33592 Federal Register / Vol. 63, No. 118 / Friday, June 19, 1998 / Proposed Rules

§ 71.1 [Amended] ingredients, danthron and further in a future issue of the Federal 2. The incorporation by reference in . 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 (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, (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), , 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 or proposed rule is consistent with the 4. Comment No. C178, Docket No. 78N– principles set out in the Executive Order ) 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 (including reformulation will be needed. There are in the rat (Ref. 6). However, the agency casanthranol), and senna (including a number of other laxative ingredients found this study deficient because of the sennosides A and B) from Category I in proposed part 334 (50 FR 2124 at limited and incomplete histopathologic (monograph) to Category III (more data 2152) or one of these ingredients, if examination of tissues (Ref. 5). The needed). The agency recommends that found safe and effective, that could be agency concludes that further testing is persons interested in testing these drugs used if product reformulation becomes necessary to assess the carcinogenic consult the agency about necessary. potential of senna products. In these carcinogenicity study requirements and The cost to reformulate a product will studies, specific analysis of the test protocols before initiating any studies. If vary greatly depending on the nature of substance should be done to enable these data are not provided or are the change in formulation, the product, quantitative estimation of each inadequate for any of these ingredients, the process, and the size of the firm. component of the preparation. The these ingredients will be placed in Because of the large number of senna dose selection should be based on Category II (nonmonograph) in a final monograph active ingredients available a 1-month dose ranging study for an rule. The agency will add any of these for substitution, no manufacturer should alternative assay or a 3-month dose ingredients that become nonmonograph need to change its dosage form; ranging study for a 2-year to the list of stimulant laxatives in however, a manufacturer would have to carcinogenicity study in the rodent § 310.545(a)(12)(iv) (21 CFR redo the validation (product, process, species and strains selected for the 310.545(a)(12)(iv)) in new new supplier), conduct stability tests, carcinogenicity studies. Histopathologic § 310.545(a)(12)(iv)(C). The agency will change master production records, and, examination of all tissues from all also amend proposed §§ 334.18, 334.30, for some dosage forms, conduct groups of animals should be conducted 334.32, 334.60, 334.66, and 334.80 to palatability tests. Competitive market (Ref. 5). remove any of these ingredients and forces and increased public awareness V. Aloe and Cascara Sagrada their labeling if any of these ingredients of a potential safety hazard of these Preparations are not included in the final monograph. ingredients would most likely lead all manufacturers to move to alternative Aloe and cascara sagrada are other VIII. Analysis of Impacts products over time. anthraquinone ingredients. Cascara FDA has examined the impacts of this Manufacturers of these products will sagrada ingredients included in the proposed rule under Executive Order also incur costs to relabel their products tentative final monograph are 12866 and the Regulatory Flexibility Act to reflect the new formulation. The casanthranol, cascara fluidextract (5 U.S.C. 601–612). Executive Order agency obtained estimates of relabeling aromatic, cascara sagrada bark, cascara 12866 directs agencies to assess all costs costs for the type of changes required by sagrada extract, and cascara sagrada and benefits of available regulatory this proposed rule ranging from $2,700 fluidextract (50 FR 2124 at 2152). The alternatives and, when regulation is to $10,000 per standard stock keeping agency has not received any necessary, to select regulatory unit (SKU) (individual products, mutagenicity, genotoxicity, or approaches that maximize net benefits packages, and sizes) for nationally carcinogenicity data for these (including potential economic, branded products and from $500 to ingredients. The agency concludes that environmental, public health and safety, $1,500 per SKU for private label these ingredients need to have these and other advantages; distributive