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CXR Biosciences Ltd. James Lindsay Place DUNDEE DD15JJ REPORT 13-WEEK STUDY TO INVESTIGATE THE REVERSIBILITY OF PERFLUOROOCTANE SULFONATE (PFOS)-INDUCED EFFECTS IN MALE SPRAGUE DAWLEY RATS. CXR STUDY NUMBER: Sponsor: Sponsors Representative: Sponsor's study identifier: Sponsor's material identifier: CXR0486s 3M Dr John Butenhoff 3M Medical Department 3M Center Building 220-06-W-08, St. Paul, Minnesota 55144-1000 06-301 MTDID-208 Study Director: Test facility "In Life" Start Date: "In Life" Finish Date: CIRCULATION B M Elcombe, CXR Biosciences CXR Biosciences, James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ. and Biological Sciences Resource Unit (BSRU), Dundee University, Dundee, DD1 5EH. 29thNovember 2006 28lhFebruary 2007 Signed Original: Copies to: Study File/Archives Sponsor Study Director Sponsor Author f t r - - ........ Barbara plconroe, Study Director ' >n } /' Date ] y 22 JjA 28& Date V CXR0486s Final Report Page 1 of 128 P-2 CONTENTS CONTENTS................................................................................................................................. 2 SUM M ARY................................................................................................................................. 4 1. INTRODUCTION................................................................................................................... 7 2. ANIMALS (Scientific Procedures) ACT 1986 COM PLIANCE......................................7 2.1 Licensee Responsibilities..................................................................................................... 8 3. MATERIALS AND M ETH ODS.......................................................................................... 8 3.1 Test Substances..................................................................................................................... 8 3.2 Safety Precautions................................................................................................................. 8 3.3 D iet.......................................................................................................................................... 8 3.4 A nim als.................................................................................................................................. 8 3.5 Animal Accommodation and Husbandry...........................................................................9 4. EXPERIMENTAL DESIGN................................................................................................. 9 5. EXPERIMENTAL PROCEDURES.................................................................................. 10 5.1 Bodyw eight........................................................................................................................ 10 5.2 Clinical Observations..........................................................................................................10 5.3 Food Consum ption.............................................................................................................. 10 5.4 Intercurrent D eaths.............................................................................................................. 10 5.5 Terminal Procedures......................................................................................................... 11 6. BIOCHEMICAL M EASUREM ENTS............................................................................. 11 6.1 Clinical Chemistry............................................................................................................. 11 6.2 Peroxisome Proliferation................................................................................................... 12 6.3 DNA Content of Liver........................................................................................................ 12 6.4 Total Cytochrome P 4 5 0 .................................................................................................... 12 6.5 Laurie Acid 12-Hydroxylation (L A H )............................................................................ 12 6.6 Pentoxyresorufm-O-depentylation (PROD).....................................................................12 6.7 Testosterone 6P-Hydroxylation......................................................................................... 12 6.8 Protein Determ ination.........................................................................................................12 6.9 Statistical A nalysis.............................................................................................................. 13 6.10 Additional A nalyses......................................................................................................... 13 7. HISTOPATHOLOGY...........................................................................................................13 8. SPECIMEN SH IPM EN T.................................................................................................... 13 9. PROTOCOL AMENDMENTS........................................................................................... 13 10. RESULTS............................................................................................................................. 13 10.1 Bodyweights, Food Consumption and Liver W eights..................................................13 10.1.1 Bodyweights....................................................................................................................13 10.1.2 Food consumption.......................................................................................................... 15 10.1.3 Liver weights...................................................................................................................15 10.2 Clinical Chemistry............................................................................................................ 18 10.3 Liver Biochemistry............................................................................................................23 10.3.1 DNA content of liver.....................................................................................................23 10.3.2 Peroxisome proliferation.............................................................................................. 25 10.3.3 Total cytochrome P450 content of liver..................................................................... 26 10.3.4 Laurie acid hydroxylation............................................................................................ 27 10.3.5 Pentoxyresorufm-O-depentylation.............................................................................. 28 10.3.6 Testosterone hydroxylation.......................................................................................... 29 10.4 Histopathology.................................................................................................................. 30 10.4.1 Liver H & E.......................................................................................................................30 10.4.2 Hepatic A poptosis......................................................................................................... 30 CXR0486s Final Report Page 2 of 128 P-3 10.4.3 Cell proliferation in liver............................................................................................... 31 10.4.4 Thyroid H& E...................................................................................................................32 10.4.5 Thyroid in situ cell death............................................................................................... 32 10.4.6 Cell proliferation in thyroid.......................................................................................... 32 11. D ISCUSSIO N...................................................................................................................... 34 12. DATA STORAGE AND ARCH IV IN G.......................................................................... 34 13. REPORT................................................................................................................................ 34 14. QUALITY A SSU R A N CE................................................................................................. 34 15. STUDY DIRECTORS STATEMENT............................................................................. 34 APPENDIX 1. PATHOLOGY R E PO R T.............................................................................. 35 CXR0486s Final Report Page 3 of 128 P-4 SUMMARY The mean ingested doses of Test Items calculated for the 7 days of administration were: 1.93 0.01 (PFOS 20ppm) and 9.65 0.08 (PFOS lOOppm) mg Test Item / kg bwt / day. No adverse clinical observations were made throughout the study. Administration of dietary PFOS (20ppm or lOOppm) to rats for 7 days did not affect body weights. Absolute liver weights were increased following exposure to PFOS lOOppm for 7 days, reaching 115% of control values. After 28 days on control diet, following exposure to PFOS 20ppm for 7 days, absolute liver weights were decreased to 87% of control values. Relative liver weights were increased following exposure to both PFOS 20ppm and PFOS lOOppm for 7 days to approximately 112% and 120% of control values, respectively. After 28 and 56 days receiving control diet relative livers weights had returned to control values. However, after 84 days on control diet, following exposure to both dietary concentrations of PFOS, relative liver weights were again increased, to approximately 113% of control values. The biological significance, if any, of this is unclear. A lack of overt hepatotoxicity was indicated for all compounds by the absence of toxicologically significant increases in plasma ALT and AST. Mean plasma cholesterol concentrations were decreased, in a dose dependant manner, by PFOS 20ppm and PFOS lOOppm after 7 days of treatment. Following a return to control diet for 28 days, plasma cholesterol concentrations were still decreased in a dose dependant manner. After 56 days reversal, cholesterol concentrations had recovered to near control levels in animals administered both concentrations of PFOS; however plasma cholesterol concentrations were still decreased after 84 days reversal in animals treated with PFOS lOOppm. Administration of PFOS lOOppm to rats for 7 days led to a small increase (127% of control) in hepatic peroxisomal (3-oxidation, as determined by measurement of CNinsensitive palmitoyl CoA oxidation (PCO). This increase was maintained after 28 and 56 days return to control diet. Eighty-four days after withdrawal of PFOS lOOppm, PCO activity was returning to control levels. Administration of PFOS 20ppm did not increase PCO activity. Administration of PFOS 20ppm and PFOS lOOppm to rats for 7 days resulted in CXR0486s Final Report Page 4 of 128 P-5 marked increases in hepatic total P450, in a dose dependent manner, to 124% and 190% of control values, respectively. Reversal to control diet for up to 84 days had no effect on the increased hepatic total P450 content. Laurie acid 12-hydroxylation (12-OH LAH) is used as a marker for cytochrome P450 4A activity. PFOS administration at 20ppm had no effect on 12-OH LAH after 7 days on diet, whilst administration at lOOppm increased the 12-OH LAH by approximately 2-fold after 7 days on diet, and 3-fold after 28 and 56 days on control diet (Table 15). After 84 days on control diet, however, 12-OH LAH activity had returned to control values. Pentoxyresorufin-O-depentylation (PROD) is used as a marker for cytochrome P450 2B activity. PFOS administration at 20ppm initially decreased the PROD activity by approximately half the control value after 7 days on diet. Reversal to control diet for up to 84 days had no effect, and the decrease in activity was maintained throughout. PFOS administration at lOOppm increased the PROD activity by approximately 3.5fold after 7 days on diet. Reversal to control diet resulted in increased activity of approximately 1.5-fold relative to control values after 28 days; a return to control values after 56 days; and a decrease of approximately half the control value after 84 days. The decreases in PROD are believed to be incidental and not of biological significance. Testosterone 6p-hydroxylation (Test-6p-OH) is used as a marker for cytochrome P450 3A activity. PFOS administration at 20ppm had no effect on the Test-6p-OH activity until, after 84 days on control diet, a slight increase was seen. This is not considered to be biologically significant. PFOS administration at lOOppm initially increased the Test-6p-OH activity by 2.3-fold after 7 days on diet. Reversal to control diet resulted in a return to control values after 28 days followed by an increase in activity of approximately 2.2- and 1.9-fold after 56 days and 84 days, respectively. In the liver, histopathology revealed slightly decreased glycogen vacuolation in animals treated with 20ppm and lOOppm PFOS at each sacrifice period. A minimal to moderate, centrilobular hepatocellular hypertrophy was noted, dose ; related in severity, in animals treated with 20ppm PFOS and lOOppm PFOS for 7 days. This finding was still present after a 4-, 8- or 12-week treatment-free recovery period. An unequivocal difference in the severity and incidence of this finding between the various recovery periods was not observed, indicating an incomplete reversibility during the various recovery periods used. Administration of PFOS 20ppm and PFOS lOOppm for 7 days decreased the hepatic apoptotic index to approximately 70% and 40% of control values, respectively. Reverting to control diet did not reverse this decrease in hepatic apoptotic index, and CXR0486s Final Report Page 5 of 128 P-6 the decrease continued, reaching a minimum of 30% of control values after 84 days for PFOS 20ppm treated animals, and 20% of control values after 56 days for PFOS lOOppm treated animals. PFOS 20ppm and PFOS lOOppm administration for 7 days both increased the hepatocellular labelling index (S-phase) by 2.5- and 5.9-fold, respectively. Reversal to control diet resulted in a return to control values after 28 days. In the thyroid gland, no microscopic findings considered to be related to the treatment with the test items were recorded. The number of apoptotic cells found in all treatment groups, at all time points, was minimal. Regardless of treatment, it was usual to find either no cells or just one cell per thyroid staining in the TUNEL assay as apoptotic. 