Document 0gV5Rv6zyvGmNG6LqpZo6Bgbx

- 226 - 1IS2 n#H Te - STUDY TITLE Analysis of Pooled Human Sera and Plasma and Monkey Sera for Fluorocarbons Using - Exygen Method ExM-023-071 DATA REQUIREMENTS . `OECD Principles of Good Laboratory Practice, ENVIMC/CHEM(98)17, November 26, 1997 - STUDY DIRECTOR Emily R. Decker STUDY COMPLETED ON : October 30, 2002 PERFORMING LABORATORY / TESTING FACILITY Exygen Research 3058 Research Drive State College, PA 16801 Phone: 814-272-1039 | STUDY SPONSOR . 3M Environmental Laboratory Building 2-35-09 . St. Paul, MN 55133-3331 . Phone: 6517786565 PROJECT Study Plan Number: ExP-023-082 - Exygen Study Number: 023-082 `Sponsor Study Number: E02-1071 i Total Pages: 111 000318 CONTAIN NO CB! - Exyeen Sudy No: 023.082 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT _ aEnxdygMeonnSkteuydySeNruambfoerrFl0u2o3r-o0c8a2r,boenntsitUlsedin"gAnEaxlyygsiesn oMfetPohooldedExHMu-m02a3n-0S7e1ra,"ancdonPdluacstmead for Lab 3M orato Environmen ry Practice tal Laboratory, was Standards (as revised per in formed 1997), in EN compliance V/MC/CHEM with (98) OECD Good 17 by Exygen } Research, with the following exceptions: 1. & 8.3 (5): The computerized system of data generation did not provide for the - retention of a full audit trail to show all changes or to associate all changes to data toa timed and dated electronic signature. 2. 62 (4): The stability of the test items under storage or the study test conditions = was not known. Also the purity of C6 acid and THPFOS was not known. 3. 52 (3): The date of receipt of for the calf serum sample ID 0204718 was not `documented. - 4. 1.22 (g): The instrument used for the analysis has not been qualified. EyR. si . Study Director Exygen Research rr William K. Reagan, Ph.D. - `Sponsor Representative 3M Environmental Date EAI Date Exygen Research. 000319 Page 20111 - Exygen Study No: 023.082 QUALITY ASSURANCE STATEMENT } `The 082 Quality Assurance Unit entitled, "Analysis of of Exygen Research reviewed Exygen Study Number 023Pooled Human Sera and Plasma and Monkey Sera for Fluorocarbons Using Exygen Method ExM-023-071" All phases were reviewed for conduct according to Exygen Research's Standard Operating Procedures, the Study _ Protocol, and all applicable Good Laboratory Practice Standards. ~All findings were reported to the Study Director and to management. - DateReported to . Due DateReporiedto Exygen Date Reported to Phase Inspected SudyDirector Management Sponsor 1 Protocol Review 10/10/02 1014102 103002 1030002 2. FEoxrttriafcitciaotni,on 1015/02 1025/02 1025/02 1030/02 3 RReapworDtawRe,viDreawft 10252802 1029/02 1030002 103002 il 4. RFienvaileRweport 103002 103002 103002 103002 ) ide Fe Mo Naomi Lovallo - Technical Lead-QA (ol30)oe Date Exygen Research. 000320 Page 3of 111 - Exygen Study No: 023.08 CERTIFICATION OF AUTHENTICITY `This report, for Exygen Study Number 023-082, is a true and complete representation of } the raw data for the study. `Submitted by: 3E0x3y8geRnesReeasrecahrcDhrive State College, PA 16801 (814) 272-1039 . Study Director, Exygen ' ily R. Becker = Scientist Exygen Research chop Date Exygen Research Facility Management: . i 22, fohn M. Flaherty Vice President . Exygen Research Lobos. Date `Sponsor Study Monitor, 3M: pie - 3WiMllEinavmirK.onRmeeangtaanl, Ph.D. . LoL Date : Exygen Research. 000321 Page dof 111 _ Exygen Study No: 023.082 STUDYIDENTIFICATION - Analysis of Pooled Human Sera and Plasma and Monkey Sera for Fluorocarbons Using Exygen Method ExM-023-071 - STUDY PLAN NUMBER: ExP-023-082 _ EXYGEN STUDY NUMBER: 023-082 SPONSOR STUDY NUMBER: ~~ E02-1071 TYPE OF STUDY: Residue - TEST SYSTEM: Human Serum, Human Plasma, and Monkey Serum - TEST ITEMS: - perfluorooctane sulfonate (PFOS), perfluorohexanoic acid (C6), perfluoroheptanoic haceipdta(dCe7c)a,fpleunotraodneocnaafnlouiocroaoccitda(nCo9i)c,acid (C8), pneornfaldueocraofulnudoercoadneociacnoaiccidac(iCd11()C,10), pteetrrfalhuyodrroodpoedrefclaunooriococatcainde(sCu1l2f)o,nate (THPFOS), and tetrahydroperfluorodecane sulfonate (THPFDS) . SPONSOR: William K. Reagan- Sponsor Study Monitor 3M Environmental Building 2-3E-09 St. Paul, MN 55133-3331 - STUDY DIRECTOR: Emily R. Decker Exygen Research - Phone: (814) 272-1039 TESTING FACILITY: Exygen Research - 3058 Research Drive StateCollege, PA 16801 ) ANALYTICAL PHASE Study Initiation Date: 10/09/02 TIMETABLE: Experimental Start Date: 10/15/02 ) SExtpuedryiCmoemnptalletTieornmiDnaattei:on Date: 10/23/02 1073002 . Exygen Research 000322 Page Sof 111 - Exygen Study No.; 023-082 PROJECT PERSONNEL - `The Study Director for this project at Exygen Research was Emily R. Decker. The following personnel from Exygen Research were associated with various phases of the study: Name Title - Paul Connolly Technical Leader-LC/MS Emily Decker Scientist Xisoming Zhu Technician - Rickey Keller Sample Custodian - Exygen Research. 000323 Page Gof 111 - _ _ -} . Exygen Study No.: 023-082 TABLE OF CONTENTS TITLE PAGEcoon eH --------Pa--ge GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT .........cooir 2 QUALITYASSURANCE STATEMENT... 3 CERTIFICATION OF AUTHENTICITY... STUDYIDENTIFICATION ccs 3 PROJECT PERSONNEL vss 6 TAOFB CONTL ENTSE ... -- LISTOF TABLES, cmmsrommmmmmmrtnstmmmmmnmrronn 3 LIST OBPIGURES. ormrmsssssssmsmsmmmmmmmmmssmssmmedd LIST OFAPPENDICES c.c.ovsmssmrsmssssssessrsamsmmeennnemmnen 10 10 SUMMARY mmission ----1 90 OBIBCTIVE. ssn ------ 20. DVIBODUCTIONmmm lL 40 TESTSYSTIM. mmm dL 50 TESTITBME sms 3 60 DESCRIPTION OFANALYTICALMETHOD... 1S 6.1 BXUGCHONPIOGEUIE crrrssrsmssrsrsnsmermeremmrnemrnee1e3 62 Preparation of Standards and FOfication SOIUtONS rrr 1S 6.4 INSUUMENE SENSUIVILY..vrrrsrrssnnne16 6.5 DescriptionofInstrument and Operating CONItions.............o.r 17 6.6 Quantitation and EXample Calculation... 11 70 EXPER DESI IONc MENo TAo L rs 300 RESULTS comms 29 9.0 100 CCIORNCUCMLSUTASNICwOEcSN.STHAT MAY HAVE AFFECTED THE DATA.....n....ncconc.. 2211 11.0 RETENTION OF DATAAND SAMPLES cones 21 - Exygen Research. 000324 Page 7of 111 - Exygen Study No. 023.082 LIST OF TABLES - Table I Summary of Recoveries for Calibration Curve inCalf Serum Compared Page to SKANGAIS i MEWNAOL..rrrer rms: 33 Table Il 1S0uSmUmAaNrAAyTAoSf RI0ecMovEeNriOesNfoc r Calibrar tion Curs ve in Humaann PrlnassmasCormrpasred2 - Table Ill Summary of Recoveries for Laboratory Fortified Matrix SpiKes............ 24 Table IV Summary of Residues for Human Serum Samp .......crce: 26 . Table V Summary of Residues for Human Plasma Samples... 26 } Table VI Summary of Residues for Monkey Serum SAmpIES........runnr. 26 - Exygen Research, 000325 Page Sof 111 - ) . -. Exygen Study No.: 023.082 Figure | Figure 2 Figure 3 Figured LI OFFS IGUT RES Page Chromatogram Representing 0.1 ng/mL Calibration Standard.................28 Chromatogram Representing a Fortified Human Plasma Sample at 0.5 (Exygen ID: 0204490 Spk J, SponsorID: TCR-674) ccc ppb 32 CSPhOrNoSmOaFtoIDg:raTmCRRe-p6r4es)entc ing a Humo an Plasmar Sample s (Exygen Ie D: 02044903,6 Chromatogram Representing a Sample Analyzed for Three Daughters for THPFDS (Exygen ID: 0204292 Dup, Sponsor ID: X328-A).....rcrrres 40 . Exygen Research. 000326 Page of 111 : Exygen Study No: 023.082 - LIST OF APPENDICES Page . Appendix A DSteuVdyIaPltainoEnxPs-.0.23.-r0r8r2 (Exygen cStusdy mNo.--023---08--2)--and--------h . Exygen Research 000327 Page 100f 111 - Exygen Study No.: 023-082 1.0 SUMMARY = Exygen Research conducted a quantitative screening on various human serum, human plasma, and monkey serum samples for the determination of perfluorooctane sulfonate (PFOS), perfluorohexanoate (C6), perfluoroheptanoate (C7), pentadecafluorooctanoate (C8), heptadecafluorononanoate acid (C9), nonadecafluorodecanoate (C10), perfluoroundecanoate (C11), perfluorododecanoate (C12), tetrahydroperfluorooctane. _ sulfonate (THPFOS), and tetrahydroperfluorodecane sulfonate (THPFDS) according to protocol ExP-023-082 (Appendix A). This screening was performed on an instrument that had not been used for routine fluorochemical analysis prior to this study. The - `method used for this study has not been validated at the levels reported for C8 and PFOS and not validated at any level for the other anions. These levels were completely dependent on instrument sensitivity. Recoveries for fortified samples are given in Tables I-III. Residues of each anion in human serum are summarized in Table IV. Residues of each anion in human plasma are - summarized in Table V. Residues of each anion in monkey serum are summarized in Table VI. - 2.0 OBJECTIVE } The objective of this study was to screen human serum, human plasma, and monkey sseenrsiutmivistaym.ples and quantitate to the lowest possible level according to instrument | 3.0 INTRODUCTION - This report details the results of the analysis for perfluorooctane sulfonate (PFOS), perfluorohexanoate (C6), perfluoroheptancate (C7), pentadecafluorooctanoate (C8), `heptadecafluorononanoate (C9), nonadecafluorodecanoate (C10), perfluoroundecanoate - (C11), perfluorododecanoate (C12), tetrahydroperfluorooctane sulfonate (THPFOS), and tetrahydroperfluorodecane sulfonate (THPFDS) in human serum, human plasma, and 3 `monkey serum samples. The study was initiated on October 09, 2002, when the study director signed study plan - number ExP-023-082. The experimental start date was October 15, 2002, and the experimental termination date was October 23, 2002. . 