products. The agency estimates the types and other toxicity data using tests impacts; and equity). Under the number of SKU’s that will need to be similar to those used and found positive Regulatory Flexibility Act, if a rule has relabeled as a result of reformulation as for phenolphthalein. a significant economic impact on a between 500 and 1,000, depending if 33594 Federal Register / Vol. 63, No. 118 / Friday, June 19, 1998 / Proposed Rules some or all of the involved ingredients earliest possible time. The agency does or distribution of any substance and are not included in the final monograph not believe that there are any significant therefore will not result in the for OTC laxative drug products. Most of alternatives to the proposed rule that production of any substance into the these label changes will be made by would adequately provide for the safe environment. private label manufacturers that tend to and effective use of these OTC drug use simpler and less expensive labeling. products. XI. Request for Comments Finally, some manufacturers that do The agency expects that this proposed Interested persons may, on or before not reformulate and validate their rule will not be economically significant products by the effective date of the under Executive Order 12866, nor September 17, 1998, submit written final rule may incur a loss of revenue. would it impose an Unfunded Mandate comments on the proposed regulation to Nevertheless, because of the large (as that term is described in the the Dockets Management Branch number of substitute products that are Unfunded Mandate Act). The agency (address above). Written comments on available, many in the same dosage also believes that it is undertaking steps the agency’s economic impact form, there should be no significant to reduce the burden to small entities. determination may be submitted on or drop in the overall consumption of Nevertheless, some entities may incur before September 17, 1998. Three copies laxative drug products. Some significant impacts, especially of all comments are to be submitted, manufacturers already have other manufacturers that may have to except that individuals may submit one laxative products. If products need to be reformulate their products and, to a copy. Comments are to be identified reformulated eventually, manufacturers lesser extent, private label with the docket number found in will be able to retain the same brand manufacturers that provide labeling for brackets in the heading of this names. Consumer loyalty to these a number of the affected products. Thus, document and may be accompanied by brands should lessen the revenue losses this economic analysis, together with a supporting memorandum or brief. to these firms. other relevant sections of this Received comments may be seen in the Because these products must be document, serves as the agency’s initial office above between 9 a.m. and 4 p.m., manufactured in compliance with the regulatory flexibility analysis, as Monday through Friday. pharmaceutical current good required under the Regulatory Interested persons may also submit manufacturing practices (21 CFR parts Flexibility Act. new data demonstrating the safety of 210 and 211), all firms have the Finally, the agency specifically invites any of those conditions not classified in necessary skills and personnel to public comment regarding any Category I on or before June 21, 1999. perform the tasks of reformulation, substantial or significant economic Written comments on the new data may validation, and relabeling either in- impact that this rulemaking would have house or by contractual arrangement. on OTC laxative drug products be submitted on or before August 19, The rule will not require any new containing aloe, bisacodyl, cascara 1999. Three copies of all data and reporting and recordkeeping activities. sagrada, and senna, particularly the comments should be submitted as stated No additional professional skills are costs associated with reformulation. previously, and received data and needed. There are no other Federal rules Comments regarding the impact of this comments may be seen as stated that duplicate, overlap, or conflict with rulemaking on OTC laxative drug previously. In establishing a final this rule. products containing any of these monograph, the agency will ordinarily Small business impact. The U.S. ingredients should be accompanied by consider only data submitted prior to Small Business Administration appropriate documentation. The agency the closing of the administrative