Document 1g9yBBeBbwgy4ZVJEaLGd3E6K

Doaerays re ont chan INSTRUCTIONS FOR STAFF WORKSHEET Contains a summary of available data and ongoing staff analysis Data and analysis are subject to change LBatst RAeevviiosnesd:: 55/23/0177 ReSuEvpapilmeamieonnotFOortiugsiendalonReKseiyewSt(ucdoimespldeteendtoend12n72U0S0E7P)A PPeerrfflluuoorrooooccttaannee SSuullffoonnaattee Supplement to Original Review (completed on 12/07/2007) Re-Evaluation Focused ~n Key Studies Identified in US EPA Health Effects Support Documents Released May 2016 Keer orginal ecw worksheet (ADASENILIACOMMON Guidance - Waters resins: Refer to original review worksheet (\\Data3fb\eh\HRA\CO3dMON\Guidance - WaterkTox reviewsComet FnPFOSFOS 200 Reew POS Foal Nov 7p) evsoped i 307 for completed\Final\PFOS\PFOS 2007Review\PFOS Final Nov 07.pdf) developed in 2007 for Fo additional intbrmation CCAASS ##ss 11776633--2233--11 ((aacciidd)) 2299008811--5566--99 ((mamnmmoonniiuumm ssaalltt)) 7700222255--1144--88 ((ddiieetthhaannoollaammiinnee ssaalltt)) 22779955--3399--33 ((ppoottaassssiiuumm ssaalltt)) 2299445577--7722--55 ((lliiththiuiumm ssaalltt)) ote: perlurooctarnoant doc ot av a pci CAS mumber [Note: perfluorooctanoate anion does not have a specific CAS number.] Synonyms: POS, Penroocane soi od. Synonyms: PFOS, Petfluorooctane sulfonic acid Chemica Formula CSHFI703:5 Chemical Formula: CS-H-F 17-O3-S Sens Structure: A | HH I EI T Initial Primal" Re-review a -- (Partial)Final Primary, Rc-rcvicw {Fy Foc rma Ri (Final) Final Prilnary Re-review Initial SecondalT Re-review (Fama Fol acon Revie (Partial) Final Secondary. Re-review (Fara) Fo Tm Roresien (Final) Final Secondary Re-review Interim Team Re-review (Partial) Final Team Re-review (Final) Final Team Re-review hitiats 17 HMG JAJ [DateStarted 5/27/2016 wants 9/6/2016 Thszsle 7/29/2016 9/15/2016 HT 8/15/2016 11/14/2016 3/31/2017 171 |DaleComple|te1d 7/1/2016 (2ndary review denon X08 discussion); 8/5, 9/12 & 12/2016 (2ndau~ review os discussion) pH 8/10/2016 9/23/2016 Hr8/30/2016 11/23/2016 4/20/2017 Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 1 of 75 22447766..00000011 EExxhhiibbiitt 22447766 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 SSTTAATTEE_0077443388009966 Current MDH Criteria: Acute nHRL (2009)* = Not iDerived (Insufficient Data)** Short-term nHRL (2009)* -Not Derived (Insufficient Data)l** SSuubbcchhrroonniicc nntH/RRLL ((22000099))** == NNoott DDeerriivveedd ((hIn~ssuuffffiicciieenntt DDaattaa))I/**** Chronic nHRL (2009)* = 0.3 ug/L (Developmem, Hepatic system, Thyroid (E)) * Values officially became HRLs (i.e., promulgated into role) in May 2009, however, the full review and values (as nHBVs) were finalized in Dec 2007. **Serum conceutrations are the best dose-metric for extrapolating to humans. At the present time the information necessary to estimate less than chronic doses (i.e., acute, short-term or subchronic) that would result in a given serum concentration is not available. Additional uncertainty exists regarding to,~cokinctics in early life. Therefore, acute, short-term and subchronic HRLs were not derived. MDH 2017 Health-Based Guidance Evaluation PFOS is a manmade chemical in a large family of chemicals called perfluoroalkyl substances (PFASs). PFOS has been used in a variety of consumer products, m~d continues to be used as a fire repellent in firefighting foams, and generated as a degradation product of other perfluorinated compounds PFOS is very persistent in the environment and the human body; it has been detected in water, wildlife, mad humans worldwide. PFOS was selected for re-evaluation under the Contaminants of Emerging Concern (CEC) program because the US EPA recently published a new final ttealth Advisor" (ILk) (USEPA 2016d) along with a ttealth Effects Support Document (HESD) (USEPA 2016c) for PFOS which contain new information and more in-depth assessments (e.g., pharmacokinetic modeling) of pre-existing studies. MDH initiated a re-evaluation of the 2009 HRL value to determine whether changes to this value are warranted. US EPA's published documents include a comprehensive review of the toxicological literature. This comprehensive review will not be duplicated in the reevaluation. Rather, the re-evaluation will focus on the key studies identified in US EPA's risk response assessment. PFOS is a highly bioaccumularive chemical. High, short-term exposures result in an internal body burden that can take years to be eliminated from the body. Therefore, a single Health-based Value has been derived that is protective of short-term exposures such as formula-fed and breast-fed infants as well as long-term exposures. Noncancer HBV - 0.027 ugiL (Development, Immune system, Liver system, Thyroid (E)) RID (MDH 2017) Cancer cHBV - Not Applicable Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 2 of 75 22447766..00000022 STATE 07438097 Note: Table below is only a partia! list andJbcuses on more recent~l, available guidance values. Value | Type/Description Source. Date 00..0077 uugg//~LL|LLififeettiimmeeddrriinnkkiinngg | ((UUSSEEPPAA22001166dd)) water health Based on: RID derived from a developmental tox stu@ in rats advisory (HA) (decreased pup BW), RSC of 0.2, and lactating women intake rate (0.054 Likg-d). HA is protective of short as well as lifetime exposure. [previous provisional HA was 0.2 ugiL (2009)] 006.6ugug/iLL| DDrraafftt GGrroouunnddwwaatteerr| AAllaasskkaa ((AAuugguusstt 2222,, 22001155)) ppeerrssoonnaall ccoommmmunuincicaattiioonn ffrroomm TTeedd W Wau ttoo value Jinamy Seow. Based on US EPA 2014 draft toxicity values. 0.2 ugiL Drinking water Delaware Dept of Resources and Environlnental Control aci (USEPA guideline valuc 2016d) 0.2 ugiL Provisional Illinois EPA aci (ASTSWMO 2015) groundwater remediation obj ective 0.1 ugiL Groundwatcr Maine DEP aci (ASTSWMO 2015) relnediation action guideline 0.11 ug/L Drinking water Michigan Dept of Environmemal Quality 2013 aci (USEPA 2016d) guideline value Michigan Dept of Environmental Quality 2013 aci (ASTSWMO 2015) 55/11199/22001166 88/22221/22001155 6/8/2016 6/8/2016 0.012 Ambient water ug/L quality standard 0.56 ugi1 Drinking watcr (TCEQ 2016) Based on RfD 0.000023 mgikg-d 0.5 ug/L wwInaatteteerrirmQQuauDlarliiittnyyk"ing h(tAutstpralsianhHeaelaltthhnsPwro.tgeocvtion ePnrivnicripoanlmCenomtfmacittsteheee2t0s1D6o)cuments/pfas- 5 ug/L Guideline interred-health-value s-ahppc.pdf Recreational Based on TDI of 0.00015 mg/kg-d. Water Guideline 0.6 ugiL Drinking water (Health Canada 2016a) Screening Value and draft proposed drinking screening value water guideline (Health Canada 2016b). Draft document included (2016a) & calculation of a cancer based value of 10 ugiL. Noncancer value b~ed proposed Drinking on POD~x,~ of 0.0015 mgikg-d (Butcnhoff ct al 2012 rat study) and Water Guideline composite UF of 25 resulting in a TDI of 0.00006 mg/kg-d. The TDI (2016b) was combined with a 0.2 RSC and 1.5I,/70 kg - d to calculate proposed guideline. Docmnents are expected to be finalized in 2017. [previous (2010) Drinking Water Guidance Value for PFOS was 0.3 ug/L] O0.. 1Tuugg//LL | DDrriinnkkiinngg W Waatteerr | ((EEnnvviirroonnmmeenntt. 22001155)) (and ground water Based on TDI of 0.00003 mg/kg-d, 'RSC' of 0.1, and intake rate of used for drinking 0.03 L/kg-d. Value is also recommended for PFOSA. water) Since tox profiles of PFOS, PFOA and PFOSA are similar complim~ce with a composite drinking water quality criteria, ie., addition of the conccntmtion/limit value ratios should be kept < 1. The water guidance for PFOA is 0.3 ug/L 6/28/2016 6/29/2016 5/27/2016 66/122/22001166 Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 3 of 75 22447766..00000033 STATE 07438098 GS0.53 ugiL 000065 | wl 0.00065 ugiL TL| 0.3 ugiL 0.106 >0.1-0.6 ullug/L "0615 >0.6-1.5 ulug/L 1550 >1.5-5.0 wlug/L Shug | 5.0 ugiL 0S ug | 0.5 ugiL 009ug 0.09 ug/L 00.33uuggl/LL | [MPC MPCd,v, water MPCs ase LTpriiefecolaonuntggionary Glue precautionary value PPArcreetcciaaouunttiiVooannlaaurreyys Action [AAVV)I (PAV) Values PAVlo D2D0uu1tt0cc)hh National National state Institute Fofor Public Public cal Health and and ththe Environment Environment (RIVN (R1VM | 2010) | MMPPCCd,~,-, vc water --bbaasseedd oonn EEFFSSAA TTDDII ooff aMndPinCshore ofb2as1e/d70onkdpr.otection and intake rate of 2L/70 kg-d. 00..0000001155 mmgg//kkgg--dd., `'RRSSCC'' for humans pon consum ooff0.10.1,, pion o f M fgfiisaPshhCyeehrrhyyp~er pporrdoo,0ddwuaukctectertss,, basd based based onon on same TDL "RSC" 0.1, and fish intake of 115 protection for humans upon consumption of same TDI, 'RSC' 0.1, and fish intake of 115 | Hgg(Hu!adieladaylaltn.hpc.eer22v007a0006l6k))egDfDorrriinankkliinnpggopW Wualtaaettreirovvnaasllugereo-oulpisfne(lofgnogmhh2ee0aa0ltt3hh)troleraable agPPcuAtAiidVoVans.nttcooPelleVevrrAaaalbbuilleeeffffoooorrrrcamalolmamppaaoxopmisumluiauotmmifonooPsffF1g1O0r0ovAyurrspas,sa, d(33f.PryoF1rmsO,,S.21| 0y30Ir1n3s,,)aooddriiimtmimomen.eddiinisatte || aeaaxcccptccieooodrrniddt.aaiPnnoVcucseeAlooyfiftsathshfeoeproDDcsroriiimbnnlkkpeiionnsagginteWW daoiatnftesePorrfFOaOOrnrAtdasninaafannindnccaePen,c,FieOfafloSforr.etrItsssnouaaarrdrecdetis0otaibobncned, mmitnahideed,a,as. eltloxoocpcasaeldscciititimrhocauuunsmmltsyshtteaaansnHccpPeeossVssaai(llbllhoolweaw.la,lnttoodbrraienesdsdoudufccheeprrcceaoocsmamfupiptoniosaosinnitctaeeirayppl eervrerafsollouruuoo)rrccooecafsarr0abb.n1oodnnnthlyleee.vveellss to less than the HPV (health-based precautionary value) of 0.1 ggiL [PAV PAV~ P[AaVv1 PPPAAAVVY.( for infu & PAV fbr infants & pregnant women S"(XSwwmeaedxdeienmn)a)lLLiitvvoslsmemreaedbdleeellssevvveeerrlkketotf((020.0101494)g),, aaLciif((oEErnnvPviiFrroOonnSmmewneatms..d22e00r1i15v5)e.)d. for (dAdr2rii0mnn0kka8iix)nnigmagnwwadalatcttoeoernlresbbriaaadbsseeelreddinlooegnnvatetnhlheeoexfTTp0DDo.s0IIu9oorgeffsg0ci.eL10.n515aforg~riargoPikweFghObebSwrdwe/da1sdd0eedrr%eiiovrvifeevddetdhbbiyyfsoEEvraFFlSSuAeA (2008) and considering an exposure scenario where 10% of this value `wwaatsearllocated to the consumptionof fant fonmul based on drinking was allocated to the consumption of infant formula based on drinking `awApAsapstlaaeirppe.rdreefccoaaruuttthiioeonnsaar~uy"mommfeesaeusvrueeren,, ttPhhEeeAllSiimmisitutvbvasatllausneoceofsf o0.u00.n909duugyi/inLLcwwoanastsaffmuuirrntthahteererd dSadurprliipnfnlokkineiiandntggefo(wwarPatFtethHerer.A:SsPPu)rem:rfflolPuufeoorsrreloovuccerttnaoanbPneuFtssAuualSlnffeoosnnusaaubttlseeftoa((nnPPacFFteOeOsSS(f)Po):;FuBPPnSede)rf:filnluoorcrohhneetsxaaamnnieenated PsPPueeelrr[rflblnuunoooartrrcoaacc(htPtaoFanaoHonrixcceSaeac)c;iciPddicd((rPPf(lFFuOFOoAHrA)o:A)b;)uPPt:aeenfrafclnluusdoourrPlootebhhrnefepalpttatcaaonrn(ooPopiFieceBnsatScac)in;idoi((ePPFaFHcApA).); Perfluorohexanoic acid (PFH~\); and Perfluoropentanoic acid HHeeaalltthh VVaalluuee ((((LPUUPenFvFniePPitltAeeeA)dd1.)K=K.iin0n.3ggdduoogmm.L. DD(croinnrskuilnitgWlWoanctaaetekrhrIeInanlsistppheecnpctrtooorfrgaeatsteesi22on00a00l77s))& monitor DW) Level Level Level 2I 2 = LOL. 0.3 ug/L 1.0 ug!% (consult local health professionals & monitor (1L0euvglL1)+ pt measuresin place 0 redutco (Level 1 + put measures in place to reduce to below DW) below Level Level 39 3 - 9 ug. ug/L 10 ug/L) Leeveyl 142+ (Level 1 + 2 + take take scion action to to reduce reduce exposure exposure wiw!i 7 7 days) G273016 6/2/2016 VET 1/5/2007 Dra Documfoerenet and dscsson purposes onl. Draftdocument docs not conse Agcy policy Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FOS Sof 75 PFOS - 4 of 75 22447766..00000044 SSTTAATTEE 704734308000909 Note: Tabte below is only a partia! list and ~ocuses on more recently reteased rewiews. Ty ofRp evie ew | (YofPe ublia catir on) | (Refer to theGeneral HRLEndNoteLibrary|) 0.00002 mg/kg-d RfD (2016) 0.00003 mg/kg-d Draft Intermediate MRL Draft Toxicological Review (2015) 0.00015 mg/kg-d Interim TDI 0.00006 mg/kg-d (proposed) 0.00003 mg/kg-d TDI 0.00015 mg/kg-d TDI (USEPA 2016c) Health Effects Support Document for Perftuorooctane Sulfonate (PFOS) (ATSDR 2015) http://www.atsdr~cdc.govitoxprofiles/tp2OO.pdf Draft Toxicological Profile for Perfluoroalkyls. MilLs were derived based on non-human primate stu@ (it was felt that extrapolating from fl~e rodent studies incurred too much uncertainty). A BMDL10 for liver weight from Seacat et al 2002 was used to generate an HED POD of 0.00252 mg/kg-d. Using a total UF of 90 (3A, 10H, 3 DB) -an intermediate MRL of 0.00003 mg/kg-d was calculated. (Australian Health Protection Principal Committee 2016) http:/Avww.hea]fl~.nsw.gov.au/environment/factsheets/Doc ~_L~!a_._q_.n__.t_~.:Ip._f_&_s_.-_ igt__.c;..r_j~A.-_b_c_'.~%h_-.__~:__:~_~.~.~.z!?~p p.:l~ ~_[ (Health Canada 2016a) Screening Value and draft proposed drinking water guideline (Health Canada 2016b). Draft docmnent included calculation of a cancer based TDI of 0.0011 mgikg-d, which was lcss conscrvat~vc than thc noncancer TDI. Noncancer value based on POD~m~ of 0.0015 lngikg-d (Butenhoffet al 2012 rat study) mad composite UF of 25 resulting in a TDI of 0.00006 mg/kgd. Candidate TDI calculations also included use of a PPOODD~;o ooff0.00.0070755 mmgg/ikkgg--dd bbaasseedd oonn tthhyyrrooiidd hhoorrmmoonnee: changes (Seacat et al 2002) candidate TDI - 0.0075/75 (composite UF) = 0.0001 mg/kg-d. Documents arc expected to be finalized in 2017. [The previous Drink#N Water Guidance Value q/'O. 3 ug/L (Health Canada 2010) was based on HI;7_) of O.O0003 mgT~g-d (based on monk~:v sin@ by Seacat eta! and serum level of14.5 ug,/m~ @ZOAEL)/. (Environmcnt. 