4.0 TEST SYSTEM - Pooled human serum samples were purchased by the sponsor from Sigma-Aldrich, Milwaukee, WI, Lampire Biological Laboratories, Pipersville, PA, Bioresource . Exygen Research. 000328 Page 11 of 111 J Exygen Study No.: 023-082 - TPeocohlneodlomgoyn,keIync.s.erFourmt sLaamupdleersdawleer,eFpLu,rcahnadseGdolbdyetnheWsepsotnsBoirolforgoicmalLsa,mpTiermeecBuiloal,ogiCcAa.l - Laboratories, sponsor from Pipersville, PA. Pooled human Lampire Biological Laboratories, plasma samples were purchased by the Pipersville, PA, Bioresource Technology, Inc., Fort Research, ILnacu.deSroduatlhei,eldF,L,MGIoldIenn adWdeitsiton,Bioblloagnikcalmsa,trTixemceocnuslias,tinCgA,of apnodolIendnohvuatmiavne - plasma collected in rural China was provided purchased from Sigma-Aldrich by Exygen by the sponsor. Also, calf serum was - [0203963 |Lot02082L| HumanSersm |__ BioResouce | |0203965 "Tot G0140604| HumanSerum | GoldenWestBiologicals | [0204335 |TN-A06332| MonkeySerum |_____Lampie | ) (0204747 |"TCR-683 | HumanPlasma | InnovativeResearch | Samples were received frozen on dry ice and then placed in frozen storage (<-10C) until - samples were logged in by Exygen personnel. All records concerning sample receipt, processing and storage can be found in the raw data package associated with this stud. 5.0 TESTITEMS ) `wTehreearnaelcyetiivceadlasttEanxdyagredns PonFOSSe,ptCe6m,beCr7,30C,8,20C092,fCr1o0m,3C1M1,EnCv1i2r,onTmHePntFaOlST,ecahnndoTlHogPyFaDnSd Services. reference The available information material was stored frozen. for the reference material is listed below. The : Compound ExygenlnvemoryNo. ~~ LotNo. Purity (%) Expiration Date PHAA (C6) 'SP0002086 NB 11773532 TBD 01/01/10 TDHA (C7) SP0002091 PUOT2I9EU 99.5 01/01/05 PFOA (C8) 5P0002087 210002 >97 0719/07 PENA (C9) cio SP0002085 5P0002090 HT568 >99 07/19/07 RIK 98 12/01/10 cit 5P0002093 UIIN >99 07/19/07 cz SP0002089 R24K 9% 12/01/10 : PFOS THPFOS SP0002084 SP0002088 217 86.9 0831/06 Q7S91 Unknown 06/07/05 THPFDS SP0002092 PMR269-83 94.7 08122112 Exygen Research. Page 120f 111 000329 : Exygen Study No. 023-082 `The molecular structures of the anions are given below. Name: PFOS Chemical Name: Perfluorooctanesulfonate Molecular Weight: 499,as shown i F E_EFLF] _FF_F]F 503 n- LL FLFFOF FFF Name: C6 : Chemical Name: Perfluorohexanoate: Molecular Weight: 31as3sho,wn . ELEF]F F 0 F F FLF 0 Name: C7 : MCohleemciuclaalrNWaemieg:ht:Pe3r6f3l,uoarsohsehpotwannoate d E_EFLFL_F F _0 F Flr 0- FFF : Name: C8 Chemical Name: Pentadecafluorooctanoate Molecular Weight: 413, as shown El EFF]FE_FF_0 F Flr 0 FOF FF . Exygen Research. 000330 Page 130f 111 - Exygen Study No: 023.082 - Name: C9 Chemical Name: Heptadecafluorononanoate: Molecular Weight: 463, as shown FFE FL 0 . F " FFlOFeeF rF | Name: C10 ) Chemical Name: Nonadecafluorodecanoate Molecular Weight: S1ass3ho,wn ) EFF EFF _F[_FFF _0 . . FFOlFrFlelFFF ? Name: C11 Chemical Name: Perfluoroundecanoate: Molecular Weight: 563, as shown EEFLF] FE E[_FF_|F F _0 . F Fleleleler 0. FOFF FF Name: C12 - Chemical Name: Perfluorododecanoate . Molecular Weight: 613, as shown : EFE EF _F _FF_FF_FF _0 . F FOfFlereF]F FlFeF 0" . Exygen Research. 000331 Page 14of 111 Exygen Study No: 023.082 Name: THPFOS Chemical Name: Tetrahydroperfluorooctane sulfonate Molecular Weight: 427, as shown F FE Fl_F E|_F F|_HH 50, . F FFF F FHH Name: THPFDS Chemical Name: Tetrahydroperfluorodecane sulfonate Molecular Weight: 527, as shown FF -- FEF F |F FHH 50; F FLFLH F F F F H 6.0 DESCRIPTION OF ANALYTICAL METHOD Analytical method entitled "Method of Analysis for the Determination of ) Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine" was used for this sptruodtyo.colFioprrotthoicsosltuddeyv,iatsieovnesr.al modifications were made and have been documented in the 6.1 Extraction Procedure a. Measure 2 mL of serum sample into a 15 mL disposable centrifuge tube and fortify, if appropriate. b. Add 5S mL of ACN and shake for ~20 minutes on a wrist action shaker. . Centrifuge tubes at ~3000 rpm for ~ 5 minutes. Carefully decant wsuapteerrnatant into a 50mL disposable centrifuge tub'and add 35 mL of . d. Load the sample onto a conditioned SPE column. Discard the eluate. Any analyte residues will betrappedon the SPE column at this point. e. Elute with 5 mL of methanol and then evaporate to less than 1 mL : using a nitrogen evaporator. Bring final volume up to 1 mL with methanol. ) . Analyze samples using electrospray LC/MS/MS. The volume of sample used and the volume of methanol used for elution were different : than those cited in the method. This was done to allow for lower quantification limits for the anions in this study. . Exygen Research. 000332 Page 150f 111 Exygen Study No.: 023-082 6.2 Preparation of Standards and Fortification Solutions Individual stock solutions of all of the anions were prepared on October 02, 2002, as specified in method ExM-023-071. The stock standard solutions were prepared at a concentration of ~ 100 pg/mL by dissolving ~10 mg of the standard (corrected for purity and salt content when appropriate) in methanol, From these solutions, a 1.0 pg/mL mixed fortification standard solution was prepared by transferring the appropriate volume (~0.4 - 1 mL) of each of the stock solutions into a 100-mL volumetric flask and bringing the volume up to the mark with methanol. `The 0.1 pg/mL mixed fortification standard was prepared by transferring 10 mL of the 1.0 pg/mL mixed fortification standard into a volumetric flask and bringing the volume up to 100 mL with methanol. A set of calibration standards were prepared by dilution in the following manner. Tnitial Conc. (ng/mL) Volume (mL) _ Diluted to(mL) Final Conc. (ng/mL : 100 1 10 100 100 0s 10 50 100 02 10 20 100 ol 10 10 - 50 1 10 05 20 1 10 02 10 1 10 01 "The stock standard solutions and all fortification and calibration standard solutions were stored in a refrigerator (6 + 2C) when not in use. 6.3 Chromatography Quantification was accomplished by electrospray LC/MS/MS analysis. An API 4000 . Sciex system was used in this study because of its greater sensitivity and also because it had not been used for fluorochemical analysis prior to this study. Peaks were detected in the control matrices corresponding to some of the target anions, especially for C8. 6.4 Instrument Sensitivity The smallest standard amount injected during the chromatographic run had a concentration of 0.1 ng/mL, which corresponds to a concentration of 0.05 ng/mL (ppb) in - the extracted samples. Residues were calculated below this level where the response of the anion was approximately three times the signal to noise ratio. The results were ` Exygen Research, Page 16.0f 111 000333 : ) : : . ] - Exygen Study No. 023-082 reported as Not Detected (ND) if the response was approximately less than three times the signal to noise ratio and Not Quantifiable (NQ) was used for negative results. All other responses were reported. 6.5 Description of Instrument and Operating Conditions Instrument: PE SCIEXAPI4000 Biomolecular Mass Analyzer, (LC/MS/MS #8) SCIEX Turbo Ion Spray Liquid Introduction Interface: Turbo lon spray temperature = 350 C Auxiliary gas flow = ~ 7.0 min Harvard Infusion Pump Computer: Software: DellOptiPlex GX 110 PE Sciex Analyst 1.2 HPLC Equipment: HPLC Column: Column Temperature: Mobile Phase (A): Mobile Phase (B): Hewlett Packard (HP) Series 1100 HP Quat Pump HP Vacuum Degasser HP Autosampler HP Column Oven Genesis C6, 5 cm x 2.1mmid. x 4p (ExygenID: 714) (JONESCHROMATOGRAPHY:PartNo. FKS962E) 35C 2 mM Ammonium Acetate in Type I Water Methanol Time0(0mn) 2500 9950 114550 200 ~~ %20A 91000 10000 90000 900 %10B0 Flow Rat0e3(mUmin) 910000 0033 1900000 0033 1100000 0033 100 03 Injected Volume: 15 pL - Tons monitored: Acnison Pare3n13tion Daug2h0t9erion Duellot(secs) Declusteri2n0gPotential Collisio-n10Energy c 363 319 cs an 30 ootl 2200 "1100 cs 63 a1 clo si3 Pe] ol1 2200 "1100 cu 563 519 ol 20 ci 613 560 01 20 "1100 PFOS 9 8 ol 5 0 TTHHPPFFDOSS 542277 88 ooii a5s 560 Exygen Research. 000334 Page 170f 111 - Exygen Study No: 023.082 ) 6.6 Quantitation and Example Calculation ) Fifteen microliters of sample or calibration standard were injected into the LC/MS/MS. The peak area was measured and the standard curve was generated (using 1/x weighted linear regression) by Analyst software using seven concentrations of standards prepared in methanol. The residue concentration for the samples was determined from the following equations: - UussiengEqtuhaetisotnand1atrod ccaulrcvuelat(e/xtheweaimgohutnetd olfinaenariornegfroeusnsdion(inpanrga/mmeLt,ersb)asgeedneornatpeedakbyartehae) Analyst software program. [Equation 1: | Analyte found (ng/mL=) (peak ar -inte ercea pt) slope . Use Equation 2 to calculate the amount of analyte found (in ppb) Equation 2: Analyte found (ppb = ng/mL) =(analytefound(ng/mL)xFV(mL)xDE sample volume (mL) FDVF == fdiinlaultivoonlfuamcteor For samples fortified with known amounts of analyte prior to extraction, use Equation 3 to calculate the percent recovery (ppb = ng/mL) " } `Equation 3: Recovery (%) = [total analyte found (ppb) - analyte found in control or sample (ppb)] 100 . analyteadded (ppb) Note: Any analyte found in the control was subtracted from analyte found. - However, the response for the sample duplicate was not used. - Exygen Research. 