Document NGa5v6OG9yeXQ6kQ7jR3KN2oV

M`MSaaucdbeejeAAvctvatoaiillPaarbbollteeecbbtyyiv33eMMOrffodorerIInnIssnppePeccattiiioomnnaevanrn.dd3CC1.ooppyNyoii.nnggC2aa.ss0CC4o-on6nf3ifid0de9enntitiaall IInnffoorrmmaattiioonn: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 11448899..00000011 Exhibit 1489 I3MMAA1100007722118822 3M CONriucivy aLRe-- Toxicology Contribution to Whi=e Paper [--" Prepared by: John Bust, 0. OABT, CI John L. Butenhoff, Ph.D.. DABT, CIH Feary 28,198 February28,1998 3M sels procs which oni eseof chemical campounds bi om he et lec, 3M sells product~ which contain the series of'chemical compounds built from the parent molecule, rharcncasenoy Tre (FOSPy scien componentsor oman, These perfluorooctanesulf'onyl fluoride (POSF), as either intentional components or residual contaminants. These mics ees noirof ntssg mu sn Peres Slot (FEO Wag] chemicals include, in order of" Lncreasin$ molecular size, Perfluorooctane Sulfonate (PFOS), N-Ethyl FPCrSu)naernse mSlr (1 FOLumie 091 Peforomne SuframioshCaenl Perfluorooctane Sulfonamide (N-Et FOSamide), N-Ethyl Perfluoroocta~e Sulfonamidoethanol (N-Et aofnneO a 1 Ea Pes Sutra opines FOSE), and the mixture ofMono-, Di- and Tri[N-Ethyl Perfluorouctane Sulf"onamidoethyl] Phosphates (Monts, Dev snd Tit pecan. Ala mcs pepo oe BS wen, (Monoester, Diester, and Triester, respectively). All of these molecules incorporate the PFOS structure, vt eo Gt mean which is not know~ to degrade metabolically. Rsk edo capo sd owiailty wl2 icy.The deo ggs with xcpicn ~sk is related to exposure =rod bioavailability as well as toxicity. The data suggest that, with the exception oersod rll iemle pesnysarod om ent pace, Spent of die=tar and ~aster, all of"these molecules ate appreciably absorbed form the di[estive system. Specific orion at how ht rp Bo Baieye res we Ch absorption, studies show that ~,orption from the disestive sy=em decreases with molecular weight, la": Ser onts EOS > 33%. EL POSE 3 7 tit onocac eos 13% other words, PFOS is > 9.~% absorbed, N-Et FOSE is > 7.~ % absorbed, Monoester is approximately 40 iin Der nd Tens Gost ve rl pion. Whe every pee absorbed, and Diester and Tdster do not have appreciable absorption. Vghile we have no specific ~ ELF Samie i gn hte wasn eps + well red the N-Et FOSamide, its significant sub- ~ronic oral toxicity suggests that it is well absorbed. Afrborof .oEC OnSEor: FSi, PEGS cabodinvisse,wih rst A~er absorption of.N-Et FOSE or N-Et FOSamide, PFOS can be found in vario= tissues, with the largest ities und dl,Bed vs io oy og FOO relative amount= formal in liver and blood. ~ on an inta'aveno= i~jection study met[ PFOS, it appem3 S255of to doe a be nd oe es her 3d 3 hs Toe oi that 25 % of the dose can be found in the liver al~er 89 days, and 3 % in the plasma. Ther~ is ii~ Concenraioin Evins eb ok OS i re bot ss gh Ayfr concentration in f~ Evidence suggests that PFOS is highly protein bound, and it has a high alTmity foe ory sdcri in. ot eet mensBk re oe eeAre h fatty acid ~='rier proteins. Other evidence suggesta that it can EtCOtTmrate into mcmbrane~ and increase EESrei membrane fluidity. Allo hs leis could se capcdto dead acaba ins proporintoe PROS All of these molecules could be expected to degrade metabolically in some propo~on to the PFOS rica en co mp el,Oe eben ar bao se oe Ei Percane sm~cture as an end-stage metabolite. Other membolite= are known, such as the N-Ethyl Perfluorooctaz~ Samim cCeor ratmi, We donne 5 FOS, Monon ns he erate Sulfonamido Acetate (for example). We do kmow teat the N-Et FOSE~ Monoester and the N-Et FOSamide orm POS mbotcaly. Tres ds oe mst dk FOE ot roe oo will form PFOS metabolically. There is also evidence to suggest that N-Et FOSE and Monoester will form ENE FOSumte x well she mea the N-Et FOSamide as well as other metabolites. PROSi vey effective onpug ih procs, ndhas igh ity four cdcir roti PFOS is very effective at ion pairing with proteins, and has a high alq'mity for fatty acid carrier proteins Sh tind m FABP,FOS oh npn oh ol