Document 851D1bOvaOezLNBQNjMdKOdnK

AfiOX-O 45/ C O R N IN G Hazleton Sponsor. 3M S t Paul, Minnesota FINAL REPORT Study Title: 5 Daily Dose Oral Toxicity Study with T-6669 in Rats Author: Susan M. Henwood, MS, DABT Study Completion Date: April 30,1997 Performing Laboratory: Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 6329-197 Page 1 of 90 00Z42J CHW 6329-197 QUALITY ASSURANCE STATEMENT This report has been reviewed by the Quality Assurance Unit of Coming Hazleton Inc., in accordance with the Food and Drug Administration (FDA) Good Laboratory Practice Regulations, 21 CFR 58 and the Organisation for Economic Cooperation and Development (OECD) Principles of Good Laboratory Practice, C(81)30(Final). The following inspections were conducted and findings reported to the Study Director and management Written status reports of inspections and findings are issued to Coming Hazleton management according to standard operating procedures. Inspection Dates Date Reported to Date to From_______ To_____________ Phase_________ Study Director Management 12/17/96 01/21/97 02/28/97 03/26/97 04/22/97 12/17/96 01/21/97 03/04/97 03/31/97 04/23/97 Protocol Review Necropsy Data Review Report Review Report Rereview 12/17/96 01/21/97 03/04/97 03/31/97 04/23/97 12/17/96 01/21/97 03/04/97 03/31/97 04/23/97 ShcutJh*/ raM jLa^J Representative Quality Assurance Unit _______ y / W ? ? Date 7 2 G 0242y CHW 6329-197 STUDY IDENTIFICATION 5 Daily Dose Oral Toxicity Study with T-6669 in Rats Test Material Sponsor Study Monitor Study Director Study Location Study Timetable Study Initiation Date In-Life Start Date In-Life End Date Study Completion Date T-6669 3M Toxicology Services Building 220-2E-02, 3M Center S t Paul, Minnesota, 55144-1000 Roger G. Perkins, PhD, DABT 3M Toxicology Services Building 220-2E-02,3M Center S t Paul, Minnesota, 55144-1000 (612) 733-3222 Susan M. Henwood, MS, DABT Coming Hazleton Inc. P.O. Box 7545 Madison, Wisconsin 53707-7545 (608) 241-7221 Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 December 20,1996 January 2, 1997 January 21,1997 April 30,1997 3 00242$ * Toxicology Susan M. Henwood, MS Diplomate, ABT Study Director Thomas Ryan Study Toxicologist Sandra L Haley Study Coordinator Toxicology Operations Pamela D. Gabris Supervisor Small Animal Toxicology Dose Formulation Dixie K. Bushee Supervisor Quality Assurance Sherry R. W. Petsel Manager CHW 6329-197 KEY PERSONNEL Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor Clinical Pathology Robert L. Hall, DVM, PhD Diplomate, ACVP Clinical Pathologist Ronald Markevitch Supervisor Anatomical Pathology Thomas E. Palmer, PhD Anatomical Pathologist Jack Serfort Supervisor Necropsy 4 00242^ * CHW 6329-197 CONTENTS Page QUALITY ASSURANCE STATEMENT ........................................................................2 STUDY IDENTIFICATION..............................................................................................3 KEY PERSONNEL............................................................................................................4 ABSTRACT........................................................................................................................8 OBJECTIVE ....................................................................................................................10 REGULATORY COMPLIANCE.................................................................................... 10 MAINTENANCE OF RAW DATA AND RECORDS.................................................... 10 TEST MATERIAL AND CARRIER................................................................................ 10 Identification and Characterization....................................... 10 Storage Conditions ......................................................................................................11 Reserve Sam ples.......................................................................................................... 11 Disposition ..................................................................................................................11 Safety Precautions........................................................................................................11 TEST SYSTEM................................................................................................................ 11 Test Anim al..................................................................................................................11 Justification.................................................................................................................. 11 Identification................................................................................................................ 12 STUDY DESIGN.............................................................................................................. 12 Dose Level Selection C riteria...................................................................................... 12 PROCEDURES................................................................................................................ 13 Acclimation.................................................................................................................. 13 Housing and Maintenance............................................................................................ 13 Placement of Animals into G roups.............................................................................. 14 Dose Preparation.......................................................................................................... 14 Dose Analyses.............................................................................................................. 14 Dose Administration.................................................................................................... 15 Antemortem Observations ..........................................................................................15 Body W eights.............................................................................................................. 15 5 00242$ CHW 6329-197 CONTENTS (Continued) Page PROCEDURES (Continued) Blood Sample Collections............................................................................................ 15 Palmitoyl CoA Oxidase Activity Analysis (Day 6 ) ...................................................... 16 Scheduled Sacrifice (Day 2 0 ) ...................................................................................... 16 Statistical Analyses...................................................................................................... 17 RESULTS ........................................................................................................................ 17 Antemortem Observations and Survival...................................................................... 17 Body Weights and Cumulative Body Weight Gains.................................................... 17 Palmitoyl CoA Oxidase Activity A nalysis.................................................................. 18 Anatomical Pathology.................................................................................................. 18 CONCLUSIONS.............................................................................................................. 18 SIGNATURES.................................................................................................................. 19 REFERENCES ................................................................................................................20 PATHOLOGY REPORT..................................................................................................21 COMMENTS ON THE D A T A ........................................................................................23 CODES, ABBREVIATIONS, AND U N ITS....................................................................24 General Codes and Abbreviations................................................................................25 Codes for Clinical Pathology ......................................................................................27 Abbreviations and Units for Clinical Chemistry..........................................................28 Codes for Anatomical Pathology ............................................................................... 29 TABLE 1 Summary of Antemortem Observations................................................................30 2 Summary of Body Weight Data (g )........................................................................31 3 Summary of Clinical Chemistry D a ta ....................................................................34 APPENDIX A ..................................................................................................................35 Protocol Deviations......................................................................................................36 Protocol TP6785 ..........................................................................................................37 Material Safety Data S h e e t..........................................................................................50 6 C0242g CHW 6329-197 CONTENTS (Continued) Page APPENDIX B ................................................................................................................. 57 Individual Antemortem Observations..........................................................................58 Individual Body Weight Data ( g ) ............................................................................... 59 Individual Body Weight Gain Data ( g ) ........................................................................62 APPENDIX C ................................................................................................................ 66 Individual Clinical Chemistry D ata............................................................................ 67 APPENDIX D ..................................................................................................................69 Individual Animal Liver Weight Values ( g ) ............................................................... 