000335 Page 18of 111 ) Exygen Study No. 023-082 An exampleof a calculation using an actual sample follows: `Human Serum Sample, Exygen ID 0204491 Spk J (Data Set: 101702), fortified with 0.5 2 ng/mL (calculation is using values for C6): i Where: peak area = 54636 intercept = eam ) slope = 504359 ndigl/utmiLonadfadcetdor(fort level) == 1 0.5 ng/mL : avg.amtincontrols = 0 (Not detected) sfianmapllveolvuolmueme == amm L From equation 1: Analyte found (ng/mL) = [54636 632.2771 594359 - = 09ngmL From equation 2: ) Analyte found (ppb) = 09ng/mLxlmL 2mL = 0.45 ppb (ng/mL) From equation 3: %Recovery = (045 ng-/0nmg/mLL) x 100 0.5 ng/mL = 90% E Note: This example calculation was done using rounded numbers, and therefore `may be slightly different from the values shown in the raw data. - Exygen Research. 000336 Page 19.0f 111 Exygen Study No. 023-082 7.0 EXPERIMENTALDESIGN : For the screening of each sample, duplicate extractions were performed. Also, cach sample was fortified at 0.5 ng/mL and 5.0 ng/mL and then taken through the extraction ) procedure. Two calibration curves were also taken through the extraction procedure, one: using calf serum and one using human plasma. These were treated as quality control fortifications in the data set and were not used for the calibration curve. Since there was ) residue detected in the samples for THPFOS and THPFDS, an additional analysis in `which a three-daughter ion confirmation was performed. 8.0 RESULTS : There was no significant residue detected in the reagent blank analyzed with these samples. Also, there was no carry-over present for any of the anions in the instrument blanks (methanol washes) analyzed in the analytical sefs, except for C8 and C9, and this : is most likely contributed to those analytes being present in the instrumental system, particularly in the mobile phase. This is especially evident with the absence of the anions. ) (except for C8 and C9) in the methanol wash analyzed after the injection of the 10 ng/mL calibration standard. All fortifications were at a level equal to or less than the 10 ng/mL. standard. Since there was no carry-over observed after the injection of this standard, the ) camy-over present after proceeding injections would be minimal. A representative chromatogram of a standard prepared in methanol can be found in Figur1e. Recoveries for fortified samples are given in Tables III. Recoveries outside the suggested range of 70% to 130% were reported, however this method has not been validated at these low levels and some of the recoveries were outside of this range because the level of residue in the sample was significantly greater than the amount fortified, especially for C8 and PFOS. Example chromatograms of fortified samples are . shown in Figure 2. . Residues of each anion in human serum are summarized in Table IV. Residues of each : anion in human plasma are summarized in Table V. Residues of each anion in monkey serum are summarized in Table VI. Example chromatograms of a human plasma sample . are given in Figure 3. The detection of THPFDS in some of the samples warranted further investigation. The presence of THPFOS and THPFDS was confirmed with a re- analysis with additional daughter ion confirmation. A chromatogram detailing the three } daughter ion confirmation of THPFDS is given in Figure 4. . Exygen Research 000337 Page 20of 111 : Exygen Study No.: 023-082 9.0 CONCLUSIONS `The quantitative screening of these serum and plasma samples produced levels of certain analytes at extremely low levels (< 100 ppt). These levels are based solely on the instrument sensitivity and not the method recovery. The results contained in this report should be evaluated as a quantitative screening. Contamination of these samples due to instrument conditions is very limited because the instrument used for the analyses had : never been used for routine fluorochemical analysis prior to the initiation of this study. No carry-over was observed throughout the injections of the analytical sets, which was demonstrated with the absence of the target analytes in the methanol washes analyzed . after the injection of the highest level of calibration standard (10 ng/mL). Two people took a set of 64 samples through the sample preparation procedure in - approximately 10 hours and the analysis by LC/MS/MS took approximately 48 hours. | 10.0 CIRCUMSTANCES THAT MAY HAVE AFFECTED THE DATA . `The method used in this study has not been validated for C8 and PFO at the levels given in this report and at any level for the rest of the anions. Residues were reported lower than the lowest calibration standard. 11.0 RETENTION OF DATA AND SAMPLES When the final report is complete, all original paper data generated by Exygen Research will be shipped to the sponsor. This does not include facility-specific raw data such as - instrument logs. Exact copies of all raw data, as well as a signed copy of the final analytical report and all original facility-specific raw data, will be retained in the archives ) of Exygen Research for the lifetime of the product. Sponsor permission will be obtained before discarding. . - Exygen Research. 000338 Page21 of L11 : Exygen Study No. 023-082 : Exygen Research. 000339 Page 22of 111 ] Exygen Study No: 023.082 | Table I Summary of Recoveries for Calibration Curve in Calf Serum Compared to Standards in Methanol %Recovery : Sample ID Sponsor ID For_(tsLgiemvl)el C6 C7 C3 C9 ClO Cli Cl2 PFOS THPFOS THPFDS Xclom2o| Na 0 -1-1-1-1-]-]- -5 Xcloro21| Na 02 f85(120{ 163 151| 155 96| 87 18 | uo xciorme2| Na os {8 [uf127 (132 135| 110| 11 159 | ae ) xciorme3| Na 10 [90 |13{ 109] 124| 12| 111 116 1a | 0 xclomos| Na 1s e213] 21 127] 121 | 120 121 57 | us xcioo2s| Na 20 [102108] 117{ 122 115| 109 110 12 | we ) Xclor026| Na 25 |97|99 [111{107| 103 98| 98 woo xciore7| Na 509s] 07100] 108] 104] 106] 105 | oe AVG: 96 109 122 124 121 107 107 + 148 131 . STANDARD DEVIATION: 62 82 19.1 150 186 82 115 *= 18 96 RELATIVE STANDARD DEVIATION: 65 75 156 121 154 76 107 ** 52 13 Table II Summary of Recoveries for Calibration Curve in Human . Plasma Compared to Standards in Methanol %Recovery. SampleID SponsoIrD FortL_e(ngvmle) l C6 C7 C8 C9 CIO Cli CI2 PFOS THPFOS THPFDS . XCI015028| TCR6M| 00 | -]-]-]-]-]-]- ". xclotso29| TcrRe74| 02 |90[120[ 126 86| 33| 11s 109 w| XCioiso2-10| TCR| 05 87121 146| 11s] 84| 132 14 0 | 10 - xcioisoz11| TCR| 10 |96(113[121{ 104] 90| 110] 108 51s xciois213| Tere| 20 |107| 114] 129107] 112 14 120 0 | 137 xciouscis| Toren| solos [or |i0s| 97 | 9 [101104 w| 3 AVG: 93 113 126 102 81 Ila LIL = 146 130 STANDARD DEVIATION:102 96 144 109 292 113 62 *= 124 116 RELATIVE STANDARD DEVIATION: 109 85 115 107 358 99 56 *= 85 90 ** Recovery not applicable because the residues detected in sample were significantly greater than the amount fortified. : Exygen Research. 000340 Page 230f 111 | Table III Summary of Recoveries for Laboratory Fortified Matrix Spikes . Calf Serum EESTI: Human Serum ) %Recover ** Recovery not applicable because the residues detected in sample were significantly . greater than the amount fortified. `Exygen Research. 000341 Page 24 0f 111 : Exygen Study No. 023-082 ] Table III (cont') Summary of Recoveries for Laboratory Fortified Matrix Spikes - `Human Plasma %Recovery. SamplelD SponsoIrDFortL_e(givmle) l C6 C7 C8 C9 CIO CII CI2 PFOSTHPFOS THPFDS 0204334 SpkH| TCR684| 05 | 69] 94| 211 [152107] 95| 103 0204490pk1| TcRe74| 05 [7878| 73 | 84 [9001 [96 = | 13 07 | 102 020491 Spk1|TN-A6337 02047475pkG | TCR683| [05 [01| 97 | 168 05 | 89| 124 406 [140/110] 91| 93 [182 143 132| 120 us | ne 159 | 146 0204334 SpkR| TCR684| 50 | 96 |100( 131 [110] 110] 98| 100 us | : 02044505pkU| TCRa74| 50 | 86 [85| 92 [9092 [9296 020491 SpkT| TN-A6337| 50 [97| 96 | 109 [101] 5| 86 | 88 09 | 02 us| 106 020s7475pkQ| Teresss | 50 | 2 [ss | 10s|920083] 83 wm| oes : AVG: 86 95 162 119 105 9 97 + 119 ill STANDARD DEVIATION: 9.4 139 1080 353 178 153 ILL ** 170 157 RELATIVE STANDARD DEVIATION: 110 147 667 297 170 160 114 * 143 141 Monkey Serum : % Recovery. Sample ID___SponsorIDFortLeve)l C6 C7 C8 Co ClO Cli C12 PFOS THPFOS THPFDS 02043355p[k|TN-A063%2| 05 [106] 91 68 | 52| 88 | 85| 95 ne | 2 . 0204492 5pk K|TN-A06333| 05 [1221112 129 138 17| 129 125 6 | 15s 0204493 Spk L|TN-A06336| 05 [123] 98| 97 [102115| 93| 94 wm | no 0200335 Spk's |TN-A06332 50 [100[93| 97 [107| 108 105 [109 07 | 104 . 0204492 5pk U|TN-A06333| 50 | 88| 85| 100{ 94| 97| 93 | 101 24 | 16 0204493 50k v |TN-A063%6| 50 | 11s 100] 116| 11a] 100] 106] 107 |0 ) AVG: 109 97 106 101 106 102 105 += 130 126 STANDARD DEVIATION: 137 93 206 274 1L1 155 115 ** 198 172 RELATIVESTANDARD DEVIATION: 125 96 20.4 212 105 152 109 * 153 139 ` ** Recovery not applicable because the residues detected in sample were significantly greater than the amount fortified. ) Exygen Research. 