20ppm PFOS and lOOppm PFOS treatment had no effect on thyroid S-phase activity at any time point studied. CXR0486s Final Report Page 6 of 128 p.7 1. INTRODUCTION A variety of non-genotoxic chemicals elicit hepatocellular adenomas and carcinomas when administered to rats in long-term studies. The appearance of tumours is preceded by the rapid and early stimulation of hepatomegaly. The liver enlargement seen following the administration of such "liver growth carcinogens" to rats is a result of both hypertrophy and hyperplasia. Depending on the particular chemical, the hypertrophy in characterised by proliferation of peroxisomes and/or smooth endoplasmic reticulum, induction of peroxisomal enzymes and induction of cytochrome P450 isoforms. The hyperplasia is characterised by stimulation of hepatocellular proliferation (S-phase, labelling index) and inhibition of apoptosis. PFOS has previously been shown to elicit marked liver growth in rats, and this study aims to characterise the reversibility of this hepatomegaly in these terms. The reversibility of thyroid effects, following the administration of PFOS to rats, will also be investigated. This study used liver, serum, thyroid and duodenal (for assessing BrdU labelling) samples generated over a time course including exposure for 7 days followed by withdrawal of treatment for 4, 8 and 12 weeks. The following parameters were studied: Bodyweights Liver weights (relative and absolute) Clinical chemistry (5 parameters). Haematoxylin and eosin (H&E) histopathology (liver and thyroid) Apoptotic indices analysed using the TUNEL assay (liver and thyroid) BrdU incorporation analysed as a measure of cell proliferation (liver and thyroid) The DNA content of liver was measured using the diphenylamine reaction Acyl CoA oxidase activity was determined in liver heavy pellets as CN'-insensitive palmitoyl CoA oxidation Total P450 content was determined in liver microsomes Laurie acid hydroxylation (LAH, CYP4A) was determined in liver microsomes Pentoxyresorufin-O-depentylation (PROD, CYP2B) was determined in liver microsomes Testosterone hydroxylation (CYP 3A) was determined in liver microsomes 2. ANIMALS (Scientific Procedures) ACT 1986 COMPLIANCE The in-life procedures undertaken during the course of this Study were subject to the provisions of the United Kingdom Animals (Scientific Procedures) Act 1986. The Act, administered by the UK Home Office, regulates all scientific procedures in living animals which may cause pain, suffering, distress or lasting harm and provides for the designation of CXR0486s Final Report Page 7 of 128 p.8 establishments where procedures may be undertaken, the licensing of trained individuals who perform the practical techniques, and the issue of project licences for specified programmes of work. This Study complied with all applicable sections of the Act and the associated Codes of Practice for the Housing and Care of Animals used in Scientific Procedures and the Humane Killing of Animals under Schedule 1 to the Act, issued under section 21 of the Act. 2.1 Licensee Responsibilities The procedure performed was PD1 as detailed in the PD project licence (60/3005). The severity limit for this procedure is MODERATE. Mr F Simeons returned the animals at the start of the study under the PD project licence. 3. MATERIALS AND METHODS 3.1 Test Substances Perfluorooctane sulfonate potassium salt (PFOS K \ Lot no. 217, purity 87.6%), supplied by 3M Company, St. Paul Minnesota, USA, was a white powder. It was handled, and its identity verified, according to CXR Biosciences SOP 0010. This SOP describes routine procedures for the receipt, identification, labelling, handling, sampling and storage of Test and Reference Items. These procedures are implemented to ensure that: Test and Reference Items used are those Items specified in Study Protocols. Handling and storage of Test and Reference Items preserves their identity and integrity during use. 3.2 Safety Precautions The normal safety precautions as detailed in the relevant Sop's and COSHH assessments were applied, no additional precautions were considered necessary. 3.3 Diet RM1 powdered diet (Special Diet Services Ltd., Stepfield, Witham, Essex, UK) was used; Biological Sciences Resource Unit (BSRU) hold the specification of the diet. The Sponsor requested the dietary route of administration. The test diets, containing 20ppm PFOS or lOOppm PFOS, were prepared by CXR Biosciences (Laboratory Method Sheet [LMS] TSC-002) and samples were retained for analysis by the Sponsor. Rats were fed RM1 powdered diet or test diets ad libitum throughout the study. 3.4 Animals A sufficient number of male 6-7 week old Charles River Sprague Dawley (CD) rats were obtained from Charles River, UK. On arrival in the BSRU the rats were housed 2 per cage on sawdust in solid -bottom, polypropylene cages. The rats were acclimatised for a period of at CXR0486s Final Report Page 8 of 128 P-9 least 5 days before use. No animals were excluded from the study. Environmental enhancing additions were not used in the cages prior to the start of the Study. The Sprague Dawley (CD) rat was the test system of choice for this study because previous work on PFOS has been undertaken using this strain. In addition, CXR Biosciences has extensive experience in the use of this strain of rat, and the strain is well accepted by the regulatory authorities. 3.5 Animal Accommodation and Husbandry The environment was controlled in the animal room to provide conditions suitable for the Sprague Dawley (CD) strain of rat. The temperature was maintained within a range of 1923C and relative humidity within a range of 40-70%. There were a nominal 14-15 air changes per hour. Twelve-hour periods of light were cycled with twelve-hour periods of darkness. Drinking water was taken from the local supply and provided in bottles. Drinking water was provided ad libitum prior to and throughout the study. Prior to the start of the study the rats were allowed powdered RM1 diet ad libitum. 4. EXPERIMENTAL DESIGN The animals were uniquely numbered by ear-punch and randomly allocated to groups up to one week after arrival. An experimental card was placed on each cage and showed the project licence code, treatment group, study number, sex and individual numbers of the rats within, and identified the Home Office Licensee. In addition, these cards were colour coded to correlate with the coding for the treatment group on the diet boxes and jars. The study consisted of one control and two test groups, each containing 40 male animals. Control animals received powdered RM1 diet ad libitum for the duration of the study. The test groups of animals were administered either 20ppm or lOOppm PFOS in the diet ad libitum for 7 days. On Day 8 the test diets were withdrawn and all animals were administered powdered RM1 diet ad libitum for the remainder of the study. The dietary concentrations of PFOS were prepared with purity correction. The corresponding PFOS concentrations in the . powdered RM1 diet will be analyzed by the Sponsor. Ten animals from each group were sacrificed on days 8, 36,64 and 92. Animals were implanted with osmotic pumps (Alzet 2ML1) containing bromodeoxyuridine (BrdU, 15mg/mL in phosphate buffered saline [PBS], pH7.4) 5 days before termination, whilst still receiving the treatment regimen (Table 1). CXR0486s Final Report Page 9 of 128 TABLE 1 EXPERIMENTAL DESIGN Group 1 2 3 Colour code Blue Green Yellow Animal No 1 - 10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91 - 100 101 - 110 111-120 Treatment Control Arrival 21/11/06 PFOS 20ppm 21/11/06 PFOS 21/11/06 lOOppm Dates Start 29/11/06 29/11/06 29/11/06 Implant 01/12/06 29/12/06 26/01/07 23/02/07 01/12/06 29/12/06 26/01/07 23/02/07 01/12/06 29/12/06 26/01/07 23/02/07 Kill 06/12/06 03/01/07 31/01/07 28/02/07 06/12/06 03/01/07 31/01/07 28/02/07 06/12/06 03/01/07 31/01/07 28/02/07 5. EXPERIMENTAL PROCEDURES 5.1 Bodyweight The bodyweight of each rat was recorded at the start of the study. The animals were weighed weekly on the same day of the week. All animals were weighed prior to termination. Bodyweights were recorded electronically and records of the weights were stored in the Study File. 5.2 Clinical Observations Prior to the start of the study, all rats were observed to ensure that they were physically normal and that they exhibited normal activity. Each rat was observed at least once daily during the study. Clinical abnormalities of individual animals were recorded in the Study Diary. This was kept in the BSRU until completion of the in life phase of the study and then transferred to the Study File for retention and archiving. 5.3 Food Consumption Food consumption was measured every time the diet jars were changed / refilled, and when the animals were sacrificed, for the first week of the study so that food consumption could be recorded. Following reversion to control diet on Day 8, food consumption was not recorded. 5.4 Intercurrent Deaths There were no rats requiring euthanasia during the study, nor were there any intercurrent deaths. CXR0486s Final Report Page 10 of 128 5.5 Terminal Procedures On the day of termination the rats were weighed and transferred to the post mortem room. The rats were killed by exposure to a rising concentration of CO2. Approximately 6 to 10 mL of venous blood was taken by cardiac puncture and dispensed at equal volume into uncoated tubes (to obtain serum) and lithium/heparin-coated tubes (to obtain plasma). The tubes were mixed on a roller for 10 min then cooled on ice. Serum and plasma were prepared by centrifugation (2,000 rpm for 10 min at 8 - 10C) then stored at approximately -70C pending analysis. The pellet was discarded. The liver was removed from each animal and weighed. 2 samples of liver, approximately 2mm strips, were taken, one from the Left lobe and one from the Median lobe. These were placed in 10% neutral buffered formaldehyde (NBF), for approximately 48hours, for BrdU immunohistochemistry and analysis of the apoptotic index. 2 samples of liver, approximately 2mm strips, were taken, one from the Left lobe and one from the Median lobe. These were placed in NBF, for at least 1 week, for H&E histopathology. 1 sample of liver, of approximately 0.25g, was weighed and then flash frozen in liquid nitrogen then stored at approximately -70C for DNA determination. 2 samples of liver, of approximately lg each, were flash frozen in liquid nitrogen then stored at approximately -70C prior to dispatch, on dry ice, to the Sponsor for further analytical determination under a separate protocol The remainder of the liver was weighed and scissor-minced in ice-cold 1.15% (w/v) KC1 prior to subcellular fractionation according to Laboratory Method Sheet (LMS) Cent-001. Samples of homogenate, heavy pellet and microsomes were stored at approximately -70C prior to analysis. Samples of cytosol were stored at approximately -70C prior to dispatch, on dry ice, to the Sponsor for further analytical determination under a separate protocol. 1 sample of duodenal small intestine, of approximately 1cm, was taken and placed in NBF, for approximately 48 hours, as a positive control for BrdU immunohistochemistry. The thyroid was removed from each animal, including the parathyroid gland together with trachea and oesophagus. This tissue was placed in NBF, for approximately 48 hours, for BrdU immunbhistochemistry, analysis of the apoptotic index and H&E histology. 6. BIOCHEMICAL MEASUREMENTS 6.1 Clinical Chemistry Plasma samples, prepared as described' above, were assayed for ALT, AST, cholesterol, CXR0486s Final Report Page 11 of 128 glucose and triglycerides using a Roche Integra 400 automated analyser according to the manufacturer's instructions. System control samples and calibration standards were those supplied by the manufacturer. Results were maintained in the Study File. 6.2 Peroxisome Proliferation CN' -insensitive acyl CoA oxidation was determined spectrophotometrically in liver heavy pellet, using palmitoyl CoA as a substrate, according to LMS Spec003. Results were expressed as nmol NAD+ reduced/min/mg protein. Results were maintained in the Study File. 6.3 DNA Content of Liver The DNA content of liver was measured spectrophotometrically in whole tissue using the diphenylamine reaction, according to LMS Spec005. Results were expressed as pg DNA/g liver and mg DNAAvhole liver. Results were maintained in the Study File. 6.4 Total Cytochrome P450 The total cytochrome P450 content of liver microsomes was determined by measuring the carbon monoxide difference spectrum of ferrocytochrome P450 according to LMS Spec002. Results were expressed as nmol total P450/mg protein. Results were maintained in the Study File. 6.5 Laurie Acid 12-Hydroxylation (LAH) The activity of CYP4A in liver microsomes was determined using lauric acid and LC-MSMS. Results were expressed as nmols 12-OH lauric acid formed/lOminutes/mg protein. Results were maintained in the Study File. 6.6 Pentoxyresorufin-O-depentylation (PROD) The activity of CYP2B in liver microsomes was determined spectrofluorometrically by the formation of resorufm from pentoxyresorufin, according to LMS Fluor-002. Results were expressed as pmols resorufm formed/minute/mg protein. Results were maintained in the Study File. 6.7 Testosterone 6|i-Hydroxylation The activity of CYP3A in liver microsomes was determined by HPLC followed by UV detection, according to LMS HPLC-006. Results were expressed as nmols hydroxytestosterone formed/minute/mg protein. Results were maintained in the Study File. 6.8 Protein Determination The protein concentration of tissue heavy pellets and microsomes was determined in aqueous solutions using a modification of the method of Lowry et a i, (1951) and bovine serum albumin standards, according to LMS SpecOOl. Results were maintained in the Study File. CXR0486s Final Report Page 12 of 128 6.9 Statistical Analysis Statistical comparisons between treated and control groups have been undertaken for all numerical data sets. The statistical analyses performed are documented with the results. 6.10 Additional Analyses The Sponsor has requested no additional analyses. 7. fflSTOPATHOLOGY Following fixation, all fixed liver and thyroid samples were processed, embedded and 5 pM sections cut according to LMS Pat-005, Pat-006 and Pat-007. Sections were: Stained using H&E, according to LMS Pat-010, Pat-011 and Pat-012. Analysed for in situ cell death. The method used was an indirect TUNEL labelling assay, according to LMS Pat-014. Analysed for BrdU incorporation as a measure of cell proliferation. The method used was an indirect BrdU labelling assay, according to LMS Pat-008. H&E sections were evaluated by Dr. med. vet. Ortwin Vogel, GoethestraBe 26, 24116 Kiel, Schleswig-Holstein, Deutschland. The histopathology report was maintained in the Study File and as an appendix to the Study Report. 