Document jgvRq9KZM2kZQMbEnMj8d8DqN

ARRRG -- 3227 409 ARARE _ 3227 SupplDeempeonnt2N9o%2| TRADE SECRET Study Title H-24043: Biopersistence Screening. 10-Dose Oral Gavage Study in Rats Supplement No. 1 Laboratory Project ID: DuPont-2932 AUTHOR: CarolFinlay, B.A. STUDY COMPLETED ON: August 29, 2000 SUPPLEMENT NO. 1 COMPLETED ON:February7, 2002 PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WORK REQUEST NuMBER:[mms] SERVICE Cope Numer: [9] orconsn compa"saniiasd- 0% TCACB! - TT Eeaw 11204-0Do4s3e; OrBailoGpearviasgieenScteudSycrieneRnaitnsg SupDpluepmeont 2N5o3.12 CERTIFICATION `We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Reviewedby: Ertl Los "PauPloMm.dHoicnodrearlFitoeer, Ph.D. o4-Fib- 2m -- pwe Reviews: PaTcihtCSaCiocSrtrbacDltAnS, 0b FEaB-g00> - LibyeStdy Divc-- ior: ltSaot4isnly Loef. feboAc2h-2r02 comeante nancB ~ --_-- 2104-0D4o3se; OrBailoGpaevrasgietnScaedlSyreinenRiatnsg SuppDluepmeonnttN2o9.312 `TABLE OF CONTENTS Page CERTIFICATION ccucnnscnnssmssssmmsesssmmssmmssesssssmmsmssmmsssssmsmssssssmmsnd LIST OF FIGURES .ccoosnemmnnmmmusmmmmmmmsesmmsesssmevssssensesssnssessinsd LIST OF APPENDICES .mmmssssimusirnsmisssssirsesssirorsosssssmessissesnssismmmnmil STUDY INFORMATION ccooccnssccnsnmsmmssmssssmsmsmsmmssssmssssssssssmmmnd REASON FOR SUPPLEMENT NO. 1 ccm MATERIALS AND METHODS ..coovsvrsressssssssssssssssssssssssssssssssssssssssssssssssssssessssssssssssssssss1s0s RESArULLTVSerANWD EDISICUSGSIHON .S.cco.mmmm.mmssu.msssmmmssssmssssssmsmsBssEssssmssssssssssssssssssssssss"s11s00s B.Liver FluorineData..............c.... A ono - CONCLUSIONS cconnsursrssmssmssssmssmmssessmsssssmssssssssssssssssssssssssssssssssssassssssssssssssssss1s TABLES cumssrsussssmmmsstsssssssssssmssesssessssssssssssmmssmssmsssssmns|n2 FIGURES ccnsrcensenssesssmesssmesssmessosmsmsssmessmsmesmmesssssssmsssssmssmso1n6 comes TSCA Ipenne =" = 2104-0D4o3se:OrBailoGpearvsaigsetnScteudSycrieneRnaitnsg LI OFTSABLTES 1. MEAN BODYAND LIVER WEIGHTS (8) cr 2. MEANLIVERFLUORINELEVELS... SE 3. MEAN LIVERFLUORINE CONCENNTORMRALAIZETD ITOODOSNE. SupplDeumpeonntt N2o9.312 Page nel 1s lS LOIFFS IGUT RES Page 1. CCOONMTPRAORLISSON OF MEANRELATIVELIVmER--WEI--GHT--S: --TES--T SUBSATNDANENGACTIEVE el 2. CCOONMTPRAORLISSON OF MEAN RELATIVE LIVE-- R WEIGHTS:-- TEST SUB-- STANCEANDPOSITIVE SE 3. C COMPOARINSONCOF FREORE HN-24L T 0L4I3VAR A ENRDWNEATEIGGAHTI TTIAVI ENVCDOMO NEE TARNONLLSIVEvR vFL.UO.R.INE dd - 4. MEANLIVERFLUORINE CONCENNTORMRALAIZTEDTIOODONSE wi 2 5. CNOMOPRARMISAONLTOOFIDMOZESAEENDBLOODvANcDMrEAN.LIVER FLUORINE CONCENTRATIm ON. th LIST OF APPENDICES Page A INDIVIDUAL FINAL BODY WEIGHTS, LIVER WEIGHTS,ANDRELATIVE LIVER TO BODY B._ INDIVIDUALFLUORINELEVELS SE 3 CompanySsniaed:`DnootcsontsenTSCACEI ees---- 11.02-4D0o4s3e: OrBaioGpaevrasgseenScteuSdeyriennRiantsg STUDY INFORMATION TEST SUBSTANCE: `Substance Tes[ ted: --) Synonyms/Codes: * fen Haskell Number: 24043 SupplDeumpeonntt N2o9.312 -- TE ---- Known Impurities: Not supplied by the sponsor --- POSITIVE CONTROL: Substance Tose -- Synonyms/Codes: H-24019 [ Haskell Number: 24019 ERE = Known Impurities: Unknown TSCACBI Company Sanitized. Does not eee H1:02-4D0o4s3e; OrBailoGpearsgiesenScteudSyreinenRiainsg STUDY INFORMATION (Continued) POSITIVE CONTROL: ssc Tec Synonyms/Codes; | H-24020 SupplDeumpeonntt N2o9521 ] Haskell Number: 24020 " Known Impuritiei s: Unknown Sponsor: WE.il1.midnugtPon,odDeelNnaewmaortuers19a8n9d8 Company USA Study Iniiated/Completed: April 30, 1999 (see report cover page) In-Life Initiated/Completed: July 11, 19/Oc9tob9er 12, 1999 _ . CompanySani ed. Dostnotcontain sca cg ee 11204-D0o4s3e: OrBailoGpearvsaigseenScuedSycrieneRnaitnsg STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Judith C. Stadler, Ph.D., DAB. Primary Technician: Richard P. Mathena Liver Fluorine Data Analysis: Paul M. Hinderliter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A BT. Toxicology Report Preparation: Wanda F. Dinbokowitz Laboratory