17022 NOTICES between Charleston, WV, and St. Interstate Hwy 70, (13) between Hen­ state Hwy 65 to junction Cumberland Louis, MO, (a) over Interstate Hwy 64, derson and Hopkinsville, KY, from Parkway, then over Cumberland Parkr and (b) from Charleston over U.S. Henderson over Pennyrile Parkway to way to Somerset, and return over the Hwy 60 to junction U.S. Hwy 52, then junction U.S. Hwy 41, then over U.S. same route, (24) between junction U.S. over U.S. Hwy 52 to junction U.S. Hwy Hwy 41 to junction Pennyrile Park­ Hwy 150 and U.S. Hwy 27 and Lexing­ 50, then over U.S. Hwy 50 to junction way, then over Pennyrile Parkway to ton, KY, over U.S. Hwy 27, (25) be­ U.S. Hwy 40, then over U.S. Hwy 40 to Hopkinsville, and return over the same tween junction U.S. Hwy 50 and IN St. Louis, and return over the same route, (14) between Stanford and Mt. Hwy 37 and junction IN Hwy 37 and route, (2) between Owensboro and Vernon, KY, over U.S. Hwy 150, (15) IN Hwy 45, over IN Hwy 37, (26) be­ Bowling Green, KY, over U.S. Hwy between Edmonton and Harrodsburg, tween junction U.S. Hwy 60 and U.S. 231, (3) between Owensboro and junc­ KY, over U.S. Hwy 68 , (16) between Hwy 52 and junction U.S. Hwy 60 and tion Green River Parkway and U.S. Indianapolis, IN, and Louisville, KY, U.S. Hwy 62, over U.S. Hwy 60 serving Hwy 231, over Green River Parkway, (a) over U.S. Hwy 31, and (b) over In­ in ( 1 ) through (26) above, all interme­ (4) between Mayfield and London, KY, terstate Hwy 65, (17) between Owens­ diate points, and the off-route points over KJT Hwy 80, (5) between London, boro, KY, and Indianapolis, IN, from of Jefferson, Fayette, Boyd, Daviess, KY, and Cincinnati, OH, (a) over U.S. Owensboro over U.S. Hwy 231 to junc­ Marshall, Warren, McCracken, Clark, Hwy 25, and (b) over Interstate Hwy tion IN Hwy 54, then over IN Hwy 54 Hardin, Franklin, Boone, Graves, 75, (6 ) between Somerset and Lexing­ to junction IN Hwy 445, then over IN Nelson, Taylor, Kénton, Oldham, Bul­ ton, KY, from Somerset over U.S. Hwy Hwy 445 to junction IN Hwy 45, then litt, Scott, Woodford, Jessamine, Bour­ 27 to junction U.S. Hwy 150, then over over IN Hwy 45 to junction IN Hwy 37, bon, Campbell, Greenup, Larue, and U.S. Hwy 150 to junction U.S. Hwy then over IN Hwy 37 to Indianapolis, Henderson Counties, KY, Ripey and 127, then over U.S. Hwy 127 to junc­ and return over the same route, ( 18 ) New Bern, TN, and Mount Vernon, IL. tion U.S. Hwy 68 , then over U.S. Hwy between Nashville, TN, and Bowling (Hearing site: Lexington and Louis­ 68 to Lexington, and return over the Green, KY, (a) over U.S. Hwy 31W, ville, KY, Memphis, TN, and St. Louis, same route, (7) between Harrodsburg, and (b) over Interstate Hwy 65, (19) MO.) KY and junction U.S. Hwy 127 and In­ between Nashville, TN, and Hopkins­ MC 146168F, filed January 20, 1979. terstate Hwy 64, over U.S. Hwy 127, ville, KY, (a) over U.S. Hwy 41, and (b) Applicant: PONCHATOULA LEAD (8 ) between junction U.S. Hwys 25 and over U.S. Hwy Alt. 41, (20) between CO., INC., Route 1, Box 66 , Poncha- 42 and Bowling Green, KY, from junc­ Lexington, KY, and Memphis, TN, toula, LA 70454. Representative: tion U.S. Hwys 25 and 42 over U.S. from Lexington over U.S. Hwy 62 to Harold R. Ainsworth, 2307 American Hwy 42 to junction U.S. Hwy 31W, junction U.S. Hwy 51, then over U.S. Bank Building, New Orleans, LA then over U.S. Hwy 31W to Bowling Hwy 51 to Memphis, and return over 70130. To operate as a common carri­ Green, and return over the same the same route, (2 1 ) between junction er, by motor vehicle, in interstate or route, (9) between junction^U.S. Hwys U.S. Hwy 60 and Blue Grass Parkway foreign commerce, over irregular 42 and 3IE and Glasgow, KY, over and junction Purchase Parkway and routes, transporting ( 1 ) antimonial U.S. Hwy 3IE, (10) between junction U.S. Hwy 51, from junction U.S. Hwy lead, from the facilities of Schuylkill Interstate Hwys 71 and 75 and junc­ 60 and Blue Grass Parkway over Blue Metals Corporation, in East Baton tion Interstate Hwy 65 and KY Hwy Grass Parkway to junction Interstate Rouge Parish, LA, to points in AR, FL, 80, from the junction of Interstate Hwy 65, then over Interstate Hwy 65 GA, IL, IN, KY, LA, MS, MO, TN, and Hwys 71 and 75 over Interstate Hwy to junction Western Kentucky Park­ TX; and (2) scrap batteries and scrap 71 to junction Interstate Hwy 65, then way, then over Western Kentucky lead, plates, from points in AR, FL, over Interstate Hwy 65 to junction In­ Parkway to junction Purchase Park­ GA, IL, IN, KY, LA, MS, MO, TN, and terstate Hwy 65 and KY Hwy 80, and way, then over Purchase Parkway to TX, to the facilities of (a) Schuylkill return over the same route, ( 11 ) be­ junction U.S. Hwy 51, and return over Metals Corporation, in East Baton tween Indianapolis, IN, and Hopkins­ the same route, (22 ) between junction Rouge Parish, LA, and (b) Poncha- ville, KY, from Indianapolis, over U.S. U.S. Hwy 60 and U.S. Hwy 62 and toula Battery Co., Inc., in Tangipahoa Hwy 40 to junction U.S. Hwy 41, then junction U.S. Hwy 45 and U.S. Hwy 51, Parish, LA, under contracts in (1) and over U.S. Hwy 41 to junction U.S. Hwy from junction U.S. Hwy 60 and U.S. (2) above with Schuylkill Metals Cor­ Alt. 41, at or near Madisonville, KY, Hwy 62 over U.S. Hwy 62 to junction poration, of Dover, DE, and Poncha- then over U.S. Hwy Alt. 41 to junction U.S. Hwy 45, then over U.S. Hwy 45 to toula Battery Co., Inc., of Poncha- U.S. Hwy 41, at or near Nortonville, junction U.S. Hwy 51, and return over toula, LA. (Hearing site: New Orleans, then over U.S. Hwy 41 to Hopkinsville, the same route, (23) between junction LA.) and return over the same route, ( 12 ) KY Hwy 80 and Interstate Hwy 65 and between Indianapolis and junction In­ Somerset, KY, from junction KY Hwy terstate Hwy 40 and U.S. Hwy 41, over 80 and Interstate Hwy 65 over Inter­ [FR Doc. 79-8242 Filed 3-19-79; 8:45 ami FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 17023 sunshine act m eetin gs This section of the FEDERAL REGISTER contains notices of meetings published under the “Government in the Sunshine Act” (Pub. L. 94 -409 ) 5 U.S.C. 552b(e)(3). CONTENTS f 6 3 2 0 -0 1 - M ] PERSON TO CONTACT: Items 2 Phyllis T. Kaylor, the Secretary, Civil Aeronautics Board............. 1 , 2? 3 202-673-5068. \ [M-203, Amdt. 3; Mar. 15, 1979] Federal Communications Com­ SUPPLEMENTARY INFORMATION: mission............................... 4 CIVIL AERONAUTICS BOARD. Because of the short time frame in Federal Election Commission.... 5 Deletion of item from the March 15, which action must be taken, the fol­ Federal Reserve System Board 1979 meeting agenda. lowing Members have voted that of Governors................... 6 agency business requires that the International Trade Commis­ TIME AND DATE: 10 a.m., March 15, sion............ 7 1979. Board meet on these items less than Metric Board......$.................... 8 seven days’ notice and no earlier an­ Nuclear Regulatory Commis­ PLACE: Room 1027, 1825 Connecticut nouncement of the meeting was possi­ sion........................................... 9 Avenue NW., Washington, D.C. 20428. ble: Postal Rate Commission............ 10 SUBJECT: Chairman, Marvin S. Cohen Railroad Retirement Board....... 11 Member, Elizabeth E. Bailey Securities and Exchange Com­ 10. Dockets 33115, 33298, 33315, 33524, Member, Gloria Schaffer 33562, 33581, 33671, 33674, 33876, 34019, mission..................................... 12 , 13 34570, and 34067; Applications for various Member O’Melia was not present. Salt Lake City markets (Memo #8412-C, Public disclosure, particularly to for­ BPDA, OGC, BLJ). eign governments of opinions, evalua­ [6320-01-M ] STATUS: Open. tions, and strategies discussed could seriously compromise the ability of 1 PERSON TO CONTACT: the United States Government to Phyllis T. Kaylor, the Secretary, achieve understanding in future rate [M-203, Amdt. 2; Mar. 13; 19791 negotiations which would be in the 202-673-5068. best interests of the United States. Ac­ CIVIL AERONAUTICS BOARD. SUPPLEMENTARY INFORMATION: cordingly, the staff believes that Addition of item to the March 15, public observation of this meeting 1979 meeting agenda. Item 10 was deleted from the March 15, 1979 agenda in order for the staff would involve matters the premature TIME AND DATE: 10 a.m., March 15, to do additional work. Accordingly, disclosure of which would be likely to 1979. the following Members have voted significantly frustrate future action PLACE: Room 1027, 1825 Connecticut that agency business requires the dele­ within the meaning of the exemption Avenue NW., Washington, D.C. 20428, tion of Item 10 from the March 15, provided Under'S U.S.C. 552b(c)(9) and 1979 agenda and that no earlier an­ 14 CFR 310b.5(9)(B). SUBJECT: nouncement of this change was possi­ Chairman, Marvin S. Cohen 26b. Revised transatlantic fares proposed ble: Member, Elizabeth E. Bailey by various carriers. T h e proposals include Chairman, Marvin S. Cohen Member, Gloria Schaffer increases in most normal and, promotional Member, Elizabeth E. Bailey fares (BPDA, BIA.) Member O’Melia was not present. Member, Gloria Schaffer STATUS: Open. P ersons E xpected To A ttend [S-551-79 Filed 3-16-79; 2:49 pm] PERSON TO CONTACT: Board Members.—Chairman, Marvin S. Cohen; Member, Elizabeth E. Bailey; Phyllis T. Kaylor, the Secretary, Member, Gloria Schaffer. * 202-673-5068. Assistants to Board Members.—Mr. Stephen [6320-01-M] H. Lachter. SUPPLEMENTARY INFORMATION: Acting Managing Director.—Mr. Sanford This memo was not submitted earlier 3 Rederer. due to the variety and timing of the Executive Assistant to Managing Director.— carriers’ proposals, each of which ne­ [M-203, Amdt. 4; March 15, 1979] Mr. John R. Hancock. cessitated alterations in the compre­ CIVIL AERONAUTICS BOARD. Bureau of Pricing and Domestic Aviation.— hensive draft order. The order must be Mr. Michael E. Levine, Ms. Barbara A. submitted to the President no later Closure and additions to the March Cliurk, Mr. James L. Deegan, Mr. Herbert than March 15. Accordingly, the fol­ 15,1979 meeting agenda. P. Aswall, and Mr. Douglas V. Leister. lowing Members have voted that Bureau of International Aviation.—Mr. TIME AND DATE: 9:30 a.m., March Donald A. Farmer, Jr., Mr. Francis S. agency business requires the addition 15,1979. Murphy, and Mr. David A. Levitt. of Item 26b to the March 15, 1979 Bureau of Consumer . Protection.—Mr agenda and that no earlier announce­ PLACE: Room 1011, 1825 Connecticut Avenue NW., Washington, D.C. 20428. Reuben B. Robertson and Ms. Patricia ment of this addition was possible. Kennedy. Chairman, Marvin S. Cohen SUBJECT: Office of Economic Analysis.—Mr. Robert Member, Richard J. O’Meila Frank and Mr. Richard Klem. A. U.S.-Canada “Seat Sale” fares proposed Office of the General Counsel.—Mr. Philip Member, Elizabeth E. Bailey by Air Canada (BPDA, OGC, BIA, BCP). J. Bakes. Jr. and Mr. Peter B. Schwarz Member, Gloria Schaffer B. U.S.-France “Vacances” fares proposed kopf by Air France (Memo 8605, BPDA, BIA;. Office of the Secretary.—Mrs. Phyllis T CS-550-79 Filed 3-16-79; 2:49 pm] STATUS: Closed. Kaylor and Ms Linda Senese. FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17024 SUNSHINE ACT MEETINGS G eneral C ounsel C ertification TIME AND DATE: 11 a.m., Friday, S-477-79 published at page 13632 in March 23,1979. the issue of Monday, March 12,1979. I certify that this meeting may be CORRECTION: The agenda items for closed to the public under 5 U.S.C. PLACE: 20th Street and Constitution 552b(c)(9) and 14 CFR 310b.5(9)(B) Avenue NW., Washington, D.C. 20551. Wednesday, April 4 were incorrectly and that the meeting may be closed to STATUS: Closed. printed. The correct listing is: public observation. MATTERS TO BE CONSIDERED: American National Standards Institute G ary J . E dles . Presentation. Report from National Confer­ 1. Proposed purchase of a telephone ence on Weights and Measures. Acting General Counsel. system, under competitive bidding, for the Presentation on Australian Experience in [S-552-79 Piled 3-16-79; 2:49 pml Federal Reserve Bank of Kansas City. Metric Conversion. 2. Proposed alternatives for promoting use CONTACT PERSON FOR MORE IN­ of the Susan B. Anthony $1 coin. 3. Personnel actions (appointments, pro­ FORMATION: [6712-01-M ] motions, assignments, reassignments, and Joan Phillips, 703-235-1933. salary actions) involving individual Federal 4 Reserve System employees. Louis F. P olk, FEDERAL COMMUNICATIONS 4. Any agenda items carried forward from Chairman, a previously announced meeting. United States Metric Board. COMMISSION. CONTACT PERSON FOR MORE IN­ [S-545-79 Filed 3-16-79 9:31] TIME AND DATE: 12:45 p.m., Thurs­ FORMATION: day, March 15,1979. .Mr. Joseph R. Coyne, Assistant to PLACE: Room 856, 1919 M Street the Board: 202-452-3204. [7590-01-M ] NW., Washington, D.C. Dated: March 15,1979. 9 STATUS: Emergency Closed Commis­ sion Meeting. G riffith G arwood, NUCLEAR REGULATORY COM­ Deputy Secretary MISSION. MATTERS TO BE CONSIDERED: of the Board. Agenda, Item No., and Subject [S-543-79 Filed 3-16-79; 9:31 a.m.] TIME AND DATE: Thursday, March 15, 1979 and Thursday, March 22, Complaints and Compliance—2—Investiga­ 1979. tion into the operation of Station WJAN (TV), Canton, Ohio. [7020-02-M] PLACE: Commissioners’ Conference If additional information is required 7 Room, 1717 H Street NW., Washing­ concerning this emergency closed ton, D.C. INTERNATIONAL TRADE COM­ meeting, it may be obtained from FCC MISSION. STATUS: Open and closed. Public Information Office, telephone MATTERS TO BE CONSIDERED: number 202-632-7260. [USITC SE-79-14] Issued: March 16, 1979. TIME AND DATE: 10 a.m., Tuesday, ADDITIONAL ITEM [S-548-79 Piled 3-16-79; 2:05 pm] March 27,1979. T hursday , M arch 15, 2 p .m . PLACE: Room 117, 701 E Street NW., 1. Discussion of litigation implications of [6715-01-M ] Washington, D.C. 20436. Commission testimony on recent shutdown orders. (Closed—exemption 10). STATUS: Parts of this meeting will be N ote .—Discussion of legislative program 5 open to the public. The rest of the was postponed. FEDERAL ELECTION COMMIS­ meeting will be closed to the public. T hursday , M arch 22, 9:30 a.m . SION. MATTERS TO BE CONSIDERED: 1. Briefing on upgrade rule and support­ “FEDERAL REGISTER" NO. FR-S- Portions open to the public: ing guidance (approximately 2 hours—open 541. 1. Agenda. portions may be closed—exemption 1). PREVIOUSLY ANNOUNCED DATE 2. Minutes. T hursday , M arch 22, 2 p .m . AND TIME: Thursday, March 22, 1979 3. Ratifications. at 10 a.m. 4. Petitions and complaints, if necessary. 1. Discussion of Staff’s final report, “Reg­ 5. Doxycycline (Inv. 337-TA-3)—vote. ulation of Federal Radioactive Waste Activi­ CHANGE IN MEETING: The follow­ 6. Any items left over from previousties" (approximately 1 hour—public meet­ ing matter has been added to the open agenda. ing). portion of the above scheduled meet­ 2. Discussion of proposed executive ing: Computer contract. Portions closed to the public. branch format for analyses of export appli­ 7. Status report on Investigation 332-101 cations (approximately 1 hour—open, por­ PERSONS TO CONTACT FOR IN­ (MTN Study), if necessary. tions may be closed—exemption 1) (post­ FORMATION: poned from Tuesday, March 20). CONTACT PERSON FOR MORE IN­ 3. Affirmation session (approximately 10 Mr. Fred S. Eiland, Public Informa­ FORMATION: minutes—public meeting). ^ tion Officer, telephone 202-523-4065. a. Amendments to 10 CFR 35. Kenneth R. Mason, Secretary, 202- b. Amendments to 10 CFR 140. M arjorie W. E mmons, 523-0161. c. Modification of Price-Anderson Act. Secretary to the Commission. [S-546-79 filed 3-16-79; 10:46 am] CONTACT PERSON FOR MORE IN­ [S-542-79 Piled 3-16-79; 9:31 am] FORMATION: [3510-13-M] Walter Magee, 202-634-1410. [6210-01-M] 8 W alter M agee, Office of the Secretary. 6 METRIC BOARD. M arch 1 5 ,1 9 7 9 . BOARD OF GOVERNORS OF THE "FEDERAL REGISTER" CITATION FEDERAL RESERVE SYSTEM. OF PREVIOUS ANNOUNCEMENT: [S-549-79 Filed 3-16-79; 2:05 pm] FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 SUNSHINE ACT MEETINGS 1 7 0 2 5 -1 7 0 6 3 [7715-01-M ] CHANGES IN MEETING: Deletion; 552b(cX4)(8)(9XA) and (10) and 17 rescheduling; additional items. CFR 200.402(a)(8X9Xi) and (10). 10 The following item scheduled was Commissioners Loomis, Evans, Pol­ POSTAL RATE COMMISSION. not considered at the closed meeting lack and Karmel determined to hold on Tuesday, March 13, 1979, at 9 a.m.: the aforesaid meetings in closed ses­ “FEDERAL REGISTER” CITATION sion. OF PREVIOUS ANNOUNCEMENT: Institution of injunctive action and ad­ ministrative proceedings. The subject m atter of the closed 44 FR 13125. March 9, 1979. meetings scheduled for Tuesday, PREVIOUSLY ANNOUNCED TIME The following items scheduled for March 20,1979, will be: AND DATE OF THE CLOSED MEET­ consideration at a closed meeting on Wednesday, March 14, 1979, immedi­ Litigation matters. ING: March 14, 1979, 8:30 a.m. ately following the open meeting at 10 Access to investigateive files by Federal, State, or Self-Regulatory Authorities. CHANGES IN THE MEETING: Meet­ a.m. have been rescheduled for Settlement of administrative proceedings ing date and time changed to March Wednesday, March 28,1979: of an enforcement nature. 20,1979, 8:30 a.m. Reports of Investigation. Formal order of investigation. Institution of administrative proceedings Meeting remains closed pursuant to Regulatory matter bearing enforcement of an enforcement nature. 5 U.S.C. 552b(c)<2)(6). implications. Institution and settlem ent of administra­ CONTACT PERSON FOR MORE IN­ The following additional items will tive proceedings of an enforcement nature. FORMATION: be considered at a closed meeting Institution and settlem ent of administra­ scheduled for Wednesday, March 14, tive proceedings of an enforcement nature Ned Callan, Information Officer, 1979, immediately following the open and settlem ent of injunctive action. Postal Rate Commission, Room 500, Freedom of Information Act appeals. meeting at 10 a.m. Chapter X proceeding. 2000 L Street N.W., Washington, D.C. 20268, telephone 202-254-5614. Settlem ent of administrative proceedings The subject m atter of the closed of an enforcement nature. [S-544-79 Filed 3-16-79; 9:31 a.m.'] Access to investigative files by Federal, meeting scheduled for Thursday, State, or Self-Regulatory Authorities. March 22,1979, immediately following the open meeting at 10 ajn., will be: Chairman Williams and Commis­ [7905-01-M ] sioners Loomis, Evans, Pollack and Opinions. 11 Karmel determined th at Commission The subject m atter of the open business required the above changes meeting scheduled for Thursday, RAILROAD RETIREMENT BOARD. and that no earlier notice thereof was March 22,1979, at 10 a.m., will be: TIME AND DATE: 9:30 a.m., March possible. 22, 1979. 1. Consideration of an order which would M arch 14,1979. make permanent a temporary exemption PLACE: Board’s meeting room on the tS-553-79 Filed 3-16-79; 3:29 pm] from the provisions of Section 9(a) of the 8th floor of its headquarters building Investment Company Act granted in July, at 844 Rush Street, Chicago, 111., 1978 (see Investment Company Act Release 60611. No. 10318) to John Nuveen & Co., Inc, and [8010-01-M ] Peter A. Leonard. For further information, STATUS: The entire meeting will be please contact G. Sundick at (202) 755-1250 closed to the public. 13 or H. Schiffman at (202) 755-1788. 2. Consideration of a proposal to adopt MATTERS TO BE CONSIDERED: SECURITIES AND EXCHANGE technical amendments to Investment Com­ (1) Appeal from referee’s denial of dis­ COMMISSION. pany Act Rule 24f-2 Notice requirements; abled child’s annuity, Mary Ann Kelly. effective April 21, 1979. For further infor­ Notice is hereby given, pursuant to mation, please contact Steven M. Felsen- (2) Appeal from referee’s denial of estab­ the provisions of the Government in stein at (202) 376-8049. lishment of a “disability freeze” period, James E. Moore. the Sunshine Act, Pub. L. 94-409, that 3. Consideration of the Freedom of Infor­ the Securities and Exchange Commis, mation Act Appeal of Joseph P. Aver ill from CONTACT PERSON FOR MORE IN­ sion will hold the following meetings a decision of the Commission’s Freedom of FORMATION: during the week of March 19, 1979, in Information Act Officer denying access to certain Commission correspondence files re­ R. F. Butler, Secretary of the Board, Room 825, 500 North Capitol Street, lating to Castlewood International Corpora­ COM No. 312-751-4920, FTS No. Washington, D.C. tion on the basis of Exemption 5 of the 387-4920. Closed meetings will be held on Freedom on Information Act, 5 U.S.C. IS-547-79 Filed 3-16-79; 11:04 am] Tuesday, March 20, 1979, at 10 a.m. 552(b)(5) (inter or intra-agency memoranda and on Thursday, March 22, 1979, im­ or letters). For further information, please mediately following the 10 a.m. open contact William Dietch at (202) 755-1342. meeting. An open meeting will be held 4. Approval of an action taken by the duty [8010-01-M ] on Thursday, March 22, 1979 at 10 officer to issue an order correcting typo­ graphical errors in its Findings and Opinion a.m. in the matter of Eastern Utilities Associates 12 The Commissioners, their legal assis­ voluntary plan of reorganization filed pur­ SECURITIES AND EXCHANGE tants, the Secretary of the Commis­ suant to § 11(e) of the Public Utility Holding COMMISSION. sion, and recording secretaries will Company Act of 1935 (HCAR No. 20931). attend the closed meetings. Certain For further information, please contact “FEDERAL REGISTER” CITATION staff members who are responsible for Grant G. Guthrie at (202) 523-5156. OF PREVIOUS ANNOUNCEMENT: the calendared matters may be pres­ 44 FR 11892, March 2,1979. ent. FOR FURTHER INFORMATION, STATUS: Closed meeting. The General Counsel of the Com­ CONTACT: PLACE: Room 825, 500 North Capitol mission, or his designee, has certified Michael Rogan at (202) 755-1638. Street, Washington, D.C. that, in his opinion, the items to be considered at the closed meetings may M arch 14,1979. d a te p r e v io u s l y a n n o u n c e d : be considered pursuant to one or more March 5,1979. of the exemptions set forth in 5 U.S.C. [S-554-79 Filed 3-16-79; 3:29 pm] FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 TUESDAY, MARCH 20,1979 PART II DEPARTMENT OF STATE FISHERY CONSERVATION A N D MANAGEMENT ACT OF 1976 A pp lication s for Permits to Fish O f f the C oasts o f the United States NOTICES 17 06 7 [4710-09-M] Fisheries Service, Department of Com­ merce, Washington, D.C. 20235, tele­ DEPARTMENT OF STATE phone (202)634-7265. O ffice o f th e S ecretary Dated: March 9,1979. B rian S. H allman, [Public Notice 653] Acting Director, FISHERY CONSERVATION AND MANAGEMENT Office of Fisheries Affairs. ACT OF 1976 Fishery codes and designation of re­ gional councils which review applica­ A pplications fo r Perm its To Fish O ff th e C oasts tions for individual fisheries are as fol­ o f th e U nited S tates lows: The Fishery Conservation and Man­ agement Act of 1976 (P.L. 94-265) as Code Fishery Regional Council amended (the “Act”) provides that no fishing shall be conducted by foreign ABS Atlantic Billfishes and New England fishing vessels in the Fishery Conser­ Sharks. Mid-Atlantic vation Zone of the United States after South Atlantic February 28, 1977, except in accord­ Gulf of Mexico ance with a valid and applicable Caribbean BSA Bering Sea and Aleutian North Pacific permit issued pursuant to Section 204 Islands Trawl, of the Act. Longline and Herring The Act also requires that a notice Gillnet. of receipt of all applications for such CRB Crab (Bering Sea)........... North Pacific GOA Gulf of Alaska................ North Pacific permits, a summary of the contents of NWA Northwest Atlantic........ New England such applications, and the names of Mid-Atlantic the Regional Fishery Management SMT Seamount Groundfish Western Pacific (Pacific Ocean). Councils that receive copies of these SNL Snails (Bering Sea)........ North Pacific applications, be published in the F ed­ woe Washington, Oregon, Pacific eral R egister. California Trawl. Individual vessel applications for fishing 1979 have been received from Activity codes specify categories of Japan, Korea and the Polish People’s fishing operations applied for as fol­ Republic and are summarized herein. lows: If additional information regarding Activity Code and Fishing Operations any applications is desired, it may be 1— Catching, processing, and other support. obtained from: Permits and Regula­ 2— Processing and other support only. tions Division (F37), National Marine 3— Other support only. Nation/vessel name/vessel type Application No. Fishery Activity Korea: Dongwon No. 31, longliner......................... KS-79-0053... .... BSA, GOA....................... 1 Japan: N ittoh Maru, longliner.............................. JA-79-0842.... .... SNA................................ 1 M is h im a Maru, cargo/transport............... JA-79-1023.... .... BSA, GOA, NWA............. 3 Y u y o Maru, cargo/transport..................... JA-79-1033.... .... BSA, CRB, GOA, NWA, 3 SMT, SNA. N ip p o n h a m Maru No. 1, cargo/transport. JA-79-1082.... .... BSA CRB. GOA NWA, 3 SMT, SNA. Seki Rex, cargo/transport......................... JA-79-1148.... .... BSA. GOA, GOA, NWA, 3 SMT, SNA. Tama Rex, cargo/transport...................... JA-79-1149.... .... BSA, CRB. GOA, NWA, 3 SMT, SNA. JunJco Maru No. 3, longliner..................... . JA-79-1320.... .... ABS................................ 1 Poland: Goplo, large side trawler............. .............. PL-79-0057.......... NWA............................... 1 M u re n a , large stem trawler....................... PL-79-0058.... .... NWA............................... 1 Wigry, large side trawler........................... PL-79-0059.... .... NWA............................... 1 Avnor, large stem trawler.......................... PL-79-0060.... .... GOA, NWA, WOC........... 1 [FR Doc. 79-8090 Piled 3-19-79; 8:45 am] FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 TUESDAY, MARCH 20, 1979 PART III DEPARTMENT OF HEALTH, EDUCATION, A N D WELFARE Food and Drug Administration CHEMICAL COM POUNDS IN FOOD-PRODUCING ANIMALS Criteria a n d Procedures for Evaluating A ssa y s for Carcinogenic Residues 17070 PROPOSED RULES [4110-03-M] withdrawal periods to prevent the oc­ proposed regulations and were not re­ currence of carcinogenic residues in published for comment. DEPARTMENT OF HEALTH, edible animal products. Based on AHI’s affidavits contend­ EDUCATION, AND WELFARE Prior to July 19, 1973, FDA had ap­ ing that the statistical procedure for plied the DES proviso on a case-by­ extrapolation of animal data adopted Food a n d Drug A dm inistration case basis, without published criteria. in the final order was significantly dif­ However, the Commissioner of Food ferent from and more complex than [21 CFR P arts 70, 500, 514, 571] and Drugs concluded that it was ap­ that proposed, and perhaps improper­ propriate to establish criteria and pro­ ly interpreted, the court remanded the [Docket No. 77N-0026] cedures for their application through case to the agency for further consid­ CHEMICAL COMPOUNDS IN FOOD- rulemaking to permit public discussion eration. The court also required the PRODUCING ANIMALS of the scientific, legal, and policy agency to assess the question raised by issues involved. Accordingly, the Com­ AHI about the technical feasibility of C riteria a n d P rocedures for E valuating A ssay s missioner proposed a set of regula­ the regulations, and it suggesed that for C arcinogenic R esidues tions, in the F ederal R egister of July the Commissioner repropose the regu­ AGENCY: Food and Drug Administra­ 19, 1973 (38 FR 19226), and afforded lations (.Animal Health Institute v. tion. 60 days for public comment. Food and Drug Administration, Civil The numerous comments received No. 77—806 (D.D.C. Feb, 8, 1978)). In ACTION: Proposal. were submitted by scientists affiliated accordance with the court’s order, the SUMMARY: The Food and Drug Ad­ with consumer groups, universities, Commissioner revoked the regulations ministration (FDA) is proposing to es­ scientific societies, State and Federal on May 26, 1978 (43 FR 22675) and is tablish procedures and minimum crite­ agencies, trade associations, and af­ now reproposing all the regulations ria to ensure the absence of cancer- fected manufacturers; some were from for public comment. In this proposal, causing residues in edible products of nonaffiliated individuals. Many com­ the Commissioner has evaluated and food-producing animals to which ments revealed a sharp divergence of responded to AHI’s allegations, the drugs, food additives, or color addi­ opinion concerning FDA’s interpreta­ court’s questions, the citizen petitions tives have been administered. This is a tion of the proviso to the aniticancer to revoke the regulations, and all com­ reproposal of regulations revoked in clauses of the act. ments filed on the final order. (For accordance with a court order. The Commissioner promulgated the the sake of clarity, the final order is DATES: Comments by July 18, 1979: final regulations in the F ederal R egis­ hereafter designated the “February Notices of participation for the public ter of February 22, 1977 (42 FR notice” or the “1977 notice”.) hearing by May 4, 1979. Public hearing 10412), but solicited comments on four Since the July 1973 proposal, the before the Commissioner June 4, 1979. specific issues: (1) The acceptable level Commissioner has used the risk assess­ of risk, (2) comparative metabolism, ment element of the regulations as the ADDRESSES: Comments and notices (3) regulation of endogenous com­ prototype