 stem cells were comparable commenter claimed that the two studies commenter indicated that the scientific to those of testosterone as established in sponsored by DEA were insufficient to literature cited in the NPRM pertaining experiments using the same or similar justify determining whether boldione to desoxymethyltestosterone was methodology (Singh et al., 2003). and 19-nor-4,9(10)-androstadienedione sufficient to meet the four criteria that Collectively, the evidence indicates that are pharmacologically related to must be satisfied for DEA to designate the pharmacology of 19-nor-4,9(10)- testosterone. the steroid as a schedule III anabolic androstadienedione is similar to DEA Response: DEA disagrees with steroid. DEA agrees with this testosterone. this statement. The study using conclusion. Therefore, DEA is placing C3H10T1/2 cells demonstrates the (C) Not Estrogens, Progestins, and desoxymethyltestosterone into schedule ability of both steroids to act like Corticosteroids III as an anabolic steroid as proposed. testosterone in binding and activation of Chemical relationship of boldione the androgen receptor resulting in As discussed in the NPRM, DEA has and 19-nor-4,9(10)-androstadienedione protein synthesis and myotube determined that boldione, to testosterone: The commenter claimed formation. The second study reveals the desoxymethyltestosterone, and 19-nor- that DEA failed to show that boldione ability of the steroids to act like 4,9(10)-androstadienedione are and 19-nor-4,9(10)-androstadienedione testosterone in reversing the effects of unrelated to estrogens, progestins, and are chemically related to testosterone. castration of the rat on the size of corticosteroids. DEA evaluated the SAR The commenter claimed that both selected androgen-selective organs for each of the substances. The chemical steroids were distinctly different from (ventral prostate, seminal vesicles, structure of each substance was testosterone in that each lacks the 17b- levator ani muscle). This particular compared to that of estrogens, hydroxyl, which is present in assay has been used in hundreds of progestins, and corticosteroids because testosterone. The commenter noted that studies within the scientific and the chemical structure can be related to DEA did not provide any authority for industrial community to evaluate its pharmacological and biological the claim made that ‘‘the human body steroids for anabolic and androgenic activity. DEA found that the three would be expected to metabolize the activity similar to that found for substances lacked the necessary ketone group at carbon 17 into a testosterone (Vida, 1969). In addition, chemical structures to impart significant hydroxyl group that is present on the effects of these two steroids on LH estrogenic activity (e.g., aromatic A ring) testosterone.’’ and FSH levels and testicular size in (Duax et al., 1988; Jordan et al., 1985; DEA Response: DEA disagrees with intact rats is also consistent with Williams and Stancel, 1996), this comment. The presence of the producing pharmacological effects progestational activity (e.g., 17b-alkyl ketone group at carbon 17 in boldione similar to those of testosterone. group) (Williams and Stancel, 1996), or and 19-nor-4,9(10)-androstadienedione Collectively, both studies demonstrate corticosteroidal activity (e.g., 17-ketone is consistent with both steroids being that boldione and 19-nor-4,9(10)- group or 11b-hydroxyl group) (Miller et chemically related to testosterone, androstadienedione are al., 2002). which has a hydroxyl group instead of pharmacologically similar to a ketone group at carbon 17. The testosterone. (D) Not Dehydroepiandrosterone enzyme 17b-hydroxysteroid DEA-sponsored study at Boston Dehydroepiandrosterone, also known dehydrogenase is known to be University: The commenter claimed that as DHEA, is exempt from control as an responsible for catalyzing the the pharmacological analysis of anabolic steroid by definition (21 U.S.C. conversion of the 17-ketone group to a boldione and 19-nor-4,9(10)- 802(41)(A)). Boldione, 17b-hydroxyl group in steroids such as androstadienedione for androgenic desoxymethyltestosterone, and 19-nor- and estrogens. This enzyme, activity using