70 Individual Animal Pathology D a ta ..............................................................................71 7 __ ___________________________________________________________ CHW 6329-197 ABSTRACT The purpose of this study was to assess the oral toxicity produced when the test material, T-6669, was administered by the oral route (gavage) to male rats for 5 consecutive days. Male Crl:CD(SD)BR VAF/Plus rats were assigned to four groups (10/group). Each group received dose preparations containing the carrier (reverse osmosis water) or 5.0, 14.0, or 42.0 mg of test material/kg of body weight/day (mg/kg) for 5 consecutive days at a dose volume of 5 mL/kg. Five animals/group were terminated on Day 6 (the day following the final dose) for hepatic palmitoyl CoA oxidase activity determinations; remaining animals were sacrificed and necropsied on Day 20. Food and water were provided ad libitum. The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity. Additionally, each animal was removed from its cage and observed for clinical signs predose and at approximately 1,2.5, and 4 hours after each dose administration and daily thereafter. Any abnormal or unusual findings were recorded. Body weight data were collected daily on Days 1 through 20. Blood samples were collected on Days -2 (pretest), 6,9, 15, and 20; serum and cellular fractions were separated and shipped to the Sponsor. On Day 6, five animals/group were sacrificed, and the liver was removed from each animal and weighed. The right lateral lobe of the liver was collected from each animal and weighed, then analyzed for palmitoyl CoA oxidase activity; the remaining liver tissue was also collected and weighed. On Day 20, the remaining five animals/group were sacrificed and subjected to an abbreviated necropsy; the liver was collected from each animal and weighed. Remaining liver tissues collected at the Day 6 sacrifice and the whole livers collected at the Day 20 necropsy were shipped to the Sponsor. All animals survived to the respective scheduled sacrifice. There were no test material-related antemortem observations. Mean body weight gains for mid- and highdose animals (14.0 and 42.0 mg/kg, respectively) were significantly reduced during the dosing period; Day 1 to 6 body weight gains were 23,23, 0, and -4 g for the control, 5.0-, 14.0-, and 42.0-mg/kg groups respectively. In general, mid- and high-dose animals showed a recovery in body weight gain over the first 3 days after completion of the dosing period. The overall mean body weight gains (Day 1 to 20) were free of significant intergroup differences and were similar for all groups. 8 002430 CHW 6329-197 Administration of the test material at all dose levels was associated with higher hepatic palmitoyl CoA oxidase activity. Mean palmitoyl CoA oxidase activities on Day 6 for control animals and animals given 5.0,14.0, and 42.0 mg/kg were 5, 24,39, and 3 9 IU/G, respectively. There were no test material-related macroscopic findings. Based on significant increases in the levels of hepatic palmitoyl CoA oxidase activity, an indication of peroxisome proliferation, at all dose levels tested, the no-effect level of T-6669 is less than 5.0 mg/kg when administered to male Crl:CD(SD)BR VAF/Plus rats for 5 consecutive days. 9 C024 OBJECTIVE CHW 6329-197 The purpose of this study was to assess the oral toxicity produced when the test material, T-6669, was administered by the oral route (gavage) to male rats for 5 consecutive days. REGULATORY COMPLIANCE All aspects of this study were in accordance with the United States Food and Drug Administration Good Laboratory Practice Regulations for Nonclinical Laboratory Studies, 21 CFR 58, and the Organisation for Economic Co-operation and Development Principles of Good Laboratory Practice, C(81)30, with the exception that analysis of the test material mixtures for concentration, solubility, homogeneity, and stability were not conducted. MAINTENANCE OF RAW DATA AND RECORDS Original paper data and a copy of the final report will be retained in the archives of the Wisconsin facility of Coming Hazleton Inc. (CHW), for 1 year following the signing of the final report One year after the signing of the final report, the Sponsor will determine the final disposition of the materials. Magnetically encoded data will be retained at CHW. TEST MATERIAL AND CARRIER Identification and Characterization Test Material. The test material, T-6669 (FC-143), Lot No. 235, is a white powder and is 93% to 97% ammonium perfluorooctanoate. It was received at CHW on September 25, 1996. Information on synthesis methods, stability, composition, or other characteristics that define the test material is on file with the Sponsor. 10 CHW 6329-197 Carrier. The carrier was reverse osmosis water and was provided by CHW. Information on source and treatment of the reverse osmosis water is on file with CHW. Storage Conditions The test material was stored at room temperature. The carrier was obtained directly from the in-house water system under ambient conditions. Reserve Samples Reserve samples were not required to be taken. Disposition Remaining test material was returned to the Sponsor on March 10,1997. Safety Precautions Personnel involved with the study wore the apparel recommended by the CHW Test Material Safety Committee (TMSC) based on the Material Safety Data Sheet (MSDS; Appendix A). CHW Standard Operating Procedures (SOPs) applied for any apparel not covered by the TMSC recommendations. TEST SYSTEM Test Animal Male Crl:CD(SD)BR VAF/Plus rats were obtained from the Portage, Michigan, facility of Charles River Laboratories, Inc., on December 5, 1996. The animals were approximately 8 weeks old and weighed from 303 to 395 g at initiation of treatment (see Protocol Deviations; Appendix A). Justification The rat is frequently used in safety evaluation studies as a representative of a rodent species. 11 C0243J CHW 6329-197 Identification Each animal was assigned a temporary number upon arrival. Before initiation of treatment, an individually coded passive integrated transponder was implanted into each animal. After randomization for placement on test, each animal was assigned a permanent number, and the transponder was coded with the permanent number. All data for an animal are recorded under these numbers. STUDY DESIGN Animals were assigned to the study according to the following design: Group 1 (Control) 2 (Low) 3 (Mid) 4 (High) T-6669 Dose Level* (mg/kg) 0.0 5.0 14.0 42.0 . Number of Animals Male" 10 10 10 10 a The control group was given the carrier (reverse osmosis water) only. The dose volume was 5 mL/kg for all groups, b Five animals in each group were sacrificed for hepatic palmitoyl CoA oxidase analysis on Day 6. The remaining animals in each group were observed for reversibility, persistence, or delayed occurrence of toxic effects until sacrifice on Day 20. Dose Level Selection Criteria Doses were selected based on the results of an acute toxicity study. In the acute toxicity study (CHW 61001760), animals were dosed with T-6669 at concentrations up to 500 mg/kg. Mortality was noted for animals given 500 mg/kg. At 250 mg/kg, clinical signs were limited to red-stained face and wet urogenital area for two of five females; all 12 002434^ CHW 6329-197 animals survived to the scheduled sacrifice. The high dose of 42.0 mg/kg selected for this study is one sixth of die acute toxicity no-adverse-effect level of 250 mg/kg. The low- and mid-dose levels were selected to provide an adequate dose response. PROCEDURES This study was conducted in accordance with CHW Protocol TP6785 dated December 20,1996. The protocol and protocol deviations are in Appendix A. Acclimation Fifty males were received on December 5, 1996, and acclimated in Animal Room 512A for 28 days before initiation of treatment In general, animals in this shipment appeared healthy. During acclimation, the animals were examined for abnormalities indicative of health problems, and body weights were recorded for all animals at randomization. Housing and Maintenance Animal Room 512A was used for this study. Environmental controls for the animal room were set to maintain 19 to 25C (66 to 77F), a relative humidity of 50% 20%, and a 12-hour light/12-hour dark cycle. The animals were housed individually (except for the first six days following arrival when the animals were group-housed) in stainless steel, screen-bottom cages. Certified Rodent Diet #5002 meal (PMI Feeds, Inc.) was provided ad libitum. The lot numbers are recorded in the data. The diet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Water was provided ad libitum. Samples of the water are analyzed for total dissolved solids and specified microbiological content and for selected elements, heavy metals, organophosphates, and chlorinated hydrocarbons. The results are on file with CHW. There were no known contaminants in the food or water that would have interfered with this study. 13 CQ243jT CHW 6329-197 Placement of Animals into Groups The animals were examined by a laboratory animal veterinarian on December 31,1996, and found to be suitable for study consideration. On Day -2, animals were ranked by body weight Animals with body weights exceeding 2 standard deviations of the mean body weight and those with significant physical abnormalities were excluded from selection. The number of animals available for selection was reduced to the required number by excluding animals at the ends of the body weight range. The animals selected for the study (40 males) were assigned a computer-generated random number and allocated to groups (10/group) according to the relative rank of the random numbers. Group mean body weights were analyzed using Bartlett's test for homogeneity of variance at the 5.0% probability level (Winer, 1971) and found to be homogeneous. Animals not used for the study (10 males) were sacrificed and discarded. Dose Preparation Carrier. The carrier was reverse osmosis water. Test Material. Dose concentrations were based on the test material as supplied. Dose preparations were mixed daily for dose administration. Each dose level was prepared independently. The specified amount of test material was weighed. A portion of the carrier was placed into a labeled container and the test material was added and then mixed with a polytron homogenizer until the test material was suspended. The mixture was then placed into a calibrated container and the appropriate volume of carrier was added to achieve the desired concentration. Dose preparations were mixed for at least 10 minutes using a