Veterinarian: Wanda L. West, D.V.M., ACLAM DuPont-2032 Supplement No | Company Sanitized. Donotceontsain TSCA CBI --- B1204-D0o1s3e: OrBailoGpaervsaigsetnScuedSycriennRiantsg SupDpulepmeont2N9o.321 REASON FOR SUPPLEMENT NO. 1 `The purpose of this supplement is to present the results from analysis of selected liver samples afnrdom2rnatesgattrievaetecdonwtirtohlsth(ectoesmt osiulbasntdanccoe m(Ho-i2l4/0a4e3t)o,ne2)positive controls (H-24019 and H-24020), Company Sanitzeq, 000snotcontain 15 gy EE H120-4D0o4s3e:OBriaolpGearvsaigseenScteudSycrieneRnaitnsg SupplDeumpeonntt-N2o0.312 SUMMARY `The objective of this study was to evaluate the potential for H-24043, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male aCdrmli:nCiDste(rSeDd)ItoGSonBeRgrroautspoefac5h rwaetrsefogrivecnon1s0e0cumtgi/vkeg/dadyasy aofndH-to24504g3ro.upTshfeortes1t0sduabysst.anOcne was selected days (5, 10, 13, 24, 52, 94) 5 rats per group were euthanized and the blood and livers. were collected. Livers were weighed and those collected on study days 10 and 94 were analyzed for total fluorine. This supplement includes liver weight data and the results of total fluorine. analyses in liver. Additionally, 2 negative controls, con oil and com oil/acetone (80:20), and a2npaolsyizteidveascodnetsroclrsi,beHd-2fo4r0H1-924(01403m,g/kg/day) and H-24020 (20 mg/kg/day), were tested and `The mean relative liver weight (liver/body weigohftra)ts dosed with the test substance, F-24043, was up to 30% higher than the negative controls on day 10. The weights were similar by day 94. On day 10, the mean relative liver weight of rats dosed with the positive control H-24019 was up to 27% higher than the negative controls. By day 94, the mean relative liver weight was up to 28% higher than the negative controls. In rats given H-24020, the mean relative liver weight was up to 75% higher than the negative controls. By day 94, the weights were similar - `The concentration of fluorine in the livers from rats dosed with the test substance, H-24043, was 1306.27 uM equivalenotns day 10 and 80.27 uM equivalents on day 94. The liver concentrations for the positive control H-24019 were approximately 4x higher (day 10) and. approximately 15x higher (end of study) than H-24043. The liver concentration for the test substance, H-24043, was slightly higher on day 10 and approximately 7x higher at the end of the study than the postive control H-24020. `The 4M equivalentsoffluorine in the livers from rats dosed with the test substance, H-24043, were higher than levels in the blood. Under the conditions of this study, there was some absorption and retention of fluorine in the livers from rats dosed with H-24043. Fluorine levels in the liver were lower than levels in rats dosed with the positive control material, H-24019. However, fluorine levels in the livers from rats dosed with the test substance were higher than levels in rats dosed with the positive control H-24020. Liver weights were elevated at the endofthe 10-day dosing period. CompanySesilicetDues natcite TSCACBI -_-- 11.02-4D04o3s:OrBailopGearvsaigsteeSntceudSycrieneRnaitnsg SupDpulpemoenntt 2No9.32| MATERIALS AND METHODS OBlnoloydthaendtesltivdearsy w1e0raencdol9l4ecltievderosnwedrayesa5n,al10y,z1e3,fo2r4,to5ta2l, falnuodri9n4e.. The livers were weighed. These time points provided sufficient data original report o determine for details of the the accumulation analysis. and persistence of fluorine in the liver. See the RESULTS AND DISCUSSION A. Liver Weights (Table1,Figures 13, Appendix A) tAhserweiwthasthaedbiofdfeyrweenicgehitns,agceombpeatrwieseonnraotfsadbossoeludtweiltihvetrhewetiegsthtssubwsatsanccoemapnlidctahtoesdebdyostehed fwaictththtahte H-24019 positive control. comparison for all rats. Therefore, liver weights relative to total body weight are presented for IL Test Substance - `HT-h2e4m0e43a,nwraelsatuipvetloi3ve0r%wehiigghhter(ltihvaenr/tbhoednyewgeailgihvte)coonftrraotlssdoonseddaywi1t0.h