for segments of the agency’s of participation are to be submitted to pounds, and (4) methods of determin­ anticancer policy. Before attempting the Hearing Clerk (HFA-305), Food ing an assay’s lowest limit of reliable to build a uniform procedure for regu­ and Drug Administration, Rm. 4-65, measureent. On March 23 and 24, lating all chemicals in the food supply, 5600 Fishers Lane, Rockville, MD 1977, the Animal Health Institute the Commissioner has adopted where 20857. (AHI) and three other groups peti­ appropriate, the best elements of the FOR INFORMATION ON THIS tioned the Commissioner to stay the emerging scientific and regulatory pro­ PROPOSAL, CONTACT: effective date of the regulations and to cedures of risk assessment, metabolism Robert J. Condon, Bureau of Veteri­ then revoke them. The Commissioner studies, in vitro mutagenesis tests, etc., nary Medicine (HFV-105), Food and denied these petitions on April 27. In for regulating residues in food derived Drug Administration, Department of response to a separate request by AHI, from food-producing animals. | Health, Education, and Welfare, however, the Commissioner extended The Commissioner selected this class 5600 Fishers Lane, Rockville, MD the comment period to July 25, 1977 of compounds as the test model be­ 20857, 301-443-1580. (42 FR 24254). cause FDA has premarket approval On May 12, AHI filed a complaint in authority over the chemicals inten­ FOR FURTHER INFORMATION ON the United States District Court for tionally used in these animals, and the THE HEARING BEFORE THE COM­ the District of Columbia alleging that DES proviso to the Delaney clause has MISSIONER CONTACT: the regulations were unlawful: (1) be­ made regulation of these compounds Constantine Zervos, Director, Se- cause they broadened the scope of the one of the agency’s most difficult cientific Liaison and Intelligence Delaney, i.e., anticancer, clause of the tasks. [ Staff (HFY-31), Food and Drug Ad­ act to include substance that have not Based on experience with the princi­ ministration, Department of Health, ■been determined to be carcinogenic, ples outlined in the proposal, gained Education, and Welfare, 5600 Fish­ and (2) because they foreclosed mar­ through several years of regulating ers Lane, Rockville, MD 20857, 301- keting of a compound unless there these chemicals on a case-by-case 443-4490. exists an assay of sufficient “senseti- basis, the Commissioner believes that SUPPLEMENTARY INFORMATION: -vity” to detect residues of the com­ they have potential applicability for These proposed regulations would pro­ pound at “theoretically” safe levels de­ regulating all compounds covered by vide an operational definition of the termined by the regulations. Also, AHI the act. Moreover, due to the exten­ no-residue requirement of the so- alleged that the regulations were im­ sive interest in the issues, the Commis­ called “DES proviso” to the anticancer practical and embodied novel on sioner now believes that the time is clauses, sections 409(c)(3)(A), highly suspect technical principles ripe for formulating a comprehensive 512(d)(1)(H), and 706(b)(5)(B), of the that would impose enormous financial approach for regulating all chemical Federal Food, Drug, and Cosmetic Act and environmental costs on the animal carcinogens. Expanding the use of the (21 U.S.C. 348(c)(3)(A), 360(d)(1)(H), health industry. Finally, it alleged principles set out in these regulations and 376(b)(5)(B)). The regulations also that the final regulations violated the into other areas regulated by the propose to establish criteria for ac­ Administrative Procedure Act (5 agency seems desirable from the per­ cepting assays and procedures for es­ U.S.C. 551 note) because they depart­ spectives of science and public health tablishing suitable postadministration ed from and radically changed the protection, but the results of their ex- FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17071 panded use, e.g., cost, cannot now be ington, DC area at a place to be an­ tion 409 was enacted to protect con­ calculated. nounced later. sumers by requiring substances that Because an error in selecting the A written notice of participation are intentionally added to food, or basic principles could lead to a future must ~be filed in accordance with may reasonably be expected to become tragedy, the principles adopted at this § 12.45 (21 CFR 12.45) with the Hear­ components or otherwise affect the time must be reasonable and must not ing Clerk (HFA-305), Food and Drug characteristics of food, to be shown to underestimate the potential risks asso­ Administration, Rm. 4-65, 5600 Fish­ be safe through rigorous scientific ciated with the use of chemicals. Ac­ ers Lane, Rockville, MD 20857, not testing procedures. As the legislative cordingly, the Commissioner is propos­ later than May 4, 1979. The envelope history of the amendment demon­ ing to adopt principles that some may containing the notice of participation, strates, one primary function was to consider too “conservative.” The term and the notice of participation itself, protect the health of consumers by re­ “conservative,” however, is relative. should be prominently marked “SOM quiring manufacturers of food addi­ Further, although the principles form Hearing.” The notice of participation tives and food processors to test any an integrated scheme of regulation, in­ must also contain Hearing Clerk potentially unsafe substances that are dividual segments can be severed and Docket No. 77N-0026, the name, ad­ added to food in accordance with prin­ replaced. dress, and telephone number of the ciples deemed appropriate by qualified For all the foregoing reasons, the person desiring to make a statement, scientists (Ref. 1). Commissioner has determined that, in along with any business affiliation, Before the amendment, FDA’s au­ addition to the 120-day comment the text of the presentation, and the thority for ensuring the safety of food period for filing written comments, an approximate length of time requested additives was limited to sections informal public hearing should be for the presentation. The Commission­ 402(a)(1) and 402(a)(2)(A) as enacted held in accordance with Part 15 (21 er is requiring submission of the text in 1938. Under these sections the CFR Part 15). The informal public of all presentations before the hearing agency must show that an intentional­ hearing will provide an open forum for to promote a comprehensive discussion ly added food substance may be injuri­ the presentation of information, views, of the issues, but the Commissioner ous to health. Thus, the agency has to and discussions on all aspects of the recognizes that some revisions in the test the poisonous or deleterious sub­ proposal. Because the general princi­ sary.text before the hearing may be neces­ stance before taking action. Therefore, ples articulated in the regulations be mailed A schedule for the hearing will the amendment shifted the burden of to each person who files a both testing and proving safety to the have widespread potential use, the notice of participation: Commissioner asks that the witnesses the schedule proponent of the additive. focus on the principles that form the will also be available from the FDA When the Committee on Interstate Hearing Clerk. Individuals and organi­ and Foreign Commerce reported the basis of the regulations, in addition to zations the issue of the technical feasibility of urged towith common interests are bill to the full House of Representa­ consolidate or coordinate tives, the bill did not contain an anti­ the required analytical technology. In their presentations. cancer clause, but it did contain a sec­ particular, the Commissioner requests If the responses to this notice of tion requiring the premarketing test­ discussion of the following: hearing are so numerous that insuffi­ ing of food additives to demonstrate 1. Threshold assessment procedures. 2. Criteria for selecting residues for cient the time is available to accommodate safety. That section is now known as full amount of time requested in the general safety provision (section chronic toxicity testing. the notices of participation received, 409(c)(3)(A)). After the bill was report­ 3. The types of investigations neces­ the Commissioner will allocate the sary to study how chemicals are me­ available time among the persons ed out, Congressman Delaney suggest­ ed the addition of the anticancer pro­ tabolized, and the role of these studies making the oral presentation to be viso to the bill, and the following pro­ in assessing the parent compound’s used as they wish. Final versions of viso was added to the bill as a Commit­ safety. written statements (preferably four tee amendment on August 13,1958: 4. The use of comparative metabo­ copies) should be presented to the pre­ lism studies for selecting the labora­ siding officer on the day of the hear­ * * * Provided, That no additive shall be tory animal species to be used as sur­ ing or submitted to the Hearing Clerk cancer deemed to be safe if it is found to induce when ingested by man or animal, or rogates for man in chronic toxicity by June 19, 1979 for inclusion in the if it is found, after tests which are appropri­ testing, administrative record. ate for the evaluation of the safety of food 5. The utility of short-term in vitro The plenary hearing will be open to additives, to induce cancer in man or animal mutagenesis tests in assessing the the public, and any interested person * * * safety of a compound. who has filed a written notice of par­ Reportedly to assure enactment of 6. Mathematical risk estimation pro­ ticipation may be heard concerning the legislation, the Committee and the cedures, including (a) methods of as­ matters raised in the written state­ Department of Health, Education, and sessing risks within a species and (b) ment which are relevant to the issues Welfare (HEW) agreed to the amend­ methods of cross-species extrapola­ under consideration. ment, but in a letter to the Chairman tion. Additional comments from interest­ of the Committee, then Assistant Sec­ 7. Procedures for combining data ed persons may be submitted during retary Elliot L. Richardson noted that from the same or different carcino­ the period following the hearing until the amendment did not change the genesis bioassays. the end of the comment period. meaning of the bill. Moreover, the 8. The regulation of endogenous sub­ letter also illustrates the interaction stances. I. I ntroduction between the general safety and anti­ 9- The acceptable level of risk. a. statutory background cancer provisions of the bill and the In preparing final regulations, the broad scope that the Delaney anti­ Commissioner will consider the admin­ 1. Food Additives Amendment of 1958 cancer clause is to be given. It makes istrative record of this hearing along Section 409 of the Federal Food, clear that the anticancer clause is a with all other written comments re­ Drug, and Cosmetic Act (Food Addi­ corollary of the general safety clause; ceived during the comment period tives Amendment of 1958, Pub. L. 85- and that compounds, even when sub­ specified in this proposal and on the 929) establishes criteria and prescribes ject to the anticancer clause, are also transcript of the Part 15 hearing. procedures for FDA’s premarket subject to the general safety clause: ioP 16 bearing will be held on June 4, review and approval of food additives This Department is in complete accord !9*9, starting at 9 a.m. in the Wash­ that have been shown to be safe. Sec­ with the intent of these suggestions—that FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17072 PROPOSED RULES no substance should be sanctioned for use in 3. Drug Amendments of 1962 duction, certain drugs are used in animal food that might produce cancer in man. feed which will leave no residue in the H.R. 13254, as approved by your committee, In 1962, Congress culminated several animal after slaughter or in any food prod­ will accomplish this intent, since it specifi­ years of hearings on the drug industry uct (such as milk or eggs) obtained from the cally instructs the Secretary not to issue a by enacting the Drug Amendments of living animal, and which are therefore per­ regulation permitting the use of an additive 1962 (Pub. L. 87-781); the infamous fectly safe for man. If this is demonstrated in food if a fair evaluation of the data thalidomide incident provided the im­ with respect to any particular additive in­ before the Secretary fails to establish that petus for the bill’s passage. The drug tended for animal feed, and the additive will the proposed use of the additive will be safe. not adversely affect the animal itself during The scientific tests that are adequate to es­ amendments brought about a compre­ its expected or intended life cycle, we can tablish the safety of an additive will give in­ hensive revision in the regulation of see no reason for not permitting such a use formation about the tendency of an additive new drugs, which at the time included of an additive which could be highly useful to produce cancer when it is present in food. both human and animal drugs. The and-beneficial in the raising of animals for Any indication that the additive may thus drug legislation also amended the anti­ food. * * * be carcinogenic would, under the terms of cancer clauses to rectify what Con­ We therefore have included in the en­ the bill, restrain the Secretary from approv­ gress perceived as the inequity associ­ closed draft bill an amendment to permit ing the proposed use of the additive unless ated with the prior sanctioned use of use of an additive in animal feed under the and until further testing shows to the point above-mentioned conditions. of reasonable certainty that the additive diethylstilbestrol (DES) in animal would not produce cancer and thus would be feed. Under the Food Additives * * • * * safe under the proposed conditions of use. Amendment of 1958, certain DES uses This would afford good, strong public in animals were prior sanctioned be­ Under the amendment, the assay methods health protection (Ref. 2). cause they were covered by an effec­ applicable in determining whether there tive New Drug Application (NDA). will be a residue shall be those prescribed or As enacted in 1958, the anticancer approved by us by regulations. This will give (or so-called Delaney) clause of section Thus, continued use in accordance reasonable certainty in that regard, al­ 409 flatly proscribed the approval of with the prior sanction was appropri­ though, of course, such regulations may any additive if after “a fair evaluation ate until that use was cancelled (the from time to time be changed as new scien­ NDA revoked), but no new uses in food tific developments demonstrate a need for of the data before the Secretary" the or food-producing animals were ap- change. It should be clearly understood that additive “is found to induce cancer provable due to the Delaney clause the industry still would have the responsi­ when ingested by man or animal, or if (Refs. 4 and 5). bility of developing adequate analytical it is found, after tests which are ap­ The act requires that compounds ad­ methods for detecting residues and furnish­ propriate for the evaluation of the ministered to animals as food addi­ ing them to the Government with a petition safety of food additives, to induce for approval of an additive (Ref. 3). tives, color additives, or animal drugs cancer in man or animal * * As ap­ be shown to be safe for use. As defined The amendments proposed by the plied to additives added directly to in section 201(u) of the act (21 U.S.C. Department had not been included in human food, this language has re­ 321(u)), the term “safe” clearly em­ the color additive legislation. During mained unchanged, although hotly de­ braces the health of man, as well as the following 2 years, however, con­ bated. Accordingly, as a legal matter, the health of the animals to which the cern had been continuing about appli­ section 409 precludes a finding by compounds are given. Thus, in evalu­ cation of the anticancer clause in sec­ FDA that a direct food additive that ating the safety of compounds to be tion 409. As a result, legislation similar has been%hown, by ingestion or other administered to animals raised or to that earlier recommended by HEW appropriate studies, to cause cancer in maintained for production of food for was introduced in 1962. The House laboratory animals (or, of course, in man, such as cattle, swine, and poul­ Committee on Interstate and Foreign man) can be safely added to food, in try, Congress has from the beginning Commerce ultimately included modifi­ any amount, for any purpose. recognized that consideration must be cations of the anticancer clause in its given to the safety of possible residues report on the Drug Amendments of 2. Color Additive Amendments of 1960 of the compounds in the products of 1962, with the following explanation: animals that become food for man, i.e., The committee amended the anticancer The Color Additive Amendments of meat, milk, and eggs. 1960 (Pub. L. 86-618) added a provi­ clause of the food additives amendment and Before 1962, the anticancer clauses the color additive amendment of the Feder­ sion to the basic act for colors that is in sections 409 and 706 did not distin­ al Food, Drug, and Cosmetic Act by fnaking directly analogous to the food addi­ guish between compounds added di­ this clause inapplicable to chemicals such as tives provision. Petitioners for color rectly to human food and compounds veterinary drugs when used in feed for food- additive regulations must demonstrate that might indirectly enter human producing animals if the Secretary finds (1) by rigorous testing the safety of these food through administration, as feed that under the conditions of use and feeding additives or drugs, to food-producing specified in the proposed labeling and rea­ additives before they can be approved sonably certain to be followed in practice, by FDA for addition to food, drugs, or animals. The act was interpreted as such additive will not adversely affect the cosmetics. In addition, the amend­ forbidding FDA to approve the use of animals for which such feed is intended, and ments added another anticancer a carcinogenic animal drug whether or (2) that no residue of the additive will be clause to the act. not the compounds might leave any found (by methods of examination pre­ The legislative history of the Color residues in the edible tissues of the scribed or approved by the Secretary by reg­ animal. ulations) in any edible portion of the animal Additive Amendments of 1960 de­ after slaughter or in any food such as milk scribes the congressional and execu­ Modification of the effect of the an- ticancer clause of section 409 had first or eggs yielded by or derived from the living tive (HEW) concern about the poten­ been suggested during congressional animal (Ref. 4). tial carcinogenicity of these color addi­ consideration of the Color Addition Representative Leonor K. Sullivan tives; nevertheless, the Secretary of Amendments of 1960. In May 1960, the objected to the proviso in the floor HEW again explained that an express then Secretary of Health, Education, debate on the amendments and pro­ anticancer clause was unnecessary to and Welfare had urged Congress to posed a separate amendment to delete prevent approval of carcinogenic or modify the act, explaining: the proviso from the bill because potentially carcinogenic color addi­ “they (the provisos to the Delaney tives because it did not provide any There is * * * one respect to which the anticancer proviso has proved to be' need­ clauses) weaken instead of strengthen public protection that is not already lessly stringent as applied to the use of addi­ consumer protection.” She reminded provided by the general safety clause tives in animal feed. For example, in the the House that DES had been regard­ (Ref. 3). case of various animals raised for food pro­ ed as safe for use in poultry at one FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17073 time because no residue was found in proviso, summarized above, does not because the Commissioner could never the meat; later, that use had to be ter­ lay to rest all doubts. find that no trace whatever would minated when DES residues were Two interpretations of the proviso remain in the edible tissues of the ani­ found as a result of improved testing are, in theory, possible. The first inter­ mals to which the compound was ad­ methods. But her amendment was de­ pretation, which in the Commission - ministered. feated principally on the argument er’s judgment is the less probable, is This interpretation would thus that, if DES were available for manu­ that Congress intended to allow FDA render the DES proviso a “Catch-22.” facture by those who obtained appro­ to approve the use of a carcinogenic The proviso would permit the Com­ vals before 1958, Le., the prior-sanc­ compound in food-producing animals missioner to approve carcinogenic tioned uses, it should be made availa­ only if the agency could be absolutely drugs for animals only when certain ble for manufacture by everyone (Ref. positive that no traces whatever—no that no residues whatever would 6). matter how small—would remain in remain, but since the Commissioner The Senate accepted the modifica­ edible tissues. could conclude only that some trace tions of the anticancer clauses in con­ This interpretation presents several might well remain, no such drug could ference while preserving, as Senator difficulties, all stemming from the fact ever be approved. Hubert Humphrey noted, the full that any introduction of a compound, Nevertheless, one comment on the vigor of consumer protection afforded whether or not carcinogenic, is likely February notice contended that Con­ by Delaney clause (Ref. 7). These to leave in edible tissues minute resi­ gress did indeed intend that the no­ modifications have come to be known dues, which are below the level of de­ residue provision be a flat prohibition as “the DES proviso.” tection of any known or likely to be on any molecules of a carcinogen in developed method of analysis, Le., food. The comment further argued 4. Animal Drug Amendments o f 1968 ' assay. It is a fundamental fact of ana­ th at Congress did not understand The animal feed industry experi­ lytical science that for every assay de­ fully the scientific ramifications of its enced an era of unprecedented growth veloped to measure the concentration action when it amended the pristine and innovation beginning in the of a chemical compound in a medium Delaney clause. 1950’s. That industry and the an im al (in this case, a residue in an edible As the Commissioner noted in the drug industry began an effort in the tissue), there is some lowest concentra­ February notice, the “absolutely no mid-1960’s to consolidate the various tion or level of the compound below molecules” interpretation seems, at provisions of the Federal Food, Drug, which the assay will not yield an inter- the very least, an improbable interpre­ and Cosmetic Act governing the pre­ pretable result (Ref. 9). If, for exam­ tation of an amendment enacted by marketing approval of drugs intended ple, an assay measures a particular Congress precisely because it wanted for use in animals, i.e., sections 409, compound in muscle tissue, i.e., an to relieve animal drugs from the rigid 505, 507 (21 U.S.C. 348, 355, and 357) edible tissue, and the assay has been strictures of the anticancer clauses. which culminated in the enactment of shown to have a lowest limit of mea­ Moreover, any interpretation of a stat­ the Animal Drug Amendments of 1968 surement of 1 part per billion (1 ppb— utory provision that would render it (Pub. L. 90-399). Neither the commit­ 1 part compound in 1 billion parts totally inoperative should be rejected tee reports on the bill nor the floor de­ tissue on a weight basis, such as 1 nan­ unless considerations of overwhelming bates raised the issue of the Delaney ogram of compound per 1 gram of persuasiveness require that interpreta­ clause. Consequently, the Animal tissue), examination of muscle tissue tion. No such considerations have been Drug Amendments of 1968 passed using this assay will reveal that the advanced in support of the “absolutely without controversy and added, under compound is present only if its concen­ no molecules” interpretation of the section 512(d)(i)(H) of the act, the fol­ tration in muscle tissue is 1 ppb or DES proviso. lowing anticancer clause and proviso: higher. If the compound is present in Furthermore, this interpretation is (H) such drug induces cancer when ingest­ the tissue at a level below 1 ppb, use of difficult to reconcile with the lan­ ed by man or animal or, after tests which the assay will yield no interpretable guage of the DES proviso itself. It are appropriate for the evaluation of the result. Thus, the assay connot distin­ specifies th at “no residue” may be safety of such drug, induces cancer in man guish between muscle tissues contain­ “found • • • by methods of examina­ or animal, except that the foregoing provi­ ing the compound at levels below 1 tion prescribed or approved by the sions of this subparagraph shall not apply ppb and muscle tissues from which the Secretary * * * in any edible portion with respect to such drug if the Secretary compound is absent in the absolute of such animals * * This language finds that, under the conditions of use speci­ sense of the term. fied in proposed labeling and reasonably conspicuously avoids such words as certain to be followed in practice (i) such Although different assays may have “occur” or “remain,” and instead, by drug will not adversely affect the animals different lowest limits of measure­ use of the word “found” emphasizes for which it is intended, and (ii) no residue ment, all assays are subject to the detectability. Moreover, the same pro­ of such drug will be found (by methods of same type of limitation. Thus, when a viso refers to “conditions of use * * * examination prescribed or approved by the tissue is examined with an assay reasonably certain to be followed in Secretary by regulations, which regulations having a lowest limit of measurement practice”, suggesting a congressional shall not be subject to subsections (c), (d), of 1 ppb and no interpretable response and (h)), in any edible portion of such ani­ recognition that some occurrences of mals after slaughter or in any food yielded is observed, the analyst can conclude these residues (i.e., resulting from un­ by or derived from the living animals, * • *. only that the compound under analy­ foreseeable misuse) might not require sis is not present at a level of 1 ppb or withdrawal of approval of a compound Again, the legislative history indi­ above. It can never be concluded that even if they were detected. cates that the legislation in no way the compound is “not present” in the A second, and in the Commissioner’s weakens FDA’s authority to regulate absolute sense. It is thus impossible to view more plausible, interpretation of new animal drugs (Ref. 8). determine the conditions under which the DES proviso accepts the words of B. STATUTORY INTERPRETATION edible tissues derived from food-pro­ the amendment and focuses on thè ducing animals that have received a previously quoted language, “no resi­ The enactment in 1962 of the so- carcinogen will contain no residue if due of such drug will be found * * * by called DES proviso to the Delaney the phrase “no residue” is to be inter­ methods of examination prescribed or clause has been a source of continuing preted literally. Accordingly, this first approved by the Secretary by regula­ controversy. There is no unanimity on possible interpretation of the DES tions * * *.” Under this interpretation, the proper interpretation of the provi­ proviso would not permit approving a sponsored compound that is carcino­ so; and the legislative history of the any known carcinogenic animal drug genic may be approved for use in ani- FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17074 PROPOSED RULES mals if examination of edible tissues term animal studies (the fundamental that, under the proposed conditions of by an assay approved by FDA reveals information for assessing a com­ use, the compound is sáfe. no residues. This interpretation also pound’s carcinogenicity), or certain “Safe” means safe in all respects—in­ appears implicit in the limited case data regarding the residues in food to cluding safe from carcinogenicity. law addressing the issue (Hess & which man will be exposed if the com­ Thus, AHI’s argument that the Clark, Division of Rhodia, Inc.