magnetic sr plate and stir bar. All completed dose preparations appeared to be solutions. The dose preparations were kept at room temperature until dosing. Dose Analyses Dose analyses were not done. 14 00243' CHW 6329-197 Dose Administration Gavage was used because historically the oral route has been the route of choice for administering a known amount of test material. The dose preparations were administered once daily for 5 consecutive days. The dose preparations were given at a dose volume of 5 mL/kg of body weight. Individual doses were calculated based on the most recently recorded body weights. Animals were dosed at approximately the same time each day. During dose administration, homogeneous test material solutions were maintained using a magnetic stir plate and stir bar. Antemortem Observations The animals were observed at least twice daily (a.m. and p.m.) for mortality and moribundity. Signs of poor health or abnormal behavior were recorded as they were observed. Predose and Postdose Observations. Each animal was removed from its cage and observed for clinical signs predose and approximately 1,2.5, and 4 hours after each dose administration and daily thereafter. Any abnormal or unusual findings were recorded. Body Weights Individual body weight data were recorded on the first day of treatment and daily thereafter. Blood Sample Collections Blood samples were collected from each animal on Days -2 (pretest; see Protocol Deviations), 9, and 15 and at the scheduled sacrifices (Days 6 and 20). Animals were not fasted before blood sampling. Blood samples (approximately 1.5 mL) were collected from a jugular vein of all animals pretest and on Days 9 and 15. At the scheduled sacrifices (Days 6 and 20), as much blood as possible was collected from the posterior vena cava from each animal. At sacrifice, the animals were anesthetized with sodium pentobarbital before blood sample collection. 15 G0243 CHW 6329-197 Following collection, the blood samples were held at room temperature until centrifuged. The serum and cellular fractions were separated and stored in a freezer set to maintain -20C 10 until packed on dry ice and shipped to the Sponsor on January 22,1997. The Sponsor is responsible for the retention or disposition of these samples. Palmitoyl CoA Oxidase Activity Analysis (Day 6) At the Day 6 scheduled sacrifice, five nonfasted animals/group were anesthetized with sodium pentobarbital, weighed, and exsanguinated in random order following the blood sample collections. The abdominal cavity of each animal was opened, and the liver was removed and weighed. The right lateral lobe of the liver was collected from each animal, weighed, and was flash-frozen in liquid nitrogen, then stored in a freezer set to maintain -70C 10 until analyzed by CHW for palmitoyl CoA oxidase activity. The remaining liver tissue was collected, weighed, and stored in a freezer set to maintain -20 C 10 until packed on dry ice and shipped to the Sponsor on January 13,1997. The Sponsor is responsible for the retention or disposition of these samples. Animal carcasses were discarded without further examination after liver tissue collection. Scheduled Sacrifice (Day 20) On Day 20, the remaining five animals/group were anesthetized with sodium pentobarbital, weighed, exsanguinated, and subjected to an abbreviated gross necropsy in random order following the blood sample collections. The necropsy included a macroscopic examination of the external surface of the body; all orifices; and the cervical, thoracic, and abdominal cavities and viscera. All abnormalities observed were recorded. The whole liver was collected, weighed, and stored in a freezer set to maintain -20C 10 until packed on dry ice and shipped to the Sponsor on January 27,1997. The Sponsor is responsible for the retention or disposition of these livers. No additional tissues were collected, and the animal carcasses were discarded after necropsy. 16 C0243 CHW 6329-197 Statistical Analyses Only data collected on or after the first day of treatment were analyzed statistically. One-way analysis of variance [ANOVA (Winer, 1971)] was used to analyze Day 1 body weights; cumulative body weight gains (Day 1 to 6 and Day 1 to 20), and palmitoyl CoA oxidase levels. Levene's test (Levene, 1960) was done to test for variance homogeneity. In the case of heterogeneity of variance at p s 0.05, transformations were used to stabilize the variance. ANOVA was done on the homogeneous or transformed data. If the ANOVA was significant, Dunnett's multiple comparison t-test (Dunnett, 1964) was used for pairwise comparisons between treated and control groups. Group comparisons were evaluated at the 5.0% two-tailed probability level. Groups 2 through 4 were compared with Group 1 (control). RESULTS Antemortem Observations and Survival Antemortem observations are summarized in Table 1; individual data are in Appendix B. All animals survived to the respective scheduled sacrifice. There were no test material-related antemortem observations. Body Weights and Cumulative Body Weight Gains Body weight data are summarized in Table 2; individual data are in Appendix B. Cumulative body weight gains over the dosing period (Days 1 to 6) and over the study duration (Days 1 to 20) are included in Table 2. Individual day-to-day body weight gains and individual cumulative body weight gains for Days 1 to 6 and Days 1 to 20 are also in Appendix B. Mean body weight gains for mid- and high-dose animals (14.0 and 42.0 mg/kg, respectively) were significantly reduced during the dosing period; Day 1 to 6 body weight gains were 23, 23,0, and -4 g for the control, 5.0-, 14.0-, and 42.0-mg/kg groups 17 0024 CHW 6329-197 respectively. In general, the mid- and high-dose animals showed a recovery in body weight gain over the first 3 days after completion of the dosing period. The overall body weight gains (Day 1 to 20) were free of significant intergroup differences and were similar for all groups. Palmitoyl CoA Oxidase Activity Analysis Day 6 palmitoyl CoA oxidase activity data are summarized in Table 3; individual data are in Appendix C. The Pathology Report contains a discussion of the data. On Day 6, palmitoyl CoA oxidase activity was significantly increased for treated animals at all dose levels. Mean hepatic palmitoyl CoA oxidase activities for the groups given 0.0,5.0,14.0, and 42.0 mg/kg were 5,24, 39, and 39 IU/G, respectively. Anatomical Pathology Results of the Day 20 necropsies and the Day 6 and Day 20 liver weight data are in Appendix D. The Pathology Report contains a discussion of the necropsy findings. At necropsy on Day 20, one animal from the group given 5.0 mg/kg had multiple, dark red foci of variable size in the right lobe of the thymus, and the pelvis of the left kidney in one animal from the group given 42.0 mg/kg was enlarged. These were considered incidental findings and unrelated to the test material. There were no macroscopic findings in the remaining animals examined. CONCLUSIONS Based on significant increases in the levels of hepatic palmitoyl CoA oxidase activity, an indication of peroxisome proliferation, at all dose levels tested, the no-effect level of T-6669 is less than 5.0 mg/kg when administered to male Crl:CD(SD)BR VAF/Plus rats for 5 consecutive days. 18 00244# r CHW 6329-197 SIGNATURES Sandra L. Haley Study Coordinator Toxicology Coming Hazleton Inc. Diplomate, ABT Study Director Toxicology Coming Hazleton Inc. Iff Date Date Vi 19 00244^ REFERENCES CHW 6329-197 Dunnett, C. W., "New Tables for Multiple Comparisons with a Control," Biometrics. 20:482-491 (1964). Levene, H., "Robust Tests for Equality of Variances," Contributions to Probability and Statistics, (eds.) L Olkin et al., Ch. 25, pp. 278-292, Stanford University Press: Stanford, California (1960). Winer, B. J., "Design and Analysis of Single-Factor Experiments," Statistical Principles in Experimental Design. Second Ed., Ch. 3, pp. 149-260, McGraw-Hill: New York, New York (1971). 20 C0244JL PATHOLOGY REPORT CHW 6329-197 SUMMARY The purpose of this study was to assess the oral toxicity produced when the test material, T-6669, was administered by the oral route (gavage) to rats for 5 consecutive days. The test material was administered at dose levels of 0.0,5.0, 14.0, and 42.0 mg/kg of body weight/day (mg/kg). Administration of the test material at all dose levels was associated with higher hepatic palmitoyl CoA oxidase activity. Mean palmitoyl CoA oxidase activities on Day 6 for control animals and animals given 5.0,14.0, and 42.0 mg/kg were 5, 24, 39, and 3 9 IU/G, respectively. There were no test material-related macroscopic findings. METHODS Four groups of male Crl:CD(SD)BR VAF/Plus rats (10/group) were administered the test material by oral gavage for 5 consecutive days at a dose level of 0.0 (control group; received reverse osmosis water), 5.0,14.0, or 42.0 mg/kg. Five animals from each group were sacrificed on Day 6 for hepatic palmitoyl CoA oxidase analyses. The whole liver was removed and weighed, and the right lateral lobe of the liver and the remaining liver were weighed. The analyses were performed on the right lateral lobe of liver, and the remaining liver was frozen for shipment to the Sponsor. All remaining animals were sacrificed and subjected to an abbreviated gross necropsy examination on Day 20. At necropsy, macroscopic observations were recorded, and the entire liver from each animal was weighed and frozen for shipment to the Sponsor. Statistically significant differences cited in the Results and Discussion section are based on comparisons between the control and treated groups. 