2015) Based on BMDLa~, of 0.033 mg/kg-d from Thomford et al 2002 rat study. Adjusted for TK difference (factor of 41, based on serum half-life of 48 days in rats), 3 for UFA and 10 UF~r. This TDI was also recommended for PFOSA. (EFSA 2008) Administered dose NOAEL of 0.03 mgNg-d (subchronic study in %~omolgus monkcys) was sclcctcd and an overall UF of 200 (10A, 10H, & 2 to compensate for uncertainties related to internal dose kinetics) resulted in a TDI of 0.00015 mg/kg-d. Obtained 5/19/2016 9/15/2015 6/2912016 6/30/2016 6/2/2016 1/14/2009 Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 5 of 75 22447766..00000055 STATE 07438100 ___- Toxicokinetics: Source: (USEPA 20 l 6d) and (USEPA 2016c) (See Chapter 2 for additiona! information) as well as prevlous ~4DH 2007 review worksheet. AAbbssoorprptitioonn:: A Distribution: B E T GS E EX wwe UUppttaakkee aanndd eeggrreessss ooff PPFFOOSS ffrroomm cceellllss iiss llaarrggeellyy rreegguullaatteedd bbyy ttrraannssppoorrtteerrss iinn cceellll mmeemmbbrraanneess bbaasseedd on data collected for PFOA, a structurally similar PFAS. PFOS is absorbed from the gastrointestinal tract as indicated by the serunr measurelneuts in treated almnals and distributed to the tissues based on the tissue concentrations found in the pharmacokinetic studies. SEL i A OTT The highest tissue concentrations are usually those in the liver. Postmortem tissues samples Ls, Immense collected from 20 adults in Spain found PFOS in liver, kidney, and lung (Pdrez et al. 2013). The i levels in brain and bone were low. In serum, it is electrostatically bound to albumin, occupying up uy to 11 sites and somctimcs displacing other substances that normally would occupy a site (Wciss ct al. 2009). Linear PFOS chains display stronger binding than branched chains (Beesoon and Martin SE 2015). Binding causes a change in the conformation of sermn albumin, thereby changing its affinity for the endogenous compounds it normally transports. PFOS binds to other serum proteins, iinncclluuddiinngg iimmmmuunnogolgolobbuulliinnss aanndd ttrraannssffeerrrriinn.. in nes FOS rs toh a Chin 1209 Latler tl 005) During pregnancy, PFOS is transferred to the fetus (Chang et al. 2009; Luebker et at. 2005b). ym Lactational transfer was not measured, but was inferred based on thc postnatal dcclincs in maternal A AL serum during lactation (Chang et al. 2009). Mondal ct al. (2014) collected serum samples from 633 breast-l~eeding women and 49 of their infants in West Virginia and Ohio. They found that each NS a, month of breast feeding lowered the maternal PFOS levels in serum by 3% (95% CI [-2%, 3%]) ms and increased the infant serum levels by 4% (95% CI [1%, 7%]). MDHNotes: Publications by (~2~riou 2015), (Kim 2OLD, (Liu 2011), (Fromme 2010), and aS A (Karrman 2007) indicate that levels' in human cord blood/serum are &pieally ~40% ofmatern!! serum concentrations and levels' in breast milk are ~. 3% of maternal serum concentrations. One stud), (l,'romme 2010) also measured serum concentrations in mothers and breastfed i~fants at 6 I months after delivery and reported similar serum concentrations in infants and their mothers'. Metabolism: PFOS is not metabolized. Elimination: enA SARSA Electrostatic interactions with proteins are an important toxicokinetic feature of PFOS. Studies demonstrate binding or interactions ~vith receptors (e.g., peroxisome proliferator activated rreecceeppttoorr--aallpphhaa [[PPPPAARRGc]z)]),, ttrraannssppoorrtt pprrootteeiinnss ((e..gg..., ttrraannsstthhyyrreettiinn [[TTTTRR]]))., ffaattttyy aacciidd bbiinnddiinngg pprrootteeiinnss,, uw and enzymes (Luebker et al. 2002; Ren et al. 2015; S. Wang et al. 2014; Weiss et al. 2009; Wolf et al. 2008, 2012; L. Zhang ct al. 2013, 2014). Saturablc renal rcsorption of PFOS from thc glomerular filtrate via transporters in the kidney tubules is believed to be a maj or contribntor to the long half-life of this compound. No studies were identified on specific tubular transporters for PFOS but many are available for PFOA. All toxicokinetic models for PFOS and PFOA are built on Lo Te the concept of saturable renal resorption first proposed by Andersen et at. (2006). Some PFOS is SE removed from the body with bile (Chang et al 2012; Harada et al. 2007), a process that also is Tis, transporter-dependent. Accordingly, the levels in fecal matter represent both unabsorbed material a and that discharged with bile. Lm An upward trend of increased urinary excretion was observed in the rats administered _>5 mg/kg/day PFOS. CR AS RA IARATE Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 6 of 75 22447766..00000066 STATE 07438101 "TwTahhsee aa5.4rriiytthehmmaeetrtiicc(m9m5ee%aacnnohnhfalilffd--eliinfcfeeiinnihhntuuemmravaannlss[ffCooTr]rooc(c3c.cu9up,ap6ta.it9ioo]n)naalHllalyyl elexxppsoosseeddfrwwoomorrakkneeirrmssa((lOOsllssieennnccleuttdeaall.1022.00800d77a)) ys wfffooearrmsamml5ooe.n4nkCkyeeDyeyas.sr,,sm33(i339c5t0eo%(33Cc55ohdndafaniygdaseefnftoocyrlremmia2nsal0tl1eee2r)vaa.annlddT[hCffeeeIm]mhaa[l3laee.9lSS, ppf6rr.9aad]ggi)uu.feefH--rDDaelanafwcw-lleilesveyeybsrreafartseos,,emaannnaddnmia3m36l.69ea.9ldsadniandaycfslueffdmoyoaerlmme1as2arl0ale.et8saadnnaddys iofoebfbmseseerarrelvveneecCddeDffsoo-1rrinPPmrFFeiOcnOaeAAl(cCwwreheerareetnginnoooenttt oaoflbb.oss2eer0rrav1vtee2,dd)a. wwnTidihttheihmhPPpaFlFliOOfeS-sSl.i.ftehTTahdhtiiisftsfheiienrnedrdneiicnccaaelatsetesbexesaetwrlaatceciekkononofmafgneadclnenrdedaescnrordrrlpfetealimatoteaendlde rats ttdirrniaafhnfneussrppmeooanrrtncteeesrrsssoirntfbolrrraebPPnoFaFrlaOOteSSoxrcyddriieffafttn~ieoirrmnffarfrlooosmrmwrtatehhtsoro,ssaeeindtfedbonrrtimiPPfFFpieOlOidAeAd.su.trhNNianootgtcchEooePmmA'rppesrnrceaahhsleseenenxssscisirvmeceetinssotttnuu.ddaiAinecdss/soorteffusdPPoyFrFpbOOtyiSSoZntthrraaannosscpptooarrtlteerrss i((in22n00vh11ou5l5m)v)eaeednvvsaianllouutraahtlteaeebdddiowwsrphahoteoestit~hht-eieraornnttirronaafasnnapssleppscoowrirtfteeeirrrcess PiiidnnEevvAmooSllivvf,eieeddidniindcnlutturhhdieeningcegnnEctFePrOroAoShh'e.seppaaUastsptiietccsascckmiierrecconuufltl.aaPttAiFiooOnsnStouofdwfbyabiisblleymeaaZccahiisdaduossraaeermtdeal. uusinssoviidnnoiggluvmhhe-ededppeianpatoetthcnoyedcteeedsnysitsfpfurrooposmtimatikbboeoonttfhhoorfhhsPuupFmmeOacaSnin.fssicTaarPnnaddFnArsraapSttosssr,twwiinoittcfhhluPaadFnnidOdngSwitPwithFahoOsouuSatt.lsssUoooddpeitivauuamkml.eu.aoTTtfehhdPeeFurrOesessSiuunllwttsssatsssahhbmoloewewaeesddured sCC(oAHHdSOOiBuTmFF)ll-.pdp-eb-lupnnteccnnaeodllltelssn.r.ttPPuFFpAOStOaBSSkTe.wwfaaosHsruttPrrmaFaanOnsnsSppo.oorrrTtgtereaaddnnibbscyypsohhrouutlmmouafannPtrFaaaOppniisSccpaaowllrstasoesodrdai(iluusOmomSdTe-e)dvpeaapeluepnandtwdeeeadnnstutasbbilniislegeo bsssataallltbt lttetrroaanntssrppaonorsrtpteeorrrt h(PPAuRFOmSOSaBS.nT.s)TT,chhboeeuntsspttnuouosddstyyirbaaalutuyttAbhhoeSorrBssaTtcc.roobHnnucctullemuuddd,aeenddaottthrhlgaaeatatnstttihhceeinslloopolnaunggttehhttoaraalftn-lrlsaiplfneosrpaatoennrrddt(ttbOhhyeSesThhoe)edppciaa(tu[t3iimccwtaaaaccsuccrauuolmmcsuhoulollaaaatbttilieeoonnctoooo-ftfraPPnFFsOOpSSoriitnn ansporing humans can transporting polypeptide (NTCP) and possibly be attributed, at polypeptide (NTCP) and ASBT. least in ASBT. part, to transport by sodium taurocholate co- CCoommmemnetnst:s: M MreDgDHioH'ns'swEEhaaossttweMMreeettrrcoooPmPeFFcCCtebbiidootmmoooannicittooonrrtiinangmgippnrraootjjeecdcttpssuabamlmippcllewdaetadaersssuuubbpsspeetltyoo.fpfTepreoeopapltlemeellniivtviin0ngg riinen mttohhveeeEEaaPssFttCMMseewttraroos a2aredd0gdd1iee0oddannt1wodhttho2hee0w1PP4eWWre(SSNaceoanlnnsddnonvevoc2olt0elu1udn6nt)tto:oeseasrcppoaanrttriacmtipiiannacttseidhhpapddaubbnbllloitocoosdwdallteeevvreelslssupmlnpeelyaa.ssuTurreredaeatadmtt etthnrrteetseottriimemmeeoppvioenitnPstsF::C22s00w0088a,,s 2222000001018080---a32n543d7952.7sg01gce4eooo(Nmmmeeeelaaasnnnonuuuggg2//Li0L.L16((()CCC:1I1332211..414 --- 442008..)53:)9;599%55papeeprrceecrnectneintliteillee691150000wuugpg/iLL.((a(ranangngegee1336.22-2--344444)88)) 2014-155 geo mean 2010 - 24.9 geo mean 2014 - 18.5 geo mean ug/Lug/L ugiL (C1(CI (CI 16.122.1 16.1 - 213): 95percentile 70 - 28); 95th percentile 69.5 - 21.3); 95th percentile 70 ug/L (range ugfL (range ugiL (range 1 -1.6 1 - 150)- 234) 180) NNHioeswtworOOicaaakklddeaaxllpeeorrseeussriieddeeonnttssth((eNNc==o11n55t6a6)m)iwwneaertreeedaallwssoaotsseaammhppelleeiddsiiennr22u00m114s4.a.mSSpiilnneecsse mtthhaeesseebsiinnrddeiivpviirddeuusaaellnssaddtiivddenonooftt ohhaanvv-ee Water expastres: 2014- 7.2 goo mean ug. (C1 6.38 0); 95 percentil21e ugL (ange 0.3430). historical exposure to the contaminated water their serum samples may be representative of non- water exposures: 2014 - 7.2 geo mean ug/L (CI 6.5-8.0); 95t~ percentile 21 ug/L (range 0.34-30). PPceeorrmssoopnnaaallrccetoodommmEmuansutinciMcaeatttiriooonn2((0SS1cc4hheelrrevDDel2s200(11a66n))d rrteeh:eFF2DD0LL11ss-tt2uu0dd1yv2iinNnddHiiccAaaNtteeEddSlloowlweeveerrlsll)ee.vveellss iinn thhiiss ppooppuullaattiioonn compared to East Metro 2014 levels (mad the 2011-2012 NHANES levels). NENnHHvAiArNNoEnEmSSenbbtiiaoolmmoConhnieittmooirrciinanlggsdda(atCtaaD--CTTh2h0ee0CC9D)DCiC'n'scsluFFdooeuudrrtethhxpNNoaasttuiirooenndaalaltRRaeeppfooorrrttPooFnnOHHSuufmmraoannm 2EE0xx0ppo3oss1uu0rre2e0t0o4 Ecctioonmllevlc,cicrcottthceneddmCbbeyynDtNCNalHHhCAaANhsNeEimESssS.icu.eadPlPsFFs(OeOCvSSeDrwwaClaa2ssu0pdd0deca9ttt)cceciesnttccoddlutiidnhnee99d9t9ea.95xbl%p%eo.soouftfTrthheheecdmaggotecasnnetfcorrarraellPcFeUUn.O.StS.S.upppfdroooapputmuleala2twti0iaoo0sn3n..rteoSSliie2nna0ccsce0e4dtthhiaantt2015 t(ilnDe,Ct2h0e1C5)DC(ChDasCis2s01u7e)d, several updates to the tables. The most recent update was released in 2015 (CDC 2015) (CDC 2017): GGweeeoromemetertriicc mean mean ug(9511% C1) ug/L (95th% CI) and and 95th 95th Percentile Percentile ug/L ug/L (9511% (95th% C1) CI) from from 1999through 1999 through 2010 2010 w211090e099re399:20022400:000:02:303007..44(((22177..1139-3393)2.9aa):nnadnd5d2377.5562..7(74(.(.55058:.3.611-6-99.)757.).95)) uguglL 2222000000005537---2222000000008664::1211770.31..127(((1111296.0226---1218024..223-))) aaaa1nnnndddd844450774...2565 ((()443542..407(1--42657766-54..6588)))) 2222000000107910--2222000010112800::91963.333.2122 ((((18532.113.3234---611108407..227))))aaaannnndddd 2432102.0..507 21((32925236..46.4--244837899..45)))) 20132014499 2011-2012:6.31 2013-2014:4.99 (150-552) (5.84-6.82) (4.50-5.52) and185 and 21.7 and 18.5 (15422.0) (19.3-23.9) (15.4-22.0) TbTeaatkkweeennettnoogg1ee9tt9hhe9erra,,ntthdhee20dd1aa4tt.aaOssvuuggeggreesshttetthhcaaottuPPrFsFeOOoSSftccohonencscetenuntdtryraa,ttiihooennssgiiennomhheuutmmraiancn msseeerrauunmmcioinnnctthehneetrUUa.StSi.oddneeoccflliinPneeFddOS DraDraft Docu-mfoerenetand between Document - for review and discussion 1999 and discussion pp2uu0rr1pp4oo.sseeOss voonPenlryly.Ot.hDSeDercafo7fttu0rdd7sooecc5uuommfeetnhn:et docs ot consi Agency policy study, the geometric mean concemration does not constitute Agency policy of PFOS PFOS - 7 of 75 22447766..00000077 SSTTAATTEE 0077443388110022 idinnechhruuemmaasaenndssfeerrruoummm75dd.e7eccrreeuaagssee/dd0Lffrro1om8m.53300e../44L.upg/D/LrLitong44..99t99hig~/tgL/eL.,aanntddherttheheeha995s5ttbhheppneerrcceennmtatiijlleeorccoornencdceuencntttriraoanttiioionnn deecnneovvcmiriprerooaounsnenmmddeensfntrtaioanlml teeh7mme5ii.Us7snssiipotigneoisdLbnbSsytytoattth1he8ees.5mmAangaangnluiyuLfsaficDsatuoucrrfeitnrtsughaeartsshNewiwsHreetAslilmlNaaeEss,Stahppe2hhr0aea0sshe3e-a--os2ou0rbte0e4eoofnpfsrpauorbmodsduaaucmjoctptrilioreoennddoeoufmcfotCCino--sn8tirnaed compounds in the United States. Analysis Hetiaglh.er20l07). lofPs ROS and PFOA in males higher lcvcls of PFOS and PFOA in males anda of the and a sight inrsase in less of PFOS NHANES 2003-2004 subsample slight increase in levels of PFOS with ge (Calafit demonstrated with age (Calafat et al. 2007). TSTooouxxrilccceao:ddyy(nnUaaSmmEicPicsAs::20164). Als se presiousfull review worksheet Source: (USEP4 2016d). ALso see previous full review worksheeto M Mooddee//M MeoecfchhAaacnntiiissommn Information: of Action Inform ation: NOrNoaonlnccaaannniccmeearrlEEsffffeetccttssuofdshioretesr and subchronic duration are available inmultiple species iiwOnenrcicagllulhutdda,iinnnigmsgurammvloionsvnktaukeldye.isyae.ssn,droraafittnsssacharonnerdadt-smtmeiedrcimcseec..arnTTuhdhmeesgssuleebusccstthoudsrdioecineslisecvrredeeluppsoroaarrttntidoddneeivvnaeesrlulcoloiappnvmmaereinslntaitabaslllteeaefifnfnfeeecmcittnussla(t(idddpueelclcerroesefpaafsessecepdidreisbbnoogdd).yy wrrceheepopilrgreohsodttdu,eucrsotcuilivr,vveipv((amamlat,attaeiinnndggstbbienaeetchhoraasevivasiis)ooe,r)d),d,esllevirvevulemropotogmxxeluinicctoiatslye(n(llIeeivuvvereerorllswwoaeienieigdighthitytnsccauooll--ionoeccrcrceduusrrisrsiiptnnaatggnicawweliittlihnheaaddmedeicucnrrlteegaaoassfnefesdddpm~g), cmfmoheerommloPeorFsrytOye).Sr),o, ldii,memhmmmeoupunannsteeticroeafsftftfeceeatcthttsoas,t,siaatsnnh),eddddcceaacvnnleccleoeorrppm((nt1hegyynrrtfooaitliddunseaausnnddroplftaiiovrvxeierirc)c).ui.ltyOOavlev(yraealrtlsaelelr,nle,sdithhtseiepveattototixiaoeilciPlitetFyyaOrssnSttiuuniddgniideeaussncaadevvdaaiillaabbllee ttl{obooxrvliiePccsiFtttyyOe.SoHHld,uuemmtmhaayonnrnoeseitppdrdiiadidtseeeemmtaihsiooaeltl.ootihggmyeymdddueaanvtaaeelrroeespppuioopnrprgtrteaafssessstsiuooosccni,iiaasttapiionoanndrsstiscbboueemlttawewrleeryeeennpsrePPonFdFsuiOOtciSStvieeevexxtoppaooPnssFduuOrrdeeSevaaiennnldddouphhcmiigegedhhntal parameters, cholesterol, parameters, including reduced fertility an fecundity thyroid disease, immune suppression, and including reduced fertility m~d fecundity. some reproductive and developmental NNFOooSpp:uubblh liisshheeddoccoohhaew essuiivvmeebeMeMrOOoAAf,teehxxeiissuttssnitthqhuatet aapccrccooopueurnntttissefsfoorortftthhheeevvcaaorriimeepddottuoonxxiidccoocloloonggtiricciaablultpperroo(ppeeirrsttiietessicooiffty P+ FOsMMSae;tetuhtaraobabowbollelieivccreessrnt,taaaablbinilrliuiettsmyyorbaapecctriccoooonmm.fptphaaenniuicenddiqbbuyyepppeerrrosspisiettreteniencsceoiinftthiisessscuuoeemss aapssouaannndaappcppoaanrrteerninbttuccteoonntsoseeiqqtsuueetonn.cc,deecooitfyf: + cEsEaolletneucfctrotarrrobomslstaetaatrttieiiocncnabblaiinnrneddsdionaicrgtpntittgovoiiotbbnyii.ooppoollyymmeerrss,, eessppeecciiaalllyy pprroottceiinnss,, wwiitthh eressuulltma~nt aallteerrataiotnosinisnn + ASAccocctnrtuuufaomalrlmaoolrarbtpiupooomtniteennantntsiiduaalclahddcitiaisssvppiflltaayatc.cteyemmaceeinndtts,oofbfeinelnddoagoceginednos,ouuspslh/aeemxxaoocggeeeuntnoiocuuasslsss,uubbsmsttiaannneccreaelsssnn,ooaranmndal3llyy bboouunndd ttoo + uRsRneeeirnnudaaemlnltrraieelfssbioouerrmdpptttiiinrooannnsus((pcAAohnrntdadeeserrsrfssageetetnnynsteattaciacildla.sl,2l3y00b00iel66en))caaaocnndiddesdbb,iifplloihiraaarrmryymaeenaxxacccgerrueeettmtiiiceooannnltstto,hhfamattinanaarreteeurarddlaesel,ppseaeunnnbdddseetTnnat3tn.cooenns unidentified transporters genetically encoded for management of natural substances (iesnldoonggeanloFuisfaen.d exogenous) that prolong systemic etcntionofabsorbed PFandOexplSain (endogenous and exogenous) that prolong systemic retention of absorbed PFOS and explain + siBBtusiipnlnpdordinengisgsnhtitgoaoolnfaa-onnlfiddfegaa.eccnttiievvaatttriiannnggscrrreeiccpeetippottnoorrss ssuucchh aass PPPPAARR,, tthheerresbbyy iinniittiiaattiinngg aaccttiivvaattiioonn oorr + sIuppnresstioneowifgtrheinnetfetrrcaeenlslcurlriaprtiocenom. mnuniccatieon Interference with intercellular communication. CACaansniccneegrrleEEfcffhfeerccottnssiccance bioassay in animals is availble for PFOS. Increased incidence of Ahhaedcpepsainatnotogomclceaeclsllc/luhuclralaoarrrncaiaidcdneeconnamonoacmmseaairsnsbtiiinohneahtshfeseeamymmaalainellesaanaatnnimddthatfeElhsemimisgaalhaclvsdeaaoastistlaettbwhhleeerhhfeiiogogrhhbPsddFeooOrssveeSe.aadnnI.nddcccreooammsbebidinnieenddcidence of adenomas/carcinomas in the females at the high dose were observed `tShSoeommleeithheruuammtuaarnenissttuiudndciieoesnssssiuusgtgaegneetsstat naadnn aasssossmooceciisaatttuiiodoinncswwaiirttehh bbclloaanddfddoeerur,n, dcceooldloonbn,y, aafnnaiddlupprrreoosstttoaatcteeoncctaarnonclceefrro,,rhhiooswvkeevre,r, factors such as the literature is factors such as smoking. inconsistent smoking. and some studies are confounded by failure to control for risk DraDraft Documen-t Document - for for ee review and and discussion discussion ppuurrppoosseessPoonnOll.yS. DDerSaffott ddoo7ccSuummeenn:t docs does nonot consi constitute Agency Agency policy policy PFOS - 8 of 75 22447766..00000088 SSTTAATTEE 0077443368110033 "Table 6:1. Study summary of KeySticComer or RID Dito ~l~l~l[ffl~3Y~[t~ Table 6-A1. Study summary of Key Studies Considered for RfD Derivation R(UeSlEaPAt2E01n60o) SseSciSoni4.13 efHarmoarefdeosrti: (USEPA 2016d) [See Section 4.1.2 for more details] Sod USEPA 20160) Se Scion: for more devi] rvby NOH tsi nosed cs] and (USEPA 2016c) [See Section 3.1 for more details] [reviewed by,~/iDH epi st~ff" no suggested edits] Numsroscidnioogy suis bv bn conducted cvsiatin occupations PFOS expos and ronal PROS expos ncldinga are Numerous epidemiology studies have been conducted evaluating occupational PFOS exposure and environmental PFOS exposure including a large Commis gh xpos 1 PFOA (he C3 kth Project andbckrude sss foplanon eralooincs Octo community highly-exposed to PFOA (the C8 Health Project) and background exposures in the general population in several countries. Occupational dcr oplaRaiecoanlss he sian ofPOS expos 0 3 of eat pois Hkh aeons assed ne ond and general populations have evaluated the association of PFOS exposure to a variety of health endpoints. Health outcomes assessed include blood Hpi sdclic chemst poi. hyrod Foc, mms nc, pins ot,Pregnancy Fd smc, Gonth ad lipid and clinical chcmist~ profiles, thyroid effects, immune function, reproductive effects, pregnancy related outcomes, fetal growth and Apc ction, at developmental outcomes, and cancer. Serum lipid~ Ni dn stoishvg ecanted sc pd sos in sisi wih PROS centro These stds proce pon or Multiple epidemiologic studies have evaluated serum lipid status in association with PFOS concentration. These studies provide support for an acon bees FOS3nd ml croolclosners: snes popes mc su ns 0012350031 g/t. association between PFOS and small increases in total cholesterol in the general population at mean serum levels of 0.0224 to 0.0361 gg/mI,. Hypercholesterolemia, which is clinically defined as cholesterol greater than 240 mgidL, was associated with PFOS exposure in a Canadian cohort andthe C Heth Prt cor, PFS levels i thse sues were 00084 gl. & 0.022 pl, respectively. Coscia and iu the C8 Health Project cohort, PFOS levels in these studies were 0.0084 ggimL & 0.022 ggimL, respectively. Cross-sectional oxcpionssds demonoidan ssociion betwen PFOSad cal cols with muchigheer r eol f apo 140 Rg. Eidocs occupational studies demonstrated an association between PFOS and total cholesterol with much higher serum levels of up to 1.40 ggimL. Evidence orcisont Rincon ler cn pd nd FOS med ncn HDL choles oe dey port DL) VLDL nd mr-iDL for associations between other scram lipids and PFOS is mixed including HDL cholesterol, low density lipoprotcin (LDL), VLDL, and non-HDL hr saeghld cholesterol, as well as triglyccridcs. Thetis onsc liipn asiscdisison ih PROSser coeaonste ly ross scons stadwer ply condced ads The studies on semln lipids in association with PFOS serum concentrations are largely cross sectional in nature and were largely conducted in adults, tome tn Cut 00hdd rg women. Lions thes sch noe Fc hgh coho btnscs PFOA 30d PROS but some studies exist on children and pregnant women. [,imitations to these studies include the frequently high correlation between PFOA and PFOS pon, ot llsus comofor othr PEAS sot PFO, sd eu Achs poplin wih kn ved Ene 9 exposure; not all studies control for other PFASs, such as PFOA, in study design. Also studied were populations with known elevated exposure to iercorm hems nig PFOA. plbrot hes(Ph BDEs),ad et priser hema. Ocal, he prime other environmental chemicals including IPFOA, polybrominated diphenyl ethers (PBDEs), and other persistent chemicals. Overall, the epidemiologic ine spor21 anion bane PEOS nd mrs cl chose evidence supports an association between PFOS and increased total cholesterol. Tid Thyroid Numerous epidemiologic studies evaluated thyroid honnone levels and/or thyroid disease in association with serum PFOS concentrations. These <oumiolocsts prove supportfor an scion beechPROS expose ad ccs opele fod dice, ad ck rs epidemiologic studies provide support for an association between PFOS exposure and incidence or prevalence ofthyroid disease, aud include large Suds epee sans of he ental US kl population In stsofpra vores, FOS was so sed wih ceased TH studies of representative samples of the general U.S. adult population, ha studies of pregnant women, PFOS was associated with increased TSH Er Preamast woes inpos ve fortheatoprose (TPO) brahFao dminis 0 dsc shed 3posi levels. Pregnant women testing positive [br the anti-thyroid peroxidase (TPO) biomarker for autoimmune thyroid disease showed a positive cas th FO and TSH Tn sch. an ots wh PROSedTScd 15 ws fod btofbe NHANES poison association with PFOS and TSH. In a second study, an association with PFOS and THS and T3 was found in a subset of the NHANES population both Todisos 2d pot rt TPO res Ths sic wed 2-TRO bod nce3 bcs of 0 Hh10d with both low-iodide status and positive anti-TPO antibodies. These studies used anti-TPO antibody levels as an indication of stress to the thyroid Sten, not cas se Tha, he asiaioconn PROS td herd hs ls cer cope for id system, not a disease state. Thus, the association between PFOS and altered thyroid hormone levels is stronger in people at risk for thyroid Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 9 of 75 22447766.0.00009 sate grsseios STATE_07438104 Tete o Tepe wb ag BdGe assod At rtoFead Gs, en Roan0e%, TS3H insufficiency or disease. In people without diagnosed thyroid disease or without biomarkers ofthyroid disease, thyroid hormones (i.e., TSH, T3 or 70tho mised ctsarn shorts. T4) show mixed effects across cohorts. Stsofthyrod dss dh Rornonconsisinchidicnnd psnann fodmised fics Studies ofthyroid disease and thyroid hormone concentrations in children and pregnant women found mixed effects. Fer, Prego, and ih Oncor Fertility, Preg~ancy, and Birth Outcomes Datisues conlatonbts higher PROS vel (> 103pp snd ossi fle um and rly, a wel sds Data also suggest a correlation between higher PFOS levels (> 0.033 btg/mL) and decreases in female fecundity and fertilib; as well as decreased Ro ws fn nd ths sor f os s sro body weights in offspring mad other measures of postnatal gro~h. Ftd roth tion scam hoaghmesure including ca bith gh ow bith wiht, snd sl fo gestions (SGA)3 Mes Fetal gro~C~h retardation was cxamincd through mcasurcs including mean birth weight, low birth wcight, and small for gcstational (SGA) age. Mean Ih eight ain oo ait them onl aad nto pegs sso sam POR birth weight examined as a continuous outcome was the most commonly examined cndpoint for cpidcmiology studies of scram/cord PFOS pons Abou rs es mrs ml Bh EHGece fo 215 Hom <r Gefeods sr ects exposures. Although three ~udies were null, birth weight deficits ranging from 29 to 149 grams ~vere detected in five stndies. Larger rednctions {6m 610 1D am) wer mcd eof Sn it don er nt ses i enmcord FFOS xpos AB oof hss (from 69 to 149 grams) were noted in three ofthe five studies based on per unit increases in serum/cord PFOS exposures. Although a t~cw of these ds ndsr SxSofdoserespons rirsss THEN tl ro eats, ans Eg1h Ftc or stndies sho~ved some suggestion of dose-response relationships across different fetal growth measures, stndy limitations, including the potential for posts slseston ls Pchlod he SAY duly Sain Epos pons oR exposure misclassification, likely precluded the ability to adequately examine exposure-response patterns. A srl stof sisobserved a ssn ih ston] diets, preadpa cg mdpuced prcsion in populations wih A small set of studies observed an association with gestational diabetes, pre-eclampsia and pregnancy-induced hypertension in populations with vm PHOSconrofr001t0o017nisn serum PFOS concentrations of 0.012 to 0.017 ggimL. Aho sam:sigestcd sian ews POS psa ad sen aly prt ssi ow sis st sis cr ely Although some suggested association between PFOS exposures and semen quality parameters exists in a tEw studies most studies were largely nae negative. Slims ds fer was odor PROS goesin td moc fssi. Oo sty ws ll for PROS xpos scited Small increased odds of intErtiliW was tbund for PFOS exposures in a limited number of studies. One study was null tbr PFOS exposures associated dcr cum ais (FR ove, sve dl Td omer 0 rans. Reesecus osbet gesteda1 ~,ith decreased fecundability ratios (FRs), however, several did find longer time to pregnancy. Reverse causality has been suggested as an pianfrhs ican. Alb so ors in ed hepi ocCation xing som revo sc sls explanation for these observations. Although some concern remains about the possibility of reverse causation explaining some previous study results, BEclin Bi act omin aio th ri nd fin ones FFOS xpos these collective findings indicate a consistent association with fertility and fecundity measures and PFOS exposures. J -- Immune ],'unction No she clastsasosstitihsoeoes icatin mncsprssion. Tosis eponcd dscs i por nso os A few studies have evaluated associations with measures indicating immunosuppression. Two studies reported decreases in response to one or more cin chidesaed. .nd 7 yas (5. sarobdy body 1) in latiotno creasing maternal seu PFOlevels (anging vaccines in children aged 3, 5, and 7 years (e.g., measured by antibody titer) in relation to increasing maternal serum PFOS levels (ranging 0008g6m)-d0in0pea2nan7cy. or 5 scarofa Grn ct 201, Grant3 2013) Dc bl abody 0.0056-0.027 ~ag/mL) during pregnancy, or at 5 years of age (Grandjean et al. 2012; Granum et al. 2013). Decreased rubella antibody Concerns reat scm PFOS coco wets Todamon 13-1 19d chr i he NHANES. parca mor concentrations in relation to serum PFOS concentration were found among 12- to 19-year-old children in the NHANES, particularly among ion hil (Sia 201) hed sayofdl fd noscat oth bods spor 0 ani vr Looker 5. seropositive children (Stein et al. 2015). A third study of adults found no associations with antibody response to influenza vaccine (Looker et al. SUD, he he siscoming expneobcskaroeund rns oschi. el pops cps sons es < 002 2014). In the three studies examining exposures in the background range among children (i.e., general population exposures, geometric means < 0.02 ete soins ih POS rt ah 50 th lo ore PEASSahai Sono dn pelo PEON ptg/nll), the associatious with PFOS were also seen with other correlated PFASs, complicating the conclusions drawn specifically for PFOS. No la smocisions wes predbev ral PROS expose sd acidsofdisf saso i hin (Ft 200, Od No clear associations were reported between prenatal PFOS exposure and incidence of infectious disease among children (Fei et al. 2010; Okada et 013) ah ancevifhss fei Gc: wa ound Ama ik, EBs ct3 her mem5) al. 2012), although an elevated risk of hospitalization for infectious disease was found among girls, suggesting an effect at the higher maternal serum Dr Docume for ie dcpo oeoD scatds tin Aces pOKY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy Trost PFOS - 10 of 75 22447766..00001100 sate orssenos STATE_07438105 Tool mee polio ar ar elwer O SETwT) Fl egad oGeues Gi. rn FEO levels measured in the Dmfish population (mean maternal plasma levels ;vere 0.0353 ggimL). With regard to other immune dysfunction, serum PFOS HEL wer ot ard ih kf vchv 1 asa ches nh NHANES ith eon Kes of 001 mt. (Hr 1 levels were not associated with risk of ever having had asthma among children in the NHANES with median levels of 0.017 gg/mL (Humblet et al. 2015) shamans childs 3Ton wih her cmPROScoocnaions (fin ihad htst 0070302059 5pi0 2014). A study among children in Taiwan ~vith higher serum PFOS concentrations (median with and without asthma: 0.0339 and 0.0289 gg/mL, TSR found her eo for physigcniaanatt wath rinscg PPS quart (ong. 013 Accsoaln respectively) found higher odds ratios for physician-diagnosed asthma with increasing serum PFOS quartile (Dong et al. 2013). Associations also Nr ound for therPEAS Amon thm. een FOS sa 500dih Gr Aer C0, sr 53 rnolobl were found for other PFASs. Among asthmatics, serum PFOS was also associated with higher severity scores, serum total immunoglobulin E, os simpcots ad cp x00 pl rov absolute eosinophil counts, and eosinophilic cationic protein levels. te: NTPely complet a dtmora (VTP20160) simiemma soca with sess1 PFOAandPROS. A pr [Note: NFP recently completed a draft monograph (SVTP 2016a) regarding the ~mmunotoxici& associated with exposure to PFOA and PFOS. A peer ew me wat dti 15 20eeF1es.DI 59) he pec edhr review meetTng was held July 19, 20] 6. (see Figures D1 D-3 7) The panel agreed that: kone cefno prcesteon fhe hod espn fom xprimcnl inl ses ast sn sesof PROS ppt The scientific evidence.for suppression qfthe antibody response.from experimental animal studies and human studies ofPFOS support a oiold ofclon, ec high and moderate level ~fevJdence, respectively. chet lot of dee nce mal oes or cht of dese resce and pression ofl lr cl cos, . ~4oderate level ofevMence in experimental a~imal studwsfor rechtctior~ ofdisease resistance and suppression qfnamral killer cell activiO,, aan oor degre ro bes) viene mans and only low or inadequate (no studies') evidence in humans. + Lowor eat 0 i)of enti esd cones oastm ltdfoci in mel sc andy loo Low or inadequate (no studies) Qt'hypersensidviO,-related outcomes or autoimmunlty-related effects in animal studies, and very low or dq cot mmr inadequate evMence in humans. he NTFmo osbes enfleh d(TFSepeber 2016) The NTP monograph has' been finalized (~TP September 2016) (~aneeF - Sct ancidmioe stdi vsltolhsaocistion ws PROScmc ning der,colon, and pros Als srs in Several human cpidcmiology studies evaluated the association between PFOS and cancers including bladder, colon, and prostate. A large increase in marl om adderonerous xd sequent stdof batecarmenthesus coor ud a tsof | 5 mortality risk from bladder cancer was demonstrated, and a subsequent study of bladder cancer incidence in the same cohort found rate ratios of 1.5 TO mh ot cmt expose cago cpr fo trl rtppbv (Neva 1 203 Aluer OF to 1.9 in the two highest cumulative exposure categories compared to an internal referent population (Alexander et al. 2003; Alexander and Olsen 5007 The ik sts hed precnonbecass h rhco ae re mall Smokin prevenwas bghr 1 die cancrcas, bt 2007). The risk estimates lacked precision because the number of cases were small. Smoking prevalence was higher in the bladder cancer cases, but AC nla dtCnr 0 hgBo ah fo Ed ORE:RTS, onCombing Oi4 Pru the analysis did not control for smoking because daika were missing for deceased ~vorkers; therefore, positive confounding by smoking is a possibility msso: Nosotros cbs ntl col sd 4Dey ahsih plas PFO coment in this analysis. No elevated bladder cancer risk was observed in a nested case-control study in a Danish coho~ with plasma PFOS concentrations at Cornea been 0003d 0151 ml.