\. FDA, pound is approved. Also, AHI argues burden is on FDA to show carcinogen­ 495 F.2d 975 (D.C. Cir. 1974), Cheme- that FDA cannot prevent a sponsor icity rather than on the sponsor to tron Corp. v. United States DHEW, 495 from marketing a. compound when any show noncarcinogenicity is contrary to F.2d 995 (D.C. Cir. 1974), and AH1 v. assay for a carcinogen is available, the clear language of the act. It would FDA, supra). even if the assay fails to exhibit a impose on FDA two burdens that Con­ This second interpretation is in es­ lowest limit of reliable measurement gress manifestly intended to impose on sence the one that FDA has followed required by the data and extrapola­ petitioners for approval of substances since the passage of the DES proviso. tion procedure proposed in the regula­ under the act—the burden of testing The agency has approved carcinogenic tions. Citing Hess & Clark, Division of for safety-and the burden of proof on compounds for use in animal feed or Rhodia, Inc. v. FDA, AHI further con­ the issue of safety. The Delaney as animal drugs on the basis of assays tends that the Delaney clause imposes clauses clarify and emphasize the con­ capable of measuring prescribed levels upon FDA a standard corresponding gressional intent to protect the public of residues. to the level of technology at the time from carcinogenic risks; AHI would the application for the compound transform them into clauses that The court in AHI v. FDA found lack­ (new animal drug application (NADA) reduce the protection from carcino­ ing the agency’s previous attempt to or food additive petition) is approved; genic risks already provided by the define and explain, as a binding rule, Moreover, AHI argues that the modi­ general safety provisions. the criteria and procedures for evalu­ fied Mantel-Bryan procedure for sta­ The general safety provisions of the ating assays for carcinogenic residues tistically assessing the risk of chemical act provide the context for the De­ in edible products of animals. The carcinogenesis, which was included in laney clauses. Under them the sponsor court held that FDA had failed to pro­ the February notice, is a theoretical of a compound must submit adequate vide adequate public notice. One pur­ procedure that would require petition­ tests by all reasonably applicable pose of this document is to correct ers to develop assays capable of meas­ methods to show that the sponsored that defect. uring residues of compounds at levels compound will be safe when used. This The Commissioner believes that the that are far too conservative and that showing, of course, requires not only criteria to be applied in evaluating are technically and economically in­ toxicity testing but also an assay suit­ assays for carcinogenic residues in the feasible. The court in AHI v. FDA re­ able for measuring the compound and edible tissue of food-producing ani­ quested FDA to consider AHI’s argu­ substances formed in or on food as a mals must further the congressional ments on technical and economic feas­ result of its use. Only after the spon­ intent to minimize public exposure to ibility. sor of a compound has conducted all carcinogens, without nullifying the de­ AHI’s argument concerning the the required tests and submitted the cision reflected in the DES proviso, as burden of proof on the issue of car­ resulting data is FDA required to the first interpretation of the proviso cinogenicity might have merit if the make any showing that the Delaney would do. As explained more fully Delaney clauses stood alone and were clause or the DES proviso is applicable below, the criteria set forth in these applied in isolation from the other or that the compound has not other­ regulations for evaluating assays for provisions of the FFDC Act. However, wise been shown to be safe. carcinogenic residues are minimum re­ ever since their enactment, the anti­ quirements. They are designed to iden­ Adoption of AÍH’s interpretation cancer clauses have been regarded as a that FDA must prove that a com­ tify assays that are (1) reliable and particularization of the general safety practical for use by a regulatory pound is a carcinogen before the nec­ sections of the act, to which they essary data are submitted requires an agency and (2). capable of measuring attach as provisos; and they have been residues at levels that have been deter­ illogical reading of the statute in light applied in conjunction with the gener­ of its overall purpose and the legisla­ mined, on the basis of animal toxicity al safety provisions. They do not tests, to present no significant increase tive mandate surrounding it. There­ expand the scope of these sections. fore, the Commissioner rejects AHI’s in human risk of cancer. An assay that Under these general safety provisions, does not meet both criteria cannot be scheme of regulating chemical carcino­ a compound cannot be approved gens and potential carcinogens. approved. The Commissioner recog­ unless it is shown to be safe and in nizes that, for some compounds cur­ every case the petitioner has the Scrutiny of the Hess & Clark deci­ rently in use, no reliable and practical burden of showing safety. Section sion shows that the court did not even assay capable of sufficiently low limits 409(c)(3)(A) prohibits approval of a consider the procedure that FDA used of measurement now exists and that food additive if “the data before the to designate requiremens for an assay approval of their continued use must Secretary * * * fails to establish that under the DES proviso to the Delaney therefore be reexamined. the proposed use of the food additive clause; rather, the court accepted as Arguing that the Commissioner has * * * will be safe * * Section valid the agency’s designation of an incorrectly interpreted the Delaney 706(b)(4) prohibits the Secretary from assay. To the extent that the proce­ clause, AHI contends that it is a pre­ approving a color additive “unless the dures and criteria set forth in this cise statutory provision that must be data before him establish that such notice for assessing assays differ from construed very narrowly. Therefore, use * * * will be safe * * Section those used in evaluating the assay in­ AHI charges that the Commissioner’s 512(d)(l)B) requires the Secretary to volved in Hess & Clark, they are being interpretation has unduly, and illegal­ deny approval of a new animal drug if adopted by rulemaking in an area in ly, broadened the scope of the anti­ “the results tof tests submitted to the which the agency has considerable ex­ cancer clause. AHI contends that FDA Secretary] show that such drug is pertise and discretion because the area must prove that a compound is a car­ unsafe for use under [the conditions involves protecting the public against cinogen before the petitioner for the prescribed, recommended, or suggest­ cancer. compound’s use is required to comply ed in the proposal labeling thereof] AHI’s allegations that the regula­ with any provision of the proposed * * * or do not show that such drug is tions are technically and economically regulations. Ostensibly, AHI argues safe * * These sections of the act infeasible is an attempt to character­ that FDA must prove that the spon­ do not impose on FDA any burden to ize the agency’s actions as arbitrary sored compound is a carcinogen before prove that a substance is unsafe. and capricious. Several environmental a petitioner is required to submit Rather, they impose on the petitioner statutes (e.g., Clean Air Act, Federal either comprehensive data from long­ for approval the burden of showing Water Pollution Control Act, Federal FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17075 Insecticide, Fungicide, and Rodenti- creased disease burden that it would tives, color additives, or animal drugs. cide Act) contain specific provisions re­ unknowingly have to bear. The agency The Commissioner’s discretion to es­ quiring the Environmental Protection recognizes that the public health is tablish “methods of examination” for Agency (EPA) in certain instances to not advanced by imposing require­ detecting residues is to be exercised so make elaborate cost/benefit calcula­ ments for what is neither economical­ as to carry out that congressional pur­ tions in setting safe levels of human ly nor technically possible. It also rec­ pose. the factor that determines the exposure to chemicals in the environ­ ognizes that public health regulation acceptable level of measurment of an ment. Also, these statutes provide that requires common sense, a sense of pro­ assay method is protection of the EPA protect the environment from portion, and awareness of economic human food supply from carcinogenic contaminants by setting standards for and technical factors. In particular, risks. If, on the basis of toxicological the discharges permitted. EPA is au­ the agency should not impose econom­ considerations, the Commissioner de­ thorized to establish two types of ic costs that are not justified by some termines that a certain level of assay standards—health-based standards reduction of risks to the public health. measurement is necessary to prevent a and technology-based standards. For Nevertheless, the agency can properly significant human cancer risk from certain health-based standards the Su­ require improvements in or develop­ use of a carcinogenic substance in food preme Court has authorized that ments beyond currently available animals, then a method having that agency to require pollution reduction technology when there is sufficient level of measurement is necessary to by methods that are neither economi­ reason to believe that those improve­ carry out the congressional purpose. If cally nor technically feasible when the ments or developments are feasible no such method is feasible, or if it is agency is not explicitly required to and are needed to protect the public too costly to develop or apply one, consider cost ( Union Electric Compa­ health. In enacting public health legis­ then the choice is between refusing to ny v. EPA, 427 U.S. 241 (1976)). The lation, Congress intends that adminis­ permit the use of the substance alto­ United States Court of Appeals for the trative agencies carry out their as­ gether and permitting its use despite District of Columbia Circuit has subse­ signed missions with intelligence, good the fact there is no method of exami­ quently reached similar conclusions sense, and an awareness of the context nation that can prevent the use of the when interpreting analogous provi­ and consequences of their actions; but substance from presenting a signifi­ sions of the Federal Water Pollution unless it has expressly said so, there is cant human cancer risk. Under the Control Act, concerning regulation of no reason to think that it intended general safety clause and the Delaney the discharge of toxaphene endrin, them to be in thrall to the technologi­ clause, that choice can be resolved in cal or economic status quo. only one way: by refusing to permit and polychlorinated biphenyls (PCB’s) (see Hercules, Inc., et al v. Environ­ In the immediate context, the statu­ the use of the substance. tory structure and language provide been During the last decade, FDA has mental Protection Agency, No. 77- monitoring significant trends in 1248. (D.C'. Cir. Nov. 3, 1978); Environ­ considerable guidance with respect to the development of chemical, physical, mental Defense Fund, et al. v. Environ­ the issue of feasibility and costs. The mental Protection Agency, No. 77-1091 language permitting the use of car­ and biochemical methods of analysis cinogenic substances under certain cir­ ces,of trace toxicants in biological matri­ (D.C. Cir. Nov. 3, 1978)). i.e., tissues, biological fluids, etc. cumstances is a proviso to a clause pro­ In some cases the agency has exam­ The two possible exceptions not ap­ hibiting the use of carcinogens, and plicable here (establishment of toler­ that clause itself is a particularization ined the available methods, and the ances for unavoidable contaminants of a provision requiring safety general­ trends, of analysis of specific toxicants under section 406 and for pesticides ly. It is clear that in enacting the DES of public health concern (Ref. 10). In under section 408(h)), the Federal proviso Congress intended to create no other cases the agency has prepared Food, Drug, and Cosmetic Act con­ additional risk of human cancer and advancing submitted to Congress reports on tains no provisions requiring the Com­ beyond what would have existed in the frontiers of the analyt­ missioner to consider costs or techni­ the absence of the DEX proviso. That the central findings 11 ical sciences (Refs. and 12). One of of this continuing cal feasibility in making any safety de­ is why Congress used the language “no cision, including any decision involving residue * * * will be found.” By en­ activity is the observation of what can cancer-causing chemicals. The distinc­ acting and twice re-enacting the De­ properly be regarded as spectacular tion between the statutory provisions laney clause, Congress made clear its scientific progress in achieving ever- applicable to food additives, color ad­ willingness to ban entirely from the decreasing lowest limits of measure­ ditives, and animal drugs and those human food supply food additives, ment. There is no reason to believe applicable to pesticides and unavoid­ color additives, and animal drugs that that this progress in analytical chem­ able contaminant tolerances demon­ istry will stop or slacken in the fore­ present a carcinogenic risk to man. it seeable strates Congress’ decision to make enacted the DES proviso with the future. costs and technical feasibility relevant intent and expectation that the provi­ Table I shows the trend of the in­ to some public health matters but not sion that “no residue * * * will be creasing capacity of analytical chemis­ to others. Nevertheless, in light of the found” would sufficiently protect the try to detect the measure the presence court’s remand order, the Commission­ human food supply from any signifi­ of chemicals. Depending on the sub­ er recognized the agency’s obligations cant cancer risk from food additives, stance or class of substances, this de­ to review this element of the proposal. color additives, and animal drugs. crease in the lowest limits of measure­ Based on the act’s legislative history, Thus, in enacting the DES proviso, ment during the last 20 years ranges the case law, and the agency’s public Congress did not change in any way between two and five orders of magni­ protection function, the Commissioner the policy of the Delaney clause to nition tude. Table I also suggests that recog­ concludes that the procedures used to protect the human food supply from ciated of a public health problem asso­ with a toxicant accelerates the designate requirements for assays can carcinogenic additives and animal improvement of analytical methods be technology-forcing if necessary. drugs; it merely eliminated an applica­ needed to detect and measure it. In The Commissioner’s interpretation tion of the clause that it considered this connection it should be noted that recognizes the tension between, the unnecessary to the complete achieve­ accelerated rates of improvement in need to provide health protection and ment of that policy. . analytical methods . have generally the costs of that protection, and it at­ From this statutory structure and cerns been the result of public health con­ tempts to spur the private sector into diffused among the members of language, it is evident that any consid­ the scientific technological change only when such community at large. eration of feasibility and costs is sub­ They have not usually been the result change is necessary for protection of sidiary to the overriding congressional of the concerted effort of a sponsor or the public health. To do otherwise purpose to permit no additional industry to gain approval for use of a might force the public to accept an in­ human cancer risk from food addi­ substance of commercial value. FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 17076 PROPOSED RULES T able I .—Trends in A nalytical Chem istry D etection Techniques Compound and date Detection technique Limit of measurement Relative specificity DDT: 1940’s, 1950’s...... ™. Colorimetric.................. ... ....... ..... 10 ppm_______ .......____ Low. 1950's, 19fl0’s_____ Paper chromatography__ _______ 1 ppm....Moderate. 1970’s __ ____ Oas chromatography. „ _____ Pew ppb.™.«™«™™™........... Do. Oas chromatography/mass spec...... Few ppb.............«............High. Dioxins: 1940’s __________ ____________ _._______________ 1950’s, 1960’s........ „ Thin layer chromatography......„.... Non quant........ .............„ Moderate. 1970’»______ ___ Gas chromatography/mass spec «— Less than .1 ppb.«™......«.™ High. Mitrosaminee: 1940’s ___________ _______ ____..._______________ 1950’s, 1960’s........ „ Thin layer chromatography______ 10-30 ppb............_.............. Moderate. 1970’s __________ Gas chromatograptiy/mass spec...... 2 ppb._.___ _____ ,....... High. Cortisone: 1940's_______ _____ _________________________________ 1950’s, I960 *..... ...... Colorimetric__ __«________ ___ 4 mg/ml................................ Low. 197Q’s ........................ High press liquid chromatography.. About 5 ng...............««.«™-. Moderate. Chlorpromazine: 1940’s, 1950’s_____ Titrimetric___ ________ _______ 50-100 meg....______ ___ Low. 1960’s, 1970’s.__ __ chromatography .................................. A few meg________ ___ - Low. Hallucinogens (LSD, mescaline): 1940 s __________ _____________________________ 1960’s ................. Gas chromatography, fluorescence. 1970’s .................. ... NMR.............................................. Sub ng........................... .... High. Reserpine: 1040’s ............. ri. , 1950’s. 1960’s 1970’S.................. High. Lead: 1940’s .................. ... Colorimetry«.«™..........™.™..™ ™™— About 10 ppm............... .... Low. Polarography .................................. About 0.1 ppm.............. .... High. 1950’s .......... .. ......... __________________________ .....do______ Do. 1 9 6 0 ' s A t o m i c absorption—.—.— .™...™..™ About 1 ppm. Do. 1970's__________ ......do_____ ......__ ......do............. Do. Cadmium: 1940’s ______...._____________________________ 1950’s, 1960’s........... Colorimetry................................... About 50 ppb„—— „«.«« Medium. 1960's, 1970’s........... Atomic absorption.™.....™....«.«..™™.. About 0.3 ppb ___......... High. Digitalis drug: 1940’s ........................ Bioassay_____ _.«...._..«_______ LDm80 mg/kg__ ............... low. 1950's .................do-.——...........—.™—......——.««. .....do.™«..«........... . Do. 1960’s ....... An, ...................... i.................... .«...do....................... . Do. 1970’s ........ ........... Radioimmunoassay______ ,™___ _ About 0.5 ppb ................... High. Carbamates: 1940’s _______ _____ _______ ____„ ______ 1950's, 1960’s.—...... Thin layer chromatography, gas 50-100 ng«—. M o d e r a t e . chromatography. 1970’s ---- — . Gas chromatography....... ......... . About 1 ng..„—.— «—.— High. Organophosphates: 1940’s..«™_______ ____ ____________________ ___ 1950’s ______________________________________ _ 1960’s —— — — Gas chromatography.. About 40 pg.....„„....«_....... Moderate. 1970's.™____«.....„........do........ «....'.... __ do..™..™______ _____ High. ', Next; Table II shows the capability of some assays that are currently being used to measure trace contaminants in food. Although the assays have not been evaluated by all the specific criteria proposed by the regulation, they are useful regulatory tools; and the lowest limits of reliable measurement for these assays (which were principally developed by the government for monitoring purposes) illustrate the forefront of current analytical chemistry. T able I I .—Som e Assays fo r Trace C ontam inants in Food T hat Reflect Current A nalytical C a p a b ilit ie s Limit Detection and con- Substance under assay Food of meas- flrmatory techniques Reference * virement1 Cadmium, copper, and lead......«« Several types....... 5 ........™. Annodic stripping voltam- Jones, et al. metry». (1977). IV-Nitrosamines.............................. Several types Id««..™. Gas-liquid chromato- Razio, et al. including meat. graphy (QLC); mass (1971); Fine, et spectrometry (MS). al. (1975). Aflatoxins, Bl, B2, Gl, G12......... Peanut butter..... 5.0 High pressure liquid chro- Panaklake and matography; flúores- Scott (1977). cence detector. Benzoiaipyrene.............................. Smoked foods.— 2.—..«.. Thin layer chromato- Howard, et al. graphy * (TLC) ultravio- (1966). let and fluorescence de­ tection. Aflatoxin M l............................. Milk „«.«,______0.1.«™«. TLC-fluore8cence detec- Official Methods tion *, chemical deriva- of Analysis of tion. the AOAC. Aflatoxin Bl. B2. Gl, 02............. Peanut butter — 5.0—..... TLC-fluorescence detec- Official Methods tion ’. of Analysis of the AOAC. Corn.™™«,— « ,™.™™.„ TLC chemical derivation... Official Methods of Analysis of the AOAC. Aflatoxin B l....«—........................ Eggs .................... 0.1...™«. TLC-flourescence detec- Nesheim, et al. tion; chemical deriva- (1978). tion. Arsenic, selenium, antimony, Several foods..... 10 to 20 Atomic absorption; spec- Florino, et al. and tellurium. trometry; chemical deri- (1976). vation. FEDERAL REGISTER, V O L 44, NO. 55—TUESDAY, MARCH 20, 1979 PROPOSED RULES 17077 T a b u II.—Some Assays for Trace Contaminants in Food That Reflect Current Analytical requirements of safety. Accordingly, Capabilities—Continued once assay methods have been ap­ proved, new methods will not be re­ Limit Detection and con- quired wthout new toxicological data under assay Pood of mesa- flrmatory techniques Reference • showing that the lowest limit of reli­ urem ent1 able measurement of residues under these regulations is inappropriate. Several chlorinated pesticides..... Several foods....... 30 to 60 GLC-2 different................. Official Methods of Analysis of It is true that these proposed regula­ the AOAC. tions will permit the approval, for use Tetrachlorodlbenzodioxin_____ Fat, milk, others. .0001 to Chromatography high O’Keefe, et al. in «.nimais feed or for use as animal .010. resolution MS (direct (1975); probe). Hummell, P. A. drugs, of carcinogenic compounds that (1977). are likely to leave residues below the lowest level of reliable measuremnt of 1Parts per billion. ___ _ , „ , any assay meeting all the criteria of ’References available from: John Arnold, Industry Information (HFV-226), Bureau of Veterinary the regulation. Indeed, as a result of Medicine, Food and Drug Administration, 5000 Fishers Lane, Rockville, MD 20857. •Found reliable in interlaboratory validation study. Congress’ enacting the DES proviso, •Sum of all four compounds. the agency will not have any certainty In view of these trends, the Commissioner has examined the general analyt­ that these residues, in amounts below ical requirements that these regulations will place on animal drug sponsors. the level of detectability, are not Table III below shows the acceptable total level of residues in the diet for always present. This result makes representative compounds believed to be carcinogens. These estimated accept­ sense in practical terms, however, for a able total dietary levels are derived from bioassay data on the parent com­ regulatory agency cannot effectively pounds alone. The lowest limits of reliable measurement for these compounds control residues—of any compound— that would be required if the compounds were subject to the proposed regula­ that are so small that they escape tion cannot be calculated in the absence of metabolism data in animals in which measurement by every available assay. a sponsored compound is proposed or intended for use (target aminals). Never­ In sum, the interpretation adopted in theless, the values do approximate the limits of measurement that would be these proposed regulations -is reconcil­ required by the regulations and are therefore suitable for comparison with the able with both the purpose and lana- current Analytical capabilities that are shown in Tables I and II. It should be guage of the DES proviso. This inter­ noted that for some compounds the lowest limit of reliable measurement de­ pretation will further the congression­ rived from toxicity data may go beyond current analytical capabilities; that it al objective of minimizing public expo­ may, however, reflects the technology-forcing aspects of the proposed regula­ sure to residues of carcinogenic com­ tion. pounds. It does not force technology beyond the point that needs to be Table III.—Estimated Acceptable Total Dietary Levels of Several Known or Suspected reached to carry out the purpose of Carcinogens for a Lifetime Risk Level of 1 in 1 Million the Delaney clause and the general safety provisions. It does not impose Compound Reference1 Dose * infeasible requirements or costs except to the extent that they are necessary DDT.................................................................................. Tomatis. et al. (1972)......... ........................... .4 to carry out that purpose. Dimethylnitrosamine..................................................... Terracini, et al. (1967).«............«................. « .06 Ethylene Thiourea._..................................................... Graham, et al...........................- ..................... 2.0 NTA__ ........______________ ....___ ---V-_......... National Cancer Institute Clearinghouse on 260.0 C. OVERVIEW OF THE REGULATIONS Carcinogenesis. Vinyl chloride..............™.....™........~..«...™...~........~~~.. Maitone ( 1975)......................................... -....- 6.7 The proviso to the anticancer clauses allows the approval of the use ■Available from John Arnold. Industry Information (HFV-226), Bureau of Veterinary Medicine, Food and Drug Administration, 5600 Fishers Lane. Rockville, MD 20857. of carcinogens in food-producing ani­ ’Calculated according to Hoel, et al. (1975) (Ref. 63). (In parts per billion.) mals if, under conditions of use "rea­ sonably certain to be followed in prac­ The Commissioner concludes that stances present health risks so great tice," no residue is found by an assay given the known trends in the develop­ that there is no current technology prescribed or approved by the Secre­ ment of improved analytical method­ available that can permit their safe tary. To ensure public protection con­ ology the imposed requirements are use. In these instances the Delaney sistent with the anticancer and the attainable at the expense of reason­ clause (including the proviso) requires general safety provisions of the act, able effort. that the Commissioner not relax the Commissioner must establish cri­ The goal of regulating compounds health standards in order to approve teria for approving assays to include, that are to be used in food-producing such substances. among other things, an adequate animals is to ensure that none is per­ From the information described lowest limit of measurement. mitted to yield residues in edible tis­ above, the Commissioner believes that Accordingly, these proposed regula­ sues at concentrations presenting a analytical science can meet these regu­ tions would establish criteria for ac­ risk of carcinogenesis above an accept­ latory requirements. The Commission­ cepting assays used to measure resi­ able level. This acceptable level of er is not aware of any data to the con­ dues of carcinogens in edible tissues of maximum allowable risk (see section trary. Based on this review, the Com­ food-producing animals to which car­ V. C. 8 in this preamble) is applied to missioner has concluded that compli­ cinogens have been administered. all carcinogens; thus, equitable treat­ ance with the proposed regulations is Such criteria cover assay attributes ment of all such substances is afforded feasible, although some technological such as dependability, practicability, by these regulatory requirements. Dif­ innovation may be necessary. specificity, accuracy, and precision. ferent carcinogens will require differ­ Questions have arisen about the Also, the regulations would establish a ent assay capabilities because of dif­ practicality, efficiency, and overall specific criterion for the lowest limit ferences in carcinogenic potency. The public protection afforded by auto­ or reliable measurement that an assay regulations are designed to require matically adopting new assays that re­ must meet, as a minimum, before it that the lowest limit of measurement liably measure lower levels of residues can be approved by the agency for of an assay be commensurate with a is such assays becomes available after control of carcinogenic residues. This compound’s carcinogenic potency. Be­ a sponsored compound has been ap­ criterion for the required lowest limit cause it is not possible to specify the proved for use. In the February notice of measurement of an assay derives required limits of measurement for the Commissioner suggested that this from toxicological data obtained from carcinogens in the absence of animal problem is largely theoretical once an carcinogenicity studies and from an bioassay data, it is not possible to assay meeting the minimum criteria is operational definition of the no-resi­ ensure in advance that all compounds approved. The decision to approve an due standard of the act. Only if an for which approval is sought in the assay for a sponsored compound under future will be able to be used in ways these principles represent^ the agen­ assay meeting the above criteria is that satisfy the requirements of the cy’s conclusion that the compound has available would the Commissioner regulations. It may be that some sub­ been shown to meet all the statutory have a mechanism to discriminate be- FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17078 PROPOSED RULES tween tissue containing a residue and b. Based on preliminary toxicological Under this proposal, if the Commis­ tissue containing no residue. Without and biochemical information, does the sioner makes a threshold determina­ such a monitoring mechanism, th e . compound have the potential to con­ tion that a sponsored compound has Commissioner would have no way to taminate human food (edible tissues) the potential to contaminate food detemine whether a carcinogenic drug with residues of carcinogenic concern? from food-producing