record designates an entity as small if it will evaluate any comments and on August 19, 1999. Data submitted employs less than 750 employees. The supporting data that are received and after the closing of the administrative agency does not believe that any small will reassess the economic impact of record will be reviewed by the agency firms will be conducting genotoxicity or this rulemaking in the preamble to the only after a final monograph is carcinogenicity studies on any of the final rule. published in the Federal Register, laxative ingredients included in this unless the Commissioner of Food and proposal. Small firms that may have to IX. Paperwork Reduction Act of 1995 Drugs finds good cause has been shown reformulate their products could incur FDA tentatively concludes that that warrants earlier consideration. significant costs as a result of this rule. labeling requirements related to this The agency is attempting to reduce this proposed rule are not subject to review List of Subjects burden by keeping industry informed of by the Office of Management and 21 CFR Part 310 the findings of new research on these Budget because they do not constitute a products through public meetings and ‘‘collection of information’’ under the Administrative practice and letters to manufacturers of products Paperwork Reduction Act of 1995 (44 procedure, Drugs, Labeling, Medical containing these ingredients. In this U.S.C. 3501 et seq.). Rather, this devices, Reporting and recordkeeping manner, manufacturers should be aware proposed rulemaking involves labeling requirements. of which ingredients are likely to be that is a ‘‘public disclosure of included or excluded from the final information originally supplied by the 21 CFR Part 334 monograph and can make their Federal government to the recipient for Labeling, Over-the-counter drugs. marketing decisions accordingly. the purpose of disclosure to the public’’ The agency considered but rejected (5 CFR 1320.3(c)(2)). Therefore, under the Federal Food, the following alternatives: (1) Fewer Drug, and Cosmetic Act and under testing requirements, and (2) an X. Environmental Impact authority delegated to the Commissioner exemption from coverage for small The agency has determined under 21 of Food and Drugs, it is proposed that entities. The agency does not consider CFR 25.30(h) that this action is of a type 21 CFR parts 310 and 334 (as proposed either of these approaches acceptable that is categorically excluded from the in the Federal Register of January 15, because they do not assure that preparation of an environmental 1985 (50 FR 2124), September 2, 1993 consumers will have safe and effective assessment because these actions, as a (58 FR 46589), and September 2, 1997 OTC laxative drug products at the class, will not result in the production (62 FR 46223)) be amended as follows: Federal Register / Vol. 63, No. 118 / Friday, June 19, 1998 / Proposed Rules 33595

PART 310ÐNEW DRUGS § 334.32 [Amended] regulations under section 367(b) are 6. Section 334.32 Bowel cleansing issued with respect to the all earnings 1. The authority citation for 21 CFR systems is amended by removing and and profits amount, such regulations part 310 continues to read as follows: reserving paragraph (a). will have a prospective effective date. Authority: 21 U.S.C. 321, 331, 351, 352, This modification may affect domestic 353, 355, 356, 357, 360b-360f, 360j, 361(a), § 334.60 [Amended] corporations in connection with an 371, 374, 375, 379e; 42 U.S.C. 216, 241, 7. Section 334.60 Labeling of acquisition of a foreign corporation in a 242(a), 262, 263b-263n. stimulant laxative drug products is liquidation described in section 332 or 2. Section 310.545 is amended by amended by removing paragraphs (b)(3), in an asset acquisition described in adding new paragraphs (a)(12)(iv)(C) (d)(1) through (d)(7), (d)(10), and (d)(11), section 368(a)(1)). and (d)(30), and by revising paragraph by removing and reserving paragraph DATES: Written comments must be (d) introductory text to read as follows: (c), and by redesignating paragraphs received by September 17, 1998. § 310.545 Drug products containing active (d)(8) and (d)(9) as paragraphs (d)(1) and ADDRESSES: Send submissions to: ingredients offered over-the-counter (OTC) (d)(2), respectively. CC:DOM:CORP:R (REG–209035–86), for certain uses. § 334.66 [Amended] Room 5228, Internal Revenue Service, POB 7604, Ben Franklin Station, (a) * * * 8. Section 334.66 Labeling of bowel Washington, DC 20044. In the (12) * * * cleansing