(Eon 200) Other chs ht sated ac for pci (6. prose, beat) enrolhnent between 0.001 and 0.0131 gg/mL (Eriksen et al. 2009). Other studies that evaluated cancer risk for specific sites (e.g., prostate, breast) in he semper rs consi (Boaltomen 011 01% Har 204 acct 201) 1s sion 41.) the general population were inconsistent (Bonefeld-Jorgensen et al. 2011, 2014; Hardell et al. 2014; hines et al. 2014) (see section 4.1.2). The scion oe mot pmol pois mind. Abu mess loa prs ns hn sis, ct) mtsof The associations for most epidemiology endpoints are mixed. Although mean seruln values are presented in the human studies, actual estimates of FOS capo 1. dose ron) rtcathy aelsbic. Tho, hc et oc wich th acts nrst mam3nd wher cn PFOS exposure (i.e., doses/duration) are not cun-ently available. Thus, the serum level at which the efIEcts were first manliest aud whether the serum hd ced sadSoe 1h he chxeunad can eins, es tt soofs ha cxphscootrsr0 e had achieved steady state at the point the effect occurred cannot be determined. It is likely that some ofthe human exposures that contribute to serum FOS vocomes fh PFO doisr prcurios tsk dow, tabla 1 PROS. Thee sonpouds ght orgs fot PrOS PFOS values come from PFOS derivatives or precursors that break down metabolically to PFOS. These compounds might originate from PFOS in ict nd ais ndhe ho, ih creas potFor onus. Analen ofbe sbi fhe PO Sic vs diet and materials used in the home, which creates potential for coufouuding. Additionally, most of the subjects of the epidemiology studies have Inn PEAS: mrcontt i od. bough: tls ss st otpli cts ong cas.th many PFASs and/or other contaminauts in their blood. Although the study designs adjust for other potential toxicants as confounding factors, their rea cons 4 neof amy wal ho1 ean Sis presence constitutes a level of uncertainty that is usually absent in the animal studies. Dr Docu for i dhs poe Df stFROdSoTs mt sinsAgeepk Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 11 of 75 22447766..00001111 sate onsseios STATE_07438106 Tn oar, gh of vinfor ds po 5St olisPROS pone 3 rn Behrd A me BPA Taken together, the weight of evidence for human studies supports the conclusion that PFOS exposure is a human health hazard. At this time, EPA Concedesheh hn scSkatTore Quote th tonWz So OpOnf 5 ns 1 EROS concludes that the human studies are adequate for use qualitatively in the identification hazard and are supportive of the findings in laborato~ pron animals. Supplementto Original Rei Completed on 12072007 Supplement to Original Review Completed on 12/07/2t!07. FOS estatecompound adhrt ppp es tic gallosofdso is cresmconcnpion Theor sine PFOS is bioaccunmlative compound and the most appropriate dose=metric regardless of duration is average serum concentration*. Therefore a single Sd sar provid lov. er oe le or cach dsc Th: Conteof Bc Dkfcc ot Kx cndpontd study summary table is provided below rather than one table ~br each duration Tbe contents of the table below ~bcuses on the key endpoints and des rel kd nh US EPA Hah Ads (HAs Heo Ft Sort Document (ESD)Rend Ma 2016For sons studies largely identified m the US EPA HeNth Advisor?' (HA) and Health Effects Suppor~ Document (HESD) Released May 2016. For additional informtion gning MDIFs piousscsmeisrto oacrshren 2007 Th acs mld in EPA's HESDad 1 wer: in fbrmation regarding MDH's previous ~sessment rcfcr to review work:sheet from 2007. The st~tdies included in EPA's tlESD and HE were mined 5 FFA 1provhiemdoes osnr d compn re dsc oh kg proprio POSadthe rk pos 0 determined by EPA to provide the most currant and comprehensive description of the toxicological properties of PFOS and the risk it poses ~o ies hough din we. Fo he ss, hrs ht pss m53ad cral 0 Rodel. cmonof HD wre humans throt~gh drinking water. From these studies, those that presented serum data amenable for modeling (i.e., determination of HEDs) were cedfordoseupon ras. Th: siictofg ts ed cause of he sd 0 ve dstadpceSpc cru vcs or selected for dose-response analysis. The resulting subset of studies is limited because ofthe need to have dose and species-specific se~m~ values for AT pt 2 xpos dara of Tt ih 1 Sch 11s caro StySt ronsof lk drop! :model input, as well as exposure dt~.rations of sufficient length to achieve values near to steady-state projections or applicable to develop:mental odpm aecose aEAktem csr. TePhanTodo veeseh au os hg endpomts with lifetime consequences following short-term exposures. 'Ihe phannacokinetically modeled average serum values )Yore the animal Studs ar reste1d theammaspecies lcd oiLooe respons 0. PHOS nah. Asin us bvben ledbs ION studies are restricted to the anim:d species selected for their low-dose response to oral PFOS imake. Additional studies have been included by" MDH Fey onde iomaton on onlcas of re ifthey provided information on additional en@omts of intereg. BE ------------ * ]~;~q used a fritter-reviewed [)harmacokinehc model developed by (}~/?~mhaugh 2013) gr~ calculate the ~.~!~(~1~ serum co.cengrations associated wi*h lhe NOEL ou F311 pt cl oc reArt nl FOS un heft dr EDacewh ,V()di~Ls and LO,4b;Zs.j)'om he toxico/oL4cM database. Average serum levels qfPb"O~5"j~'om the mode[ were used to de~ermme the lIf?l) assoczated w~lh the NEcdPLAE To Handout 3015 mel etc. cr1 0 cp lertbs le on ~V()Ai~L and LOA];L. The ~Zambau,~q~ et aL (2013) mo~L~l ix based o~ the Anderse~ et a/. (2006) concept tha~ saturable renal resorption is resg)onsib/e f!~r the reg men oi em s oe ovn ate es 9 of sl no et et oo er serum ha~/~five.~' seen in humans and animals', d unique.fi~alure (~i/he pharmacokinet~c ~]r~proac'h is [he use ~a singl~ mode[Jot ihe d~tree .~,ecies and reliance on Rr PRONota he nt of po Fo chsec, oe comecp st rae ac an Th the serum PF()S Mvel as ~he measure ofexposure./~?)r each spec'~es, the model accommodated fl~e app~"ogriate oxicokine~c variab{es~r I/~e specie~s:'~'lrain, The reste afd vos Comin Ptr as ed1h 4a loch Po sh PES pha~macoMnetic ana@sis ~hc~fta~ed examina~ion fbr consistency in ~he average serum values associated wid7 ~ffbc~ and ~o-~ffi~ct doses.~kom the m~ma/ i aA ve mabat fRttpoma isee ofcte HberRhSe S Amcrrbdec es he sero ire s~uches. ~ .o.hierarchical model./he parameger values wax a,~:~'umed wherein a single numeric value rel~resenled cd] imhviduaZq ~(the xat~e .~,ecies, gem~a; Dr Docu for i dhs poe Df stFdRosOmSt sTinsAgeepk Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 12 of 75 22447766..00001122 sate onsseror STATE_07438107 StyDecipion | Nim De | ect)ObrSaem~~ StyPOD | UF Cate | Reerece Study Description dries | | Conntto nAbinoDeny | (mig 0" | fone duration, route/ eed pcr phn | insia vehicle, species/ rin ding | fers commeni) strain, age @dosing, Neurouese. | epimcisen ferumcszor N/sex/group, etc. Admin Dose (rng/kg!d) [average serum c'oncer~ [~" Effect(s) Observed at each Serum Concentration (or Adrnin Dose) Study POOHED (mg/kg/d) (e.g. NOAELHED) [serum co~we~.~]# [Candidate RfD mg/kg-d Reference (note lirnitations in cornrnent filed) An A ha mnmCBiSeasN:OuNpcEe0 8L)vOdNd IhfeaBNae OtNEmogldLdOmsNbo.TbHyrWEasmbraghkt20a1flFad Oteotn0vmcg]osn2etneoonvcmmatDon ln,s sSviomrs 3i10 ReprOducti~e~ ~ve{op~hi~i Ff~ts FE Nr & Dic ony Developmental 0, 1, 2, 3, 5, or Ga A emermnen (hom Garage Stu@ 10 SieBoRtas | Mca |= CoWpeocmsPiym4Teodt| 176uginl Sr Sprague-Dawlcy Rats Measuredfinal EamoGn32 | ror ee cio kpet | EPA NREL SE dvs Dosed beginning GD2 en CGORY | tun: | TS vassiedblo oan until term (~GD21) COKICeKI tr(.l~O!TA 2 Smoimiioton | Bi | comic; 351 wnt soma mothers killed on !9.69, 44.33, Covet sons | 10 733% | 21wp51BW, fod wate | EPA LONBaiE ming GD18 other ~ allowed 70.62, 79.39, pr iat | retn as t meio:| mp mana pr to deliver !89.4 ug/mL SyDuin 19 | Pred AUC | VS pontarim TneGe5sown || BWianpesaomips nrinonn Study Duration .... 19 bd SSiaymthonma,n,|| 3543r0r001rh456o0maadnnen&tdd5de.srhctarAlr tY] || o rords]iigi n f[|io30Giy oGwns i{hDFauornsrsoannn days Predicted AUC ug/mL*h 8,020, 16,000, 24,000, 40,100, 79,800 (Table 4-3) Avene | S3 reanrd4 m1o3% rnedsB|Y4 |Ura8mnt Cpriom N Average serum STR kwnr a 55 di [ro concentration ma | Gear in Predicted Moca jr Contr AUCi(19 d x 24 Re" anmets. sai re |b hr-d) = own | Mosman's anny vtmmtemel | | compar(MoogToo 17.6 ug/mL a mils mrt Ww eon" sh 35.1 a el mineines | mpi [0 |S 52.6 3 Chive eyaes) 50 | Gomi ans |G moots [1 879 a premi 10n1gt 5tn5tpn| oi Tron Thine 175 3/lalernal ~17.6 ug/mL ~b TT4 & FT4 by GD7 (>40% estimated from Fig 4), ~' T3 but to lesser extent (no feedback response of TSH was observed based on circulating sermn levels); >_35.1 ugimL - BW; ,~food & water consmnp profound at two highest doses; 175 ug/mL - ~ rel liver wt (20%); ' serum triglyercides & cholesterol (34% triglycerides & 14% cholesterol) A uthor BMD/BA4L)L: for ~ maternal B W 0.224/'0.150 admm close &for ~T4 (GD7) 0.234/0. 046 admin dose. [ML)H eslnuated serum co,we~7lrations 4.3,1.0 ug/~TL T4. Now: AIDH O,pical~v u~ves BA4R q/!O%jbr maternal BtV & 20%,/br change in ~DH BMD ModeBng : MaWrncd B W on GD ] 5 (mode#ng with all dose grps not succes@d Removed highest dose grp, which was severely affects) 23.0/20.6 ug,mL Maternal tT4 GD7 (BMR20%) (hlghesz dose grp removed) ~ O. L,Z.57 ug,)r~L Maternal & Develop 17.6 ug/mL EPA NOAEL 35.1 ug/mL EPA LOAEL based on ,~ pup & maternal BW; ~ pup survival; delayed eye opening ~&OA EL/LOA EI4zeD ~ O. 0014/0. 0028 Maternal 5.57 MDH BMDL 10.1 ug)nL MDH BMD Based on maternal tT4 [B)VIDL/B~4DzzsD ~ O. 00045/0. 00082 m g/kg-d/ Dorc ionu ndScim onpee po,D dot ost os Ass Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy TT PFOS - 13 of 75 30 i 0.00005 (3A, i (EPA) 10H - ErA) (Lau 2003) and (Yhibodeaux 2003) and aci (US EPA 2016a) ~[DtI B2VID modeling: requested & received f!"om authors dam reported in figures, etc. 100 (3A, 10H, 3 DB i For i comparison i purposes i 0.0000045 22447766..00001133 rare,onaseios STATE_07438108 StudyDescription | AdminDose Study Description durian,route | Ag duration, route/ hide specs vehicle, species/ Srveido,sing| fre strain, age @dosing, Ne ete | suman N/sex/group, etc. Admin Dose (mg/kg!d) [(werage serum |Effects)ObsearcavchSeradm |Sindy POD | UF Effect(s) Observed at each Serum | ConcatorrAdamiinDoosne a6 iNoeAFLw) Concentration (or Admin Dose) Study PODnE~ (mg/kg/d) (e.g. NOA~L~) Ducpnenl fDuerwaSinocmoranaednm)[ND Developmental TTC gin rs peru)| ADH BDL > 17.6 ug/mL - ~stemal defects (# per leeds) fiEsriebeineystacy 0 (1.7, 2.1% 2.6, 2.1, & 3.4* vs 1.2 in Col pop liner ADEE| f0%mt [OA controls); ?pup rel liver wt @PND2 & 9 nocoe m hos wivrss| pi | fo only (10-14% vs control, however, no Sewdnseons pbs| Ralonpi7p4 [305 clear dose response); hypothyroxinemia iy (i Bs (low T4) S60 {pup iva (BW ND. | Cons 00005? | Di 35.1 ug/mL - + pup survival; d,BW (PND0 a NGS17.20830% |mie] > 8, 10, & 15%; PND3 - 17, 21, & 30% BW hsdm o psrl (BW @ highest dose not reposed as all psdd dexcepedn. pups died)) ; delayed eye opening; ~pup Kr IDS 5 1581 rcl liver wt @PNDS~ 9~ 15~ & 21 (10TR ool bor20k os: 17% vs control howcvcr~ no clc~x dose repos) response) 26am Sigma pps 52.6 ug/mL - ~50% pup survival; ~pup rel THC sls ont GND3c? liver wt, staffs signif @P~2 & 5 only Reon) (10-14% vs control) 87.9 ughnL - <5% pup su~:ival Tet BY 5%) 1 tess 175 ug/mL - ~fetal BW (13%), ~ incidence p GPst com & cleft palate (60% vs 0 in controls), & Sann. opp ann ~as~xca (edema); 0% pup survival vrsBODBADE orlsom Authors BMD~L~forfetai sWmal em 315(o0m br1e 3or3p &J~cts 0.313/0.122 (saWn dose) c~ Jbr pup me (PN) 705 dn) survival (PNDS) ]. 07/0.58 (adm dose) i midcorninrig [MDH estimated corre.v~onding xerum Comes 34mi31593103 concentrations ~-~ 506)'2. 3 ug..)nL cq~ 18. (2~70. 3 nt] ug/mL] /serum conce~q Developmental 8.5~ ug,)nL MDH BMDL l O. 8 ug/)nL MDH B~SvID Based on pup ~BMDL/~BMD~ O. 00069/0. 0008 7 ere MDH :B,adD =!rio deli l,br ~compariso~ puq~oses only' since CpomelBD rdcourbe opHmai B~&ID n,odeY**g couM not be Coucdbveedoaanvoesl conducted because we do not have eae dt hah vod nested dataset, which wouM require UF~'" MDH ) 100 (3A, 10H, 3DB MDH ) Dr Docume i dhcp Df stFdRoOstScT s Agee py individual armorial Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 14 of 75 Can"diDdeo|rReeference [CanRdfiDdate mast |Commtmaeinontsiiend) mgtkg-d Reference (note limitations in comment filed) aorw)s|Ta i0.0000069 ux,~Lau2OO3.xls i(MD~) 22447766..00001144. sate onsseion STATE_07438109 Su Dein | Nii Dose |EcOrdaSr Sod FOB Study Description atone |r| Conair mabey | tosh duration, route/ ee Ee vehicle, species/ rem dog| rene strain, age @dosing, Ee as PP PFP opoi pode ajrrpyroiprdttaepte a ro ea o rtraPsma fRrrOe d et eneenmdn rseeni7ttt o7idnie a N/sex/group, etc. Admin Dose (mg/kg!d) [cwerage serum content~ Effect(s) Observed at each Serum Concentration (or Admin Dose) Fetal sternal defects" BMRos no models fit data. Pup sumqval BMRos (h~ghest close grp removed no pups survived) no models fit data (variance not we# modeled and other problems even when included all dose groups or taking out top two dose groupa) Pup BW B~o5 ~ighest ~,o dose grps removed no or mo few pups) !2. !