21 CQ244$ RESULTS AND DISCUSSION CHW 6329-197 Mortality All animals survived to the respective scheduled sacrifice. Clinical Pathology Individual values for hepatic palmitoyi CoA oxidase activity are in Appendix C. Mean values and the results of statistical comparisons are in Table 3. On Day 6, palmitoyi CoA oxidase activity was significantly increased for treated animals at all dose levels. Mean palmitoyi CoA oxidase activities for the groups given 0.0,5.0, 14.0, and 42.0 mg/kg were 5,24, 39, and 3 9 IU/G, respectively. Anatomical Pathology Individual anatomical pathology data for the animals necropsied on Day 20 are in Appendix D. Individual liver weight values for the animals sacrificed on Day 6 are also in Appendix D. Day 20. At necropsy, one animal from the group given 5.0 mg/kg had multiple, dark red foci of variable size in the right lobe of the thymus, and the pelvis of the left kidney in one animal from the group given 42.0 mg/kg was enlarged. These were considered incidental findings and unrelated to the test material. There were no macroscopic findings in the remaining animals examined. Pathologists: Robert L. Hall, DVM, PhD Diplomate, ACVP (Clinical Pathology) Date Pathologist Date 22 00244^ COMMENTS ON THE DATA CHW 6329-197 Various models of calculators, computers, and computer programs were used to analyze data 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 differ slightly firom those in other tables, from individually calculated data, or from statistical analysis data. Neither the integrity nor the interpretation of the data was affected by these differences. The units for dose levels on the Hazleton Path/Tox System (HPTS) summary tables are "mg/kg/day." The number of animals listed in the heading of the summary tables for antemortem observations reflects the number of animals assigned to each group at the start of the study. The summary tables for antemortem observations indicate the number of animals for which a condition was observed without regard to the specific nature, severity, reversibility, number of incidences per animal, or the length of time the condition persisted. Only observations for each animal other than normal are indicated on the summary and individual antemortem observations tables. HPTS considers the day of initiation of treatment as "Day 1, Week 1. Body weight data are entered at the start of a study week (e.g., a body weight recorded on Day 1 is considered a Week 1 body weight, a body weight recorded on Day 8 is considered a Week 2 body weight). Daily body weight gain data are calculated from day to day and are indicated in the appendix by the end point day (e.g., body weight gain from Day 1 to 2 is shown as Day 2 gain, Day 2 to 3 as Day 3 gain, etc.). Cumulative body weight gain data are calculated from the first day of the study to the appropriate day (e.g., Days 1 to 6 and Days 1 to 20) and are indicated in the tables as 1 - 6 CHNG and 1 - 2 0 CHNG. 23 C0244^" CODES, ABBREVIATIONS, AND UNITS General Codes and Abbreviations Codes for Clinical Pathology Abbreviations and Units for Clinical Chemistry Codes for Anatomical Pathology CHW 6329-197 Note: The following lists of codes, abbreviations, and units are used by CHW. Some, but not necessarily all, of this information may be needed for this report 24 C0244& CHW 6329-197 General Codes and Abbreviations WK Week. N Number of measurements in a group. Mean; MEAN Arithmetic mean. SD; S.D.; STAND DEV; STANDARD DEV; sd Standard deviation. CHNG Change. PRE/DLY * Predose observation; daily observation once dosing is completed. Group mean is significantly different from the mean of the control group (Group 1) at p s 0.05. t Indicates body weight data that was analyzed statistically. -; NA No value; not applicable; not present P Present 25 eo244y CHW 6329-197 General Codes and Abbreviations (Continued) DISPATCH Observations dispatched from the in-life module of the Hazleton Path/Tox System (HPTS) to the necropsy module for data collection purposes. Observations are duplicates of the last in-life observations. TBW Terminal body weight #, No. Number. Animal Death Codes: 1 Terminal sacrifice at Day 6. T Terminal sacrifice at Day 20. 26 G0 2 4 4 7 NS QS/QNS NR TJ TE RE EE SE CHW 6329-197 Codes for Clinical Pathology GENERAL CODES No sample Quantity not sufficient No repeat (sample volume not sufficient for repeat analysis) Technician judgment to repeat test Technical error (instrument or technician error that results in unacceptable data, e.g., unacceptable instrument output, sample spilled, entry of invalid data) Recording error (recorded incorrect data, e.g., wrong number, spelling error, incorrect date) Entry error (incorrect keyboard entry) Sampling error 27 0024 CHW 6329-197 Abbreviations and Units for Clinical Chemistry Test Abbreviation (Units) Palmitoyl CoA oxidase PCOAO (IU/G) 28 CO2450 CHW 6329-197 ( Codes for Anatomical Pathology Code Definition ANIMAL DEATH CODES 1 Terminal sacrifice at Day 6 T Terminal sacrifice at Day 20 TISSUE ABBREVIATIONS LN GL STOMACH, GL STOMACH, NONGL SALIV GL, MANDIB LN, ANT MES/PANC AUDITORY SEB GL LACRIMAL GLAND, EX HEMATO NEOPLASIA LACRIMAL GL, INT CAVITY, ABDOM SALIV GL,PAROTID LN, TRACHEOBRON Lymph node Gland Glandular stomach Nonglandular Mandibular salivary gland Anterior mesenteric/pancreatic lymph node Auditory sebaceous gland Exorbital lacrimal gland Hematopoietic neoplasia Internal lacrimal gland Abdominal cavity Parotid salivary gland Tracheobronchial lymph node 29 C0245JJ, Corning Hazleton Inc. Madison, Wisconsin USA DAYS 1-20 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE SWOLLEN NOSE *** END OF LIST *** UO> Table 1 Summary of Antemortem Observations NUMBER OF ANIMALS AFFECTED SEX: GROUP: DOSE: -- JALE--1234 0 5 14 42 NUMBER: 10 10 10 10 0 10 0 CHW 6329-197 PAGE: 1 002453 Corning Hazleton Inc. Madison, Wisconsin USA Table 2 Summary of Body Weight Data (g) GROUP: DOSE: DAY UNITS: 1 0 MG/KG It N MEAN S.D. 10 349 27.5 2N 10 MEAN 357 S.D. 31.1 3N 10 MEAN 360 S.D. 30.5 4N 10 MEAN 365 S.D. 31.7 5N 10 MEAN 366 S.D. 32.8 6N 10 MEAN 372 S.D. 34.6 l-6t N CHNG MEAN S.D. CHNG AS % OF CONTROL 10 23 8.3 - 2 5 MG/KG 10 359 22.5 10 362 23.4 10 367 23.2 10 373 23.4 10 375 24.7 10 382 25.2 10 23 6.3 99 3 14 MG/KG 10 372 16.5 10 378 16.7 10 382 18.8 10 382 18.8 10 376 23.1 10 372 28.1 10 0* 22.1 0 t Indicates data was analyzed statistically. * Denotes statistical significance at ps 0.05 4 42 MG/KG 10 349 15.0 10 352 13.8 10 349 13.8 .. 10 343 15.6 10 339 21.4 10 345 23.6 10 -4* 20.6 -17 CHW 6329-197 PAGE: 1 Corning Hazleton Inc. Madison. Wisconsin USA Table 2 Summary of Body Weight Data (g) SEX: GROUP: DOSE: UNITS: 1 0 MG/KG -MALE--------- 23 5 14 MG/KG MG/KG 4 42 MG/KG 7N 5 MEAN 375 S.D. 33.2 8N 5 MEAN 374 S.D. 36.1 9N 5 MEAN 389 S.D. 35.9 10 N 5 MEAN 384 S.D. 36.5 5 375 25.8 5 373 27.0 5 389 26.2 5 385 29.1 5 376 35.9 5 374 37.6 5 395 34.0 5 392 29.4 5 351 27.4 5 355 19.5 5 374 16.1 5 373 14.2 11 N 5 MEAN 386 S.D. 36.1 12 N 5 MEAN 403 S.D. 37.9 13 N 5 MEAN 407 S.D. 40.3 14 N 5 MEAN 413 S.D. 40.9 5 388 28.8 5 402 28.8 5 407 29.9 5 412 31.4 5 396 27.7 5 412 27.9 5 415 28.3 5 422 28.8 5 376 13.1 5 390 12.6 5 394 12.1 5 400 12.6 n & CA CHW 6329-197 PAGE: 2 Corning Hazleton Inc. Madison, Wisconsin USA Table 2 Summary of Body Weight Data (g) SEX: -------------------- MALE GROUP: 1 2 3 DOSE: 0 5 14 UNITS: MG /KG MG/KG MG/KG 15 N 5 MEAN 414 S.D. 39.7 16 N 5 MEAN 413 S.D. 43.1 17 N 5 MEAN 421 S.D. 42.0 18 N 5 MEAN 428 S.D. 44.3 19 N 5 MEAN 431 S.D. 44.1 20 N 5 MEAN 438 S.D. 43.9 5 414 30.8 5 411 32.4 5 421 32.6 5 426 33.5 5 431 36.0 5 434 33.9 5 425 28.1 5 423 26.6 5 436 26.1 5 443 28.8 5 445 27.7 5 450 28.8 4 42 MG/KG 5 405 13.2 5 404 11.3 5 414 10.8 5 419 9.6 5 424 11.6 5 431 14.3 l-20t N CHNG MEAN S.D. AS OF CONTROL 5 88 20.2 - 5 83 10.2 94 5 81 13.1 92 5 83 8.0 94 o t Indicates data was analyzed statistically. * Denotes statistical significance at p 0.05. CHW 6329-197 pages 3 Table 3 Summary of Clinical Chemistry Data Males Day 6 DOSE mg/kg PCOAO I/G CHW 6329-197 0.0 MEAN S.D. N 5 1.4 5 5.0 MEAN S.D. N 24 * 1.8 5 14.0 MEAN 39 * S.D. 3.3 U4a)- N 5 42.0 MEAN 39 * S.D. 5.4 N5 CHW 6329-197 i APPENDIX A Protocol Deviations Protocol TP6785 Material Safety Data Sheet 35 002457 Protocol Deviations CHW 6329-197 Protocol. Animals. Weight at Initiation of Treatment "210 to 250 g" Actual Procedure. All animals assigned to study exceeded 250 g at initiation: body weights at study initiation ranged from 303 to 395 g. Protocol. Blood Sample Collections. Frequency. "Predose (1 day before the initial dose administration to Day 1), on Days 9 and 15, at the scheduled sacrifice intervals (Days 6 and 20), and at unscheduled sacrifice intervals." Actual Procedure. The predose (pretest) blood samples were collected on Day -2. These deviations are not expected to have affected the results of the study. 36 09245g C O R N IN G Hazleton Sponsor: 3M S t Paul, Minnesota PROTOCOL TP6785 Study Title: S Dsily Dose Oral Toxicity Study with T-6669 in Ras Date: December 20,1996 Performing Laboratory: Coining Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 6329-197 37 C 924^ CHW 6329-197 f TP6785 Page 2 STUDY IDENTIFICATION S Daily Dose Oral Toxicity Study with T-6669 in Rats Test Material Sponsor Sponsor Representative Study Director Study Location Proposed Study Timetable In-Life (Experimental) StartDate In-Life Termination Date Experimental Termination Date T-6669 3M Toxicology Services Building 220-2E-02,3M Center S t Paul, Minnesota, 55144-1000 Roger O. Perkins, PhD, DABT 3M Toxicology Services Building 220-2E-02,3M Center S t Paul, Minnesota, 55144-1000 (612) 733-3222 Facsimile No. (612) 733-1773 Susan M. Henwood, MS, DABT Coming Hazleton Inc. P.O.Box 7545 Madison, WI 53707-7545 (608)241-7221 Facsimile No. (608) 242-2736 Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 January 2,1997 January 21,1997 To be determined 38 C024S if 1. Study 5 Daily Dose Oral Toxicity Study with T-6669 in Rats CHW 6329-197 TP6785 Page 3 2. Purpose To assess the oral toxicity produced when the test material is administered by the oral route (gavage) to rats for 5 consecutive days 3. Regulatory Compliance This study will be conducted in accordance with the Food and Drug Administration Good Laboratory Practice Regulations forNonclinical Laboratory Studies, 21 CFR 58 and the Organisation for Economic Co-operation and Development Principles of Good Laboratory Practice, C(81)30, with the exception that analysis o f the test material mixtures for concentration, solubility, homogeneity, and stability will not be conducted. 4. Quality Assurance The protocol, study conduct, and final report will be audited by the Quality Assurance Unit in accordance with die Standard Operating Procedures (SOPs) o f the Wisconsin facility o f Corning Hazleton Inc. (CHW). 5. Test Material A. Identification T-6669 B. Physical Description To be documented in the raw data C. Purity and Stability Responsibility o f the Sponsor (including under test conditions). Samples o f test material and carrier mixtures for concentration, homogeneity, solubility, and stability analyses will not be taken before administration. D. Storage Conditions Room temperature E. Reserve Samples Reserve samples o f test material are not required to be taken. 