systems identified in § 334.32 alternative, submissions may be hand (iv)(C) Stimulant laxatives— is amended in paragraph (a) by delivered between the hours of 8 a.m. Approved as of (date of publication in removing ‘‘§ 334.32(a)’’ and adding in and 5 p.m. to: CC:DOM:CORP:R (REG– the Federal Register). its place ‘‘§ 334.32’’and by removing 209035–86), Courier’s Desk, Internal Aloe and reserving paragraphs (c)(1) and Revenue Service, 1111 Constitution Bisacodyl (d)(3)(iii)(A). Cascara sagrada in any form (e.g., Ave. NW., Washington, DC. casanthranol, cascara fluidextract § 334.80 [Amended] FOR FURTHER INFORMATION CONTACT: aromatic, cascara sagrada bark, cascara 9. Section 334.80 Professional Philip L. Tretiak at (202) 622–3860 (not sagrada extract, cascara sagrada labeling is amended in paragraph (a)(2) a toll-free call). fluidextract) by removing the words ‘‘or bisacodyl SUPPLEMENTARY INFORMATION: Senna in any form (e.g., senna identified in § 334.18(b)’’, by removing Background fluidextract, senna fruit extract, senna paragraphs (a)(4) and (c)(5) through leaf powder, senna pod concentrate, (c)(10), and by adding the word ‘‘or’’ Section 367(b) was enacted in its senna syrup, or sennosides A and B) after ‘‘§ 334.16(a)’’ in paragraph (a)(2), current form by the Tax Reform Act of * * * * * and by redesignating paragraphs (c)(11), 1976. On December 27, 1977, proposed (d) Any OTC drug product that is not (c)(12), and (c)(13) as paragraphs (c)(5), and temporary regulations §§ 7.367(b)–1 in compliance with this section is (c)(6), (c)(7), respectively. through 7.367(b)–12 were adopted (TD 7530, 1978–1 C.B. 92). Prior to the subject to regulatory action if initially Dated: June 9, 1998. issuance of a notice of proposed introduced or initially delivered for William K. Hubbard, introduction into interstate commerce rulemaking in 1991 (the 1991 proposed Associate Commissioner for Policy regulations), discussed below, the after the dates specified in paragraphs Coordination. (d)(1) through (d)(30) of this section. regulations under section 367(b) were [FR Doc. 98–16290 Filed 6–18–98; 8:45 am] amended on several occasions. The * * * * * BILLING CODE 4160±01±F 1991 proposed regulations, which were (30) (Date 6 months after date of published in the Federal Register on publication in the Federal Register), for August 26, 1991 (56 FR 41993), propose products subject to paragraph DEPARTMENT OF THE TREASURY to completely revise the regulations (a)(12)(iv)(C) of this section. under section 367(b), as well as the Internal Revenue Service PART 334ÐLAXATIVE DRUG rules under section 367(a) with respect to certain transfers of stock or securities PRODUCTS FOR OVER-THE- 26 CFR Part 1 COUNTER HUMAN USE by U.S. persons to foreign corporations. [REG±209035±86] Section 1.367(b)–6(a) of the proposed 3. The authority citation for 21 CFR regulations provides that the rules RIN 1545±AI32 part 334 is revised to read as follows: contained in the section 367(b) Authority: 21 U.S.C. 321, 351, 352, 353, Foreign Liquidations and proposed regulations will be effective 355, 360, 371. Reorganizations for exchanges that occur on or after the date that is 30 days after final § 334.18 [Amended] AGENCY: Internal Revenue Service (IRS), regulations are published. However, an 4. Section 334.18 Stimulant laxative Treasury. exception to the general effective date active ingredients is amended by ACTION: Amendment to notice of provides that § 1.367(b)–2(d) (relating to removing paragraphs (a), (b), (c)(1) proposed rulemaking. the definition and computation of the through (c)(5), and (f) and redesignating ‘‘all earnings and profits amount’’) is paragraphs (d) and (e) as paragraphs (a) SUMMARY: This document removes from effective for exchanges that occur on or and (b), respectively. an existing (1991) notice of proposed after August 26, 1991. rulemaking the special (August 26, A package of final regulations, § 334.30 [Amended] 1991) effective date rule for the published elsewhere in this issue of the 5. Section 334.30 Permitted definition of the all earnings and profits Federal Register, contains final rules combinations of active laxative amount. The IRS and the Treasury with respect to the section 367(a) ingredients is amended by removing and Department believe that issues regarding portion of the 1991 proposed reserving paragraphs (c), (e), (g), (h), and the all earnings and profits amount regulations (to the extent that such rules (i). should be studied; thus, when final were not previously finalized) and final