tOhentedsatyssu1bs3taanncde,24 (recovery), the weights were 37 or 27% higher similar to the negative controls on days 52 and than 94 the negative controls. The weights were 2. Positive Controls s"Tihmeilmaeraon trheelaltiivveerlwievierghwtesigohftrsatosfdaotsseddowsietdh wtihthteosntesuobfstthaencpeo,siHt-i2v4e0c4o3n.troTlsh,eHm-e2a4n01r9e,lawteivree tlihvaenrtwheeiglihvterowferiagtshtdoosferdatwsidthostehde woitthehrpHo-s2i4t0i4v3e.coOnntodla,yH-1324(0r2ec0o,vewrays),3t5he%mheiaghnerreolantidvaeyli1v0er weight of H-24043. rats On ddaoyssed24w,it5h2,Ha-n2d40924,0 twhaeswe1i9g%hthsiwgehrere tshiamniltahre. liver weight of rats dosed with "tThheenmegeaatnivreelcaotnitvreolligverrouwpesi.ghBtyofdaryats94d,ostheedmweiathnHr-el2a4ti0v1e9liwvaesr wuepigthot27of%rahtisgdheorseatd dwaiyth10 than dHo-s2e4d01wi9twhaHs-2up40t2o02w8a%shuipghte0r7t5ha%nhtihgehneergaatidvaeyc1on0ttrohlasn. thTehneegmaetainverceolnattriovlesl.ivTerhewemieghatnof ats arenldatwieverelisviemriwleairgbhytsteotf draatys 9do4steodtwheitnhegHa-t2i4ve02c0ontbreoglasn. to decrease during the recovery period _ wTheeirgehftorbey,tlhieveernwdeoifghrtescowveerreyeilnervaattseddoisnedatwsitdhostehde tweistthstuhbesttaesntcesuwbastsansciem.ilaTrhteo rtehleatiivveerliver weights of rats dosed with the positive controls, H-24019 and H-24020. `Doss not contain TSCA C21 Company Saniized: _-- 1H.02-4D0o4s3e:OrBailopGearvsaigseteSncteudSycrienenRiantgs, - B. Liver Fluorine Data (Tables 2.and 3, Figures 3 - 5, Appendix B) SupplDeumPeontn2N9o32| 1 Positive Controls dTahye 1p0osfirtiovmercaotnstdroolssedwewriethHt-h2e4p0o1s9itainved cHo-n2t4r0ol20m.ateTrhiealcsownceernetr5a0t4i5o.n8so5fafnlduo1r1i2n7e.2in5 tuhMe livers on equivalents for H-24019 and H-24020, respectively. and 10.72 uM equivalents. By day 94, the concentrations were 1190.15 2. Test Substance tLheavneltsheofletvoetlals ifnluloirvienres ifnrolimverrastsfrdoomserdatwsidthostehde wpiotsihttihvee cteosnttrsoulbsmtaatnecrei,alH-H2-42044031,9wbeurtehliogwheerr than the levels in livers from rats dosed with the positive control material H-24020. The total fluorine concentration in the liver day 10 and 80.27 uM equivalents from rats at day 94. dosed with H-24043 was For the positive control 1306.27 uM H-24019, the equivalents liver at concentrations were study) than H-24043. approximately 4x higher The liver concentration (day was 10) and approximately slightlyhigheron day 15x 10 in higher (end of rats dosed with the test substance than in rats dosed with the positive control H-24020. On day 94, the concentration H-24020. was approximately 7x higher in ras dosed with H-24043 than in rats dosed with - `The uM equivalents of fluorine in theliver were higher than levels in the blood. CONCLUSIONS lUinvdererfotlhleocwoinndgidtoisonisngowfitthhisHs-t2u4d0y,43t.herFeluwoarsinseolmeevealbssionrptthieolnivaenrdwreerteenltoiownerofthfalnuolreivneelsininthreats hdiogsheedrwtihtahn tthheeploesvietlisviencloinvterroslfmraotmerriaatls Hd-o2s4e0d1w9i.thHtohweepvoesri,tifvleucoornitnreollevHe-l2s4i0n20th.e Lliivveerrwweerieghts were elevated at the end of the 10-day dosing period. rod, Doss potcortain TSCACE! Company Sanftized: TY - 21400Do4s3e: OrBailoGpearvsaigseenScteudSycrieneRnaitnsg `SuppDluePmeonnt.N2o9.312 - TABLES contain TSCACE! = Company sanitized. Dossnet 0" n- H1-02-4D0o4s3e: OrBailopGeervsaigsteenScteudSycrinerRiatnsg `SuppDluePmoenntt-N2o9.32| TestDays 5 10 13 2 52 9 TABLE | MEAN BODY AND LIVER WEIGHTS (g) CORN OIL (NEGATIVE CONTROL) Absolute Body Weight Liver Weight 2593 12620 3111 15.861 329 14.906 3912 16.635 464.7 17.240 557.8 20.118 Mean Relative: Liver Weight(% of Body Weight 0.049 0.051 0046 0043 0037 0.036 CORN OIL:ACETONE (NEGATIVE CONTROL) -- Absolute. Mean Relative, Test Days Body Weight Liver Weight __ Liver Weight(% of Body Weight) 5 3134 13.632 0.043 10 3565 15597 3 3776 17.715 0.044 0.047 24 4235 17.1712 0.041 52 5276 21275 9 567.8 