8. SPECIMEN SHIPMENT The powdered RM1 diets, cytosol, serum, and the liver samples designated for further analytical determination by the Sponsor were shipped on dry ice and sent to: Dave Ehresman 3M Company 3M Center Building 236-C148 St. Paul, MN 55144 9. PROTOCOL AMENDMENTS There were no changes to the protocol, and no Protocol Amendments have been signed by the Study Director. 10. RESULTS 10.1 Bodyweights, Food Consumption and Liver Weights. 10.1.1 Body>veights. r Administration of dietary PFOS (20ppm) to rats for 7 days followed by 28 days on control CXR0486s Final Report Page 13 of 128 diet lead to decreased body weights (Table 2). This effect was not deemed toxicologically significant. No adverse clinical observations accompanied the decreased body weights. Table 2. Terminal Bodyweights Days on diet/reversal Oppm Bodyweight (g) PFOS 20ppm PFOS lOOppm 7/0 296.4130. l a 286.5134.1 282.0132.5 (100 1 10.2) (96.7111.5) (95.1111.0) 7/28 423.3 46.0 382.2130.8* 378.2159.9 (100 10.9) (90.317.3) (89.4114.1) 7/56 504.3161.4 456.1157.8 476.6132.8 (100 12.2) (90.5111.5) (94.5 16.5) 7/84 557.8 78.7 524.3189.5 509.8154.1 (100 14.1) (94.01 16.1) (91.419.7) d Values are Mean SD. Values in parenthesis are mean % control 1 SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** p<0.001. Terminal Bodyweights Control ! PFOS 20ppm , a PFOS 10Oppm i a O) 400 7 Days on test diet 28 Days reversal 56 Days re\ersal Days on diet 84 Days reversal CXR0486s Final Report Page 14 of 128 10.1.2 Food consumption. The food consumption of the PFOS 20ppm and PFOS lOOppm-treated rats were essentially the same as control values throughout the experimental period (Table 3.). When diet consumption was calculated per unit body weight, the PFOS 20ppm and PFOS lOOppm-treated rats were essentially the same as control values throughout the experimental period. Table 3. Food Consumption Days on diet Oppm PFOS 20ppm PFOS lOOppm Diet consumed (g) / Rat / Week 7 194.1 12.7 191.7 15.1 188.8 23.1 (100 6.5) (98.7 7.8) (97.3 11.9) Diet consumed (g) / Kg Bwt / Day 7 94.2 3.6 96.7 4.4 96.5 8.0 (100 3.78) (102.6 4.7) (102.5 8.5) Test Item Consumption: mg Test Item / Kg Bwt / Day 7 00 1.93 0.01 9.65 0.08 a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; ** p<0.01; *** p<0.001. 10.1.3 Liver weights. Absolute liver weights were increased following exposure to PFOS lOOppm for 7 days, reaching 115% of control values (Table 4). After 28 days on control diet, following exposure to PFOS 20ppm for 7 days, absolute liver weights were decreased to 87% of control values. Table 4. Absolute Liver Weights Liver weight (g) Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 13.40 1.38a 14.45 1.71 15.42 1.85* (100 10.31) (107.86 12.78) (115.08 13.80) 7/28 18.04 2.88 15.76 1.24* 17.46 3.46 (100 15.95) (87.36 6.86) (96.80 19.18) 7/56 20.19 2.61 18.23 3.48 19.19 1.76 (100 12.92) (90.30 17.23) (95.07 8.73) 7/84 20.23 3.40 21.56 5.20 21.03 2.74 (100 16.79) (106.58 25.72) (103.95 13.55) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.OOl. CXR0486s Final Report Page 15 of 128  Control PFOS 20ppm PFOS 100ppm 84 Days reversal After normalisation with respect to bodyweight, relative liver weights were increased following exposure to both PFOS 20ppm and PFOS lOOppm for 7 days to approximately 112% and 120% of control values, respectively (Table 5). After 84 days on control diet, following exposure to both dietary concentrations of PFOS, relative liver weights were again increased, to approximately 113% of control values. Table 5. Liver/bodyweight ratio (%) Liver/bodyweight ratio (%) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 4.53 0.29a 5.0610.38** 5.4810.36*** (10016.46) (111.7318.40) (120.9117.86) 7/28 4.2510.34 4.0710.34 4.6110.44 (10018.12) (95.7118.02) (108.50110.27) 7/56 4.0210.36 3.9810.38 4.0310.27 (10019.05) (99.0319.58) (100.2716.68) 7/84 3.6310.39 4.0910.51* 4.1210.25** (1001 10.62) (112.781 14.03) (113.5817.01) a Values are Mean 1 SD. Values in parenthesis are mean % control 1 SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.OOl. CXR0486s Final Report Page 16 of 128 Liver/bodyweight ratio (%) 7 6 5 4 3 2 1 0 7 Days on test diet Relative Liver Weights 28 Days reversal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 17 of 128 10.2 Clinical Chemistry The lack of overt hepatotoxicity was indicated by the absence of toxicologically significant increases in plasma ALT and AST (Tables 6 and 7). Table 6. Plasma Alanine Aminotransferase Activity Days on diet/reversal 7/0 Oppm 110.60 18.64a ALT (U/L) PFOS 20ppm 93.97 10.47* PFOS lOOppm 90.04 16.66* (100 16.86) (84.96 9.47) (81.41 15.06) 7/28 110.32 17.16 117.56 54.52 102.78 22.45 (100 15.56) (106.56 49.42) (93.17 20.35) 7/56 90.54 15.55 89.07 22.47 103.85 29.44 (100 17.18) (98.38 24.82) (114.70 32.52) 7/84 84.15 16.68 84.82 18.03 99.36 36.44 (100 19.83) (100.80 21.42) (118.07 43.31) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** pcO.OOl. Plasma ALT 7 Days on test diet 28 Days reversal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 18 of 128 Table 7. Plasma Aspartate Transaminase Activity AST (U/L) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 102.25 12.09a 103.94 10.47 109.97 12.75 (100 11.83) (101.65 10.24) (107.55 12.47) 7/28 168.98 38.11 151.51 58.79 136.02 28.85* (100 22.55) (89.66 34.79) (80.49 17.07) 7/56 124.75 24.75 128.30 26.87 120.31 22.49 (100 19.84) (102.85 21.54) (96.44 18.03) 7/84 184.34 44.30 186.13 40.44 177.97 66.32 (100 24.03) (100.97 21.94) (96.54 35.98) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** pcO.OOl. 300 T ----------------------------------------- ----------------- - - - - Plasma AST - ------------------ 250 f - ------------------------------ - Control ; PFOS 20ppm I PFOS lOOppm ! 200 7 Days on test diet 28 Days reversal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 19 of 128 Mean plasma cholesterol concentrations were decreased, in a dose dependant manner, by PFOS 20ppm and PFOS lOOppm after 7 days of treatment (Table 8). Following a return to control diet for 28 days, plasma cholesterol concentrations were still decreased in a dose dependant manner. After 56 days reversal, cholesterol concentrations were recovered to near control levels in animals administered both concentrations of PFOS; however this recovery was not present after 84 days reversal in animals treated with PFOS lOOppm. Table 8. Plasma Total Cholesterol Concentration Total Cholesterol (mmol/L) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 2.73 0.44a 2.1710.37** 1.7710.39*** (100116.16) (79.63113.49) (64.84114.15) 7/28 2.29 0.24 1.6110.33*** 1.4310.44*** (100110.49) (70.19114.30) (62.59119.26) 7/56 2.1910.35 1.9610.26 2.0010.37 (100115.93) (89.441 11.77) (91.36116.87) 7/84 2.1710.36 1.9810.40 1.7510.38* (100116.68) (91.371 18.49) (80.70117.63) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** pcO.OOl. 3 5 y --------- ------------ ---------- - ------------3.0 * Plasma Cholesterol Control PFOS 20ppm PFOS 100ppm 2.5 g 2.0 o o2 1 .5 ----- 1.0 ! I 0.5 0.0 i- 28 Days reversal 56 Days re\rsal Days on diet 84 Days reversal CXR0486s Final Report Page 20 of 128 Mean plasma glucose concentrations showed only one significantly different value after 56 days reversal following 7 days of PFOS at lOOppm (Table 9). This is not considered to be biologically significant. Table 9. Plasma Glucose Concentration Glucose (mmol/L) Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 22.51 3.47a 22.92 3.58 22.26 2.93 (100 15.44) (101.82 15.90) (98.92 13.02) 7/28 19.98 3.75 19.43 4.98 20.40 2.81 (100 18.76) (97.28 24.94) (102.12 14.06) 7/56 17.87 2.67 19.34 2.82 23.18 3.29*** (100 14.96) (108.24 15.77) (129.71 18.44) 7/84 18.43 2.24 17.70 2.20 19.86 2.21 (100 12.17) (96.02 11.92) (107.76 11.97) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. a Control PFOS 20ppm PFOS lOOppm CXR0486s Final Report 84 Days resersal Page 21 of 128 After 7 days on diet there was a marked reduction in mean plasma triglyceride levels following administration of lOOppm PPFOS. The mean plasma triglyceride concentrations recovered to near control levels upon reversal to control diet (Table 10). Table 10. Plasma Triglyceride Concentration Days on diet/reversal Oppm Triglycerides (mmol/L) PFOS 20ppm PFOS lOOppm 7/0 1.51 0.44a 1.58 0.53 1.02 0.41* (100 28.92) (104.65 35.48) (67.44 27.17) 7/28 1.72 0.74 1.32 0.32 1.26 0.24 (100 43.17) (76.92 18.60) (73.31 13.84) 7/56 1.70 0.63 2.02 0.70 1.26 0.34 (100 36.74) (118.81 41.38) (74.25 19.80) 7/84 1.66 0.50 2.35 0.99 1.58 0.65 (100 30.09) (141.35 59.47) (95.02 39.18) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. Plasma Triglycerides Control PFOS 20ppm , PFOS 100ppm 2.5 7 Days on test diet 28 Days reusrsal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 22 of 128 10.3 Liver Biochemistry 10.3.1 DNA content of liver The mean hepatic concentration of DNA was decreased by PFOS 20ppm and PFOS lOOppm treatments after 7 days on diet. Upon reversal to control diet, PFOS 20ppm treated animals recovered to near control levels after 28 days, whilst PFOS lOOppm treated animals did not recover to this level until 84 days (Table 11). Table 11. Liver DNA Concentration (mg DNA/g liver) Liver DNA (mg/g liver) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 2.253 0.163a 2.04310.165* 1.66910.406*** (10017.23) (90.6517.34) (74.07118.04) 7/28 2.17910.132 2.10910.339 1.56210.355*** (100 1 6.04) (96.771 15.56) (71.69116.28) 7/56 2.16210.504 1.844 1 0.259 1.65510.325* (100123.30) (85.281 11.96) (76.52115.03) 7/84 1.91510.226 1.91810.408 1.74010.153 (100111.78) (100.12121.28) (90.87 1 7.97) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** p<0.001. 3.0 j --------------- -- - Liver DNA concentration (mg DNA/g liver) ___________ __________ __________ __________ _____________ _______________ Control __ PFOS 20ppm PFOS lOOppm 7 Days on test diet 28 Days reversal Days on diet 56 Days reversal CXR0486s Final Report Page 23 of 128 84 Days reversal Although neither PFOS administration at 20ppm nor lOOppm decreased the total liver content of DNA after 7 days on diet, upon reversal to control diet they both decreased the total liver content of DNA after 28 and 56 days of reversal. A return to control levels was seen after 84 days on control diet for both dose levels (Table 12). Table 12. Total Liver DNA Content (mg DNA/whole liver) Liver DNA (mg/whole liver) Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 30.21 3.95a 29.43 3.33 25.59 6.37 (100 13.08) (97.43 11.02) (84.72 21.09) 7/28 39.10 5.30 31.71 3.74** 26.83 6.27*** (100 13.56) (81.09 9.57) (68.61 16.03) 7/56 43.45 10.91 33.14 5.09* 32.10 8.08* (100 25.10) (76.26 11.72) (73.87 18.59) 7/84 38.80 7.55 40.44 9.99 36.91 4.37 (100 19.45) (104.22 25.74) (95.12 11.25) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. Total liver DNA content (mg DNA/whole liver) Control PFOS 20ppm PFOS 100ppm 7 Days on test diet 28 Days reversal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 24 of 128 10.3.2 Peroxisome proliferation Administration of PFOS lOOppm to rats for 7 days followed by up to 84 days reversal on control diet resulted in marked increases in hepatic peroxisomal (3-oxidation, as determined by measurement of CN-insensitive palmitoyl CoA (PCO) oxidation, at all time points studied. Administration of PFOS 20ppm, however, had no effect or a slight decrease in PCO (Table 13). Table 13. Hepatic Cyanide-insensitive Palmitoyl CoA Oxidation (PCO) PCO (nmol NAD+ reduced/minute/mg protein) Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 11.51 1.10* 9.64 2.09* 14.66 2.37** (100 9.59) (83.73 18.15) (127.31 20.57) 7/28 15.31 1.57 14.67 2.71 21.63 2.01*** (100 10.25) (95.77 17.67) (141.24 13.16) 7/56 16.49 1.87 16.23 1.40 21.40 1.53*** (100 11.34) (98.44 8.48) (129.80 9.28) 7/84 15.17 1.51 13.20 2.18* 16.47 1.21* (100 9.97) (86.99 14.36) (108.59 7.99) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.OOl. PCoA Oxidation 25 -[------------------------------- - - -------------------------------------- -- -------------------------- - - 20 1 P Control 1 PFOS 20ppm I PFOS 100ppm 1 I 7 Days on test diet 28 Days reversal 56 Days reversal 84 Days reversal CXR0486s Final Report Page 25 of 128 10.3.3 Total cytochrome P450 content of liver Administration of PFOS 20ppm and PFOS lOOppm to rats resulted in marked increases in hepatic total P450. Administration of PFOS increased total P450 in a dose dependent manner. Reversal to control diet for up to 84 days had no effect on hepatic total P450 content (Table 14). Table 14. Hepatic Total P450 Content Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 0.860.12a 1.07 0.24* 1.63 0.17*** (100 13.90) (123.53 27.82) (189.47 20.09) 7/28 0.65 0.05 0.87 0.17*** 1.33 0.18*** (100 7.70) (134.16 26.38) (205.06 28.35) 7/56 0.68 0.14 0.95 0.16*** 1.12 0.18*** (100 20.27) (139.08 22.86) (164.68 26.70) 7/84 0.60 0.15 0.80 0.12** 1.01 0.11*** (100 25.40) (132.12 19.85) (167.27 18.81) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.OOl. 7 Days on test diet 28 Days reversal 56 Days retrersal Days on diet 84 Days re\ersal CXR0486s Final Report Page 26 of 128 10.3.4 Laurie acid hydroxylation Laurie acid 12-hydroxylation (12-OH LAH) is used as a marker for cytochrome P450 4A activity. PFOS administration at 20ppm had no effect on 12-OH LAH after 7 days on diet, whilst administration at lOOppm increased the 12-OH LAH by approximately 2-fold after 7 days on diet, and 3-fold after 28 and 56 days on control diet (Table 15). After 84 days on control diet, however, 12-OH LAH activity had returned to control values. Table 15. Laurie Acid 12-Hydroxylation Laurie Acid 12 Hydroxylation (nmol/10minutes/mg protein) Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 5.95 2.24" 6.62 2.12 12.28 1.73*** (100 37.62) (111.34 35.65) (206.35 29.09) 7/28 2.40 1.09 2.75 0.48 6.91 2.40*** (100 45.65) (114.96 19.92) (288.53 100.13) 7/56 2.01 0.76 1.89 0.53 5.72 1.92*** (100 38.10) (94.18 26.23) (285.20 95.70) 7/84 2.56 1.16 2.48 0.79 3.41 1.73 (100 45.436) (97.05 31.04) (133.23 67.75) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. 