2001/18/EC. It contains Monsanto confidential - Inf'OGM · 3 of 1139 COMPLIANCE STATEMENT 13-Week...

NOTE: The study report MSL 18175 describes a 90-day rat feeding study for MON 863 YieldGard Rootworm corn that was part of an application to European Union regulatory authorities under Directive 2001/18/EC. It contains Monsanto confidential business information. The European Food Safety Authority reviewed this report along with the rest of the dossier, and concluded in April 2004 that the placing on the market of MON 863 is unlikely to have an adverse effect on human and animal health or the environment in the context of its proposed use. Monsanto reserves all rights with respect to this report and the confidential information contained herein, and grants no rights to any party to use this report or any information contained herein for commercial purposes. Monsanto specifically reserves its right to protect confidential business information contained within other study reports provided to regulatory authorities around the world for our products in support of the regulatory review and approvals processes.

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Final ReportStudy Title 13-Week Dietary Subchronic Comparison Study with

MON 863 Corn in Rats Preceded by a 1-Week BaselineFood Consumption Determination with PMI CertifiedRodent Diet #5002

Data Requirement Guidelines: OECD 408

Test Article Event MON 863 Corn Grain

Author John M. Burns, MS, DVM, MBA, MA

Sponsor Monsanto Company800 North Lindbergh BoulevardSt. Louis, MO 63167

Test Facilities Covance Laboratories Inc.9200 Leesburg PikeVienna, Virginia 22182-1699

Covance Laboratories3301 Kinsman BoulevardMadison, WI 53704

Monsanto Company700 Chesterfield Parkway NorthSt. Louis, Missouri 63198

Purina TestDiet1050 Progress DriveRichmond, IN 47374

Covance Study Number 6103-293

Report Issued 17 December 2002

Volume 1 of 2

Unpublished work (2002) Monsanto Company. All rights reserved.

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STATEMENT OF NO DATA CONFIDENTIALITY

13-Week Dietary Subchronic Comparison Study with MON 863 Corn in RatsPreceded by a 1-Week Baseline Food Consumption Determination with PMI

Certified Rodent Diet #5002

No claim of confidentiality is made for any information contained in this study on thebasis of its falling within the scope of FIFRA 10(d)(1)(A), (B), or (C). Some pages ofthis report may be stamped with the following, CONTAINS TRADE SECRET ORMONSANTO COMPANY CONFIDENTIAL INFORMATION. This claim ofconfidentiality is not meant to convey supplemental claims of confidentiality regardingdata subject to disclosure under sections 10(d) and (e) of FIFRA. In submitting thismaterial to the EPA according to method and format requirements contained in PRNotice 86-5, we do not waive any protection rights involving this material that wouldhave been claimed by the company if this material had not been submitted to the EPA.

Company: Monsanto Company800 North Lindbergh BoulevardSt. Louis, MO 63167

Company Agent:Title:

Signature: ____________________________ Date: __________________

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COMPLIANCE STATEMENT



Except for the regulatory deviations below, this study, as performed by CovanceLaboratories Inc., was conducted in compliance with the appropriate provisions ofOECD (1997) and MHLW GLPs Regulations and any applicable amendments.

Prestudy procedures, such as general husbandry, health screening activities, testing forassignment to study, and collection of baseline data, were conducted prior to finalizationof the protocol. The protocol was finalized on 13 March 2001.

The formulation of the diets was performed by Purina TestDiets in Richmond, Indiana,which is not a GLP facility; therefore, the diets were not prepared according to GLPs atthis facility. Diet preparation was, however, conducted under the guidance of Monsantotoxicologists and Purina TestDiet is an ISO 9002-certified facility which has beenperiodically inspected by Monsantos Quality Assurance Unit. Formulation and testingfor the confirmation of identity of the diets were initiated prior to signing of theMonsanto protocol 01-01-39-24 and reference standards used in compositional analysispresented in the subreport were not retained as required by GLPs (Appendix 6). Stabilityanalysis was not performed; however, the diets were formulated according to thespecifications for PMI #5002 diets which are considered by Purina to be nutritionallystable for at least 6 months. The rat feeding study was completed within 6 months ofmanufacture.

Homogeneity surrogate (salt content) analysis was conducted at Covance-Madison incompliance with section 160.135(b) of the United States Environmental ProtectionAgency (EPA) Federal Insecticide, Fungicide and Rodenticide Act (FIFRA); GoodLaboratory Practice Standards (40 CFR Part 160) intended to characterize the physicaland/or chemical properties of a potential commercial product. Analysis was conducted incompliance with all requirements of section 160.135(b) with the exception that:

The report consisted of a QA accepted spreadsheet only.The reference standards were not be listed in the protocolThe reference standards were not characterized per GLPReserve samples from each batch of reference standard were not retainedReserve samples of the test, control and reference material were not taken byCovance-Madison.The final analytical sub-report is not in full accordance with EPA PesticideRegulation Notice 86-5.

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While these events represent regulatory deviations, they did not affect either the outcomeor the interpretation of the data.

This study was conducted in accordance with Covance Protocol 6103-293 as amended.Protocol deviations appear following the text portion of this report.

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QUALITY ASSURANCE STATEMENT



This report has been reviewed by the Quality Assurance Unit of Covance LaboratoriesInc. and accurately reflects the raw data. The following inspections were conducted andfindings reported to the study director (SD) and associated management.

Inspection Dates Date Reported to SDFrom To Phase and SD Management

16 Mar 2001 16 Mar 2001 Protocol Review 16 Mar 200106 Apr 2001 06 Apr 2001 Body Weights 10 Apr 200108 Jun 2001 08 Jun 2001 Clinical Observations 25 Jul 200118 Jun 2001 18 Jun 2001 Clinical Chemistry 25 Jul 200117 Jul 2001 20 Jul 2001 Data Review 25 Jul 200117 Jul 2001 17 Jul 2001 Protocol Amendment Review 25 Jul 200129 Oct 2001 30 Oct 2001 Draft Report and Data Review 30 Oct 200118 Jan 2002 21 Jan 2002 Draft Report and Data Review 21 Jan 200219 Apr 2002 19 Apr 2002 Data Review 19 Apr 200215 Oct 2002 21 Oct 2002 Draft Report and Data Review 21 Oct 200228 Jun 2002 28 Jun 2002 Protocol Amendment Review 11 Nov 200211 Nov 2002 11 Nov 2002 Protocol Amendment Review 11 Nov 200216 Dec 2002 17 Dec 2002 Revised Draft Report Review 17 Dec 2002

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SIGNATURE PAGE



Covance 6103-293

STUDY IDENTIFICATION

13-Week Dietary Subchronic Comparison Study with MON 863 Corn in Rats Preceded by a 1-Week Baseline Food Consumption Determination with PMI


Test Material Event MON 863 Corn Grain Sponsor Monsanto Company

800 North Lindbergh Boulevard St. Louis, Missouri 63167

Study Monitor ___________________________ Monsanto Company 800 North Lindbergh Boulevard, O3D St. Louis, Missouri 63167

Alternate Study Monitor ___________________________ Monsanto Company 800 North Lindbergh Boulevard, O3F St. Louis, Missouri 63167

Study Location Covance Laboratories Inc. 9200 Leesburg Pike Vienna, Virginia 22182-1699

Study Director John M. Burns, MS, DVM, MBA, MA Study Timetable

Study Initiation Date 13 March 2001 Experimental Start Date 28 February 2001 Inlife Start Date 16 March 2001 Inlife End Date (Terminal Sacrifice) 18-22 June 2001 Experimental End Date 01 August 2001 Study Completion Date 17 December 2002

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KEY PERSONNEL

13-Week Dietary Subchronic Comparison Study with MON 863 Corn in Rats Preceded by a 1-Week Baseline Food Consumption Determination with PMI


Study Director John M. Burns, MS, DVM, MBA, MA Study Monitors ___________________________

(effective 15 January 2002) ___________________________

(study initiation to 14 January 2002) Monsanto Company

Alternate Study Monitor ___________________________ Monsanto Company Study Toxicologist ___________________________ (effective 15 January 2002) ___________________________ (study initiation to 14 January 2002) Report Coordinator ___________________________ Clinical Pathologist ___________________________ Anatomic Pathologist ___________________________ Supervisor, Laboratory Animal Medicine ___________________________ Supervisor, Small-Animal Toxicology ___________________________ Supervisor, Postlife and Clinical Pathology Laboratories ___________________________