18.447 0.040 0032 TestDays 5 10 13 24 52 9% H-24019 (POSITIVE CONTROL) Absolute Body Weight Liver Weight 306.6 15.436 310.1 17.336 3448 22049 3879 21313 438.1 19.826 597.9 24.455 Mean Relative Liver Weight(%ofBody Weight) 0.050 0056 0.064 0.055 0.045 0.041 Company Sausud.U0SS 10x Gund + 3CA CBI -_--ms m 'mss;s ::s sm <--__-_@ -- 102D4o0s43e;OrBailopGearvsaigsteeSntceudSycrieneRnaitnsg DuPont2932 `Supplement No. | TestDays 5 10 3 2% 52 9 TABLE I (Continued) MEAN BODY AND LIVER WEIGHTS (g) H-24020 (POSITIVE CONTROL) Absolute Body Weight Liver Weight 24438 17.052 2844 21.944 289.1 21.780 3703 20619 436.7 1.713 5387 18.205 Mean Relative Liver Weight(% of Body Weight) 0.070 0077 0075 0056 0039 0034 H-24043 (TEST SUBSTANCE) - Absolute Mean Relative, TestDays Body Weight Liver Weight Liver Weight(% of Body Weight) 5 2538 14049 0055 10 2980 17.077 0057 13 3213 20332 0.063 u 379.1 19.642 0052 52 4365 19.101 0039 9 606.7 2411 0.037 -_ - Company Sani0. Does not canta Tp gy L H1-02-4D00 o4s3e;OrDBailoGpeao rvsaigstew eSntceudO SycrieneRn nainsg lCrageSudyinSSwuppRpllDeeumPo meonenttmN2e N9o3o2|l TABLE? | MEAN LIVER FLUORINE LEVELS Negative Controls Positive Controls Test Substance: Com Test ComOil OilAcetone H-24019 H-24020 H24043 Days (ppm) 0 <2 (ppm) 05 (ppm) (ppm) (ppm) 328.18 (193) 155.76 (292) 196.1 (16.13) 94 06" 2 7756 (101) 168 (0.3) 122 (1.64) ab OStnaendvaalrude.devFioautrioonfitheinvpaalrueensthweesrees.below the levelofdetection (LOD)o levelof quantification (LOQ). TABLE3 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE Positive Controls Test H24019 H-24020 Days uMF Equivalents uM F Equivalents 10 504585 (296917 112725 (1137) 94 1190.15 (15605) 1072 2.14) a Standard deviation i in parentheses Test Substance H-24043 uMF Equivalents 130627 (107.50) 80.27 (1094) _ Company Sani1550 Doesnot contain Tc gy --_--m-- ER -------- 11.024D0o83s:e5OralBiCaovpaegreiSnetySeSrieneeRiantgs |onDDuroinm20s32 FIGURES - COmDany Saniizeq,Doe:0 ontin 750 -- x :| | : [fs | gg E23 -- T1E28 ||| | pe-- , iidgE EX |i a E EE se Rca 2 88 | 5Eae | -3 zg _ ES 2z id:; I - Zz 38 f E [C--------------: | g zz | - gm - 2 Sg ||| | a i 55 | Tecomm-- E2A | e. z= gS | |I | i oN NNT 8% | 23] || - F2H v8\ NNTN NN--_ 5 5 8 5 2 =z 8 3 sg 28 [a CompanySanifized. Dose not contain TSCA CBI i it 23 2 = . 4L3E 2 gl 3 3 ~ gt 1 1 se5 | | | | 1EE% | |E&3 || Iss! 2 $5: | g, || | lecasss || 11f3i53i [ o em0 - 1 2 | 88 || I=z5g] | || 8 z8Eg a 28 | | g =2a E3 azt%22 55 | 8z 32 | ! g2%o gE | g ||| a | 5y F< - "= = I Ll NON NN NN s : = + 3: 2 $2 s 2 3 S Cm osp o) " NN & +2 3s 8 =: CompanySaniticed.Does not containTSCA CBI -_ fT | | | 3To 2] gg z 28 g 23 sg A HHTH LI | i CELT | [lll | TTTTTTR. FT i iN || I | 3 2 aa 288 |WLL\ L L LL { 5& zg EEE Fi -= 2% ssere2S 8 n i gif . - g iz 2g EEgg Co | .| bEiLe gseisg > E 1s 22 SEE ee 5 2 es 25 2322 gg2S [|| I || . cd= , 3 ;i 2i23 : mil 2 fS N3N&N3Y TT owe Company Sanlized.Doesnotcontain TSCACBI Ts i 44 - os is I3H i 38 Ti Ce 37 || FE || || s | 1%233 ||| le $55 | g | 133% | [ | .] Sg [Es=so ||| : a| 85 | | | | | : - zgg:: | | | | 53 | i| i | ) E i EiAE | || | EEgl8g | | F|o | | 2 z: | a | . g&g | || | 5 | g - - 5zz | 5| \ a |iL |\ L I( !( L v Hg:::1 swareAba 1 Wi Cormpany entire. DossotconTtSaCAiCnE! HEH E2 a - 3 4i3t i2 ~525}2 is gg8 | | gTz3Z| | o | z au 85 | EiS f rt 323Nz 32i3zz | | zoz | cs | | ||| sE | || g | | agg i| 8 | L gl | w 3S 32:9s | | I! gE | = 2 | 28 <l | Egz5 | | | < || | | | =2 | || | | 82Z | Jf2 | | 2 | gl z 32 g | Eg I] 25 | | | | 2 5 23 a2 =3: 3 a = ' : i2} Z \-- N \ N\ N \ NA ZC5g sgg 8H sg 88 ---- \oN 8g Company Seniized. Doss wet contain TSCA Cal 11.02'4D0o4s5e: OrBailopGearvsaigsteenScteudSyrienrRiantsg SupDpulermoennt N2o9.32| APPENDICES CompanySentra Pmrtnae cre Tara ot = --- 11.02-4D0o4s3e:OrBailopGearvsaigsteeSntceudSycrienenRiantgs, SuppDleumPeonnt.N2o0.32| APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight eee Company Sanilizad. Doss not