39 CHW 6329-197 TP6785 Page 4 F. Disposition o f Test Material Any unused test material will be returnedto the Sponsor after completion o f in-life testing. G. Safety Precautions As required by CHW SOPs and policies 6. Carrier A. Identification Reverse osmosis water (R water) B. Physical Description Gear, colorless liquid C Storage Conditions Ambient 7. Experimental Design A. Animals a ) Species Rat (2) Strain Cri:CD*(SD)BR VAF/Plus- <3) Source Charles River Laboratories, Inc. (4) Age at Initiation of Treatment Young adult (5) Weight at Initiation of Treatment 210 to 250 g (<D Number and Sex 40 males (7) Identification Individually coded passive integrated transponder implants 40 02465* (8) Husbandry CHW 6329-197 TP6785 PageS (a) Housing Individual (may be group-housed during acclimation) (b) Food Certified Rodent Diet #5002 meal (PMI Feeds, Inc.) a d libitum , unless otherwise specified The food is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. (c) Water A d libitum. Samples of the water are analyzed for total dissolved solids and specified microbiological content and for selected elements, heavy metals, organophosphates, and chlorinated hydrocarbons. (d) Contaminants There are no known contaminants in the food or water that would interfere with tins study. (e) Environment Environmental controls for the animal room will be set to maintain 19 to 25C (66* to 77F), a relative humidity o f 50% 20%, and a 12-hour light/12-hour dark cycle. (f) Acclimation At least 1 week (9) Randomization Via computer-generated random numbers for assignment to groups. The animals will be weighed. The weight variation o f the animals selected for the study will not exceed 2 standard deviations of the mean weights. (10) Justification The rat is frequently used in safety evaluation studies as a representative o f a rodent species. 41 G024S B. Group Designations CHW 6329-197 TP6785 Page 6 Group Dose Level* (mg/kg) Number o f Males* 1 (Control) 2 (Low) 3 (Mid) 4 (High) 0.0 5.0 14.0 4X0 10 10 10 10 a The control group will receive RO water only. The dose volume will be 5 mL/kg. b Five animals in each group will be sacrificed for palmitoyl-CoA oxidase analysis on Day 6. The remaining animals in each group will be observed for reversibility, persistence, or delayed occurrence o f toxic effects until sacrificed on Day 20. C Dosing Procedures (1) Dosing Route Oral gavage (2) Reason for Dosing Route Historically, the oral route has been the route o f choice for administering a known amount o f test material. (3) Dosing Duration Five consecutive days o f dose administration. The first day o f treatment will be designated as Day 1. The doses will be administered at approximately foe same time each day. (4) Dose Preparation The control animals will receive RO water only. Test mixtures will be prepared on each day o f administration. The test material will be mixed in RO water at a specific concentration for each dose level. The dose for each animal for each day o f dosing will be based on the most recently recorded body weight. The prepared test mixtures will be stored at room temperature until administration. During dose administration, homogeneous test material mixtures will be maintained using a magnetic stir plate and stir bar. 42 00246ff CHW 6329-197 TP6785 Page 7 D. Observation o f Animals (1) Clinical Observations Twice daily (am. and pun.) for mortality through Day 20 (a m mortality only on Day 20. Animals will be observed predose; at approximately 1, 2.5, and 4 hours after each dose; and daily thereafter for clinical signs. Observations may be extended when directed by the study director. (2) Body Weights For randomization, before initiation o f treatment (Day 1), daily thereafter, at scheduled sacrifices (Days 6 and 20), and at death (when survival exceeds 1 day). (3) Blood Sample Collections (a) Frequency Predose (1 day before the initial dose administration to Day 1), on Days 9 and 15, at the scheduled sacrifice intervals (Days 6 and 20), and at unscheduled sacrifice intervals (b) Method of Collection/Nnmber o f Animals Animals will not be fasted overnight for scheduled collections. Blood samples (approximately 1.5 mL) will be collected from a jugular vein o f all animals at the predose interval and on Days 9 and 15. A blood sample (as much as possible) will also be collected from the posterior vena cava o f each animal sacrificed in a moribund condition (if possible) and from each animal at scheduled sacrifices (Days 6 and 20). The blood samples will be stored at room temperature and then centrifuged; the separate serum and cellular fractions will be stored in a freezer set to maintain -20C 10. The serum and cellular fractions vli be packed on dry ice and sent to the Sponsor within 1 week after in-life termination. The Sponsor is responsible for the retention and disposition ofthe samples. 43 C 0 2 4 6 " CHW 6329-197 TP6785 Page 8 The serum and cellular fraction samples w ill be shipped to: James D. Johnson 3M E.T.& S Bldg. 2-3E-09 935 Bush Avenue S t Paul, Minnesota 55106 James D. Johnson or his alternate will be notified regarding die shipment o fthe samples. E. Palmitoyl-CoA Oxidase Analysis (1) Frequency and Number of Animals Five animals/group on Day 6 in random order (2) Method o f Collection On die day o f die scheduled sacrifice, nonfasted animal will be anesthetized with sodium pentobarbital, weighed, and exsanguinated. The abdominal cavity o f euch animal will be opened, and the liver will be removed and weighed. The right lateral lobe o f the liver will be collected from each animal, weighed, and flash-frozen in liquid nitrogen. The liver tissue will be stored in a freezer set to maintain -70C 10 until analyzed by CHW for palmitoyl-CoA oxidase activity. The remaining liver will be collected, weighed, and placed into a freezer set to maintain -20C 10*. The livers will be packed on dry ice and dripped to James D. Johnson within 1 week after in-life termination. The Sponsor is responsible for the retention and disposition o f fire livers. Animals will be discarded after scheduled liver tissue collection. Any animal selected for palmitoyl-CoA oxidase analysis that dies or is sacrificed in a moribund condition will be subjected to an abbreviated gross necropsy examination, and all abnormalities will be recorded. Tissues will be discarded after necropsy. 44 C924sti> CHW 6329-197 TP6785 Page 9 F. Termination (animals not designated for palmitoyl-CoA oxidase analysis ) (1) Unscheduled Sacrifices and Deaths Any animal that is found dead or is sacrificed in a moribund condition 'will be subjected to an abbreviated gross necropsy examination and all abnormalities will be recorded. Animals to be sacrificed will be anesthetized with sodium pentobarbital, weighed, bled via the posterior vena cava, and exsanguinated. The whole liver will be collected, weighed, and placed into a freezer set to maintain -20C 10*. The livers will be packed on dry ice and shipped to James D. Johnson within 1 week after in-life termination. The Sponsor is responsible for the retention or disposition of the livers. The animal will be discarded after necropsy. (2) Scheduled Sacrifice On Day 20, the animals voli be anesthetized with sodium pentobarbital, weighed, bled via the posterior vena cava, exsanguinated, and subjected to an abbreviated gross necropsy examinatioa The animals will be necropsied in random order, and all abnormalities will be recorded. The whole liver will be collected, weighed, and placed into a freezer set to maintain -20C 10*. The livers will be packed on dry ice and shipped to James D. Johnson within 1 week after in-life termination. The Sponsor is responsible for the retention or disposition o f tire livers. The animals will be discarded after necropsy. G. Statistical Analyses Statistical analyses will be performed on Day 1 body weights, cumulative body weight gains (Day 2 through termination), and palmitoyl-CoA oxidase levels. A description o f statistical analyses is in Attachment 1. Groups 2 through 4 will be compared with Group 1 (control). Report A final report including those items listed below will be submitted. Description of the control and test materials Description of the test system Procedures Dates of experimental initiation and termination Tabulation o f mortality data by dose level Description o f any toxic effects Tabulation ofmean body weights by dose level Macroscopic observations 45 C*024S<y Pathology report Palmitoyl-CoA oxidase levels Statistical findings CHW 6329-197 TP6785 Page 10 9. Location of Raw Data, Records, and Final Report Original data, or copies thereof will be available at CHW to facilitate auditing die study during its progress and before acceptance o f die final report When die final report is completed, all original paper date, including those items listed below will be retained in die archives o f CHW for a period o f 1 year following signing o f die final report One year after signing o f die final report, all o f the aforementioned materials will be sent to the Sponsor, and a return fee will be charged. The Sponsor may elect to have the materials retained in the CHW archives for an additional time and CHW will charge a storage fee. If the Sponsor chooses to have CHW dispose o f the materials, a disposal fee will be charged. Protocol and protocol amendments Dose preparation records In-life records Body weights Randomization data Dose administration Antemortem observations Anatomical pathology records Palmitoyl-CoA oxidase analysis records Statistical records Sample collection records Shipping records Study correspondence Final report (original signed copy) The following supporting records will be retained at CHWbut will not be archived with the study data. Animal receipt and acclimation records Water analysis records Animal room temperature and humidity records Refrigerator and freezer temperature records Instrument calibration and maintenance records 46 C 024S^ PROTOCOL APPROVAL CHW 6329-197 TP6785 Page 11 Diplomate, ABT Sponsor Representative 3M Study Director Toxicology Corning Hazleton Inc. Represseennttative j Quality Assurance Unit Coming Hazleton Inc. Date ____ l h h L Date I Z - Z 0 -9 C Date 47 0024i/Sf ATTACHMENT 1 CHW 6329-197 TP6785 Pag 12 Statistical Methods The statistical methodsthat "willbe used are described below. Levene's test (Levene, 1960) will be done to test for variance homogeneity. In the case o f heterogeneity o f variance at p * 0.05, transformations will be used to stabilize the variance. Analysis o f variance [ANOVA (Winer, 1971a)] will be done on the homogeneous or transformed data If the ANOVA is significant, Dunnetfs t-test (Dunnett, 1964) will be used for pairwise comparisons between treated and control groups. One-way ANOVA will be used (if applicable) to analyze Day 1 body weights, cumulative body weight grins (Days 2 through termination), and palmitoyl-CoA oxidase levels. If the ANOVA shows significance for body weights at initiation o f treatment (Day 1), one-way analysis o f covariance [ANCOVA (Winer, 1971b)] will be used to analyze body weights, with the initial body weights as foe covariate. Although Levene's test for variance homogeneity will be done (see above), no transformations will be used because covariance adjustment removes extraneous heterogeneity. If tire ANCOVA is significant, least squares means t-test (SAS, 1989) will be used for pairwise comparisons between treated and control groups. Group comparisons will be evaluated at the 5.0% two-tailed probability level. References Dunnett, C. W., "New Tables for Multiple Comparisons with a Control," Biometrics. 