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CONTENTS

STATEMENT OF NO DATA CONFIDENTIALITY ....................................................... 2

COMPLIANCE STATEMENT .......................................................................................... 3

QUALITY ASSURANCE STATEMENT.......................................................................... 5

SIGNATURE PAGE........................................................................................................... 6

STUDY IDENTIFICATION............................................................................................... 7

KEY PERSONNEL............................................................................................................. 8

CONTENTS........................................................................................................................ 9

ABSTRACT...................................................................................................................... 12

STUDY CONDUCT ......................................................................................................... 13Purpose.......................................................................................................................... 13Regulatory Guidelines and Protocol Adherance ........................................................... 13Major Computer Systems.............................................................................................. 13Record Retention........................................................................................................... 13

METHODOLOGY............................................................................................................ 14Study Design ................................................................................................................. 14Animal Husbandry ........................................................................................................ 16Test and Control Materials............................................................................................ 17

PROCEDURES................................................................................................................. 18Diet Preparation, Sampling, and Analyses.................................................................... 18Diet Administration....................................................................................................... 19Observation of Animals ................................................................................................ 19Anatomic Pathology...................................................................................................... 21Data Analyses................................................................................................................ 23

RESULTS AND DISCUSSION ....................................................................................... 24Dose Analyses ............................................................................................................... 24Observation of Animals ................................................................................................ 25Clinical Pathology......................................................................................................... 25Anatomic Pathology...................................................................................................... 26

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CONCLUSION ................................................................................................................. 27

PROTOCOL DEVIATIONS............................................................................................. 28

COMMENTS ON THE DATA......................................................................................... 30

CODES, ABBREVIATIONS, AND UNITS .................................................................... 32General Codes and Abbreviations................................................................................. 33Codes for Clinical Pathology ........................................................................................ 35Abbreviations for Clinical Hematology ........................................................................ 38Abbreviations for Clinical Chemistry ........................................................................... 39Codes for Anatomic Pathology ..................................................................................... 40

TABLES............................................................................................................................ 42Table 1 Summary of Clinical Observations .................................................................. 43Table 2 Summary of Pretest (Week 1) and Week 1 Food Consumption Data (g)...... 46Table 3 Incidence of Macroscopic Observations Unscheduled Deaths ..................... 50Table 4 Incidence of Macroscopic Observations Terminal Sacrifice ........................ 64Table 5 Incidence of Macroscopic Observations All Deaths..................................... 78Table 6 Incidence of Microscopic Observations All Deaths ..................................... 92

APPENDIX 1 .................................................................................................................. 100Pathology Report......................................................................................................... 101

APPENDIX 2 .................................................................................................................. 106Individual Animal Fate Data....................................................................................... 107Individual Clinical Observations................................................................................. 117Individual Body Weight Data (g)................................................................................ 161Individual Body Weight Change Data (g) .................................................................. 201Individual Food Consumption Data (g) ...................................................................... 231

APPENDIX 3 .................................................................................................................. 280Individual Clinical Hematology Values...................................................................... 281Individual Serum and Urine Chemistry Data.............................................................. 322Individual Clinical Urinalysis Values ......................................................................... 371

APPENDIX 4 .................................................................................................................. 403Individual Anatomic Pathology Data.......................................................................... 404

APPENDIX 5 .................................................................................................................. 885Salt Analysis................................................................................................................ 886

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APPENDIX 6 .................................................................................................................. 889Formulation and Analysis of Rodent Diets Report Containing Grain From the Test

Event Mon Reference Control Lines....................................................................... 890

APPENDIX 7 .................................................................................................................. 987Statistical Report ......................................................................................................... 988Statistical Report Quality Assurance Statement ....................................................... 1139

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ABSTRACT

This study compared various toxicologic parameters in rats fed a diet containing grainderived from corn event MON 863 (11 and 33% w/w in the diets) to (1) rats fed a dietcontaining the non-transgenic control line LH82xA634 corn grain (11 and 33% w/w inthe diets), which has background genetics representative of event MON 863 but does notcontain the cry3Bb1 coding sequence, and (2) a population of rats fed diets containinggrain from six commercial non-transgenic corn reference control varieties (33% w/w inthe diets) for at least 13 weeks.

Toxicological parameters evaluated were survival, clinical signs, body weights, foodconsumption, clinical pathology, organ weights, and macroscopic and microscopicpathology. There were no test article related changes in any of the aforementionedtoxicological parameters. The response of rats fed either 11 or 33% w/w corn eventMON 863 in the diet was comparable to rats fed diets containing the non-transgeniccontrol line LH82xA634 and corn from six commercial non-transgenic reference controlvarieties.

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STUDY CONDUCT

PurposeThis study was designed to compare the parameters in rats fed a diet containing grainderived from corn event MON 863 to (1) rats fed a diet containing corn grain from thenon-transgenic control line LH82xA634, which has background genetics representativeof the event MON 863 grain but does not contain the cry3Bb1 coding sequence, and (2) apopulation of rats fed diets containing grain from commercial non-transgenic cornvarieties (all reference controls) for at least 13 weeks.

Regulatory Guidelines and Protocol AdheranceThe study design was based on the Organization for Economic Co-operation andDevelopment Guidelines (1981) for the testing of chemicals, Section 4, Health Effects,No. 408.

This study was conducted in accordance with Covance Protocol 6103-293 as amended.Protocol deviations appear following the text portion of this report.

Major Computer SystemsThe major computer systems used on this study included the Path/Tox System (PTS)application (supplied by Xybion Medical Systems Corporation), used for the direct onlinecapture of inlife toxicology and anatomic pathology data; Randomization and DataExtension Systems (RADES) and Automatic Form and Label Generation System(AFLGS) applications, used in conjunction with the PTS system to randomize animalsand produce labels and forms, respectively; Millennium system, used for the collection ofthe dose analysis data; Clinical System, used for the collection of clinical pathology data;Online Room Log (ORL), used for the direct online capture of study room maintenanceinformation; and Environmental Control Monitoring System (EMCS), used for the directonline capture of continuous study room environmental control data. All versionnumbers of the applications are maintained by Information Technology at Covance.

Record RetentionAll original records and raw data generated at Covance, retained tissues and relatedspecimens (including slides), the final report, and the protocol will be maintained in theCovance Archives. Raw data associated with diet formulation are maintained at PurinaTestDiets in Richmond, Indiana, and certified copies of batch records were sent to thestudy director. Data from the molecular analysis are retained at the Monsanto

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Chesterfield facility. The statistical analysis data provided by Monsanto StatisticsTechnology Center will be archived by Monsanto Company. Records for the Covance-Madison diet certification subreport will be archived as follows: Original data or copieswill be available at Covance to facilitate auditing the study during its progress and beforeacceptance of Covance quality assurance unit which will include: (1) a spreadsheet thatsummarizes the analytical report for each sample; (2) information on reference standardsused (where applicable); and (3) analytical method summaries. Information regardingarchiving of the study records for the Monsanto Biotech Regulatory Sciences Study(Study #01-01-39-24) is provided in the report for that study which is appended(Appendix 6) to this study report.

When the final report is completed, original study documentation, such as paper data,computer printouts, chromatograms, worksheets, data sheets, notes by investigators,forms specified by SOP, and magnetically encoded records will be retained in thearchives of Covance-Vienna (compositional data, etc.). Ten years after signing of thefinal report, all original or copies of data will be sent to the sponsor. Supporting facilityrecords, to include refrigerator and freezer temperature records, instrument calibration,and maintenance records, will be retained at Covance but will not be archived with thestudy data.

METHODOLOGY

Study DesignSpecies, Source and JustificationFour hundred sixty (230/sex), approximately 4 week-old, Crl:CD(SD) IGS BR rats werereceived on 28 February 2001, from Charles River Laboratories, Inc., Kingston,New York.

Rats historically have been used in safety evaluation studies and are recommended byappropriate regulatory agencies.