containinTSCA CBI =-------------------------- H1.02-4D0o4s3e: OrBailopGearvsaisgteenScteudSycrieneRniantgs. DuPon2932 Supplement No. 1 CORN OIL (NEGATIVE CONTROL) INDIVIDURAELLAFTIINVAEL LBIOVDEYR W7E0IGBHOTDSY W(gE)I,GHLTIVOEFR MWAELIEGHRTASTS(g). AND GROUP T Aunmibmaelr BoFdiynaWlt. Liver Wt. RetloatBiovdey LWiev.er Test Day S ee T ots e 627801 200.1 12.216 0.051 5 627805 283.9 14.081 0.050 5 627810 265.0 13.395 0.051 5 627818 260.2 11.981 0.086 s GrovP 11 NAnuimmbaelr BoFdiynawle. Liver We. RetloatBiovdey Luitv.er Test pay 27753 283.5 15.257 0.05% 0 627797 320.2 15.803 0.085 10 627799 294.7 14.285 0.048 10 627800 331.3 16.340 0.089 10 - 627808 3218 17.580 0.085 10 BE HAunmibmearl. 627506 627807 627809 627816 BFodyinault. 320.3 305.2 336.2 330.2 GROUP 111 Liver we 15.413 14.935 14.967 15.811 RetloatBiovdye Lwirv.er 0.048 0.089 0.085 0.048 Test pa 13 1 3 13 - Company Sanhized. Doesnotcontain TSCA CBI H1-02-4D0o4s3e:OraBiloGpaervsaigsetSentcuedSycrieneRnaitnsg `SuppDluemPeonnt 2N9o.321 CORN OIL (NEGATIVE CONTROL} INDIVIDURAELLAFTIINVAEL LBIOVDEYR W7E0IGBHOTDSY (W9E)Z,GHLTIVOEFR MWAELIEGHRTASTS(5), AND aNnuimmbaerl. Tern 627794 627804 27812 627817 BFodiynault. ese 116.7 378.1 388.4 407.3 Grou? TV Li1ve8r.w1e 19.105 15.326 16.775 16.600 RetloatBiovdey Lwitver 0.042 0.046 0.041 0.083 0.041 Testwm Day 2 2 2 2 Grove v ANnuimmbaelr BodFyinault. Liver we. RetloatBiovdey Luitv.er Test pay Steert. estbay 627798 517.3 19.203 0.037 52 627813 a16.8 15.230 0.037 52 627814 386.9 14.358 0.037 52 - 627815 505.9 20.958 0.041 52 Grove v1 a ANnuimmbaelr BFodiynault. Liver wt. RetloatBiovdey Lwiev.er Test paay d 627811 511.6 17.405 0.03 1 627819 653.1 21.828 0.033 91 627820 618.0 26.766 0.083 % 627821 521.5 17.943 0.03 9 _ -_-- `SBa ooswf tcone taind TSCA. ce 25 110..2D4o0s4e3:OraBliGoapvesgreinSetuSdciryneeRntinsg SupplDeumpeonntcN2o0.312 CORN OTL:ACETONE (NEGATIVE CONTROL) RDIVIOURAELLAPTIINVAEL LBIOVDEYR WTE0IGBHOTDSY (WqE)I,GHLTIVOEFR MWABLISGHFTASTS(3), AWD Group 1 To eANmnimsbeear moasFyg ienawlt Liaever we e. Retloatmiovbey Lcieve er Test ay ssa2ss336683 206.7 s12.0 1.236 13.805 0.039 0.044 s s csaass3a0s0 a205a.5 1133..02256 00..000632 s s aroue 1x aNSnu5im3mb5aeElr mo3Fai5ynwa%le. Liiveir sws. Retloat5seidy5v5e%Luirv.er testTovay sasacz 33203 re [= 136 16.139 0.083 0.040 10 10 - sasace 386.7 casare or 17.745 15.328 0.016 0.002 20 10 rove 73 TesnMsinembaelr maFoeidsnyalw. ieiveer ws. RetloatBpioevdteyeLWie.ver Test bay-- caass3ams0s 310.7 07.0 12.950 21.654 0.038 0.053 n n csaassa3n0sa 57.1 ame 16.520 17.355 0.04 0.046 1 n --~ `Company Santized. Doesnot containTSCA can t-- ~~ ------=----m---- F1-02-4D0o4s3e: OBriaolpe Gearsviasgtey enScteuSdcyreinenRiantsg. Su`pSulppeDluemmPeeonmnt2NN9oo.%l2| _ CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDURAELLAFTIINVAEL LBIOVDEYR WTEOIGBHOTDSY (WgE)I,GHLTIVOEFR MWAELIEGHRTASTS(3), AND GROUP IV. T ANnuimmbaelr BoFdE iynault. LTiveer wR e. Retloar tBiodvy e LWe iev.E er r Test e Day 625365 59.6 18.313 0.080 2 625371 17.3 17.859 0.040 2a 625376 432.9 19.168 0.044 20 625381 381.8 14.135 0.037 2 Grove v ANnuimmbaelr 525356 BFoidnyawlt. 535.7 Li2v0e.r45W8e. RetloatBiovdey Lwitver 0.058 TestEd Day 625359 530.3 22.901 0.043 52 625360 555.4 23.312 0.042 s2 625372 506.2 21.287 0.082 52 - 625374 512.3 18.378 0.036 52 ANnuimmbearl. TEES 625369 625373 625375 625377 BoFdiynawle. sess s1a.8 673.7 588.8 496.6 Grove VI LiIverswr. 