000342 Page 25 of 111 - Exygen Study No.: 023-082 : Table IV SummaryofResiduesfor Human Serum Samples Amount Found (ng/mL) `va, Sampled SpowoID C6 C7 CS C0 CIO Cl CI2 POS THPFOS THPIDS fun 60 aid, [|009206396D3u| p| LLoto02v08o21 |[0.x02061|] NNDD (22s.s8l5a/s0.s6s8l30.02228|| 00.33771 |j0o.m0a3e323|( 353230|| NNDD | o0.o07m43 : Gog | 1020030936946D4up|| LLoott2222KK009966S5|| NNDD. [_|000.9049076/]11..6455/(00:320776(/00..11008]7 000.1514520[000112722{ 889654|| NNDD || 00004s0t22 0203965 |LoxGO140604 0.0687] 0.145[593{05080214] 0207 [0.0199] 20.7| 0.0840| 00845 Cold WA 0203965 Dup|Lot GO140604 |0.0884| 0.170[6.00(0.5570.204 0236 [0.0184 29.3| 0.0436| 00944 - 20022045229u2p] Xx3s2288-.A4 | NwDp| [00.11215 J|s3.n5f8o0r.m6z3l4/o0z.a1n8l9 00..113479 [l0o.o0s1e6]9 2160.66|| 00.003202s1 || 00.0079s1 Table V Summary of Residues for Human Plasma Samples ' AmountFound (ng/mL) SumplelD SponsorID C6 C7 C3 Co CIO _Cli_CI2 PROSTHPFOSTHPFDS Gln WA oo0usse T tere [ND [00] 257 | 010% | 0108 oor] ND| 163] 0010| 06s _ _|020042303444D0up|| TTCcRra67844| [NNDD|[0N.0D875|[02068847]| 0N.1o98||002.15202 [[0o.00s69s5|| NNDD [[417683|| ooNuDs||00n6D09 fours 0204490 Dup| TCR 674 |ND| ND [0130| NQ [00167 00357]ND [434| ND | ND Lf [on0t20491up|mTNe.aA6s3r37|| NDo|noNDn|| 225233|| 00.210686 0[0008854s0 o[0a0s5e0s1) 0ND|| 1112.46] N>D|| 022 0204747 | TCR68 | ND|00897| 209| 0287 [ 0121|0.105| ND| 14.1| 00193 | 00843 wl lo204747 Dup| TcR683| ND [00876] 292| 0416| 0.163 [0178| wp[19.4] 0.0202 | 0100 ) Table VI SummaryofResiduesfor Monkey Serum Samples AmountFound (gn) . N SamplIDe _SpomsorID C6 C7 C8 _CO_CI0_ClL_CI2_ PROS THPEOS THPFDS . mp" |o200a230s43s3D5upTN[TaN0-A6-30633232){ NNDD|| NNDD|| 11.7225| [34.3274 |[00.329866|| 00.55400 [|00.00s366s5|| 2172.42 | | NNDD || 00w1D41 . LeprY 0200240449249D2up{TNT-N2-.A-0066333333]) NNDD|| NNDD|| NNQo||NNQe|[0o.01ss0o3|| 00.1113s7|| NNDD| 1[16654|| NNDD|| 00w1D30 020493 [TN-A06336 ND | ND| NQ|Na| ND [00939l00z2r| 148| ND | wD Compr 0204493 DuplTi-a-06336] ND| ND| NQ | No| ND [0.06 00x21) 18.1| Np | ND ND =NotDetected | NQ = Not Quantifiable (negative residue calculated) : Exygen Research. 000343 Page 260f 11 : Exygen Study No: 023.082 i Exygen Research 000324 Page 2700111 ee . Exygen Study No.: 023-082 Figure 1 Chromatogram Representing 0.1 ng/mL Calibration Standard AERE | 21 i | : [rE || . Exygen Research. 000345 . an Page 28 of 111 : nso335 - Figure 1 (cont) ~Chromatogram Representing 0.1 ng/mL Calibration Standard } Ee, PE - 2s 3 lal iT | . Exygen Research. 000346 Page 29 of 111 - Figure 1 (cont) ~Chromatogram Representing 0.1 ng/mL Calibration Standard " Cpr m-- | bl men mpanm EEE ED | : | 1 eps etor vente oan RRR 000347 - Exygen Study No: 023.052 - Figure 1 (cont) Chromatogram Representing 0.1 ng/mL Calibration Standard - [Ea | - | ir - " | TN . Exygen Research, 000348 Page Sof 111 - Exygen Study No.: 023.082 = Figure2 Chromatogram Representing a Fortified Human Plasma Sample at 0.5 ppb (Exygen ID: 0204490 Spk J, Sponsor ID: - TCR-674) IE | BT mn ee Nl br EE | - Exygen Research. 000349 Page 320f 111 - Exygen Study No: 023-082 - Figure 2 (cont') Chromatogram Representing a Fortified Human Plasma Sample at 0.5 ppb _ 0 \ i (Exygen ID: 0204490 Spk J, Sponsor ID: TCR-674) | - F ET B Ee E HE || | i yd| - EBeXE vRiE toiz9 | LTi ae cm comme0 Bol . Exygen Research. 000350 Page 33 of 111 . Exygen Study No: 023-082 - Figure 2 (cont') Chromatogram Representing a Fortified Human Plasma Sample at 0.5 ppb } (Exygen ID: 0204490 Spk J, Sponsor ID: TCR-674) Ee . i BBaFE E | 3 Be EE | al | pIS | J Exygen Research. 000351 Page 34 of 111 3 Exygen Study No: 023.052 - Figure 2 (cont') Chromatogram Representing a Fortified Human Plasma Sample at 0.5 ppb (Exygen ID: 0204490 Spk J, Sponsor ID: TCR-674) [Eraa | |. . Exygen Research. 000352 Pa35gof1e11 . Figure 3 Chromatogram Representing a Human Plasma EEE Sample (Exygen ID: 0204490, Sponsor ID: TCR-674) ' Bird -i - He SE J EI 77 | TO . Exygen Research. 000353 A Page 360f 111 - Exygen Study No.: 023-082 . Figure 3 (cont') Chromatogram Representing a Human Plasma --Sample (Exygen ID: 0204490, Sponsor ID: TCR-674) EEE] -Lo ue pr murs co | - vad] . mas EE lw, | | Er. 11 eT | : || -To rpms = 0=) i Bog Resch Ex peor - ExygenStudy No.; 023-082 WT... Figure 3 (cont') Chromatogram Representing a Human Plasma . Sample (Exygen ID: 0204490, Sponsor ID: TCR-674) o Be RET E==" - EEE /] | T ! - EEL E10 aE Ba BE . i . Exygen Research. | ! i [| al G -- 000355 Page 38of111 - Exygen Study No.: 023-082 . Figure 3 (cont') Chromatogram Representing a Human Plasma = ....._ Sample (Exygen ID: 0204490, Sponsor ID: TCR-674) - - E --"TY aver i Forge Basas 000356 wget , Exygen Study No.: 023-082 . Figured Chromatogram Representing a Sample Analyzed for Three spar yDaue ghten rIsDfo0r2T0H42P5F2DDSup, Sponsor ID: X328-A). ) er BE | e3 r TATTiree oam op eTmsiiheen TR op =e ||| Bi EE Fila dn T piiinl! nM iad "Te HTT, | | } ExygenResearch.y Ns?] Pageage 4000 111 | APPENDIX A Exygen Study Plan } ExP-023-082 - (Exygen Study No. 023-082) and Deviations - Exygen Research. 00358 Pagedlof 111 - Exygen Study No. 023-082 : . EoStmy pa epoo05n2 . a STUDY PLAN ' ) Study Title: i oe AnalfyosriFsolufoProooclaerdboHnusmUasinngSeErxayagnedn PMleatshmoadaEnXdVM-0o2n3k-e0y71Sera ! Study Plan Number: ExP-023.082 Exygen Study Number: 023-082 | ) i `PE3e0rx5f8oorRnmeisRneegasrLecaahbrocDrhraitvoery: `3BSutMiuldEdyniSvnpigorn2os3nom6re.:n0t9al Laborsiory i! SPthaotneeC:ol(l8e1g4e),2P7A2-110638901 SPth.oPnaeu:l,(6M51N) 757561-3635-635331 - i|| i . ! . ; |i! i | . Exygen Research. - 0poasD Page lof$9 ! Page 20f111 Exygen Study No. 023082 : SutyPs 13.01 `Exygen StudyNo.: 023-082 pet Ly 1EailyR.Decker, SayDito,BeygenResearch 2) WilliamK.Reagen, Sponsor StudyMonitor, 3M. ! .4 3)ExygenResearch QualityAssurance Unit i oi|) | oo | || : i i i | } Exygen Research. TTT aw ! 000360 Page 430f 111 . i : i i :i i - i; | i ) -| Cd | ) ! ii | { ! . - Exygen Study No.: 023-082 EaSsetSuyiyENox.pzC2o0n82 Study Title: FAlnuaclryosciasboofnsUPsoionlgedEHxyugmeannMeStehroadaEnXdMP-0l2a3s-m0a71andMonkey Sera for ii i ``SEtxuydgyePnlSatnudNyumNbuemrb:eErx:P0-2032.30-80282 i b "Thisstudyplan wasauditedbythe QualityAssurance UtofExygenResearch. Soom ova Ut dnl Technical Lead-QA Dtouleer !:! | APPROVALS yRiDecker, SnIody Director if3)oDzat.e Exygen | " wey } ExyJoghneFnlaherty, Vice Prsident, Facility Management. - Date i i i "alMiamResges, Sponsor Sly Moir em Exygen Research. ~ 000361 PrTEeT. i Pag4ed of 111 \ 1000 143 RSD be TE ER + EID | 4 : iLo } Co : Exygen Study No. 023-082 ros ro ESstyoxoB s0o02 ai : iStadyTitle:"APnuaclryosciastobofnsPUosoilnegdEHxuygmeenMseSherosdBanOd PUlaTsOmaTs]ndMonkey Sera for it 4 1. i:| SedyPlmNumber: EXPO2-082 t | ith odylanwasmindbytheQualltyAssesUs of ypeResearch. ! Ls 8. ou i : i ical Lead QA 1.00 ---- i i . | . : APPROVALS NE i HYrm . eg ow g :; PR . i 0 ami,viePenFyMngt -- = ! . . aE{Boye i ) i ' Wer = -- -- isle _t0/gBsetbr. ! | fl i ETT vpo edo Ea-- p -- ote -- 3 -- s : ) ERE FTE we pn 000362 : Bogen Sty No 03002 SsRrR son n | . I :4 : i TRINGrrrsmsssassmermrerresemeemm DISTRIBUTION oceans ssn3 4 STUDY PLANAPPROVAL mmr ess i et -------- { INTRODUCTION ccm 8. $ J ------------ -------------- STUDY DIRECTOR woeesemeemermmseremmsmsssssesssssessesmssssenesmmme - |ii - -; . i| `SPONSORSTUDY MONITOR erences i C Rcao EBm AaaTRATION : IDENTIFICATIONANDTUSTIFCATION OFTHETETSYST 3 1 SAMPLEPROCREU CEIPR TANE DRETM ENTIE ONcN c. T, coccsmimsmmmss i SamsERO ANALYTICALPROCEDURE SUMMARY veces 10. Se emosseronecorn ms Er ere ---- ---- STATISTICALMETHODS cmnrscsmmssnmmesmsrrsesssssssmsamssmsmsmesasssmssens 12 i i ei A ------------------ SAFETY AND HEALTH ecommerce 13 i QUALITY ASSURANCE cerneseseesemsenrsssesemsmmsmmsssssssssssmssonsses 15 i {; { . . Exygen Research. - 000363 -- T_ S 1 Page d6 of 111 ssipern hB e ce t tsefeete s s ise | a. :: EpE m EBeTntTadeecDale lauI oroocTtoanncsicbaci4mdpeC((C08),mhpOeptadr eieecenaeflusotroCen nonpDaanciS1c2na,c1i1dee()sCd9d), i| = FREohna st Hna--,0CSS i ie iy i te dr coms wih G5 pcp Ga iJ `LQaubaloirtaytAosrsyurPraanccteiUcnei(taosfrEexvyigseedn Riense1a99r7c)h,. ENV/MC/CHEM(98)17 by the i t | .i iss cisalin GR] |{ F So Tpuirm ee S5C8lls,)eppC=i trreeo2enGC82 t ii mi tetrshydroperfsullufoonartoe(dTeHPcFaDnS)e.Al test items wersreceived | NafserC:prosn }; F TF TF ! -]|| I i . . E-- - 000364 Page Sof9 ! Page 47 of 111 - : i ! : ! | f i | : -; -{ Exygen Study No. 023-082 cs . ne Fens `Molecular Weight: 31ass3ho,wn m rumm i - i Name: Ce o7 neaa E F EF i FRA0- |i _-- A me Tote i A F- 0" i i Name: C5sittin :{ Moleclar Weight 468 3sho,wn i NNN F 13 F F 0 : ` ; . - [Exygen Research. 000365 PageGof 5H Page 48 of 111 i - ii ) | i }| i od| - :i < :ii . - Exygen Study Noi 023.052 ---- ExSty udy g No.:e 023-a 082 Name:CCh1e0micaName: Nomdecalorodcanci id MoleculseWeight: $1ass3ho,wn [EEE {| {t --ChiaName: ecsoromdesseic sid `MolecularWeight: 56ass3ho,wn | EEE f ok |! 0 } i Name: CC1h2emica Nam: Pectlorodotacanic sid Moleclsr Weght 611 3sho,wn PoE Pe : +7 - i| Nam:THPROS . | `Chemical Name:Tetrahydroperfluorooctanesulfonate. i MolecularWeight: 42 ass7ho, wn : e ePlhee . feiln" ; F- 503 Exygen Research. ee " Page 7of59 i Page 4901111 000366 i i| 3 !|| . |i : ; -i i - | . - .! . - Exygen Study No.: 023-082 ExSytinytPloadsENpo.: 002233008822 Name: TCHhPeFmiDcSal Name: Tetrahydroperfiuorodecane sulfonate Molecular Weight: 527,18shown FoP F L u Wo 50 i|i 3 f pTohoelpeudrhpuomsaenofstehriusms,tfuoduyrids tio pefrlfooftsrmoeafnpaorloylseeidshonunmftaonurpdlaisfmear,aatnldostshoref. loaFnteaslhyotufimcablpeoomlmeeednthmioocdn,oknee"yM.esteh(rouTdmHfoo,fr tAPhneeatilayosgsiesotcmffoeuromritochceoomnDpseo.tuenrd(msiFnasOtiiSnognt1h0oe4f |! Pentadecafluorooctancic Acid(PFOA)inRatLiver,Serum ndUrine." i i E3x0y3g8ReensReeasrecahrcDhrive SPthoanteC:o(l8l1eg4e),27P2A-110635901 SEUDVIDIRECLORS So FREES ii S`cEimeinltyiDsetcker } . i P`Ehxoyngee:n(R8e1s4e)a2r7c2h-1039 ii emilydecker@exygceonm Bu3iMldEinnvigr2o3nEme-n0t9al Laboratory PShtoPnaeu:l,(6M5N1) 757581-3653635331 -- : Exygen Research. 