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Federal Register/Vol. 63, No. 118/Friday, June 19, 1998

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Federal Register/Vol. 63, No. 118/Friday, June 19, 1998 33592 Federal Register / Vol. 63, No. 118 / Friday, June 19, 1998 / Proposed Rules § 71.1 [Amended] laxative ingredients, danthron and further in a future issue of the Federal 2. The incorporation by reference in phenolphthalein. This proposal is part Register. of the ongoing review of OTC drug 14 CFR 71.1 of Federal Aviation III. Bisacodyl Administration Order 7400.9D, Airspace products conducted by FDA. Designations and Reporting Points, DATES: Submit written comments by The FDA Center for Drug Evaluation dated September 10, 1997, and effective September 17, 1998. Written comments and Research (CDER) Carcinogenicity September 16, 1997, is amended as on the agency's economic impact Assessment Committee (CAC) has follows: determination by September 17, 1998. recommended that the anthraquinone New data by June 21, 1999. Comments laxatives (aloe, cascara sagrada, and Paragraph 6005 Class E airspace areas on the new data by August 19, 1999. senna) and bisacodyl be tested in the extending upward from 700 feet or more standard battery of genotoxicity tests above the surface of the earth. ADDRESSES: Submit written comments and new data to the Dockets and under the test conditions by which Spruce Creek Airport Management Branch (HFA±305), Food phenolphthalein was found to be (Lat. 29°04′49′′ N, long. 81°03′27′′ W) and Drug Administration, 12420 positive (Ref. 1). Phenolphthalein and bisacodyl are diphenylmethane Ormond Beach Municipal Airport Parklawn Dr., rm. 1±23, Rockville, MD 20857. derivatives with a similar chemical (Lat. 29°18′04′′ N, long. 81°06′50′′ W) structure and pharmacological FOR FURTHER INFORMATION CONTACT: That airspace extending upward from 700 characteristics. The CAC recommended feet or more above the surface of the earth Gerald M. Rachanow, Center for Drug the Syrian Hamster Embryo (SHE) cell within a 10-mile radius of Daytona Beach Evaluation and Research (HFD±560), transformation assay as an early screen International Airport, within a 6.4-mile Food and Drug Administration, 5600 for bisacodyl and, based on its results, radius of Spruce creek Airport and within a Fishers Lane, Rockville, MD 20857, either the p53 transgenic mouse assay or 7.3-mile radius of Ormond Beach Municipal 301±827±2307. Airport. another in vivo alternative assay, as SUPPLEMENTARY INFORMATION: appropriate, follow. Two-year * * * * * carcinogenicity studies would then be Issued in College Park, Georgia, on June 10, I. Background 1998. contingent upon the results of these In the Federal Register of March 21, assays. Nancy B. Shelton, 1975 (40 FR 12902), FDA published, The agency has informed industry Acting Manager, Air Traffic Division, under § 330.10(a)(6) (21 CFR that additional testing for bisacodyl will Southern Region. 330.10(a)(6)), an advance notice of be necessary (Ref. 2). Subsequently, [FR Doc. 98±16354 Filed 6±18±98; 8:45 am] proposed rulemaking to establish a industry submitted data from two BILLING CODE 4910±13±M monograph for OTC laxative, mutagenicity studies (Ames test and rat antidiarrheal, emetic, and antiemetic bone marrow micronucleus assay) and a drug products, together with the chromosomal aberration study in DEPARTMENT OF HEALTH AND recommendations of the Advisory Chinese hamster ovary cells. The agency HUMAN SERVICES Review Panel on OTC Laxative, has reviewed these studies and Antidiarrheal, Emetic, and Antiemetic determined that the results of all of the Food and Drug Administration Drug Products (the Panel), which was tests were negative (Ref. 3). the advisory review panel responsible Phenolphthalein was tested in two of 21 CFR Parts 310 and 334 for evaluating data on the active these tests and was found negative in [Docket No. 78N±036L] ingredients in these classes. In the one (Ames test). However, findings from advance notice of proposed rulemaking, further studies indicated that RIN 0910±AA01 the Panel recommended Category I phenolphthalein presents a potential Laxative Drug Products for Over-the- status for the OTC stimulant laxative carcinogenic risk. Thus, because of the Counter Human Use; Proposed ingredients aloe, bisacodyl, cascara chemical similarity of bisacodyl to Amendment to the Tentative Final sagrada preparations, danthron, phenolphthalein and the lack of Monograph phenolphthalein, and senna previous carcinogenicity testing of preparations (40 FR 12902 at 12908 to bisacodyl, the agency is requesting that AGENCY: Food and Drug Administration, 12910). The agency concurred with the bisacodyl undergo further testing to HHS. Panel's Category I classification of these assess its carcinogenic potential. ACTION: Notice of proposed rulemaking. ingredients in the tentative final Industry has completed dose range