17.379 20.073 18.869 17.261 RetloatBiodvye LWitv.er poh 0.034 0.030 0.032 0.035 TestgrDay -- 94 9 9a 91 _ _-- `SDa eusnt otcoa ntend Ts .gy En H1240043:O-rBailopDGearvsoiasgteeSsncteySecirneeRnaitnsg SupDpulepmoenntt2No9.321 H-24015 (7OSTTIVE CoNTROL) INDIVIDURAELLAFTIINVAEL LBIOVDEYR WTEOIGBHOTDSY (W9E)L.GHLTIVOEFR MWAELIEGHRTASTS(3), AND AMnoimmbaelr _moPayinailt EET Ee 625323 298.0 625336 ae 625343 298.0 sasaa0 203.7 Grows LiTveer swe. 14.830 16.545 13.809 15.685 RetloatBiovdey Luitv.er pe 0.050 0.052 0.067 0.053 Tostethpeay s s s 5 Grove 11 AMneimmbaelr 25330 moFaiynawlt 1 LiTvoer5w5e. RetloatBiovdey Lwirv.er 02060 mestTopay 625330 310.1 625332 316.3 16.383 17.526 0.053 0.055 0 10 - 25341 325.6 s2s350 208.3 18.256 15.709 0.056 0.055 10 10 Grove 111 Ta EaNnRoimmbTaelr moFm ianawlt. Liver m we. Retlooatbiogvaey Lwiev.a er Test pay -- 625327 355.3 22.259 0.063 625242 326.4 20.718 0.056 1 1 625345 336.9 26.403 25308 336.4 20.501 0.072 0.061 n 1 Bom SitGoeesnoteontain Tsca ogy --ET-- H L11204.D00 o4s3e;OBD rialopGeaorvsaigseseSnuedScycrieneRO naitnsg mCragesudyioSSuuR pppllDeumma peeonmtn2NNs9oo%.2l1 _ H-24019 (POSITIVE CONTROL) INDIVIDURAELLAFTIINVAEL LBIOVDEYR WTEOIGBHOTDSY (W9E)I,GHLTIVOEFR WWAELIEGHRTASTS(g), AND ANnuimnbaelr 2532 625320 625338 625340 25352 poFdiynawlt. 3or3 423.9 339.9 115.0 375.3 rove 1v Li2v3e.r47w5e. 22.100 18.018 nan 21.835 RetloatBiovdey Lwei.ver 0.055 0.052 0.053 0.055 0.058 Test27 pay 2 2 2 24 Grove v TenNumimabelr BFoidnyawlt. and Li2v0e.r90w0e. RetloatBiovdey Lwirver oar Testoepa -- 625329 as8.1 625333 ara 20.911 20.508 0.002 0.088 s2 52 - 625334 426.5 s25344 391.0 19.104 17.666 0.085 0.05 52 52 Grove vi TB eANmnuimmbeaelr BoFSdiyTnaswle o Liver we. Re"ltoatBie ovdey Luitver Test oa 625335 625346 519.5 556.9 21.508 23.945 0.037 0.03 5 4 626347 638.9 27.426 625351 636.8 25.615 0.083 0.080 24 5 - --_---- ER So,Motcon "TSCAce T 101.02DD4o04s3e:OOBnrioalpCeGoravsviaasggteeeSnSucteduSdycyireinneknReaitsnsgs eee _ H-24020 (POSITIVE CONTROL) S`wSpuplpDleuePmmeonenttmN2No9.3o121 INDIVIDURAELLAFTIINVAEL LBIOVDEYR W7E0IGBHOTDSY (WgE)I,GHLTIVOEFR MWAELIEGHRTASTS(3), AND ANunnibnearl TEE 627767 621771 627773 27m BFoidnyablit. 25 248.6 239.6 262.3 236.0 Grove Li1ve5r9W0e. 19.033 16.968 17.629 16.268 RetloatBiovdey LWitv.er Does 0.077 0.071 0.067 0.069 Tesst epa -- 5 5 5 5 Grove 11 NAunnibmearl BFoidnyaWle. Liver we RetloaBtoidvye Ltitver Test. pa BO a I a 627770 338.2 27.332 0.081 10 627776 254.0 18.821 0.07 10 627782 265.2 20.172 0.075 10 - 627785 267.9 20.857 0.078 10 iANnuinmbaerl 27763 627760 627787 627788 BFoianawlt 265.8 306.7 234.9 309.4 Group 111 Liver we 22.123 21.526 16.498 22.730 RetloatBiovdey LWiev.er 0.077 0.070 0.070 0.073 Test Day 3 3 13 3 "7SaOM2Do0sdm.yeontainTSCAcay --- L11o.02DD4o0o8s3e:OOruBaiiloGGpuaevvraiggseeeSnducdeyySiennirRaealsns SSuuppplDleuempmeonent.mN2No9.3o12t #-24020 (ros1TIvE CONTROL) INDIVIDURAELLAFTIINVAEL LBIOVDEYR WTEOIGBHOTDSY (W9E)I.GHLTIVOEFR MWAELIEGHRTASYS(3), AND AN2n7ui7bm5easlr ssaamr6o1 sams cares BoSFdoiyrnaWle. 335199.84 406.2 326.1 Grove 1v Li2vermwe. 1199..550709 24.858 16.420 RetloatB5io0vde6y0Liiev.er 00..005514 0.061 0.050 rest3 pay 2 2 2 2 Grove v TEASRnuimmbTaelr soePniynTailr: Lilveermwse. Retloatbl iovdey Liitv.ere est pa -- asarr6s0 asas6s..s 1168..520650 00..00380 s2 s2 - saarmme sus alo 2106..262055 00..003150 52 s2 Grove vz AMnuiI bmealr mFoidnyaWle. _ Liverws. a RetloatBiovdey LWie.ver cares 609.6 617s ss2.6 19.324 17.296 0.032 0.0m ame asa came ss72 15.628 21.00 0.035 0.03 Test oaa d os 2% 0 2% _ - TY Sei, ot contai,n Teaogy H1:240043:-OBriaoDlpGearvosasgteseSntcueedSycrienRReaneitnsg H-24043 (TEST SUBSTANCE) SuSupplplDeeummPeoennmttN2No9o_3l2| INDIVIDURAELLAFTIINVAEL LBIOVDEYR W7E0IGBHOTDSY W(gE)I,GHLTIVOEFR MWAELIEGHRTASTS(g), AND BE ANnuimmbaerl 620266 628267 628270 626279 BFoidnyawle. 240.2 260.3 281.0 202.9 Group 1 Liver We. 12.948 14.289 15.256 13.318 RetloatBiovdey LWiever 0.050 0.055 0.054 0.055 Test pa; s 5 5 s Group ANnuinmbearl 253 BFoidnyault. 775.6 Li1v5e.r66w9e RetloatBiovdey LWiev.er 0.057 Test10 Day 628256 274.0 14.854 0.054 10 628258 319.9 19.664 0.061 10 - 628276 286.7 16.531 0.058 628278 329.7 18.469 0.056 10 10 NAunmibmearl TTemaEl 628271 628275 628280 628280 BoFdiynailt mss 303.2 345.6 271.8 351.0 Grove 111 Li1v.esrawst. 