/R 7! ug/mL Pup <ve opening no models adequately fit data Pup tTg B~:o on PND9 (highest ~'o dose g~s removed no or mo ~'w pups) lO. 8/8.56 ug/mL Study PODHED (mg/kg/d) (e.g. NOAELn~) /serum Ted TSS ro Developmental 0, 1, 5, 10, 15 or ~vlaWrnal - 33.1 ug/mL Saar [5 Tolaherdesnima| ANON Garage Study - CD-1 20 > 33.1 ughnL -,~ triglycerides (star sign at EPA NOAEL fara ad Ti Female Mice >_ 141 ug/mL); rapid q~ T4 but BT [sna to | tg Dosed GD1-17 similar to controls at last week of 141 ug/mL iiss [Sots | poi error V~ mothers killed on concentrations pregnancy EPA LOAEL based ant Sr | 21 dp tic | di GD 18 other allowed weP~~ Hot >_141 ug/mL - dose-dependent 'lx rel liver on ~liv u,~, delayed nai ped TLE |a to deliver reported. weight (22%/65 %/95 %/109%) eye opening ont en 289 ug/mL - + BW gain SdDuin 17 | AUC our 00t1. Study Duratiou -- 17 Predicted AUC bs ne ausnas,inn|i 1 days u11g33/.m,550L000*,,h3577.,770000,,| A1135u..t11h55o1/3r'3.B.11M44 Dau/dBdmMminDdLdo.o~sseejS;; rTtli4ive~ermr awwttet r22n.6a61ll/1B1.W .3311 |mg ged] sto Te 1081680.,690,000000,0,, /(a~dMlmlD)iHnHdeeosss#temm;aa&s~ee~ddcTco4orr0rr~.e5s~1p73o/)n0od.n3idn5g~2saseedrnmu~mmm dose. Iman |e TESTI, 118,000 (Table [evelsf!~r T4 33~30 ug/mL. Nble: we h~we By a 4-3) O~pic'ally used B~ qf 20%j J---- Average serum Developmental Da rio sm cions pos. D EtEt o A concentration = Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 15 of 75 [UF Coie | Rr Candidate oe RfD wap rimeisneer mg/kg-d Reference (note limitations in comment filed) a (Lau 2003) and (in (Thibodeaux e Sat 2003) and aci (US EPA 2016a) sonmo ~IDH B_ZvID po modeling mae [imitatior~s: ard A4aterna[ T4 data jl eeu only presented in pa figures have Fmd requested data mi f!'om authors' nae Pup survival only rm reported in .figure. 276.0015 2476.0015 snare arseno STATE_07438110 Sty Dorion | Nm Dve | Ect) vera st cach Seam [Sty POD Study Description duran rons |hal Concnraon orAma DI) | (hai duration, route/ Seed ENON vehicle, species/ ran, sing| fev strain, age @dosing, Nrevimapte |afilrTS0nieaesgnieclA)eU|C |SiEasSLTSSSaotoenwewr,wdRnG oey ekmsFcrsnopop-- eeomLD dgsT2Gmn)RO-- ooWA iOr hnpI (nSepm-- 6g7peearIsltA 2 pr N/sex/group, etc. Admin Dose (mg/kg!d) [average serum concerti Predicted AUC/ (17 dx 24 hr-d) 33~ 1 ug/mL 141 218 260 289 Effect(s) Observed at each Serum Concentration (or Admin Dose) > _ ~. 1 ug/mL "lx pup rcl liver weight, stat sign @PND14 & 21 only (6-9% vs control); delayed eye opening > 141 ug/mL- ~anomalies (defective sternebrae);/b pup tel liver weight, star sign @PND0, 3, 7, 14, & 21 (9-23% vs control) >_ 218 ug/mL - ,1~ fetal BW; ~" mortality (>_ 50%); "~ growth lags; ~ pup rel liver weight, stat sign @PND0, 3, 7. 14. & 21 (20-28% vs control) 289 ughnL - ~' post-implantation loss Study PODHED (mg/kg/d) (e.g. NOAEL~) /serum tor BDBDL orttsel Author's BMD/BMDLssjbrfetal sternal ln, 0083a00i1o6r: cif poise defects, O. 055/0. 0!6 a(knm dose; cl~ palate 708553cn do: al 0238 Z 03,/3.53 admin dose: & sun:ival Z 02~3.88 lide. ID cmt coreroning admin dose. ~tD.{t estimaWa corres~,o~ding Sm of 23535 md serum levels" of23.5/22.8 ug/mL (~bta! Sematary Sousa. (po) sternal d~A'cl.~), 1~5/94 ~@~mL (cl~ftpalate), ET wad arnt] & 165,/~01 ug/mL &u~'iva~).] rm MDH BMD mode#rig: Fartopo ms ns sce l,br ~compariso~ purposes only' since rina OD nade optimcd BMD modeYr~g cou/d ~ot be itecont vedota conc[uc~ed becouse we do not haveft,'l[ ates hh dirt nexted dataseL which wouM require v apeatolad etdeo gan20ctes Pup [iver wt (Table 3 ofLau et a12003) states mand reas Sao dam reported represents mean ~SEf!"om 20Cometarmed 325 mart kd 40 mice derivedJ?om 21-22 litters. ~{ocle%d me erp doa mos assuming 22 litters per dose - all models unusable. [UF Coie| Reece Candidate RD" | mie RfD ihr |cmomimenntseat) mgtkg-d Reference (note limitations in comment filed) FT Pup BW (table l ates ofLau el al) frm provides mean & Sn SE of8-12 pups chi obtained from pr ! 7-2,~ litters rhe (specific # of poume p~ps or litters' er per data point So are not provided) - ineiee Delayed we opening data ein reported in narraOve Onean Snr SE) but no mfo ail on number of rmo e pups or fitterx rien per dose Dr Doc or viandpri ssDds Fodsositeetn A ky Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 16 of 75 22447766..00001166. saeonaeint STATE_07438111 Sy on | iB Oh Sor SPy o Study Description ara |waa | Contre mao | ke duration, route/ ns EBs vehicle, species/ naomi| fv strain, age @dosing, ee oe gs N/sex/group, etc. EE fn Developmental or A Tar smi,| Byuwal Gavage StudyBw RETIRES | aa Crl:CD(SD)IGS VAF Ge So viseieasig Rats penn (Se | CLANS| eer 6 wks prior to mating Tr [Te | ee | through LD4 Cae piste ea on 186. -20/dose sii Wa ING Additional 8/grp in SRATE |pparue |PEEAS control, 1.6 & 2.0 Shea (Ta | nd enn mg/kg-d only were WI Yh| esteem] sac'd on GD20 for EEE [Bem eTLe assessment Susur | Kryoo |, SSSa PE Stady Duration = 63 ane iFS E">2BrlooNg|m| D||| |a e hVB i B AiapkimAe ii mmi1eaoT nom(ir 1r y sve l 9Raer As&m KTa3ish5e Se0tie0idSpese)st days Admin Dose (mg/kg!d) [average serum co,ce, [~ 0, 0.4, 0.8, 1.0, 1.2, 1.6, & 2.0 concentration wePe 1.7or meastlred. Predicted AUC ug/mL*h 30,100, 60,100, 75,000, 90,000, 120,000, 150,000 (Table 4-3) Average serum concentration Predicted AU C/ (63 d x 24 hr-d) 19.9 ugimL 39.7 49.6 5905 79.4 99.2 Effect(s) Observed at each Serum Concentration (or Admin Dose) Maternal: ~ 19.9 ug/mL - ,~ serum cholesterol (16'*, **=p<0.01); v 19-84% tT4when using analog RIA kits (Note: when measured using equilibrium dialysis appeared to be normal) >_ 39.7 ug/mL - ,~ BWG during gestation (75*, 77*, 57, 94**, & 120%*, *p20.05, **p<_0.01) & food consumption; gestation duration 11.7', 2.2**, 2.6**, 3.9'*, & 3%**, p<0.01); star signif J" rel. liver weight (10, 17 & 12%) > 59.5 ug/mL - ,~ serum triglycerides (37, 39', & 44%**); ~, liver triglycerides (26, 74**, & 108%**); ,1, 30-38% T3 when using analog RIA kits but suspect negative bias (see above comment for tT4) > 79.4 ng/mL - T # dams w/all pups dying PND1-5 (23.5 & 73.7**, p<0.01); LviabiliD- index (49** & 82%**, p<_0.01); ,~ serum glucose (8 & 14%**) A uthors Ba4D/BA4DL~: O. 45/0. 31 mg/lcg-d gestation duration). Note: authors state that ~gestation length may have pAg~ed a role in isurvival ofneonates. !,4/IDH estimated corresponding s~erum &vels of22/!5 ug/mL] Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum co,ce~q Maternal." 19.9 ugimL EPA NOAEL 39.7 ugimL EPA LOAEL based on ,~BWG Dutmant Developmental: fe ~ 1'9BB.9W WuGgG/m((%Lno-notsttgagitivvseiegnnnaiafs,s~ddapatutaappprBreeWsseen&ntteedd. mEi o rn e| abu graphically); ~,>96%** tT4 but no dose ay Qf~A'pring : NA EPA NOAEL ei pe ih es ps Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy Cra PFOS - 17 of 75 UF oi UF1'2 [Candidate ooRfD ies mg/kg-d |e Reference [fe(note ftoisntaer limitations in comment filed) Ga (Luebkcr 2005 a) SE and aci (US ae EPA 2016a) ?vIDH modeling aassis limitations: Gora Gestation fy duration data Ea on onO: prexented in povigma- Developmental Pup B LE/B ret data only oy reported in foj~gHres |G 110000 i 000.000000022 (3A, i (EPA) 276.0017 2476.0017 ena cron: STATE_07438112 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete | suman rhaSa oS Aa 0nTVBSiInTom1t Hi6edSuG3hp sflfAdbraehn5n LiIOaB5rymog uNe0eoDRmeDsa DsambspSIAo0SLmmI.tuiyD)s2oIDint0&mtr3RGc01tt3 t 4k5DsoA7urm)oeo0s3in9.0s ea2Dmenu3Gm1et7de3y renE(tLh1On1:gt]eSsie0Tdr0c.6mtdb,h3paTrB0(mi oaoyo9eoee5bmt0ni(6De2i0ura8dr(1371A)&dsese(7(b xo6i13papOr0n$0p7ws0dr501F8oneRp.05.sI1b)N |||oNENrnPAUpaAEDL1mOL9WN9IoEuOLngNkblFedL] [[oBSnPLAY N/sex/group, etc. Admin Dose (mg/kg!d) [(werage serum Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODnEI) (mg/kg/d) (e.g. NOAEL~) rcsponsc & not when mcasurcd by RIA m~alog kits but not when measured by chemiluminometric methods > 46.9 ug/mL - ~ liver triglycerides (M/F 29"/36"*, 34"*/37"*, 37"/36", & 40/57%*, *p<_0.05, ** p<_0.01) > 59.5 ug/ml~- ~ sun4val (81.7, 49.3**, & 17.1 **%) :Z 79.4 ug/mL - ~ serum cholesterol on GD21 (21" & 21%*) on LD5 (17 & 13%) but not star signif but large SD; ~" serum LDL on GD21 (64** & 66%**) on LD5 20 & 42% but not star signif but large SD; Authors BMD/BMDL~ 0.39/0.27 (~pup B ~ (~P~'D~), O. 41/0.28 (~ pup B W gai~0 , 0.6~0.~ ~trth BN);L06/0.89 (pup sun,iraO. [MDH estimated c'orresporMing serum levels' c~! l 9/i 3 ug/mL (B t~, "~ ) / u,g,4nL (pup B~ZG), 3L,'79 ug,L ~fr~i~ wO d53/44 ug/7nL (X~um,ivaO.] /serum 19.9 ugimL EPA LOAEL based on + pup BW NOAEL/LOAEL~ Nd/0. O0 ! 6 mg/kg-d] 10H, 3L- EPA) Candidate RfD mgtkg-d Reference (note limitations in comment filed) M'DH BMD modeling: ~'TabiIi& index reported in 7bble 4 BU7" number of dams is not reported. Assumed 20~ose group.fbr mode#rig. :~[odel/ing results' - - all models unusable TGacan he Ws Pt Figs 2 GeFl~Fa|iorl Repmivine Grogs | 001.04,16, | orm Reproductive Gavage SO 32 Con4rOWaEsianklfst | MOWEPANONEL Stud:, CiCorspics var mon Crl:CD(SD)IGS VAF Raw no 197 sn role prime | 07g Rats Detbucskepin | 001804 | wags,shpgso Slurmal Dosed 6 weeks prior F00, 0.1, 0.4, 1.6, &3.2 ~/[aternaZ/Paternal F0: >_ 99.7 ug/mL - 4' BW/BW gain & food consumption; 197 ug/mL - ~, seminal vesicle & prostate weights, ~ stillborn pups, ~,duration of o..ff~'pring : 25.0 ugimL MDH/EPA NOAEL 99.7 ug/mL oct 2005) (Luebker 2005b) Dr Du i dc hco p oh Df stFROdSoTs mt ns Agee py to mating Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 18 of 75 22447766..00001188. sateorssenns STATE_07438113 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | UF Candide| Reference Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete | sumcon uma N/sex/group, etc. NSS) |Meade| asin & nro mpm | NDWEFA LOAEL (N=35!sexidosc) Fey | enn Ba Sader pp Female groups Comciols | neers fee consisted of 2 Sopa Lotod | 55.363 13.| Detopmertl tegns 8a197 subgroups: 1 dosed TRCN Khitan | 155 cml |comsiPNn D shd eo |NOAEL LOL until GD10 & killed at dross 2d rt pod se 1] Sonam) end ofgestation; 2nd Sond ndier |Pediat AUC | 1 nei allmved to deliver Toa logon | ven 20nd ine naturally & killed on Edondn 21 | Tbs, | bey WIN 21SD SE | Pog lactation day 21. F1 ipo: aio St weamBGbPDdI- | Roum offspring Bboydred |SRMo0 Tale| 2 ATP S WevsR cs)- | MOWEPANOAEL (25/sex/dose) dosed Kemmag 043) teas 490 al: gh dined beginning LD22 Fon concn Sout F2 killed LD21 SiDuin81 | ecrce rmm ||290 HTiugsptonukpe ienleds6r6.e80l%s),|| b NDHcEonPpAoLd pOBAENL, Study Duration - 84 ane pPr55@4H7rIeNHAAUDC)H|aNCAnepoioDtodBHmencseeRV:tectlmRtDkidxsnDimegcr)naeowin(htnnravigeevnsdsioceogooadpdeohormervssr.eenpnons |noNoOenUesELiIoOnNeFLco |iG0OSA>1o0AAno[9on.n- ooEDPwiAom)mst day-s Admin Dose (mg/kg!d) [average serum concenf~ Measured final COFICelq traitORS." 4.52, 26.2, 136, & ]55 ug/mL. Predicted AUC ug/mL*h 12,600, 50,400, 201,000, 398,000 (Table 4-3) Average scrmn concentration Predicted AU C/ (84 d x 24 hr-d) 6.26 ugimL 25 0 99.7 197 Effect(s) Observed at each Serum Concentration (or Admin Dose) gestation & number of implantation sites Developmental [!V)~te no pups @197 ug/mL survived past PND4 & eJJ~cts below are not reporWdfor thix dose g~7~] 25.0 ug/mL transient delay in righting reflex; ,~ BW (PND1 - 21 ~3-5% & M4-26% vs control) & BWG (PND1 21 ~2-7% & M5-38% vs control) staffs sign @99.7 ug/lnl_4 slight ddayed eye opening >_99.7 ug/mL - + pup viabili~ (66 & 0%); ,blactafion index; delayed startle reflex, surface righting; delayed physical development (e.g., eye opening, pinna unflalding) No BMD modeling re,writs reported in publication. MDH BMD mode#ng (using m,e serum COIqC~H) ; t~or 'comgariso~q purposes on@'since optimai BMD modefi~g couM not be conducted because we do not have nested da~aset, which wouM require Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum co,ce~,~] MDHiEPA LOAEL based on ;pup viability & BW NOAEL/LOAkZ O. 0020/0.0081 m g/kg-d] of~'pring 6.26 ugimL MDH/~PA NOAEL 25.0 ug/mL MDH/~PA LOAEL, based on ;pup BW NOAEL/LOA ELvz,.~) O. 0005!/0. 002 mg/kg-d] Candidate RfD mg/kg-d 30 i 0.00002 (3A, i (EPA) 10H EPA) 100 i 0.0000051 i (3A, 10H, MDH 3 DB MDH ) Reference (note limitations in comment filed) i RAammB 1a9d9o16B 3gm.IFpT BMD/BMDLo.s ]9.~/16.8 ugm.L (F] pup BW NDqn 5016109 PND 7)(Ht:D equivalent mgt BSR for PAD vis mg/Xg-d); B~4L)/BA4DLfor ]'ND4 v~abili~' oktle mode[ results - unusable Dr Docume i dhcpohDf stFdRo OmSt cT s Agee py F2: Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 19 of 75 22447766..00001199 sateonssene STATE_07438114 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose pe "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete | suman MTpCpIIme FDoNoeoeDrCImolRndI wBE eRmLayoitmaoMG)AIr LrMnllHeDuapSNENDsOmnt soDTcDnrpmEa9copIW r.t0ain wokt2vnaOe i4Bprden1nW5dsgnnrs e-aeoaNcr5s4nT s2aica2eoon O 1nD3t73clnone.vhty08sRn eTiorg0onsrg1s5en020iI .eneeet36Tu%os3n92vp)n3E0a0&vo0o8 ramon N/sex/group, etc. Admin Dose (mg/kg!d) [(werage serum Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODHEo (mg/kg/d) (e.g. NOAELn~) 6.26 ug/mL - ;pup BW (PND1 - 1 ~6% & ~2-13% vs control - statis sign @25.0 ug/mL on PND7-14 w/13 & 10% +) & BWG (PND1 - 21 ~2-4% & ~3-25% vs control - staffs sign @25.0 ug/mL on PND4 & 7-14 w~19 & 7%~) ~IDH BMD modeling (using ave serum ~b~" 'co~parison pu,~g~oses on@' since optimai BMD modeYr~g couAt ~ot be co~duczed because we do not have nexle'c[ data.seL which would require indiWdual armnal BMDiBMDLo_s 9, d~/5.91 ug/mL (~2 pup BW PNDT) )(H~Z) equivalent O. 00078/"0. 00048 mg/!