C3H10T1/2 stem cells did 4,9(10)-androstadienedione are not in various isoenzymatic forms, has been not show a pharmacological dehydroepiandrosterone and are documented in many body tissues in relationship. According to the humans and various animal species commenter, this failure was due to: (1) 4 The study by Boston University may be found (Payne and Hales, 2004; Peltoketo et al., Failure to obtain a random sample of at http://www.regulations.gov in the electronic 1999; Moghrabi and Andersson, 1998; C3H10T1/2 cells; (2) erroneously docket associated with this rulemaking. Melewich et al., 1981). Considering the assuming that mere binding to an

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00076 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63607

androgen receptor and translocation to produce pharmacological effects like still produced pharmacological effects the nucleus is sufficient to show that of testosterone. Although body similar to that of testosterone when androgenic activity; and (3) the lower weight was recorded in the study, it was administered to rats. potency of boldione and 19-nor-4,9(10)- not used as an endpoint for determining DEA has evaluated the comment androstadienedione compared to anabolic or androgenic effects. This was received and finds that it does not in the assay. due to the fact that the regulation of provide any justification to dispute the DEA Response: DEA disagrees with body weight is complex, involving, determination that boldione, these comments. First, to conduct the among other factors, food intake, desoxymethyltestosterone and 19-nor- study it was necessary, as provided in changes in fat mass, and changes in lean 4,9(10)-androstadienedione are anabolic the protocol, to identify batches of body mass. Instead, the androgenic and steroids. C3H10T1/2 cells that had the potential anabolic effects of both steroids were IV. Conclusion and Impact of Final to differentiate into myogenic cells demonstrated by their ability to reverse Rule when exposed to anabolic steroids. This the effects of castration of male rats on was done and verified using the the size of the ventral prostate, seminal Conclusion schedule III anabolic steroid vesicles, and levator ani muscle, all dihydrotestosterone as a positive Therefore, based on the above, DEA three being androgen sensitive tissues. concludes that boldione, control. Second, this study did not As discussed in the NPRM, numerous simply examine androgen receptor desoxymethyltestosterone, and 19-nor- scientific studies have shown that 4,9(10)-androstadienedione meet the binding and subsequent translocation of exogenous testosterone administered to the bound receptor to the nucleus. CSA definition of ‘‘anabolic steroid’’ castrated rats can reverse the effects of because each substance is: (A) Instead, with respect to boldione, 19- castration on the ventral prostate, nor-4,9(10)-androstadienedione, and Chemically related to testosterone; (B) seminal vesicles, and levator ani muscle pharmacologically related to dihydrotestosterone, the study also (Biskind and Meyer, 1941; Dorfman and demonstrated that this binding and testosterone; (C) not an estrogen, Dorfman, 1963; Kincl and Dorfman, progestin, or a corticosteroid; and (D) translocation to the nucleus lead to the 1964; Nelson et al., 1940; Scow, 1952; commitment of these cells to form not DHEA (21 U.S.C. 802(41)(A)). All and Wainman and Shipounoff, 1941). anabolic steroids are classified as muscle cells as evidenced by selected This particular assay has been used protein expression and the creation of schedule III controlled substances (21 extensively over the years by the U.S.C. 812(e) schedule III). Once a myotubes. These various effects have scientific community, including the previously been induced by exposure of substance is determined to be an pharmaceutical industry, to evaluate anabolic steroid, DEA has no discretion C3H10T1/2 cells to the schedule III steroids for anabolic and androgenic anabolic steroids testosterone, regarding the scheduling of these activity (Vida, 1969). The authors of the substances. As discussed further below, , and DEA sponsored study specifically (Singh et al., 2003; upon the effective date of this