17.968 21.913 17.147 24.682 RetloatBiovdey LWiev.er 0.088 0.055 0.063 0.063 0.070 TestoTpay -- 13 It 3 13 - "7SRE. nest go , "TSCACB L11.02.4D0oo4s3e:ODrBaioGpoaervsaigssetenScuecdSycirneORenaisngnlGrageSudyinSSuuppRlpDieeummpaeeonmtn2NNs9o3o.12t H-26043 (TEST SUBSTANCE) INDIVIDURAELLAFTIINVAEL LBIOVDEYR WTEOIGBHOTDSY (WgE)I.GHLTIVOEFR MWAELISGHRTASTS(5), AND aNnuimmbaelr BC poFiynailt Er 626255 a20265 en. prow 28274 362.3 52626 353.8 Grove Tv Liver we. 18.307 23.561 18.561 16.298 Re"ltoatsiovdey LWit.ver mest pay 0.067 LE Sd 2 0.057 0.054 24 24 0.051 2 Grour v TTeAENnuEimambeaerlr Bo4Fd5iy0n.aW5lt. Liivenreswe. Retloatbiovdey Lwirv.er oor Testeg pa 52626 2026 ass 469.9 18.601 17.36 0.03 0.037 52 52 - 28272 626281 505.9 pe 21.200 19.485 0.062 0.061 52 52 Grove v1 a ANnuimmbaeIlr BoFidnayl. Liver we. RetloatBiovdey LWiiv.er Test pay 620264 a28260 am.2 560.3 26.072 19.762 0.038 0.035 9 0 626265 s20205 ars. 665.2 16.116 25.123 0.03 0.038 54 5 - TT Pot Contain1,Scace, ees H1D-02-4oD0o4sc3e:OOrmBailoOpGvearavsagigseteeSSntucueddSyyciirnenenRRiaantgss. SSuuppplDleeumPmeonenttmN2No9.o312l APPENDIX B Individual Fluorine Levels Comaany Sanit'z0d. Dons memntain Toca ogy EB 0H120.4D0oD 4s3e:Oro BaioGpeas rvsaigseee nScteudSycOrieneRnaiu tnsg iOugeSudyinSwSupRplplDeeumme peeonmnttNN2s oo9..%12| T --_-- ERMSANTEDRMSCANA D CALLCUCLATUIONL S ATIONS Terms: Active Fluorine containing compound % Active "cTohmep%oneofntfsormulation that is made up of flucrine containing Mol Wt Active Formulation Dose `The molecular weight of the fluorine containing components (g/mole) `The mg of formulation given per kg of animal body weight %Fin Active "fTohremu%laftliuoonri(nweeiinghtthebafsliuso)rine containing components of the Mol WF "The molecular weight of fluorine g/mol Compound Caleulations: Dose Active (mg/kg) Tanhiemamleboofdfyluwoeriignhet.containing compound administered per kg of = (% active/100) x Formulation Dose Dose Active (mmole/kg) aTnhiemamlmobloedyowfefilguhotrine containing compound administered per ke of = dose [mg/kg] / Mol W Active [mg/mmol] Dose F (mg/kg) `The=m(g%FlFuionriancetiavdem/i1n0i0s)txerDeodspeerAcktgiovfe a[nmigm/aklg]body weight Dose F (mmol/kg) The=mDmoosleeFof[mfglu/okrgi]ne/ aMdomlinWistteFre[dmpge/rmkmgolo]f animal body weight Molar Ratio (Active/F) The=mDoloesseoAfctfiluvoeri[nmemcooln/tkagi]ni/nDgocsoemFpo[umnmdolp/ekrgm]ole of fluorine NFoorrmmaulliaztaitoinoDnoFsaector o`Tfhaectfiovremunleaetdieodn tdoosaechtiheavtewtohuelndobremarleiqzueidreddotsoeadminister the amount = ((Nmomromla/lkigz)edxdFoosremuoflaAtcitoinveDo[smem.ol/kg] / Dose Active -_-- BS TY Sard. Oe,T otcone es TScace D H1:02-4D0oD 4s3e:OrBao ilopGearvsae igsteenSctO eudSycrienm eRnaitnsg_O__m _ geSudyinSuR SuppplDleea ummPeonetnm2s NN9o.3o21l A --_-- NDeATTL EKRMDSC ANDu CALCL ULATA IONSTIoNs Individual Animal Measurement: ppm Fin liver `The ppm fluoride measured in liver Individual Animal Calculations: ppm Fin Liver minus Bkg 0.2 ppm Tmheaespurpemd filnuocroindteromleaansiumraeld liinvelri.veIrnmtihnisuscatshee tbhaecvkaglruoeuwnadsfluoride established at 0.2 ppm. ppm Fin Liver normalized to 0.1 mmol/kg Dose a`cTthievpepdmosfeluwoarsid0e.1mimnmuoslb/akcgkginrsotuenadd tohfatthweoaucltudalbeacetxipveecdtoesde.if tThheis abustsuismenseeldienedarbietcyabuestewdeiefnfeardenmtindiossteesreodf adcotsieveanwderleiveursefdluionritnheelsetvuedlys., = (0.1 [mmol/kg]/ Active dose [mmol/kg]) x (ppmF in liver `minus background) - sumolar equivalents of active in liver iTnhleivmeorlbaasred[moonlt/hLe]pcpomncfelnutorraitnieoinnolfivfelruonroirnmeacloinzteadintoin0g.1commmpoolu/nkdg active dose. This assumes that all liver fluorine is derived from the flmuorgine/cLontaining component in the formulation. Note: 1 ppm -- = (Normalized ppm [mg/L] fluorine in live/r Mol Wt F [mg/mmol}) x molar 1000 mol/mol ratio active/F [mmol active/mmol F] x -_-- CompanySentized.Doesnot contain TSCA CBI 6 LH1-o02.D4D0oo4s3e:OOrnBailioGGpaeuvrgasgseetSnScuteuddSyycriienReRnaaitnssg SwSupplplDeeumPmeoennttm.NN2o0o_31l2 -- CFAATCOTORR0STIPNLFLUURECNICNINGGIINNTTEERRPPRREETTAATTIIOONNOOFFKKIINNEETTIICCAANNAALLYYSSIISS