000367 TT racia ! Page SO Of 111 Exygen Study No.: 023-082 ExSytgyePnaSruNdEoyx:p002233..008822 i SON ORSU ONCORM ST a ir shy |i B`WSutii.llPldaiiualnm,gRMe2.aN3g8Se.5n01933:3331 ii ii PWhoine:r(e6@51am)7mg78m-e6c5on6m5 { i ; PROPOSEDRPERE ENI TRSTAR DATES ENIEEETE NaATEeN 0) Sai Sd| 1 is propose thttheanalyticalportionofthisstudybe conductedfrom !! teOrmtiniastion14dtteos.wOicltlobbeeirn2c1l,ude2d0i0n8,the Tfihnael sreepomrt. exsenmsernt ianld t{ CONT CATE SEN PFiie si i BU LE | :: A`lSlpoonsmomrunwiiclabteiodnisrebcettewdeetnhtrohueghTetshteinSgtuFadcyilDitiy,smceoth(oodrddeevseilgonpeeres), aanndc tthheo , `SStpuodnysDoirreScttuodry.Monitor, Communications will be fully documented by the i { Tl ROS HESTSYSTEM EET 2 OETm pre oy i ; | `Pooledhumanseraandplasmaand monkeyseraareusedasthe test systems i - ibnetheipsrsetsuednyt.aTtvheeomfatthraitcfeosrwwihlilcbhetphriosviadnealdybtiyctahlmeestphoonsdorwa.sThdeesmigantedr.icweilsl Hi -To i SAVPEEPPeRdOChUmREsMeEmNTsRaisEweCr pEEuAtNPedR by EiE NTpoOT orRfRomESim i ABilodriecsho,urMcielwTaeuckheneo,loWgIy,, LIunncp,irFeorBtiolLoaguidcearldaLlaeb,oraFtLo,rieasn,dPiGpoelrdsielne,WPeAs,t bByiotlhoegiscpaolns,soTrefmreocmulLau,mpCiAr.e BPiooolloegdicmaloLnakbeoryatsoerriuesm,saimppelsesvlwle,rePAp.urPcohoalseedd human plasma. samples Wee purchased by the sponsor from Lampe Exygen Research. - 000368 Page9of 9 ! Page SLof 111 . 3 |. |:|i : ;{! i| -} i i! i _ Eaygen Std Nos 023082 . Sr enRs ree aieon thece a seadtideesweedslhoerSceiirnoi35n3p,o1tiodfnse ! identicaltothesamples,using bovineserumandalso asetusing human : modoboats i `acctoothre dfolilonwigng table: i Conc. Of Mixed _ Fortification Volume (dL) Volume of Control Conc. of Exwacted 3 { Fortification Sample (mL) Calibration ! TowL L enh)oo m o%o0m%wnB 00%% nSa508aB !{ 10 300 20 15 ; 2g ting fy il bi hee llywisboJnfs oche nyseoonnr ts A T aeo nepo tewepdbve ysosoffaisbetsafeccionns Te he:Bpootential existso for interference fwn roem.flvoS rochemiu caals sfionn trro1dduc1wes dihfrom || tk an addedtothe matrices via amicropipette. Fortified saples will | beprocessed throughthedescribedproceduresto easuremethodaccuracyand i i `to check for bias. cou 03h%e.aton oct we 2 be ovr Recoveries should be between sponsor may accept occasional 70% and recoveries 130% of the fortified outsideofthis range. levels. "The The relative. A Err yb Spin a Sd Drer Anymodificationstotheanalyticalmethod willbedocumentedinthestudy t I Page 11/59 Exygen Research. 000369 Page 3 of 111 - ); || i - | || .: i |! .i i Exygen Study No: 023.052 ESyuetySPeadnyENop:o0n00882 NE OCR ONRO ED Ee SE Se Fre Cahononamtlorygoselinnogeafobtuisessamwtiixlotlvurboeelaeodvfderlcseasocsfhefdmrbaiytcittxaikfioonnrgsnreepsretseendtactoinvtersoulbssaammpplelse,s afrnodmbya !|| aSltealiattieowniolfalvbeetligmsitreedctoovtehteons, stpreacpipfticesdbne.thesubjectmethodandto the : AlOENElVCasMDpCecItPrsCioHnfcEtiphMli(esssStEou)fdy.GshoTaolhdlebeLfiapnbeaolrrfaroteropmorreytdoParnadcdtaritecapeopra(tcerkdaeigvneicos(smeupdplpilaiinendce1ow9i97tt)hh,e i Siptohnscoru)crsahtalancdonstpapilnicsslseeGmeLnPtstthaantdtahredsstaunddywwialslcuonldiunctaendyindcevoimspiloinasncien tDhierescttoary1nfdroSmpotnhsosoerstandards, This ssement will be signed by the dy cAfoinanlcsploorutftswhiisltloubdenyp.reTphaerreedpboryttwhiellsntayodirdebcutetorwo,irlnthoeibdeeisignee 1a0td,tthhee :i following: i + Ttehsetinngamfe acnd address ofthe Study Directo, Sponsor Moritor andofthe + chAin-suotfe.mceunsttoodfyGreLcPordcso,mmpelsittnbceefn(hsaeysreeldatreedcodrodcsu)m.entation, such 3s : + TAshseursaingcneedUraindredgaureidngstdaattesmeonft sbtuydythienspEexcytigoenns 2Rnedsedarecsh fQiunadliintgys : werereported to he StudyDirectorandManagement. Exygen Research. 000370 ma ! Page sof111 Exygen Study No: 023.082 os ; i i| : i: ii | } i i| i|} i oo i -: . . EStxySPytaynNEixop..e002130n08812 A hdeesscurbijpetctiomnetohfotdhewaesxacftolalmoawleydicealxocnldiitoisnnseccaesmspalrtioyonyitenhcdlusdetdayl.yIaf coipnyocfothreaipnnatolytrtichsalrtmeepetorhdto.dI.fAtnheymemthooddis iphotfotrcehdiusamceedtd,thhooedpwrinoljlsebce ; umberan pagenumbermust beincluded onexch age. | + orAndyirsetcetpisoncsomnussid:ebreedfoclriltoicwaeld,piree.cisseeplys where ll vasiaion i allowable |i + Descriptionofthensiumentuasidaonnd operating conditions. + Thofesanmupmlebse.r of workerhoursorcalendar daysrguied 0complet omesek Alsalmprleessu,ltasnfdiionmtahleldsaetatstaabnlaeliynzceldu.deTdseanmdpilfeynualmbecro,nftoorltiafincdatfioorntliefvieel,d `nd queidenificaion numberbysumplese. i t| + cRheprreosmenotagtievnecohfromaatnodgararmasndorecaocnthroalnsaalmyplie,eaancdhamcahrtoim,atinocglruadminag it 2defnoirieidaiaolnllhervoelmatTohgeramlosc.ation of the analyte peas wil be clearly + AdlaltCwiirlulbmsodtncoesctuhamtmieantynhehtraevpeeoardftf.ectedthequltyot ntegityofthe + Locationswhere rawdataandthefinal reportae tobearchived. + A`dmdeintdiiomnesnotrbycotmheecStoundsytDoitrhecetof.inaTlhreepaomretsnhdamlelnbteshianlthceleafrolrymidoefntaifny hatpastofthe report thatisbeing liered.andthereasonsforthe |i ! Dirsiiornsse.adctThheteSpaoonmseronrdmSetundtyMwioltlobre.signed anddatedbythie) Sudy i + Laborsony personnel wil pragcodtsritacdoensn healt abs. + Avenrysbeleysalfcecotnttheisntudoyfwaibllobretrreyppoeesdn10ntlhetSatdmyaDyirbeectcoro.nsidered 1 + sAtnuydyiwnijlurlybetroeIpoarbtoerdtortyhepesrtsaondnyedliorcctu.ring during the conduct of this Exygen Research. 000371 rang | Page ss of 111 od: ; odi Cdii | !i i oo i - ExygenStudy No. 023.082 e JR , + rfyilreisognrpeeceanbshalebemen to peghniimitneirn `substance(s). || Al signifiecanntanachhaynogEwestithtonbotyeheosetSadyydpolainnoutllt inead boeprevooo fwostivlFlybrSepbetexnn prsMeshseandogiFn i ne an saodnhsoenyln, bSntsdyo oDewsartay twoe livovaseaiooofps wra ittenamendmentwihlibeethreedastieodftohhedoScuomenctedcshoanygei.sCcoopoifetohsee i oE riginal amey ndmE ent willpn beimoainato ainedawityyh thste oritoginyalsMstoudoypnplvant. Any i!i } Recon ob mind cad sallow (os popes: + Sune cienpo asnhieosnr )sh e dasorskd, hoiessofcustoudtyrtion) LR E domheen enaoirsn |}| Aaeotsyrpeeasons csgottonsds :| + to assy re bonoof he sy Chronological presentation of al study correspondence. } Chromatograms. Allchromatograms wil containth following: + Sample eniScaton, di, Exyen sy sumbe, arow or ater findricamtionofthe area of interest, and injection number corresponding to i + Ae dorat , rcatonsawniglalioe thoe ahmo,ur of sly sided nd TTT rae 3 Exygen Research. 000372 Page 56.0f 111 ); i | . i { . |i | 2 Exygen Study No: 023.082 . SEauytgeynPSuad:yENxop:0C223.308822 + Acomnicyenttcraaltionst(aon.d5a.rHdg/mcLh)r.omatograms will addtonally include the + Aspart of th documentationthefollowingsheetswill be includedineach i iannsatlymtuimceanltsceotn:daitriuonnsshseheeteltisdteisncgrtihbeinsgatmhpelienssttorburesnrutntiynpteahaedseotp,earnadtianng ti conditions. ! `1T0haesQsuAreUcnoimtpolfitEnxcyegweintRheGsLePa'rsc,hwtinldlwiinlslperceptotrthetshtefuidnydainignstoefrvaaulsdaidteqoutahtee StudyDirector, ExygenManagement, andthe Sponsor Study Monitor. EE EON ESOT RC ! cAlhlromhaartdogrcaomp,y wroarwkshedaettas,, cioncmleusdpiongn,denbcuet, nnotd lriemsuilttesd s(h0a,ll tbhee ionrcgliundaeld !!{ `twhiethotrghindaaltsatpuadcypklaagne,saumbemnidtmeednttost,hfeinSaplornespoorrt.,Tahnedsael pwirl ibneatrincfhorimavwtieitodhn from the Sponsor. Tehqueiptmeesntitn,gafnadcilsittoyrasghealllogkseefpoaltlhelleicftertoinmiecofratwhedparaodaunctd aanndy sihnasltroubmteanitn, pecmission ofthesponsorbeforediscarding. | - i i i Exygen Research. TT 000373 Fanam Page S7of 111 _ - - i . :i | i | . ! ) -) |i :! | Exygen Study No: 023.082 - ESots y hBesey oresn r i APPENDIX I METHOD : "MethPoedroflfuAonraolhyexsainsefsourlftohneaDteet(erPmFiEn)a,tion of if PentadePcearfflluuoorrooooccttaannoeisculAfcoindat(eP(FPOFAO)S)inaRnadt Liver, : Serum and Urine * |; { . | ; Exygen Research, - 000374 i Page 160/39 Page S8of 111 - Expeen Sudy No: 023.082 ESonty nus Ex0p00 Sa. - i1! : mz a MethodofAstafo. BherDoeecSmAatonofTelesees oemetleets (0PFE), LivenSem Ge FROM ina : o :i i :. Fiber,KAiUTRHuORS BlyDec DAwTEIoSSmUED i bio + :! ; ii . ! i 1 :| MM sponP sCoorpsTs orti . SPN S10 3MCenter,Building220-2802 SEAT, . EERFORMING LABORATORY StateCollege, PA 16801 : S--_-- Eason tsaasin - | i ii | ; l1o |o | Exygen Research. 000375 ` 1 A| oPa 59g of1e 11 - Exygen Study No.: 023-082 . i ~ i| .d : i : | [I Co | : | i i! ! ESotymsmp2o3p.0e2 - aMattesBassnt MANAGEMENTAPPROVAL palay gESl `BrypenResearch | . Aed d, a-- = hoes Po VBATakdf] Gully 25, 2002. , i SRRoEoNtEaTte,Corpor Totty | : - | . Boras roa i| |; i!i i po! iEo Po | ; |i | t| i ii | DE Exygengon Research,y -- 000376 Fd i Paage ge60ooff111 - Exygen Study No. 023.082 - - ; = - i: i Co: :: { }!I{ : :| i i| 1 : SEutyr SP oyNy Eops 3n0602 Boreasan `TABLEOFCONTENTS rE | EMLTARoSANTBEALOGEREOMMFGEcVNoR-- TNRTASRFNTRS-- OVAL -- e ---- e --e ---- poe TTT ) Bl 32 so-- i oa s -- T ------T ------ -- --T --------) ---- EETE 3$i 5321 SF ee knto en--tr-- eo-- --m-- T-- a T---- t ---- e -- +y4H2hRmS3o3u3wmT .T CBmlebd Sade ia l l TT ) 4A3B14a4mr2asLsT BeeimnemnaUsnoBion T i 351. LSTOBMlAiSmSCroannieO--.rin--gG--om--a -------- 46 A4c5a3r,mSutaeptlceuams,ia TTT &$Sh8s 47t,PouaLRmraoonmssoT Qa nuAair y l y ) B i +i 1. : i }| 1 ii; i | ii : ; ii ii | i{ i: Boreas !: [EE = --- | Exygen Research. 