Final conclude that ‘‘In summary, we found Rule all requirements pertaining to Jasuja et al., 2005a,b). The fact that that, 1,4-androstadien-3,17-dione boldione and 19-nor-4,9(10)- controlled substances in schedule III (A0100) and 4,9-estradien-3,17-dione pertain to these three substances. androstadienedione were less potent (E0160) demonstrated both androgenic than dihydrotestosterone at producing activity, as evidenced by stimulation of Impact of Classifying These Substances these effects does not preclude using the androgenic tissues (prostate and as Anabolic Steroids this information to support the seminal vesicles) and anabolic activity, pharmacological similarity of these The classification of boldione, as evidenced by stimulation of the steroids to testosterone. It simply means desoxymethyltestosterone, and 19-nor- levator ani muscle growth in castrated that a higher dose of the two steroids is 4,9(10)-androstadienedione as schedule male rats.’’ required to produce the effects. III anabolic steroids makes these three DEA-sponsored study by the Veteran’s In regard to androgenic activity substances subject to CSA requirements. Administration Puget Sound Health comment, the commenter did not Any person who manufactures, Care System: The commenter also provide the full statement from the distributes, dispenses, imports, or asserted that DEA failed to show in the report which reads: ‘‘The direct exports boldione, rat study that boldione and 19-nor- androgenic and anabolic activity of 1,4- desoxymethyltestosterone, or 19-nor- 4,9(10)-androstadienedione produced androstadien-3,17-dione in sham 4,9(10)-androstadienedione, or who androgenic and anabolic effects, thereby operated rats is less clear because of the engages in research or conducts failing to show a pharmacological measured increases in serum T levels instructional activities with respect to relationship to testosterone. The that could mediate the androgenic and these three substances, must obtain a commenter indicated that this anabolic activities of 1,4-androstadien- schedule III registration in accordance conclusion was based on the limited 3,17-dione.’’ This statement in the with the CSA and its implementing weight gain or lack of weight gain found report mentioned the possibility that the regulations. in animals given these steroids pharmacological effects (reduction in As of January 4, 2010, manufacture, compared to control animals not LH and FSH levels and testes size) of import, export, distribution, or sale of exposed to the steroids. Additionally, 1,4-androstadien-3,17-dione could boldione, desoxymethyltestosterone, the commenter noted as evidence for a result indirectly by metabolism to an and 19-nor-4,9(10)-androstadienedione, failure to demonstrate androgenic active steroid such as testosterone. As except by DEA registrants, is a violation activity the statement in the study noted in the report, it was not possible of the CSA that may result in report that read ‘‘[t]he direct androgenic to determine whether or not 1,4- imprisonment and fines (21 U.S.C. 841 and anabolic activity of 1,4- androstadien-3,17-dione actually and 960). Possession of these three androstadien-3,17-dione in sham metabolized to testosterone or some steroids, unless legally obtained, is also operated rats is less clear.’’ other substance that cross reacted in the subject to criminal penalties (21 U.S.C. DEA Response: DEA disagrees with testosterone assay. Regardless of 844). this comment. DEA believes that using whether 1,4-androstadien-3,17-dione In addition, under the CSA, these this assay, both steroids were found to acts directly or serves as a prodrug, it three substances may be imported only

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00077 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES 63608 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations

for medical, scientific, or other Records. All registrants are required purported to contain boldione, legitimate uses (21 U.S.C. 952(b)) under to keep records pursuant to 21 CFR desoxymethyltestosterone, or 19-nor- an import declaration filed with DEA 1304.03, 1304.04, 1304.05, 1304.21, 4,9(10)-androstadienedione also sell a (21 CFR 1312.18). Importation of these 1304.22, 1304.23. variety of other dietary supplements. substances will be illegal unless the Prescriptions. All prescriptions for DEA has identified a substantial number person importing these substances is these schedule III substances or for of Internet distributors that sell these registered with DEA as an importer or products containing these schedule III dietary supplements. However, these researcher and files the required substances are required to be issued distributors also sell a variety of other declaration for each shipment. An pursuant to 21 CFR 1306.03–1306.06 nutritional products. DEA did not individual who purchases any of these and 1306.21–1306.27. All prescriptions receive any information regarding the substances directly from foreign for these schedule III compounds or for percentage of revenues derived from companies and has them shipped to the products containing these schedule III these dietary supplements. DEA did not U.S. is considered to be importing even substances, if authorized for refilling, receive any comments regarding if the steroids are intended for personal are limited to five refills within six legitimate uses of these three use. Illegal importation of these months of the date of issuance of the substances. DEA has not identified any substances is a violation of the CSA that prescription. chemical manufacturers that are may result in imprisonment and fines Importation and Exportation. All currently using these substances as (21 U.S.C. 960). importation and exportation of any intermediates in their manufacturing substance defined as an anabolic steroid process(es). Requirements for Handling Substances must be in compliance with 21 CFR part As of August 2008, DEA identified 32 Defined as Anabolic Steroids 1312. chemical manufacturers and distributors Effective January 4, 2010, boldione, Criminal Liability. Any activity with that sell at least one of the three desoxymethyltestosterone, and 19-nor- any substance defined as an anabolic substances. Most of the companies are 4,9(10)-androstadienedione are subject steroid not authorized by, or in violation located in China and sell a variety of to CSA regulatory controls and of, the Controlled Substances Act or the steroids. DEA notes that, as the vast administrative, civil, and criminal Controlled Substances Import and majority of entities handling these sanctions applicable to the manufacture, Export Act occurring on or after January substances are Internet based, it is distribution, dispensing, importation, 4, 2010 is unlawful. virtually impossible to accurately and exportation of a schedule III Disposal of Anabolic Steroids quantify the number of persons controlled substance, including the handling these substances at any given Persons who possess substances time. Further, DEA has no information following: classified as anabolic steroids and who Registration. Any person who regarding the percentage of revenue wish to dispose of them rather than these substances constitute for each manufactures, distributes, dispenses, becoming registered to handle them imports, exports, or engages in research handler. should contact their local DEA DEA has identified five companies or conducts instructional activities with Diversion field office for assistance in based in the U.S. that are DEA a substance defined as an anabolic disposing of these substances legally. registrants that manufacture and/or steroid, or who desires to engage in such DEA Diversion field offices will provide distribute at least one of these activities, must be registered to conduct the person with instructions regarding substances as reference products for such activities with schedule III the disposal. A list of local DEA testing laboratories. DEA notes, upon controlled substances in accordance Diversion field offices may be found at placement into schedule III, these with 21 CFR part 1301. http://www.deadiversion.usdoj.gov. substances may be used for analytical Security. Substances defined as Regulatory Certifications purposes. These companies are anabolic steroids are subject to schedule registered with DEA and are already in III–V security requirements and must be Regulatory Flexibility Act compliance with the CSA and DEA manufactured, distributed, and stored in The Deputy Administrator hereby implementing regulations regarding the accordance with 21 CFR 1301.71, certifies that this rulemaking has been handling of schedule III substances. 