Acclimation, Randomization, and IdentificationRats were assigned temporary numbers upon arrival, acclimated to laboratory conditionsfor approximately one week and released for study use by a staff veterinarian. Ratsconsidered acceptable for study use, based upon data collected during acclimation, wererandomized into 10 groups using a computerized blocking procedure designed to achievebody weight balance with respect to treatment group. At randomization, the weight

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variation of the rats selected did not exceed 2 standard deviations of the mean bodyweight for each sex, and the mean body weight for each group of each sex was not

statistically different at p0.05. Following randomization, each study rat was assigned aunique number and implanted with a subcutaneous microchip identification device thatwas used for subsequent identification.

Group Designations and Dietary LevelsThe dietary treatment consisted of two levels of corn grain containing the test and controlmaterials (event MON 863 and LH82 X A634), approximately 11 and 33% (w/w),respectively, and six reference groups each containing corn grain at approximately 33%(w/w). Ten groups of 20 rats/sex were assigned to study groups as follows:

Number of Animals Dose Level Animal NumbersGroup (%w/w) Male Female ppm Male Female

1. LH82 X A634 (11%) 20 20 110000 B38602 - B38621 B38802 - B388212. LH82 X A634 (33%) 20 20 330000 B38622 - B38641 B38822 - B388413. MON 863 (11%) 20 20 110000 B38642 - B38661 B38842 - B388614. MON 863 (33%) 20 20 330000 B38662 - B38681 B38862 - B388815. MON 847 Rep-1 (33%) 20 20 330000 B38682 - B38701 B38882 - B389016. Asgrow RX-770 (33%) 20 20 330000 B38702 - B38721 B38902 - B389217. LH235 X LH185 (33%) 20 20 330000 B38722 - B38741 B38922 - B389418. LH200 X LH172 (33%) 20 20 330000 B38742 - B38761 B38942 - B389619. B73HT X LH82 (33%) 20 20 330000 B38762 - B38781 B38962 - B3898110. Burrus BX-86 (33%) 20 20 330000 B38782 - B38801 B38982 - B39001

At initiation of administration of test, control, and reference control diets, the rats wereapproximately 6 weeks old with body weights ranging from 198.4 to 259.8 g for themales and 132.1 to 185.3 g for the females.

Rats not used on study were appropriately euthanized with CO2/Beuthanasia-D anddiscarded.

Experimental Design and Justification for Route of ExposureThe treatment structure was factorial with two factors: sex and dietary treatment. Therewere two levels of the non-transgenic corn grain LH82xA634 (which has backgroundgenetics representative of the event MON 863 but does not contain the cry3Bb1 codingsequence), 11 and 33% (w/w) respectively, and two levels of the corn event MON 863grain; 11 and 33% (w/w) respectively. There were six reference control groups eachcontaining corn grain at approximately 33% (w/w).

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Since corn is normally consumed as a human or animal food, the oral route ofadministration was chosen for this study.

Animal HusbandryHousingRats of the same sex were housed two/cage in stainless-steel, hanging, wire-mesh cagesupon receipt. Following assignment to study, each rat was individually housed. Cageracks were rotated every 7 days (2 days) clockwise within the animal room. The cageof each rat was identified with a color coded cage tag containing the appropriate studynumber, animal number, treatment group, and sex.

Environmental ConditionsEnvironmental controls were set to maintain the following animal room conditions:temperature range of 18 to 26C, relative humidity range of 30 to 70%, 10 or greater airchanges/hour, and a 12-hour light/12-hour dark cycle. Temperature and humidity wererecorded at least once daily. Any variations to these conditions are documented in theraw data and had no effect on the outcome of the study.

Environmental Enrichment and Dietary SupplementsNo environmental enrichment or dietary supplements were provided.

Diet, Water, and ContaminantsPMI Certified Rodent Diet #5002 (PMI Nutrition International) was available adlibitum prior to study Day 1. Rats received either test, control, or reference control dietsstarting on Day 1. PMI Certified Rodent Diet #5002 was analyzed by the manufacturerfor nutritional components and environmental contaminants. Tap water, via an automaticwatering system (and water bottles when deemed necessary), was available ad libitumunless otherwise noted. Samples of the water are routinely analyzed for specifiedmicroorganisms and environmental contaminants. Results of the diet and water analysesare reviewed and are on file at Covance-Virginia. Formulated diet certification tests(pesticide and myotoxin residue analysis, nutrient profile) are presented in Appendix 6.No contaminants were known to be present in the diet or water at levels which mightinterfere with this study.

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Test and Control MaterialsTest MaterialAll formulated diets containing test materials were received from Monsanto Company,St. Louis, Missouri, as follows:

Test Material (w/w) Lot Number Date Received

MON 863 11% 850526-000070 13 Mar 01MON 863 33% 850526-000080 13 Mar 01

All lots were stored at room temperature and described as a brown meal.

Control MaterialAll diets containing control and reference materials were received from MonsantoCompany, St. Louis, Missouri, as follows:

Control and Reference Material Lot Number Date Received

LH82xA634 11% 850526-000090 13 Mar 01LH82xA634 33% 850526-000100 13 Mar 01MON 847 Rep-1 33% 850526-000010 13 Mar 01Asgrow RX-770 33% 850526-000020 13 Mar 01LH235xLH185 33% 850526-000030 13 Mar 01LH200xLH172 33% 850526-000040 13 Mar 01B73HTxLH82 33% 850526-000050 13 Mar 01Burrus BX-86 33% 850526-000060 13 Mar 01

All lots were stored at room temperature and described as a brown meal.

Six (6) reference control lines of grain from corn varieties grown at differentgeographical locations in the United States were designated as follows: MON 847 Rep-1,Asgrow RX-770, LH235xLH185, LH200xLH172, B73HTxLH82, and Burrus BX-86.One non-transgenic corn grain line designated as LH82xA634 has background geneticsrepresentative of event MON 863 but does not contain the cry3Bb1 coding sequence andserved as the control.

Information on composition or other characteristics that define the test, control andreference materials is on file with the sponsor. Certificates of Analyses that summarizethe molecular analysis to confirm the identity of test and control diets, e.g. theabsence/presence of the cry3Bb1 insect control gene in formulated diets is presented inAppendix 6.

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Archive Samples and Test Diet DispositionReserve (archive) samples of the test and control materials were taken (100 grams of eachdiet) and stored frozen at approximately -20C. All reserve samples were shipped to thesponsor on 30 October 2002. All remaining test, control, and reference control diets weredestroyed by incineration.

PROCEDURES

The sponsor provided gravimetric records of dietary mixing, Certificates of Analysisindicating the presence or absence of event MON 863 in each of the diet preparations,pesticide profile, and compositional and mycotoxin analyses. A salt content analysis wasconducted on diets received at Covance in an effort to establish box-to-box homogeneityfor each dietary formulation.

Diet Preparation, Sampling, and AnalysesDiet PreparationDiets were formulated prior to study initiation to be as nutritionally close as possible toPMI Certified Rodent Diet #5002. Diets were formulated by Purina TestDiets inRichmond, Indiana. Documentation of formulation was provided by Purina TestDiets.The same lot of base ingredients (except for corn grain provided by Monsanto) was usedto make all test, control and reference diets. The diets were temporarily stored atMonsanto Company, St. Louis, Missouri under refrigeration for approximately 2 monthsprior to shipping to Covance. Following receipt at Covance, the test, control andreference diet feed allotments were dispensed weekly to the animal laboratory.

Test Substance LevelsThere were two levels of event MON 863 corn grain tested: approximately 11%w/w (110,000 ppm) and 33% w/w (330,000 ppm) in the diet.

Control and Reference LevelsThere was one level of approximately 33% w/w (330,000 ppm) corn in the diet for eachof the six reference control groups and two levels (11% and 33% w/w) of the non-transgenic corn control LH82xA634.

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Sampling for Dietary AnalysesSamples of the test, control and reference diets were collected at Purina TestDiet formolecular identification, pesticide residues, and mycotoxin and compositional analyses(nutrient profile). The sampling schematic is presented below:

Approximately 200 g of each of the test, control and reference diets were collected afterproduction at Purina TestDiets and shipped at room temperature to Monsanto,Chesterfield, Missouri.

Approximately 200 g of each of the test, control and reference diets were taken afterproduction at Purina TestDiets and shipped to Covance-Madison.

Documentation of sample collection and shipment was placed in the study file. Thesediet samples were stored at Purina and shipped at room temperature.