000377 Page 61 of 111 - Exygen Study No: 023.082 3 ; - a: : ii od | . E StyPy dyNEaox.pe 203: 2.008822 Bm LISTOFTABLES TDl"bTele2..BRReeoccoovreecryyySSSuumemmamyry ooofffFRREEOOSS biaRRtaa LLisivvee,sSbrcsmsdtnUseor : macnn 3201 i |ii }! |! :i | | i! . i i : || | Ports Brggm Research . ly ob i | oie ! mes | 000378 PageG2of 111 | } EugenSudy No. 023082 i E sur E asan i - -i . 4i :!: _ . i||1 ) ||| i ; JLo Co i bo !i : |i Pi od| Pio i . BergenMeNto:Bhabod FmFe iegs1.SCuhlbreioenConve oLeIPRSSToOFoFoIGU-- RES Roms. Remmi mip trop er Figured. CReopnretsciatgatPivPeECSho romatogramsof 40.1 g/l.D Standard FRTeiogaommrsek.6,. Rom RARRReporeeesctiotatetiverCoCherommappptognr odfr19o05.s1snh0ghhakl.eSmStaatditatrdcCnGoonttainiinrgPRnoeOAe.5g.21 F`FiFiiiggeso111241...BRReegppereersmereunaativvesCChuroroemmnattpoogegaeennsoofodss1R$5.t00ensfgtllBk..SSkutanddiSsaramdgCCoonrFnaaysiiiooEggrPRROOAS..2290 oe Rae me Ro R m O prt eCEe Beapo ete itlee aRrSCoi p Ce otBbna FBMiegisen1,8.RRm epmrsecioataiveCooCe hroomattmeogrpamesoCm f CCooosttareLeitvre erSaemmpleeAsais ynzed Re.Ra irpima -- CCoteSersironot RFpi.2 RR RiTmpsosC OCmorroomemuoogas rof CCCrooaorelitbintsSSeemisAorvidtd Tamme Figure24.RepresentativeChiomatograrmof 8ContrlLives SampleFortified , | :; |ii |{ : ||||; i| !| || ; || i |!|i |! Sd ; Beeps esas ; `Exygen Research. 000379 Pagel of 59 : i Page 63 of 111 - - bo -i : .3 : ;| ii1: - . -} ; -i Cb]| i! | Exygen Study No: 023.02 Co BaysiwySpyemhaesoanoon Spb mac, i FF2ii 52.5.RRleempowenenngttavLCICroSorrTsoOomo FupoFgIrGooUffo RECCoSo(ocoLLntvinueeSeadlm)epeoFritiedd Fig 7,Rh eipoascinvo CFrOvaRtogra e of Cong LiveSei elrFocii e FBiim215.,RRAeevpepintatrCCorrscaaotogp eooff CCoortLLivsSSamspoFFroii Fi 20.Ri epairsACRoOtAi o of C--o --See --Sam--pR oF--ind---- Fi Fi 12.a.lRaRlgaeblev papogeeoinlvtehCCi FooRtotAoo n ooffm CCoorrn SSeevSSaui mpge FFoeidee FF3ii3s.M4.RREeenpopgeremegtnalvtewP iC CFOoSro oo ofn Co CooameSSt emeneSSeo oTopgeFeFa Trotiiedded FF3i i5n.36.RFwReehppocacTtgnnatilvvs-- eCCFhoootskoa po sooff G-- CoomeeleUiisuSr oop-- Foiiedd Fi7.Rcrtnie ve hostopai nof Coo Dn S-- ues--s ] Fie 5.RfeggpmuswCahFi RtOAoLo ofs GeolU-- i Se uge-- Fe iiod - : ; i;i iJ :! ! ;| !i} i i: ; i I 3 |! ::| !i i Porapas Exygen Rese-arch. 000380 roses | i wm | aPagege644. of 11 Exygen Study No 023052 : M d * :. !|; _ 1Eo !i . Co : Diloo . m--a-- r BrynMethodNe:BMS 1 SUMMARY ! SEtoasrFeitneeorieWeO tt frm mt wi T(hPiFsEr)e,parPtedestuaolrlosoacmtemtmheosdfooofutsasly(sPiRafOoSr)res1i2dduePseonfaPdeercfiavlooraorboecxainnecsiuclfoAncaitde ii i SscSS S ciEoenitocm li en. h ThiedtcetomtQ neiame i leexttracte1es ae u ddedSnto wnaterHeane dloeuhaded ssame 3. I ; EeDaaemtito10nrogoftppttieny00h0o8oPEteRSsFeto tinnptttyy280 | iti EET RinnmeE mEnmR SEEET EaTE Thetheoreticallimitofdetection(LOD)willbebasedonthesignaltonoiseratio Timevtrrdsiag bbrr,seeemtiie,, ydeet || ; : ET mme Y taYYe EE mre ms aenmE = wmre m][mlSveesomesm] EE| | i|: | Reem to Fre 0; Representaivecalibrationcurves wre showninFigures 13. Representative |;: Pores -- `Exygen Research. 000381 [a wm | Pag6e5 of 111 . i i } - |) || |: bo C|| o i Exygen Sudy No: 023.082 EoStyPaxEeroon [S-- 2 EERDENALCOMPORNDS hee PS,17081dPO eeeon: Bow see PiFEStm + peters Fh Fepe pC SOE, meh 8 mM OCousmli clNemr s a = g Paficre oocasenitions |} Pod i |: i }bo H i EOSpd1 8ptC50 st ign5 co Coinrms + Pstct Molecularweight = 41ass3ho,ws I | | Ente Exygen Research. : 000382 | [| Page24of $9 - i Pa66gof1e11 - Exygen Study Noi 023.052 _ . ESotysiyhepos csro0s2 2 - - a i : ; . i o iiii . - . - i|!i !iii ii ! :: + i iii|! | [E---- 3 camcApasutpp s ALSCa efeomlaedceussO lr s AH EC Se es T A Waiter eo as TBiwv eElali mEa xiayglen. VE r aNbAs i | { !i 22. Stamos = Tomi Standard EETCRaNamba Port(8) Sours" i { |t bo aFrmEoeeSttues spats frLanye TW 6 aawa !| i !i 32 Kaoasm ors i r pews i DiinmcrasC3100 UDELL)oDrt ess) SWe0ii lostdRSpsChipakeoprComrtsn sits Diope `Burrell Scientific: ii :i frhS 15memLs A pont iE pDolCyehI yitnscmC niegsat hAesT wsen !| |}! Soler LCRA Senitteyes, ClAapispestsandvolumetricflasks iVeapa vasioussuppliers i ! :i Ee cette Eons : preundpspctchm due? KeSicin i Emon | Sm J -- HPLC] (LC-10AD) `Shimadzs i Boptaes resto | -_ - --s | Exygen Research. 000383 Page 67 of 111 2 Exygen Study No: 023.082 2 oSty Pt ar apas08 - - oo - od ii :: i i; i) . iIo . N : C|o i| : 1{ / BaygenMethodNoxBMAZ3071. i| 1 R mea n,t eer Notas: 1. Inonderto avaidcontamination,theuseofdisposable Iabware(containers, pio 3 ii > E T R a Dne o emmybfot hrE ecoayievP(ocercE sieTlmsEapd)reurtes |i 4somo ,i O 2MMEaLmEmeRnIsNc LIIn TwaLs bIs TpepLaedYbyweighinges i i @ ERE EEpEeEcr h fLeaom tapnt1hwe LarteLraiI,T pTrTe eoEdbA SfymSEeein nngEt tH eS 1iwpeaenS {| ire ; S FRIi t ------e -- mtv-- vhs 35.Parsasmonor SumussSaums :|i J EomRuTA ASfS r iy T setts Analyticalstandardsarsusedfo threepurposes: | SEommmaEEEIERLET meeri n 4 BnTes | mmEaEEE . EtrESeoerh mThm enomn peepdb7y nin tn6S i `Thperainaolnysstmofay sv ir * vary theabsolutevolumesofthestandardsasJongasthecorrect : Praha rewss | Exygen Research. r 000384 Page 260f59 T i Pa"geage68of 111 - Exygen Study No: 023.082 . . Esutty aasvEotsmos0sf Pos - oo ko : ] |;} - Poy ) : i !| || Cd| | : i; |i|i Cd| mpeomen RR | i i BermMadBes 1 ! FPR2rr3Ea1tbsyaowodikdnmoscoctkm 1simstofsseh10m0tycs.eSfe tFEiSG,oPrEnS1nd i! | iDnisPeEpaoTraotei1e00m-msL.bvoilumstetesoitc n+flasks. Tthiepstiock pi solutions(in125ml. ! : E+25PE2oFSpoesrGsSttdStFtrnosntysece1ho0fplr.e100sgt) of be e P aTfeoh tr asnernh0k1pr eStr.yr 0 set= )of ; !! Bafsorltieficeationsdolutionitor10i0 s a m0e3tphaonal i bs &volumetric 1 ask. i !i SFerlefW t teatnmtboms.oe tipoebe2a5. FE. | : I ELpT2O5N3a.aSCIokS0tC1t,rml0ti3na,s0n3er.1mm8si.2ot0smicdoS stingo7n,SpPROSwrd EiOaAewed | The loin il cal, ond cet ma Yo wo o 3 u de 1 1B 2B00 oaow mm10 10d d0e w&10 TThasmdismsybtc 0 ppotlof ne a a 125,075 i| i; || !! I t i Pod FR. renee 1 Exygen Research. nE 000385 Page27of $9 ! Page 69 of 11 - Exygen StudyNo.:023-082 - . ExSptySPulda: ENoxp1z23.008822 . . - . - iy i . . ) | -; ? !. : , i . i| : : BopMest scam Tm et ey 4. METHOD 41 PowDug The flow Sagan of he metodogh below, flowedby dnted MatodFoxDiss > sty mWeoighl1 goliverormeasur e1msLf .ofsery um oeeeie. i) Ad move 19oe din eg Ro tse Dt peso 3stwe . a Ee] LOMAS Assis 42 Suourocsmo FoirgiteebteiaE opewC,ptaxnlCfOr,aboslfpsicieinof,nnfS:eNL do1psdripoclsspornnhdeBongopgrcpebies vwiitnh v0e1ddoccduompmlylnth.eH0aovoreE, rgnert,e i gissot05 tors rosea ! || if i : | :. i |; !! i ; }i i |i | i{} i i ;i || - : Exygen Research. 000386 mam Page 00f 111 - ExygenStudyNo: 023-082 Soypa ap2302 . `ExygenStudy No. 023-082 . - i :i - |ii | y I : } x i || ;i ii i- |ii . |:| ;i ;| i| ! . | * Ey MachodNo:EMT Bacasmr Abc tel hod cnt mer 2Skee A.BSahboirheocorrlymena1i0 0osds0etwcgmoo ae,coo tees cilo ad ety pdmyos [rp dd erly AtmloeawsntcoonncoefniteraltdsioanmptloedIcneaacdhbtartocuhmguhtshteaplsoocbadesieepsatraoteelytfoyrtriefcieodvearty.4 4 Al ieppnfe in. [r-- . 442, LheBacon 5 Weiaghh e1 tpofoolvres:utmeplfofof25h0mmLe. disp5os.sleCcenptitfug.sto: be sod fiCrT oiogroT vhisoht e3t0n o0tlrne5egmessgoteF-oyompyradeiootCretadmlte1dd3eemt]L i i 0 ti ctooh oh LB oeudiiheenmh 2plPoRrrci oomcondiCondnSnPEcah olLofdUe oiciontpit enndetd3,5 Rin tsmigseccoyLOSS. - 442.Sen andUr Erection Moser 121ofsmowinesalefs 4 0sl.dip A`caendtri19fugetuobfeavnadfrortifey,ifn CapSty1nd vrsfr iv, "Thencontioue with steps d-hinsection 4.4.1. : i :! i! i} ;:ii ;; I |i ii i:' ! i, !| i|i ! ;|; i i ;i i } [-- ronan | } TT TTTana ! . ExygenResearch. 000387 Page Motil - Exygen Study No.: 023-082 _ . EoSmeayopayhtep1o1t008023 Po. - _3 |: ! - || . 2 .oo |i; :i y - |i2 :i mr ERA | Basan i 443. $98Clem Contitring !{ SPPB laEcehhremsent ncboyhptowinegdeShPe1Eo0cfoo1 ifnoymaeetbsheopiacBotnmytsildpS ,Condw itione2 ii } ! SRR ns owtope i 45.Quarta i ; 451. LOMSAS to ndOCpeoins i` MaCrsosmeSppeerc: oCM FOUlti EAlQcPQW uror avtteitpro daoUa nilytm Grahs(a t Mics roamas e sAss)r a. , i bi ii| HC Ban=SkaDGnygSe100 . :: . No e41y0imapiaCayloseGneaphmceccaaerpEityidooy t IrLtCGoi Gree Go hme mT . MDMoeclaorehVnolul(me:32M530a0.ArnionAxi yp vis 4 | |i; | ! TiwFL noIe o2%A nook i2n%HB Faar FowRue(mlmin) %3 i i ii| nu5oo0oo0o8%a P. i3 H b3ao a ii; : pm edonubaecvcy ,eCrolyumnswifthdtiffPeLdEipesioni(f1n5t.t 2.t1 x30 p5iarcommms :i i Povo fa. | i -_-- Exygen Research. 000388 gs + | Pagee208 111 - Exygen Study No.: 023-082 [Snipnterris Bi = 3 . || ; =i ) i |] S)E |i . i Co i; Co 1 !