211:482-491 (1964). Levene, H., "Robust Tests for Equality o f Variances," Contributions to Probability and Statistics, (eds.) I. Olkin etal., Ch. 25, pp. 278-292, Stanford University Press: Stanford, California (1960). SAS Institute Inc., SAS/STAT* User's Guide, Version 6, Fourth Ed., Vol. 2, p. 909, SAS Institute Inc.: Cary, North Carolina (1989). 48 C 02470 Attachment 1 (Continued) CHW 6329-197 TP6785 Page 13 Winer, B. J., "Design and Analysis o f Single-Factor Experiments," Statistical Principles in Experimental Design. Second Ed, Ch. 3,pp. 149-260, McGraw-Hill: New York, New York (1971a). Winer, B. J., "Analysis o f Covariance," Statistical Principles in Experimental Design. Second E d , Ch. 10, pp. 752-812, McGraw-Hill: New York, New York (1971b). 49 C Q 2 4 7 j^ MATERIAL SAFETY OATA SHEET 3M 3M Center ------ St. Paul, Minnesota 55144-1000 (612) 733-1110 C H W 6329-197 T - t> yb9 Copyright* 1996, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreement is obtained from 3Mt and 2 ) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: SPECIALTY CHEMICALS DIVISION TRADE NAME.* FC-143 FLUORAD Brand Fluorochemical Surfactant 10 NUMBER/U.PiC.: 98-0211-0006-0 00-51135-09138-8 98-0211-0891-9 98-0211-5489-7 00-51135-02941-1 98-0211-6581-0 98-0211-7394-7 00-51135-10762-1 2F-0002-0378-4 ISSUED: August 23, 1996 SUPERSEDES: May 20, 1996 DOCUMENT: 10-3808-2 00-51135*09365-B 00-51135-10405-7 1. INGREDIENT C.A.S. NO. PERCENT AMMONIUM PERFLUOROOCTANQATE. AMMONIUM PERFLUOROHEPTANQATE AMMONIUM PERFLUOROPENTANOATE AMMONIUM PERFLUOROHEXANOATE. 3825-26-1 6130-43-4 68259-11-0 21615-47-4 93 1 1 0.1 - 97 -3 -3 -1 2. PHYSICAL DATA BOILING POINT:................ N/A VAPOR PRESSURE:............... N/A VAPOR DENSITY:................. N/A EVAPORATION RATE:............. N/A SOLUBILITY IN WATER:.......... apprec. SPECIFIC GRAVITY:.............. 0.4 - 0.5 Water*1 (Bulk) PERCENT VOLATILE:.............. N/A pH:..... .............. ca.5 (0.5Y Aqueous) VISCOSITY:............ N/D MELTING POINT:................. N/A APPEARANCE ANO ODOR: Light colored powder; slight odor. A b b r e v i a t i o n s : N/D Not D e te rm in e d N/A - Not A p p l i c a b l e 50 00247^, MSDS: F C - U 3 FLUORAD B ran d F luoroch em ical S u r f a c t a n t August 23/ 19S6 3. FIRE AND EXPLOSION HAZARD DATA CHW 6329-197 PAGE 2 FLASH POINT:.................. Non-flammable FLAMMABLE LIMITS - LEI:...... N/A FLAMMABLE LIMITS - U E U ...... N/A AUTOIGNITION TEMPERATURE:..... N/A EXTINGUISHING MEDIA: Hater, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around ares, waist and legs, face mask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: Not Applicable HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Hydrogen Fluoride, Ammonia. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions from other sections. Collect spilled material. Use wet sweeping compound or water to avoid dusting. Clean up residue. Place in a closed container. RECOMMENDED DISPOSAL: Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will Include HF. Disposal alternative: Dispose of Naste product in a facility permitted to accept chemical waste. A b b r e v i a t i o n s ; N/D - Not D e t e r m in e d N/A - Not A p p l i c a b l e 51 MSDS: F C - 143 FLUORAD B r a n d F l u o r o c h e m i c a l S u r f a c t a n t A u g u s t 2 3 , 199 5. ENVIRONMENTAL INFORMATION (continued) CHW 6329-197 PAGE 3 environmental data: Chemical Oxygen Demand (COO) * Nil(.00070 g/g); 20-Day Biochemical Oxygen Demand (BOO2 0 ) * Nil; Theoretical Oxygen Demand (ThOD) = 0.32 g/g; Fathead Minnow (Pimephales prornelas) 96*hr LC50 = 740 mg/L; Water flea (Daphnia aagna) 48-hr E050 * 460 mg/L; Green Algae (Selenastrum capricornatun) 14-day EC50 (cell dry weight) * 73 ag/L; Green Algae (Selenastrum caprlcornutum) 14-day EC50 (cell count) = 43 mg/L bioconcentration factor (8CF) for ammonium perfluorooctanoate (PFO) = 1.6 REGULATORY INFORMATION: Volatile Oroanic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Number = None (Not U.S. EPA Hazardous). The components of this product are in compliance with the chemical registration requirements of TSCA, EINECS, CDSL, AICS, MITI and KTCCL. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: NO ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYE CONTACT: Immediately flush eyes with large amounts of water Tor at least 15 minutes. Get immediate medical attention. SKIN CONTACT: Flush skin with large amounts of water. If irritation persists, get medical attention. INHALATION: If signs/syaDtoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: Do not induoe vomiting. Drink two glasses of water. Call a physician. Abbreviations: N/D - Not Determined N/A - Not Applicable 00247^ USDS : F C - 143 FLUORAD B ra n d F l u o r o c h e m i c a l S u r f a c t a n t August 23, 1996 7. PRECAUTIONARY INFORMATION CHW 6329-197 PAGE 4 EYE PROTECTION: Avoid eya contact. Wear vented goggles. SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of Qloves made froa the following aaterial(s) are reconnended: butyl rubber. Use one or ore of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garments (other than gloves) should be made of either of the following materials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NI03H approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: full-face highefficiency filter respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat I drink or smoke when using this product. Hash exposed areas thoroughly with soap and water. Mash hands after handling and before eatii)g. RECOMMENDED STORAGE! Do not store containers on their sides. Store at room temperature. Keep container dry. Keep container closed when not in use. " PREVENT MOISTURE CONTAMINATION TO KEEP POWDER FREE FLOWING.* FIRE AND EXPLOSION AVOIDANCE: Keep container tightly closed. No smoking while handling this material. HMIS HAZARD RATINGS: HEALTH: 3 FLAMMABILITY: 0 REACTIVITY: 9 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT AMMONIUM PERFLUOROOCTANOATE...... AMMONIUM PERFLUOROHEPTANOATE..... AMMONIUM PERFLUOROPENTANOATE..... AMMONIUM PERFLUOROHEXANOATE...... VALUE UNIT MG/M3 MG/M3 MG/M3 MG/M3 TYPE TWA TWA TWA TWA AUTH SKIN* ACGIH 3M 3M 3M Y Y Y Y Abbreviations 1 N/D - Not Determined N/A - Not Applicable 002475" USDS: F C - 143 FLUORAD B rand F l u o r o c h e m l c a l S u r f a c t a n t August 2 3 , 1996 EXPOSURE LIMITS (contJnuad) INGREDIENT VALUE UNIT CHW 6329-197 PAGE 5 TYPE AUTH SKIN* * SKIN NOTATION: Listed substances indicated with * V under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - ACGIH: American Conference of Governmental Industrial Hygienists - 3M: 3M Recommended Exposure Guidelines 8. HEALTH HAZARD DATA EYE CONTACT: Moderate Eye Irritation: signs/symptoms can Include redness, swelling, pain, tearing, and hazy vision. Airborne product may cause eye injury consisting of corneal opacity. SKIN CONTACT: Product is not expected to be irritating to the skin. Mild Skin Irritation (after prolonged or repeated contact): signs/synptbns can include redness, swelling, and itching. May be absorbed through the skin and persist in the body for an extended tiee. INHALATION: Illness requiring medical attention may result from a single exposure by inhalation to moderate quantities of this material. May be absorbed by inhalation and persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. Prolonged op repeated overexposure, above recommended guidelines, aay cause: Liver Effects: signs/symptoms can include yellow skin(jaundice) and tenderness of upper abdomen. Repeated inhalation of airborne product above the exposure guideline can result in elevated organofluoride levels in the blood. A b b r e v i a t i o n s : N/D * Not D e te rm in e d N/A - Not A p p lic a b le 54 C0247V MSDS: F C - 143 FLUORad B ra n d F l u o r o c h e a i c a l S u r f a c t a n t A u g u st 23, 1996 0. HEALTH HAZARD DATA (continued) CHW 6329-197 PAGE 6 IF SWALLOWED*. Ingestion is not a likely route of exposure to this product. Illness aay result froa a single swallowing of a noderate quantity of this naterial. CANCER: A mixture of ammonium perfluorooctanoate, ammonium perfluoroheptanoate, ammonium perfluoropentanoate and ammonium perfluorohexanoate, that was 93 to 97* AMMONIUM PERFLUOROOCTANOATE (3825-26-1) was fed to albino rats for 2 years, no compound induced carcinogenicity was found in the study. There were statistically significant compound related benign testicular tumors. In a second two-year study there were statistically significant compound related benign tumoFs in the liver, pancreas, and testis when compared to ad libitum and pair-fed controls. Based on the current knowledge, these findings have no human health implications. (1983 and 1993 studies conducted Jointly by 3H and DuPont). MUTAGENICITY*. Not mutagenic in lnvltro mutagenicity assays. Did not cause cell transformation in a mammalian cell transformation assay. REPRODUCTIVE/OEVELOPMENTAL TOXINS: Not teratogenic in rabbits by oral administration. Not teratogenic to rats by gavage or inhalation exposures. OTHER HEALTH HAZARD INFORMATION: A 3M Product Toxicity Summary. Sheet is available. SECTION CHANGE DATES HEADING SECTION CHANGED SINCE May 20, 1996 ISSUE A b b r e v i a t i o n s : N/D - Not D e t e r m in e d N/A - Not A p p l i c a b l e 55 C0 2 4 7 7 USDS: FC -143 FLUORAD B ra n d F l u o r o c h e m i c a l S u r f a c t a n t August 2 3 , 1996 CHW 6329-197 PAGE The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's aethod of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, It Is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application. 