Sampling for Salt (Sodium Chloride) Content in Diets to Confirm Homogeneity ofMixing During Diet FormulationThe samples provided to Covance-Madison for compositional and contaminant analyseswere also used for salt analysis. This analysis was a surrogate for homogeneity testing asthere is no practical method available to determine the homogeneity of corn grain mixedinto formulated diet.

Diet AdministrationAll test, control and reference diets were available 7 days/week for at least 13 weeks, adlibitum, until the day prior to scheduled necropsy.

Observation of AnimalsClinical ObservationsEach rat was observed twice daily (a.m. and p.m.) for mortality and moribundity;findings were recorded as they were observed.

Cageside observations were made for each animal once daily; abnormal findings wererecorded.

Detailed observations were made for each animal once prior to treatment and weeklyduring treatment; abnormal findings (ranked/graded, if appropriate) or an indication theanimal appears normal was recorded.

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Body WeightBody weights were recorded twice prior to treatment (at randomization and on Day 7),on the first day of treatment, and weekly thereafter.

Food ConsumptionFood consumption was measured weekly, except for Weeks -1 and 1. During pretest(Week 1), food consumption (PMI #5002) was measured daily for Days -7, -6, -5, andthe 4-day interval between Days -4 through -1. During Week 1 (after removal of PMI#5002 diet and presentation of the appropriate test/control/reference diet), foodconsumption was measured for Days 1, 2, 3 and Days 4 through 7.

Individual food consumption was measured weekly thereafter.

The amount of spillage was determined daily for pretest (Week 1) and Week 1 and thenweekly thereafter. The procedure for determination of spillage is documented in the data.Spillage was weighed and recorded to the nearest 0.1 gram if the diet was not visiblydamp, in which case spillage was documented but not weighed. When obvious spillageor wastage was recorded for a rat during the detailed physical examination, the estimateof the food consumed by the rat was excluded from the group mean calculation for thatparticular interval.

Clinical PathologyThe first 10 surviving rats/sex/group (numerically sequential) were sampled forhematology, clinical and urine chemistry, and urinalysis during Week 5 and at terminalsacrifice (Week 14); coagulation samples were taken at terminal sacrifice (Week 14).Prior to each clinical sampling, the first 10 surviving rats were placed in urine collectionracks (approximately for 18 to 20 hours) and fasted overnight with water available.Blood samples for hematology, coagulation, and clinical chemistry evaluations werecollected from the jugular vein from unanesthetized rats. Blood samples were collectedfrom Group 2 male B38640 prior to being sacrificed in a moribund condition. Theanticoagulants for the hematology and coagulation samples were potassium EDTA andsodium citrate, respectively. No anticoagulant was used for the chemistry samples.Blood obtained was processed in the priority of hematology, serum chemistry, andcoagulation assays, respectively. The following parameters were determined:

Hematologyred blood cell (erythrocyte) count platelet count

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hemoglobinhematocritmean corpuscular volumemean corpuscular hemoglobinmean corpuscular hemoglobin concentration

white blood cell (leukocyte) countdifferential blood cell countblood cell morphologyreticulocyte count

Coagulationprothrombin time activated partial thromboplastin time

Serum Chemistryglucoseurea nitrogencreatininetotal proteinalbuminglobulinalbumin/globulin ratiocholesteroltriglyceridestotal and direct bilirubin

alanine aminotransferasealkaline phosphatasegamma glutamyltransferaseaspartate aminotransferasecalciuminorganic phosphorussodiumpotassiumchloride

Urinalysisappearancespecific gravitypHproteinurobilinogen

glucoseketonesbilirubinbloodmicroscopic examination of sediment

Urine Chemistrysodiumpotassiumchloridephosphorusproteincalcium

creatininesodium excretionpotassium excretionchloride excretionvolume

Anatomic PathologyNecropsyAll rats found dead or sacrificed in extremis during the study were subjected to a grosspostmortem examination. After 13 weeks of treatment, all surviving rats were fastedovernight, weighed, anesthetized with sodium methohexital, and exsanguinated. Anecropsy was performed on each rat by appropriately trained personnel using proceduresapproved by board-certified pathologists. The necropsy included an examination of the

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external features of the carcass, external body orifices, the abdominal, thoracic, andcranial cavities, and organs/tissues. In addition, two slides were prepared from thefemoral marrow of each animal and retained for possible future evaluation.

Organ WeightsAt scheduled sacrifice, the following organs (when present) were weighed after carefuldissection and trimming of fat and other contiguous tissue:

adrenal (2)brainkidney (2)heart

liverovary (2)spleentestis with epididymis (2)

Paired organs were weighed together; organ-to-body weight and brain weight percentageswere calculated.

Tissue PreservationThe following tissues (when present) from each rat were preserved in 10% neutral-buffered formalin:

adrenal (2)aorta (thoracic)brain (medulla/pons, cerebellar cortex and cerebral cortex)cecumcervixcolonduodenumepididymis (2)esophaguseye (2)femur with bone marrow (articular surface of the distal end)heartileumjejunumkidney (2)lacrimal glandlesionsliverlung with mainstem bronchilymph node (mesenteric)

mammary gland (females)ovary (2)pancreaspituitaryprostaterectumsalivary gland [mandibular (2)]sciatic nerveseminal vesicle (2)skeletal muscle (thigh)skinspinal cord (cervical, thoracic, and lumbar)spleensternum with bone marrowstomachtestis (2)thymusthyroid (2) with parathyroidtracheaurinary bladderuterusvagina

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HistopathologyThe following tissues from all animals in Groups 2 and 4 were embedded in paraffin,sectioned, stained with hematoxylin and eosin, and examined microscopically:

adrenalsbraincolonduodenumheartileumjejunumkidneysliver

lymph node (mesenteric)ovariespancreasrectumspleenstomachtestesthyroid/parathyroid

All other tissues were saved but not examined.

Data AnalysesThe statistical analysis was managed and a report was provided by the MonsantoStatistics Technology Center, Dr. Margaret Nemeth, Team Leader. The statistical reportis presented in Appendix 7. Quality Assurance oversight of the statistical analyses wasprovided by Monsanto Regulatory Quality Assurance. A Quality Assurance Statement isincluded/provided.

For quantitative measures, the transgenic line was compared with (1) its non-transgenicparental counterpart and (2) the population of reference control hybrids. For each sex,the data were fit by a simple one-way analysis of variance model and specific treatmentcombinations compared using contrasts. Differences were considered statisticallysignificant at p

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RESULTS AND DISCUSSION

Dose Analyses(1) Test, control and reference corn grainInformation on the characterization of test (event MON 863) and control corn grain usedin this study is found in Appendix 6. Results of the compositional analyses of the test,control and reference grain (e.g., protein, fat, amino acid composition, etc.) were similarand established that the grain samples were suitable for use in a rat feeding study. Nodetectable pesticide residue (M304 screen) was found in the grain of corn lines selectedfor the study. Low levels of fumonisins were detected in the grain from five referencecontrol corn hybrids selected for the study, however, these were below the level ofconcern (

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Observation of AnimalsSurvival and Clinical ObservationsIndividual animal fate data are presented in Appendix 2. Clinical observations aresummarized in Table 1 and presented individually in Appendix 2.

There were no test article related clinical signs or mortality during the study. On Day 92,event MON 863 (33% w/w) male B38667 died; neither macroscopic nor microscopicexamination of tissue found any relationship of this death to the test article. In the non-transgenic groups, LH82xA634 (33% w/w) male B38640 was sacrificed (a brokenmaxilla was found at necropsy) on Day 64; Asgrow RX-770 (33%) male B38719 wasfound dead of undetermined causes on Day 88; and LH235xLH185 (33% w/w) femaleB38923 and B73HTxLH82 (33% w/w) female B38967 died shortly after Week 5 bloodcollection.

Body WeightMean body weight and weekly body weight change data are presented in the statisticalreport. Individual data are presented in Appendix 2.

No test-article-related differences in body weight or changes in body weight wereobserved.

Food ConsumptionMean food consumption data are presented in the statistical report and for pretest(Week 1) and Week 1 in Table 2. Individual data are presented in Appendix 2.

No test-article-related changes in food consumption were observed. There was noevidence of test article-related taste aversion or inappetence in comparing pretest(Week 1) with Week 1 data.