animals with resi­ or additive administered to a food-pro­ c. If so, what is the chemical nature dues whose consumption would pose a ducing animal is being or even can be of the residues of the compound? in human risk of carcinogenesis, the peti­ used in compliance with the act. what tissues are they found? at what tioner will be required to undertake In these regulations the Commis­ levels? and for what length of time? the following six-step procedure for sioner proposes to establish a rigorous d. Is the sponsored compound or any data collection and evaluation. premarket testing process for spon­ of the residues it produces in edible a. A metabolic study in the target sored compounds intended for use in tissue carcinogenic in experimental animals designed to identify edible food-pfoducing animals. As proposed, animals or man? tissue residues of carcinogenic con­ all sponsored compounds must initial­ e. If so, what level of residues can be cern. ly undergo a threshold assessment for operationally defined as satisfying the b. Metabolic studies of the sponsored carcinogenic potential. For those spon­ no-residue requirement of the act? compound in different species/strains sored compounds having a carcinogen­ f. Can a reliable and practical assay of experimental animals designed to ic potential, a procedure is prescribed be developed to measure the edible aid in selecting the test animal species to determine the minimally acceptable tissue residues at levels equal to or to be used in chronic toxicity bioas­ lowest limit of reliable measurement greater than those which operational­ says and in assessing the carcinogen­ for a regulatory assay. Because this ly satisfy the no-residue requirement icity of residues that cannot practica­ limit is determined on the basis of tox­ of the act? bly be tested individually (“intractable icity data, the Commissioner may con­ g. At what time after exposure to residues”). clude that an assay satisfying the re­ the compound ceases do the edible tis­ c. Chronic toxicity testing to assess quirements of the regulations is capa­ sues of exposed food-producing ani­ the carcinogenic potential of residues ble of demonstrating the absence in mals satisfy the no-residue require­ of the sponsored compound and to fur­ food of residues that present a risk of ment of the act, i.e., what is the neces­ nish data suitable for statistical treat­ cancer to man. By thus particularizing sary withdrawal time? ment so that the no-residue require­ the statutory requirements, the Com­ ment of the act can be applied and im­ 2. Date collection process. To answer plemented. missioner proposes to establish the the preceding questions, a petitioner basis for accepting or rejecting com­ must gather pertinent scientific infor­ d. A detailed metabolic study of the pounds which the sponsor claims satis­ mation, the nature of which is particu­ sponsored compound in target animals fy the no-residue standards. designed to identify both a residue and 1. Fundamental questions. For every larizedregulations in this document. These pro­ tissue that can serve as indicators drug of additive proposed for use in posed would establish the (“marker residue” and “target tissue”) food-producing animals (the sponsored procedure for gathering and evaluat­ ing the requisite scientific informa­ to determine whether the no-residue compound), the Commissioner is re­ tion. requirement of the act is satisfied. quired by the act to determine wheth­ lutionary The process is stepwise and evo­ e. Development of a regulatory assay er that sponsored compound can be because the need, as well as to measure the marker residue in the used in ways that are safe for the ani­ ability, to proceed to the next step of target tissue at and above the level es­ mals to which the compound will be data collection depends upon the re­ tablished in step d. administered (target animals) and sults obtained at each preceding step. f. Establishment of the prémarket­ whether food (meat, milk, and eggs) If the evaluation of the data collected ing withdrawal period required for the derived from such animals (edible tis­ at each step indicates that questions safe use of the sponsored compound. sues) will be safe for human consump­ on residues of carcinogenic concern Although the particular provisos to tion. The sponsor of the compound is remain, data collection must continue. the anticancer clauses of the act, sec­ therefore required to furnish the If at some point in the data collection tions 409(c)(3)*A), 512(d)(1)(H), and Commissioner the scientific and tech­ process it can be decided that the 706(b)(5)(B), vary slightly in their lan­ nical information necessary for that sponsored compound presents no guage, they have a common purpose. determination; the Commissioner in human risk of carcinogenesis, the Therefore, the Commissioner believes turn is required by the act to deter­ sponsored compound must be evaluat­ that the criteria for their implementa­ mine on the basis of all available data ed for any other health concerns tion should be identical. To avoid whether, in actual practice, the spon­ under the general safety provisions of needless repetition, the Commissioner sored compound can be used in compli­ the act. In this case, the compound has used the language of section 512 ance with the law. may be assigned a safe tolerance level of the act in discussing specific generic Although a petitioner proposing to in human food if the petitioner pro­ issues because the primary impact of use a carcinogenic compound in food- vides the data necessary to establish these proposed regulations would be producing animals has a major obliga­ that the compound can be used safely. on new animal drugs regulated under tion to develop a practical and reliable These proposed regulations deal that statute. The criteria set forth in assay capable of discriminating tissues with carcinogenesis, which is a domi­ this proposal would, however, apply to that contain residues from tissues free nant concern in appraising the safety all chemicals intended for use in food- of such residues, as defined operation­ of any sponsored compound intended producing animals, and the appropri­ ally, such an assay cannot be devel­ for use in food-producing animals. ate regulations would be amended to oped without certain scientific and Nevertheless, each compound must adopt these criteria by reference. technical information. also be evaluated for other potential II. T h r esh o ld A sse ssm en t Specifically, for every sponsored adverse effects. Thus, for example, if compound, several questions must be the available information raises an In the 1973 notice of proposed rule- answered before an assay can be devel­ issue as to the health of progeny, mul­ making, the Commissioner proposed oped or approval of the compound tigeneration studies of the sponsored that carcinogenicity testing not be re­ considered: compound and/or its residues must be quired for every sponsored compound. a. What is the chemical nature of codesigned and conducted as part of Rather, the Commissioner concluded the sponsored compound and how is it the process of collection and evalua­ that the necessity for such testing will to be used? tion of data. be dictated by an evaluation of the ex- FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17079 isting evidence from metabolic studies, compound if the preliminary data solely according to the general food toxicity testing, structural relation­ available justify the determination safety requirements of the act and ships of the sponsored compound and that public health can be protected those compounds that will, in addi­ its metabolites to known carcinogens, without so proceeding. tion, be subject to this proposed regu­ modes of physiological actions and in­ For the sake of clarity, “the total lation. This system will provide uni­ teractions, and the intended method residue of the sponsored compound” formity to the threshold assessment of of use of the sponsored compound. and “residue of toxicological concern” the risk to the public hfealth from a Comments of two types were re­ are defined in proposed § 500.83 as fol­ sponsored compound’s residues. ceived on this feature of the proposal. lows: When the only preliminary informa­ The first suggested that extensive “The total residue of a sponsored com­ tion available is the proposed pattern studies should be conducted from pound” means all compounds present in of use (factor 1 above), the sponsored every sponsored compound to deter­ edible tissues of target animals that result compounds will be subject to step 1 of mine whether it is a carcinogen. One from the use of the sponsored compound, the proposed regulations comment insisted that extensive car­ including the sponsored compound, its me­ (§ 500.80 that the residue) to the total residue in each of With the quantitative relationships only residues of P are the parent com­ the various edible tissues th at might established, it will be possible to select pound, P, and a metabolite, P,Gi®(iii) that serve as target tissues. Further, be­ one of the residues as a marker. Ordi­ tl is 3; Civ) that Sm for the sponsored cause these relationships change with narily, the residue selected will have compound is 29 parts per billion; and time, the levels of potential marker the following characteristics: (i) It will (v) th at the following is a chart of the residues in the potential target tissues represent at least 10 percent, and usu­ depletion profile of the drug. must be measured over time, and ally more, of the total residue burden tissue concentration-time profiles at the time the total residue was de­ Total must be constructed. These depletion pleted to Sm; 01} it will be stable, easily Time residue P P, burden profiles will be derived from measure­ isolated and characterized, and suscep­ ments made in target animal tissues tible to manipulation for assay devel­ 0 ------------------- 100.00 75.0 25.0 after cessation of exposure to the opment and implementation; and (ill) 1 ---------------------------- 65.4 41.6 21.8 sponsored compound. Finally, because it will be undergoing relatively rapid 2 ---------------------------- 42.0 25.3 17.3 the results of carcinogenicity testing change in concentration at the time 3 --------- 29.0 15.0 14.0 4............. 21.0 9.0 12.0 have been used to set limits for total the total residue burden is at or near 5------------------------------- 15.0 5.0 10.0 potential undetected residues in each Sm (i.e., a change in its concentration of the individual edible tissues, the de­ will be a sensitive indicator of the time In this case, before the drug can be pletion profiles must include measure­ when the total residue burden has de­ approved for use, the petitioner must ments of the total residue in each po­ pleted below Sm). Although other con­ develop an assay that will satisfy the tential target tissue to levels at least siderations may enter into the selec­ evaluation criteria in liver for either P as low as the Sm appropriate to the tion of a marker residue, these three at least as low as 15 parts per billion or tissue. Also, depletion profiles for one will ordinarily be most important. Pi at least as low as 14 parts per bil­ or more potential marker residues There may be instances in which no lion. Because P is depleting faster must be constructed and include mea­ single residue can adequately fulfill than Pi, when the total residue burden surements of levels of residues corre­ the requirements a marker residue is 29 parts per billion, P may be the sponding to the times when the total must meet. In such instances, it may preferred compound to select as the residue has reached Sm(Plates I and II be necessary to select some combina­ market residue because ft provides a set forth in proposed § 500.89). tion of residues which, taken together, more sensitive assessment of when the Part III of this preamble describes can represent the total residue burden. total residue burden reaches 29 parts the requirements for the study of the It should be noted that a marker resi­ per billion (Sm). Another example is metabolic fate of a sponsored com­ due can be a compound which is not a provided in Plate II in proposed pound in target animals. Although the carcinogen, but is an unambiguous in­ § 500.89. purpose of this earlier metabolic study dicator, in the manner already de­ Comments on the marker residue- is to provide information for selecting scribed, of the presence or absence of target tissue segment of the regula­ residues for carcinogenicity testing, carcinogenic residues. tions posed questions about the defini­ the same principles and requirements 2. Target tissue. Selecting a target tion of terms and the implementation are applicable here and must be fol­ tissue requires a comparison of the de­ of procedures. One comment request­ lowed in acquiring the information pletion profiles for each of the edible ed that the Commissioner add a table necessary to construct depletion pro­ tissues (Plate I set forth in proposed of definitions for the entire subpart, files. However, to meet the depletion § 500.89). A target tissue will be select­ and it suggested that the agency coin profile requirements prescribed by the ed on the basis of assurance that the a new term for the “marker residues.” regulations, a second metabolic study absence of the market residue at or Another comment questioned whether of the sponsored compound in the above Rmmeans that carcinogenic resi­ the studies required to identify the target animals may be necessary. This dues are absent from the tissue that marker residue and target tissue are second and possibly more refined requires the longest time to achieve its truly “metabolism” studies. The Feb­ study may require using a larger Sm, and thus that the entire animal is ruary 1977 notice stated that the Com­ number of animals. It will be neces­ free of carcinogenic residues. missioner would select the target sary to determine the total number When a compound is to be used in tissue and marker residue, and one and the quantities of residues at sever­ milk- or egg-producing animals, milk comment suggested that they be se­ al appropriate times, starting immedi­ and eggs will be target tissues in addi­ lected by the petitioner, who has a ately after cessation of exposure and tion to one tissue selected as the better knowledge of both the spon­ continuing until the residues in each target tissue to represent the deple­ sored compound and of the availabil­ of the potential target tissues have tion of residues in all of the edible car­ ity of technology to develop assays for reached a level CQrresponding to a cass. In these cases, it may be neces­ metabolities. Another comment ques­ total residue level of the appropriate sary to select a marker residue for tioned whether the agency is request­ Smfor that tissue. If the initial meta­ milk or eggs that is different from the ing sufficient information on edible FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 17096 PROPOSED RULES tissues to permit a determination of a VII. S po nso red C o m po un ds A ffectin g considered exogenous, as the true marker residue or target tissue. It also P ools o f C a r cino gen ic or P oten ­ meaning of the term implies. questioned why the most slowly de- tia ll y C arcino gen ic S ubstances E n ­ Other comments suggested that en­ pletirtg tissue is not always the target dogenous T o T arget A n im a ls dogenous substances of interest be tissue. It further requested that the subjected to toxicological testing and target tissue concept be clarified when A. APPLICABILITY OF NO-RESIDUE tolerances be set, if such substances REQUIREMENT are found to be not carcinogenic. Some a target animal is used for milk or egg production. The act requires that in making food doubted that available technology The terms “marker residue” and safety decisions, the Commissioner could meet the proposed requirements. “target tissue” are defined in proposed take into account all substances They contended that the terms §500.83, and their meanings will be formed in or on food by the adminis­ “normal conditions of use” arid codified by the final regulations. For tration of sponsored compounds to “normal background levels of endog­ clarity, a new section is added to food-producing animals. It is well rec­ enous compounds” would be either ex­ define all new terms for the subpart. ognized that: (i) Several substances en­ tremely difficult or impossible to dogenous to food-producing animals define. While recognizing the difficul­ The term “metabolic study” has been ty of the task, the Commissioner con­ used by FDA to describe the types of are suspect or proven carcinogens (Ref. 64); (ii) in any given animal spe­ cluded that administered compounds studies called for by the regulations that increase the naturally occurring for many years. The Commissioner cies or breed, the size of pools of such endogenous substances may vary level of potentially carcinogenic en­ disagrees that the term is inappropri­ dogenous compounds present special ate. widely and are affected by such fac­ tors as sex, age, lactation, state of problems of control, which the pro­ The Commissioner agrees that the posed regulations had to address and petitioner for a sponsored compound estrus, pregnancy, and geographic lo­ cation; and (iii) humans have had sus­ resolve. has a role in selecting the marker resi­ tained exposure to such endogenous As the Commissioner explained in due and target tissue. Under current substances for centuries. Whether the February 1977 notice, an endog­ agency procedures, the selections are normal levels of human exposure to enous compound is any compound made with the opportunity for partici­ these substances are responsible for that is metabolically produced by and pation by the petitioner, and thus the human carcinogenesis is unknown, but is present in untreated target animals. petitioner’s knowledge and proponent using drugs that can cause an increase Any sponsored compound which, when status are recognized. Because the- in human exposure to these com­ administered to a target animal, is agency must make the decision on pounds has the potential of increasing found to increase the normal back­ whether the sponsored compound can the risk of human carcinogenesis. ground levels of a potentially carcino­ be safely used, however, it must Under the act, therefore, the use of genic endogenous compound is subject remain the ultimate decisionmaker. to these proposed regulations, regard­ such drugs must be controlled. less of how the increase is brought The regulations require petitioners In dealing with potentially carcino­ to determine the tissue depletion pro­ about. For instance, estradiol benzo­ genic endogenous compounds, the ate, which by the above definition files for residues, and for a sponsored 1973 proposal declared that the intent clearly is not an endogenous com­ compound a considerable part of this of the no-residue requirement of the pound, is metabolically converted to information will already have been act is the maintenance of the normal the endogenous compound estradiol gathered by the initial metabolism human dietary content. Thus, the Feb­ and may thus cause an increase in study. (See section III of the pream­ ruary 1977 notice required the deter­ normal background levels of that sub­ ble.) The Commissioner concludes mination of the effects of sponsored stance. Estradiol may itself be admin­ that it is appropriate to select the compounds on the normal background istered and possibly cause target target tissue from among tissues likely levels of potentially carcinogenic en­ animal pools of estradiol to increase to become storage depots or to be in­ dogenous compounds. If a compound above background. Finally, a spon­ volved in metabolism and excretion of is found to increase these levels, condi­ sored compound may indirectly cause the sponsored compound. Routinely tions of use are to be established so an increase in tissue levels of estradiol examining other more specialized tis­ that normal background levels are not by affecting any number of hormonal sues in great detail will yield little ad­ exceeded in the animal when the regulatory systems in the target ani­ ditional useful information. Material animal is slaughtered. The notice also mals. balance calculations will be used as required development of practical Although in each of the above-cited necessary to determine whether other assays for measuring levels of endog­ cases the cause of the increases in tissues are potential storage depots enous compounds. normal background levels of estradiol and therefore may be target tissues. Several comments on this segment is different, the result is the same. The criteria for selecting the marker of thé 1973 proposal expressed con­ And it is the result that must be moni­ residue and target tissue are such cern over the meaning of the term tored and controlled. It is thus of little that, when the marker residue concen­ “endogenous compounds” and ques­ use to distinguish between “endog­ tration passes through its Rm in the tioned how these compounds are to be enous” and “exogenous” administered distinguished from “exogenous com­ compounds. Rather, it is useful only to target tissue, an other residues in the pounds.” Others questioned whether tissues, including the most slowly de­ distinguish between administered com­ the former term includes chemical de­ pounds that can cause changes in pleting tissues, will have passed rivatives (estradiol benzoate) of bona normal background levels of potential­ through their Rm. Therefore, the most fide endogenous compounds (estradiol) ly carcinogenic endogenous com­ slowly depleting tissue need not be the or essential nutrients (some amino pounds and those administered com­ target tissue. acids, minerals, vitamins). Comments pounds that do not affect such levels. Finally, the Commissioner explained also expressed doubt about the distinc­ Essential nutrients are not included in the February notice that for milk- tion between endogenous and exoge­ in the definition of the classes of com­ and egg-producing animals, it is neces­ nous compounds when the adminis­ pounds that will be regulated by these sary to have a target tissue in addition tered compound can be metabolized to proposed regulations. In a strict sense, to the milk or eggs. To clarify this residues of both classes. Some com­ essential nutrients are not endog­ matter, the Commissioner added this ments also argued that all externally enous. Although present in the tissues requirement to the regulations. administered compounds should be of animals and required for growth FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17097 and health, they are not produced by The median and shape of the fre­ two-thirds of the points on the distri­ the animals and must be supplied quency distribution must be known so bution curve. The same assay evalua­ from external sources. These features that shifts in the norm can be meas­ tion criteria apply to endogenous com­ place essential nutrients in a distinct ured. For this reason, the assay used pounds as to other compounds covered class of “required exogenous com­ to determine a norm must yield values by these proposed regulations. pounds,” which must continue to be for the endogenous compound differ­ Accordingly, the commissioner in regulated in a unique manner. Deter­ ent from zero for at least two-thirds of the February 1977 notice revised the mination of the allowable use of essen­ the untreated target animals. This provisions which, as proposed, would tial nutrients must reflect the target latter requirement is a compromise be­ have originally established the lowest animals’ nutritional requirements. tween the need to determine the fre­ limit of reliable measurement at the When used according to label direc­ quency distribution with a high degree 99th percentile Of the norm. As the tions, supplements of essential nutri­ of reliability and at the same time to comments noted, as assay that can ents that present carcinogenic risks recognize the difficulties thay may be measure only the upper 99th percen­ should restore, but must not exceed, encountered in measuring levels at the tile would not be able to detect any the essential nutrient levels found in lower end of the norm. shifts in the norm, which is its prima­ natural foods adequately sustaining The petitioner would then deter­ ry function. The proposed regulations normal growth of healthy animals. mine the effects of the sponsored com­ require an assay capable of a lowest Furthermore, the levels of such essen­ pound on the norm and provide data limit of reliable measurement of the tial animal nutrients found in human on the postexposure decay of any ob­ 33d percentile of the norm, which will food derived from animals with diets served increases in the norm. The readily detect any shifts in the median supplemented with essential nutrients norm is considered restored when the or mean of the norm. Determination must not exceed the levels in food de­ distribution of values for the endog­ of compliance depends on a regulatory rived from normal healthy animals fed enous substance of concern observed system that monitors shifts in the a nutritionally adequate natural diet. in a group of treated animals is, with norms and not levels of endogenous 99 percent confidence, the same as the substances in individual animals. B. GENERAL PROCEDURES norm. The norm, as defined, takes into ac­ E. ALTERNATIVE PROCEDURE If available information shows that count those variables that affect back­ a sponsored compound might affect Earlier comments contended that an pools of potentially carcinogenic en­ ground levels. The proposed regula­ alternative to the foregoing procedure dogenous substances above the level tions thus resolve the difficulties should be available for regulating en­ considered to be safe under the crite­ raised by 1973 comments suggesting dogenous substances. It was suggested ria of these proposed regulations, the that “normal background levels” th at a tolerance for an endogenous petitioner would be required to investi­ would be difficult to define. compound can be established at levels gate whether such effects occur under D. ENDOGENOUS MARKER RESIDUE! above the norm, provided that appro­ the conditions of the compound’s pro­ CALCULATION OF Rm priate toxicity testing on the com­ posed use. pound is carried out and a safe level The Commissioner proposes the fol­ If the norm of an endogenous sub­ can be established in accordance with lowing requirements: (i) Establishment stance of carcinogenic concern can be sections IV through VI of this pream­ of normal background levels (or increased by the administration of a ble and proposed §§ 500.84 through “norm”) of the endogenous compound sponsored compound, the endogenous 50090. of carcinogenic concern in the target substance can become an endogenous Separate mechanisms with distinctly animals; (ii) determination of the ef­ marker residue, i.e., its presence above different rationales have been devel­ fects of the sponsored compound on certain levels can be considered an in­ oped to measure compliance with the the norm; (iii) establishment of safe dicator of potentially carcinogenic res­ no-residue standard of the act for en­ conditions of use of the sponsored idues in food. Approval of the use of dogenous and exogenous compounds. compound by demonstrating how the such a sponsored compound is contin­ As noted earlier, for exogenous com­ compound can be used in a way that gent upon the petitioner’s furnishing pounds, the regulations would require ensures that the norm is -restored in of data demonstrating that the norms development of an assay with a lowest the target animals before slaughter; are restored in the target animals limit of reliable measurement at or and (iv) development and validation of before slaughter, and upon the avail­ below the level needed to ensure that a practical assay to measure the en­ ability of a practical assay that can re­ any undetected residues pose essen­ dogenous compound at levels specified liably measure the endogenous marker tially no increased risk of cancer in by the norm. The proposed regula­ residue in target animals. This regula­ the population. On the other hand, tions specify how each of these steps is tory assay must be capable of measur­ the method for measuring compliance to be accomplished. ing the marker residue at the level, with the no-residue standard for an Rm, corresponding to the 33d percen­ endogenous substance is based on the C. SPECIFIC STEPS REQUIRED tile of the norm (Plate III set forth in norm. proposed § 500.89). In the absence of toxicology data of The petitioner would first be re­ The Rm for an endogenous marker the type needed to determine a safe quired to determine experimentally residue derives from a conceptual ap­ level for exogenous compounds, de­ the normal background levels, or proach entirely different from that scribed in section V of this preamble, norms, of the potentially carcinogenic used for the derivation of an Rmfor an the Commissioner maintains that re­ endogenous compounds of concern in exogenous marker residue. To monitor storing the norm is the only way to untreated target animals. A norm shifts in the norm, the Commissioner ensure the absence of unaccepatble must be specific for the untreated must be able to measure the median risks resulting from the use of com­ target animals. The petitioner would and to determine the shape of the dis­ pounds that may increase pools of po­ provide the norm in the form