1301.72(b), (c), and (d), 1301.73, drafted in accordance with the Executive Order 12866 1301.74, 1301.75(b) and (c), 1301.76 and Regulatory Flexibility Act (5 U.S.C. 1301.77. 601–612). This regulation will not have The Deputy Administrator hereby Labeling and Packaging. All labels a significant economic impact on a certifies that this rulemaking has been and labeling for commercial containers substantial number of small entities. As drafted in accordance with Executive of substances defined as anabolic of August 2008, DEA identified 61 Order 12866 section 1(b). It has been steroids which are distributed on or dietary supplements promoted for determined that this rule is a significant after January 4, 2010, shall comply with building muscle and increasing strength regulatory action. Therefore, this action requirements of 21 CFR 1302.03– that are purported to contain boldione, has been reviewed by the Office of 1302.07. desoxymethyltestosterone, or 19-nor- Management and Budget. Inventory. Every registrant required to 4,9(10)-androstadienedione. Seven As discussed above, the effect of this keep records and who possesses any dietary supplements purport to contain rule removes products containing these quantity of any substance defined as an boldione; twenty-three dietary substances from the over-the-counter anabolic steroid is required to keep an supplements purport to contain marketplace. DEA has no basis for inventory of all stocks of the substances desoxymethyltestosterone; and thirty- estimating the size of the market for on hand pursuant to 21 CFR 1304.03, one dietary supplements purport to these products. DEA notes, however, 1304.04 and 1304.11. Every registrant contain 19-nor-4,9(10)- that virtually all of the substances are who desires registration in schedule III androstadienedione. All 61 dietary imported. According to U.S. for any substance defined as an anabolic supplements are marketed and sold on International Trade Commission data, steroid shall conduct an inventory of all the Internet. the import value of all anabolic steroids stocks of the substances on hand at the The manufacturers and distributors of for the first eleven months of 2008 was time of registration. the 61 identified dietary supplements $2.1 million. These three substances are

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00078 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations 63609

a subset of those imports. The value of Unfunded Mandates Reform Act of 1995 (xvii) desoxymethyltestosterone (17a- anabolic steroid imports for the first methyl-5a-androst-2-en-17b-ol) (a.k.a., This rule will not result in the eleven months of 2008 declined by 28.1 madol) expenditure by state, local, and tribal percent over the comparable period in governments, in the aggregate or by the * * * * * 2007; the quantity imported during the private sector, of $120,000,000 or more (xlvii) 19-nor-4,9(10)- first eleven months decreased by 60.1 (adjusted for inflation) in any one year androstadienedione (estra-4,9(10)-diene- percent over the comparable period in and will not significantly or uniquely 3,17-dione) 2007. The total market for these affect small governments. Therefore, no * * * * * products containing these substances, actions were deemed necessary under Dated: November 20, 2009. therefore, is probably quite small. the provisions of the Unfunded Moreover, DEA believes that the Mandates Reform Act of 1995. Michele M. Leonhart, importation of these three substances is Deputy Administrator. for illegitimate purposes. Congressional Review Act List of References The benefit of controlling these This rule is not a major rule as defined by Section 804 of the Small Ayotte, C., Goudreault, D., Gauthier, J., substances is to remove from the Ayotte, P., Larochelle, C., and Poirier, D. marketplace substances that have Business Regulatory Enforcement (2006). Characterization of chemical and dangerous side effects and no legitimate Fairness Act of 1996 (Congressional hormonal properties of new steroid medical use in treatment in the United Review Act). This rule will not result in related to doping of athletes. Presented at States. As discussed in detail above, an annual effect on the economy of the Cologne Workshop on Dope these substances can produce serious $100,000,000 or more; a major increase Analysis, June 2006. health effects in adolescents and adults. in cost or prices; or significant adverse Bhasin, S. (2005). [Pharmacological analysis If medical uses for these substances are effects on competition, employment, of boldione and 19-nor-4,9(10)- androstadienedione for androgenic developed and approved, the drugs will investment, productivity, innovation, or on the ability of United States-based activity using C3H10T1/2 stem cells]. be available as schedule III controlled Unpublished report. substances in response to a prescription companies to compete with foreign- Biskind, G.R. and Meyer, M.A. (1941). The issued by a medical professional for a based companies in domestic and comparative androgenic potency of legitimate medical purpose. Until that export markets. testosterone, and time, however, this action bars the List of Subjects in 21 CFR Part 1300 administered in importation, exportation, and sale of pellet form. Endocrinology, 28(2): 217– Chemicals, Drug traffic control. 221. these three substances except for Boris, A., Stevenson, R.H., and Trmal,- T. legitimate research or industrial uses. ■ For the reasons set out above, 21 CFR (1970). Comparative androgenic, Executive Order 12988 Part 1300 is amended as follows: myotrophic and antigonadotrophic properties of some anabolic steroids. This regulation meets the applicable PART 1300—DEFINITIONS Steroids, 15(1): 61–71. standards set forth in Sections 3(a) and Brueggemeier, R.W., Miller, D.D., and Dalton, ■ 1. The authority citation for part 1300 J.T. (2002). Estrogen, Progestins and 3(b)(2) of Executive Order 12988 Civil continues to read as follows: Androgens. In D.A. Williams and T.L. Justice Reform. Authority: 21 U.S.C. 802, 821, 829, 871(b), Lemke (Eds.) Foye’s Principle of Executive Order 13132 951, 958(f). Medicinal Chemistry (5th ed.). Philadelphia, Lippincott Williams and This rulemaking does not preempt or ■ 2. Section 1300.01 is amended in Wilkins. Dorfman, R.I. and Dorfman, A.S. (1963). The modify any provision of state law; nor paragraph (b)(4) by: ■ A. Redesignating paragraphs assay of subcutaneously injected does it impose enforcement androgens in the castrated rat. ACTA responsibilities on any state; nor does it (b)(4)(xiii) through (b)(4)(lx) as Endocrinologica, 42: 245–253. diminish the power of any state to (b)(4)(xiv) through (b)(4)(lxi), Dorfman, R.I. and Kincl, F.A. (1963). Relative enforce its own laws. Accordingly, this ■ B. Adding a new paragraph potency of various steroids in an rulemaking does not have federalism (b)(4)(xiii), anabolic-androgenic assay using the implications warranting the application ■ C. Further redesignating newly castrated rat. Endocrinology, 72: 259– of Executive Order 13132. designated paragraphs (b)(4)(xvii) 266. through (b)(4)(lxi) as (b)(4)(xviii) Duax, W.L., Griffin, J.F., Weeks, C.M., and Paperwork Reduction Act Wawrzak, Z. (1988). The mechanism of through (b)(4)(lxii), action of steroid antagonists: Insights This rule regulates three anabolic ■ D. Adding new paragraph (b)(4)(xvii), from crystallographic studies. Journal of steroids, which are neither approved for ■ E. Further redesignating newly Steroid Biochemistry and Molecular medical use in humans nor approved for designated paragraphs (b)(4)(xlvii) Biology, 31: 481–492. Eisenberg, E., Gordan, G.S. and Elliott, H.W. administration to cattle or other non- through (b)(4)(lxii) as (b)(4)(xlviii) through (b)(4)(lxiii), and (1949). Testosterone and tissue humans. Only chemical manufacturers respiration of the castrate male rat with ■ who may use these substances as F. Adding new paragraph (b)(4)(xlvii) possible test for myotrophic activity. chemical intermediates for the synthesis to read as follows: Endocrinology, 45(2): 113–119. Galletti, F. and Gardi, R. (1971). Metabolism of other steroids are required to register § 1300.01 Definitions relating