Clinical PathologyMean hematology and coagulation values and mean clinical and urine chemistry valuesare presented in the statistical report. Individual data (including urinalysis) are presentedin Appendix 3.

Hematology and CoagulationThere were no alterations in the hematology and coagulation data, differential leukocytecounts, or cellular morphology results that would indicate an effect from the feeding of

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any of the test diets. The values were generally unremarkable and comparable betweenthe groups at Weeks 5 (coagulation not performed) and 14. The importance of fourisolated statistical findings related to high-dose MON 863 could not be evaluated basedsolely upon the statistical criteria used. The statistical findings included the mean valuesin the male group for hemoglobin at Week 5 and white cell count, absolute lymphocytecount, and absolute basophil count at Week 14. While statistically significant, these mildalterations are of no biologic importance and not attributed to event MON 863.

Serum and Urine ChemistryThe mean and individual values for the clinical chemistry parameters were generallyunremarkable and similar among the groups at Weeks 5 and 14. The association of oneisolated statistical finding to high dose MON 863 administration could not be confirmedbased solely on the statistical criteria used. This single finding (female group mean valuefor triglycerides at Week 5), while statistically significant, is of no biologic consequenceand not attributed to event MON 863.

UrinalysisThe urinalysis results were unremarkable and comparable between the rats at Weeks 5and 14.

Unscheduled CollectionThe total leukocyte and neutrophil counts were elevated in control group male B38640that was sacrificed at Week 10 (Day 64) relative to control males at Weeks 5 and 14.These higher values are consistent with active inflammation and were accompanied byhigher concentrations of total protein and globulin. The coagulation data, cellularmorphology results, and remaining hematology values were unremarkable. Theincreased glucose concentration is likely the result of endogenous glucocorticoid (stress)or epinephrine (excitement) release. These findings may be associated with the brokenmaxilla noted at necropsy.

Anatomic PathologyMacroscopic findings (unscheduled deaths, terminal sacrifices, and all deaths) aresummarized in Tables 3, 4, and 5, respectively. Microscopic findings are summarized inTable 6. Individual animal organ weight, macroscopic, and microscopic data arepresented in Appendix 4. Findings are further discussed in the Pathology Report inAppendix 1.

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No test-article-related changes in organ weights, macroscopic findings, or microscopicfindings were observed. One isolated statistical finding related to high dose MON 863was identified: decreased incidence of renal tubular mineralization in females. Whilestatically significant, this reduction was not considered to be biologically important and isnot test-article related since it is in the opposite direction of that produced by atoxicologic response.

CONCLUSION

This study compared the numerous toxicologic parameters in rats fed a diet containinggrain derived from corn event MON 863 (11 and 33 % w/w in the diets) to (1) rats fed adiet containing corn grain the non-transgenic control line LH82xA634 (11 and 33 % w/win the diets), which has background genetics representative of event MON 863 but doesnot contain the cry3Bb1 coding sequence, and (2) a population of rats fed diets containinggrain from six commercial non-transgenic corn reference control varieties (33 % w/w inthe diets) for at least 13 weeks.

Toxicological parameters evaluated were survival, clinical signs, body weights, bodyweight changes, food consumption, clinical pathology, organ weights, and macroscopicand microscopic pathology. There were no test article related changes in any of theaforementioned toxicological parameters. The response of rats fed either 11 or 33 % w/wcorn event MON 863 in the diet was comparable to rats fed diets containing the non-transgenic control line LH82xA634 and corn from six commercial non-transgenicreference control varieties.

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PROTOCOL DEVIATIONS

The following protocol deviations were noted:

The following males exceeded the protocol-specified weight range of 75 to 250 g atinitiation of treatment:

Number Group Weight

B38656 3 253.5B38679 4 250.3B38696 5 256.3B38716 6 254.0B38717 6 250.3B38725 7 253.8B38757 8 253.3B38768 9 257.3B38794 10 259.8B38795 10 255.1

There was no documentation of when the animals were actually implanted with themicrochip identification devices.

The morning mortality check was not performed on 10 May 2001.

Cageside observations were not documented on 2, 11, and 15 April and 10-13 May 2001.

On Day 31, the water line to the rack housing the Group 10 rats was not fully connected.The maximum time these animals were without water/water pressure was 18 hours.

On Day 35, Group 7 female B38924 was found out of its urine collection cage. Themaximum time out of the cage was 15 hours. The urine volume may not be accurate.

Cell morphology data was inadvertently not collected for Group 4 male B38672(replacement due to death of B38667) at Week 14.

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Week 14 urine data for the following reference control rats were inadvertently lost:

Group Sex Animal Number

5 M B386855 F B388845 F B388906 F B389076 F B389117 F B389258 M B387439 F B389629 F B38965

10 F B38989

Though required by protocol, creatinine clearance was not calculated.

The biomedic implants for Group 2 male B38634 and Group 3 male B38650 could not belocated at necropsy. The animals were identified by cage tag instead of the implant asrequired by protocol.

The pituitary gland for Group 6 female B38921 was damaged at necropsy and notcollected as required by protocol.

The thyroid and parathyroid for Group 4 females B38863 and B38866 were missing attissue trimming and not microscopically examined.

The residual test, control, and reference control diets were destroyed by incineration; theprotocol directed that any remaining test and control diets would returned to MonsantoCompany following authorization from the Sponsor. In addition, the archive reservesamples were sent to Monsanto on 30 October 2002; these samples were to have beenarchived at Covance, Virginia.

NONE OF THE NOTED PROTOCOL DEVIATIONS AFFECTED THEINTEGRITY OF THE STUDY OR THE INTERPRETATION OF THEFINDINGS.

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COMMENTS ON THE DATA

Various models of calculators, computers, and computer programs were used to analyzedata in this study. Because different models round off or truncate numbers differently,values in some tables (e.g., means, standard deviations, or individual values) may differslightly from those in other tables, from individually calculated data, or from statisticalanalysis data. Neither the integrity nor the interpretation of the data was affected by thesedifferences.

Survival data are adjusted for deaths unrelated to treatment.

The number of animals listed in the heading of the summary table for clinicalobservations reflects the number of animals assigned to each group at the start of thestudy.

The summary table for clinical observations indicates the number of animals for which acondition was observed without regard to the specific nature, severity, reversibility,number of incidences/animal, or the length of time the condition persisted.

Each animal with observations recorded as Normal throughout the study has thecomment Animal has no significant findings indicated on the individual clinicalobservations tables.

The day of initiation of treatment is Day 1, Week 1. Body weight data are entered atthe start of a study week (e.g., a body weight recorded on Day 1 is considered a Week 1body weight, a body weight recorded on Day 8 is considered a Week 2 body weight).Body weight gain data are calculated from the first day of the study to the first day of thefollowing study week (e.g., Week 1 values are calculated from Day 1 through 7).Weekly food consumption is calculated from the first day of the study week to the firstday of the following study week (e.g., Week 2 values are calculated from fresh dietpresentation on Day 8 to diet removal on Day 15).

The comment SPILLED on individual food consumption data tables indicates that foodconsumption was not recorded due to spillage or contamination during the interval.

The comment NOT TAKEN on individual food consumption data tables indicates theanimal died before the end of the food consumption interval.

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The spelling of Burrus varies throughout the protocol and report but describes the samematerial.

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CODES, ABBREVIATIONS, AND UNITS

General Codes and AbbreviationsCodes for Clinical Pathology

Abbreviations for Clinical HematologyAbbreviations for Clinical Chemistry

Codes for Anatomic Pathology

Note: The following lists of codes, abbreviations, and units are used by Covance.Some, but not necessarily all, of this information may be needed for this report.