of a cu­ tribution. An assay capable of measur­ tentially carcinogenic endogenous sub­ mulative frequency distribution of the ing the 33d percentile of the norm pro­ stances. If the toxicology data are observed levels of the endogenous vides the analytical capability neces­ available, however, and are suitable compound. This curve must also in­ sary to determine whether the norm for extrapolation by the procedures clude 99 percent confidence limits has been shifted by administering the described in section V of this pream­ (Plate III appearing in proposed sponsored compound to the target ani­ ble, the Commissioner will permit a § 500.89). mals because it permits measuring shift in the norm equal to the incre- FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17098 PROPOSED RULES ment shown to produce a lifetime cy’s policy to encourage joint funding VIII. R egulatory A ssa y : E valuation cancer risk no greater than 1 in 1 mil­ of tests. C r it e r ia and A pproval P rocess lion. The Commissioner believes it inap­ a. in t r o d u c t io n The 1977 notice announced that the propriate to establish, as part of the Commissioner was receptive to sugges­ regulations, detailed protocols for The Commissioner can approve a tions for other alternative mechanisms studies required to establish norms. sponsored compound for use in food- of control. Two comments argued that However, the following example is of­ producing animals only if the intended the Commissioner has no authority to fered as a guideline. To determine, use of the compound does not result in regulate increases in potentially car­ with a high degree of confidence (99 the accumulation of potentially car­ cinogenic endogenous substances that percent), the characteristics of the dis­ cinogenic residues in edible tissues and occur “indirectly” from the adminis­ tribution of the individual values that if an assay is available that can reli­ tration of the sponsored compound. constitute the norm, the petitioner ably measure such residues at and They contended that the Commission­ will ordinarily be required to examine above the Rm. The assay must also be er can only regulate substances that a reasonable number of animals in suitable for monitoring food from ani­ derive directly from the sponsored each production class of target ani­ mals administered the compound to compound, not from its use. The Com­ prevent food from reaching the mar­ missioner rejects these comments, mals in which the sponsored com­ ketplace if it is adulterated with po­ which are analogous to the earlier pound is proposed for use, both treat­ tentially carcinogenic residues result­ comments that the agency can regu­ ed and untreated. In each group, 450 ing from misuse of the compound. late only a parent compound, not me­ to 500 animals will be sufficient to de­ Many comments in response to the tabolites, under the Delaney clause. As termine with 99 percent confidence: 1973 notice contended that more ex­ explained in the February 1977 notice, (1) That the 99th percentile of the plicit criteria and evaluation proce­ the Commissioner is concerned about norm is less than the largest observed dures should be specified. the use of compounds that may in­ value; and The Commissioner agrees with these crease the pools of potentially danger­ (2) That the cumulative frequency comments. Because the assays re­ ous endogenous substances that may distributions of the observed levels of quired by these proposed regulations be formed in or on food because of a the endogenous compound in untreat­ are to be used for regulatory monitor­ sponsored compound’s use. The gener­ ed target animals and in the treated ing of residues of potential carcinogen­ al safety provisons of the act clearly target animals do not differ by more ic concern in food, rigorous criteria cover all substances formed in or on than .10 at any specific point. must be established for approval of food due to the use of a sponsored To test whether the norm for the these assays. Furthermore, the pro­ compound, and it is proper to consider sample of untreated animals and the posed assay must be subjected to an excess levels of endogenous com­ values for the sample of treated ani­ objective evaluation to determine pounds of carcinogenic concern as mals came from the same population, whether it meets the criteria. Only such substances. i.e., there was no effect due to treat­ then can there be assurance that an A comment requested that the Com­ ment with the drug, the petitioner assay will provide a reliable and practi­ missioner specify which potentially may use the Kolmogorov-Smimov cal monitoring device to prevent vio­ carcinogenic endogenous compounds two-sample test. This test is concerned lated residues in food. Most of the are within the purview of this section. with the agreement between two cu­ questions raised in the comments The Commissioner concludes that the arose because the 1973 notice con­ mulative frequency distributions. This tained only a brief description of the proposed regulation covers all endog­ test is sensitive to any type of differ­ assay evaluation criteria and proce­ enous compounds that animal or ence in the distributions from which dures. Accordingly, the following dis­ human data show may present a car­ the two samples (treated and untreat­ cussion sets forth, as in the 1977 cinogenic risk. ed) were taken, e.g., differences in lo­ notice, the evaluation criteria and Concerning the comment that all en­ cation (mean, median, etc.), differ­ their bases. dogenous substances should be pro­ ences in variation, differences in skew­ Any assay used for regulatory pur­ scribed from use in animals, the Com­ ness, etc. poses is characterized by a set of attri­ missioner advises that there is no legal The only assumptions required for butes that determine its quality: de­ basis for their outright prohibition. this test are— pendability, practicability, specificity, Furthermore, the regulations pre­ (1) That the samples are random accuracy, and precision. These regula­ scribe procedures for use of these sub­ samples; tions specify objective criteria for stances that ensure the same degree of (2) That the two samples are mutu­ these attributes. A proposed assay safety as that required for the use of ally independent; and must be shown to meet these criteria exogenous compounds. (3) That the samples are from a con­ during studies in a single laboratory Finally, a comment stated that the and also in interlaboratory studies in studies described in the February 1977 tinuous population. Specifically, the Kolmogorov-Smir- government regulatory laboratories. notice are costly, and it contended The latter requirement is essential be­ that, unless the data collected are con­ nov test evaluates the probability of the maximum absolute difference that cause the assays are to be used in Fed­ sidered proprietary, the requirement eral regulatory laboratories (FDA, puts pioneers in the field at a disad­ would occur between two cumulative distributions if they were obtained USDA) and State laboratories, and the vantage. The comment also requested Commissioner must determine in ad­ that the Commissioner specify the from the same population. For the de­ vance that an assay will perform satis­ studies required to define the norm tails of conducting the test see Refs. factorily in more than one such labo­ and measure its restoration. 77 and 78. It must also be remembered ratory. The proposed regulations Under the current law, the Commis­ that the above-described study may be specify that the interlaboratory vali­ sioner concludes that data on the conducted in lieu of chronic toxicity dation study must be carried out in norm are safety data required for tests, and it can be conducted during those laboratories (USDA and FDA) every application and are proprietary the effectiveness studies. Thus the that will be using the method in sur­ data for new animal drugs. However, costs of developing and marketing an veillance and enforcement programs. to reduce unnecessary testing, ex­ endogenous compound will be compa­ The steps in obtaining approval of penses to the regulated industry, and rable to the corresponding costs for an an assay are—(i) assay development costs to the government, it is the agen- exogenous compound. and study by the petitioner to deter- FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 1 7 09 9 mine whether the assay satisfies the C. SUBMISSION OF DATA assay validation study should be inti- acceptability criteria; (ii) FDA review tiated, however, in no way guarantees Agency resources for reviewing and that a proposed assay will eventually of the petitioner’s study to determine validating assays are limited. The suitability of the assay for evaluation be approved. Commissioner therefore would estab­ The assay criteria and attributes set in interlaboratory study; and (iii) in­ lish in this proposal a precise format terlaboratory validation study, again out in the proposed regulations repre­ for submitting the data to support ac­ sent and amalgamation of statutory with approval contingent upon satis­ ceptance of an assay. It is a well-recog­ and scientific standards. Because a va­ faction of acceptability criteria. nized principle, applied both by the riety of terms are in use, the Commis­ B. SOURCES OF DATA TO SUPPORT THE courts and administrative agencies, sioner is proposing to adopt and define ASSAY th at a standard format can be re­ the basic terms in the regulations in quired for pleadings, requests for li­ simple language for the sake of clar­ Data from studies of an assay using censes, and other applications. This ity. Accordingly, an assay must meet three types of samples are necessary format may also designate special the following attributes and criteria to support approval. The petitioner types of information that must be con­ for approval: must prepare and analyze samples of tained in the submission. Therefore, 1. Dependability. Dependability is target tissue to which known and vary­ the agency would refuse to accept a the likelihood that the proposed assay ing concentrations of marker residue, petition or review an assay when the will not fail to yield a result because of including Rmand concentrations above request for approval fails to conform uncontrollable features inherent in its and below Rm, are added (“spiked” tis­ to the format outlined below. design. Almost all assays will, on occa­ sues). The petitioner must also com­ 1. Assay description and petitioner’s sion, fail to yield any result. Often this evaluation. The petitioner must pro­ failure occurs due to mishandling by pare responses obtained from assays vide a complete description of the using these tissues with responses ob­ assay to allow FDA to determine the analyst, but sometimes failure tained from assays of target tissues whether it is potentially acceptable. may be the result of some aspect of known to be free of marker residues Because this threshold determination the assay itself that may have been in­ (control tissues). In plotting observed of acceptability will trigger an exten­ adequately studied and defined or that instrumental response versus concen­ sive interlaboratory validation proce­ cannot be controlled. For example, tration of marker residue, i.e., in con­ dure, the discussion must be suffi­ assays depends upon the availability structing the analytical curve from ciently rigorous to minimize waste of of a standard against which measure­ these data, as many samples as possi­ agency resources. Therefore, the sub­ ments are compared. If the integrity ble should be run, preferably by dif­ mission must discuss in detail— of the standard depends on certian en­ ferent analysts, because interlabora­ (a) What equipment and reagents vironmental factors (e.g., purity of the tory validation of the assay will even­ are necessary; solvent in which it is maintained, tem­ tually be required. The variability (b) How the assay is performed; and perature, light intensity, etc.) and (c) How the assay complies with the these factors are understood, it may among different analysts can be deter­ be possible to prevent assay failure. If mined at the developmental stage and criteria of dependability, practicabil­ ity, specificity, accuracy, and lowest this dependence is not know, however, adjustments made before the assay is the assay may fail and may fail often submitted for FDA review. limit of reliable measurement pre­ scribed in proposed § 500.90(d) and dis­ depending on the effect of the envi­ Before submitting an assay to FDA cussed under section VIII. E. below in ronmental factor of importance on sta­ for review, a sponsor should be satis­ this preamble. bility of the standard. In this example, fied that it meets all of the evaluation 2. Data. The data and worksheets, failure can mean a highly inaccurate criteria and also that it is consistent including spectrograms, chromato­ result, assuming some fraction of the with general principles of good analyt­ grams, etc., from the spiked tissue, standard’s intergrity is retained, or it ical practice. Past experience shows dosed tissue, and control tissue analy­ can mean no result at all, assuming that a petitioner’s failure to follow ses and the external standard and complete loss of integrity. good analytical practices during initial quality control data are also necessary Assays used to monitor carcinogenic assay studies often results in interla­ for the preliminary review of the assay residues in food must be free of such boratory failure even though the ini­ to determine whether it actually com­ uncontrollable features. Failure of a tial results may appear satisfactory plies with the evaluation criteria. proposed assay to yield results during during a paper review of the assay by the petitioner’s assay development FDA. A petitioner should assure that D. FDA REVIEW studies or interlaboratory validation no results enter the construction of an The agency will conduct a paper study can be a ground for refusing to analytical curve when it is known that review of a petitioner’s submission to accept the assay and for denying the determine whether an assay complies underlying petition. Accordingly, the the results were obtained using other regulations require a petitioner to fur­ than acceptable principles of analyt­ with the acceptability criteria. These nish information on, and provide an ical practice. regulations generally alert potential explanation of, runs of the assay that In addition to the spiked tissue tests, petitioners to the applicable statutory are begun, but never finished, during a petitioner must also submit data standards and criteria, which should the analyses of samples used to con­ showing the applicability of the pro­ permit a petitioner to assess prelimi­ struct the submitted analytical curve. posed assay to target tissues taken narily the acceptability of an assay 2. Practicability. Proposed from target animals treated with the before filing & petition, and thereby § 500.90(d)(2) defines the practicability sponsored compound (“dosed” tissues). reduce the agency’s workload. attribute as follows: If on preliminary review an assay ap­ Validation of the assay requires dosed pears to comply with the evaluation The assay is considered practicable only if tissue samples that contain the criteria, it will then be subjected to it is suitable for routine use in a government marker residue at a level approximat­ the interlaboratory assay validation regulatory laboratory. The time required to ing Rm. The petitioner is required also study to determine whether it is complete the assay must be consistent with to submit a standard analytical curve regulatory objectives, monitoring, compli­ indeed a practicable and reliable regu­ ance, etc. All supplies, equipment, reagents, constructed by taking the marker resi­ latory tool. Should the initial review standards, and other materials necessary to due of known purity at different con­ establish the assay fails to meet these conduct the assay must be either commer­ centrations, determining the response, criteria, the petition will be denied. A cially available, or readily available from and plotting the relationship. conclusion that an interlaboratory the petitioner, on request. The Commission- FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17100 PROPOSED RULES er will withdraw approval of any assay and pects of specificity, are central to good One type of study must yield graphs initiate regulatory action against the spon­ analytical practices. The regulations of the observed concentrations of the sored compound if such a condition of the consider both the qualitative and marker residues, as determined by compound’s approval is no longer satisfied. quantitative aspects and groups them analysis, plotted against the corre­ The Commissioner has established together under the general attribute sponding levels of marker residue criteria for practicability in terms that of “specificity.” The Commissioner’s added to the analyzed target tissue. relate specifically to the nature of the objective is to assure that, whatever The plot is to be used to asceftain laboratories in which the assay will be the observed response, it is uniquely whether the assay meets the above- used, i.e., regulatory laboratories related to the marker residue both specified criteria. where the time and availability of qualitatively and quantitatively. The other type of study must meas­ equipment and reagents are critical The establishment of an analytical ure the assay’s recovery of marker res­ factors in their ability to perform sat­ curve (not simple a standard curve, idue from target tissue of target ani­ isfactorily the mandate functions. but one derived from actual measure­ mals exposed to the sponsored com­ The inability to use an assay at a ments obtained on tissue samples con­ pound. If target animals exposed to a regulatory laboratory because a taining known amounts of marker resi­ radiolabeled sponored compound pro­ needed reagent is not readily available due at different levels and from con­ duce radiolabeled marker residue, it or because excessive time is requred to trol samples) provides the means to will always be possible to measure the complete the assay presents potential detemine whether the responses pro­ proposed assay’s recovery by directly risks to publish health and, therefore, duced by an assay are single-valued, as comparing measurements obtained precludes approval of the assay. Obvi­ they must be if an assay is to be con­ from the proposed assay and appropri­ ously, some assays will require some sidered fully specific. Only assays that ate measurements of radioactivity. If unique items, particularly reference yield continuously increasing or de­ it is not possible to have radiolabeled standards. The Commissoner agrees creasing analytical curves will satisfy marker residue, the true concentration with comments suggesting that, as the criterion of single-valuedness. The of marker residue in target tissue from long as a sponsor makes reference criterion of single-valuedness, or mon­ exposed animals must be determined standards available to all persons tonicity, must be established for the by exhaustive extraction of such tis­ having an interest, this requirement of full range of possible contamination of sues after appropriate standard treat­ the regulation will be met. A conimit- residues, i.e., from zero residue levels ments which hydrolytic enzymes. ment to supply reference standards up to levels of residues that will be The regulations prescribe specific ac­ when they are not commercially avail­ present if no withdrawal period is ob­ curacy criteria-The average of ob­ able may be made a condition of the served. served responses must be between 60 sponsored compound’s approval, and The regulations require that the and 110 percent of the true level of failure to supply the governmental or assay contain a sufficient number of the marker residue when the lowest other laboratories as required is a independent measurements utilizing limit of reliable measurement, Lm, basis for withdrawing a compound’s independent physicochemical princi­ which is described in the next para­ approval. The Commissioner con­ ples to assure specificity (i.e., the iden- graph, is less than 100 parts per billion cludes that an assay is not practical if ity of the marker residue must be con­ and between 80 and 100 percent of .the it is dependent on the use of any other firmed). There are many ways in true value if La, is equal to or greater unique equipment or materials that which specificity can be demonstrated than 100 parts per billion. These crite­ are not commercially available. experimentally. A petitioner may use ria need not be satified throughout 3. Specifity. The regulations providehighly sophisticated research tools to the full range of the analytical curve, that, for an assay to be accepted, and demonstrate that a proposed assay is but they must be satified in the range observed response must be due to the specific in the ways discussed above. from Lm to three times Lm. These crite­ compound that is being measured, and However, a regulatory analyst, using ria are consonant with current good to that compound only. It is a funda­ an approved assay, must have availa­ analytical practice. mental part of the development of an ble some technique that can provide 5. Lowest lim it of reliable measure­ assay to determine whether or not it assurance that an observed response is ment (.L m). To be accepted for regula­ possesses this important attribute. due to the market residue. At present, tory purposes, an assay must be able Among analytical chemists and bio­ although there are other possibilities, to distinguish, with a high degree of chemists, an “assay” that does not mass spectrometry is probably an ideal confidence, target tissues that contain demonstrate this attribute is of little choice for acquiring the requisite spec­ levels of the marker residue at or value; and indeed, in a regulatory set­ ificity. Some determinations (e.g., above Rmfrorn target tissues that do ting, such an assay could be danger­ those requiring enzymes) may have an not. This distinction must be repro­ ously misleading. For this reason, the inherent high specificity, but others ducible and capable of supporting Commissioner has established rigorous have low specificity (e.g., gas, thin- legal action when violative residues of specifications for this attribute. layer, and liquid chromatography) and the sponsored compound occur. In general terms, “specificity” refers require other independent types of To provide the necessary degree of to the uniqueness of the relationship measurements to achive the requiste discrimination, the regulations require between the observed effect (or re­ confirmation of identity. The require­ that the assay be capable of producing sponse) and the applied stimulus (in ment in the regulations that an assay when the marker residue is present in this case the chemical under analysis). contain a sufficient number of inde­ target tissue at or above R m a re­ In analytical chemistry and biochemis­ pendent measurements negates the sponse that is, with 99 percent confi­ try, the term “specificity” is common­ effect of a false positive measurement. dence, different from the response in ly used to refer to the uniqueness of a 4. Accuracy. Assays yield measure­ nontreated (control) target tissue, i.e., response resulting from the applica­ ments of concentration that are in the difference between the responses tion of a stimulus having specific char­ some proportion to the true concentra­ of control target tissue and target acteristics; that is, the term has a tion of the compound being measured. tissue containing the marker residue qualitative dimension only in that it The ratio of the measured to the true at or above Rmis, with 99 percent con­ does not relate to either the quality of concentration of the compound, ex­ fidence, greater than zero. response or stimulus or to the nature pressed as a percentage, is a measure The actual lowest limit of reliable of the relationship between response of the assay’s accuracy. The accuracy measurement for the proposed assay is and stimulus. Both of the latter crite­ of an assay is determined from data termed the “L*", and it will be deter­ ria, which might also be considered as­ collected from two types of studies. mined by reference to the analytical FEDERAL REGISTER, V O L 44, NO. 55—TUESDAY, MARCH 20, 1979 PROPOSED RULES 17101 curve of the proposed assay. The La potentially violative exogenous marker an assay before it can be determined will be the level of marker residue that residues must be the lowest limit of re­ that use of a sponsored compound can gives a response above the expected liable measurement, 1^, of the ap­ be approved. This requirement is nec­ blank value that is greater than, or proved assay. essary because of the delicate nature equal to, 0.75 times the spread of the Several comments on the 1977 notice of the assays, their importance in as­ 99 percent confidence limits of a single stated that the definition of Ln, and suring that no residues of carcinogenic assay response measured parallel to the procedures for determining 1^ concern will occur in food of animal the observed assay response axis (see were incompletely specified. Most origin, and the practical limitations on Plate IV in proposed § 500.90(d)(5)). comments applauded the Commission­ the government’s capacity to monitor If the determined lowest limit of re­ er’s attempts to specify analytical at­ food production and distribution. liable measurement, La, of the pro­ tributes and agreed that the criteria These three laboratories must study posed assay is equal to or less than the were in accord with current good ana­ an assay sufficiently to assure that all Rm, this criterion will be considered lytical practice. Several comments sug­ criteria are met and that the petition­ satisfied. This procedure takes into ac­ gested th at further specification of er has drawn correct conclusions in count the attribute of precision. Thus, the interagency validation procedure the submission about the assay’s ac­ an assay that satisfies this criterion might be desirable, and thus offered ceptability. will provide a reliable regulatory tool assistance if detailed guidelines were A comment on the 1977 notice sug­ to enable the Commissioner to dis­ to be drafted in the future. gested that FDA adopt the Association criminate safe from unsafe food. The Commissioner agrees with these of Analytical Chemists’ procedure for The Commissioner recognizes that comments and is proposing to define validating the assays. At this time, the the term “method sensitivity” is Ln, in detail in the regulation as de­ Commissioner believes the AOAC widely used to describe the lowest scribed above. process is inappropriate. It is very time level of a compound under analysis There was some confusion regarding consuming and permits testing in labo­ that can be detected and measured the definition of “accuracy,” and one ratories other those of FDA or USDA, with an analytical assay. Indeed, the comment stated th at the regulations where the assay will be used as a regu­ original proposal used this term to de­ confused the terms “accuracy” and latory tool. Because of the delicate scribe what is now termed “the lowest “recovery.” The Commissioner agrees nature of the assays covered by these limit of reliable measurement.” How­ that in the February notice the term regulations and the time periods im­ ever, there is some confusion sur­ “accuracy” is used in a manner equiva­ posed for evaluating applications, the rounding the term “sensitivity.” It de­ lent to what is normally termed “re­ Commissioner declines to adopt the rives in part from the fact that the covery.” The term “accuracy,” howev­ AOAC procedure. When the agency term has been used in two senses: (1) er, is more in line with analytical gains experience with the assays, how­ As the lowest level of a compound that chemistry terminology, and the differ­ ever, the Commissioner will reconsider can be detected by an assay; and (2) as ences between accuracy and recovery adopting in the regulations the AOAC the lowest level of a compound that occur only when dealing with absolute assay validation process. can be measured reliably by an assay. analytical methods, which will not be In fact, the correct meaning of the of concern here. For these reasons the F. CONCLUSION term “method sensitivity” is unrelated Commissioner is proposing to retain If an assay complies with the criteria to a particular level of compound con­ the term “accuracy.” described above and prescribed by the centration, but rather relates to the proposed regulations, and compliance ratio of change in instrument response E. INTERLABORATORY VALIDATIONS OF to the change in compound concentra­ ASSAY can be verified under actual conditions tion. The term “sensitivity” has there­ of regulatory use (see section IX of Although FDA will review the assays this preamble), the Commissioner will fore been dropped from this proposal. for each sponsored compound, the approve the assay. A full description The Commissioner has adopted the actual regulatory field examination of of the approved assay will be pub­ term “lowest level of reliable measure­ foods of animal origin will be primar­ lished in the F e d er a l R e g is t e r upon ment” because that term more accu­ ily performed by USDA under the approval of the petition, in accordance rately describes the attribute. Meat and Poultry Products Inspection with the provisos