| vectra fproim dciftfeent gig manatactarers bat (Keyvione Betas] Cpet.) coudbe used,provided. [---- ) bTnhe,k DTeesMeee TFoOSn NNepewmhe ospowsy Elima Tiimm E eel eS SERiRsSinT ta nnn4B B2 eattewn Thereteation timesmay acy,on #daytodaybasi,dependingoathebatchof Not: hireEMSA pre uybo do Tnmiatl, ns tfcx i by ag 10g. Pi = C o R tth od e Be mmCneboT r i lyyrerTm SpeT ne `stndardsolution(at 10WL/min, usinganinfusion:permp)via a"TTMinto astream {k Po! ! |i # ;i | || i | i Ryn 4i 52.gCalaibpratesionCutrveProcevduerenes 11o30: D0opf chct iesedt LAE : 5. Fd Doe edeteoeasweecmrifdek po qinn.sgeirntcsSe? | |. |i sE S ctanodavrta anjlcfteed.nstCem).eAny lairbleue t eieMonEsania m fTouo ndtoed ce Seiet ]:|i }i rr aT a a hma Sh ome, 2 0% 1 209(R9*22 0985 5). Ifcalibrationresults falloutsidetheselimits, then i . BaygenResearch Ppsao | i -- : repr. +} : Exygen Research, 000389 Page Tor 111 - Exygen Study No. 023-082 - ExpStySPaayENop:Co0n080s22 i. - :% - |i - || . ||; : = . i - i| ii . i}: ; i| . ii i Ba etve Badan. T2yp eincavefcPES,FOSi PFOAckbe dis rs c- : b' i 453.Semplera. ts Co Tt eyecsoen iiaveLesMS10 05s0i0)ofechade,eps, i Stdrs iLecomepingow)et Soiesscodmeing 1 SiAanltpivlceoerwterdabSofyceleubetrfio1oonnosssfsaabnocdsdrth1opldoftoeuarcaadapypaemshdenbeyfemdinhgeSo1fh15e1. :|: {:{; eEpiien hot naed ponpi . ch scsss ;} }! 4TRehdpeesociodnn,mceenuytnSreiatd,icobnoefehtdaaocahpspacp11m3ipk0looe%efof25hoordooepffco8eiahccosaaouteesniidbeenoytoceneer/mephihcnsieoedkfsneoratosms.mrebtosvahele ii i: * -- NE Font eons linil 010 150%wscomsledcple Suomen th red edbet C1 6 i ws : 8fomSharmhpgilpmesaIasntswehoiyfcdhUelnithdedr50sp5eaekcshaprresdeteecwtTeydCoiruupsetakdsleeasbis)etohaCnootrhsSerulnonwigeosgt omr hhLn 00sdEpre IoRcGa hoy wsccn na of iT51oe00s1erad i30 saRgepOeSoeof.nnFdTPdSRpdOtnogd nvtheeos1o0de dsd9c5ei0embperefp 20ntsgofaFaodFVet pnEiOSnv5ioF1nFdA |ii{ i i |I i !i! ! i: . ii i| - Berta mowas | i . eee e----, i . BeigenResearch, 000390 Pagege T4of111 ) Exygen Study No: 023.082 v . ErSgtySPuad:yNEox:p007133..008822 Lo Serna Bsrs i ) ,L ., - ||| . |:| . - :ii i} - i ! |ii . . ;i} _ {| : i - 4D8e hAccogr on eCat rma 2 cn ert 0S md 1.TP5o9EchoGmmm3aoc9tPoRptOaoSmm,xaedtPEs4dhSo,w hdekgonof 3d6g5 49amtfsmr0mepsafuooftm41of5. fark, 2.MSBaiakhokedclaoekntseianmttohosrscOtlyconstsitnonadroellGpretvas e1s0Sehr La 8t6udLOQ4s,oIw 3. RsT ecceopvbeO lonoofnftcT ek,ohum0 olewinisv% saintdeao.sipelscpohceoGl1disay)omiu-snitnboeewbde.stwAeneyn cmmsospllfsvcairdae T0-w0%itdod.dbn evlskesby hesvts 4.EAHrnorwyecTriet,rhmoeanyasbaencduebdedfrofrdcnebnebstcsalstaoidnna aotftihactblykwbdinpve Hoovgde, tecand3 ofho mb of ant id 5.2T0oh5p5c 2p5 s(2e05so 8m9.s1bcn m ll(Ronftonrocmisle ioonflcnaovdtn esepdpneendint k,mo,stB5bao a dot lien hot amy, t 6. Ri4eh%nvnaibtiyinmemesbsmetoweyeonsanrnad.atdsIseab dnamopnltemsommldtfnoknilfsmirsltihkn. 47.PraromaavceCarman. . Tbfeooetalhleowcinogmetmdwoofcarrnertnesfnsbspewthoemeidannce11Fa3 mycamniomn bvtpGstk, R(BuoGakOGsiLaodnianmsioldosonLOMgSadSocoimseporndiongtsothte csxtimatiodiLnOofQ Si1c5h1in,eciomnprpoerannntpaeki.nI (niaonncnaencttcionio,of sepia. Fotos reran :|| : {| i1 |i 1i , :i |1 | || i | | :;i ii :i! i {| - . ExygeneenResearch 000391 aw } Pa75 gof 1e11 Exygen Study Nos 023-082 i Co SParttyirrioponmtsr00d2 : SE } i ii i )i . i: iy |i i| | - . ii iCo : i - EmMadBsrt ii ! LSGie0ocGnoc.ndCpfric otersioan:nu gshofcfl osamrosri eoJemtdn de1snh ehva +eBl,ttompranly ow 3 i: |i Cho, ny lr confficlent ofdetermiaation(R') of a ileast0.985frosr the pen mualyin.Once this i O4n2eTpaecna exRceaqukmhnmofrnoxTAe2rlaslstionghhseSppEaionpcs ! | | nyi i py pe | =e i 1d 12 5. CALCULATIONS i ! i} UToTimkBaanai)nci1.1tcntyosMassccotvwof(sn0lywpfegodnGn,pbiu ecso !i| | omit i Asiefnoo =oksieca) xD xbe ior : DRE tcreby iohshf3 volunwsie, csr. . i i . Foa samplesfriedwithknoownn ss of solspi fo exracion,we ! i| Sass | } Recover (= - !i ttmn nfei-mdab(y gtLom)tincom] ii i a {inap mcmmcap msBen 00.rte s, |: } Bovmtena aa 2b - ----------g Ct. |} - Exygen Research. 000392 Pagese T60f 111 Exygen Study No. 023.082 } : * : : i{ |} | : |i . i| i| : StyPu:Expamron2 `ESxtudy y Nog.0e 23-n 082 . BryonMachodNesBAMA) 1 UeBeintocan scatofmysoda) . }: Atre_E eme ct y 1 Vn tee !| : SF1ociorrreaseppaorinetntiwnegghpouiwbrcpeopescaesk,snoaseimpcdlnesescianfwhtaicwh8i0elitcbhbaserrgsnpoo.naidnngd=selNsyD etor, hendo . ii reeatoonimLOXisdrmiprdncont hoime:canon of i !! 6 SAFETY - 1 | ToessttyiaeboupreoadtmhemhttdmtaftydUnssihoevsfor ellcsatnodsvsiond +i} i abnrgyscaouc,stsadyBeog,odcfooeg.win1sFeHos wont : ; . | :i - | i| - { { | Boban ' . Exygen Research. 000393 ? i i revaa | i 7 i Page 77 of 111 Exygen Study Noi 023082 : - od; odi | . Lo . i | Sty a: s2p3.52 `ExygeaStudyNo. 023-082 3 Sovaeet Bz "Table1.RecorerSummaryof PFS nRatLiver1nd Sem snRecovermy Sume maryos f PFHSsInRate Livers fe Ziu]m --cHt -- S =8BE fre etnion) reine BEenm :2 zz = RacorSummaryofPHS naSer mo 2 EemEe ---- m E2n me tise mene Lo Sm 8 = }} i i };} i . Lor! bo 4| | i }} . 1 io ] a - 2 ExygennResReesaeracrh } 000394 ve 7 1} Faw | Page T80f111 Exygen Study No: 023-082 ExSpttySpuuty: ENxopa0n2r.o0n822 " -4 - i ! || . |; | - "t ; - !iPo | | -ii i - xy MethodNeeBAMA) Table.RecoerySummaryofFFOS1 RtLive, Serumand Use FacorsySummaryofPROSInRat Live toe mimi reese Sm i$ = --8 serpmemerasiio alge, mein) ete Ser 8 r-- a Smao a AA * sane 2 5 ---- " Sm mmae n:eig22 n) viei=ne) OR i !P | i i } Pol i :i i' |i |1 i. i i : i | SSaat nntt try 2 E, Pro5Hien . t SSsmSmupeuRatRePt 22RS r53a Tm Son ii ood | ii !i i Bopetas [| i -- - - Exygen Research 000395 Fmwa | Page 79of111 . ExygenStudy No.: 023-082 ) Sotssn ExSty udy g No.:e 023.n 082 . - : - =| !| - CPoo ) i i !| . ro 4 Erma ssianan "Tale. RecomrySommeofPROA RtLive,Sern dUrn deresceoginPOAee Z=E --8 -- er -- a ES .3 .. Z J---- BEE : eyeen Er wo wr S --m-- 8 e 28 o5 &: Soro . RecoverySummaryofPEOAInit tna EH itn, :ee : sme er emer Ts s ---- fF a a Lo f ! 4| L|o ] | t : | !} Po i i i ' Exygen Research, - 000396 Page38of 9 2 i Page 800f 111 . Exygen Study No: 023.082 . ; EStxySPyiayENgope1233..n00882 SorBaocat Figure L. CalibrationCurvefor BFS . f |i ||i . | vi i > EERE ne : : TS . i! i {_-- |i Lo |. | Bopanna - |i ii i! |: wn 1 Exygen Research. : 000397 Twas Page 81 of 111 - ) i: i ! ) i: SE : Exygen Study No: 023.052 SE utySpy ayENop:e 00s80022 opener maces | Figure2. CalibCurrvaeftoriPoROnS i Quezon pros ESp RinTIa I ESI,wecre te mre |}t WET nwa Ea | i { ! | i , . : i i| i i ' ERs i . ExygenResearch. : : 000398 -h i ; i russ 1 i Faroa 4 i| Pa82gof1e11 ! x ; i er -i || : : Exygen Study No: 023-082 Sty pu02300 ExSty udy g No:e 023-a 082 . omens i: Figuce3. CallCabrvre atortPoFOnA } * Gop mr ESE mearmr arA , -- i f i! TEE EE ERE EER i{ t ti |! i| : x ii|| ) Britis Exygen Research. = 000399 b{ oy} Cy i; i !i rosa 1 Page 41of$9 E i Pa83gof1e11 . | bos |! i Exygen Study No.: 023-082 . StyPa Exp23:082 ExStyudyNgo.e023.n082 ermMeat Bd sar. 3i :| Figured. RepresentartieveaCthromattooggrraammof 0.1 `ng/ml. Standard . it Farm mune eg i i ; i | } .i; | Lo Figures. R2epresentatrive egentol0. ng/mLStandard Sma ~=z Co /} i |i po | i i - i Ls : : i: PoreRs P| } ---- Fmaw | - Exygen Research. ) 000400 Page 84 of 111  Exygen Study No. 023-082 - : lL Sty asBir 202 ExSty udy g No.:e 023-n 082 mesa Figures. CRoepmreisnesgtaPieFCOhAroz:togeamof 0. nl,Standard , it! =b = |: i | ! Cd | -i , oo Co | : i bi odi : EEE Em Figure?. CRoenptreasiennitnagtiPvFeECSh.romatogramof a0.) 5 ng/mLStandard oe 5 RZ . } = - = 1 it k| t i |i bo i | !i i : Eomatena rosa | ; --_-- ew i ! Exygen Research. 000401 Page BSof11L _ - i : oo Exygen Study No.: 023-082 . SJysVen.n ret. iost tat i | Sr So ByeMod NesBXM23071 ; Eg | ]} .b Po , Pies. BTprantuteCats ` att s Sa ante .: oLyo mm sam 1= Po : | ! : i| i i ) re rT a | i y Borba nora i ) --_---- ! ) Exygen Research. 000402 Pa86gof1e11 - ) [I - Cy ; | 1 Cd} .: . SEE|! | : i| . - Exygen Study No.: 023-082 . ESaut inveoroaosn Bop oteBaas Figure10.CRoeuptraelsennitoagtPivReECShromatogram of a$9ugh.Standard cman mmo . dr : :| 1 ii || | ! i bi ol Figure11. RCeporlesienntaatiFvie0ChSromatogramof* a 0ng/mL Standard :| | mm . TEE | | L |! |; i. i = Po - ; i i ;i Boston resus ; _ | `Exygen Research. 000403 Page 87 of 111 - i ! - - Exygen Study No.: 023-082 Po-- nlrd-- cred BaypenMathodNoxE3071. i Figure12. RepresentativeCoromatogramof 50nga. Standard Containing PFOA i . f | - : i{ |} IE : i ! :; - Lo !| { = Figure13.RefprersenetateiverChromatogeamof aReagentBlankSample : . i } |i " | | pian ves? L d Exygen Research. 000404 Page 88 of 111 . Exygen StudyNo.: 023-082 : PoSematyPiuesrpiosnen] i. [rm :i Fie4,BArpmdtrPRCOhSmmsog of Rego Sele : } Co | ! ! ) i, Cb i i } i i : |ip|o i! i ! L Whipsdyendati A hl Figure15. procera Representative Chromatogramof =ReagentBlankSample ties -- - = . i ;i :! ii i t i wis Por . !i ` } re - ii : 1 rein | Exygen Research. + 000405 Page47 of ! Pa89gof1e11 - ) i3 -i =i | . i Exygen Study No.: 023-082 . E Sty ay apo2s3s0o0n2 ByeMadoEb 071 : ! Figure16. Representative ChromofaaCtontroolgLivrerSaampmle f Analyzed torPFES === TE ii iii : t : ii | bo i - Figure 17. Representative Chromatogramof aControlLiverSample + Analyzed forPFOS. - : . i : : Io (i :i i ne . Pte _-- : ExygenygenRReesseeaarrch. spe 000406 ! ! | 1 reso | ; Paegee0t111 - ! : - i} i ExygenStudy No.: 023-082 sA im Bygen Mathod NoxBXMAZS-71 Fi 18. RIemgretChevmatogramof CotoLive Spe }: : |i od | : Co i Co Co i i {| - aa - prorat ae Figure19. RepresentativeChromatogramof a ControlSerumSample m= = k 3 : + to i i - i t i (Ral ii I . ii Bopatees PEs i i | - `Exygen Research. 