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General Codes and AbbreviationsWK WeekN Number of measurements in a groupWT WeightMean; MEAN Arithmetic meanSD; S.D.; STAND DEV; STANDARD DEV; sd STD. DEV

Standard deviation

% RSD Relative standard deviation#; N; No. NumberDLAM Department of Laboratory Animal MedicineGLP Good Laboratory Practice RegulationsSOP Standard operating proceduresNVL No visible lesionsP PresentC Comment found at the end of each group for each

sexUNSCHED or SCHED Unscheduled or scheduledBT Body temperatureHR Heart rateRR Respiration rateCO Clinical observationM or MalesF or Females

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Units of MeasureG GramKG KilogramMG MilligramPG PicogramL LiterDL DeciliterFL FemtoliterML, mL MilliliterMI MillionTH ThousandMEQ MilliequivalentsEU Ehrlich unitsPPM Parts per millionUL, L MicroliterU UnitsMN MinuteS SecondsUMOL MicromolesMMOL MillimolesMOS MilliosmolesBPM Beats per minute

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Codes for Clinical PathologyGeneral CodesQS/QNS Quantity not sufficientNR/QNR No repeat (sample volume not sufficient for repeat

analysis)PLASMO PlasmodiumNO AGG No aggregationUTD Unable to determineNO COAG No coagulationNOCG Hypocoagulability; no clotCGERR Hypercoagulability; clots too fastQCD Quick clot detectedNCD No clot detectedLNCD Long test, no clot detectedEDTA Ethylenediaminetetraacetate (anticoagulant)PER HPF Microscopic findings per high-power fieldPER LPF Microscopic findings per low-power fieldNT No test performedNSR No sample receivedBDL Below detectable limitCLOT Clotted sampleSUFA Sample unsuitable for analysisND None detectedTNTC Too numerous to countAB, A Absolute count

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Codes for Clinical Pathology (Continued)Hemolysis and Blood Cell MorphologyThe following scales were used for hemolysis in serum and plasma and for blood cell morphology:

Hemolysis Cell Morphology

0 Not present - None present - None present1 Trace T Trace numbers present F Few present2 Slight 1 Slight numbers present MOD Moderate present3 Moderate 2 Moderate numbers present M Many present4 Marked 3 Marked numbers present5 Severe 4 Severe numbers present

Urine Appearance

Color Abbreviation Clarity

Straw S Green G Clear CLYellow Y Brown BR Slightly cloudy SCDark yellow D Blue BL Cloudy CYAmber A Colorless CO Turbid TRed/red-brown R Other OOrange OR

Microscopic Examination of Urine

GradingsCasts, red and white blood cells, andepithelial cells

Amorphous, crystals, bacteria, yeast, sperm, andmucus

- none seen - none seenT 1-4 T occasional1 5-10 1 few2 11-50 2 moderate3 >50 3 many

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Codes for Clinical Pathology (Continued)Urine and Fecal Analysis

Multistix StripUrine Glucose Urine Ketones Urine Blood

- Negative - Negative - NegativeT 100 mg/dL T 5 mg/dL T Trace1 250 mg/dL 1 15 mg/dL 1 Small2 500 mg/dL 2 40 mg/dL 2 Moderate3 3 3 Large

Urine Nitrite Urine Protein Urine Bilirubin

- Negative - Negative - Negative+ Positive T Trace 1 Small

1 30 mg/dL 2 Moderate2 100 mg/dL 3 Large3

Clinitek 200+ AnalyzerUrine Glucose Urine Ketones Urine Blood

NEG Negative NEG Negative NEG NegativeTR 100 mg/dL TR 5 mg/dL TR Trace1 250 mg/dL 1 15 mg/dL 1 Small2 500 mg/dL 2 40 mg/dL 2 Moderate3 3 3 Large

Urine Nitrite Urine Protein Urine Bilirubin

NEG Negative NEG Negative NEG NegativePOS Positive TR Trace 1 Small

1 30 mg/dL 2 Moderate2 100 mg/dL 3 Large3

IctotestUrine Bilirubin

ClinitestUrine Reducing Substances

HemoccultFecal Occult Blood

- Negative - Negative - Negative+ Positive T % + Positive

1 %2 %3 1 %4 2 %

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Abbreviations for Clinical HematologyAbbreviation TestHCT HematocritHGB HemoglobinRBC Red Blood CellWBC White Blood CellMPV Mean Platelet ValueRDW Red Cell Distribution WidthHDW Hemoglobin Distribution WidthPDW Platelet Distribution WidthPCT Platelet CritMCV Mean Corpuscular VolumeMCH Mean Corpuscular HemoglobinMCHC Mean Corpuscular Hemoglobin ConcentrationRETIC ReticulocyteNEUT or SEG Segmented NeutrophilsLYMPH LymphocytesMONO MonocytesEOSIN EosinophilsBASO BasophilsANISO AnisocytesHYPO Hypochromic CellsPOIK PoikilocytesPOLY Polychromatophilic CellsTOXIC Toxic GranulationCOAGHEM Coagulation HemolysisPT Prothrombin TimeAPTT Activated Partial Thromboplastin TimeFIBRIN FibrinogenPAGG/INH Platelet Aggregation - InhibitionPAGG/ADP Platelet Aggregation - ADPFDP Fibrin Degradation Products - D-DimerM/E Myeloid/ErythroidESR Erythrocyte Sedimentation RateXDP D-DimerBASOSTIP Basophilic Stip Cells

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Abbreviations for Clinical ChemistryAbbreviation TestPLHEM Plasma HemolysisSERUMHEM Serum HemolysisT PROT Total ProteinA/G Albumin/GlobulinALK P Alkaline PhosphataseT BILI Total BilirubinUREA N Urea NitrogenCREAT CreatinineAST Aspartate AminotransferaseALT Alanine AminotransferaseCK Creatine KinaseLDH Lactate DehydrogenaseGGT Gamma-GlutamyltransferaseUAC Uric AcidIN PHOS Inorganic PhosphorusMAGNES MagnesiumT CHOL Total CholesterolTRIGLY TriglyceridesPOTAS PotassiumNA/K Sodium/Potassium RatioHDL or HDLCHOL High-Density LipoproteinLDL or LDLCHOL Low-Density LipoproteinVLDL or VLDLCHOL Very Low-Density LipoproteinSDH Sorbitol Dehydrogenase5NT 5'NucleotidaseSELA-A1 Serum Electrophoresis - Alpha 1SELA-A2 Serum Electrophoresis - Alpha 2SELA-B Serum Electrophoresis - BetaSELA-G Serum Electrophoresis - GammaCSF Cerebrospinal FluidFFA Free Fatty AcidsIONCA Ionized CalciumPTH Parathyroid Hormone

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Codes for Anatomic PathologyAnimal Death Codes1-5 Interim sacrifices 1 through 5 D Found dead6 Scheduled sacrifice without necropsy M Moribund sacrificeT Terminal sacrifice P Returned to stockU Postrecovery sacrifice 1 R Removed from studyV Postrecovery sacrifice 2 O Other type of unscheduled deathA Accidental Death UNSCHED Unscheduled deathB Unscheduled moribund sacrifice or

without necropsySCHED Scheduled death

Organ Weighing StatusesNOT TAKEN Organ weight not taken; no explanation givenMISSING Organ missing or lostUNSUITABLE Organ technically unsuitable for weighingAUTOLYTIC Organ autolytic and could not be weighedEXCLUDE Weight has been taken, but will be excluded from all calculations

Other Symbols and NotationsH- Finding noted during processing of tissues in histology (precedes keyword).

Symbols Prefacing Neoplastic FindingsB- Primary, benign neoplasm I- Locally invasive neoplasmM- Primary, malignant neoplasm X- Other neoplasmN- Metastatic neoplasm

Locations of Tissue Masses Observed GrosslyDFL Dorsal-Front-Left VFL Ventral-Front-LeftDFR Dorsal-Front-Right VFR Ventral-Front-RightDHL Dorsal-Hind-Left VHL Ventral-Hind-LeftDHR Dorsal-Hind-Right VHR Ventral-Hind-RightDFM Dorsal-Front-Mid VFM Ventral-Front-MidDHM Dorsal-Hind-Mid VHM Ventral-Hind-Mid

Distribution of Findings Other Microscopic CodesFocal TL TotalDiffuse P Finding presentMultifocal - Finding not present

MN Mean

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Codes for Anatomic Pathology (Continued)Grades for Severity or Amount1 Minimal - the least amount of change observed with the light microscope2 Slight - less than average amount of change, but readily discernible as abnormal3 Moderate - the average amount of change expected for a lesion4 Moderately severe (marked) - a marked amount of change with possible loss of function of the affected

cells or organs5 Severe - a great amount of change with probable loss of function of the affected cell or organs and

frequently involves large areas of the organ

Organ/Tissue/Site Abbreviations DefinitionLN Lymph nodeGALLBLADD GallbladderGL Gland or GlandularNONGL NonglandularSALIV GL Salivary glandMAND or MANDIB MandibularMESEN or MES MesentericABDOM AbdominalTRACHEOBRON TracheobronchialEPIDID Epididymis or EpididymidesPARATHYR ParathyroidHEMATO HematopoieticTIS TissueINT IntraorbitalEX ExorbitalCATHETER EXIT Catheterization site: exit site from the bodyCATHETER ENTRANC Catheterization site: entrance site into the vesselCATHETER EXIT Catheterization site: tissues (vascular or

extravascular) associated with the catheter near its tip

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TABLES

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Table 1Summary of Clinical Observations