16 Microsomal Laurie Acid 12 Hydroxylation -------------------- -------------------- - - ----------------------------------------------------------------------------------------- Control PFOS 20ppm PFOS 10Oppm CXR0486s Final Report Page 27 of 128 Days reversai 10.3.5 Pentoxyresorufin-O-depentylation Pentoxyresorufm-D-depentylation (PROD) is used as a marker for cytochrome P450 2B activity. PFOS administration at 20ppm initially decreased the PROD activity by approximately half the control value after 7 days on diet. Reversal to control diet for up to 84 days had no effect, and the decrease in activity was maintained throughout (Table 16). PFOS administration at lOOppm increased the PROD activity by approximately 3.5-fold after 7 days on diet. Reversal to control diet resulted in an increase in activity of approximately 1.5fold after 28 days; a return to control values after 56 days; and a decrease of approximately half the control value after 84 days. Table 16. Pentoxyresorufin-O-depentylation Days on diet/reversal 7/0 PROD (pmols resorufm formed/minute/mg protein) Oppm PFOS PFOS 20ppm lOOppm 3.97 1 0.84a 1.9510.61*** 14.3613.51*** (10021.22) (49.191 15.48) (361.52188.35) 7/28 3.1211.12 1.5710.58** 5.061 1.95* (100135.97) (50.161 18.44) (161.99162.37) 7/56 2.6610.54 1.1710.49*** 2.5610.86 (100120.32) (43.991 18.55) (95.91 132.30) 7/84 2.7110.97 1.2010.37*** 1.1810.38*** (100135.86) (44.371 13.77) (43.73 114.05) a Values are N ean 1 SD. Values in parenthesis are mean % control 1 SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.OOl. Pentoxyresorufin-O depentylation Q Control ; PFOS 20ppm ' Q PFOS 10Oppm ! CXR0486s Final Report Page 28 of 128 .... 84 Days reuarsal 10.3.6 Testosterone hydroxylation Testosterone 6(3-hydroxylation (Test-6(3-OH) is used as a marker for cytochrome P450 3A activity. PFOS administration at 20ppm had no effect on the Test-6p-OH activity until after 84 days on control diet. This is not considered to be biologically significant (Table 17). PFOS administration at lOOppm initially increased the Test-6p-OH activity by 2.3-fold after 7 days on diet. Reversal to control diet resulted in a return to control values after 28 days followed by an increase in activity of approximately 2.2- and 1.9-fold after 56 days and 84 days, respectively. Table 17. Testosterone 6p hydroxylation Test-6p-OH (nmols 6P-OH formed/minute/mg protein Days on Oppm PFOS PFOS diet/reversal 20ppm lOOppm 7/0 3.660.93a 4.2411.27 8.4812.34*** (100 25.45) (115.88134.87) (231.87164.06) 7/28 2.920.63 3.4311.20 3.3910.63 (100121.63) (117.51141.17) (116.10121.48) 7/56 2.5410.54 1.6311.35 5.601 1.93*** (100121.29) (64.34153.22) (220.67175.84) 7/84 2.1210.74 2.9710.89* 4.0611.31*** (100134.66) (139.72141.84) (191.09161.70) a Values are fv' ean 1 SD. Values in parenthesis are mean % control 1 SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; *statistically different from control p<0.05; **p<0.01; *** pcO.OOl. 12 r 10 - Microsomal Testosterone 6beta Hydroxylation B Control PFOS 20ppm PFOS 100ppm CXR0486s Final Report 28 Days reversal 56 Days reversal 84 Days reversal Page 29 of 128 10.4 Histopathology 10.4.1 Liver H&E Microscopically, treatment related findings were recorded in the liver. When compared with the control animals, a slight decrease in the usual glycogen induced hepatocellular vacuolation was noted in the animals of the 20ppm and lOOppm PFOS groups at each sacrifice period. Additionally, a minimal to moderate, centrilobular hepatocellular hypertrophy was noted, dose related in severity, in the animals of the 20ppm PFOS and lOOppm PFOS after 7 days of treatment. This finding was still present after a 4-, 8- or 12-week treatment-free recovery period. An unequivocal difference in the severity and incidence of this finding between the various recovery periods was not observed, indicating an incomplete reversibility during the various recovery periods used. 10.4.2 Hepatic Apoptosis Administration of PFOS 20ppm and PFOS lOOppm for 7 days decreased the hepatic apoptotic index to approximately 70% and 40% of control values, respectively. Reverting to control diet did not reverse this decrease in hepatic apoptotic index, and the decrease continued, reaching a minimum of 30% of control values after 84 days for PFOS 20ppm treated animals, and 20% of control values after 56 days for PFOS lOOppm treated animals (Table 18). Table 18. Hepatic Apoptotic Indices Apoptotic Index (%) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 0.22 0.07a 0.15 0.07* 0.09 0.03*** (100 32.73) (69.92 30.44) (41.76 13.93) 7/28 0.23 0.13 0.10 0.04** 0.08 0.03** (100 53.68) (41.79 17.86) (32.68 14.03) 7/56 0.21 0.08 0.10 0.06** 0.04 0.03*** (100 36.82) (47.26 27.49) (19.17 13.62) 7/84 0.23 0.07 0.07 0.05*** 0.07 0.02*** (100 29.79) (30.70 22.55) (29.24 9.73) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. CXR0486s Final Report Page 30 of 128 0.4 0.35 0.3 - - Hepatic Apoptotic Indices Control PFOS 20ppm - PFOS IQOppm 7 Days on test diet 28 Days re\rsal 56 Days reversal Days on diet 84 Days reversal 10.4.3 Cell proliferation in liver PFOS 20ppm and PFOS lOOppm administration for 7 days both increased the hepatocellular labelling index (S-phase) by 2.5- and 5.9-fold, respectively (Table 19). Reversal to control diet resulted in a return to control values after 28 days. Table 19. Hepatic S-phase Labelling Indices Labelling Index (%) Days on diet/reversal Oppm PFOS 20ppm PFOS lOOppm 7/0 1.220.80a 2.83 0.85*** 7.14 3.93*** (100 65.77) (231.97 69.58) (585.99 322.37) 7/28 1.41 0.68 2.44 2.09 1.77 1.13 (100 48.23) (173.23 148.40) (126.01 80.52) 7/56 0.50 0.22 1.00 1.00 0.68 0.54 (100 43.81) (200.05 200.63) (136.91 107.27) 7/84 1.30 0.44 0.67 0.46** 1.08 0.60 (100 34.16) (51.43 35.53) (83.07 46.08) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** pcO.001. CXR0486s Final Report Page 31 of 128 12- - ---- - Hepatic S-Phase - - - ......... . . . - 10 - 8- 6 <0 4- 2 0 *7 Days on test diet 28 Days reversal 56 Days reversal Days on diet Control PFOS 20ppm PFOS lOOppm 84 Days reversal 10.4.4 Thyroid H&E In the thyroid gland, no microscopic findings considered to be related to the treatment with the test items were recorded. 10.4.5 Thyroid in situ cell death The level of apoptosis found in both treatment groups, at all time points, was minimal. It was usual to find either no cells, or just one cell per thyroid, staining in the TUNEL assay as apoptotic, regardless of treatment. 10.4.6 Cell proliferation in thyroid PFOS 20ppm and PFOS lOOppm treatment had no effect on S-phase at any time point studied (Table 20). CXR0486s Final Report Page 32 of 128 Table 20. Thyroid S-phase Labelling Indices Labelling Index (%) Days on Oppm PFOS1 PFOS1 diet/reversal 20ppm lOOppm 7/0 2.62 0.21a 2.7010.56 3.2811.10 (100 8.14) (103.16121.38) (125.34142.08) 7/28 1.50 0.33 1.7010.27 1.8210.38 (10021.81) (113.49118.00) (121.56125.44) 7/56 1.1210.33 1.3010.26 1.3210.25 (100 1 29.70) (116.27123.60) (118.41 122.55) 7/84 1.0210.31 1.2110.24 1.1810.07 (100130.58) (118.61 123.52) (115.0316.57) a Values are Mean SD. Values in parenthesis are mean % control SD. n = 10 per group; 1n = 5 per group. A Student's t-test (2-sided) was performed on the results; ^statistically different from control p<0.05; **p<0.01; *** p<0.001. 7 Days on test diet 28 Days reversal 56 Days reversal Days on diet 84 Days reversal CXR0486s Final Report Page 33 of 128 11. DISCUSSION In this study, PFOS appeared to exhibit the combined hepatic effects of a peroxisome proliferator and "phenobarbital-like" enzyme inducer. Thus, PFOS administration for 7 days generally reflected the results obtained in a previous study, CXR0481. As in the earlier study no effects of PFOS on the thyroid were observed. Both histopathologically and biochemically, reversibility was not complete after 7 days of PFOS treatment followed by up to an 84 day treatment-free recovery period. Hepatic apoptosis, particularly, was still severely inhibited after this reversal time. Likewise the induced microsomal cytochrome P450 content and representative monoxygenase activities were maintained throughout the treatment-free recovery period. This latter observation was reflected by the maintenance of hepatocellular hypertrophy. 12. DATA STORAGE AND ARCHIVING The data has been held in a Study File according to CXR Biosciences SOPs 0003 and 0005. On completion of the study, the following items will be retained in the CXR Archive: Study protocol and possible amendments Study Report and possible amendments Study File (including Study Diary) Relevant correspondence All items will be kept for two years from the date of signing the Study Report unless, in the opinion of CXR Biosciences, the quality of the specimens no longer allows evaluation. At the end of the two-year period, the Study Sponsor will be contacted and the items either sent to the Study Sponsor or retained by CXR Biosciences under a separate agreement. 13. REPORT The Study Report has been prepared as described in CXR Biosciences SOP 0004. 14. QUALITY ASSURANCE Study activities at the Test Facility (CXR Biosciences Ltd and BSRU) have been conducted according to relevant SOPs. There were no deviations from this protocol. No claim of GLP compliance has been made for this study. 15. STUDY DIRECTORS STATEMENT Final Report signature by the Study Director indicates acceptance of responsibility for the validity and integrity of the Study data. CXR0486s Final Report Page 34 of 128 APPENDIX 1. PATHOLOGY REPORT p. 35 CXR0486s Final Report Page 35 of 128 PATHOLOGY REPORT TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. CXR : 0486s PATHOL. NO. 07059 VOO DATE 19-MAR-08 PathDataSystem V6.2dl PREPARED BY: Dr. med. vet. Ortwin Vogel Veterinary Pathologist CXR0486s Final Report Page 36 of 128 PATHOLOGY REPORT TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TABLE OF CONTENTS AUTHENTICATION PAGE CXR I 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl PAGE 1 PRINCIPAL SECTION SUMMARY METHODS RESULTS CONCLUSIONS REFERENCES CO 1 kO 2- 3 4- 5 6- 7 10 EXPLANATION OF CODES AND SYMBOLS SUMMARY TABLES SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX NECROPSY STATUS: TERMINAL SACRIFICE GROUP (K0) SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX NECROPSY STATUS: RECOVERY / POST-TREATMENT GROUP (Rl) SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX NECROPSY STATUS: RECOVERY / POST-TREATMENT GROUP (R2) SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX NECROPSY STATUS: RECOVERY / POST-TREATMENT GROUP (R3) INDIVIDUAL ANIMAL DATA TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) ANIMAL HEADING DATA DOSE GROUP 01 TEXT OF MICROSCOPIC FINDINGS DOSE GROUP 01 ANIMAL HEADING DATA DOSE GROUP 02 11 12 13 14 15 16 29 - 27 28 48 49 CXR0486s Final Report Page 37 of 128 PATHOLOGY REPORT TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TABLE OF CONTENTS TEXT OF MICROSCOPIC FINDINGS DOSE GROUP 02 ANIMAL HEADING DATA DOSE GROUP 03 TEXT OF MICROSCOPIC FINDINGS DOSE GROUP 03 PAGE CXR II 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl PAGE : 50 - 69 70 71-90 CXR0486s Final Report Page 38 of 128 PATHOLOGY REPORT PAGE CXR : 1/90 : 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl AUTHENTICATION The undersigned hereby declares that the histopathology data in this re port were compiled by him, and that they reflect accurately the raw data records. Dr. med. vet. Ortwin Vogel Veterinary Pathologist TPC Toxicologic Pathology Consultancy Goethestr. 26 D-24116 Kiel CXR0486s Final Report Page 33 of 128 p. 40 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR SUMMARY : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PAGE CXR : 2/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl To investigate the reversibility of Perfluorooctane Sulfonate (PFOS)-in duced effects, pathomorphological examinations were performed on 120 male Sprague Dawley rats. The rats were allocated to 3 dose groups each con sisting of 40 males and received the test item via the feed at dose levels of 20 ppm "PFOS" or, 100 ppm "PFOS" (groups 02 and 03, respective ly) for a treatment period of 7 days. The rats of group 01 received the same diet without any test item and served as control animals. Ten rats of each group were assigned for the sacrifice at the end of the treatment period (test day 8) and ten animals each were assigned to the sacrifices after a 4-week (Rl), 8-week (R2) and 12-week (R3) recovery period. At the end of the treatment/recovery periods, the rats were sacrificed and de tailed necropsies performed. Histopathological examination was performed on the liver and thyroid from all animals of all groups. Microscopically, treatment related findings were recorded in the liver. When compared with the control animals, a slight decrease in the usual glycogen induced hepatocellular vacuolation was noted in the animals of groups 02 (20 ppm PFOS) and 03 (100 ppm PFOS) on each sacrifice period. In addition, a minimal to moderate, centrilobular hepatocellular hyper trophy was noted, dose related in severity, in the animals of groups 02 (20 ppm PFOS) and 03 (100 ppm PFOS) after 7 days of treatment. This find ing was still present in animals of groups 02 and 03 sacrificed after a 4-, 8- or 12-week treatment-free recovery period. An unequivocal differ ence in the severity and incidence of this finding between the various recovery periods was not observed indicating an incomplete reversibility during the various recovery periods used in this study. In the thyroid gland, no microscopic finding was recorded, that is con sidered to be related to the treatment with the test items. All other microscopic findings recorded did not distinguish significantly treated rats from vehicle control rats or the differences noted were re garded as random events. All these findings are considered to be sponta neous in nature and within the normal background pathology commonly seen in rats of these strains and age. CXR0486s Final Report Page 40 of 128 p. 41 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. SUMMARY PAGE CXR : 3/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl Under the conditions of this study, the repeated administration of 20 or 100 ppm "PFOS" via the feed to rats of the Sprague Dawley strain for a treatment period of 7 days produced a centrilobular hepatocellular hyper trophy, that was not completely reversible during a 4-, 8- or 12-week treatment-free recovery period. CXR0486s Final Report Page 41 of 128 p. 42 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. METHODS PAGE CXR : 4/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl Group Design for Pathological Evaluation Dose Group 01 Pathdata Test item+ Group 01 0 (Control) 02 02 20 ppm PFOS 03 03 100 ppm PFOS Number of Rats* Males 10** IQkkk ^Qk k k k ^Q*k k k k 10** 2 Q * *k ^Q k k k ^Q k k k k k 10** 10*** ^Q k k k k kkkkk