ENVIRONMENTAL ASSESSMENT - SOHETRIBOVE-ZINC COMPLEX THE AGRICULTURAL GROUP OF HONSANTO COMPANY TABLE OF CONTENTS Volume NO. Pase NO. Environ mental Assessment Environmental 1 1 1. Date 1 1 2. Name of applicant/petitioner 1 1 3. Address 1 1 4. Description of proposed action 1 1 5. Identification of chemical substances that are subject of proposed action 1 5 6. Introduction of substances into the environment 11 7. Fate of emitted substances 51 8. Environmental effects of released substances 70 9. Use of resources and energy 82 10. Mitigation measures 110 11. Alternatives to the proposed action 111 12. List of preparers 113 13. Certification 116-1 References 2 117 Attachments 1 BiochemieGmbH OperatingPermits 4 788 A. Approval for production of BST, May 25, 1987, Republic of Austria, Minister forHealth and Public Service 4 789 B. Approval for expanded productionof BST, April 19, 1990, Republic of Austria, Minister forHealth and Public Service 4 796 C. Waste water - water rights, March 14, 1975, Tirolean State Government 4 a03 D. Waste water disposal - existing facility, April 30, 1987, Tirolean State Government 4 819 E. Waste water - Permit for construction and operation for waste water treatment plant No. 2, March 24, 1988, Tirolean Provincial Government 4 839 F. Approval to expand BST production facility, June 30, 1989, Kufstein Regional Management 4 865 2 NIH Guidelines - Department of Health and Human Services, National Institutesof Health "Guidelines for Research Involving Recombinant DNA MOleCUles; Notice". Federal Reaiater Vol. 51,No. 88, Wednesday,May 7, 1986 4 886 i TABLE OF CONTENTS (continuedl Volume No. Pase No. Attachments (continuedl 3 Bibliography: sensitization of Susceptible Individuals toForeign Proteins 4 916 4 Biochemie Institutional Biosafety Committee 4 963 5 Material SafetyData Sheets 4 973 e sometribove-Zinc Complex Bovine Somatotropin 4 974 0 POSILACO (Sometribove-Zinc Complex) Bovine Somatotropin 4 978 6 Final Report: Determination of the Viability of Escherichia K-12 Strains W3110G fRBGHll, LBB269. and LBB269 [pBGHl] i: Wisiiouri River 4 983 Water. J.F. Kane, 1991 7 A. Literature Review: Fate of Recombinant Escherichia' K-12 Strains in the Environment. G. Bogosian and J.P. Kane, 1990 4 1093 B. Selected References 5 1157 8 Supplemental Commentson Literature Review. J.F. Kane, 1991 6 1521 9 A. Final Report. Study of the Potential for Gene Transferof --E. coli StrainW311OG (pBGHl] to Indigenous Bacteriain Wieeouri River Water. J.F. Kane, 1991 6 1600 B. ReferencesforAttachments 6 and 9 6 1690 10 Proteolytic Degradationof Bovine Somatotropin. B.N. Violand, 1989 8 2179 11 Environmental Effects of the Introduction of Bovine Somatotropin under Alternative Dairy Price Support Programs. P.V. Preckel, R.F. Turco, M.A. Martin, and C.H. Noller, 1988 8 2186 @ Registered trademark of Monaa_nto Company ii TABLE OF CONTENTS (continuedl Volume No. Paqe No. Attachments (continuedl 12 Addendum to Attachment 11. Result0 of Prior Analysie for Fallert Scenario IV. P. Preckel, H. Martin, and R. Turco, 1990 8 2315 13 Refining Estimates of Preckel, & aJ., of the Environmental Effects of Bovine Somatotropin. H.W. Furchgott-Roth, 1990 a 2354 14 A. Potential Effects of PoSILAC Approval in the United States on Emissions of Carbon Dioxide and Methane from Dairy Cattle and their Manure. G.P. Hartnell, 1991 9 2373 B. References 9 2393 15 A. Emiseions of the Greenhouse Gaeeee Carbon Dioxide andMethane Resulting from Manufacture and Transportof POSILAC. G.H. Irwin, 1992 9 2650 B. References 9 2668 . iii Section 10. Environmental Assessment - Sometribove-Zinc Complex 1. -.Date- September, 1992 2. Name of Amlicant/Petitioner: Animal Sciences Division The Agricultural Groupof Monsanto Company 3. Address: 800 North Lindbergh Boulevard St. Louis, Missouri 63167, U.S.A. 4. DescriDtion of the proposed action: Sometribove-zinc complex isa recombinant-derived methionyl bovine somatotropinto be marketed by Monsanto Company in the United States under the trademark name ttPOSILACtt as an over-the-counter new animal drugfor use in healthy lactating dairy cowsto increase milk production. The production of sometribove including fermentation, purification, formulation, filling, and packaging will take place at Biochemie GmbH in Kundl, Austria. Kundl is in western Austria, approximately35 miles NE of Innsbruck and approximately 75 miles SE of Munich. Biochemie is a subsidiary of Sandoz. The controlled-access production facility is in the village of Kundl proper with residential areas on two sides and open fields and/or onhighway the remaining sides. 