13-WEEK DIETARY SUBCHRONIC COMPARISON STUDY WITH MON 863 CORN IN RATS PRECEDEDBY A 1-WEEK BASELINE FOOD CONSUMPTION DETERMINATION WITH PMI CERTIFIED RODENT DIET #5002

------------------------------------------------------------------------------------------------------------------------------------

NUMBER OF ANIMALS AFFECTED WEEKS 1-15 SEX: ----------------------MALE------------------------ GROUP: 1 2 3 4 5 6 7 8 9 10 CATEGORY DOSE: %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% KEYWORD QUALIFIER NUMBER: 20 20 20 20 20 20 20 20 20 20 ------------------------------------------------------------------------------------------------------------------------------------*** TOP OF LIST *** APPEARANCE MALOCCLUSION 2 2 5 0 2 4 5 3 1 3 MISSING DIGIT 0 0 1 0 0 0 0 0 0 0 SWOLLEN DIGIT(S)-FRONT-RIGHT 0 0 1 0 0 0 0 0 0 0 THIN 0 0 1 0 0 0 0 0 0 1

BEHAVIOR VOCALIZATION 0 0 0 0 0 0 0 1 0 0

DISCHARGE GENITAL RED IN COLOR 0 0 0 0 1 0 0 0 0 0 NASAL RED IN COLOR 0 2 2 0 0 1 1 0 0 0 RED-ORAL 0 0 0 0 0 1 0 0 0 0

EXCRETION DISCOLORED URINE YELLOW IN COLOR 0 0 1 0 0 0 0 0 0 0 RED IN COLOR 0 0 0 0 0 0 0 1 0 0 NONFORMED FECES 1 0 0 0 0 2 0 1 1 1

EYES RED DISCHARGE EYE-LEFT 0 1 1 0 0 1 1 0 0 0 EYE-RIGHT 1 0 0 0 1 0 0 2 0 1 EYES 0 1 1 0 0 1 1 0 1 0

RESPIRATION AUDIBLE 0 1 0 0 0 1 1 0 0 0

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TABLE 1SUMMARY OF CLINICAL OBSERVATIONS


------------------------------------------------------------------------------------------------------------------------------------

NUMBER OF ANIMALS AFFECTED WEEKS 1-15 SEX: ----------------------MALE------------------------ GROUP: 1 2 3 4 5 6 7 8 9 10 CATEGORY DOSE: %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% KEYWORD QUALIFIER NUMBER: 20 20 20 20 20 20 20 20 20 20 ------------------------------------------------------------------------------------------------------------------------------------

SKIN & PELAGE ALOPECIA 1 3 1 0 0 2 0 1 1 0 SORE/SCAB AXILLARY REGION-RIGHT 1 0 0 0 0 0 0 0 0 0 DORSAL-CERVICAL 0 0 0 0 1 0 0 0 0 0 DORSAL-CERVICAL-LEFT 0 0 0 0 0 0 1 0 0 0 DORSAL-CERVICAL-RIGHT 0 0 0 0 0 1 1 0 0 0 DORSAL-THORACIC-LEFT 0 0 0 0 0 1 0 0 0 0 DORSAL-THORACIC-RIGHT 0 0 0 0 0 1 0 0 0 0 HEAD-MAXILLARY-RIGHT 0 0 0 0 1 0 0 0 0 0 LATERAL-CERVICAL-LEFT 0 0 0 0 0 0 0 0 1 0 LATERAL-CERVICAL-RIGHT 0 0 0 0 0 0 1 0 0 0 PAW-FRONT-RIGHT 0 0 0 0 0 1 0 0 1 0 *** END OF LIST ***

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TABLE 1SUMMARY OF CLINICAL OBSERVATIONS


------------------------------------------------------------------------------------------------------------------------------------

NUMBER OF ANIMALS AFFECTED WEEKS 1-15 SEX: ---------------------FEMALE----------------------- GROUP: 1 2 3 4 5 6 7 8 9 10 CATEGORY DOSE: %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% KEYWORD QUALIFIER NUMBER: 20 20 20 20 20 20 20 20 20 20 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** APPEARANCE BENT TAIL 0 0 0 0 0 1 0 0 0 0 MALOCCLUSION 1 2 1 0 0 0 1 0 0 0 MISSING DIGIT 0 0 0 0 1 0 0 0 0 0 SWOLLEN PAW-FRONT-RIGHT 0 0 0 0 1 0 0 0 0 0 OTHER MOUTH TRAPPED IN CAGE, LIP CUT 0 0 0 0 0 0 0 0 0 1

DISCHARGE NASAL RED IN COLOR 0 0 1 0 1 0 0 0 0 1 RED-ORAL 0 0 0 0 0 0 0 0 0 2

EYES RED DISCHARGE EYE-RIGHT 1 0 0 0 0 0 0 0 0 0 EYE-LEFT 0 0 0 0 0 0 2 0 0 0 EYES 0 1 0 0 0 0 0 0 0 1

SKIN & PELAGE ALOPECIA 2 2 0 0 1 0 0 0 0 0 SORE/SCAB MOUTH 0 1 0 0 0 0 0 0 0 1 *** END OF LIST ***

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Table 2Summary of Pretest (Week 1) and Week 1 Food Consumption Data (g)


PRETREATMENT

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SEX: ---------------------------------------------------MALE------------------------------------------------------------ GROUP: 1 2 3 4 5 6 7 8 9 10 DAY(S) ------------------------------------------------------------------------------------------------------------------------------------

-7 N 20 20 20 20 20 20 20 20 20 20 MEAN 21.9 22.3 22.5 22.1 22.2 22.7 22.3 22.3 22.3 22.3 S.D. 1.37 1.38 1.61 1.51 1.69 1.38 1.40 1.80 1.87 1.54

-6 N 20 20 20 20 20 20 20 20 20 20 MEAN 23.4 23.5 23.2 23.1 23.2 24.0 23.7 24.1 23.1 22.9 S.D. 1.67 1.23 1.71 1.60 1.68 1.49 1.45 1.55 1.69 1.53

-5 N 20 20 20 20 20 20 20 20 20 20 MEAN 24.6 24.7 25.0 24.6 24.6 26.0 25.8 26.4 25.2 26.2 S.D. 1.63 1.68 1.92 1.70 1.89 1.81 1.80 1.92 2.07 2.23

-4 TO 1 N 20 20 20 20 20 20 20 20 20 20 MEAN 100.3 100.4 99.9 98.2 99.4 101.3 99.7 100.1 95.1 97.8 S.D. 6.10 5.39 6.46 5.87 6.86 6.20 5.64 6.16 7.05 6.59

-7 TO -1 N 20 20 20 20 20 20 20 20 20 20(WEEK 1)MEAN 170.2 170.9 170.7 168.0 169.4 173.9 171.6 173.0 165.7 169.1 S.D. 9.80 8.97 11.21 10.11 11.61 10.21 9.62 10.78 12.26 11.10

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TABLE 2SUMMARY OF WEEKS 1 AND 1 FOOD CONSUMPTION DATA (G)


PRETREATMENT

------------------------------------------------------------------------------------------------------------------------------------

SEX: ---------------------------------------------------FEMALE-------------------------------------------------------------- GROUP: 1 2 3 4 5 6 7 8 9 10 DAY(S) ------------------------------------------------------------------------------------------------------------------------------------

-7 N 20 20 20 20 20 20 20 20 20 20 MEAN 18.0 17.5 17.8 18.1 17.7 17.4 17.6 17.5 17.4 17.4 S.D. 1.29 1.69 2.26 1.43 1.86 2.01 1.83 1.46 1.41 1.68