to the anticancer In response to comments urging that Acts, and by the States under the clauses and section 512(i) of the act. any "detected residue” should be sub­ Public Health Service Act. The Food ject to regulatory control, the Com­ and Drug Aministration performs a IX. W it h d r a w a l P e r io d s missioner points out that it is an in- complementary regulatory function: a . in t r o d u c t io n herent characteristic of almost all ana­ Followup analytical and field investi­ lytical methods th at componds can gations of violative residues to assem­ The regulations propose to define sometimes be detected at levels below ble evidence for use in regulatory ac­ the withdrawal period for a sponsored the levels at which they can be reli­ tions. compound as the time required, after ably measured. More precisely, detec­ The initial paper review by FDA of cessation of target animal exposure to tion of a compound simply means that material in a petition permits the the sponsored compound, for the there is some instrument response agency to make initial determination marker residue to deplete to Lm in the above background levels that could be of the acceptability of an assay. Ade­ target tissue. The withdrawal period the compound of interest, but this re­ quate protection of the public health, must also be compatible with actual sponse cannot be considered a reliable however, requires assurance that these conditions of livestock management measurement or identification of the assays will function in the govern­ and reasonably certain to be followed compound (Ref. 9). Since public pro­ ment’s regulatory laboratories. There­ in practice. Because of the way in tection is the goal, the Commissioner fore, these regulations also prescribe which the regulations define “marker must be in a position to document con­ the procedure that will be used to residue,” “target tissue,” and “Ln,,” the clusions based on analytical data, assure that an assay is appropriate for use of a sponsored compound in ac­ often in a court of law. A major aim of use as as regulatory tool by govern­ cordance with the prescribed with­ these proposed regulations is to assure ment laboratories. drawal period will assure that no car­ that assays used to obtain such data The Commissioner is proposing to cinogenic residues of the compound can reliably measure residues. Hence, require that three government labora­ will be present in human food derived the Commissioner concludes that the tories (two FDA facilities and one from treated animals. At any point discriminant for samples containing USDA facility) independently validate after cessation of exposure but before FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17102 PROPOSED RULES the determined withdrawal period, tion of marker residue in target tissue dence limits, as used elsewhere in this treated animal tissues must be consid­ versus time). regulation, estimate population pa­ ered as containing residues of carcino­ The analysis of the data must in- rameters (e.g., 99 percent confidence genic concern. Thus, the withdrawal cludé the estimated depletion curve, limits will result in an interval that period specifies the length of time which in most instances may be ade­ contains the true respònse rate 99 after the last treatment with a spon­ quately approximated by a first-order times out of 100). Statistical tolerance sored compound in which animals decay process. The statistical toler­ limits, however, are used to provide a must not be slaughtered for food and ance limit for the 99th percentile will specified degree of confidence that a during which milk or eggs must be dis­ be determined for the samples from specified portion of a population is carded. individual target animals, and the time below a given value (e.g., 99 percent Several comments on the 1973 pro­ of intersection of this limit with the confidence that, if the withdrawal posal addressed the procedures for es­ Lro value will be determined. The with­ period is followed, 99 percent of the tablishing post treatment withdrawal drawal period is the interval of time target tissues will contain residue periods. Some contended that the re­ between the last administration of the levels below L,„). quirement for tissue equilibration (no compound and the time of intersection One comment on the February change in concentration of residues in of this statistical tolerance limit on notice argued that withdrawal periods the tissue with change in time) with the observations and the 1%, of the ap­ are unenforceable and contrary to the residues in the experimental proce­ proved regulatory assay, plus an addi­ normal practices of the meat industry. dure for establishing withdrawal times tional interval determined by round­ Section 512(dX2)(D) of the act (21 was inappropriate for therapeutic ing out this time interval to provide a U.S.C. 360b(d)(2)(D)) provides express­ drugs. Other comments suggested that practical withdrawal period compati­ ly that, in determining whether a com­ the withdrawal periods be established ble with animal management practices pound is approvable, the Commission­ to assure the absence of residues from (Ref. 79). er is to consider whether the condi­ edible tissues only, because they are For example, if the time of intersec­ tions of use of a sponsored compound the ones destined for human consump­ tion of the statistical tolerance limit are reasonably certain to be followed tion. Some of these comments ex­ for the 99th percentile on the individ­ in practice. Historically, safe condi­ pressed concern about the practicality ual tissue determinations and the L,,, tions of use have included a pre- of applying confidence-interval tech­ for the marker residue is 39 hours, the slaughter withdrawal period for many niques to establishing withdrawal peri­ withdrawal period (preslaughter inter­ compounds intended for food-produc­ ods, especially when dealing with large val) case would be established as 2 days. In ing animals, and the compound’s label­ animals. Finally, one comment re­ the of milk samples, if the time of intersection were 63 hours, a with­ ing requires th at this period be dis­ quested clarification on whether confi­ drawal time of cussed. In the Commissioner’s opinion, dence limits or tolerance limits were to milkings) would72 hours (discard of six be established. withdrawal periods are being followed be used in setting withdrawal periods. for most compounds, although some The use of a compound will not be The following paragraphs contain the approved violation will always occur. However, Commissioner’s response. if the necessary withdrawal one of the primary functions of this period is incompatible with animal regulation is to improve the procedure B. DATA TO SUPPORT WITHDRAWAL management practices. For example, for setting withdrawal periods and PERIODS the use of a compound in lactating thereby provide FDA with stronger animals will not be approved if the re­ tools for enforcing compliance with The depletion studies required by quired withdrawal time for milk ex­ withdrawal periods "and for taking reg­ the proposed regulations to establish ceeds 96 hours (4 days) because the ulatory action if violative residues are withdrawal periods must take into ac­ management practices of milk produc­ detected. count the biological variability among tion make observance of such discard Three comments raised questions animals and other vairables, e.g., assay times unlikely, or at least not reason­ about the use of the term “99 percent variability, that may influence deple­ ably certain, to be followed in practice. confidence interval.” Another com­ tion times. When the marker residue is an en­ ment suggested that using the 99 per­ Residue depletion studies must be dogenous compound, the withdrawal cent confidence limits on the data in conducted under conditions of the period is the time after cessation of calculating the withdrawal period is sponsored compound’s maximum pro­ administration of the sponsored com­ too conservative and will result in posed use. If a sponsor can demon­ pound required for the norm to be re­ unduly long withdrawal periods. strate target tissue equilibration with stored (see sections VII., C, D, and E To clarify, the Commissioner has de­ the marker residue, however, a shorter above) and extended if necessary to be fined the term “99 percent confidence period of administration than the compatible with conditions of live­ interval” in the proposed definition maximum dose for the longest pro­ stock management. The validated reg­ section. The Commissioner does not posed conditions of use will be permit­ ulatory assay must be used to collect agree that the proposed approach is ted. The conditions of the study must this information. “too conservative.” By using the statis­ also simulate actual use conditions. tical tolerance limit on the data, the The commissioner agrees that a com­ C. RATIONALE FOR USING THE STATISTICAL Commissioner ensures with 99 percent pound intended for therapeutic use TOLERANCE LIMITS APPROACH confidence that in 100 sampled tissues need only be administered according To establish that carcinogenic resi­ there is no more than one violative to the compound’s maximum condi­ dues are absent from edible tissues of residue when the labeled withdrawal tions of proposed use. The proposed food-producing animals treated with period is followed. Minimizing the like­ regulatory assay must be used to the sponsored compound, the Commis­ lihood th at a violative residue will measure the marker residue in the sioner must have information about occur is an important public health target tissue, including milk and eggs the rate of residue depletion and the objective, and the Commissioner main* where appropriate, because it is this inherent metabolic variabilities among tains that the procedures provided in assay that will be used for regulatory individual target animals. these regulations (the use of a validat­ monitoring. The Commissioner is proposing to ed assay to collect residue data under All relevant data and evaluations use statistical tolerance limits for this proposed conditions of use; the use of must be submitted with the petition, section to provide the degree of confi­ statistical tolerance limits to establish along with a graphical presentation of dence <99 percent) necessary to ensure withdrawal periods; and the use of the tissue depletion curve (concentra- protection of the public health. Confi­ good animal husbandry practice to aid FEDERAL REGISTER, V O L 4 4 , N O . 55— TUESDAY, MARCH 20, 19T9 G PROPOSED RULES 17103 In determining whether withdrawal tion data (i.e., standard curves, spiked due is unsafe (an adulterant) within periods will actually be followed) pro­ tissue, and background values). the meaning of sections 409 and 512 of vide the proper balance in setting a the act, the agency must establish withdrawal period that ensures that X . C om plia n c e that the detected residue actually is a (1) the food consumed, if the with­ When a target tissue is examined residue of the sponsored compound; drawal period is followed, will be safe, with the approved assay and is found and when the agency can prove this (2) the withdrawal period is in accord to contain the marker residue at or point, it has proved that the food is with good animal husbandry practice above its Ln,, the Commissioner will adulterated as a m atter of law. and will be followed, and (3) violations conclude that the carcass from which The proposed regulation requires can and will be detected. the target tissue was taken contains each assay to meet specific criteria Two comments raised questions carcinogenic residues and, therefore, before the Commissioner will approve about collecting data with the validat­ that the sponsored compound has the sponsored compound or use, and ed assay in the tissue depletion studies been used in violation of the act. an assay satisfying these criteria will to determine the withdrawal period. When target animals are found to permit the agency to discriminate be­ Because assays are not validated until contain an endogenous marker residue tween target tissue background re­ the final stages of a petition’s review, at or above the 99th percentile of the sponses and responses due to the the comments stated that it is impossi­ norm (Plate III in proposed - ble to collect data to establish a with­ § 500.89(c)(l)(ii)), they will be desig­ marker are residue. Levels of residues that below the Ln, value cannot be dis­ drawal period with the validated nated as potentially violative. Because assay. there is at least a 1-percent probability tinguished from background with con­ The Commissioner disagrees. For th at untreated target animals will con­ fidence, and the results of these find­ reasons already stated, the withdrawal tain endogenous marker residue above ings are inadequate to support a regu­ period must be established with the the 99th percentile of the norm, fur­ latory action. On the other hand, assay for which approval is sought. ther investigation will be necessary to when marker residues are detected Further, collecting the data by any determine whether the sponsored and measured at or above L„ with the method not proposed for validation compound has been used in violation approved regulatory assay, this find­ imposes a repetitive administrative of the act. The function of this investi­ ing will unquestionably support regu­ burden on the agency that is costly gation will be to determine whether latory action since it constitutes evi­ and unwarranted. When the data are the potentially violative sample origi­ dence that the food is adulterated collected with a different assay, the nated from target animals whose within the meaning of section agency must first assess the quality of median level of the endogenous 402(a)(2) of the act. (See United States the data-collection assay and the ap­ mark»' residue is greater than the v. Ewing Bros. Co., Inc., 502 F.2d 715, propriateness of the data submitted. median of the norm (and hence, the 725-726 (7th Cir. 1974), cert, denied Then it must attempt to compare the need for a regulatory assay having an 420 U.S. 945 (1975).) Moreover, a find­ data-collection assay with the one pro­ Lm at the 33d percentile of the norm). ing of a violative residue will warrant posed for validation. In the Commis­ The proposed regulation also requires further administrative action because sioner’s opinion this simply is an unac­ that, before regulatory action is it will constitute a prima facie case ceptable waste of limited government begun, it must be determined whether th at the compound has not been used resources; therefore, the Commission­ or not the approved compound was in accordance with its conditions of er rejects any suggestion th at the used to treat the target animals under approval, and the agency will conduct withdrawal period be established using investigation. an assay that is not submitted for vali­ Guarding against any shifts in the a further investigation to determine dation. norms should allay all fears expressed what additional regulatory action, if A comment on withdrawal periods in comments that monitoring only at any, is appropriate. for endogenous substances contended the 99th percentile, as proposed, XI. W a iv er o f R e q u ir em en ts that it is unnecessary to show when would not permit detection of any gen­ the norm is restored. The comment eral increase in human exposure to po­ The proposal would permit the Com­ argued that merely showing th at the tentially carcinogenic endogenous sub­ missioner, in response to a petitioner’s norm is restored is adequate, regard­ stances. request or on the Commissioner’s own less of when the restoration takes Food containing residues of any ap­ initiative, to waive, in whole or in part, place. The Commissioner disagrees be­ proved sponsored compound that has any of the foregoing requirements for cause the rate of the norm’s restora­ been used in accordance with the con­ the scientific evaluation of sponsored tion is an important consideration in ditions of the compound’s approval is compounds that have the potential to setting the withdrawal period. It de­ specifically excluded from the adul­ contaminate hum an. food with resi­ termines when food derived from teration provisions of section 402(a)l) dues whose consumption could engen­ treated target animals will be safe for of the act by sections 409(a), 512(k), der a human risk of carcinogenesis. It human consumption. Only with such and 706(a). Thus, administration of has long been settled that an agency information can the necessary with­ the sponsored compound according to may adopt a rule shown to be appro­ drawal periods be established. the approved labeling is a defense to priate for the generality of instances Finally, two comments found un­ any criminal action that might arise clear the statement that sponsors for a violation of section 402(a)(1) of and leave the correction of injustices shall submit all raw data collected in the act. However, within the meaning to applications by those concerned determining withdrawal periods. They of section 402(a)(2) of the act, such (e.g., National Nutritional Foods Ass‘n suggested that the regulation be food is adulterated if it contains a resi­ v. Food and Drug Administration, 504 reworded to require submission of all due of the approved sponsored com­ F.2d 761, 784 (2d Cir. 1974) cert, appropriate supporting data. The pound which is unsafe within the denied 420 U.S. 946 (1975)). For these Commissioner agrees and intends to meaning of sections 409, 512, and 706. reasons, the Commissioner has ex­ require submission only of all data A residue is unsafe under those sec­ pressly included the waiver provision. that are relevant to determining with­ tions when it occurs in food at levels The Commissioner advises, however, drawal periods. Relevant data include, above those approved for use, and any that a waiver will be granted only in for example, descriptions of all assays residue found at levels equal to or exceptional circumstances, and, as the on specific tissues, worksheets, and above the L„ is unapproved and there­ regulation provides, the basis for any calculations, as well as daily calibra­ fore illegal. To establish that the resi­ waiver must be documented. FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17104 PROPOSED RULES XII. I m plem en ta tio n s One comment argued th at the final fended on th at ground. The agency The criteria set forth in the regula­ regulations, when promulgated, recognizes, however, that the totality tions are based on generally recog­ should apply only to all applications of these decisions may impose a set of nized scientific principles for testing pending approval at that time. For requirements that cannot feasibly be and evaluating chemical compounds previously approved compounds, the met by sponsors of compounds—for for potential carcinogenesis. Congress comment stated that the holders of economic, technical, or other reasons. comtemplated that FDA would adhere the approvals should be required to The agency, therefore, invites com­ to these principles when it enacted the submit data for at least a threshold as­ ments on whether the regulation im­ Food Additives Amendment of 1958 sessment. For any compound found to poses requirements that, as a totality, and the Animal Drug Amendments of require submission of additional data are unreasonable; and, if so, comments 1968 (21 U.S.C. 348 (b) and (c) and as set forth in the proposed regula­ áre invited on what specific provisions 360b (b) and (d)>. tions, the comment argued that the should be modified so that the re­ The 1973 proposal would have ap­ petitions for those compounds should quirements imposed by tlie modified plied the regulatory requirements to immediately be suspended. Another regulation would be reasonable. Pro­ all new applications (basic or supple­ comment, however, argued that the posed modifications should be ana­ mental) filed or approved after the ef­ Commissioner lacks authority to apply lyzed with respect to their impact on fective date of the regulations. Prior the regulations to any previously ap­ protection of the public health. No approvals were to be dealt with on a proved compound without new evi­ modification or set of modifications class-by-class basis, and the classes, in dence. would be acceptable if its effect would order of decreasing priority, were The Commissioner disagrees with be that the regulation would fail to known carcinogens, suspected carcino­ both comments. The act expressly provide satisfactory assurance that gens, and continuing through all com­ deals with these situations. It defines compounds approved for use pursuant pounds previously approved on the the new evidence that the Commis­ to the regulation will not subject basis of zero tolerance. These were to sioner can consider in determining humans to any significant increase in be reviewed as part of the agency's whether a previously approved com­ carcinogenic risk. general safety review for previously pound is safe to include: “Tests by new The Commissioner has carefully approved new animal drugs. methods, or tests by methods not considered the environmental effects The February 1977 notice an­ deemed reasonably applicable when of the regulations and, because this nounced that the regulations would such application was approve^, evalu­ action will not significantly affect the apply to all new animal drug applica­ ated together with the evidence quality of the human environment, tions, feed additive petitions, and ap­ available * * * when the application has concluded that an environmental propriate color additive petitions, in­ was approved” (section 512(e)(1)(B)). impact statement is not required. A cluding appropriate supplemental ap­ The tests proposed in these 'Regula­ copy of the environmental impact as­ plications, submitted after the effec­ tions are necessary to show that a sessment is on file with the Hearing tive date of the regulations. In addi­ sponsored compound is safe under the Clerk. (HFA-305), Food and Drug Ad­ tion, the regulations would apply to all act. For that reason, the absence of ministration, Rm. 4-65, 5600 Fishers pending petitions and applications data satisfying the above criteria, in Lane, Rockville, MD 20857. Unless the Commissioner determined conjunction with the evidence already that compliance with the act could be available about a compound, clearly R eferen ces adequately assured by requiring com­ can support the withdrawal of approv­ The following references are availa­ pletion of one or more of the required al of an application. A reasonable im­ studies subsequent to approval. plementation program is, of course, ble in the office of the Hearing Clerk (HFA-305), Food and Drug Adminis­ necessary to avoid chaos in the mar­ tration. Because some standards are needed for the day to day evaluation of peti­ ketplace, permit an efficient applica­ tions under sections 409 and 512, FDA tion of /the criteria, and provide the 1. H.R. Report No. 2284, 85th Cong., 2d has applied all the basic aspects of maximum public health protection. Sess. 1, 1958. Proposed §500.98 provides for such a 2. C. W. Dunn, Legislative Record of the these proposed standards on a case-by­ 1958 Food Additives Amendment of the Fed­ case basis for several years (e.g., dieth- plan. eral Food, Drug, and Cosmetic Act, p. 40 ylstilbestrol published in the F ederal XIII. C o n c lu sio n (1958 Ed.) citing Congressional Record of R eg ist e r of November 26, 1976 (41 FR August 13, 1958, 85th Cong., 2d Sess., 1958. 52105) and the nitrofurans published The proposed regulations are de­ 3. H.R. Report No. 86-1761 (H.R. 7624) in the F ederal R e g ist er of May 13, signed to provide a comprehensive, Committee on Interstate and Foreign Com- 1976 (41 FR 19906) and August 17, systematic data collection procedure nierce, 86th Cong., 2d Sess., 1960. 1976 (41 FR 34883)). It continues to for evaluating the carcinogenic poten­ 1962; 4. S. Report No. 1744, 87th Cong., 2d Sess., H.R. Report No. 2464, 87th Cong., 2d apply them to compounds currently tial of chemical compounds intended Sess., 1962; H.R. Report No. 2526, 87th being evaluated for approval or sub­ for use in food-producing animals and Cong., 2d Sess., 1962. ject to proposals to withdraw approv­ to ensure that edible tissues derived 5. 108 Congressional Record 19916, Sept. al. from such animals are safe. The 27.1962 (remarks of Rep. Sullivaii). All previously approved applications system is constructed with severable 6. 108 Congressional Record 19916, Sept, for compounds will be reviewed as part portions that can be modified or re­ 27.1962 (remarks of Rep. Sullivan). of the cyclic review of the safety of placed as the capacity of science to re­ ber7. 3,1962 108 Congressional Record 22053, Octo­ (remarks of Sen. Humphrey). marketed animal drugs, which will be solve, or the need for resolving, the 8. S. Report No. 1308, 90th Cong., 2d Sess., described in detail in a separate forth­ issues improves. 1968. coming notice in the F ederal R e g is ­ This regulation establishes a multis­ 9. Kaiser, H, “Guiding Concepts Relating t e r . When the agency finds deficien­ tep procedure for evaluating the car­ to Trace Analysis,” Pure and Applied Chem­ cies in the data supporting a prior ap­ cinogenic risk presented by a spon­ istry, Vol. 34, No. 1, pp. 35-65, 1973. proval, it will issue either a F ederal sored compound and criteria for the 10. “Symposium on Microscopy of Micro­ R eg ist e r notice or a letter in accor- conduct of each step. In developing fibers,” Proceedings of the First FDA Office ance with section 512(e) of the act. the steps and criteria, FDA applied licationof Science Summer Symposium, HEW Pub­ The criteria of these regulations will No. (FDA) 1701033. high standards of scientific acceptabil­ 11. Hearings before a subcommitte of the be used to determine whether the data ity and public health protection. In Committee on Appropriations of the House supporting applications are acceptable the agency’s view, each decision re­ of Representatives, 94th Cong., 2d Sess., PP- and adequate. flected in the regulations can be de­ 76-225, 1977. FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17105 12. Hearings before a subcommittee of the opment and Definition of the System,” Mu­ 40. Cooper, Terrance, “Tools of Biochem­ Committee on Appropriations of the House tation Research, 45:91-101, 1977. istry,” Chap. 3, John Wiley & Sons, Inc., of Representatives, 93d Cong., 2d Sess., p. 7, 26. Umeda, M., and M. Saito, “Mutageni­ NY, 1977. 1975. city of Dimethylinitrosamine to Mammalian 41. Gillette, J. R., “Environmental Factors 13. “General Criteria for Assessing the Cells as Determined by the Use of Mouse in Drug Metabolism,” Federation Proceed­ Evidence for Carcinogenicity of Chemical Liver Microsomes,” M utation Research, ings, 35:1142-1147, 1976. Substances,” Report of the Subcommittee 30:249-254,1975. 42. Shanker, L. S., “Drug Absorption” in on Environmental Carcinogenesis, National 27. Huberman, E., and L. Sachs, “Mutabil­ “Fundamentals of Drug Metabolism and Cancer Advisory Board, June 2,1976. ity of Different Genetic Loci in Mammalian Drug Disposition,” Edited by La Du, B. N„ 14. “Symposium Structural Correlates of Cells by Metabolicaily Activated Carcino­ H. G. Mandel, and E. L. Way, The Williams Carcinogenesis and Mutagenesis,” Proceed­ genic Polycyclic Hydrocarbons,” Proceed­ and Wilkins Co., Baltimore, MD, pp. 22-43, ings of the Second PDA Office of Science ings o f the N ational Academy of Sciences, 1971. Summer Symposium, HEW Publication No. U.S.A., 73:188-192,1976. 43. Baer, J. E., T. A. Jacob, and F. J. Wolf, (PDA) 78-1046. 28. Krahn, D. F., and C. Heidelberger, “Cambendazole and Nondrug Macromole­ 15. “Approaches to Determing the Muta­ “Liver Homogenate-Mediated Mutagenesis cules in Tissue Residues,” Journal of Toxi­ genic Potential of Chemicals: Risk To in Chinese Hamster V79 Cells by Polycyclic cology and Environmental Health, 2:895- Future Generations,” Journal o f Environ­ Aromatic Hydrocarbons and Aflatoxins,” 903,1977 mental Pathology and Toxicology, 1:301-352, M utation Research, 46:27-44,1977. 44. Hutson, D. H., “Glutathione Conju­ Prepared for the DHEW Committee to Co­ 29. Nakamura, N., N. Suzuki, and S. gates” in “ACS Symposium Series No. 29 on ordinate Toxicology and Related Programs Okada, “Mutagenecity of Furylfuramine, a Bound and Conjugated Pesticide Residues,” by Working Group of the Subcommittee on Food Preservative, Tested by Using Alanine- Edited by Kaufman, D. D., G. G. Still, G. D. Environmental Mutagenesis, 1977, Requiring Mouse L5178Y Cells In Vitro and Paulson, and S. K. Bandal, American 16. “A Catalogue of Structural Moieties In Vivo,” M utation Research, 46:355-364. Chemical Society, Washington, DC, 103-131, ..Required For the Activity of Chemical Car­ 30. Stich, H. F., and R. H. C. San, “DNA 1976. cinogens. A Guide For Predicting Potential Repair and Chromatid Anomalies in Mam­ 45. Ryan, J. J., and B. Hoffman, “Trenbo- New Carcinogens on the Basis of Molecular malian Cells Exposed to 4-Nitroquinoline-l- lone Acetate: Experiences with Bound Resi­ Structure,” Prepared by Bureau of Foods, oxide,” M utation Research, 10:389-404,1970. dues in Cattle Tissue,” Journal o f the Asso­ Food and Drug Administration. 