Considerations: ~The data used cautiously. for kinetic analysis was from a limited screen and extrapolation should be done - Sample size is low - Analytical data used without Steady-state not reached validation - Terminal phase may not be reached - SDiofmfeerecnotmapcotuivnedasnadrefomrimxutluarteisonofdofsleusorwinearteeducseodmpounds - EDiafcfherceontmpvoehuincdlemsawyerheavuesevdertyo ddieflfievreernftopromtuelnactyiofnosr producing toxicity Assumptions: (May or may not bejustified in all cases) - - ALniavleyrtifcluaolrimneetchoondceinstarpaptrioopnrsiaatree floirnaalrl wtiytphesroesfpcecotmptooudonsde.s - Elimination kinetics can individual components be determinedbasedon total fluorine rather than on concentrations of - Background Fluorine is 0.2 ppm - M%oFlecdualtaarswtehiegh%t Fislutohreimnoeloefcutlhearacwteiivgeh(tFolfuotrhieneacctoinvteacinoimnpgocnoemnptoninentthe(sf)orimnutlhaetifoonrmulation) Company Saniized. Doss not coriain TSCA CBI ET H1204-D0o4s3e:OrBailoGpearvsaigseenScteudSycrieneRnaitnsg _ Data for H- 24019 SuSpuplpleDeummPeoennmtt:NN2oo0.32| Given: Mol Wt. Active (g/mol): Formulation Dose (mg/kg): 497 10 % Active (F Containing) in Formulation: ~ 100 % Fin Active 65 Mol Wt. F (g/mol): 19 Calculated Values: Dose Active (mg/kg): 10 Dose Active (mmole/kg): Formulation Dose Normalization Factor: 0020 _49.7 Dose F (mmol/kg): 0342 Molar Ratio (Active/F): 0.059 Dose F (mg/kg): 65 Test ppmF Rat Day in Number Sample _ Liver ppm Fin ppm Fin Liver Liver Normalized to MinusBkg ~~ 0.mmoleskg 0.2ppm Dose pmolar Equivalents of Activein Liver Group II 625320 10 3194 3192 - 625330 62532 10 3554 10 3384 3552 3382 62531 10 3050 625350 10 3227 3048 3225 1586.42 1765.34 1680.85 1514.86 1602.83 4910.77 5464.62 5203.08 4689.23 4961.54 Group VI 625326 94 798 625335 94 896 625346 94 73g 625347 94 625 626323535511 9944 882211 796 395.61 89.4 4432 736 365.79 623 309.63 881199 0 440077.044 122462 1375.38 113231 958.46 1212660.000 TTT Tees Sanitized. Does notontaincontaTSCA CBI H1-02-4D0o4s3e: OrBaile oGpaervsaigsey tnScteudSycrinerRiotnsg -- Data for H- 24020 Su`SpuplpDleuempmeoenntmtN2No9.o3a2| Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): 426 20 Fin Active: Mol Wt. F (g/mol): 69 19 % Active(F Containing) in Formulation: 100 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): 20 0047 Formulation Dose Normalization Factor: _42.6 Dose F (mmol/kg): 0726 Molar Ratio (Active/F): 0.065 Dose F (mg/kg): 138 Rat Test ppmF Day in Number Sample _ Liver ppm Fin Liver MinusBkg 0.2 ppm ppm Fin Liver Normalized to 0.1 mmoleskg Dose molar Equivalents of Active in Liver Group IT 627768 10 1825 627774 10 1090 1823 1088 - 627776 10 1740 1738 627782 10 1475 627785 10 1658 1473 165.6 38830 23174 370.19 31375 35273 1321.01 788.41 1259.42 1067.39 1200.00 Group VI 627778 94 19 627783 94 12 17 10 362 213 1232 7.25 627762 94 19 621775 9a 16 17 14 362 298 1232 10.14 627169 94 18 16 341 1159 _-- - Company Saniized. Dossnotcontain TSCA CBI H1204-D0o4s3e:OrBailopGearvsaigsteeSncteudSycrieneRnaitnsg Data for H-24043 Given: Mol Wt. Active (g/mol): 494 . Formulation Dose (mg/kg): % Active (F Containing) in Formulation: 100 25 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/ke): 25 0.051 Formulation Dose Normalization Factor: _197.6 SupplDeumPeonnt2N9o.32| % Fin Active: 60 Mol Wt. F(g/mol): 19 Dose F (mmol/kg): 0.789 Molar Ratio (Active/F): 0.064 Dose F (mg/kg) 15 Rat Test ppmF Day in Number_ Sample Liver ppm Fin Liver MinusBkg 0.2 ppm ppm F in Liver Normalizedto 0.1 mmoleskg Dose molar Equivalents of Active in Liver Group IT 628258 10 1785 1783 - 628278 10 1932 62825 10 2140 1930 2138 628276 10 2116 2114 628253 10 1834 1832 35232 381.37 42247 417.73 362.00 1188.67 1286.67 142533 1409.33 1221.33 Group VI 628269 94 128 628268 94 101 126 9.9 24.90 19.56 84.00 66.00 628257 94 146 628285 94 119 144 7 2845 2.12 96.00 78.00 628264 94 118 16 29 7.33 --- - CompanySafed.Bucs ofcontainTSCACBI