0000 1 Address: Biochemie GmbH Dr. Hans Bachmann Strasse7 A6250 Kundl-Tirol AUSTRIA Biochemie manufactures and exports human drug products to the United States including several penicillin products.It also exports an animal drug intermediate. The facility has been inspected routinely by the Food and Drug Administration (FDA) since 1959, annually for 22 years and more recentlyon a bi-annual basis. In May, 1988, the FDA inspected the sometribove production facilities (fermentation, purification, and formulation) and they were foundto be satisfactory. The Biochemie filling operations for sometribove-zinc complex were inspected the by FDA in October, 1990, and also were foundto be satisfactory. In addition, an October,1991, FDA environmental inspection found operations to be acceptable. The sometribove production facility was the subject of an inspection (March 3-6, 1987) by the Austrian Ministry of Health and Environment for the purposeof licensing production of sometribove at the new facility.A permit was issued in May, 1987. A second inspection was conducted by the Austrian Federal Chancery in November,1989, to approve expanded operations at Biochemie including the addition of filling and packaging operations (product finalization) anda permit for the same was issued in April,1990. Relevant Biochemie permits are included in Attachment1. 00002 Following bulk formulation, the product can also be filled into the final container (plastic, disposable syringes) and packaged at Solvay Duphar B.V., Olst,The Netherlands. Olst is located in northeastern Holland, approximately75 miles from Amsterdam. The filling and packaging facility is surrounded by residential areason three sides anda canal on the fourth. Address: Solvay Duphar B.V. Veerweg 12 8121 AA Olst HOLLAND Solvay Duphar is currently licensed to a sellsmooth muscle relaxer (Yutopar*) in the United States. Solvay Duphar's facility at Olst has been inspected by the FDA. Sometribove filling and packaging operations were inspected FDAby the in June,1988, and again in October,1991, and were foundto be satisfactory. Figure 1 is a flow diagram of the sometribove-zinc complex production process. Finished product, securely packaged, will be shipped to and stored in distribution warehouses until shipmentto distributors/customers. Ultimately, sometribove will be used throughout the world at dairy facilities which, generally, are located in predominantly rural areas. * Registered trademark,Solvay Duphar B.V. 00003 Figure 1 POSILACO (SOMETRIBOVE-ZINC COMPLW BOVINE SOMATOTROPIN PRODUCTION FLOW DIAGRAM SOLUTION PREPARATION I Nutrient solutions formulated to support organism growth are prepared. I \k FERMENTATION I Recombinant E. organismcontaining sometribove molecule is grown to high density in fermentor and inducedto produce sornetribove in refractile bodies inside the cell. ISOLATION3. I Refractile bodies are isolated from othercell components by homogenization and centrifugation andare subsequently solubilized in an aqueous urea solution. Any remaining viable E. coli organisms are inactivated by this step. - PURIFICATION-5. I Product Is purified by precipitation and chromatographic techniques. LYOPHILIZATION4 I Product is lyophilized (freeze-dried) to produce sterile bulk sometribove-zinc complex powder. FORMULATION I Bulk powder is mixed with sterilized excipient composed of vegetable oil and a gelling agent to produce sterile, bulk formulated sometribove-zinc complex. FILLING,\1 LABELING & PACKAGING Formulated product Is asepticallyI filled into unitdose syringes which are then labeled and packagedas POSllAC (sometribove-zinc complex1 Bovine Somatotropin forfinal use. I' I 8 RegisteredTrademark of MonsantoCompany 00004 5. Identification of chemical substances that arethe subject of the DroDosed action: Nomenclature: British Approved Name (BAN): sometribove International Non-Proprietary Name(INN): sometribove U.S. Adopted Name (USAN): sometribove Chemical Name(s): i-L-methionine-127-L-leucinesomatotropin (0x1 l-L-methionine-127-L-leucinegrowth hormone (0x1 N-L-methionylgrowth hormone (ox). methionyl bovine growth hormone. Othernames: MBS - methionylbovine somatotropin. _- ZnMBS - methionyl bovine somatotropin, zinc. BST - bovine somatotropin. bGH; BGH - bovine growth hormone. rBGH - recombinant bovine growth hormone. CP-115099 - sometribove-zinc complex. CP-104301 - sometribove without zinc. 00005 Proprietary Name: POSILACQ CAS Res. No: 102744-97-8 Molecular Weiqht: 21,872 + 1 to 3 zinc atoms Structural Formula: See Figure 2 Sometribove isa recombinant analogueof bovine pituitary somatotropin (BPS). BPS exists naturally as four molecular variants, differing only by two specific amino acid additions or substitutions.' Sometribove is the amino- terminal methionylated analogueof the molecular variant having LEU at position127 and lackingALA at the amino terminal. 'Known molecular variantsof bovine pituitary somatotropin*: 1 2 3 127 191 ALA PHE PRO ..... LEU, .....PHE