pte fo such as albumin a~d L-FABP. PFOS also has an amphoteric nature which would suggest an atTmJt7 foe incorporaion membranes Because of hse proper, hotabn a PHOS ly incorporation in membrane~. Becaus~ ofthese properzie~ it is not surp~sing that PFOS is slowly iSom ox boyace esnr. ni pri 6 ea end wi sl rset eliminated from the body, once absorbed, in rats, approximately 60 % of a given dose was still present S018cys WA goo rion 5% nk cles oe oy, reron after 89 days. With good abso~m (> 95 %) and slow clearance from the body, chronic insestion can Toney course ocd lal 6s dt mon oFPROS significantly ona'ibute to otnerved biological effects due to accumulation of PFOS. Wl the xcepion ofthe Mosse, Dieser, nd Tria, which have nos bee sid 1 ure With the exception of the Monoesler, Diester, and Triester, which have not been studied as pure CIe oc mespSeocsuppnsodrsi mas ole cof vee we hts eis compounds, these molecules appear to share the similar toxic effect of severe weight loss and anorexia. ae ofFOS, N-EL OSE. N.E1 FOR nd Most er potent{ov umlave ny `ooInvveetrhrtetiimmcaees..eToThhfeePsFisOmimiSli,laaNrr-vvEataluFelO~ouSofEeft,thhsNee-EpprrtooFddOuucScttoaomffdiddoeossaeenxxd Monoester, there ttiimmee wwiitthh rreessppeecctt is ttoo potential for cumulative toxicity ttootaall dosee ((mmg[//kkgg//dd xx ddaayyss)) oidbe xe 1nd dos pps a 14 sil ep of iy Thepce tST would be expected to and does appear to lead to a similar degree of toxicity. The primary toxic effect Soper 04 able simi abl wAAE Ths hpope t0ae hfe cc appea~ to be metabolic stimulation or metabolic wasting. This is hypothesized to be due to an effect on Ey cd meat. meas ncn. on ya dr mena Bose The larry acid metabolLm~, membrane function, protein synthesis and/or mitochondriai bioenergetics. These Compouns ah fon be NONELS LORELStery ete of B11 VAG compounds lack genotoxicity but have NOAELs or LOAELS generally in the range of 0. I-I mgAg/d. ie och nd oc ndpmt i rns Ses suo of CONES oy NOE Cumulative toxicity and toxic endpoint will certainly affect the value of the LOAEL or HOAEL. Lp -- Made Available by 3M for Inspection and Copying as Confidential Information: Sic Protecive Order n Palmer v. 3 No. 62.04.5508 Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 11448899..0000002 aatoor21es 3MA10072183 A CCOONNFFIIDDEENNTTIIAALL RReessttrriicctteedd Ove~iew Assessment of Information Adequacy J-- Prepared by: eb. But1.0o. ABhT.,Cl John L. Butenhoff, Ph.D., DABT, CIH . ey hi February 2g, 1998 Ae nt aySob MD At the direction of Larry Zobel, MD TT ----__----_, Note bone: This ~ble should not be consn'ued to suggest that all a~eas not noted as adequate should require te or ea oc en teming afnames es ot este specific studies in those areas. For example, a be~er understanding ofmonoester metabolism may preclude cemd an ss oe one fo oes mais Tues men specific studies on monoester, if studies a~e adequate for known metaboiites. This table is meant ~ a Eme en is, framework for the prioritization process. Information I Information Adequacy by Molecule (Adequate means no additional work warranted) [" i Fale GI Absorption Good Good Fair (toxic) Fair (toxic) Fair (impurip!) Disl~'ibution Fife Acme Toxicit~ See Asean Sub-Chronic Good Good Goal Adequate Adequate Good Fair romGood Adequate Adequate None None oTNone Goal None Poor Fai- rane Unknown Adeq-~te Adequate Good Fair ter] Good Poor err None or Poor ena (m extent ~hmt monoesxer is a Sroepnel component of he FC-807) Chro~nic (Ntooenxeteo~ntPtohnatt (to ~-nt thin a Neteoutof metabolite of Fair (impurity) None H((t1oo0 enexext~oe.rnnttPtohoart La amide is e Norenof me~oli~e of' None N-EU~ose) [Reproductive |NNoonnee | None [NHoomnee N-E~ose) |AAddeeqquua~e |NNoonnee | Adequate None Adequ~e None Adequate Adeq~mt.. Adequ~_~_e None [mmuntox. NNoonnee [NNoonnee [NNoonnee | UUnk~moow~s |NNoomnee | [Bioenergetics Good [GGoooodd [GGGooooooddd None | NNoomnee [GG oo~d None [WNoomnee | Good [FoodTransfer| Poor Noee "AAdedqeuqaut~ee [PoNPoooornrietooGGoooodd | None None P= oor [MilkTransfer [PPoooorr [PoPooorr [NNoonnee PoPo~rr [NNeonnee | (PlacenalTrans[NNoonnee | NNooonee [NNoomnee NNoonnee [NNeonnee | or esofveignioctonssibe O~her areas of investigation to be considered: -- Additional mechanistic work I tere epanaecov an Scien Sources of exposure other than Scotchban Lote ts cn esto sed onbse. ics ere Prercntial pa~ifionin&, dbu'ibution, metabolism based on branch.! vs. linear i~mcr swucn~r pa rapinon Multisource risk Wace Avaliable by 3 or nsecion and Copying as Gnfiental fomatn Made Available by 3M for Inspection and Copying as Confidential Information: Siftio rotecave Orga It Palmerv. 3 No. C2.04.6308 Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 11448899..00000033 awatoor2184 3MA10072184 . 1] Hei.l 1ii | i ] His * iHiisn hE 1 Sith H..2 ithitl; iid l1Hi5al1i8i5l! iil ih 1 ny ilial of] F EHlildin ili "HaT Le ih Li d hile fii | Hi pHisatliHnngi, Bill ddlid jldlnliny | fits JH i HE [RI Lisfsid hi i Giit; hai iilsi a iiAaAi] ih pant g Hist: HY [aii 133: i] id: i LiEy 10 i [1 lliill adi iFH iinHiif = ] Made Available by 3M for Inspection and Copying as Confidential Information: 3MA10072185 Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0004 i ;iil IilRiiIdlsnlY n i dEHHii}tltl]g||||| z0 EI Ei fiRn aIif iH,~ oI _lLm n Hhii !!'- Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0005 3MA10072186 bbinkgd, li 7 : jis: Bao o Ei if HE hdif ET | pd AE Ed din HsE i hy Ea Rn Edi0 | || F1f fhaEji hEE iadtesd | WE 2 :i 31 RNc i R Ei ai |B FH 3 Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0006 3MA10072187 g | $s i i i HE | Bik Fh : geiillni HBi lit H fq it il n ii ih iiil: mBihl m HY is gf ii, 1 be iii LilpiliaeHa LE hh Tp end tHHHe HERiHn Y Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0007 3MA10072188 Po i :i iHl y ; LH :i ii3 i i i: hh i i alsa Hab Hl End i i i ii li HIE Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0008 3MA10072189 fina hil :1 5d lig ; istEihHinsHhiiUnHny ET i Hk PshE sepE42 lis shih inhib 3:3 Hlhi aBhe ai 5 iE BL hid i Th i: : LbPs i bl Ini aibf [Heslii piiyn d1i 1h Ei li BRig [pn ailn| i ig nal Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0009 3MA10072190 ibf 2Hd i5l | mfiyo GiRfi le gH Hh | i EE ii 18 aBLEEH P hi (2:1 iii i hE hin lh Hjiissst EE Ebb alii SrBpouli|i oLEh B [ELE e iitii p Bl h B Rl Sai ll . 2 bf4i3sE[1 E olex i Ebi iia 1E]Sawllel ]$i[s zii2l Bil : i: i: fii i hE 233 3: Eh (3: 2 Biidy , BS Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0010 3MA10072191 iiii]i i259 iz Hi 1:2 HEH : |3 FIERY i i. 323333 I [Fassel 8 & < Tr | feeediid Wace Avaliable by 3 fo Inspection and Copying as Canfdenta format Made Available by 3M for Inspection and Copying as Confidential Information: Sic Protecive Order n Palmerv. 3 No. 62.04.5508 Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 11448899..00001111 awtoorz1s2 3MA10072192 M<a3$egth |, | 8hii: f HHihpH nt|e||| | fHflyyl TenidHi || bi i 1 i 3 i at Hig ii ie E1A iigss 113 i il ] po vhs PPoEoTf oh : HEH 2 fs i | il fe di(fa:Hai sh RH [s80RSs1 Made Available by 3M for Inspection and Copying as Confidential Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0012 3MA10072193 iF1lH8 ikdlTby iHi HhHeHLlit ffiy EH] di is $i, HE 1 le fish ti H hint [i nt ly sli : it dit it i II r 353 li : hi i Bis fi sd Hi I HiiLgdile i FdalHe iAta ih igli an 3 a 5 ls flili ai R hill Poids HH a t EH Hi jel iti HHBi HihHHHHEH fBill IEIH i i hi LhLiHtil ii i o 2: H pHll (Na iti fli } --- Made Available by 3M for Inspection and Copying as Confidential Information: 2 Pt] ire : iit i i2s fai 3MA10072194 Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 1489.0013 2 2 I Hif | |3 . 5 J i5 : g z s 3 MSMauadbdejeeAAcvtvataoiPillarabboltleeecbbiyyv33eMOrffdooerrrIInnIssnppPeecactiiioomnneaarnn.dd3CCM,ooppyNyoii.nnggC2aa.ss0CC4o-on6nf3ifid0de9ennttiiaall Information Information: Subject to Protective Order In Palmer v. 3M, No. C2-04-6309 11448899..00001144 . 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