Animal numbers Males 111 21 31 - 10 20 30 40 41 51 61 71 - 50 60 70 80 81 - 90 91 - 100 101 - 110 111 - 120 + Perfluorooctane sulfonate potassium salt (PFOS K+), 3M Company, St. Paul, Minnesota, USA. strain: Sprague Dawley (CD), (Breeder: Charles River, UK); * * These animals are listed in the tables under necropsy status KO. k k k These animals are listed in the tables under necropsy status Rl. * These animals are listed in the tables under necropsy status R2. -k These animals are listed in the tables under necropsy status R3. Administration of the Test Item The in-life part of the study was performed at CXR Biosciences Ltd., James Lindsay Place, Dundee DD1 5JJ, UK. The animals were administered 20 ppm PFOS (group 02) or 100 ppm PFOS (group 03) in the diet ad libitum for 7 days. The animals of group 01 received the same diet without the test item and served as control animals. Necropsy and Histopathology At the end of the assigned study periods (test days 8, (sacrifice group K0), 36 (sacrifice group Rl), 64 (sacrifice group R2) and 92 (sacrifice CXR0486s Final Report Page 42 of 128 p. 43 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. METHODS PAGE CXR : 5/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl group R3), the rats were killed by exposure to a rising concentration of C02. Two samples of the liver (one from the left lobe, one from the median lobe) and the thyroid including parathyroid gland together with trachea and oesophagus were taken and preserved in 10% neutral buffered formaldehyde (NBF). Histotechnique was performed at Progenix Research UK Ltd., Suite 1 Forth House, Burnside Business Court, Inverkeithing, Fife, KY11 1NZ, Scotland. The preserved liver and thyroid samples of all rats of all groups were trimmed, processed, embedded in paraffin wax and sectioned at a nominal thickness of about 5 pm. All sections were stained with haematoxylin and eosin. One section of each organ sample was examined by the undersigned pathologist by light microscope. Data compilation The animal heading data recorded by CXR at postmortem examination were taken from the post-mortem records and entered manually into the PathData Computer system, current version, under Pathology No. 07059 (PathData is a registered trademark of Pathology Data Systems, Inc.). Microscopic findings are recorded by the undersigned pathologist during histopathological examination using on-line data input into the pathology computer system. All microscopic observations are presented for each rat in the "Table of Individual Microscopic Findings" as well as in full descriptive terms in the "Individual Animal Data - Text of Gross and Microscopic Findings". The incidence of microscopic findings is also presented in tabular form. Incidence tables were created by the Pathdata software. Histologic alter ations were described, wherever possible, according to their distribu tion, severity and morphologic character. Severity scores were assigned as given under "Explanation of Codes and Symbols". The slides were evaluated on December 19/20, 2007. Archive For archiving purposes, the raw data including a CD-ROM containing the electronic study data and the microscopic slides will be returned to CXR Biosciences Ltd., James Lindsay Place, Dundee DD1 5JJ, UK. CXR0486s Final Report Page 43 of 128 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. RESULTS PAGE CXR 6/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl Microscopic findings At histopathologic examination, few microscopic findings were recorded. These findings are described in detail in the "Individual Animal Data Text of Gross and Microscopic Findings". THYROID: There were no microscopic findings recorded that are considered to be related to the treatment with any test items in either sacrifice group. LIVER: Sacrifice at the end of the treatment period (sacrifice K0): A minimal to moderate, periportal hepatocellular vacuolation that is con sidered to be due to an intracytoplasmic glycogen accumulation was promi nent in the control animals of group 01. Hepatocellular vacuolation was also present, similar in incidence and severity, in the animals of group 02 (20 ppm PFOS) and, with a slight decreased mean severity (mean 2.0) when compared with the control animals (mean 2.5), of group 03 (100 ppm PFOS) Centrilobular hepatocellular hypertrophy was noted, minimal to slight in degree, in treated rats only. This finding occurred in 8 animals of group 02 (20 ppm PFOS, mean severity 1.0) and all animals of group 03 (100 ppm PFOS, mean severity 1.8). Sacrifice after a 4-week treatment-free recovery period (sacrifice Rl): Hepatocellular vacuolation similar to the finding noted in the animals of the KO-sacrifice was recorded also in all control animals of this sacrifice group. A slight decrease in incidence and severity of this finding was noted in groups 02 (20 ppm PFOS, 7 animals affected, mean severity 1.9) and 03 (100 ppm PFOS, 6 animals affected, mean severity 1.8) when compared with the control group (all ten animals affected, mean severity 2.0). A minimal to moderate hepatocellular hypertrophy was noted in treated animals only occurring in 5 rats of group 02 (20 ppm PFOS, mean severi ty 1.2) and all ten rats of group 03 (PFOS 100 ppm, mean severity 2.1). CXR0486s Final Report Page 44 of 128 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. RESULTS PAGE CXR 7/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl Sacrifice after a 8-week treatment-free recovery period (sacrifice R2): A similar hepatocellular vacuolation as recorded in the liver of the animals sacrificed at the end of the treatment period (KO-sacrifice) was also noted, minimal to moderate in degree, in all control rats of groups 01 and almost all treated animals of groups 02 and 03. A slight decrease in incidence and severity of this finding was noted in groups 02 (20 ppm PFOS, 9 animals affected, mean severity 2.1) and 03 (100 ppm PFOS, 9 animals affected, mean severity 1.7) when compared with the con trol group (mean severity 2.4). Hepatocellular hypertrophy occurred only in treated animals. This finding was noted, minimal in degree, in 4 animals of group 02 (20 ppm PFOS, mean severity 1,0) and, slight to moderate in degree, in all ten animals of group 03 (100 PFOS, mean severity 2.1). Sacrifice after a 12-week treatment-free recovery period (sacrifice R3): Hepatocellular vacuolation similar to the finding noted in the animals of the KO-sacrifice was recorded also in all control animals. A slight decrease in the incidence and/or severity of this finding was noted in groups 02 (20 ppm PFOS, 10 animals affected, mean severity 2.0) and 03 (100 ppm PFOS, 7 animals affected, mean severity 1.7) when compared with the control group (all 10 animals affected, mean severity 2.6). Hepatocellular hypertrophy occurred in treated animals only. This finding was recorded, minimal in degree, in 5 males of group 02 (20 ppm PFOS, mean severity 1.0) and in all 10 males of group 03 (100 pph PFOS, mean severity 1.7). The type, incidence and severity of all other microscopic alterations re corded did not indicate a relationship to the treatment with the test item or the differences noted were regarded as random events. These findings were regarded to be spontaneous in nature and within the normal background pathology commonly seen in rats of these strains and age. CXR0486s Final Report Page 45 of 128 p. 46 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. CONCLUSIONS PAGE CXR 8/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl In this 13-week toxicity study of the test item "PFOS" administered with the feed to Sprague Dawley rats at dose levels of 0 ppm (control), 20 ppm PFOS or 100 ppm PFOS, a hepatocellular vacuolation occurred in rats of all groups and sacrifice periods. The severity of this finding appeared to be decreased in treated groups when compared with the control group in all sacrifice periods. This kind of vacuolation is considered to be due to the intracytoplasmic presence of glycogen and is quite commonly ob served in well-fed, untreated rodents. The difference between control and treated animals noted in this study at different sacrifice periods is considered to be related to the treatment with the test items. A minimal to slight centrilobular hepatocellular hypertrophy was noted, dose related in severity, in the animals of groups 02 and 03 sacrificed at the end of the 7-day treatment period (K0). In the absence of any hepatocellular hypertrophy in the control animals, this alteration is considered to be related to the treatment with the test item. A large number of medicinal agents with different chemical structures and thera peutic activities produce liver enlargement when given in high doses to species used in toxicity studies (Greaves, 1990). This enlargement that may be characterized morphologically by hepatocyte hypertrophy, hepatocyte hyperplasia or both may be accompanied by an increase in activity of the hepatic microsomal drug metabolizing enzymes in the absence of any morphogical evidence of hepatocellular damage. The changes are typically reversible on cessation of treatment. In this study, however, hepatocel lular hypertrophy was also present, similar in incidence and severity, in both treated groups sacrificed after a 4-, 8- or 12-week treatment-free observation period. An unequivocal difference in the severity and in cidence of this finding between the various recovery periods was not ob served. This indicates, that a complete recovery did not occur during the recovery periods used in this study. In the thyroid gland, there were no microscopic findings recorded that are considered to be related to the treatment with any test items in either sacrifice group. All other microscopic findings recorded did not distinguish significantly treated rats from vehicle control rats or the differences noted were regarded as random effects. All these findings are considered to be spon taneous in nature and within the normal background pathology commonly seen in rats of these strains and age. CXR0486s Final Report Page 46 of 128 p. 47 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. CONCLUSIONS PAGE CXR : 9/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl Under the conditions of this study, the repeated administration of 20 or 100 ppm "PFOS" via the feed to rats of the Sprague Dawley strain for a treatment period of 7 days produced a centrilobular hepatocellular hyper trophy, that was not completely reversible during a 4-, 8- or 12-week treatment-free recovery period. CXR0486s Final Report Page 47 of 128 p. 48 PATHOLOGY REPORT PRINCIPAL SECTION TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. REFERENCES PAGE CXR :: 10/ 90 :: 0486s PATHOL. NO.:: 07059 VOO DATE :: 19-MAR-08 PathDataOSystem V6.2dl Greaves P. (1990): Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation. Digestive System I, 278-392. Elsevier, Amsterdam New York Oxford CXR0486s Final Report Page 48 of 128 p. 49 PATHOLOGY REPORT TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. EXPLANATION OF CODES AND SYMBOLS PAGE CXR : 11/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl CODES AND SYMBOLS USED AT ANIMAL LEVEL: M = Male animal K0 = Terminal sacrifice group R1...R9 = Recovery / post-treatment group 1...9 CODES AND SYMBOLS USED AT ORGAN LEVEL: 0 = Tissue not present for histologic examination ' = Histologic examination not required + = Organ examined, findings present - = Organ examined, no pathologic findings noted (AOFT only) ( = Only one of paired organs examined/present CODES AND SYMBOLS USED AT FINDING LEVEL: GRADE 1 = Minimal / very few / very small GRADE 2 = Slight / few / small GRADE 3 = Moderate / moderate number / moderate size P = Finding present, severity not scored ( = Finding unilateral in paired organs CXR0486s Final Report Page 49 of 128 PATHOLOGY REPORT SUMMARY TABLES TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PAGE CXR : 12/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX Necropsy Status: TERMINAL SACRIFICE GROUP (K0) Sex Males Dose Group No. Animals per Dose Group 01 02 03 01 10 10 10 LIVER No.Examined 10 10 10 - mononuclear cell GRADE 1 5 3 3 infiltrate(s) - TOTAL AFFECTED 5 3 3 MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - (mixed) inflammatory GRADE 1 7 8 6 cell infiltration TOTAL AFFECTED 7 8 6 MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - vacuolation GRADE 1 1 - 1 GRADE 2 3 2 8 GRADE 3 6 8 1 TOTAL AFFECTED 10 10 10 MEAN GRADE/TISS.AFFECTED 2.5 2.8 2.0 - hepatocellular hypertrophy GRADE 1 GRADE 2 TOTAL AFFECTED MEAN GRADE/TISS.AFFECTED - 82 --8 _ 8 10 - 1 .0 1.8 _ - _ - _ - - _ - " - - mitotic figures GRADE 1 7 7 8 - TOTAL AFFECTED 7 7 8 MEAN GRADE/TISS.AFFECTED 1 .0 1 .0 1 .0 - THYROID GLAND No.Examined 9 9 4 - - branchiogenic cyst GRADE 1 - 1 - " TOTAL AFFECTED - 1 - - MEAN GRADE/TISS.AFFECTED - 1 .0 -" Females 02 - - - - _ - - - - - - - - " " " 03 - - - - - - * - - - - - " " - - " " CXR0486S Final Report Page 50 f 128 PATHOLOGY REPORT SUMMARY TABLES TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PAGE CXR : 13/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX Necropsy Status: RECOVERY / POST-TREATMENT GROUP (Rl) Sex Males Females Dose Group 01 02 03 01 02 No. Animals per Dose Group 10 10 10 - - LIVER No. Examined 10 10 10 _ _ - congestion GRADE 1 - 1- - - GRADE 2 - 1 - - - TOTAL AFFECTED _ 2 - _ _ MEAN GRADE/TISS.AFFECTED - 1.5 - - - - mononuclear cell GRADE 1 6 5 3 _ _ infiltrate(s) TOTAL AFFECTED 6 5 3 MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - - (mixed) inflaircnatory GRADE 1 9 6 9 - _ cell infiltration TOTAL AFFECTED 9 6 9 _ _ MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - - vacuolation GRADE 1 1 1 1 _ _ GRADE 2 8 6 5 - - GRADE 3 1 - - - - TOTAL AFFECTED 10 7 6 _ _ MEAN GRADE/TISS.AFFECTED 2.0 1.9 1.8 - - - hepatocellular GRADE 1 4_ _ hypertrophy GRADE 2 - 19- - GRADE 3 - - 1- - TOTAL AFFECTED _ 5 10 _ __ MEAN GRADE/TISS.AFFECTED " 1.2 2.1 - - - mitotic figures GRADE 1 4 8 e - - TOTAL AFFECTED 4 8 e _ _ MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - THYROID GLAND N o .Examined 8 10 10 _ _ - branchiogenic cyst GRADE 1 - - 2 - - TOTAL AFFECTED _ _ 2 _ _ MEAN GRADE/TISS.AFFECTED - 1.0 - - 03 " _ - - _ - - _ - _ _ - _ - - _ - - - _ - - _ - _ - _ - CXR0486s Final Report Page 51 of 128 PATHOLOGY REPORT SUMMARY TABLES TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. PAGE CXR : 14/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX Necropsy Status: RECOVERY / POST-TREATMENT GROUP (R2) Sex Males Females Dose Group No. Animals per Dose Group 01 02 03 01 02 10 10 10 - - LIVER - congestion N o .Examined 10 10 10 _ _ GRADE 1 - 1 - -- TOTAL AFFECTED _ 1 _ _ MEAN GRADE/TISS.AFFECTED - 1.0 - -- - mononuclear cell GRADE 1 5 _ 3 _ _ infiltrate(s) TOTAL AFFECTED 5 _ 3 _ - MEAN GRADE/TISS.AFFECTED 1.0 - 1.0 - - - (mixed) inflammatory GRADE 1 8 9 10 _ _ cell infiltration TOTAL AFFECTED 8 9 10 _ _ MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - - vacuolation GRADE 1 1 2 3 - - GRADE 2 4 4 6- - GRADE 3 5 3 - - - TOTAL AFFECTED 10 9 9 _ _ MEAN GRADE/TISS.AFFECTED 2.4 2.1 1.7 - - - hepatocellular hypertrophy GRADE 1 - 4- -- GRADE 2 GRADE 3 - - 9-1- - TOTAL AFFECTED MEAN GRADE/TISS.AFFECTED _ 4 10 - 1.0 2.1 - _ - - mitotic figures GRADE 1 1 3 2 - - TOTAL AFFECTED 1 3 2 - _ MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - 03 _ - _ _ _ " _ _ _ - _ - - CXR0486s Final Report Page 52 of 128 PATHOLOGY REPORT SUMMARY TABLES TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PAGE CXR : 15/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX Necropsy Status: RECOVERY / POST-TREATMENT GROUP (R3) Sex Males Females Dose Group No. Animals per Dose Group 01 02 03 01 02 10 10 10 - - LIVER No. Examined 10 10 10 - mononuclear cell GRADE 1 6 7 4 infiltrate(s) _ _ __ TOTAL AFFECTED 6 7 4 . MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - _- (mixed) inflammatory GRADE 1 10 6 8 _ cell infiltration TOTAL AFFECTED 10 68_ _ MEAN GRADE/TISS.AFFECTED 1.0 1.0 1.0 - - - vacuolation GRADE 1 _ 3 1_ _ GRADE 2 4 4 6 - GRADE 3 6 3 - - - TOTAL AFFECTED 10 10 7 _ _ MEAN GRADE/TISS.AFFECTED 2.6 2.0 1.9 - - - hepatocellular GRADE 1 _ 53_ hypertrophy GRADE 2 - - 7 - - TOTAL AFFECTED _ 5 10 . MEAN GRADE/TISS.AFFECTED - 1.0 1.7 - - - mitotic figures GRADE 1 - 1 2 - - TOTAL AFFECTED _ 12_ _ MEAN GRADE/TISS.AFFECTED - 1.0 1.0 - - 03 - __ - _ - _ _ - - _ - - - CXR0486s Final Report Page 53 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 16/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, Control ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MKO MKO MKO MKO MKO MKO MKO MKO MKO MKO LIVER - mononuclear infilt . - inflammatory cell - vacuolation, hepat . - mitotic figures ++++++++++ . 