monograph published in the Federal finding studies intended to select SUMMARY: The Food and Drug Register of January 15, 1985 (50 FR 2124 bisacodyl doses for a 6-month oral Administration (FDA) is reopening the at 2152 to 2156). gavage carcinogenicity study in the p53 administrative record and proposing to transgenic mouse (Ref. 4). amend the tentative final monograph II. Danthron and Phenolphthalein (proposed rule) for over-the-counter In the Federal Register of September IV. Senna (OTC) laxative drug products to 2, 1997 (62 FR 46223), the agency The agency has reviewed metabolic, reclassify the stimulant laxative reopened the administrative record for genotoxicity, and carcinogenicity data ingredients aloe, bisacodyl, cascara this rulemaking, discussed the on senna and its components (Ref. 5). sagrada, and senna (including carcinogenic risk of danthron and Senna contains a number of sennosides A and B) from Category I phenolphthalein, and proposed to components, including but not limited (generally recognized as safe and reclassify these two anthraquinone to: Sennosides A and B, sennosides C effective and not misbranded) to laxative ingredients from Category I to and D, rhein (including rhein anthrone- Category III (further testing is required). Category II (not generally recognized as 8-monoglucoside and rhein-8- FDA is issuing this proposed safe and effective or misbranded). The monoglucoside), chrysophanol, emodin, rulemaking after considering data and agency is evaluating the data and and aloe-emodin. The metabolic studies information on the safety of bisacodyl, comments submitted in response to that show that varying amounts of senna and senna, and two related stimulant proposal and will discuss this subject its metabolites are absorbed into the Federal Register / Vol. 63, No. 118 / Friday, June 19, 1998 / Proposed Rules 33593 systemic circulation. The data do not VI. References substantial number of small entities, an present conclusive absorption The following references have been agency must analyze regulatory options information, nor indicate whether any placed on display in the Dockets that would minimize any significant of the metabolites present a safety Management Branch (address above) impact of the rule on small entities. hazard, if absorbed. and may be seen by interested persons Title II of the Unfunded Mandates The agency believes that there are between 9 a.m. and 4 p.m., Monday Reform Act (2 U.S.C. 1501 et seq.) sufficient mutagenicity (Ames test) data through Friday. requires that agencies prepare a written in the literature on the senna extracts 1. Comment No. MM13, Docket No. 78N± statement and economic analysis before sennosides A and B, aloe-emodin, 036L, Dockets Management Branch. proposing any rule that may result in an chrysophanol, and emodin. The data 2. Letter from D. Bowen, FDA, to R. W. expenditure in any 1 year by State, indicate that sennosides A and B are Soller, Nonprescription Drug Manufacturers local, and tribal governments, in the negative, while the senna extracts aloe- Association (NDMA), coded LET111, Docket aggregate, or by the private sector, of emodin, emodin, and chrysophanol are No. 78N±036L, Dockets Management Branch. $100 million (adjusted annually for 3. Letter from D. Bowen, FDA, to L. positively genotoxic (Ref. 5). Thus, inflation). Totman, NDMA, coded LET175, Docket No. The agency believes that this senna preparations containing any of 78N±036L, Dockets Management Branch. these components (or kaempferol or proposed rule is consistent with the 4. Comment No. C178, Docket No. 78N± principles set out in the Executive Order quercetin) may have mutagenic 036L, Dockets Management Branch. properties. These potentially mutagenic 5. Letter from D. Bowen, FDA, to J. and in these two statutes. The purpose anthrones are found in the dried leaves Conover, The Purdue Frederick Co., coded of this proposed rule is to establish and pods of senna. Therefore, until LET173, Docket No. 78N±036L, Dockets conditions under which the OTC manufacturers can show that Management Branch. stimulant laxative ingredients aloe, 6. Comment No. LET113, Docket No. 78N± bisacodyl, cascara sagrada, and senna commercially available senna 036L, Dockets Management Branch. are or are not generally recognized as preparations do not contain mutagenic/ safe and effective. If the ingredients are genotoxic components, the agency is VII. Summary of the Agency's Changes determined to be safe and effective, no unable to state that sennosides A and B to the Proposed Rule product reformulation will be necessary. do not pose a relative risk to humans. The agency is proposing to reclassify If the ingredients are not determined to The agency also reviewed a 2-year the stimulant laxative ingredients aloe, be safe and effective, product carcinogenicity study with sennosides bisacodyl, cascara sagrada
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