~g-d) *NOTE: 0~71)' one control a~d two dosed grozws in model, Net@re results are used to support selection oJW(MEL as Candidate RfD mg/kg-d Reference (note limitations in comment filed) POD. ososrmg ol Dor mie:| men BY Go sy: in os Cross-fostering oral ed enh somberofpi3 t garage studyCITOEDIGS VAP |Fouraps nac&e ns , CrI:CD(SD)IGS VAF Rus aon Rats Dnsprsets | Conlon |Visit 15% Expopup oaddst 42 days prior to my hon | Epona| by IND compact on mating throughout stnodainn | Colin | Exonin |1%in Cong gcstafion and lactation Emerton p|eEe oansxrn epdpyr|r1o (ppEsBOxiNEl plPDeNICalDonnmsEmElxe oxpooepr)d poodsn, 25 females/dose 0 or 1.6 mg/kgd Four grps (in uterodactation): Control/control Expo/control Control/cxpo Expo/expo Measured pup seY~lm concentrations: ~maternal BW (gestation only); +gestation length, number of hnplantation sites, total litter size, & live litter size Viabilib; - 19% Exp/expo pups tbund dead by PND2-4 compared to 9% in Expo/control m~d I. 1% in Control/cxpo (similar to Control/control) +Pup BW PND 1 in Expo/expo & Expo/control grps +Pup BW PND4-21 in all exposed grps, greatest effect in Expo!expo grp. == (Luebker 2005b) Dr Docume for i dhs poe oh Df stFdRosOmSt T nsAgee py Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 20 of 75 22447766..00002200 sate onssens STATE_07438115 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie duration, route/ hide specs 6NoAFLw) vehicle, species/ Srveido,sing| fre strain, age @dosing, Ne ete | sE7 Crcihooaiemnrdretooern ramon N/sex/group, etc. Admin Dose (mg/kg!d) [average serum concen [~ Expo/control: 47.6-59.2 ug/mL ControZ ~ea-po.' <DL 35. 7 Expoiexpo : 79.5-96. 9 Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum Col ONT [GTOor Denar Oral garage DNT Rome | Vomghaiin | 217apm.sigh ootsts LBVG pe stud?, - Female Spee Ras EPANOREL Sprague-Dawley Rats COTOPDID |Meafso | Decipeeral GD 0 to PND 20 Hlamestons Seno | 57sg mor cits (ca PDI?| 347 mt 25 females/dose Offing moar | rng Bhona AIS3t rh).| EPA LOAFhad Offspring monitored fobtecul oko (ya PADI | on me sii& through PND72 Sibson | 35ennds.or Tiaton Study duration anion ds NORLIONLy (gestation) 22 days gsss+PiNoD n | Rpoom ndeoedna (gestation + PND) 41 bs S05invda days 0, 0.1, 0.3, or 1.0 mg/kgiday Me as,~v d.final sermn levels during Gestation: 1.72, 6.245, or 26. 63 ug/mL Gestation + Postnatal: 3.16, 8.98& 30.48 ug/mL 34.7 ug/mL - slight but not starts +BWG Developmental 34.7 ug/lnL - ?motor activib" (M) on PND17 (but not observed on PND13, 21 or 61 ); lack of habituation (M) on PNDI 7 Developmental: 10.5 ug/mL EPA NOAEL 34.7 ugimL EPA LOAEL based on T motor activity & habituation ~OEL'LOAELz~D O. 00085/0. 0028 m g /kg-d] Prt AUC Predicted AUC wath ug/mL*h Cotman Gestation an Si 1,060, 3,180, 10,600 Gepost Gest+Postnat Silo Ton 3,410, 10,300, Silo Tae 34,100 (Table Arg om 4-3) Average serum Dr Docume for i dhs poe oh Df stFdRoOstST ns Agee py concentration Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 21 of 75 UF CCmaannRa"ddfsiDidDtadteeo||rR(mRneteoeffateeeirreeonnnccseein mg/kg-d Comment ied) limitations in comment filed) B0more Butenhoff et al 2009 [30 ovoors 30 i 0.00003 onan (3A, i (EPA) fon1 OH EN~PA) 109 omoonns 100 ox | (oy (3A, on10H, oi3 DB [0.0000085 (MDH) NowMDH >) 22447766..00002211 sate onssenie STATE_07438116 StudyDescription | AdminDose |Effects)ObsearcavchSeradm Study Description durian,route | Ag | ConcatorrAdamiinDoosne duration, route/ hide specs vehicle, species/ Srveido,sing| fre strain, age @dosing, Ne ete |FospruirymoadcautAnCntT N/sex/group, etc. Admin Dose (mg/kg!d) [average serum conceder Predicted AUC/ (study duration days x 24 hr-d) Effect(s) Observed at each Serum Concentration (or Admin Dose) pa Gestation Sov 2.0 ug/rnL 6.0 20 Gio ND Gestation-@ND Sl 3.5 ugknL |Sindy POD | UF Candide| Reference Study PODHEo aie "Dore (mg/kg/d) 6NoAFLw) mast | mtaionsin (e.g. NOAELn~) ramon Comment ied) /serum Candidate RfD mg/kg-d Reference (note limitations in comment filed) Dring ar ONT. Tg 50% idS eT Dnnking water 'DNT' beg |PON ae | Incas | (mcmd&tg mcto | EPANOAEL stu@ - Pregnant Wore Doc eo lan saes Wista3: Rats COUmDN p|cerrorwnranwiiwed||2f4 (eosmnrdo ppsive oss o| SenEPA2m i4eLdOnNmieEsLchp)d GD1 - PND21 ]O5 34.7 0, 5 or 15 mg PFOS/L water Doses to ~7ot ca'ulaled tmd B W & water consuml) lion >_ 0.8 (adm dose) - water maze escape latency ~" (swimrning speed & time to reach visible platform similar across all groups) 2.4 (adm dose) - ~,pup survival before crossfostering (I.8 (adm dose) EPA NOAEL 2.4 (adm dose) EPA LOAEL based on ~'w ater maze escape distance & escape latency pr reporWd Rt mo EPA estimaWd rrr doses: O, 0.8 or imgiyd 2. 4 mg~kg-d oar TOL06oc |Sodo mamer GFAP) pone Oral Nardechpocnl |20mpAgd |cosa bppocimpesdcomer Neurodevelopmental Coe pA prsin of Garage studyFnSse eames ces (rin | Pregnam SpragueDov as Id ener rtfron Dawley Rats [oe a Rnoaonm proaPca cD]:asPs RtDmNpDApl, oeecrsof GD2-21 0, 0.1, 0.6, or 2.0 mg/kg-d >0.1 (adm dose) - ]" number GFAP positive cells in hippoeampus & cortex of pups;TmRNA expression of two inflammatow cytokines (interleukin 1 beta & tumor necrosis factor-a) in hippocampus PND0; ]'mRNA levels of pro-intlammato~~ transcription factor activation protein- 1 @PND0 Dr Du i dc hs po ps Df stdos mt sinsAgee py Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FROST PFOS - 22 of 75 Wag Wang et al 2015 En aci (US EPA os 2016a) eng aon Zeng et al 2011 ey aci (US EPA Soa) 2016a) 22447766..00002222 sate onssen? STATE_07438117 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete | suman SSDireennnsRcl ndnhL1eonadiTkunrpgRTmrprA&ioESpec niNocPTGnoiIk taapopNd&oosn.cons pment N/sex/group, etc. Admin Dose (mg/kg!d) [(werage serum conce, [~ Effect(s) Observed at each Serum Concentration (or Admin Dose) >--0.6 (adm dosc) - ~'S 100 calcium binding protein B in pup hippocampus & cortex on PND21; ~mRNA levels of proinflaanmalory tra~ascription factors nucleax factor-kB & cAMP response element-binding protein @PND0 Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum an gael | 00357535 53S wed ak doe] rca | 25dao oy 28 day gavage study Ck makme |Simghed | asin domgomenot sl ORE in ICR male mice nso os. dupont (20/dose) comic | mSfwJ NmSfLmSeeaeiolal0empdemdEaca3eitlbisyld3| s|0|||| to dPio3Rmeo 0pm m eos0om0mrcee.tm(8td(arm B3inrrad Tiei ,RmlF)pskGdSs iscoeecoeeepllChbpsee oe8fnldvdxrdGeedinimntssm ciethmp1mae)bea0od8mlpo2meo0sfs820e0)| 28 LaOmRdEos) corn oil vehicle 0, 0.25, 2.5, 25 or 50 mg/kg-d Serum levels repoded in Figure 7 unable to est lcvcl at 0.25 mg/kg-& Est level @2.5, 25, & 50 mg/kg-d adm dose .... ~.44, 233, & 320 ug/m L > 2.5 mg/kg-d [adm dose] - TSertoli cell vacuolization & derangement of cell layers; disruption of blood-testieular barrier (BTB); ,~epididymal sperm count (reported in Figure 4, estimated +vs control - 28*, 60**, & 68**%, p<0.05" or 0.01"*) 50 mg/kg-d [adm dose] - dislocated immature germ cells found in lumen of seminiferous tubules I~ vitro (primary Sertoli cell assay') demonstrated a dose dependent ~.in cell permeability barrier ('threshold' between 20 & 30 uM) & mansepithelial electrical resistance ('threshold' between 10 & 20 uM) 0.25 (adm dose) NOAEL 2.5 (adm dose) LOAEL Fie $2 showsPFOS didntsigns Figure $2 shows PFOS did not significantly China moins of Be opt,oso chauge morphology of the caput, corpus, or Tomb cauda of epididymis Topabaime: [0S 20S md fern HE x persia Hypothalamicpine | Yori cma (1a ogo FSH, | Aus NONEL. SEs pituitary-testicular FT) 33dy ct | myn reams ipa Eaten (HPT) axis 28 day oral ne Ad ronson) 05 aim dese) garage study - Adult Se Die Wk 21 atm oy gs chs in| Aus LOAEL, Sprague-Dawley Male hoy Choma mmics | don LIE Rats [2 fromieie sy 19igrp 0, 0.5, 1, 3, or6 mg/kg!day >_ 0.5 (adm dose) - [serum LH & testosterone (flat dose response), "FSH, .~gene expression for GnRH (but inverse dose response shown) >_ 1 (adm dose) - histological changes in testes (edelna around seminiferous NA Authors NOAEL 0.5 (adm dose) Authors LOAEL, based on ; LH & testosterone & "[ FSH Dr Docu for i dhs pps Df stdos mt sinsAgeepk Draft Document - for review and discussion purposes only. Draft document does not constitute Ageucy policy FROST PFOS - 23 of 75 Candidate RfD mg/kg-d Reference (note limitations in comment filed) (Qiu 2!)13) Lopez-Duval et a12014 aci (US EPA 2016a) 22447766..00002233 sate onssene STATE_07438118 Study Description | Admin Dose |Effects) Observed a cach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne eve | suman ramon N/sex/group, etc. Sa ms To od er) Small nmnber of ind 3) Ching in sorb concen animals (2-5) Cad etcodon EpSSeeeeJ plprshlippseeetnssopnae orouaToynsncsoo(orer pnsoHdhpod eopihTbkihr ienp oeSinfSHt)dsoc ew"l--sens"ee,& examined per endpoint Admin Dose (mg/kg!d) [(werage serum conceder Effect(s) Observed at each Serum Concentration (or Admin Dose) tubules & malformed spcmaatids); chax~ges h~ norepinephrine concen >3 (adm dose) - most active pituitary gonadotrophic cells classified as inactive based on the lack of homogeneous endoplasmic reticulum & well developed Golgi complex, many cells in process of degeneration were observed. Histological cha~ges in hypothalamus (basophilia, vacnolation, and irregular nuclear borders). "gene expression [br LH 8: FSH (but ,~ @highest dose) Study PODHEO (mg/kg/d) (e.g. NOAELn~) /serum thors se re resrst Authors state resu#s are consistent iionf repring ~/ink~bition of the reproductive bompono tnt is h~wothalamus-pituitao'-testicular axis at > 5m ry O. 5 mg/kg/day. Tosod [0153 TwTip do] [Con Topo HPT axis 28 day oral moos Adak | mien esting horns ecg (Cake, 20ey garage stu@ - Adult SmsDoe Ml lane protien pay Doctorper Sprague-Dawley Male by lesCei n sind) Cake igen Rats 0, 1, 3, or 6 mg/kg/day Neston ePec tevdesnredep)p&o"sGhe: moeranecrod N 6!dose Tuc 201k erS Sr pRcSaierionoennran n cnsnmnmroianni yfooomrttonme,E)sned(lTmat a LF&ioanoobpcweoospdnlobasuottpmrastnio:cee Swolgrzpc Tween 20 vehicle >1 mg/kg-d [adm dose] - ;Gonadotropinreleasing hormone receptor (GnRHr) relative protein expression in pituita&, (largest effect @lowest dose); ;GnRHr gene (flat dose response) & }GnRHr protein (inverse dose response) relative expression in testis, ]'LHr relative gene expression & J, LHr relative protein expression in testes; ;Folliclcstimulating hormone receptor (FSHr) relative gene (low dose only) & relative protein expression (all doses but fairly flat dose-response) in hypothalamus; ;FSHr relative gene & relative protein expression in testes; ~Androgen Candidate RfD mg/kg-d Reference (note limitations in comment filed) (Lopez-Doval 2016) Does' ~ot appear that histological assessments' were conducted Small group size Dr Docume for i dhs poe Df sFtdRosOmSt sTinsAgee py receptor (Ar) relative protein expression Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 24 of 75 22447766..00002244 state orssenns STATE_07438119 SudDscrpion | Ni Do EG)Orne Serv Sy POD UF Study Description dori row | (AE | Conentotr daniDoiny | (mg duration, route/ hte EFNet vehicle, species/ i Sie.| (ve strain, age @dosing, Admin Dose (mg/kg!d) [(werage Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODHEo (mg/kg/d) (e.g. NOAELn~) N/sex/group, etc.- Tos cpm [TTT S >mSiSpSSn Sosey dooorlivosrbsori mieeenetrppa peeoiiaOnxlmdstvOpa3vop Lnel)Aeai3erGe&e7oermn n lnvscidnmev4tnveiFtseepaniOes)i)en| OF Lung Developmental frre Tremor hash cages | 15s oral garage stu@ Soto oe Phe hatemarit Nor Sprague-Dawley Rats oi enrol| vet abaatpe e GD1-21 wipnto p|amyain| iTnheor mcoithneey |LOAEsLbtetmn n=6/group (no torte | Trent [rr mention regarding - Es renin sex) Sty int | Ped ALC Noau01ns Stu@ duration 2I or frrSora pei day's serum conceder 0, 0.1, or 2 mg/kg/day Measured final S~Htg4 concentmdons !. 7 ug/mL 47.5 inn yhyppoothatlamhusa&&lrreealaabtimvveegugmesnsc expression in testes; ~Ar relative gene expression in pituita~~ (low dose only) > 3 mg/&g-d [adm dose] - ,LLuteinizing hormone receptor (LHr) relative protein expression in hypothalamus; ]'Ar relative gene expression in hypothalamus; +Ar) relative protein expression in pituitary & testes 6 mg/kg-d [adm dose] - "LHr relative gene expression in hypoflmlamus 38.5 ug/mL - ,, Pup BW @20% @ PND21); J'pup mortali~; histopath changes in pup lungs (alveolar hemorrhage, thickened intcralveolar septum & infloanmatory cell infiltration); Tbiomarkers for oxidative stress Predicted AUC ug/mL*h 968, 19,400 (Wmnbaugh et al 2013) O(Apring 1.9 ug/mL NOAEL 38.5 ugimL LOAEL based on histopathological cha~ges in lungs, BW & " lnortality [NOA b;L/LOA O. 00015/0. mg/kg-d] Average serum concentration = Pred AUC Predicted AUC meri) ug/mL-hr/(21 d ee x 24 hr/d) = 1.9 ug/mL 38.5 Dr vsumot orion ndcinpepo, Dd r o TORcr osAss spy Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 25 of 75 Cane | Rr Candidate Rf RfD wha|cFommimoennniitn) mg/kg-d Reference (note limitations in comment filed) Cm (Chen 2012) and Sst aci(US EPA Shi 2016a) 22447766..00002255 eureares STATE_07438120 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete |somcon frmoer N/sex/group, etc. Dovdopmen [0.01 ors Tl Go) spN p ey | 01 (Fim Tra Dcvdopmental nance | mAs raise E58 21) do USER immune oral gavage Suis CTL Same) ppNK sdti EnANONEL a study - C57BL/6N FoieNoms ANSE ST pac ming Female Mouse GB lpfo SRn BCI pdcion | 1S din doe GDI-17 Ohio BBN 51, 4CD3 Coir | FPALONEL bed 10-12/dose Imma ea on NKsl ein Immunotox rte ouprs Fusoropes eine podcio0n evaluations on pups preeririey LPS& orpanaby tos performed at 4 & 8 WA TF per phe weein wks (1M & 1F per wash fran litter were tested) Admin Dose (mg/kg!d) [(werage serum conceder 0, 0.1, 1, or5 mg/kg Effect(s) Observed at each Serum Concentration (or Admin Dose) >_ 1 (adm dose) - suppressed NK activity @Swks (Ms -42.5 & 32.1%)) 5 (adm dose) - suppressed NK activi.ty @8wks (Fs 35.1%); ,, plaque-fonming cell response for SRBC IgM production by B cells (M 35%); ,bCD3 + & CD4~ in thylnocytes. Functional responses (nitrite production) to LPS & interferon-gmnma by peritoneal macrophages were not al'fected with treatment Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum co,ce~,~/# 0.1/1 (M/F) admin dose EPA NOAEL 1/5 admin dose EPA LOAEL based on ,~NK cell activity Ce pd [OTST SOS aBWd GT de x Ta Glucose & lipid lonmiconl | mind "eed Toe moans, bono | EPANOAEL Users homeostasis oral pre Soca cpg powdi Soa) gavage study - Wistar fa mn 03 mde) Rats Boro EPA LONEL bd GD0-PND20 CaryBed amples on ott; 6/grp; Blood samples Coat 16 ied collected at 10 and 15 lim for eos weeks (fasted) for [gine lipids mad glucose 0, 0.5 or 1.5 mg/kg -d > 0.5 (adm dose) - +BW (5-15%); doserelated ]'glucose intolerance; ,~sepam adiponectin; "[epigonadal fat pad ~,t & fat accumulation NA EPA NOAEL 0.5 (adm dose) EPA LOAEL, based on + offspring body wt, impaired glucose tolerance Gucoeipd [003003 | 207 smdoe singgse| 01 mdse Wongas Glucose & lipid Menmitonl | mye adi, TONAL mic SNS | EPANOAEL Wihaas homeostasis oral ae C1 Dia) Eades gavage study CD-1 fis Sam newse togpm) sonet | 3 aindo) Mice Expos G0. CYRIALL poem pw. ay sci| EPALORELbred Exposure GD3fm docsLp mneid | 0 tw dams PND21. Pups assessed rire Imrotha ioc ges or | Nal @PND21 & PND63. Offg fd dor ineye te poh||ing Offspring fed std or Vikan F{{eCodBhriahenTgOaeMdiARgrioucn Ga mPlO1| vii hi-fat diet 0, 0.3 or 3 mg/kg-d >_ 0.3 (adra dose) - ]'fasting serum glucose (std diet); ]'HOMA-IR index @PND63 (hi-fat diet) 3 (adm dose) - ~ liver wts; ~expression of CYP4A 14, lipoprotein lipase, fatty acids translocase, hepatic insulin receptor, and insulin-like growth factor-1 ; +genes prolactin receptor & insulin-like growth factor-I ; ]'HOMA-IR index @PND63 (std diet); changed glucose tolerance test (hi-fat diet); ]'fasting serum insulin (both diets) 0.3 (adm dose) EPA NOAEL 3 (adm dose) EPA LOAEL, based on " liver wt in dmns & M offspring, ]' fasting semrn insulin Ms Candidate RfD mg/kg-d Reference (note limitations in comment filed) Kcil ct al 2008 aci (US EPA 2016a) (Lv 2013) and aci (US EPA 2016a) Wang et al 2014b aei (US EPA 2016a) Dr Docume for i dh poe oh Df stFdRoOtSsT s Ae py Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 26 of 75 22447766..00002266 STATEgraseizt STATE_07438121 Study Description | Admin Dose |Effects) Observed a cach Sram |Sindy POD | Study Descriptiondurian, route | Ag | Concatraion orAdmin Dose aie duration, route/ hide specs 6 NoAFLw) vehicle, species/ Sri, ve dosing| fre strain, age @dosing, Ne ete | cman framcomer N/sex/group, etc. Admin Dose (mg/kg!d) [c~erage serum conce~/# Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODHED (mg/kg/d) (e.g. NOAELH~D) /serum conce~.