to controlled of 1-dehydroandrostanes in man: 1. with DEA under the CSA. However, substances. DEA has not identified any chemical Metabolism of 17beta-hydroxyandrosta- * * * * * manufacturers that are currently using 1,4-dien-3-one, 17beta-cyclopent-1’- these substances as intermediates in (b) * * * enloxyandrosta-1,4-dien-3-one (4) * * * () and androst-1,4-diene-3,17- their manufacturing process(es). Thus, dione. Steroids, 18(1): 39–50. DEA does not expect this rule to impose (xiii) boldione (androsta-1,4-diene- Gay, V.L. and Bogdanove, E.M. (1969). any additional paperwork burden on the 3,17-dione) Plasma and pituitary LH and FSH in the regulated industry. * * * * * castrated rat following short-term steroid

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00079 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES 63610 Federal Register / Vol. 74, No. 232 / Friday, December 4, 2009 / Rules and Regulations

treatment. Endocrinology, 84: 1132– (1981). Metabolism of 1,4-androstadiene- Effects of testosterone propionate, 1142. 3,17-dione by human placental 5alpha-dihydrotestosterone propionate Hartig, P.C., Bobseine, K.L., Britt, B.H., microsomes. Enzyme properties and and oestradiol benzoate on serum levels Cardon, M.C., Lambright, C.R., Wilson, kinetic parameters in the formation of of LH and FSH in the castrated adult V.S., and Gray, L.E. (2002). Development estrogens and 17beta-hydroxy-1,4- male rat. ACTA Endocrinologica, 77: of two androgen receptor assays using androstadien-3-one. Journal of Steroid 643–654. adenoviral transduction of MMTV-Luc Biochemistry, 14: 1115–1125. Vida, J.A. (1969). Androgens and Anabolic reporter and/or hAR for endocrine Miller, D.D., Brueggemeier, R.W., and Dalton, Agents: Chemistry and Pharmacology. screening. Toxicological Sciences, 66: J.T. (2002). Adrenocorticoids. In D.A. New York: Academic Press. 82–90. Williams and T.L. Lemke (Eds.) Foye’s Wainman, P. and Shipounoff, G.C. (1941). Jasuja, R., Catlin, D.H., Miller, A., Chang, Y.- Principle of Medicinal Chemistry (5th The effects of castration and testosterone C., Herbst, K.L., Starcevic, B., Artaza, ed.). Philadelphia, Lippincott Williams propionate on the striated perineal J.N., Singh, R., Datta, G., Sarkissian, A., and Wilkins. musculature in the rat. Endocrinology, Chandsawangbhuwana, C., Baker, M., Moghrabi, N. and Andersson, S. (1998). 29(6): 975–978. and Bhasin, S. (2005a). 17Beta-Hydroxysteroid dehydrogenases: Williams, C.L. and Stancel, G.M. (1996). Tetrahydrogestrinone is an androgenic Physiological roles in health and disease. Estrogens and Progestins. In J.G. steroid that stimulates androgen Trends in Endocrinology and Hardman, L.E. Limbird, P.B. Molinoff, receptor-mediated, myogenic Metabolism, 9(7): 265–270. R.W. Ruddon, A. Goodman Gilman differentiation in C3H10T1/2 Moore, C.R. and Price, D. (1938). Some (Eds.) Goodman and Gilman’s The multipotent mesenchymal cells and effects of testosterone and testosterone- Pharmacological Basis of Therapeutics promotes muscle accretion in propionate in the rat. The Anatominal (9th ed.). New York: McGraw-Hill, 1411– orchidectomized male rats. Record, 71(1): 59–78. 1440. Endocrinology, 146(10): 4472–4478. Nelson, D., Greene, R.R. and Wells, J.A. Wilson, V.S., Bobseine, K., Lambright, C.R., Jasuja, R., Ramaraj, P., Mac, R.P., Singh, A.B., (1940). Variations in the effectiveness of and Gray, L.E. (2002). A novel cell line, Storer, T.W., Artaza, J., Miller, A., Singh, percutaneously applied androgens in the MDA-kb2, that stably expresses an R., Taylor, W.E., Lee, M.L., Davidson, T., rat. Endocrinology, 26: 651–655. androgen- and glucocorticoid-responsive Sinha-Hikim, I., Gonzalez-Cadavid, N.F., Nutting, E.F., Klimstra, P.D., and Counsell, reporter for the detection of hormone and Bhasin, S. (2005b). Delta-4- R.E. (1966). Anabolic-androgenic activity receptor agonists and antagonists. Androstene-3,17-dione binds androgen of A-ring modified Toxicological Sciences, 66: 69–81. receptor, promotes myogenesis in vitro, derivatives. Part I: A comparison of and increases serum testosterone levels, parenteral activity. ACTA [FR Doc. E9–28572 Filed 12–3–09; 8:45 am] fat-free mass, and muscle strength in Endocrinologica, 53: 627–634. BILLING CODE 4410–09–P hypogonadal men. Journal of Clinical Payne A.H. and Hales D.B. (2004). Overview Endocrinology and Metabolism, 90(2): of steroidogenic enzymes in the pathway 855–863. from cholesterol to active steroid DEPARTMENT OF HOMELAND Jordan, V.C., Mittal, S., Gosden, B., Koch, R., hormones. Endocrine Reviews, 25(6): and Lieberman, M.E. (1985). Structure- 947–970. SECURITY activity relationships of estrogen. Peltoketo, H., Luu-The, V., Simard, J. and Environmental Health Perspectives, 61: Adamski, J. (1999). 