-6 N 20 20 20 20 20 20 20 20 20 20 MEAN 19.3 18.4 18.6 19.3 19.3 19.2 18.6 18.6 18.2 18.8 S.D. 1.18 1.04 1.45 1.41 1.96 1.62 1.40 1.65 1.27 1.45

-5 N 20 20 20 20 20 20 20 20 20 20 MEAN 19.8 19.3 19.3 19.9 20.1 20.8 20.2 19.9 20.1 19.9 S.D. 1.43 1.38 1.59 1.60 2.14 1.86 1.96 1.78 1.54 1.36

-4 TO -1 N 20 20 20 20 20 20 20 20 20 20 MEAN 77.9 75.0 77.1 81.3 78.3 76.8 75.6 74.1 73.4 73.8 S.D. 5.54 5.71 7.95 10.38 8.26 6.05 6.12 6.37 4.80 4.38

-7 TO 1 N 20 20 20 20 20 20 20 20 20 20(WEEK 1)MEAN 135.0 130.3 132.8 138.6 135.4 134.1 132.1 130.1 129.0 129.9 S.D. 8.58 9.09 10.37 13.12 13.46 9.66 10.07 10.22 8.17 8.08

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WEEK 1 OF TREATMENT

------------------------------------------------------------------------------------------------------------------------------------

SEX: ---------------------------------------------------MALE-------------------------------------------------------------- GROUP: 1 2 3 4 5 6 7 8 9 10 DAY ------------------------------------------------------------------------------------------------------------------------------------

1 N 20 20 20 20 20 20 20 20 20 20 MEAN 24.1 23.3 24.5 23.8 24.0 25.2 24.7 24.4 24.0 25.0 S.D. 2.02 1.80 1.48 2.08 2.03 2.40 2.21 2.28 2.38 2.52

2 N 20 20 20 20 20 20 20 20 20 20 MEAN 26.8 26.7 27.1 27.1 25.7 25.9 26.1 26.8 27.6 27.3 S.D. 1.54 1.34 3.65 1.82 2.16 2.54 1.26 1.59 8.73 2.91

3 N 20 20 20 20 20 20 20 20 20 20 MEAN 26.5 26.2 26.3 26.5 25.8 26.9 26.6 27.0 24.6 27.8 S.D. 2.26 1.80 3.17 1.95 1.97 2.35 2.06 2.18 4.01 2.52

4-7 N 20 20 20 20 20 20 20 20 20 20 MEAN 104.0 105.4 105.8 106.0 105.6 105.0 103.0 104.2 102.6 110.1 S.D. 7.37 6.87 7.00 9.92 7.93 9.42 5.11 9.31 7.79 8.96

1-7 N 20 20 20 20 20 20 20 20 20 20 MEAN 181.5 181.6 183.6 183.5 181.2 183.1 180.4 182.5 178.9 190.3 S.D. 11.37 10.89 12.13 14.46 12.54 15.79 9.55 14.42 14.45 15.68

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WEEK 1 OF TREATMENT

------------------------------------------------------------------------------------------------------------------------------------

SEX: ---------------------------------------------------FEMALE-------------------------------------------------------------- GROUP: 1 2 3 4 5 6 7 8 9 10 DAY -------------------------------------------------------------------------------------------------------------------------------------

1 N 20 20 20 20 20 20 20 20 20 20 MEAN 17.6 16.1 16.3 17.9 17.9 16.7 17.1 17.1 16.8 17.2 S.D. 1.81 1.50 1.47 7.08 4.13 1.78 2.42 2.77 1.59 1.36

2 N 20 20 20 20 20 20 20 20 20 20 MEAN 21.1 20.0 21.5 21.0 19.1 20.8 20.0 18.8 18.7 20.0 S.D. 3.75 3.37 3.22 3.79 2.92 6.22 3.10 2.19 2.39 1.97

3 N 20 20 20 20 20 20 20 20 20 20 MEAN 20.0 19.5 19.8 20.6 23.6 19.4 19.6 18.9 19.4 20.4 S.D. 2.42 3.57 2.37 3.29 14.94 1.99 2.47 1.81 2.01 1.96

4-7 N 20 20 19 19 18 20 20 18 19 20 MEAN 77.9 79.0 78.0 81.6 73.0 74.7 76.1 73.5 74.2 78.7 S.D. 6.90 14.24 7.59 15.74 5.26 5.13 8.32 5.59 5.89 6.39

1-7 N 20 20 19 19 18 20 20 18 19 20 MEAN 136.6 134.6 135.4 141.1 131.1 131.6 132.8 128.5 129.1 136.2 S.D. 11.92 18.05 12.81 24.92 12.88 11.04 14.99 10.52 9.35 9.56

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Table 3Incidence of Macroscopic Observations Unscheduled Deaths


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-- N U M B E R - O F - A N I M A L S - A F F E C T E D -- TABLE INCLUDES: SEX=M;GROUP=ALL;WEEKS=1-15 SEX: ----------------------MALE---------------------- DEATH=UNSCHED; SUBSET=ALL GROUP: -1- -2- -3- -4- -5- -6- -7- -8- -9- -10-

ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 0 1 0 1 0 1 0 0 0 0 ------------------------------------------------------------------------ -=- -=- -=- -=- -=- -=- -=- -=- -=- -=- *** TOP OF LIST *** BRAIN (BR) ........................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

CORD, CERVICAL (CS) .................................. NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

CORD, THORACIC (TC) .................................. NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

CORD, LUMBAR (LC) .................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

PITUITARY (PI) ....................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

ADRENAL, CORTEX (AC) ................................. NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

ADRENAL, MEDULLA (AM) ................................ NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

THYROID (TY) ......................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

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TABLE 3INCIDENCE OF MACROSCOPIC OBSERVATIONS UNSCHEDULED DEATHS


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-- N U M B E R - O F - A N I M A L S - A F F E C T E D -- TABLE INCLUDES: SEX=M;GROUP=ALL;WEEKS=1-15 SEX: ----------------------MALE---------------------- DEATH=UNSCHED;SUBSET=ALL GROUP: -1- -2- -3- -4- -5- -6- -7- -8- -9- -10- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 0 1 0 1 0 1 0 0 0 0 ------------------------------------------------------------------------ -=- -=- -=- -=- -=- -=- -=- -=- -=- -=-

PARATHYROID (PT) ..................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

ESOPHAGUS (ES) ....................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

TRACHEA (TR) ......................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

LUNG (LU) ............................................ NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 0 0 0 0 0 0 0

DARK 0 0 0 1 0 0 0 0 0 0 MOTTLED 0 0 0 0 0 1 0 0 0 0

HEART (HT) ........................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

SPLEEN (SP) .......................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

LIVER (LI) ........................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 0 0 0 0 0

ENLARGED 0 0 0 0 0 1 0 0 0 0

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-- N U M B E R - O F - A N I M A L S - A F F E C T E D -- TABLE INCLUDES: SEX=M;GROUP=ALL;WEEKS=1-15 SEX: ----------------------MALE---------------------- DEATH=UNSCHED;SUBSET=ALL GROUP: -1- -2- -3- -4- -5- -6- -7- -8- -9- -10- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 0 1 0 1 0 1 0 0 0 0 ------------------------------------------------------------------------ -=- -=- -=- -=- -=- -=- -=- -=- -=- -=-

KIDNEY (KD) .......................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 0 0 1 0 0 0 0

PELVIS, DILATED 0 0 0 1 0 0 0 0 0 0 PELVIS, FLUID 0 0 0 1 0 0 0 0 0 0

STOMACH, NONGL (SU) .................................. NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

STOMACH, GL (ST) ..................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

DUODENUM (DU) ........................................ NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

JEJUNUM (JE) ......................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

ILEUM (IL) ........................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

PANCREAS (PA) ........................................ NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

CECUM (CE) ........................................... NUMBER EXAMINED: 0 1 0 1 0 1 0 0 0 0 NOT REMARKABLE: 0 1 0 1 0 1 0 0 0 0

Covance 6103-293

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-- N U M B E R - O F - A N I M A L S - A F F E C T E D -- TABLE INCLUDES: SEX=M;GROUP=ALL;WEEKS=1-15 SEX: ----------------------MALE---------------------- DEATH=UNSCHED;SUBSET=ALL GROUP: -1- -2- -3- -4- -5- -6- -7- -8- -9- -10- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 0 1 0 1 0 1 0 0 0

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