~]# SNiobheSrttgmaEgfe o(h0s0c4D52T1So50r55253165 (admD) rsunEk7o38y5 TE md 3 month oral gavage CB Ne [1075 pe les mentqin| EPANOAEL study - C57BL6 Mice frre rmot nt opon 15/dose (sex not sid) 10H725or1pGClcD sKSGeAdOir8oavkoiBnImiiunAnReTemLnnnr))oeoaiostnecGr mrpnk&onDyg(aupmAosa1mLeiaawYisetptipRmpnahosp&aOicptVie bSncmsooinriapmAmRpetiopgsPronlEr(ToneoneyesnLSVynloiapssrAeDoolrOMkS)iDnPotomLAnlsCt.||ot EnP2aA1 cmLnrOAomEmLeebo)red specified) 0, 0.43, 2.15, or 10.75 mg/kg/day >_ 2.15 (adm dose) signif ]'latency to escape & less time in target quadrant in water maze test; signif ]'% apoptotic cells in hippocampus 10.75 (adm dose) - +dopamine & DOPAC levels; "~ glutamate levels. (HVA & GABA levels ~vere unchanged), Changes in differential protein expression: Down-regulation of Mib 1 protein (an E3 ubiquitin-protein ligase), Here5 (hect domain & RLD 5 isofovm 2), & Tyro3 (TYRO3 protein ~rosine kinase 3). Up-regulation of succinate dehydrogenase flavoprotein subunit (SDHA), Gzma (Isofonn HF1 of Gran~me A precursor), Plan (Urokinase-Wpe plasminogen activator precursor), & Lig4 (DNA ligase 4). 0.43 (adm dose) EPA NOAEL 2.15 (adm dose) EPA LOAEL based on water maze performance Ti Dn ici nnTEA { Oiseas~/Func'{io~ a~dS~m~ipid Effects SanOnt 101 Sc | 1(lm Gergen toed p | (im Gy 3 - 21 day Oral 0, 1, 5~ or l 0 >_ 1 (adm dose) - signif ~mitochondrial [3 mone CD [men ion EPARONEL gavage stu@ - CD-1 mg~Kg!day oxidation Rie 28 Emde wodn nTi Mice >_ 5 (adm dose) - ~ liv ~ (only @ day 7 in Smo odo Tires& | 3 dose) 4 males/dose low dose grp), ]'liver triglycerides, & Sel Aehoval sn, gat vps| EA LOREL bd Stu@ exmnined yellowish coloration; signif ?transcripts a Refoepm rinonR sl saA l CoA |nner mechanistic aspects for mRNA for peroxisomal acyl-CoA netamest de Cop 14 ECR |Shins onto related to role of oxidase, Cyp 4a14, & acyl-CoA FrOSictng mig bencst PFOS leading to dehydrogenase, [etary 10 in do) monsoas | pram hepatic stcatosis @10 (adm dose) - microvcsieular steatosis a 1 OA& princen at day 14, ~'mRNA & protein expression Ref sod vamos& pops for fatty acid translocase & lipoprotein pt dtbaitnl lipase, slight but sign Ttotal & som ouisicn peroxisomal [3 oxidation 1 (adm dose) EPA NOAEL 5 (adm dose) EPA LOAEL, based on T liver wt, cha~ges m oxidation biochemical parameters Dr Docume for i dh poe oh Df stFdRoOstSsT s Agee py Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 27 of 75 UF Candide| Reference UFI'2 i Candidate "Dore ~ RfD mast | mtaionsin mg/kg-d Comment ied) ~ Reference (note limitations in comment filed) Tonga 205 Long et al 2013 Wan el al 2012 22447766..00002277 sate orssenzz STATE_07438122 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete | suman framconn N/sex/group, etc. TdOnt pe 0 S00 55 addo ni RST NA Re 14 day Oral gavagc suis VA BALD| mpg mS ercome. ie EPANOAEL Us study - Male BALB/c Nie w hcosen pabolpi hanes Bani Mice Wilruluorbih | miosis | hepa moe nee pete | Sal de) With regulax or high a 2T Smoi0kwnnamsio,bb|nyiere Tpr )DRmeLBeceVgh n ahoWGa meLCc mOFp8hLo)die(ncRl 1eec0and7usm.|||s4EmP6t A LONnELbbe hd Cprp#rrr4rmaronnhitaeteodHneda, fat diet Admin Dose (mg/kg!d) [average serum concerti~ 0, 5, or 20 mg/kg!day 16 males/dose/diet Effect(s) Observed at each Serum Concentration (or Admin Dose) >_ 5 (adm dose) - "[liv wt (Reg/Hi - 81/56 % 99/73%), T liver fat content, ~,liver glycogen, pathological changes in hepatocytes (more severe @ next dose & HiFat grp more susceptible), ]'serum albumin, +HDL & cholesterol (HiFat); nonsig ~ serum testosterone (lrg variability); ,, BWG (HiFat) @ 20 (adm dose) - ;BWG & food consump; ~ fat wt; ;serum glucose, triglycerides, cholesterol (RegFat) & LDL (RegFat) Study PODHEo (mg/kg/d) (e.g. NOAELn~) 5 (adm dose) EPA LOAEL, based on wt loss on high fat diet Rego it 2.00 1 asi) ner oposkcer Regular diet - ~2-fold ~ (star sig) liver fat content HighTa dt sgh &enn Ter id High fat diet - slight & nonsign ]'liver fat pe tsfie] ines content along with ~.serum glucose and en erp lipid levels PPAR prion HOS 150 hme PTEiOcNatas p PPARc~ expression - w!PFOS trt no change Res gr, bt | rt rcp ot arto in RegFat group, but !, HiFat groups (signif le) Epe soe s ge pescmichr @ hi dose). Expression of several genes oii pd mbt (CPTIA ross involved with lipid metabolism (CPT1A & CP wescA md CPTI ic bing CYP7A1) were examined. CPT1A - role in rp oats dk hod aafo trm~sport of fatty acid into the nfitochondria for beta oxidation & CYP7A 1 - involved homo holo Conor w/transformation of cholesterol into bile Si WHmCRAcOprS ol dn acids. W/PFOS trt CPT1A expression ~ WegF|wtiofdus WHTOiS me ron w/RegFat but + w/HiFat diet. W/PFOS trt CIPIAT posnchiah Rega ner CYP7A 1 - no sign change with RegFat but SWHFAARLThds oppor posse opanehros +w/HiFat diet. The data support a possible eloFROS hing pn or a penint role tbr PFOS in inhibiting pathways for oirmela pafin ra cholesterol metabolism & export of liver ie dru some FOS ried rane lipids & identi~" some PFOS associated herpes th pen of mann liver responses that axe independent of FAR PPARc~ activation. Dr Docume i dhcp Df stdost cs Agee py Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FROST PFOS - 28 of 75 Candidate RfD mg/kg-d Reference (note limitations in comment filed) (Wang 2014) ,~x~d aci (US EPA 2016a) EPA (2016a) states that Wang et al 2014 demonstrates a c#ar influence of diet alone on the #ver d: l&id prof!# that comb#~ed with som~ relawd d~fferences the resioonses to PbDS exposure. ~e data support a possible P~OS [n pathways'for metabo#sm export qf liver some PFOS aSSOC responses that are independent PPARa ac#vation. 22447766..00002288 state orssenzs STATE_07438123 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | UF Candide| Reference Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete | scan furmeonen N/sex/group, etc. Tanoortian TOTO SIT we ARETE | 27nNL AUF) Cor 28 day oral dietaxy Spa 13308 BLE EPAXOAEL ao study- Sprague Dime on SAT asma t dia bs rd users Dawley Rats icine SS| Tee eve. | 35907apil Bo 15/sex/dose Om | magn TETRA 1) T4 (IF 248, our (0, 2, 20, 50, or 100 mikeden Prive) EPA LONEL bt mg/kg diet) Sib dion 2s | Mad | > 612602S12u831gA fiondcJnWaO.F |an inert Study duration 28 ane PwSSCaNpA WABCraTITcla1Shlaieotsm2ooooSTnib0TiaassshcnSa)nnC ieisHs?gsuoscAOhoArncioLtaUlmdtC||||||||| m6Fa aG aimegeBS(N|"ssh oneediNdsdioSdemnsTit3heneEe0Aiehfoo,5pSntveT(1 od3oo pFhk,&o)ECi8ph3atrPiooosWncdhlrcgArpt8roSdotetatnmep D0gsIotpt88 .toohe0csokpp,DveTbmrSmocrneoh(iEeeoscmscostiBsrhhonnee)nyeo)nesoS,ralsared|).A(||||(2SNsmNi i[0huwo6oen2r]OOmini5woeooL0dnNrrsbcmn1Lh1oimon09lImtm de45ssN,e|| 40 | ioorempmleonn days Admin Dose (mg/kg!d) leverage serum concert f 0.14/0.15, 1.33/1.43, 3.21/3.73, 6.34/7.58 (M!F) mg/kg!day Measured SCFI,II?7 O. 95/7.5 ug/mL [3,45/75.4 20.93/31.93 29, 88/43.2 Predicted AUC ug/mL*h 1,840/2,500 17,400/23,800 42,1 {i}{i}/62,100 83,100/126,000 (Wambaugh et al 2013) Average serum concentration = Predicted AUC ug/mL-hr/(28 d x 24 hr/d) 2.7/3.7 ug/mL Effect(s) Observed at each Serum Concentration (or Admin Dose) >_ 3.7 ug!mL - stat sign q'rcl liver x~ (F - 12, 22, 41, & 71%) > 25.9/35.4 ug/mL - stat sign ~abs & rel liver wt (M - 12, 35, & 57% rel wt), J'CYP4A22 (M), ,~T4 (M/F 82/48, 84/6(I, & 83/57%) > 62.6/924 ugimL - star sign ~BW (M/F 12/12 & 21/20%) & food consump; liver histopath changes (hepatocyte hypertrophy & " cytoplasmic homogeneiU), signif ~' expression of gene for peroxisomal acyl-coenzyme, A oxidase, ~CYP4A22 (F), W conjug bilirubin (F 63 & 400%), ~.cholesterol (M!F 36/33 & 88/75%), Briglycerides (M/F 43/34 & 89/63%); ,~T3 (F 23 & 31%) @123.7i187.5ug/mL - ~'total & conjug bilirubin, IT3 (M24%) 67 different fatty acid profiles were exanined. Authors state that liver fatty acid profiles shmved ]" total monounsaturated fatW acid levels & ~ total polyunsaturated fatty acids, which were similar to chauges induced by weak peroxisome proliferators. Study POOHED (mg/kg/d) (e.g. NOAELn~) /serum conce~.;]# 2.7/NA ug/mL (M/F) EPA NOAEL 25.9/3.7 ug/mL (M/F) EPA LOAEL based on T liver wt /N OA ELl L OA EL NA/O. 00030 mg/kg-d (F)I [~VID H N OAEL/LOA EL ~u> 2.7/25. 9 ,tg/mL ~ O. 00022,'0. 0021 mg/kg-d, based on liver wt change w/histological changes at next dose #vel up & T4) Candidate RfD mg/kg-d Reference (note limitations in comment filed) Cu~a~ etal 2008 act(US EPA 2016a) i 0.0000073 i[ro~ i co~tparison purposes] 7s 25.9/35.4 62.602.4 123.7/187.5 Dr Docu for i dhs poe Df stTdoOs mtSsinsAgeepk Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy Pros - 29 of 75 22447766..00002299 sateonssenze STATE_07438124 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | UF Candide| Reference Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete |somcon foramen N/sex/group, etc. Tinenm6 000% | Nocw ba aBW Tod | 1633Ou Sn 14 wcck thnc point fond van | D501 |clic, svn cnn.or EPANONEL Per from 2 yr dietary cncetogsn. |0340M0or |pout: plinin pai C10 Bani cancer bioassay on) Syme | 1351S00)| nce ans wnt (below) - SpragueDo shyt EPALONEL Dawley Cicisiosme 646108 Safomdn. m: os |Bden T, Crl:CD(SD)IGS BR fn Messe Rl rath ATA BUN Rats Siete sion fp 5 rats/sex!dose BOSTUT ert | Semone | TR ALTOS ore | NOAEL LOM 0, 0.5, 2.0, 5.0, or 20 won rid en (FBO) amis. 0 om ppm Sidnsosas | 3i5s5s05 GGmsosmmgiacg | {lGoak EN Study duration 98 bs Tot335 wm ih days Admin Dose (mg/kg!d) [(werage serum conce, /' 0, 0.03/0.04, 0.13/0.15, 0.34/0.40 or 1.33/1 56 (M/F) mg/kg!day Measured SCFHlll 4.04/'6.96, ! 7. !,'27.3, 43.9/64.4, !48/223 ug/mL, Effect(s) Observed at each Serum Concentration (or Admin Dose) No effects were observed on BW, food efficiency, urinalysis evaluation, or peroxisome proliferation (hepatic PCoAO was unchanged). @64.6/108.8 ug/mL - +food consump; ~" abs & ml (M/F 34*/30%*) liver wt & histopath changes; ~cholesterol (M 72%*) & "[ ALT (M 80%*) & urea nitrogen (M/F 23*/42%*) Study POOHED (mg/kg/d) (e.g. NOAELn~) /serum co,ce~,~]# 16.5/28.0 ughnL EPA NOAEL 64.6/108.8 ug/mL EPA LOAEL based on qiv wt, ALT & BUN 0.0013O. 0023/0.0052- Prt AUC Predicted AUC ey ug/mL*h Soi 3,430/6,620 Tsien 14,900/24,800 38,900/65,800 iam 152,000/256,00 ERA Tait 0 (EPA Table 453) Candidate RfD mg/kg-d reference (note limitations in comment filed) (Scacat 2003) ,~x~d aci (US EPA 2016a) 30 ~ 0.00004 (3A, [ (EPA) 10H EPA) Averag~ sermn concentration ebmALC Predicted AUC aleond ug/mL-hr/(98 Noi x 24 hr/d) 12S wml 1.5/2.8 ug/mL 6.3/10.5 16.5/28.0 64.6/108.8 Dr Docu for i dhs poe Df stFdRosOmSt sTinsAgeepk Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 30 of 75 22447766..00003300 sate onssenas STATE_07438125 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | UF Candide| Reference Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie "Dore duration, route/ hide specs 6NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete | someon fram omen N/sex/group, etc. Tard suis 01 SOTO om dep || 024012s Thomo 0 2-yr dietary study Sevier | 00003,|dscns tracerdoe dns EPANOREL Baht Sprague-Da~vley CIDOB | DAO.| repos) mii Crl:CD (SD)IGS BR Ru BE {USE oa) Rats 0.08.2 50pm| 03840251 (Fa 5vio. Thimoptolosial re 0, 0.5, 2, 5, or 20 ppm J OFmoksst| hae mer ND] enioble |EPALONEL Noize in diet. Overs ers bons mcdomine po Observations wcre mad nd 3 0200ch3mdo5) msrp | Wop: oncenraon made at 4, 14 and 53 een 0Tum cTrro59cmagrmoeeo.cnwscrpeo8ohgorrpee o edhspnomsocee0oAehnrtnm LrodecvTisoo s1moL(ieenm NaemBoncngsWt2tg(shshees a T M8cscEsh6h3vlhooFevs8lenpad)nsS4i|||||| Vo1A0c103Nk50e4Or4HF30rL8aan3dvtvi6eec0 po inDi m y weeks oftreatment Admin Dose (mg/kg!d) [average serum conee~7 [~ 0/0, 0.024/0.029, 0.098/0.120, 0.24/0.299, or 0.984/1.251 (M/F) mgA:g-d Effect(s) Observed at each Serum Concentration (or Admin Dose) Study PODHEI) (mg/kg/d) (e.g. NOAELn~) >_ 0.024/0.029 (adm dose) - Thcpatic cystic degeneration (but no clear dose response) > 0.098/0 12 (adm dose) - ~,semm glucose (F @ 53 wks), ~" histomorphological changes in liver (M) (~" centrilobular hy#ertrophy > 0.24/0.299 (adm dose) -~macroscopic findings in liver (incl enlarged, mottled, diftSsely darkended or focally lightened livers), hepatotoxicity characterized by histomorphological ch~ges (M & F) 0.984/1.251 (adm dose)- ~, BW (F); ~' tel. liver ~veight; ~ALT (Ms) (83 -- 84 vs 54 + 66 in controls; ,~cholesterol; ,Lsemm glucose; ]'serum urea nitrogen (no nricroscopic renal findings or changes in serum creatJnine); ]'severity of hepatic microscopic changes /serum co,ce~,~]# 0.