3M provides information In electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database nay not be as current as the information in the MSD3 available directly from 3M. 56 00247^ APPENDIX B Individual Antemortem Observations Individual Body Weight Data (g) Individual Body Weight Gain Data (g) CHW 6329-197 57 0024^ Corning Hazleton Inc. Hadison, Wisconsin USA Appendix B Individual Antemortem Observations (Only Findings Other Than Normal) CHW 6329-197 PAGE: 1 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M2 DOSE: 5 MG/KG DAYS 1-20 C77265 T 3 APPEARANCE SWOLLEN NOSE DAY 2 'C* - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM CHECK PRE/DLY 2.5 HR DISPATCH PM CHECK 1.0 HR 4.0 HR UNSCHED PP PP Ul 00 C024S `O fs^Z O Corning Hazleton Inc. Madison, Wisconsin USA ANIMAL DAY DAY NUMBER 12 GROUP: MALE 1 - 0 MG/KG C77251 C77252 C77253 C77254 C77255 C77256 C77257 C77258 C77259 C77260 380 376 359 344 311 333 342 356 303 382 392 384 377 350 316 335 352 365 304 392 GROUP: MALE 2 - 5 MG/KG C77261 C77262 C77263 C77264 C77265 C77266 C77267 C77268 C77269 C77270 390 384 345 360 341 351 386 320 348 362 390 389 356 366 342 352 392 319 351 365 GROUP: MALE 3 - 1 4 MG/KG C77271 C77272 C77273 C77274 C77275 345 349 395 360 382 349 359 404 369 389 Appendix B Individual Body Weight Data (g) CHW 6329-197 PAGE: 1 DAY 3 DAY 4 DAY 5 DAY 67 DAY 8 DAY 9 DAY DAY 10 392 400 399 408 389 396 397 404 379 381 390 390 391 397 407 404 355 361 361 367 371 367 384 378 315 318 318 320 321 315 330 324 345 342 345 352 358 364 365 374 366 374 371 381 383 386 404 398 309 314 311 312 395 399 401 408 409 406 422 417 397 405 405 410 393 397 399 410 411 410 426 429 361 370 365 379 364 375 378 384 350 357 361 363 368 365 381 374 357 362 361 368 375 367 385 377 397 404 411 417 325 331 330 335 339 337 354 351 355 359 361 371 371 372 375 378 380 385 398 395 350 349 345 341 354 355 371 369 360 363 350 347 412 413 411 407 417 421 439 434 371 374 371 378 387 382 401 394 393 396 389 391 Corning Hazleton Inc. Madison, Wisconsin USA ANIMAL DAY DAY NUMBER 1 2 GROUP: MALE 3 -- 14 MG/KG C77276 C77277 C77278 C77279 C77280 370 383 376 369 388 373 387 375 378 396 GROUP: MALE 4 - 42 MG/KG C77281 C77282 C77283 C77284 C77285 C77286 C77287 C77288 C77289 C77290 359 324 345 353 332 352 331 362 367 361 366 326 352 350 335 354 342 367 365 360 DAY 3 377 391 380 385 402 361 322 354 351 331 341 345 357 364 360 Appendix B Individual Body Weight Data (g) DAY 4 377 386 376 385 403 359 312 331 352 328 340 347 358 359 347 DAY 5 369 368 360 384 412 362 295 308 347 332 343 349 352 356 342 DAY 6 366 346 339 388 415 367 316 294 356 337 352 356 371 347 351 DAY 7 326 395 371 303 366 357 358 DAY 8 322 392 369 321 367 359 357 CHW 6329-197 PAGE: 2 DAY DAY 9 10 352 360 410 404 387 385 348 351 386 383 380 378 371 366  & Z Q O Corning Hazleton Inc. Madison, Wisconsin USA ANIMAL DAY DAY NUMBER 11 12 GROUP: C77253 C77254 C77255 C77258 C77260 MALE 1 -- 0 MG/KG 408 421 381 396 326 340 402 419 415 437 GROUP: MALE 2 -- 5 MG/KG C77262 C77265 C77266 C77268 C77270 430 377 381 352 398 444 393 397 365 411 GROUP: MALE 3 -- 14 MG/KG C77271 C77273 C77274 C77270 C77279 373 438 396 369 403 384 454 411 390 421 GROUP: MALE 4 -- 42 MG/KG C77281 C77283 C77284 C77286 C77287 383 360 394 373 369 399 375 405 389 380 DAY 13 428 400 341 424 444 449 396 403 368 419 386 456 414 392 427 404 382 409 394 383 Appendix B Individual Body Weight Data (g) DAY 14 436 404 346 432 448 458 400 407 373 424 389 463 423 402 434 410 386 416 398 391 DAY 15 437 405 349 430 449 458 403 412 373 422 395 468 422 407 434 417 393 421 402 393 DAY 16 445 408 341 426 445 457 399 403 370 425 390 461 419 410 434 410 391 419 405 395 DAY 17 443 417 350 443 453 469 411 417 379 429 403 473 433 424 447 424 402 426 415 405 DAY 18 456 424 353 446 461 476 414 421 384 433 406 484 438 433 455 432 409 425 418 411 CHW 6329-197 PAGE: 3 DAY 19 461 424 358 445 467 482 419 424 384 444 408 483 444 433 456 439 411 433 420 417 DAY 20 466 431 365 454 474 482 421 431 390 447 411 489 441 446 463 448 418 443 427 417 jErs^zoo Corning Hazleton Inc. Madison, Wisconsin USA ANIMAL DAY DAY NUMBER 1-2 2-3 GROUP: MALE 1 - 0 MG/KG C77251 C77252 C77253 C77254 C77255 C77256 C77257 C77258 C77259 C77260 12 8 18 6 5 2 10 9 1 10 0 5 2 5 -1 10 6 1 5 3 GROUP: MALE 2 - 5 MG/KG C77261 C77262 C77263 C77264 C77265 C77266 C77267 C77268 C77269 C77270 0 5 11 6 1 1 6 -1 3 3 7 4 5 -2 8 5 5 6 4 6 GROUP: MALE 3 - 14 MG/KG C77271 C77272 C77273 C77274 C77275 4 10 9 9 7 1 1 8 2 4 Appendix B Individual Body Weight Gain Data (g) Days 1 - 6 DAY DAY DAY TOTAL 3-4 4-5 5-6 1-6 8 -1 9 28 7 1 7 28 2 9 0 31 6 0 6 23 3 02 9 -3 3 7 19 6 1 9 32 8 -3 10 25 5 -3 1 9 4 2 7 26 8 0 5 20 4 2 11 26 9 -5 14 34 11 3 6 24 7 4 2 22 5 -1 7 17 7 7 6 31 6 -1 5 15 4 2 10 23 1 3 3 16 -1 -4 -4 -4 3 -13 -3 -2 1 -2 -4 12 3 -3 7 18 3 -7 2 9 CHW 6329-197 PAGE: 1 ^ S i^ O O Corning Hazleton Inc. Madison. Wisconsin USA ANIMAL DAY DAY NUMBER 1-2 2-3 GROUP: MALE 3 - 14 MG/KG C77276 C77277 C77278 C77279 C77280 3 4 -1 9 8 4 4 5 7 6 GROUP: MALE 4 - 42 MG/KG C77281 7 -5 C77282 2 -4 C77283 7 2 C77284 -3 1 C77285 3 -4 C77286 2 -13 C77287 11 3 C77288 5 -10 C77289 -2 -1 C77290 -1 0 Appendix B Individual Body Weight Gain Data (g) Days 1 - 6 DAY 3-4 0 -5 -4 0 1 -2 -10 -23 1 -3 -1 2 1 -5 -13 DAY 4-5 -8 -18 -16 -1 9 3 -17 -23 -5 4 3 2 -6 -3 -5 DAY 5-6 -3 -22 -21 4 3 5 21 -14 9 5 9 7 19 -9 9 TOTAL 1-6 -4 -37 -37 19 27 8 -8 -51 3 5 0 25 9 -20 -10 CHW 6329-197 PAGEi 2 Corning Hazleton Inc. Madison. Wisconsin USA ANIMAL NUMBER DAY 1-2 DAY 2-3 GROUP: MALE 1 - 0 MG/KG C77253 C77254 C77255 C77258 C77260 18 6 5 9 10 2 5 -1 1 3 GROUP: MALE 2 - 5 MG/KG C77262 C77265 C77266 C7726B C77270 5 1 1 -1 3 4 8 5 6 6 GROUP: MALE 3 - 1 4 MG/KG C77271 C77273 C77274 C77278 C77279 4 9 9 -1 9 1 8 2 5 7 GROUP: MALE 4 - 42 MG/KG C77281 7 -5 C77283 7 2 C77284 -3 1 C77286 2 -13 C77287 11 3 Appendix B Individual Body Weight Gain Data (g) Days 1 - 2 0 DAY 3-4 2 6 3 8 4 4 7 5 6 1 -1 1 3 -4 0 -2 -23 1 -1 2 DAY 4-5 9 0 0 -3 2 2 4 -1 -1 3 -4 -2 -3 -16 -1 3 -23 -5 3 2 DAY 5-6 0 6 2 10 7 11 2 7 5 3 -4 -4 7 -21 4 5 -14 9 9 7 DAY 6-7 1 4 1 2 1 1 5 7 4 2 13 10 9 -13 7 4 9 10 5 2 DAY 7-8 6 -4 -6 3 -3 -1 -3 -8 -2 5 1 4 -5 -4 -3 -2 18 1 2 -1 CHW 6329-197 PAGE: 1 DAY DAY DAY 8-9 9-10 10-11 10 -3 4 17 -6 3 15 -6 2 18 -6 4 16 -5 -2 16 3 16 -7 18 -8 17 -3 13 -3 1 3 4 1 3 16 -2 4 18 -5 4 19 -7 2 30 8 9 18 -6 -1 18 -2 -2 27 3 9 19 -3 11 21 -2 -5 14 -5 3 SlrZG Corning Hazleton Inc. Madison, Wisconsin USA ON r> ANIMAL NUMBER DAY 11-12 DAY 12-13 GROUP: MALE 1 - 0 MG/KG C77253 C77254 C77255 C77258 C77260 13 15 14 17 22 7 4 1 5 7 GROUP: MALE 2 - 5 MG/KG C77262 C77265 C77266 C77268 C77270 14 16 16 13 13 5 3 6 3 8 GROUP: MALE 3 - 14 MG/KG C77271 C77273 C77274 C77278 C77279 11 16 15 21 18 2 2 3 2 6 GROUP: MALE 4 - 42 MG/KG C77281 C77283 C77284 C77286 C77287 16 15 11 16 11 5 7 4 5 3 Appendix B Individual Body Weight Gain Data (g) Days 1 - 2 0 DAY 13-14 8 4 5 8 4 9 4 4 5 5 3 7 9 10 7 6 4 7 4 8 DAY 14-15 1 1 3 -2 1 0 3 5 0 -2 6 5 -1 5 0 7 7 5 4 2 DAY 15-16 8 3 -8 -4 -4 -1 -4 -9 -3 3 -5 -7 -3 3 0 -7 -2 -2 3 2 DAY 16-17 -2 9 9 17 8 12 12 14 9 4 13 12 14 14 13 14 11 7 10 10 DAY 17-18 13 7 3 3 8 7 3 4 5 4 3 11 5 9 8 8 7 -1 3 6 DAY 18-19 5 0 5 -1 6 6 5 3 0 11 2 -1 6 0 1 7 2 8 2 6 CHM 6329-197 PAGE: 2 DAY 19-20 TOTAL 1-20 5 107 7 87 7 54 9 98 7 92 0 98 2 80 7 80 6 70 3 85 3 66 6 94 -3 81 13 70 7 94 9 89 7 73 10 90 7 75 0 86 APPENDIX C Individual Clinical Chemistry Data (Day 6 Palmitoyl CoA oxidase activity) CHW 6329-197 66 CG24S0 Appendix C Individual Clinical Chemistry Pata Hales Day 6 ANIMAL NUHBER PCOAO IU/G CHW 6329-197 Group: 1 Dose Level : 0.0 Dosage Unit: mg/kg C77251 C77252 C77256 C77257 C77259 4 7 6 4 4 MEAN S.D. N 5 1.4 5 Group; 2 Dose Level: 5.0 Dosage Unit: mg/kg C77261 24 O-Jn C77263 C77264 24 27 C77267 24 C77269 22 MEAN S.D. N 24 1.6 5 Group: 3 Dose Level: 14.0 Dosage Unit: mg/kg C77272 C77275 C77276 C77277 C77280 41 38 42 34 41 MEAN S.D. N 39 3.3 5 ^ g 'Z O O 000\ e K CO Appendix C Individual Clinical Chemistry Data Males Day 6 ANIMAL NUMBER PCOAO IU/G Group: 4 C77282 C77285 C77288 C77289 C77290 MEAN S.D. N Dose Level 42.0 40 42 45 33 33 39 5.4 5 Dosage Unit: mg/kg CHW 6329-197 APPENDIX D CHW 6329-197 Individual Animal Liver Weight Values (g) - Day 6 Sacrifice Individual Animal Pathology Data - Day 20 Sacrifice 69 00249^ Corning Hazleton Inc. Hadison, Wisconsin USA APPENDIX D Individual Animal Liver Weight Values (g) Day 6 Sacrifice CHW 6329-197 PAGE: 1 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH 1jSUBSET=ALL ORGAN ABBREVIATION: LIO - WHOLE LIVER. SEX DOSE ANIMAL TERMINAL GROUP NUMBER BODY WT (g) LIO LU LI2 LI1 - LIVER, RIGHT LATERAL LOBE, LI2 - REMAINING LIVER M 1 C77251 M 1 C77252 M 1 C77256 M 1 C77257 M 1 C77259 .0 mg/ta 400.4 394.5 341.5 368.5 306.8 17.7972 16.4199 16.7503 17.8283 11.9291 2.8690 2.5533 2.4016 2.5079 1.7788 14.8583 13.8876 14.2603 15.1980 10.1344 M 2 C77261 M 2 C77263 M 2 C77264 M 2 C77267 M 2 C77269 .0 ma/ka 403.4 370.1 378.9 408.6 363.6 24.1163 20.6942 21.0651 24.2954 18.5405 3.4006 2.8659 2.7795 3.7472 2.3964 20.5802 17.6999 18.2230 20.4106 16.0782 M 3 C77272 M 3 C77275 M 3 C77276 M 3 C77277 M 3 C77280 il .0 mo/ko 343.2 380.2 360.7 346.9 411.8 23.2873 24.3657 20.5304 16.1233 28.2782 3.1381 3.8794 2.7287 2.4445 4.6752 20.0752 20.4197 17.7335 13.6463 23.4964 M 4 C77282 M 4 C77285 M 4 C77288 M 4 C77289 M 4 C77290 12 .0 ma/ka 306.8 328.8 363.5 344.7 345.7 17.2123 22.4106 23.7435 21.1160 24.1904 2.3432 3.6637 3.3208 3.2493 3.5439 14.8110 18.6428 20.3694 17.7983 20.5800 *6V?:oo Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE; 1 ANIMAL NUMBER: C77253 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 461.B GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:48 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LIO) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 