000407 Page 90/59 $ | Pag9e1 of 111 - ExygenStudy No.: 023-082 - io: od4 . E [n -- as ooh BvpesitoteBatasan Figure20,Representative Ch.romofaaCotntrool SgerurmSaampmle AnalyzedforPROS : ib -- -- _--1 Po o| | || -i . 2 pe ! :| .} Ii | | I. . | i E Lo co i . |: Ba21. tre a |Serum i| -- EE ; j = EET |i ob ;[I Press Po i a 1} ; BxygenResearch, T 000408 raewa } Page 920111 - ' - Exygen Study No.: 023-082 SoyPu Exp 02 `ESx tudy y Nog .:0e 23-n 082 RryyenMethod Ne:BMAZ71 i Figure2. RepresentativeChromoafatCaontoglUrrinaeSammpsle } AnalyzedforPFOS. i | . |i - . ii|| nN i!; i Figure23.ARseaprleyszeendtfatoirvPe FCOAhrom ofa aCotntroolUgrinreSa ampmle = TRE : y} |!i | ro . || : i rin ExygenResearch, | 000209 i! Po |i i nosea {| i IE Page 93of111 - ExygenStudy No. 023.082 SeyPsExpoznoms - BoSuydyNgo:0e23.a082 : - i -i . _| EE i. : od - i|Po i! . p|o : | . Bp ats. . T =3 Figure24. RFeoprretsiendtaatt1iv0enCghrowmiatthoFgFrEaSm.of aControlLiverSample Te---- fo 1 : t |. i : b = wr 4 = : | Sho }i Figure25.RFeproesernt1a1tt1i0vienCgh/frgoWimaBteoPgRrdOamSof aControl LiverSample i os .. pe , = : {| |{| - 1| marr : Bova }: i i rosea ) . Exygen Research, " 000410 Page 52of$9 b | Pa94 gof1e11 - Exygen Study No.: 023-082 - . ESyoyPSastByaaornst2 | N -i od . i BorgenMashodNoxBMQ23.071. Figure26.Representative ChromoafatConotrogl LirvearSanmpmle Fortifaite1d0ng/g withPFOA i : i aman _ | . | !y | ;: Cy Pood 4 i : i i i| g | - . i .: ii ti a, =" t! : Figure27.FRoeprretseentaatti0venCghrwoimtahtoFgrEaSmof aControlLiver Sample fa == = ohbo = Ea !i ) i i { i | . : : Foret -- `Exygen Research. 000411 wm | Page 95 of 111 T Exygen Study No.: 023-082 } #} - iio =| od ; o | - i : -Co | | . apn StudyPlac:ExP-023-082 ---- Figs e28.eLRneeprresent"ativeCChrmomattosgramsCo_n--LtiverSaomplle } i Pooodd} . mi Figure29, F Repreo sent1atf5i0venigwitnEpdpof+aContCraoAivLieverrSemple ToCo 5 EmTE | Po |i I :| i I Co . :| : - Ce L b | ii | Poa ent | } : -- i : Exygen Research. : 000412 Page 96 of 111 - Exygen Study No. 023.082 ] : -- `ESx tudy yNog .:0e 23.n 082 : Fir: e1. RersestateChromiogramof BypenMushod Cntrl Sec NecBM23.071. Sample & || Co --Fortifaite1d0ng/mL.with PFES ons ;| ii . i | - - i Cd Fis1.`Roerplreedestti1e0nChhrolmwsiotghrFaFmOoSta Coste SuSemple == 5 SEE : Codi| i} i !i broodd i | : : - Tors i: Pod wns | er i [Exygen Research. Page97 of 111 M3 Exygen Study No: 023-052 : ErSmtySpuaiy ENop2s3o08m2 ! - :! 4 i| } : - | BoyeMoshodNoxBADIM. i Figure32.* RF epreso entaattir1v0enCgtimhlwi rithoFdRmOoAfaaCotntroolSgerurmSaampmle = - EE ) ii | : i | mn Ral33. mirve ierof aControl Serum Samale = :{ i ii + i 1 i | ii ! | - a a :i ii : Ported ows | i -------- ------ = Page S609 " i| Exygen Research. 000414 Page 98 of 111 - Exygen Study No.: 023-082 . EsoEreSs i| r BypenMoshodNosBRURITTI Fp. BratGesesCooeaSrnSutle ;i Fortified a- t $0 nginLwithPROS .| i; ; od | . aR | i Co L > Lge |i mmo Figure.Representative ChrororfaCaonttroloSegrurmSaampmle :: = | bod SE ' i i Sas Ser = i I avs 1 ) [rm -- ? 000415 Fase AS ! Page990 111 [Exygen Study No.: 023-082 } } ' } | | : o : i! i i : `Study Plan:ExP-023-082 - `ESx tudy yNeg .:0e 23-n 082 BygenMatod No:BaM23-071 Figure36.RFepresoentar4t1iv0eniCihuriomaatetoorgardoamnoafControlUreSemple Sor : . LTEz } . me bs o Fis7, RferrunsaCsmie ro CostUoSemple .. |t; :t i i | Po t i : || | err. - ! P| o Co Fmt ass | Exygen Research 000416 mms retort - Exygen Study No.: 023-082 - . EoStyo spe 23.02 i, - .4 odi . . iPoodi i i i i Co1 i ByMedNeEb. Figure38. RepresentativeChromatogram ofa Fortifaite5d0 ng/mLwithPROS ControlUrine Sample - == Rg | Figure39. RT epresee ntsatti5v0r esClhraoti matAoLge rFaRmOoNf aControlUrineSample ------ E=E= = . | i B |Podi | i bo !! ! ; | i| !i Fo f-- reas 1 | ; e----rr--------s | Bxygen Research. 0002417 Page 101of111 - Exygen Study No.: 023-082 | \ : J| od X\\\ PROoTp OCeOLrDl EV.IATISONa Le ;!| Sen's Nunber: 2082 Proce Nurser 23082 f i- | tree r\c sans nl 1.50425 le AnalyticalProcedureSummary-ilCalibrationStandards | protocol deviationsued, : i \ | i RecovrytfeldY2o Derk" oe ale i i Monegatveimpactbecausecot Wd fhcommearandithe lnearrange ofthe i |wasstilestablishedwithoutthasetwo levels. - ase om ||! \\ ii \ 1 Pir eg Sinai -- wm i i| Hil) SR Det e (peeCLT No \\ tae lesle i ExyQAgURe evinew AVC foie Exygen Research. : : 000418 Kez nReay ! Page 1020f 111 2 Exygen Study No.: 023-082 | \ . i \N\ 3 ------ ! Page 1 of T 1 PROTOCOL DEVIATION b `Deviation Number: 2 4 i 3 - ro seserer SERRE ExygenStudyNumber: 023-082 Protocol Number: "DESCROIFPDETVIIATOIONN. ExP-023.082 Eluted with TS Eg eb stes 5filofmethanoland ratedto lessth1 a mLn using a. mera rtsm enEE ; : \ } \ ! .| | : i | i a eer oRecmore, rE fy L DeA ckerR ous ha \ i I (ear gas a ats a N = } No \ CAelokegn :} oe \om Exygen QAU Review gi Lef3)er. TER ) a i i900 Exygen Research. 000219 Page 103 of 111 g Exygen Sudy No: 023.082 XYs EARCH i \ - |; i <\\ PRDOoTvOaCteOnLNDuEmVbeIrA:T3ION FagsTdT i}i \ OatofCerin: STORET i Ese ua Nn umba E3082 [Ey i - Looaet1t03a0PrhoececdouvreeSummaryHethodSecon4:5..--everalsampleswere quantified i 2.AnalyticalProcedure Summary-MethodSection4.5.3.e---the acceptancecriteriafor QC spike |i| f 2r e odadr S\a. rs i\ . {ii | < ZCTIONSTAKEN t - i|i | | :; i i |7 ! : - RecoyoAtukoDdD ks owe: fs 2aM0n4o5in3daSoketainecftthebCceciafuvosefarrmWepPslUFeswaAk3c0nr3<do5TanaHPnnsFDT9SHkowOeToe4ys5DctouthuoA p vraetifooCnaerde cthaortssnadnmrpsl.e olor af herece ere 8, i 2.imrpeactnoetsde evttearnmydiocunmeentded inc thNysmethodhas notbeen validated forthese !i L Fr d Sy 5 S oe -- i| Gflanit Deke \ a odes !; Tenis \ Te ponsor A-- i RTA] ExyQAg U Re evinew + UC jo/seclhrzil Exygen Research, 000420 a RSEIn : Page 1040f 111 = Exygen Study No.: 023-082 XYSen.. i \ | em - ||| kN\ \ \ PROPTCOooCtOreLmrDEbVoItATr +ION yPoe Lo TL t|t| - | Exygen StudyNumber: 023082 ProtocolNumber: _Ex2-023-0 i - .Pi o. ann.aheA coeansra tssaaereees edEE pTw.hEtEekEdATtRd nd or the < - :i Ermey5 sean SAECTER ie ; ; 3| arm ints i : \ | N\ ! - :| .| nemistsar ) BR. Deg, ou ofscl 106 egmapctbvec e TcmEof Tosvee ery hsbn sted. r2.v0ssa0cpaco tbcbetahctxitocnstadtver rendBought heset hich ]| ! .i - .| i \ ! Pr 7 Sore NT == ii EE Ce ~ a. aloen Wy fainntses (spas \\ hpEbs \\ - ; Son ReonLCL Iolo ! } X= Rom | Exygen Research. 000421 S002a21n5000 i Page 105 of 111 Exygen Study Noi: 023-082 -| r \\ PRODToOtCaOLNuDmEVbIeArT3ION Fogo Lo ii{ \ Datsof Cocumence: Urauhautstudy ! -+ ExygenStudy umber:_ 0 __ Protoco Number:E2-00308 ! :{i . Fyola5loccursSumma DtEodSSCectRioInOFPDTE4V51IItAhOTIGNOaNrstonmortredfor FOSwas | i : _. i . . 1;i -{ ! - . f < TOR TE f 1 pratocol deviation sud, : \ \ | rocstea yo 1 SDheDerkrs [E---- = ous File \ f PT 7Sw SEuTl)P Decks Tiaragelmenlt Slanat, < N oo = ii No ww l ! AY Tae 7S EE Ca agen QAURMmLCiLoe]sowln Exygen Research. 000422 zz HenanRmca,n i Page 106 of 111 : Exygen Study No.: 023-082 C--O.B---------------- : EXVE ze ras Po Co ! ; Vemmm \\ . . . \VE anil PRETRIES TocoLDaRnVoATnION. | To : ~ exrieregion BEERpro i Sia- + [parerm i3 dardEi nia na 1523 gs. . obi: i 2 ol || i | - i | || .{ fv : r; ips Ae : \ DCU ei EGiiNmNEeed - . SeeRd ye nis aii he EEN : I a , e R chrp, E Dated ourhe- TL [peglP es \ lef } Ssonsey) Dro? r7 \oLak/Aulon. Du To PAin X\ p ARE en, { | i{ : :! ! : Sd Lo ii :| | i i| i - Exygen Research. onoaza Page 1070f 111 Exygen Study No: 023-052 EE -- EEETR-------- : Exvt wn roves ov 3 RR : del CL ` TLEid glesSOLDEVSe IATIO=N | T he ii re TERE Cd = RCR OFBRAA TION A} SE Bi REA E CET R EEerI eFeee n | CO TTT Te Lek pd LT Fond Sh fn ER EE 3 SEE] TE CU Tr AL sh be ips dee ii Pod RRR LL : HI Cheat DT o E ET EE n RER E NG EN Ey : TE plo EEA fol RE SU ! po = Susie AHP LN emeden Pg oT Noe . | :_ Kir Even ARon dice mln | i ih LE + CHO . . hsal : TNSEEEko api dTEa LR a IEE Le dl _ Exygen Research. 000424 Page io3etin ExygenStudy No.: 023-082 } EE-- EE -- OCT-30-22 12:24 Pav EXyge 1m. . Ce Reem . : : i; Pp \. Pema : Nn De bm e TT: } Evgaols LL pecanspbion | } : ;| c oT ;ea " EE gea----na \ | aedi emtEr BL I SE ! i : . Fe Tah Bo, of | : -- N bora EN *% plEh Sabai ! ) |Cs eS[mREteiEmepactsNa on TSESER coocrcs foraCandOlf aste : CE 9 mo pth md in L i I } } ; _ i! |. ) ; aEa Se all: Ser So.Z r--} -------- Vi : :: iyLT td T EN Tabb \=pgilanda A E bh n Reine e %b( eda F ig g|| |}! 5i i| | TNi CE n yen E Exygen Research. 000425 Page 109of 111 Exygen Study Noi 023-082 rS r -- E ---------------- -- rom ros | (RE, CL sO con NG 5, roo Riana; i i TT ei Y gen Oe Cen S Pr EomRbr R210E00, . := E mapper eae TacianT td ciwae sians FE mmission omissioni | | i TN Dameron S a R I :! Poet] eH ded i cE a Sai FL rA e DG eT RSRET swig | | J epi Se eeryR binsaie | BR ; Popol VL hela Coal ef 8 ! Cfalld p RBay CLTAny vo BIh t DWT T pl o E :i i Co Lah Soonin) Zr \gaan 1 LT mein ekg AE Tee gm Ty ee : LE | Lon LEERY LD TTR !i i ExygenResearch. 000426 Page 1100f 111 Exygen Study No.: 023-082 C--O------------ ---- nse EXyNogen.sean : Cd CL = N, SiT gama oN 2i TE wr Es i = RE, i |EpratoeadR LaLin i C redeC ppm | Pevor tere s A RNe ERiS nAE Afe Eg EL y 3 JETER eT i. on ren hein TET wake al Ia: : i Fondoal TRT TIEN Ha e vi Lie S:le fibRiS E T TRE E Re N BNOEETL he Fe | : ii Sd o|y eee Lo ee ee Cn ee EREr ba he Sl Galante aa - [ po OEIER CHERBETE ELRrR RL ECS E ER UK SNE COREE TN Se - | an ! Lm CU emoki ewAtalt silin| | NR J - fii cE Ey WEETota bok | - Exygen Research. 000427 Page 111 of 111