31. Trosko, J. E., and J. D. Yager, “A Sen­ ciation o f Official A nalytical Chemists, 17. McCann, J., E. Choi, E. Yamasaki, and sitive Method to Measure Physical and 61:1274-1279,1978. B. N. Ames, "Detection of Carcinogens as Chemical Carcinogen-Induced ‘Unscheduled 46. Jaglan, P. S., M. W. Glenn, and A. W. Mutagens in the Salmonella/Microsome DNA Synthesis’ in Rapidly Dividing Eukar­ Neff, “Experiences with Drug-related Test: Assay of 300 Chemicals,” Proceedings yotic Cells,” Experimental Cell Research, Bound Residues,” Journal o f Toxicology of the National Academy of Sciences, U.S.A., 88:47-55 (1974). and Environm ental Health, 2:815-826, 1977. 72:5135-5139, 1975. 47. Lijinsky, W., and H. W. Taylor, “Nitro- 18. McCann, J., and B. N. Ames, “Detec­ 32. Stich, H. F., R. H. C. San, P.P.S. Lam, samines and their Precursors in Food,” in tion of Carcinogens as Mutagens in the Sal­ D. J. Koropatnick, L. W. Lo, and B. A. “Origins of Human Cancer,” p. 1579. monella/Microsome Test: Assay of 300 Laishes, “DNA Fragmentation and DNA 48. “Handbook of Physiology,” Section 9, Chemicals: Discussion,” Proceedings o f the Repair as an In Vitro and In Vivo Assay for “Reactions to Environmental Agents,” ed. National Academy o f Sciences, V.S.A., Chemical Procarcinogens, Carcinogens, and Carcinogenic Nitrosations Products,” in by Lee, D. H. et al., American Physiological 73:950-954, 1976. Society, Chapters 23, 24, and 27,1977. 19. Sugimura, T., S. Sato, M. Nagao, T. “Screening Tests in Chemical Carcinogene­ 49. Tomatis, Lorenzo, et al., “Evaluation Yahagi, T. Matsushima, Y. Seino, M. Takeu- sis,” Edited by Montesano, R., H. Bartsch, of Carcinogenicity of Chemicals: A Review chi, and T. Kawachi, “Overlapping of Car­ and L. Tomatis, International Agency for of the Monograph Programs of the Interna­ cinogens and Mutagens,” in “Fundamentals Research in Cancer, Scientific Publication tional Agency for Research on Cancer,” in Cancer Prevention,” Edited by Magee, P. No. 12, Lyon, pp. 617-638, 1976. 33. Martin, C. N., A. C. McDermid, and R. Cancer Research, 38:877-885, April 1978. N., et al., University Park Press, Baltimore, 50. Sontag, J. M., N. P. Page, and Umberto MD, pp. 191-215, 1976. C. Gamer, “Testing of Known Carcinogens and Non-Carcinogens for their Ability to Saffiotti, "Guidelines for Carcinogen Bioas­ 20. Purchase, I. F., H. Longstaff, J. Ashby, says in Small Rodents,” National Cancer In­ J. A. Styles, and D. Anderson, “An Evalua- i Induce Unscheduled DNA Synthesis in Hela stitute, carcinogenesis Technical Report tion of 6 Short-Term Tests for Detecting Cells,” Cancer Research, 38:2621-2627, 1978. Series No. 1. HEW Publication No. (NIH) Organic Chemical Carcinogens,” British 34. Williams, G., “Detection of Chemical 76-8601, 1976. Journal o f Cancer, 37:873-959,1978. Carcinogens by Unscheduled DNA Synthe­ 51. Occupational Safety and Health Ad­ 21. Hsie, A. W., P. O’Neill, J. C. Fuscoe, J. sis in Rat Liver Primary Cell Cultures,” ministration, Proposal to add 29 CFR Part R. San Sebastian, D. B. Couch, W. N. C. Cancer Research, 37:1845-1851,1977. 1990—Identification, Classification and Reg­ Sun, P. A. Brimer, R. Machanoff, J. C. 35. McNamara, P. B., “Concepts in Health ulation of Toxic Substances Posing a Poten­ Riddle, N. L. Forbes, and M. H. Hsie, “Muta­ Evaluation of Commercial and Industrial tial Occupational carcinogenic Risk, F eder­ genicity of Carcinogens: Study of 101 Chemicals,” Advances in M odem Technol­ al R egister , October 4, 1977 (42 FR 54148). Agents in a Quantitatively Mammalian Cell ogy, Vol. 1, Part 1, Mehlman, M., et al. Ed, 52. Consumer Product Safety Commission, Mutation System,” Federation Proceedings, Hemisphere Publishing Company, pp. 87-92, Final Rule adding 16 CFR Part 1040—Inter­ 37:1384, 1978. 1976. im Policy and Procedures for Classifying, 22. Ames, B. N., J. McCann, and E. Yama­ 36. Nelson, S. D., J. R. Mitchell, J. A. Tim- Evaluating and Regulating carcinogens in saki, “Methods for Detecting Carcinogens brell, W. R. Snodgrass, and G. B. Corcoran Consumer Products, F ederal R egister, and Mutagens with the Salmonella/Mam- III, “Isoniazid and Improniazid: Activation June 13, 1978 (43 FR 25658). malian-Microsome Mutagenicity Test,” Mu­ of Metabolites to Toxic Intermediates in 53. Environmental Protection Agency, tation Research, 31, 347-364,1975. Man and Rats,” Science, 193:901-903, 1976. Notice of Interim Policy and Guidelines 23. Yahagi, T., M. Degawa, Y. Seino, T. 37. Jenner, Peter, and Bernard Testa, Concerning Health Risks and Economic Matsushima, M. Nagao, T. Sugimura, and Y. Review Article, “Novel Pathways in Drug Impact Assessments of Suspected carcino­ Hashimoto, “Mutagenicity of Carcinogenic Metabolism.” gens, F ederal R egister, May 25, 1976 (41 Azo Dyes and Their Derivatives,” Cancer 38. Rannug, U., A. Sundvall, and C. Pamel, FR 21402). Letters, 1:91-96, 1975. “The Mutagenic Effect of 1,2-dichloroeth- 54. Peto, R., “Epidemiology, Multistage 24. Clive, D., and J. F. S. Spector, “Labora­ ane on Salmonella typhimurium I. Activa­ Models and Short-Term Mutagenicity tory Procedure for Assessing Specific Locus tion through Conjugation with Glutathione Tests,” Origins o f Human Cancer, 38:1403- Mutations at the TK Locus in Cultured in Vitro,” Chemical-Biological Interactions, 1426, April 1978. L5178Y Mouse Lymphoma Cells,” Mutation 20:1-16, 1978. 55. Wilson, R., “Risks Caused by Low Research, 31:17-29,1975. 39. Kuntzman, R., “Application of Tracer Levels of Pollution,” Yale Journal o f Biol­ 25. O’Neill, J. P., p. A. Brimer, R. Machan­ Techniques in Drug Metabolism Studies” in ogy and Medicine, 51:37,1978. off, G. P. Hirsch, and A. W. Hsie, “A Quani- “Fundamentals of Drug Metabolism and 56. Finney, D. J., “Probit Analysis,” Chap­ tative Assay of Mutation Induction at the Drug Disposition,” Edited by La Du, B. N., ters 2 and 6, Cambridge University Press, Hypoxanthine-Guanine Phosphoriboxyl H. G. Mandel, and E. L. Wuy, The Williams, 1977. Transferase Locus in Chinese Hamster and Wilkins Co., Baltimore, MD, pp. 489- 57. Mantel, N., and W. R. Bryan, “Safety Ovary Cells (CHO/HGPRT System): Devel­ 504,1972. Testing of carcinogenic Agents,” Journal o f FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17106 PROPOSED RULES „ the National Cancer Institute, 27(2):455-470, 77. Seigel, S., “Nonparametric Statistics Stat. 1785-1788 as amended. 74 Stat. 399-403 1961. for the Behavioral Sciences,” McGraw Hill as amended, 82 Stat. 343-351 (21 U.S.C. 342, 58. Mantel, N., et al., “Improved Mantel- Book Co., New York, pp. 127-136,1956. 343, 348, 360b, 371(a), 376). Bryan Procedure for Safety Testing of car­ 78. Hollander, M., and D. A. Wolfe, “Non­ cinogens,” Cancer Research, 35:865-872, parametric Statistical Methods,” John S u b p art E—C riteria a n d P rocedures fo r Evalu­ 1975. Wiley and Sons, New York, pp. 219-228, a tin g A ssa y s fo r C arcinogenic R esidues in 59. Hartley, H. S., and R. L. Sielken, Jr., 1973. Edible P roducts o f Anim als “Estimation of ‘Safe Doses’ in carcinogenic 79. Owen, D. B., “A Survey of Properties Experiments,” Biometrics, 33:1-30, 1977. and Applications of the Noncentral t-Distri- § 500.80 Chemical compounds used in 60. Crump, K. S., H. A. Guess, and K. L. bution,” T e c h n o m e tr ic s, 10(3):445-0478, food-producing animals: Procedures Deal, “Confidence Intervals and Tests of August 1968. and criteria for determining acceptabil­ Hypotheses Concenting Dose Response Re­ Therefore, under the Federal Food, ity of assays for carcinogenic residues lations Inferred from Animal carcinogencity Drug, and Cosmetic Act (sections 402, in edible products. Data,” Biometrics, 33:437-451, September 1977. 403, 409, 512, 701(a), 706, 52 Stat. 1046- (a) Scope of this subpart. (1) The 61. Guess, H., C. Crump, and R. Peto, “Un­ 1048 as amended, 1055, 72 Stat. 1785- Food, Drug, and Cosmetic Act requires certainty Estimates for Low-Dose-Rate Ex­ 1788 as amended, 74 Stat. 399-403 as th at compounds intended for use in trapolations of Animal carcinogencity amended, 82 Stat. 343-351 (21 U.S.C. food-producing animals be shown to be Data,” Cancer Research, 37:3475-3483, Octo­ 342, 343, 348, 360b, 371(a), 376)) and safe and that food produced from ani­ ber 1977. under authority delegated to him (21 mals exposed to these compounds be 62. Gross, M. A., et al., “Evaluation of CFR 5.1), the Commissioner proposes shown to be safe for human consump­ Safety of Pood Additives,” Biometrics, to amend Chapter I of Title 21 of the tion. The statute prohibits the use in 26( 21:181-194,1970. 63. Hoel, D. G., et al., “Estimation of Risks Code of Federal Regulations as fol­ food-producing animals of any com­ of Irreversible Delayed Toxicity,” Journal lows: pound found to induce cancer when in­ o f Toxicology Envim om ental Health, 1:133- gested by human or animal unless it PART 70— COLOR ADDITIVES can be determined by methods of ex­ 151,1975. 64. Cornfield, Jerome, “carcinogenic Risk 1. In Part 70, by amending § 70.50 by amination prescribed or approved by Assessment,” Science, 198:18, November adding new paragraph (c), to read as the Secretary (a function delegated to 1977, and comments. follows: the Commissioner of Food and Drugs 65. Albert, R., and B. Altshuler, “Consider­ under §5.1 of this chapter) that no ations Relating to the Formulation of § 70.50 Application o f the cancer clause o f residue of that compound will be Limits for Unavoidable Populatioh Expo­ section 706 o f the act. found in the food produced from those sures to Environmental carcinogens,” Ap­ pendix, Radio-nuclide Carcinogenesis AEC animals under conditions of use rea­ Symposium Series, Conf. 72050.1, National * * * * * sonably certain to be followed in prac­ Technical Information Service, 233-253. (c) Color additives for use as an in­tice. 66. Saffiotti, Umberto, “Experimental gredient of feed for animals that are use (2) Petitions for the approval of the Identification of Chemical carcinogens, Risk raised for food production. Color addi­ animals of a compound in food-producing Evaluation, and Animal to Human Correla­ must include adequate data tions,” Environmental Health, 22:107-113, tives that are an ingredient of the feed for establishing the absence of resi­ 1978. for animals raised for food production dues of carcinogenic concern in the 67. Mantel, N. and M. Schniderman, “Esti­ must satisfy the requirments of sub­ food produced from those animals. mating Safe Levels, A Hazardous Undertak­ part E of Part 500 of this chapter. (3) This subpart establishes the fol­ ing,” Cancer Research, 35:1379-1386, 1975. 68. Fialkow, P. J., “Use of Genetic Mark­ PART 500— GENERAL lowing: (i) The lowest limit of reliable ers to Study Cellular Origin and Develop­ measurement for the regulatory assay ment of Tumors in Human Females,” Ad­ 2. In Part 500, by adding a new Sub­ required for carcinogenic residues by vanced Cancer Research, 15:191-226, 1972. part E, consisting of §§ 500.80 through sections 409(c)(3)(A), 512(d)(1)(H), and 69. Cooper, R. M., “The Role of Regula­ 500.98, to read as follows: 706(b)(5)(B) and sections 409(b)(2)(D), tory Agencies in Risk-Benefit Decision 512(b)(7) and 706(b)(5)(A)(iv) of the Subpart E—Criteria and Procedures for Evaluating Making,” Food Drug and Cosmetic Law Assays for Carcinogenic Residues in Edible Products act. Journal, pp. 755-773, December 1978. of Animals (ii) The procedures and criteria for 70. Reactor Safety Study (WHSH-1400): A Review of the Final Report,” U.S. Environ­ evaluation and approval of such Sec. assays. mental protection Agency, Office of Radi­ 500.80 Chemical compounds used in food- ation Programs, 1976. producing animals: Procedures and crite­ (iii) The procedures and criteria for 71. Starr, Chauncey, “Social Benefit V. ria for determining acceptability of establishing the premarketing with­ Technological Risk,” Science, 165:1232-1238, assays for carcinogenic residues in edible drawal period for use of compounds 1969. products. likely to produce such residues. 72. Hutt, P. B., “Public Policy Issues in 500.83 Definitions. (4) This subpart applies specifically Regulating Carcinogens in Food,” Confer­ 500.84 Metabolic study in target animals to to the use in food-producing animals ence on the Scientific Basis for Interpreta­ identify residues for chronic testing. and in their feed of compounds that tion of the Delaney Clause, International 500.85 Criteria for test animal selection; Academy of Environmental Safety, Feb, 6, comparative metabolic studies to aid in have the potential to contaminate 1978. assessing the carcinogenicity of intracta­ human food with residues whose con­ 73. Lowrance, W., “Of Acceptable Risk,” ble residues. sumption could present a human risk William Kaufmann, Inc., 1976. 500.87 Chronic testing. of cancer. The determination of this 74. National Academy of Sciences, “Drink­ 500.89 Metabolic study to identify the potential will be based on consider­ ing Water and Health,” Safe Drinking marker residue and target tissue. ations of chemical, biochemical, phys­ Water Committee Advisory Center on Toxi­ 500.90 Evaluation and approval of a regula­ iological, and toxicological data de­ cology, 1977. tory assay. 500.92 Withdrawal periods. rived from the scientific literature and 75. National Academy of Sciences, “Pest Control: An Assessment of Present and Al­ 500.94 Publication of the approved regula­ from other sources available to the pe­ ternative Technologies,” in Vol. I, “Contem­ tory assay. titioner or to the Commissioner and porary Pest Control Practices and Pros­ 500.95 Compliance. on the proposed patterns of compound pects,” pp. 54-101,1975. 500.96 Waiver of requirements. use. This subpart establishes a sequen­ 76. Miller, J. A., “Toxicants Occurring 500.98 Implementation. tial process for the collection of other Naturally in Foods,” National Academy of A uthority : Secs. 402, 403, 409, 512, 701(a), chemical, biochemical, physiological, Sciences, Washington, DC. 706, 52 Stat. 1046-1048 as amended, 1055, 72 and toxicological data pertinent to the FEDERAL REGISTER, VOL. 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17 10 7 safety of the proposed use of the spon­ (2) If, at any point in the sequential tabolism studies will assist in assessing sored compound. process of data collection set forth in the toxicity of intrectable residues and (5) This subpart does not apply to paragraph (b)(1) of this section, the in selecting species/strains of test ani­ essential nutrients. evaluation of the data satisfies the mals for bioassays of selected tractable (b) General approach. (1) When the Commissioner th at no human risk of residues. Commissioner determines that a spon­ carcinogenesis arises from the pro­ (k) “S0” means the residue level of a sored compound has the potential to posed use of the sponsored compound, sponsored Compound in a total test contaminate food from food-producing the compound will be considered for diet of animals that corresponds to a animals with residues (the sponsored approval under the general safety pro­ lifetime risk of cancer of 1 in 1 million compound, metabolites, or any other visions of the act for risks other than in the test animals. For the purpose of substances formed in or on food (e.g., cancer. this subpart, this SDlevel in the test endogenous substances) because of the animal corresponds to a level in the compound’s use) whose consumption § 500.83 Definitions. total human diet that is assumed to could present a human risk of cancer, The following definitions apply to represent a level of risk to humans of the following procedure for data col­ this subpart: no more than 1 in 1 million over a life­ lection and evaluation will apply: (a) “Sponsored compound” means (i) A metabolic study in the animals any drug or additive proposed for use, time. in which the sponsored compound is or used in, food-producing animals. (l) “Sm” means the level of total resi­ intended for use (target animals) de­ dues of carcinogenic concern for a spe­ (b) “Target animals” means the pro­ cific edible tissue as determined by the signed to identify metabolites of con­ duction class of animals in which a cern and, when appropriate, to deter­ sponsored compound is proposed or in­ formula in § 500.87(d). mine if normal levels of carcinogenic tended for use. (m) “Marker residue” means the se­ or potentially carcinogenic endog­ lected residue whose level in a particu­ (c) “Sponsor” means the person pro­ lar tissue is in a known relationship to enous substances are affected. posing or holding an approval by the (ii) Metabolic studies of the spon­ Food and Drug Administration for the the level of the total residue of car­ sored compound in different species of use of a sponsored compound. cinogenic concern in all edible tissues experimental animals designed to aid (d) “Threshold assessment” means and that can be taken as a measure of in selecting the appropriate species for the Food and Drug Administration’s the total residue of concern in the chronic toxicity testing and in assess­ review of data and information availa­ target animal. ing the carcinogenicity of residues (n) “Target tissue” means the tissue that cannot practicably be tested indi­ ble about a sponsored compound to de­ termine whether the compound selected to monitor for residues in the vidually (intractable residues). be subject to regulation under target animal. The target tissue is se­ (iii) Chronic testing in test animal to should this subpart as well as under the other lected so that the absence of marker assess the-'carcinogenic potential of general safety of the Feder­ residue at or above the required level residues of the sponsored compound, al Food, Drug,provisions and Cosmetic Act for of measurement (Rm) can be taken as to furnish data suitable for statistical risks other than cancer. confirmation that the safe, or accept­ treament by the linear extrapolation (e) “Total residue of the sponsored able, residue level (Sm) is not exceeded procedure of Gross, M. A., O. G. Fitz- compound” means all compounds pres­ in any of the edible tissues of the hugh, and N. Mantel, “Evaluation o*f target animal. Safety of Pood Additives,” Biometrics, ent in edible tissues of the target (o) “Rm” means the level of the 26 (2): 181-194 (1970) and Hoel, D. G., animal that result from the use of the marker residue(s) in the target tissue et al., “Estimation of Risks of Irrevers­ sponsored compound, including the when the sum of the levels of the resi­ ible, Delayed Toxicity,” Journal of sponsored compound, its metabolites, dues of toxicological concern is equal Toxicology and Environmental and any other substances formed in or to Sm for the edible tissue requiring Health, 1:133-151 (1975)1 (which are on food because of the sponsored com­ the longest time to deplete to its Sm. incorporated by reference), and to pound’s use. (p) “Endogenous compound” means permit the no-residue requirement of (f) “Residue” means any single com­ pound present among the total resi­ any compound that its metabolically the act to be operationally defined for produced by and is present in untreat­ purposes of establishing a lowest limit due. of reliable measurement for an assay (g) “Residue of toxicological con­ ed target animals. to measure residues of the sponsored cern” means all compounds in the compounds (q) “Essential nutrients” means compound. total residue minus any compounds th at are found in the tis­ (iv) A detailed metabolic study of shown to be safe. sues of untreated target animals and the sponsored compound in target ani­ (h) “Metabolic studies” means stud­ required for the animals’ growth, and mals designed to identify a specific ies designed to identify the residues that must be supplied from external residue and tissue to serve as indica­ th at occur in edible tissues when the sources, e.g., essential amino acids. tors (marker residue and target tissue) sponsored compound is administered (r) “Norm” means the normal back­ to determine whether the no-residue to target animals and to determine the ground levels of an endogenous sub­ requirement of act is satisfied. depletion characteristics of the resi­ stance in untreated target animals, (v) Development of a regulatory dues. plotted as a cumulative frequency dis­ assay to measure the marker residue (i) “Intracable residues” means resi­ tribution of levels. in the target tissue at and above the dues of the sponsored compond that, (s) “Rm for an endogenous marker level operationally defined as satisfy­ using the best available technology, residue” means the level of the endog­ ing the no-residue requirement of the cannot be obtained, by isolation, syn­ enous marker residue that corresponds act. thesis, etc., in sufficient amounts for to the 33d percentile of the norm. (vi) Establishment of the prémarket­ carcinogenicity testing. (t) “Spiked tissue samples” means ing withdrawal period required for the (j) “Comparative metabolism” samples of target tissue to which safe use of the sponsored compound. means the study of the metabolism of known amounts of marker residue a sponsored compound in different have been added. 'Copies may be obtained from: Industry species/strains of test animals that are (u) “Control tissue samples” means Information (HFV-226), Bureau of Veteri­ potential surrogates for man in chron­ samples of target tissue from untreat­ nary Medicine, Food and Drug Administra­ ic toxicity testing. Comparative metab­ ed target animals. tion, 5600 Fishers Lane, Rockville, MD olism studies will assist in assessing (v) “Dosed tissue samples” means 20857. the toxicity testing. Comparative me­ samples of target tissues from target FEDERAL REGISTER, V O L 44, NO. 55—TUESDAY, MARCH 20, 1979 1 7 10 8 PROPOSED RULES animals administered the sponsored priate radiolabels, unless other experi­ (e) Reisidues in edible tissues of compound. mental methods permit measurement target animals that are intermediate (w) “Lm” means the level of marker of total residues with accuracy and metabolites in metabolic pathways residue in target tissue that gives a re­ precision equivalent to radiolabel that are reasonably expected to be sponse greater than, or equal to, 0.75 methods. Such labels shall assure that similar in humans and the selected times the spread of the 99 percent con­ residues containing structural moieties test animal species/strain need not be fidence bounds of a single assay re­ of potenetial carcinogenic concern are subjected to independent chronic tox­ sponse measured parallel to the ob­ detected and measured in edible tis­ icity testing. Testing the leading sub­ served assay response axis based on sues at levels as low as the best availa­ strate in each metabolic pathway is the analytical curve of the assay. (See ble technology will permit. Hypoth­ sufficient. In the absence of informa­ Plate IV in § 500.90(d)(5>.) eses about the sponsored compound’s tion that the leading substrate is non- (x) “Assay” means the aggregate of projected metabolic pathways may be carcinogenic, tractable residues that all experimental procedures for meas­ used as a guide to experimentation, are produced in the target animals but uring the presence of the marker resi­ but they are not a substitute for that are not produced in the test due of the sponsored compound in the actual experimentation. animal species/strain shall be subject­ target tissue of the target animals at (2) The dosipg regimen shall be the ed to independent chronic toxicity or above the 1^. It includes the proce­ maximum proposed use level and pro­ testing. dures for sample of instrument prepa­ posed duration of exposure to the (f) Section 500.85 describes an alter­ ration. The assay must satisfy criteria sponsored compound. For a compound native means of assessing the carcino­ set forth in § 500.90, and it will usually th at is proposed for continuous or re­ genic potency of residues whose isola­ consist of multiple measurement pro­ peated use in target animals, adminis­ tion or synthesis in sufficient quanti­ cedures that utilize different physioco- tration for the metabolic study need ties for chronic testing proves to be chemial principles, e.g., gas chromato­ continue only until tissue saturation beyond the practical limits of current graphy-mass spectrometry, to assure has been demonstrated. If tissue satu­ chemical technology (intractable resi­ compliance with the regulatory re­ ration cannot be attained, residue dues) by establishing additional crite­ quirements. equilibration or showing a stable meta­ ria for selecting test animal species/ (y) “Withdrawal period” means the strains used to conduct chronic toxic­ time required, after cessation of target bolite profile will be adequate. ity testing of the sponsored compound. animal exposure to the sponsored (3) The metabolic study shall be de­ compound, for the marker residue to signed to yield the following informa­ § 500.85 Criteria for test animal selection: deplete to Lm in the target tissue. tion: Comparative metabolic studies to aid (z) “Analytical curve” means the (i) The concentrations and total in assessing the carcinogenicity plot of the observed responses of the number of residues detacted in edible (a) The primary criterion for select­ regulatory assay when analyzing tissues of target animals immediately ing species or strains of test animals “spiked” tissues compared to the following cessation of exposure. for chronic testing of both the spon­ amount of marker residue added to (ii) The concentrations and total sored compound and any metabolities the “spiked” tissues. number of residues detacted in edible selected in accordance with §500.84 (aa) “Ninety nine percent confi­ tissues of target animals at a sufficient shall be the suitability of the species dence interval” means an interval, de­ number of different time intervals, fol­ or strain as a model for man. termined by confidence limits, that is lowing the initial measurement, to de­ (b) If one or more intratable resi­ expected to contain the population pa­ termine the depletion trend of individ­ dues are also selected for chronic test­ rameter being estimated 99 times out ual residues. ing based upon the matabolic study in of 100 times. (iii) The physicochemical properties target animals, a secondary criterion (bb) “Upper ninety nine percent of the detected residues to identify shall be employed for selecting species confidence limit” means a value that is compounds of potential carcinogenic or strains of animals for testing the expected to be equal to or larger than concern. sponsored compound. Metabolic stud­ the population parameter being esti­ (4) The results of the metabolic ies of the sponsored compound in test mated 99 times out of 100 times. study shall be submitted in the form animal species or strains determined (cc) “Statistical tolerance limits” of a detailed report conforming to the to be suitable for chronic testing by means upper and lower values between standards required of scientific manu­ the primary criterion shall be conduct­ which it can be stated with a given scripts submitted for publication in ed to determine whether the intracta- level of confidence that a specified the journals of professional scientific bel residues present in the tissues of portion of the population will be in­ societies, such as the American Chemi­ target animals are also produced in cluded. cal Society and the American Society the test animals. Chronic testing of of Biological Chemists. In addition, all the sponsored compound in a species § 509.84 Metabolic study in target animals raw data shall accompany and be ref­ or strain of test animals in which the to identify residues for chronic testing. erenced in the report. complement of residues produced is (a) A metabolic study, described in (c) If the Commissioner determines similar to the complement of residues paragraph (b) of this section, shall be that a sponsored compound has poten­ produced in the tissues of the target conducted in target animals to provide tial to contaminate food with residues animals is considered an appropriate data on the physicochemical charac­ whose consumption presents a human method of assessing the carcinogenic teristics of residues, their relative pro­ risk of cancer, the petitioner shall de­ potency of the intractable residues. portions, their distribution among the termine the carcinogenic potency of various edible tissues (which include the sponsored compound and those § 500.87 Chronic testing. milk or eggs when applicable), and residues that may be of public health (a) Chronic toxicity tests shall be their retention and depletion in concern due to chemical structure or conducted to assess the carcinogenic animal tissues. persistence and concentration in potential of the residues of the spon­ (b) The metabolic target animal edible tissues. sored compound. study shall satisfy the following mini­ (d) Ordinarily, chronic testing of the (1) The sponsored compound and mum requirements: sponsored compound and selected resi­ any residues selected for chronic toxic­ (l) The metabolic study shall be con­ dues in experimental animals will be ity testing shall be subjected to oral, ducted in target animals with the the preferred means of assessing car­ lifetime, dose-response studies in the sponsored compound bearing appro­ cinogenic potency. test animal species or strains selected FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17 10 9 in accordance with §500.85. Each of bioassays may be combined for analy­ in paragraph (c) of this section) are as these studies shall be designed to de­ sis. follows: termine whether the test compound is (5) All tumors, benign and/or malig­ carcinogenic. Protocols for these stud­ nant, shall be considered in the analy­ Edible tissue T S» ies should be submitted to the Food sis. 3S0 and Drug Administration for review (6) The number of animals at risk Muscle.................................... .................... Milk........................................