1 . 1. 1 . 1. 1. 1. . 1. 1. 1. 1. 1. 1. 3. 3 . 2. 2 . 3. 2. 3. 1. 3. 3. 1 1 . 1. 1. 1. 1. 1. THYROID GLAND (- - - (- 0 - - - - - CXR0486s Final Report Page 54 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR : 17/90 : 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 .2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, Control ANIMAL NUMBER : 11 12 13 14 15 16 17 18 19 20 MR1 MR1 MRI MR1 MR1 MRI MRl MRl MRl MRl LIVER - mononuclear infilt. - inflammatory cell - vacuolation, hepat. - mitotic figures THYROID GLAND ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1 . 1. . 1. 1. 1. 1. 1. 1. 2. 2 . 1. 2. 2. 2. 3. 2. 2. 2. . . . 1. 1. . 1. 1. - - - - - - - 0 0 (- CXR0486S Final Report Page. 55. of. 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 18/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, Control ANIMAL NUMBER 21 22 23 24 25 26 27 28 29 30 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 LIVER - mononuclear infilt , - inflammatory cell - vacuolation, hepat . - mitotic figures ++++++++++ . 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. . 1. 1. 1. 3. 3. 3. 2. 3. 2. 1. 2. 3. 2. 1. THYROID GLAND - - - (- (- - - - - - CXR0486S Final Report Page 56 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 1 9 / 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, Control ANIMAL NUMBER ; 31 32 33 34 35 36 37 38 39 40 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 LIVER - mononuclear infilt . - inflammatory cell - vacuolation, hepat . ++++++++++ 1. . 1. . . . 1. 1. 1. 1. 1. 1 . 1. 1 . 1. 1. 1. 1. 1. 1. 3. 2 . 3. 3 . 3. 2. 3. 3. 2. 2. THYROID GLAND - - - - - - - - - (- CXR0486S Final Report Rage 57 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 20/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, PFOS 20 ppm ANIMAL NUMBER 41 42 43 44 45 46 47 48 49 50 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 LIVER - mononuclear infilt. - inflammatory cell - vacuolation, hepat. - hypertrophy, hepat. - mitotic figures ++++++++++ 1. 1. 1. 1 . 1 . 1 . 1. 1. 1 . 1 . 1. 3. 3. 3. 3. 3. 2. 2. 3. 3. 3. 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1. 1 . 1 . 1. 1. 1. 1 . 1. THYROID GLAND (- (- (- 0 - + - (- (- + - ectopic thymus ( P. - branchiogenic cyst ( l' CXR0486s Final Report Page 58 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 21/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, PFOS 20 ppm ANIMAL NUMBER : 51 52 53 54 55 56 57 58 59 60 MR1 MR1 MRl MR1 MRl MRl MRl MRl MRl MRl LIVER - congestion - mononuclear infilt , - inflammatory cell - vacuolation, hepat . - hypertrophy, hepat . - mitotic figures ++++++++++ , 1. 2. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 2. 2. 2. 1. 2. 2. 2. 1. 2. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. THYROID GLAND __________ CXR0486s Final Report Page 59 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 22/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP 02, PFOS 20 ppm ANIMAL NUMBER 61 62 63 64 65 66 67 68 69 70 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 LIVER - congestion - inflammatory cell - vacuolation, hepat . - hypertrophy, hepat . - mitotic figures ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 3. 3. 1. 2. 2. 1. 2. 2. 3. 1. 1. 1. 1. 1. 1. 1. THYROID GLAND (- - - (- 0 - - - - - CXR0486S Final Report Pa'ge 60 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 23/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, PFOS 20 ppm ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 LIVER - mononuclear infilt . - inflammatory cell - vacuolation, hepat . - hypertrophy, hepat . - mitotic figures THYROID GLAND ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 3. . 2. 1. 1. 1. 1. 2. 1. 1. 2. 1. 3. 2. 3. 1. 1. -- 0 (- - - - - - - CXR0486S Final Report Page.61-of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 24/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, PFOS 100 ppm ANIMAL NUMBER 81 82 83 84 85 86 87 88 89 90 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 LIVER - mononuclear infilt. - inflammatory cell - vacuolation, hepat. - hypertrophy, hepat. - mitotic figures ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1. 1. 2. 1. 2. 3. 2. 2. 2. 2. 2. 2. 2. 1. 1. 2. 2. 2. 2. 2. 2. 2. 1. 1. 1. 1. 1. 1. 1. 1. THYROID GLAND 0 0 0 0 0 - - - 0 (- CXR0486S Final Report Page 62 Of T28 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 25/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PPOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOET) DOSE GROUP : 03, PFOS 100 ppm ANIMAL NUMBER : 91 92 93 94 95 96 97 98 99 100 MR1 MR1 MRl MRl MRl MRl MRl MRl MRl MRl LIVER - mononuclear infilt. - inflammatory cell - vacuolation, hepat. - hypertrophy, hepat. - mitotic figures ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 2. 2. 2. 2. 1. 2. 3. 2. 2. 2. 2. 2. 2. 2. 2. 2. 1. 1. 1. 1. 1. 1. THYROID GLAND - branchiogenic cyst + +- - _ _ _ _ _ _ ( 1. ( 1. CXR0486s Final Report Page 63 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR 26/ 90 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, PFOS 100 ppm ANIMAL NUMBER : 101 102 103 104 105 106 107 108 109 110 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 MR2 LIVER - mononuclear infilt. - inflammatory cell - vacuolation, hepat. - hypertrophy, hepat. - mitotic figures ++++++++++ 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 2. 1 . 2. 2. 2. 2. 2. 1. 1. 3. 2. 2. 2. 2. 2. 2. 2. 2. 2. 1. 1. THYROID GLAND - - (- - (- ----- CXR0486S Final Report Page 64 of 428 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE CXR : 27/ 90 : 0486s TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. PATHOL NO. 07059 voo DATE 19-MAR-08 PathDataSystem V6 .2dl TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, PFOS 100 ppm ANIMAL NUMBER : 111 112 113 114 1,15 116 117 118 119 120 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 MR3 LIVER - mononuclear infilt , - inflammatory cell - vacuolation, hepat . - hypertrophy. hepat . - mitotic figures ++++++++++ , 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 2. 2. 1. 2. 2. 2. 2. 1. 2. 2. 2. 1. 2. 2. 1. 2. 2. 1. 1. THYROID GLAND - (- (- - - - - - - - CXR0486s Final Report Page 65 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. ANIMAL HEADING DATA DOSE GROUP 01, Control PAGE CXR 28/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl ANIMAL SEX NUMBER M/F 1M 2M 3M 4M 5M 6M 7M 8M 9M 10 M 11 M 12 M 13 M 14 M 15 M 16 M 17 M 18 M 19 M 20 M 21 M 22 M 23 M 24 M 25 M 26 M 27 M 28 M 29 M 30 M 31 M 32 M 33 M 34 M 35 M 36 M 37 M 38 M 39 M 40 M DEFINED .AND FINAL STATE OF NECROPSY K0 KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO Rl Rl RI Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 64 29-NOV-06 31-JAN-07 31-JN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 CXR0486S Final Report Page 66 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 29/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 1 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted* * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 2 CXR0486s Final Report Rege 67 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 30/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 ** ANIMAL NO. : 3 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 4 CXR0486s Final Report Page 68 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 31/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL'NO. : 5 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 6 CXR0486s Final Report Rage 69 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 32/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 7 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory-cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted ' 8 CXR0486s Final Report Rage 70 of428 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 33/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 9 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 10 CXR0486s Final Report Page 71 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 34/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 11 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 12 CXR0486s Final Report Page 72 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 35/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 13 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 14 CXR0486s Final Report Page 73 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 36/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 15 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 16 CXR0486s Final Report Page 74 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 37/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : 17 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination 18 CXR0486S Final Report Pagd 75 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 38/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 19 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination* * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES) : Only one of paired organs examined/present Organ examined, no pathologic findings noted 20 CXR0486s Final Report Page 76 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PROS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 39/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataOSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 **ANIMAL NO. : 21 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS . LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 22 * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 23 CXR0486s Final Report Page 77 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR : 40/ 90 : 0486s PATHOL. NO. 07059 VOO DATE 19-MAR-08 PathDataSystem V6.2dl MALE CONT./FF. ANIMAL NO. 23 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 24 * STATE AT NECROPSY: R2 DAYS ON TEST : 64* * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 25 CXR0486s Final Report Pge 78 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 41/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 26 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, -vacuolation, hepatocellular, periportal, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted grade 1 27 CXR0486s Final Report Page 79 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 42/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 28 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 29 CXR0486s Final Report Page 80 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 43/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 30 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, fiocal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 31 CXR0486s Final Report Page4M p f128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PROS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 44/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 32 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 33 CXR0486s Final Report Page 82 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFDS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 45/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 34 * MICROSCOPIC FINDINGS LIVER: - (mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted grade 1 35 CXR0486s Final Report Page 83 of ,128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 46/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 36 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 37 CXR0486s Final Report Page 84 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 47/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 38 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 39 CXR0486s Final Report Page 85 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 01, Control PAGE CXR 48/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 40 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted CXR0486s Final Report Page 86 of.128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR Perfluorooctane Sulfonate (PFOS) RAT, 13 weeks, feeding CXR Biosciences Ltd. ANIMAL HEADING DATA DOSE GROUP 02, PFOS 20 ppm PAGE CXR 49/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl ANIMAL SEX NUMBER M/F 41 M 42 M 43 M 44 M 45 M 46 M 47 M 48 M 49 M 50 M 51 M 52 M 53 M 54 M 55 M 56 M 57 M 58 M 59 M 60 M 61 M 62 M 63 M 64 M 65 M 66 M 67 M 68 M 69 M 70 M 71 M 72 M 73 M 74 M 75 M 76 M 77 M 78 M 79 M 80 M DEFINED AND FINAL STATE OF NECROPSY K0 KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI RI R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 TEST DAYS FIRST AND LAST DATE OF DAY UNDER TEST NECROPSY 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 CXR0486S Final Report Page 87 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 50/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 41 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 42 CXR0486s Final Report Page 88 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 51/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 43 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination 44 CXR0486s Final Report Page 89 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 52/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 45 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, hepatocellular, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES) : -ectopic thymus, unilateral 46 CXR0486s Final Report Page 90 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PPOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 53/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 47 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, diffuse, grade 3 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 48 CXR0486s Final Report Page 91 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT,. 