17Beta- Coast Guard 97–110. Hydroxysteroid dehydrogenase (HSD)/ Kim, Y., Jun, M., and Lee, W. (2006). 17-ketosteroid reductase (KSR) family; 33 CFR Part 117 Characterization of boldione and its nomenclature and main characteristics of [Docket No. USCG–2009–0968] metabolites in human urine by liquid the 17HSD/KSR enzymes. Journal of chromatography/electrospray ionization Molecular Endocrinology, 23: 1–11. RIN 1625–AA09 mass spectrometry and gas Scow, R.O. (1952). Effect of testosterone on chromatography/mass spectrometry. muscle and other tissues and on carcass Drawbridge Operation Regulation; Rapid Communications in Mass composition in hypophysectomized, Automated and Remotely Operated Spectrometry, 20: 9–20. thyroidectomized, and gonadectomized Bridges Kincl, F.A. and Dorfman, R.I. (1964). male rats. Endocrinology, 51: 42–51. Anabolic-androgenic potency of various Singh, R., Artaza, J.N., Taylor, W.E., AGENCY: Coast Guard, DHS. steroids in a castrated rat assay. Steroids, Gonzalez-Cadavid, N.F., and Bhasin, S. ACTION: Final rule. 3: 109–122. (2003). Androgens stimulate myogenic Marck, B.T., Wolden-Hanson, T., Tolliver, differentiation and inhibit adipogenesis SUMMARY: The Commander, Ninth Coast J.M., Matsumoto, A.M. (2003). Use of in C3H10T1/2 pluripotent cells through Guard District, is identifying all DEXA to assess the anabolic actions of an androgen receptor-mediated pathway. androgens on relative lean body mass Endocrinology, 144(11): 5081–5088. remotely operated or automated and bone mineral density in Swerdloff, R.S., Grover, P.K., Jacobs, H.S., drawbridges in his area of responsibility orchidectomized prepubertal rats. and Bain, J. (1973). Search for a in subpart B of this part. This rule Unpublished manuscript, Veteran’s substance which selectively inhibits identifies all the remotely operated or Affairs Puget Sound Health Care System, FSH—Effects of steroids and automated drawbridges in this district Seattle, WA. prostaglandins on serum FSH and LH that currently open on signal to Matsumoto, A.M. and Marck, B.T. (2006). levels. Steroids, 21(5): 703–722. navigation. This rule does not revise the DEA Agreement No. DEA–04–P0007 Swerdloff, R.S. and Walsh, P.C. (1973). operating schedule or conditions for any Final Report [Analysis of the androgenic Testosterone and oestradiol suppression of the identified drawbridges. and anabolic activities of 1,4- of LH and FSH in adult male rats: androstadien-3,17-dione and 19-nor- Duration of castration, duration of DATES: This rule is effective December 4,9(10)-androstadienedione in male treatment and combined treatment. 15, 2009. Sprague Dawley rats]. Unpublished ACTA Endocrinologica, 73: 11–21. ADDRESSES: Comments and material report. Swerdloff, R.S., Walsh, P.C., and Odell, W.D. received from the public as well as McEuen, C.S., Selye, H., and Collip, J.B. (1972). Control of LH and FSH secretion documents mentioned in this preamble (1937). Effects of testosterone on somatic in the male: Evidence that aromatization growth. Proceedings of the Society for of androgens to is not required as being available in the docket, are part Experimental Biology and Medicine, 36: for inhibition of gonadotropin secretion. of docket USCG–2009–0968 and are 390–394. Steroids, 20(1): 13–22. available online by going to http:// Melewich, L., Bradfield, D.J., Coe, L.D., Verjans, H.L., Eik-Nes, K.B., Aafjes, J.H., Vels, www.regulations.gov, inserting USCG– Masters, B.S.S. and MacDonald, P.C. F.J.M., and van der Molen, H.J. (1974). 2009–0968 in the ‘‘Keyword’’ box, and

VerDate Nov<24>2008 17:09 Dec 03, 2009 Jkt 220001 PO 00000 Frm 00080 Fmt 4700 Sfmt 4700 E:\FR\FM\04DER1.SGM 04DER1 jlentini on DSKJ8SOYB1PROD with RULES