________ 1 Mi s. before commencing testing. may be adjusted for competing risks Eggs------- -------------...------- .................... 3S„ Mi (2) On the basis of the results of unrelated to compound-induced car­ these chronic toxicity studies and cinogenesis only when the data clearly (2) Calculation of Sm for tissues con­ other available information, the Com­ support such an adjustment. sumed less frequently than muscle missioner will determine whether any (7) When only the sponsored com­ may take into consideration the fre­ of the compounds tested is carcinogen­ pound is subjected to chronic testing, quency of consumption of those tis­ ic. If this evidence is equivocal, the the calculated “acceptable” level is to sues if it can be clearly shown that S0 compound will be regulated as a car­ be designated as S0. When more than will not be exceeded in the total cinogen until further testing resolves one compound is subjected to chronic human diet. the remaining questions regarding car­ testing, the lowest of all calculated ac­ § 500.89 Metabolic study to identify the cinogenicity. ceptable levels is to be designated S0. marker residue and target tissue. (b) When the Commissioner deter­ S0 shall be expressed as the fraction of (a) The petitioner shall conduct a mines that a sponsored compound has the diet fed the test animals, e.g., study of the metabolic fate of the the potential to increase the normal parts per million, parts per billion. sponsored compound in target animals levels (pools) of carcinogenic and po­ (8) The no-residue requirement of adequate to provide the data necessary tentially carcinogenic substances en­ the act is considered satisfied when for selecting a marker residue in dogenous to the target animals, the conditions and use of the compound, target tissue. petitioner shall meet the requirements including any required withdrawal (1) The target tissue is that tissue in of § 500.89(c), (d), and (e) or (f ). period, can be prescribed to assure which measurement of the total resi­ (c) For each tested compound regu­ th at the sum of the levels of all poten­ due burden of carcinogenic concern is lated as a carcinogen, the appropriate tial residues of carcinogenic concern a reliable measure of the total residue data from the chronic dose-response will not exceed S0 in the total diet of burden of carcinogenic concern in all studies shall be analyzed according to man, and a regulatory assay is availa­ edible tissues. procedures described by Gross, et al. ble that is capable of reliably measur­ (2) The marker residue for the spon­ and Hoel, et al. subject to the modifi­ ing such residues at and above that sored compound is that residue (the cations and restrictions set forth in level. All residues of the sponsored sponsored or more than compound, any metabolite, one of these) whose level paragraph (c)(1) through (8) of this compound are regulated as carcinogen­ ic except those that have been shown in the target tissue is a reliable meas­ section. The purpose of this analysis is ure of the total burden of all residues to interpret the “no residue” require­ to be noncarcinogenic. ment of the act as it applies to the (d) The S0 value represents the sum of carcinogenic concern in all edible tissues. total residue of carcinogenic concern of all residues of carcinogenic concern (b) The metabolic study to establish of the sponsored compound and there­ th at shall not be exceeded in the total the marker residue and target tissue by to determine the lowest level of re­ diet of man. For individual edible tis­ shall comply with the requirements liable measuremènt required for a reg­ sues, the value that shall not be ex­ set forth in § 500.84(b) (2) and (4), ulatory assay to be approved for the ceeded is to be designated Sm and cal­ with the following additional specifica­ monitoring of the total residue. culated according to the following for­ tions: (1) The administered dose of each mula: (1) For each edible tissue, the deple­ test compound shall be expressed as a Sm=S0/T tion profile of the total residue of car­ fraction of the total diet fed the test Note.—T is the fraction of the total daily cinogenic concern shall be constructed animal species/strains, e.g., parts per diet of man represented by an individual and shall include measurements of edible tissue. million, parts per billion. levels at least as low as the Sm appro­ (2) The permissible level, determined (1) The principal Smcalculations (de­priate to the tissue under study, as set by the linear extrapolation model for fining T as noted in the formula above forth in Plate I as follows: each test compound in accordance PLATE I. RE 5IDUE DEPLETION CURVES TO BE USED with this section, shall be expressed as IN THE DETERMINATION OF MARKER RESIDUE AND a fraction of the total diet fed the test TARGET TISSUE. animal species/strains. It shall be cal­ culated using the 99 percent confi­ dence limit of the observations for a maximum lifetime risk that is essen­ tially zero but never expected to exceed 1 in 1 million. (3) Data obtained from more than one dose level fed to groups of experi­ mental animals of the same strain shall be combined as described by Gross, et al. and Hoel, et al. and are subject to the restrictions specified by these authors. (4) Pooling data from various chron­ ic tests using different animal sexes, species, or strains is permitted if it can be demonstrated th at the protocols are of compatible design. If statistical­ ly significant biological differences in tumorigenic responses are observed be­ tween sexes or among species or strains of experiental animals, only subsets of data representing statisti­ cally and biologically compatible FEDERAL REGISTER. VOL. 44, NO. 55—TUESDAY, MARCH 20, 1979 17 11 0 PROPOSED RULES (2) Depletion profiles for one or time when the total residue level has more potential marker residues shall reached Sm in the edible tissue requir­ be constructed as set forth in Plate II ing the longest time to deplete to Sm as follows, and shall include measure­ (Tl of Plate I in paragraph (bXl) of ments of levels corresponding to the this section). PLATE II. SELECTION OF M ARKER • RESIDUE A N D ITS LEVEL Rm THAT M UST BE M EA SU RED BY THE REGULATORY ASSAY. TIME (IN APPROPRIATE UNITS) (3) If these specifications have been (c) When the Commissioner deter­ met by the metabolic study required mines on the basis of available scien­ by § 500.84(b), a second metabolic tific information th at a sponsored study need not be performed to satisfy compound has the potential to in­ the section. crease the normal levels (pools) of po­ (4) From these data, the Commis­ tentially carcinogenic substances edo- sioner will select a marker residue and genous to target animals, the petition­ target tissue and will also designate er shall provide the following addition­ the required level of marker residue, al data: Rm (set forth in Plate II in paragraph (b)(2) of this section), that regulatory (1) An experimental determination assays shall be capable of measuring of the background levels (norm) of in the target tissue. The selection of each of the potentially carcinogenic Rm will be such th at the absence of endogenous substances of concern in the marker residue in the target tissue untreated target animals that are in­ above Rm can be taken as confirmation creased by administration of the spon­ that the total residue burden of car­ sored compound. cinogenic concern does not exceed Sm (i) The norm shall be specific for the in each of the various edible tissues untreated target animals. # and therefore th at the total burden of carcinogenic concern in the human (ii) Each norm shall be submitted in diet does not exceed So. When a com­ the form of a graph of the cumulative pound is to be used in milk- or egg-pro­ frequency distribution versus the ob­ ducing animals, milk or eggs will be served naturally occurring levels, in­ the target tissue in addition to one cluding the upper 99 percent confi­ tissue selected to represent the deple­ dence limit set forth in Plate III as fol­ tion of residues in the edible carcass. lows: FEDERAL REGISTER, V O L 44, NO. 55—TUESDAY, MARCH 20, 1979 PROPOSED RULES 17111 PLATE III. SAMPLE OF A NORM LEVEL O F E N D O G EN O U S SU BST A N C E IN TARGET A N IM A L S (APPROPRIATE UNITS. I.O., M G O R M G PER M L) (iii) An assay will be acceptable for enous compound is increased by ad­ § 500.90 Evaluation and approval of a reg­ the determination of a norm only if it ministration of the sponsored com­ ulatory assay. yields values for the endogenous com­ pound, the market residue for all en­ pound of interest greater than zero in dogenous compounds of concern is (a) Before an application is consid­ at least two-thirds of the untreated that endogenous compound whose ered for approval, the petitioner shall target animals. norm requires the longest time for res­ submit for evaluation and validation a (2) Studies to measure the effect of toration. regulatory assay developed to monitor the sponsored compound on the norm compliance with the no-residue re­ and the postexposure decay of any in­ (e) For an endogenous compound se­ quirement of the act. The regulatory crease in the norm caused by adminis­ lected to be a marker residue, the re­ assay shall reliably measure the tration of the sponsored compound. quired level of measurement, Rm, for marker residue in the target tissue at AH data from these studies submitted the regulatory assay is the level of levels at least equal to and above Rm, in accordance with the requirements that endogenous compound corre­ as defined in § 500.89(b), (e), and (f). of § 500.84(b)(4). sponding to the 33d percentile of the The criteria and procedures in para­ norm, set forth in Plate III in para­ graphs (b) through (g) of this section (d) For a potentially carcinogenic en­graph (c)(l)(ii) of this section. apply to the evaluation and approval dogenous compound whose norm is in­ of assays. creased by the administration of a (f) The Commissioner will permit a (b) The regulatory assay will be eval­ sponsored compound, the no-residue shift in the norm of a potentially car­ uated and validated using data collect­ requirement of the act is considered cinogenic endogenous compound if ed from three types of samples: satisified when the norm is restored. there are available toxicology data of (1) Samples containing various (1) The norm is considered restored the type specified by §§ 500.84, 500.85, known concentrations of marker resi­ when, with 99 percent confidence, the 500.87, and 500.89 that permit estima­ due added to the target tissue, i.e., cumulative frequency distributions of tio n of a permissible level correspond­ “spiked” tissue samples. the observed levels of the endogenous ing to a lifetime cancer risk increment (2) Samples containing various levels compound in the untreated target ani- no greater than 1 in 1 million. If the of the marker residue obtained from uials and in the treated target a n im a ls endogenous compound is also selected target tissue at appropriate time inter­ do not differ by more than 0.1 at any to be the marker residue, the required vals after the sponsored compound is specific point. level of measurement,* Rm, for the reg­ administered in accordance with the (2) The market residue is the affect­ ulatory assay is the level of that en­ dogenous compound corresponding to proposed labeling, i.e., “dosed” tissue ed endogenous substance. samples. the 33d percentile of the norm set (3) Samples obtained from untreated (3) When the norm of more than forth in Plate III in paragraph one potentially carcinogenic endog­ (cXIKiD of this section. target animals, i.e., “control” tissue samples. FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17112 PROPOSED ItUtES (c) The petition for approval of the in an unreasonable number of failures principles to ensure that the identity proposed regulatory assay shall con­ due to unknown, uncontrollable, or of the marker residue is confirmed. tain the following: random factors. Evaluation of the data (4) Accuracy. The assay is considered (1) A complete description of the to determine dependability will be accurate if the averages of the ob­ assay. based on the total number of assay served responses fall within 80 to 110 (2) A list of all necessary equipment runs that are started to provide data percent of the true value when the and reagents. points for the analytical curve re­ lowest level of reliable measurement (3) A standard curve prepared from quired by paragraph (c)(4) of this sec­ (Ln.) is equal to or greater than 100 samples of the marker residue of tion. An explanation will be required parts per billion and within 60 to 110 known purity. for any assay run started that yields percent of the true value when Ln, is below 100 parts per billion. This re­ (4) An analytical curve of the ob­ no(2) final determination. Practicability. The assay is con­ quirement need not be met through­ served assay response compared to the sidered practicable only if it is suitable out the full range of the analytical tissue concentrations of the marker for routine use in a government regu­ curve; it shall be met in the range be­ residue in spiked target tissue. The tween Lm and 31^,. curve shall include the 99 percent con­ latory laboratory. The time required fidence limits for individual predicted to complete the assay shall be consist­ ent with regulatory objectives, e.g., (5) Lowest limit of reliable measure­ ment. The regulatory assay is consid­ assay responses. monitoring, compliance, etc. All sup­ ered approvable if it can reliably dis­ (5) All relevant data, including work­ plies, equipment, reagents, standards, criminate with 99 percent confidence sheets, calculations, any statistical and other materials necessary to con­ the marker residue response from the analyses, spectrograms, chromato­ duct the assay shall either be commer­ target tissue background response at grams, etc., from the analyses of cially available or readily available or below the required lowest limit of spiked, dosed, and control tissue sam­ from the petitioner upon request. The reliable measurement, the Rm, defined ples, and from the analysis used in Commissioner will withdraw approval in § 500.89(b), (e), or (f). The lowest preparing the standard curve includ­ of any assay and initiate regulatory limit of reliable measurement of the ing data on runs started but not com­ action against the sponsored com­ proposed assay is that level, Lm, which pleted. pound if such a condition of the com­ gives a response above _the expected (6) A discussion of the data collected pound’s approval is no longer satisfied. blank value that is greater than or in the assay development process per­ equal to 0.75 times the spread of the (3) Specificity. The assay is consid­ 99 percent confidence limits on a tinent to the evaluation criteria set ered specific if the observed response single assay response measured paralle forth in paragraph (d) of this section is a smooth and continuously decreas­ to the observed assay response axis explaining how the data show that the ing or increasing function of the con­ (Plate IV below in this paragraph). If proposed assay conforms to those cri­ centration of the marker residue and the Lm for the assay is at or below the teria. of that compound only. The regula­ applicable Rmof § 500.89(b), (e), or (f), (d) A regulatory assay shall satisfy tory assay shall be composed of a suf­ the Commissioner will approve the the following criteria: ficient number of independent mea­ compound for use only under condi­ (1) Dependability. The assay is con­ surements based on different biologi­ tions that will not result in residues sidered dependable if it does not result cal, biochemical, or physicochemical above that level. PLATE IV. ANALYTICAL CURVE OF A REGULATORY A SSA Y (APPROPRIATE UNITS SU CH A S ppm , ppb. etc.) FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 PROPOSED RULES 17113 (e) The Commissioner will review / statistical tolerance limits for the 99th the lowest level of reliable measure­ and evaluate the data submitted in ac­ percentile of the expected marker resi­ ment (Lm), the Commissioner will con­ cordance with paragraphs (a), (b), and due concentrations for individual ani­ clude (1) that the carcass from which (c) of this section. If the assay satisfies mals. the target tissue was taken is unsafe the evaluation criteria of paragraph (2) All relevant data, including work-1 for human consumption; and (2) that (d) of this section, it will then be sub­ sheets, calculations, and statistical the sponsored compound may have jected to the interlaboratory valida­ analyses, shall be submitted along been used in violation of the act. tion study described in paragraph (f) with a referenced discussion of the re­ (b) When animals are found to con­ of this section. sults. tain an endogenous marker residue at (f) Two Food and Drug Administra­ (3) Use of the sponsored compound or above the 99th percentile of the tion laboratories and one U.S. Depart­ will be approved only if the available norm (I*late III under ment of Agriculture laboratory will in­ evidence demonstrates that the pro­ §500.89(c)(l)(ii))» they will be desig­ dependently run a number of assays to posed conditions of use, including any nated as potentially violative. Before ascertain whether the regulatory withdrawal period, are reasonably cer­ regulatory action will be initiated, and assay conforms to the criteria set tain to be followed in practice. investigation will be undertaken. This forth in paragraph (d) of this section. (c) When the marker-residue is an investigation is to determine whether (1) The petitioner shall supply the endogenous compound, the withdraw­ the potentially violative sample came validating laboratories with the al period will be the time required from target animals adminstered the number and amount of dosed and con­ after cessation of administration of sponsored compound whose median trol tissue samples, requested by the the sponsored compound for the norm level of the endogenous marker resi­ Commissioner. to be restored, as described in due is greater than the median of the (2) The petitioner shall supply rea­ § 500.89(d)(1). The time will be ex­ norm. gents, standards, supplies, and equip­ tended if necessary, but not reduced, ment to the validating laboratories, as to be compatible with conditions of requested by the Commissioner. livestock management so that the di­ § 500.96 Waiver of requirements. (g) The Commissioner will evaluate rections for use of the compound with the data gathered from the study run respect to the withdrawal period will In response to a petition or on the by the three validating laboratories be reasonably certain to be followed in Commissioner’s own initiative, the described in paragraph (f) of this sec­ practice. The validated regulatory Commissioner may waive, in whole or tion. The assay will be approved if it assay shall be used to collect data on in part, any of the requirements of meets the criteria set forth in para­ the rate of restoration of the norm. this subpart for the scientific evalua­ graph (d) of this section in each labo­ (1) The petitioner shall submit a tion of sponsored compounds that ratory. series of curves that demonstrate the have the potential to contaminate time required for restoration of the food with residues which, when con­ § 500.92 Withdrawal periods. norm. , sumed, could engender a human risk (a) The withdrawal period is the (2) All relevant data including work­ of cancer. A petition for this waiver time after cessation of administration sheets, calculations, and statistical may be filed by any person who would of the sponsored compound necessary analyses shall be submitted along with be adversely affected by the applica­ for the marker residue to deplete to a referenced discussion of the results. tion of the requirements to a particu­ the lowest level of reliable measure­ (3) Approval of the petition for the lar compound. The petition shall ex­ ment (Ln,) in the target tissue. This sponsored compound will be granted plain and document why some or all of time is the interval required for the only if the available evidence demon­ the requirements are not reasonably statistical tolerance limit for the 99th strates that the proposed labeling is applicable to the compound, and de­ percentile of the marker residue con­ reasonably certain to be followed in scribe the alternative procedures that practice. have been, or could be, followed to centration for individual animals to assure th at use of the compound will deplete to L„. The time will be ex­ § 500.94 Publication of the approved regu­ not contaminate human food with res­ tended if necessary to be consistent latory assay. idues whose consumption could engen­ with conditions of livestock manage­ The lowest level of reliable measure­ der a human risk of cancer and that ment so th at directions for use of the ment (Lm), the complete regulatory an assay exists th at satisfies the re­ compound with respect to the with­ assay for measuring the marker resi­ quirements of § 500.90(d)(1) through drawal period will be reasonably cer­ due in the target tissue, and the ana­ (5) and th at is capable of measuring tain to be followed in practice. lytical curve will be published in the any residues th at might occur when (b) The sponsor shall submit studies F ederal R egister , in accordance with the compound was improperly used. of the marker residue’s depletion from the provisions of sections 409(c)(3)(A), Interagency validation of the assay the target tissue of animals dosed ac­ 512(d)(1)(H) and (i), and 706(b)(5)(B) will always be required. The petition cording to the maximum level of use of the act. For an endogenous marker shall set forth clearly the reasons why proposed in the petition and main­ -residue, the norm will also be pub­ the alternative procedures will provide tained under field conditions. The vali­ lished. the basis for concluding that approval dated regulatory assay shall be used to of the compound satisfies the require­ collect these data. § 500.95 Compliance. ments of the anticancer provisions of (1) The petitioner shall submit a Compliance with the act will be de­ the act. If the Commissioner deter­ Plot of the concentration of marker termined as follows: mines that waiver of any of the re­ residues in target tissue as a function (a) When a target tissue is found to quirements of this subpart is appropri­ of time (depletion curve) including the contain the marker residue at or above ate, the Commissioner will state the FEDERAL REGISTER, V O L 44, NO. 55— TUESDAY, MARCH 20, 1979 17 11 4 PROPOSED RULES basis for the determination in the reg­ a. By amending §514.1, by revising other substances found in or on food ulation approving marketing of the paragraph (b)(7) to read as follows: because of the drug’s use) whose con­ sponsored compound. sumption could engender a human § 514.1 Applications. risk of carcinogenicity, the applicant § 500.98 Implementation. and the new animal drug are subject • * • * • to the requirements of Subpart E of (a) This subpart applies to all new animal drug applications, feed additive (b) • • * Part 500 of this chapter. petitions, and relevant color additive (7) Assays for residues. A description petitions (i.e., applications and peti­ of practicable methods for determin­ • * * * • tions concerning any compound in­ ing the quantity, if any, of the new * b. By amending §514.111, by adding tended for use in food-producing ani­ animal drug in or on food, and any a new paragraph (a)(10) to read as fol­ mals) submitted to the Food and Drug substance formed in or on food be­ lows: Administration, including relevant cause of its use, and the proposed tol­ supplemental applications and amend­ erance or withdrawal period or other §514.111 Refusal to approve an applica­ ments to petitions, and to all these ap­ use restrictions for this drug if any tol­ tion. plications or petitions on file with the erance or withdrawal period or other agency. If the Commissioner deter­ use restrictions are required to ensure (a) • *• mines that consumer protection can be th at the proposed use of this drug will (10) The drug fails to satisfy the re­ adequately ensured by imposing the be safe. quirements of Subpart E of Part 500 requirements under paragraph (b) of (i) The required information may in­ of this chapter. this section, the Commissioner will do clude: Complete experimental proto­ so. * • • * • cols for determining drug residue (b) This subpart also applies to the levels in the edible products, and the following compounds already ap­ time required for residues to be elimi­ PART 571— FOOD ADDITIVE PETITIONS proved: nated from the edible products follow­ (1) Those compounds th at the Com- 4. In Part 571, by adding new ing the drug’s use; residue studies con­ § 571.115, to read as follows: missoner determines, on the basis of ducted under appropriate (i. e., con­ s available information, have been sistent with the proposed usage) con­ § 571.115 Application of the anticancer shown to induce cancer when ingested ditions of dosage, time, and route of by man or animals. clause of section 409. administration to show levels, if any, (2) Those compounds that the Com­ of the drug and/or its metabolites in Food additives intended for use as missioner determines may induce test animals during and upon ceasing an ingredient in food for animals that cancer when ingested by man or ani­ treatment and at intervals thereafter are raised for food production must mals, i.e., suspect carcinogens. to establish a depletion curve; if the satisfy the requirements of Subpart E (3) Any compound for which the drug is to be used in combination with of Part 500 of this chapter. Commissioner concludes sufficient in­ other drugs, possible effects of interac­ formation has not been provided to de­ Interested persons may, on or before tion demonstrated by the appropriate May 21, 1979, submit to the hearing termine whether residues of the spon­ disappearance curve or depletion pat­ Clerk (HFA-305), Food and Drug Ad­ sored compound present a risk of terns after drug withdrawal under ap­ ministration, Rin. 4-65, 5600 fishers cancer to man. propriate (i. e., consistent with the Lane, Rockville, MD 20857, written (c) Any compound already approved, proposed usage) conditions of dosage, comments regarding this proposal. to which the Commissioner deter­ time, and route of administration; if Four copies of all comments shall be mines the anticancer provisions of the the drug is given in the feed or water, submitted, except th at individuals act apply, or for which additional data appropriate consumption records of may submit single copies of comments, are required for such a determination, the medicated feed or water and ap­ and shall be identified with the hear­ will be the subject of a notice pub­ propriate performance data in the ing Clerk docket number found in lished in the F ederal R egister or a letter issued under section 512(e) of treated animal; if the drug is to be brackets in the heading of this docu­ the act establishing the time within used in more than one species, drug ment. Received comments may be seen which the requirements of this sub­ residue studies or appropriate meta­ in the above office between the hours part shall be satisfied. bolic studies conducted for each food- of 9 a.m. and 4 p.m., Monday through (1) Notices already published in the producing species. Appropriate use of Friday. F ederal R egister and letters already labeled compounds (e.g., radioactive In accordance with Executive Order sent by the Food and Drug Adminis­ tracers) may be u£ed to establish me­ 12044, the economic effects of this tration requiring additional studies or tabolism and depletion curves. Drug proposal have been carefully analyzed, submission of an improved regulatory residue levels ordinarily should be de­ and it has been determined th at the assay will remain in effect, and this termined in muscle, liver, kidney, fat, proposed rulemaking does not involve subpart will be used in determining and where applicable, in skin, milk, major economic consequences as de­ compliance with the requirements of and eggs (yolk and white). As a part of fined by that order. A copy of the reg­ the act identified in those notices and the metabolic studies, levels of the ulatory analysis assessment support­ letters. drug or metabolite should be deter­ ing this determination is on file with (2) The Commissioner will proceed mined in blood when feasible. Samples the Hearing Clerk, Food and Drug Ad­ to withdraw approval of any com­ may be combined if necessary. When ministration. pound on the basis of data or informa­ residues are suspected or known to be tion indicating a health hazard or in present in litter from treated animals, Dated: February 26,1979. response to any failure to undertake it may be necessary to include data on S h e r w in G ardner , studies necessary to comply with this those residues’ becoming components Acting Commissioner of subpart. of other agricultural commodities be­ Food and Drugs. cause of the use of litter from treated animals. N ote.—Incorporations by reference provi­ PART 514— NEW ANIMAL DRUG (ii) If the new animal drug has the sions approved by the Director of the Office APPLICATIONS potential to contaminate human food of the Federal Register on December 21, with residues (parent compound, me­ 1978 and on file in the library of that office. 3. In Part 514: tabolites, conversion products, or [FR Doc. 79-8215 Filed 3-19-79; 8:45 am] FEDERAL REGISTER, V O L 44, NO. 55—TUESDAY, MARCH 20, 1979