18.6810 ------------- 4.0453 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S * * * SEVERITY, KEYWORD(S> OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) ................... -- -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Z G O Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 page; 2 ANIMAL NUMBER: C77254 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 423.7 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:40 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LIl) REMAINING LIV (LI2) 15.3258 ------------- 3.6171 t ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S * * * SEVERITY. KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) .................... tO -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM f l 6frZ00 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 3 ANIMAL NUMBER: C77255 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 355.3 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:53 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (*) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 13.7530 ------------- 3.8708 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES -J GENERAL COMMENT (GC) .................... U> -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM C0249$7 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGEi 4 ANIMAL NUMBER: C77258 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 444.9 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:13 PROSECTOR: NANCY DIEDRICH RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 17.8225 ------------- 4.0060 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * G R O S S P A T H O L O G Y O B S E R V A T I O N S ** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES -- ) GENERAL COMMENT (GC) .................... -P- -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM (T\ N Corning Hazleton Inc. Madison. Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 5 ANIMAL NUMBER: C77260 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 462.8 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:20 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LIO) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 17.6747 ------------- 3.8191 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN * * * GROSS PATHOLOGY OBSERVATIONS * * * ORGAN NAME *J SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES ---------------------------------------- LA GENERAL COMMENT (GC) ......................................................................... -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 6 ANIMAL NUMBER: C77262 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 476.3 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:34 PROSECTOR: DEBBIE PIRKEL RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 21.8525 ------------- 4.5880 t ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) .................... -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM $ 6 1 -2 0 0 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE; 7 ANIMAL NUMBER: C77265 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 415.3 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:34 PROSECTOR: NANCY DIEDRICH RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 18.8251 ------------- 4.5329 * ------------- .... -- ------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S ** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) .................... "J -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 8 ANIMAL NUMBER: C77266 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 424.6 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 11:07 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (L12) 20.5301 ------------- 4.8352 % -------------- -------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) .................... OO -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM QQszoo Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 9 ANIMAL NUMBER: C77268 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED. TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 378.9 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:20 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (t) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 16.0923 ------------- 4.2471 ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES V-JO GENERAL COMMENT (GC) -ABBR NEC PERFORM THYMUS (TH) . . . . -RED FOCUS(I)/AREA(S) -RIGHT LOBE: MULTIPLE DARK RED FOCI, UP TO 1 MM IN DIAMETER foszoo Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 10 ANIMAL NUMBER: C77270 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 441.9 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:08 PROSECTOR: NANCY DIEDRICH RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 20.4477 4.6272 % ----- -------------------------- ------- ---- -- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) .................... -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM T tfo S 2 G D Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 11 ANIMAL NUMBER: C77271 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 404.5 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:26 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT () ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1> REMAINING LIV (LI2) 20.9805 ------------- 5.1868 * ------------- ....... ------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM S20J Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 12 ANIMAL NUMBER: C77273 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED. TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 480.9 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:40 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (t) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 24.5697 ------------- 5.1091 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY. KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES oo GENERAL COMMENT (GC) ..................... (O -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 13 ANIMAL NUMBER: C77274 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 436.9 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:07 PROSECTOR: DEBBIE PIRKEL RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 23.1173 ------------- 5.2912 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) .................... UJ -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM r> O W c/l o Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHM 6329-197 PAGE: 14 ANIMAL NUMBER: C77278 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 440.8 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:13 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT () ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 22.4307 ------------- 5.0886 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) ..................... -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: IS ANIHAL NUMBER: C77279 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 450.7 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 11:07 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%> ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 20.6890 ------------- 4.5904 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) ..................... Ch -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 16 ANIMAL NUMBER: C77281 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 441.4 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 11:00 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 21.3918 ------------- 4.8464 % ------------- -------------- ..... WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * G R O S S P A T H O L O G Y O B S E R V A T I O N S *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES oo GENERAL COMMENT (GC) .................... 0\ -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM B o szo o Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 17 ANIMAL NUMBER: C77283 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 413.4 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:53 PROSECTOR: NANCY DIEDRICH RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 20.9047 ------------- 5.0568 % ----------- -- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME ** G R O S S P A T H O L O G Y O B S E R V A T I O N S * * * SEVERITY. KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) .................... -J -NO MACROSCOPIC LESIONS -ABER NEC PERFORM > N in Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 18 ANIMAL NUMBER; C77284 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 436.5 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:26 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKBR ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LIO) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 21.2416 ------------- 4.8663 % ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) ................... OO -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM 0TS2O D Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 19 ANIMAL NUMBER: C77286 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 419.5 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 11:00 PROSECTOR: DEBBIE PIRKEL RECORDER: DEBBIE PIRKEL POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 24.6307 ------------- 5.8714 % ------------- ...... ------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OO GENERAL COMMENT (GC) .................... O -NO MACROSCOPIC LESIONS -ABBR NEC PERFORM C'0251 Corning Hazleton Inc. Hadison, Wisconsin USA APPENDIX D Individual Animal Pathology Data Day 20 Sacrifice CHW 6329-197 PAGE: 20 ANIMAL NUMBER: C77287 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 01/21/97 STUDY DAY OF DEATH: 20 STUDY WEEK OF DEATH: 3 TERMINAL BODY WEIGHT: 411.2 GRAMS DATE AND TIME OF NECROPSY: 01/21/97 10:47 PROSECTOR: NANCY DIEDRICH RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: TROY ELLENBECKER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS WHOLE LIVER (LI0) RT LAT LOBE LIV (LI1) REMAINING LIV (LI2) 18.9698 ------------- 4.6133 * ------------- ------------------- WEIGHT TAKEN NOT TAKEN NOT TAKEN ORGAN NAME *** G R O S S P A T H O L O G Y O B S E R V A T I O N S * * * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES s GENERAL COMMENT (GC) -ABBR NEC PERFORM KIDNEY (KD) . . . . -LARGE PELVIS(ES) LEFT T0TSZOO