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 54/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 49 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): -branchiogenic cyst, unilateral, grade 1 50 CXR0486s Final Report PageQ2 of*128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 55/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : 51 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 52 CXR0486s Final Report Page 93 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 56/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : 53 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 54 CXR0486s Final Report Page 94 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 57/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 55 * MICROSCOPIC FINDINGS LIVER: -congestion, grade 2 -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -congestion, grade 1 -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 56 CXR0486s Final Report Page 95 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 58/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 57 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 58 CXR0486s Final Report Page 9 6b f 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 59/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 59 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : .36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): . Organ examined, no pathologic findings noted 60 CXR0486s Final Report Page 97 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 60/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 61 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 62 CXR0486s Final Report Page^SS of 428 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR 61/ 90 0486s PATHOL. NO.: 07059 VOO DATE , : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 63 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 64 CXR0486s Final Report Page 99 of 128 p. 100 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 62/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 65 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 66 CXR0486s Final Report Page 100 of 128 p. 101 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PEOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 63/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 67 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, diffuse, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -congestion, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 68 CXR0486s Final Report f 'ag 101 of 128 p. 102 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 64/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 69 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 70 CXR0486s Final Report Page 102 of 128 p. 103 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PPOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 65/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 71 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 72 CXR0486s Final Report Page 103 of 128 p. 104 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 66/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 73 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, diffuse, grade 1 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 74 CXR0486s Final Report Page 104 of 128 p. 105 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PEOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 67/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 75 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted grade 1 * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 76 CXR0486s Final Report Page 105 of 128 p. 106 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 68/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 77 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 78 CXR0486s Final Report Pag 06 oM28 p. 107 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PPOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 02, PFOS 20 ppm PAGE CXR : 69/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 79 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 80 CXR0486s Final Report Page 107:of 128 p. 108 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. ANIMAL HEADING DATA DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 70/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl ANIMAL SEX NUMBER M/F 81 M 82 M 83 M 84 M 85 M 86 M 87 M 88 M 89 M 90 M 91 M 92 M 93 M 94 M 95 M 96 M 97 M 98 M 99 M 100 M 101 M 102 M 103 M 104 M 105 M 106 M 107 M 108 M 109 M 110 M 111 M 112 M 113 M 114 M 115 M 116 M 117 M 118 M 119 M 120 M DEFINED AND FINAL STATE OF NECROPSY K0 KO KO KO KO KO KO KO KO KO RI RI RI Rl RI Rl Rl Rl Rl Rl R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 KO KO KO KO KO KO KO KO KO KO Rl Rl Rl Rl Rl Rl Rl Rl Rl Rl R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R3 R3 R3 R3 R3 R3 R3 R3 R3 R3 TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 8 29-NOV-06 06-DEC-06 06-DEC-06 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 36 29-NOV-06 03-JN-07 03-JAN-07 36 29-NOV-06 03-JAN-07 03-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 64 29-NOV-06 31-JAN-07 31-JAN-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 92 29-NOV-06 28-FEB-07 28-FEB-07 CXR0486s Final Report Page 106'6f-128 p. 109 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 71/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. 81 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination 82 CXR0486s Final Report Page 109,of 128 r p. 110 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 72/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 83 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination grade 1 * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 3 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination 84 CXR0486S Final Report Page 11Oof128 p. 111 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 73/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. 85 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 86 CXR0486s Final Report Page 111;of 128 p. 112 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS . DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 74/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 87 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 88 CXR0486s Final Report Page 1l2of 128 p. 113 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm . PAGE CXR : 75/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : 89 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Tissue not present for histologic examination * STATE AT NECROPSY: K0 DAYS ON TEST :8 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 90 CXR0486s Final Report Page 113 of 128 p. 114 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 76/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 91 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 92 CXR0486s Final Report Page 114 of 128 p. 115 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PEOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 77/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 93 * MICROSCOPIC FINDINGS LIVER: -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 94 CXR0486s Final Report Rage 115 of 128 p. 116 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 78/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 95 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: Rl DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS ' LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 96 CXR0486s Final Report Page 116 of 128 p. 117 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PROS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 79/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 97 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): -branchiogenic cyst, unilateral, grade 1 98 CXR0486s Final Report Rage 117 of 128 p. 118 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 80/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : 99 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R1 DAYS ON TEST : 36 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): -branchiogenic cyst, unilateral, grade 1 100 CXR0486s Final Report Page 118 of 128 p. 119 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 81/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 101 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 3 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: . -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 102 CXR0486s Final Report Page 119 of 128 p. 120 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 82/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. 103 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 104 CXR0486s Final Report Page 12of 128 i p. 121 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 83/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 105 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 106 CXR0486s Final Report P^ge 1211 of 128 w p. 122 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PROS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 84/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 107 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 108 CXR0486s Final Report Page 122 of 128 p. 123 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 85/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : 109 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R2 DAYS ON TEST : 64 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 110 CXR0486s Final Report Pgge 1,23of 1.28 p. 124 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 86/90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataOSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 111 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate (s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 112 CXR0486s Final Report Page 124 of 128 p. 125 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PPOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 87/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS . LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present Organ examined, no pathologic findings noted 113 * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 114 CXR0486s Final Report Page 125,of 128 p. 126 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 88/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataOSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 115 * MICROSCOPIC FINDINGS LIVER: -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 116 CXR0486s Final Report Page 126 of 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PROS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR 89/ 90 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl , MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 117 * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 1 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted 118 CXR0486s Final Report Page 127 of 128 r p. 128 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ITEM TEST SYSTEM SPONSOR : Perfluorooctane Sulfonate (PFOS) : RAT, 13 weeks, feeding : CXR Biosciences Ltd. TEXT OF MICROSCOPIC FINDINGS DOSE GROUP : 03, PFOS 100 ppm PAGE CXR : 90/ 90 : 0486s PATHOL. NO.: 07059 VOO DATE : 19-MAR-08 PathDataSystem V6.2dl MALE * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : 119 * MICROSCOPIC FINDINGS LIVER: ' -mononuclear cell infiltrate(s), periportal-/biliar, grade 1 -(mixed) inflammatory cell infiltration, focal, grade 1 -vacuolation, hepatocellular, periportal, grade 2 -hepatocellular hypertrophy, centrilobular, grade 2 THYROID GLAND (BOTH LOBES): Organ examined, no pathologic findings noted * STATE AT NECROPSY: R3 DAYS ON TEST : 92 * ANIMAL NO. : * MICROSCOPIC FINDINGS LIVER: -hepatocellular hypertrophy, centrilobular, grade 2 -mitotic figures, grade 1 THYROID GLAND (BOTH LOBES): . Organ examined, no pathologic findings noted 120 CXR0486s Final Report Page 128 of 128 Ethics & Compliance Officer Association | Agenda Page 1 o f 11 evnie* eoM#t,i*Nee a r r i e e n a s s o c ia t io n - About Governance Membership Professional Standards Member Resource Center Global Ethics & Compliance Events & Education Annual Conference European Conference Past Events ECOA Foundation Home Events & Education Annual Conference ECOA 2008 Annual Business Ethics & Compliance Conference AGENDA Updated 8/11/08 [ Tuesday - Pre-conference workshops! [ Wednesday ] [ Thursday ] [ Friday ] r Back to conference general information page 1 Tuesday, September 23, 2008 Pre-conference workshops 9:00 a.m. - 4:00 p.m. T h is ye a r's p re -co n fe re n ce w o rk sh o p s a re sch e d u led fo r T u e sd a y , S eptem ber 23, 2008. Fullda y w o rksh o p tim e s a re 9:00 a.m . to 4:00 p.m . H alf-day w o rk sh o p tim e s a re 9:00 a.m . to 12:00 p.m . an d 1:00 p.m . to 4:00 p.m . Pre-registration is required. Pre -con fere nce w o rk sh o p s in clu d e co n tin e n ta l breakfast, c o ffe e breaks, an d lunch. P le a se u se th e re g istra tio n co d e to th e le ft o f th e w o rk sh o p title to re g iste r fo r th e w ork sh op you w ou ld lik e to a tte n d . A s th e y becom e av a ila b le , you can c lic k on th e reg istra tio n co d e to read a d e scrip tio n o f th e w orksh op . W h en reg iste rin g fo r tw o se ssio n s (o n e h alf-d a y A M an d o n e half-d a y P M ) u se th e a p p ro p ria te co m b in a tio n co d e In th e se co n d list below . If you have previously registered for the conference, please call the ECOA at 1.781.647.9333 to register by phone for your pre-conference workshops. Single pre-conference workshops: Code Session Titles http://www.theecoa.org/Content/NavigationMenuyEvents/AnnualConference/AC_Agenda.htm 8/14/2008 p. 129 p. 130 Ethics & Compliance Officer Association | Agenda Page 2 o f 11 PC-BEECP P C -T Y PT N L PC-TATM PC -A E E C P P C -C II (PC-CECB) B u ild in g an E ffe ctiv e E th ics & C om p lia n ce Program [9 am -4 pm ] T a k in g Y o u r Program to th e N e xt Level [9 am -4 pm ] C lick on th e reg istration co d e to v ie w a d e scrip tio n . S hapin g th e M iddle: H ow to C reate and D rive th e T o n e D ow n to A ll Levels o f M anagem en t [9 am -12 pm ] C lick on th e reg istration co d e to v iew a d e scrip tio n . A ssessin g th e E ffe ctiv e n e ss o f Y o u r E th ics & C om p lia n ce Program [9 am -12 pm ] C o n d u ctin g In te rn a l In v e stig a tio n s [1-4 pm ] C re a tiv e E n gag em en t an d C om m un ication 10 1/D irector's S how case [1-4 pm ] C lick on th e reg istration co d e to v ie w a d e scrip tio n . AM/PM Com binations Combination Code Session Titles PC-TATM/CII S hapin g th e M iddle: H o w to C reate an d D rive th e T o n e D ow n to A ll Le vels o f M a n a gem e n t [9 am -12 pm ] C on d u ctin g In te rn a l In v e stig a tio n s [1-4 pm ] PC-TATM/CECB S hapin g th e M iddle: H ow to C reate an d D rive th e T o n e D ow n to A ll Le vels o f M a n a g em e n t [9 am -12 pm ] C reativ e E n gag em en t an d C om m un ication 1 0 1/D irector's S how case [1-4 pm] PC-AEECP/CECB A ssessin g th e E ffe ctiv e n e ss o f Y o u r E th ics an d C om p lia n ce Program [9 am -12 pm] C reativ e E n g ag em en t an d C om m un ication 1 0 1/D irector's S how case [1-4 pm ] PC-AEECP/CII A ssessin g th e E ffe ctiv e n e ss o f Y o u r E th ics an d C om p lia n ce Program [9 am -12 pm] C o n d u ctin g In te rn a l In v e stig a tio n s [1-4 pm ] http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm [return to t o p ] 8/14/2008 Ethics & Compliance Officer Association | Agenda Page 3 o f 11 New Conference Attendee Orientation 4:30 p.m. - 5:30 p.m. C reated especially fo r first-tim e attendees. Since many new ECOA members attend the annual conference, and there are a number o f first-tim e conference participants, w e invite you to a special orientation session to learn more about the Ethics & Compliance O fficer Association and our largest conference o f the year. This is a perfect tim e to: (1) begin networking with other ECOA members; (2) learn more about ECOA programs, services, and benefits, and; (3) learn how to navigate the conference so that it maximally meets your interests and needs. It's also a good tim e to meet members o f the ECOA staff and board. W e look forward to meeting you! Retail & Consumer Products Industry Group Meeting * Tim e to be determined. Wednesday, September 24, 2008 Registration & Networking Breakfast Vendor E xh ib itA rea O pens 7:00 - 9:00 a.m. An opportunity to visit with providers o f ethics and com pliance products and services in the vendor exhibit area. W elcom e 9:00 - 9:45 a.m. Keith Darcy, Executive Director, Ethics & Com pliance O fficer Association Plenary Session http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 p. 131 p. 132 Ethics & Compliance Officer Association | Agenda 10:00 - 11:45 a.m. The Ethics & Com pliance Handbook-. An Analysis in Relation to the U.S. Sentencing Guidelines H on orab le Ruben C a stillo (U .S. S en ten cing C om m ission) Beryl H o w e ll (U.S. S en ten cing C om m ission) A n d rew W eissm an n (Je n n e r & B lock LLP) A nd rea B on im e-B lan c (D a y lig h t Fo re n sic & A d v iso ry LLP; C h air, G lo bal S trategy C om m ittee, EC O A B oard o f D irectors) M O D ER A TO R : Keith D arcy (E th ics and C om p lia n ce O ffic e r A sso ciatio n ) Page 4 o f 11 Lunch & Keynote Speaker 12:15 - 1:45 p.m. Frank Bucaro (Frank C. Bucaro and Associates) Taking the High Road: How to Succeed Ethically When Others Bend the Rules Concurrent Sessions 2:00 - 3:15 p.m. The Role o f the Ethics Officer in Creating Culture in the Corporation C h arles C h a d w ick (B A E S ystem s) Evaluating Next-Generation Employee Training and Communication Tools Je rem y W ilson (C isco S ystem s In c.) Benchmarking Hotline Data: How Does Your Hotline Measure Up? C arrie Penm an (E th ica l Le a d e rsh ip G rou p , a G lo b al C o m p lia n ce com p an y) Global Privacy and Data Protection Lisa S otto (H u n ton & W illia m s) Isa b e lle T h e ise n (F irs t A dvan tage) R ebecca H erald (R e b e cca H erald & A sso cia te s, LLC ) Managing Ethics and Com pliance Crises W illiam S en h au ser (Fa n n ie M ae) Engaging Senior Management http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 Ethics & Compliance Officer Association | Agenda Page 5 o f 11 Karen M o o re (P h ilip M o rris In te rn a tio n a l) How to W ork with and Not W ork with the GC's Office B iz S cott (P atton B oggs LLP) Sotiete Generate: Anatomy o f an Ethics and Com pliance Failure G ary B row n (B aker, D on elson , B earm an, C ald w e ll & B erkow itz LLP) Concurrent Sessions 3:30 - 4:45 p.m. [return to tool DPAs and Corporate Monitors: W hat Are the Ethical Upsides and Downsides? Ryan M cC on n e ll (O ffice o f th e U.S. A ttorn ey) Larry Fin d e r (H ayn es B oon e LLP) Creating High-Im pact Annual Reports Joan D ub in sky (In te rn a tio n a l M o n e tary Fund) Com pliance Programs under Cross Examination S cott A v e lin o (K P M G LLP) Dangerous Silence: W hat Employees W on't Tell You, Why, and W hat You Can Do about It G ary E d w ard s (E th o s In te rn a tio n a l) Cyclic Training: Integrating M ultiple Forms o f E-Learning Training and Com m unications T in a W y d e r (A ccen tu re) Re-Imagining the Third Iteration o f Your Risk Assessment John Stoxen (3M ) The State o f Corporate Social Responsibility (CSR) in Korea You n g -C h an Nam (SK telecom ) Justin Tegrity Trains the Board - An Interactive Mock Board Training * D onna B oeh m e (P rin cip a l, C o m p lia n ce S tra teg ists LLC ) S teve G ru b b (D iag e o) Jo Pease (fo rm e r C h ie f E th ics an d C o m p lia n ce O ffice r, S hell O il C om pany) W in S w enson (C o m p lian ce S ystem s Le g al G rou p ) * e x te n d e d se ssio n u n til 5 :3 0 p.m . Networking Reception freturn to top) p. 133 http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 Ethics & Compliance Officer Association | Agenda 6:00 - 7:00 p.m. Page 6 o f 11 p. 134 Annual Conference Dinner 7:00 - 9:00 p.m. After a full day o f conference activities, this w ill be an opportunity to meet new ECOA members and network with colleagues. Guests are welcom e to attend at no additional fee. Thursday, September 25, 2008 Networking Breakfast & Vendor Exhibit Area Opens Registration Open 7:00 - 8:00 a.m. ECOA MEMBER MEETING 8:00 - 9:00 a.m. M em bers a re in vited to th e a sso cia tio n 's an n u al m eeting. Plenary Session 9:00 -10:45 a.m. The Great Debate: Righting the Balance If Sarbanes-Oxley Is Ruled Unconstitutional, W hat Should Replace It: Improved Legislation (emphasis on rules and com pliance) or Something Global and Principles-based (emphasis on ethics and CSR)? Debaters TBA Concurrent Sessions 11:00 a.m. - 12:15 p.m. http://www.theecoa.org/ContentyNavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 Ethics & Compliance Officer Association | Agenda Page 7 o f 11 Investigations 101 for the Non-Investigator M eric B loch (A d ecco G ro u p N orth A m erica) The Latest on the Recent Changes to the Federal Acquisition Regulations (FAR) D avid Laufm an (K elley D rye & W arre n LLP) Cross-Cultural Issues in Business Ethics Sim on W e b le y (In stitu te o f B u sin ess E th ics) Surveys, Rating^, and Metrics: Ethical Issues in Data Collection and Analysis Brad A g le (U n iv ersity o f Pittsb u rg h ) Analysis o f DOJ Convictions against CEOs G reg R ig g s (C o m p lian ce S ystem s Le g a l G rou p ) Fine Tuning Your Code o f Conduct When It's Up for Revision R andall Pe terson (S m pra E n erg y) Difficult but Not Impossible: Developing and Measuring an Ethical Corporate Culture Ln B rooks (U n iv e rsity o f T o ro n to ) Integrating the ECOA's Eth ics on Trial DVD into Your Organization's Training D avid S ch m idt (O M I, an ID N A com pan y) Treturn to top i Lunch and Keynote Speaker 12:30 -1 :4 5 p.m. Lynn E. Turner Member, Advisory Committee on the Auditing Profession, U.S. Treasury Department Member, Standards Advisory Group, PCAOB Member, FASB Investor Technical Advisory Committee Former Chief Accountant, U.S. Securities and Exchange Commission p. 135 Concurrent Sessions 2:00 - 3:15 p.m. Culture Matters: FCPA and Anti-Corruption Initiatives in Europe La u ren ce H arris (E d w a rd s A n g e ll P a lm e r & D odg e U K LLP) Sam Yo o n (T extron In d u stria l Segm ent) Optimizing Corporate Ethics and Com pliance Programs in the Federal G overn m ent M ich ael K orw in (FD IC ) http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 p. 136 Ethics & Compliance Officer Association | Agenda Page 8 o f 11 Em il M o s c h d la (fo rm e rly w ith th e FB I) Using Crisis Com munications to Manage Your Company's Reputation through Tough Tim es Lee Essrig Data Mining to Detect Fraud, Waste, and Abuse M ia O kin aga (K a ise r Perm an en te) "Reporting on Responsibility: The New Ethics Challenge" A n ita B aker (U n iv e rsity o f M aryland U n iv ersity C olleg e) S an tiago R eich (E th ica l Le a d e rsh ip G roup, A G lo bal C om p lia n ce C om pany) A Prindples-Based Approach to Integrating Governance, Risk, and Compliance B obby K ip p (P ricew ate rh o u seC o o p e rs) How Effective Is Your Employee Training? Le slie A ltiz e r (E th ics R e so u rce C en ter) Kevin C a ffre y (E th ics R e so u rce C en ter) On ttie Road Again: Cultural Considerations in Developing Effective Ethics and Com pliance Programs W in S w enson (C om p lian ce System s Legal G rou p ) Treturn to topi Concurrent Sessions 3:30 - 4:45 p.m. The Latest Research on Ethical Decision-Making and Culture Je rry G o ld ste in (W a sh in g ton S tate U n iv ersity a t V an cou ve r) Fran cesca G in o (U n iv e rsity o f N orth C arolin a a t C h apel H ill) M O D ER A TO R : G re tch en W in te r (U n iv ersity o f Illin o is a t U rban a-C h am p aign ) Rock and a Hard Place: Maintaining an Ethics Program in Tim es o f Transition M aria C o n n e r (U S A S pace O p eratio n s) Brian S ears (Lo ck h e ed M a rtin C om pany) Lan i d e B en ed ictis (N A S A J e t Pro p u lsion La boratory) C h arles G ie stin g (R olls-R oy ce ) Organizing and Maintaining a Regional Ethics and Com pliance Network D anna W alton (S outh T e x a s C o lle g e o f Law ) Lin da Lip p s (C e n te rP o in t En ergy, In c.) Ethics and Com pliance Issues in Latin America Zeke B a rrio s (K ra ft Fo o d s G lo b al, In c.) Using Outcome Data to Demonstrate the Effectiveness o f an Ethics and Com pliance Program http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 Ethics & Compliance Officer Association | Agenda A rt W e iss (Tam ko) Ethics Education through an Engaging Series o f Custom Video Vignettes D avid La Jo ie (R ayth eon ) Conducting Third Party FCPA Due Diligence S cott M o ritz (D a y lig h t F o re n sic & A d v iso ry LLC ) Ja y Perlm an (D a y lig h t F o re n sic & A d v iso ry LLC ) Compliance and Ethics Moot Court J e ff K aplan (K aplan & W a lk e r LLP) R ebecca W a lke r (K aplan & W a lk e r LLP) * * e x te n d e d se ssio n u n til 5 :1 5 p.m . Page 9 o f 11 [return to top i Thursday Evening Reception & Dinner 6:00 - 9:00 p.m. Conference attendees, speakers and exhibitors w ill enjoy an evening o f entertainm ent and activities. Guests & children are welcom e to attend but require separate registration. Guest Fees: $50 for 1 guest $80 for 2 or more guests Friday, September 26, 2008 Networking Breakfast 7:00 - 8:00 a.m. p. 137 Plenary Session 8:00 - 9:45 a.m. Measuring the Divide between HR and Ethics Patricia Harned, Ph.D. (Ethics Resource Center) http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 p. 138 Ethics & Compliance Officer Association | Agenda Deborah Keary (Society for Human Resources and Management) Keith Darcy (Ethics and Com pliance O fficer Association) Page 10 o f 11 Concurrent Sessions 10:00 -11:15 a.m. Can They Sue Me, Too? Personal Liability Issues for Chief Ethics and Compliance Officers Ian R offm an (N u tte r M cC len n en 8i Fish LLP) Jon ath an K o tlie r (N u tte r M cC len n en 8i Fish LLP) Making the Business Case for Anti-Corruption Initiatives M ich ael Pe d e rsen (W o rld E con om ic Forum ) M ark S nyderm an (C oca-C ola) G lenn T . W a re (P rice w a te rh o u se C o o p e rs LLP) College Bowls: Leveraging the Relationship between Business Schools and Organizational Ethics and Com pliance Programs T o m W h ite (Lo yo la M a rym ou n t U n iversity) D ebb ie A sirvath am (M cG ill U n iversity) C e cile D upin (M cG ill U n iversity) T iffa n y U m an (M cG ill U n iversity) Completing the Circle: W hat Corporate Ethics Managers Can Learn from the Public Sector D eni E llio tt (M e tro p o lita n W a te r D istrict o f S outhern C a lifo rn ia ) C arla M ille r (C ity o f Ja ck so n v ille ) Stark Lessons in Conflict o f Interest from the 2007 U.S. Student Loan Scandal Leigh -A n n e W a lk e r (E th ica l Le a d e rsh ip G rou p , A G lo b al C om p lia n ce C om pany) The Latest Labor-Related Gotchas You Need to Know M in dy C hapm an (M in d y C hapm an 8i A sso cia te s LLP) A lice Pe terson (S yrus G lo b al) Industry Group Meetings http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008 Ethics & Compliance Officer Association | Agenda 11:30 a.m. - 12:30 p.m. Cross-Industry Group Financial Services Industry Group Healthcare Industry Group Utility Industry Group 12:30 p.m. CONFERENCE ENDS A boxed lunch w ill be p ro vid ed to go. , Agenda subject to change. O reck th is page often fo r updates! Page 11 o f 11 [return to top] \ Tuesday 1 [W edn esday] [ Thursday ] [ Friday ] If you're having trouble with this site, please notify the Webmaster at suDDort@theecoa.oro Copyright 2008 Ethics 8 Compliance Officer Association. All Rights Reserved. p. 139 http://www.theecoa.org/Content/NavigationMenu/Events/AnnualConference/AC_Agenda.htm 8/14/2008