(24/0.1~ admin dose EPA NOAEL 0.098/0.299 admin dose EPA LOAEL bascd on livcr histopathology Measured serum co~cenO'atiot~ @NOAEL was 4.0~/6.96 ug,)nL at week ~ 4 and 1.31/~.35 at week 105 [r-- Neoplastic effects: Ni hepancl sno (40.6.6. Males - hepatocellular adenoma (Ms 0, 6, 6, 28 17 need hod li 2, & 12% - positive trend); thyroid follicular ll &care men 10.1310 1, cell adenoma & carcinoma (10, 12, 10, 10, ES & 8.5%) Fen epoca sons 0.2.2 Females - hepatocellular adenoma (0, 2, 2, TR pansadh |cuca 2, & 8*% - positive trend), 1 carcinoma in Kibopp rod liar sms highest dose grp; thyroid follicular adenoma mo0,0n 00 420n Coch & carcinomas (0, 0, 0, 6* & 2%) & C-cell Sco ues30 14.13 108 adenoma & carcinoma (20, 14, 12, 16 & Em ectonsssoms 8*%); mammary fibroadcnoma~/adcnoma 636.938 25 ndcum) monis (38, 60*, 46, 52, & 25*%) and carcinomas (08,34273%1i:gh2b2ar.d8 (18, 24, 31, 22, & 23%) [high backgrd in Comet controls] Docu i dio poena Df dt Ss Ae PY Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FROST PFOS - 31 of 75 Candidate RfD mg/kg-d Reference (note limitations in comment filed) Thomford 2002, (Butenhoff 2012) and aci (US EPA 2016a) No cn,erage S~Fl2t~l concentration predicted by PK model in EPA, 20 l 6 HESD 22447766..00003311 sate onssenze STATE_07438126 Sty Den | Ne BG) be Sr SayFO UF Cai |i Study Description ri | ws Comoros mbes | ehh oe duration, route/ ces Ee wana [intima vehicle, species/ rin si| ove reser strain, age @dosing, Es | rare smn N/sex/group, etc. et ret amesr | owek Som 26 Week Stu@ Gmomnckos [0 eghoin| Iie Grobion ats | HARON Sn Cynomolgus monkeys BS 0! Soke Fab PFOS administered in tie [wees IRSEEIN0S) | wet a capsule by gastric x ra atbu am Rss, | ALONE intubation. ES wots || TaN bade (6/se~dose - 0, O. 15 smn |a Sra sia | Kt fer or 0.75 mg/kg-d & ew |B GEESTARINGT,,| 4/sex/dose 0.03 orem G6E | ard ior |deenimtr mg/kg-d. Two animals OTRO |Win | lin omar sie |e from 0, 0.15 & 0.75 an es Sn, otic mg/kg/day groups RAL {met| 1 hom tse were assigned to a oma wen | URGE | parioue. recovery group & SR en|Bi lids buOW. | were not treated for at Ewes | io, en coon [41 least 52 weeks Cepia | hime Ss following the last CH administration of ES EVRY | eles | dn. PFOS. stm | Sn, -- Study duration 182 ds s ePwTveagseoln smiewn||||m TeE eldem ehcnteoomo abnd moder| e| m|MDnHiBMmtDehosed days Admin Dose (mg/kg!d) [average serum conce,f 0, 0.03, 0.15, or 0.75 mg/kg/day Predicted AUC ug/mL*h 33,800, 166,000, 684,000 (no M/F difference) (EPA Table 4- 3) Average senlm concentration .... Predicted AUC ug/mL-hr (Table 43)/(182 d x 24 hr/d) .... 7.7 ug/mL Effect(s) Observed at each Serum Concentration (or Admin Dose) 7.7 ughnL - ,l, cholesterol (M/F 28"*/24, 3/19, & 68**/49%**, **p<0.01), ,~ HDL cholesterol (M/F 33"*/25, 24/36"*, & 79**/63%**, **p<0.01)) >_ 38.0 ug/mL - "[ abs (M!F 4/12 & 55/47%*, *p<0.05) & tel (M/F 12.5/17 & 69*/61%*, *p<0.05) liver wt; ~, T3 (M/F 12/22 & 48**/33%**, **p<0.01); "~TSH (M/q? 151/30 & 160*/82%, *p<0.05); ,1, estradiol (M!F <1/52 & 97**/73%, **p<0.01); 156.6 ug/mL - 2 of 6 males did not survive until scheduled sacrifice date; ~, BWG; liver histological changes (lnottled livers, centrilobular or diffuse hepatocellul~x hypertrophy or vacuolation); hepatic peroxisome proliferation (measured by PCoAO) signif "[ (but <2-fold) Drafi A1SDR (20~5) B34DL~o for absolute liver wt of23.28 ug/mL (HED 0.0016 mg/kg-d) but selected the NOAEL as the basts of the intermediate ~4RL. ?dDH BMD modeling using m,e serum concemmtion: BMD/B~VIDL ~o 29. 0/24. 7 uy,/mL (--0 0023/0~ 0020 mg~:g-c0 tel liver wt ~I); cholesterol and HDL did not model Study POOHED (mg/kg/d) (e.g. NOAELn~) /serum co,ce~,~]# 38.0 ugimL EPA NOAEL 156.6 ug/mL EPA LOAEL based on +BWG, ;cholesterol & ~'liver wt & histology but no clear evidence of peroxisomal or cell proliferation [NOA EL/L OA EL ~-~ 0.0031,,0.013 rag&g- 24. 7 ug/mL MDH BMDL ~ o 29. 0 ug;mL MDH BMD~o, based on rel liver wt [B3dDL/BMDn~,~.D O. 002 L/O. 024 mg/XN- Candidate RfD mg/kg-d Reference (note limitations in comment filed) (Seacat 2002) ~xad aci (US EPA 2016a) 38.0 156.6 4 week western-type TE [St diet study - APOE*3- {ae ERD my med Leiden. CETP Mice (a SEI strain that e:dfibits 0 or 3 mg/kg-d Signif ]. triglycerides (50%), total cholesterol (60%), HDL (74%), non-HDL (60%), & VLDL (only presented Da rarm iopi s. D Cttt o A Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy a Fath (Bijla~d 2011) and aci (U S EPA 2016a) PFOS - 32 of 75 276.0002 2476.0032 snarearse STATE_07438127 Study Description| Admin Dose |Effects) Observed a cach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete | sumcon ramon N/sex/group, etc. Bema bpp rR)Pa VLDeedL $5 humaxMikc lipoprotcin ln) ierprda15c72iToin metabolism) Admin Dose (mg/kg!d) [(werage serum concerti~ Effect(s) Observed at each Serum Concentration (or Admin Dose) graphically). Plasma VLDL reduced by 55% & liver production ~. 87%; "[liv wt. Study PODHEo (mg/kg/d) (e.g. NOAELn~) PROS was md | epi VLDL PFOS was found to + hepatic VLDL prion enn 0 ction production leading to ]" retention of egh ns) bones triglycerides (steatosis) & hepatomegaly. GasSeon suns vel. Gcnc expression was evaluated: overall, Sonsp1e 02od)l we hore genes upregulated (1- to 2-fold) were those ET ay v&e pen& involved w/fatty acid uptake & transport & Cash, honk bos catabolism; triglyceride synthesis; ioeSore, & VLDLrss cholesterol storage; & VLDL synthesis. Cncdomarge aohoS WHOL Genes downregulated were involved w/HDL ht, mara corse, ik ad syn/hesis, maturation, clearance, & bile acid Toms & soon 1 old or mosgn formation & secretion (1-fold for most genes 7 fo pn merdin to ~4-fold for genes involved in secretion). Nofhn od to a M~xb~ of the activated genes are assoc Waar reneX per (FR) 03 w/nuclear pregnane X receptor (PXR) to a tua nh PPAR greater extent than PPARa. Si Sb Sd rs Tam Single or 3 repeat dose Oral gavage stu@ - YousNat 09mgs |Thos do pp(ncn nmconn 0 0, Young Adult ConomotgnsMoskos | Gilecsn| 36 300 0 TO. 0 108. Cynomolgus Monkeys psa SDlooerit | & Basu) DLAI 6/seUdose Foocftuds wasn| (Teasampips aE pode Focus of stu@ was on Chg nn | doancSBeE |Nottshied hangin cr sams changes in serum Chm. |35835 | Re pramsweesch Doron clinical chcmist~~. Blouses were | Sram DL 114 (hitremnant Blood samples were prio |main| ogospebeReescdowish drawn prior to bie doingmd | SDS TISR | Dayna poet fs fo (baseline), during, mid ioral PEGS.| 120ml | thor conoct BMDmaligof HDL. up to 1 yr after PFOS Simnarmion|| S5o0bTHR,SD || fFina ano rcommoedfechanrl en administration SD = study day 0, 9 mg/kg (single dose on SD106) or 1117.2 mg/kg (three separate doses on SD43, 288, & 35~) Serum concen. measured on SD 8, 113, & 420 in single dose grp & SD 8, 50, 295,365, Single dose grp (lnean serum concen SD 113 &420-67.7& 14.1 ug/mL)- Three dose grp (me,'m serum concen SD 50, 295,365, & 420 - 104.8, 141.0, 160.8, & 130.5 ng/lnL) - ,~HDL (4 & 12% @l & 3 wk post-dose) No trt related changes in liver enzy~nes or kich~ey parameters were noted. Decreases in HDL & tT4 (while remaining w/i normal rouge) appeared to be associated with trt. Data was only reported in figure form. Authors conducted BMD modeling of HDL. tT4 was not considered clinically-relev~Jat for interpreting thyroid function by the Candidate RfD mg/kg-d Reference (note limitations in comment filed) (Chang 2016) Dr Docume for i dhs poe oh Df stFRdOoSs Tmt ns Agee py Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 33 of 75 22447766..00003333 sate onssenzs STATE_07438128 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | Study Description durian, route | Ag | Concatraion orAdmin Dose pe duration, route/ hide specs 6 NoAFLw) vehicle, species/ Srveido,sing| fre strain, age @dosing, Ne ete | s2Gomi0engasr ||SHologkalh Bmayionendreenee Eo ramon N/sex/group, etc. Admin Dose (mg/kg!d) Effect(s) Observed at each Serum Concentration (or Admin Dose) [(werage serum conee~v [~ & 420 in three dosing grp authors since they considered it reflective of biologically-inactive thyroxine. Study PODnE~ (mg/kg/d) (e.g. NOAEL~) /serum thor corNDemodde in Authors conducted BMD modeling using R5f D(ie. reoin of BAdR oflSD (Note: Bayesian analysis of Atondoakes wi pefmoreADdL background values was performedfor HDL, led AID mon CRC followed by B3/tD modeling): B~IC/BMC~ 104274230 0) 081487073) !04.409/74.259 ~t) & [06.!48/76.373 (F) ug~mL Shen hth mans 102 *Authors noted that halj:life estimations (J 02 ovcomea t st errrod to 124 days) were consistent w/those reported nic Th kes 10153 dr m single dose TK studies (110-!32 days) & rs rs nape or hin that no sex difference in uptake or elimination Cor pomonnehrts were obsem~ed (agait7 consistent with previous EsWor[Q. Tamgosta [0.5Tor [> andor) withDEL TT:k hExa 7 day garage study Clie | med Gsmcl ropens 77| EPANOAEL. C57BL/6 Mice 0, 5, 20, or 40 mg/kg-d TNi am 0 {G02S08pi iTPls(Peiyyedmemrooiyeemrm cs4a)oBdfhsWoeaant,nptpsLphroCeenosa Dissiooe8d:lrsfInrseNposKsinnoe.f||||||PEpsPPeeAeELSnOrfaNoenEmtdLibno)dll. 21 day immune Cgc | 002Smihg| comokyaiesclged wih challenge studyBUCH Nike han B6C3F1 Mice mdemest. 30 female miee/grp. Exped1dvs hen Exposed 21 days then 0, 0.005, or 0.025 mg/kg > 5 (adm dose) - ~" liv wt (34, 79 & 117%); ,~plaque-forming cell response (63, 77 & 86%) > 20 (adm dose) - q/BW, splenic & thymic wts; "]'serum cortieosterone; q, splenic & thymic eelluloxi.ty; 4,CD4+ & CDS+ cells (maxkers of functional cell types of spleen & thymic lymphocytes); 4,NK activi~~ (note no data presented for low dose grp) NA EPA NOAEL 5 (adm dose) EPA LOAEL based on liver ~vt & suppression of plaque-forming cell response 0.025 (adm dose) - ,1~ survival (17% \.s 46% h~ controls) when challenged with h~fluenza A Dr Docume for i dio ppnohDf stFRdOtSST sAe py exposed intranasally to Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 34 of 75 UF Can"diDdeo|rReeference i Candidate RfD mast |Commtmaeinontsiiend) mg/kg-d Reference (note limitations in comment filed) EbL Then L 2007 Zheng et al 2009 sina aci (US EPA Siw 2016a) Gamal Gumge et al BOS 2009 aci (US fosEPA 2016a) 22447766..00003344 sate orssenzs STATE_07438129 StudyDescription | AdminDose |Effects)ObsearcavchSeradm |Sindy POD | UF Candide| Reference Study Description durian,route | Ag | ConcatorrAdamiinDoosne aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Srveido,sing| fre Comment ied) strain, age @dosing, Ne ete | sumcon ramon N/sex/group, etc. Tops omg 100 plaque forming wn mass Avis units influenza A vires suspension. Comeddisc20 Observed for add's 20 days yogage {GOTT Soa hboywr hpn Fed dam 28 day oral garage Sis BCE Ne| OD0I7 01055 | yma ins ponresh, | 00082015 gn. a2 study - B6C3F1 Mice Nor 001700536|sd hmplocicposi erro | (F) FPANOAFL sens N:5/g Seddon? | amiespey ec sn o0ssnots wnt Bi Study duration 28 ans pPSSBooroOMTrroorirosNynaDoismotpDdnbnasosArU| C ||LSiWuepKnnsHcSSn2amileRtatsltTooiSd)aclci1iepnnaeAomimnLlyi1meEnp01gS2a4r(5eew1p1rhao57ns8anse09e5Ftd122sdo760e,emo0:11d65||E0iPtAsLeeOmeNEmsLibnagd days Admin Dose (mg/kg!d) [(werage serum conce, [~ 0, 0.00017, 0.0017, 0.0033, 0.017, 0.033, & 0.166 mg/kg/day Measure~(final S~I'Hm concentradons O'F) as reported in ~mbaugh 2013 O. 012 ]/ND, O. O178/0.0881, O. 0915/0.666, ND/~, rNO~, or ~/ND Predicted AUC Effect(s) Observed at each Serum Concentration (or Admin Dose) Survival, behavior, body weight, spleen, thymus, kidney, gonad ,and liver weights, and b~nphocytic proliferation were not affected by treatment. Lysozyme activ@ - ~ @ 1.83 & 9.14 ugimL (F) (response was not doserelated) NK cell activity - ~" (2-2.5 fold) 0.827, 1.65 & ~.24 (M) Splenic T-cell immunophenotypes - altered >_ 0.165 ug/mL (M) Thymic T-cell - " (F) 1.83 & 9.14 ug/mL SRBC plaque-forming response dose related suppressed (52-78% in M >_0.083 ug/mL & 50-74/; in F ;>0.915 ugimL Study PODHEO (mg/kg/d) (e.g. NOAELn~) /serum 0. )082~0.183 ugM~Ii, (M/F) EPA NOAEL 0.083/0.915 ug/mL EPA LOAEL based on +plaque forming cell response Candidate RfD mg/kg-d Reference (note limitations in comment filed) Peden-Adams et a12008 aci (US EPA 2016a) ug!mL*h 5.5, 55.7, 111, Simo 556, lll0,& ke)5540 ants (Wa~nbaugh et Sa a12013) Ave sm Average serum Dr Docume for i dhs poe oh Df stFdRoOstST ns Agee py concentration Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 35 of 75 22447766..00003355 sate onssenso STATE_07438130 SudDscrpion | Ni Do EG)Orne Serv Sy POD UF Cane | Rr Study Description - Admin Dose Effect(s) Observed at each Serum Study PODHEo Candidate Reference Stone | pha | Concur mins | noha Rf duration, route/ hte CNEL wha| Fmionnin vehicle, species/ (mg/kg!d) Concentration (or Admin Dose) (mg/kg/d) (e.g. NOAELn~) RfD mg/kg-d (note limitations in r3ids,o | ee commenit) strain, age @dosing, [average comment filed) vm | mean ---- N/sex/group, etc. serum concert/# i ....based on it AUC Predicted AUC Cig ug/mL-hri(28 d Hn x 24 hr/d) Sonsini 0.0082/0.0092 pieug/mL ion. 0.083/0.092, Sn 0.165/0.183, 0.827/0.915, tin, 1.65/1.83, sit 8.24/9.14 gee Touldoe 0 | FO TRRIL TB | On For Toy 60 day garage study TRCN[0% 85%50 | Sl pans CrANOALL omprion | mie C57BL/6 Adult Male ie 2 |r me cat | Ey Mice Re airings [tml ee| | [ee [FAS 10igrp Total dose: 0, 0.5, 5, 25, 50 & 125 mg/kg spn | ELON hr | ee SSutudd};dduurraatiioonn6600 it O2000308I5a0m41d7| .| 0HJDTadupAeTdnfL,eInNG| rome [a iLe fd | |oicnTe days | 00,, 00..000088,, 0.083, 0.417, 0.833, and 2.083 vay | sou secoutin | bommar ones |, A mg/kg/day Monon| TR BELOE 16305 on do cfg M~(lsHred.f]~lH] am| RCODNSN 72R0C3O DIS | Wo [--on mpereea xerum concentrado~s Serio| S moR ma(mCe e5I C20O1R9n O.3N1%| aiid [aes ErEe, ~) as reported bs a ey ro 25% po [204574 in Wambaugh Te | DNiR ecou 2023 so, 8 odor |r 0.674, Z 132, HEI ||amBtesanot pi i | Tans 21.63& 65.426, ois sro cho dabpia hvit d | or 120.67 EE pl ug/mL > 0.75 ug/mL - ~" rel liv wt (8, 12", 29*, 0.75 ugimL For (Dong 2009) 58*, & 122*%, *p<_0.05) EPA N OAEL [comparison and aci (U S >7.4 ug/mL - 38//o "splenic NK cell [purposes EPA 2016a) activity w/~ @> 73.6 ug/mL @35* & 7.4 ug/mL minim [only: 5,I~0S*RS%B,RCd-asBtpaepcCirfoicvsIiIdggpeMMd(ei@n-3fc3i00g%u%ir1et0of57)78;i5%%caatt | Eo0PnS ASRLBORCA&&EB LNN,KKbcC aceselelldl | LLaOlouAsE |i00..000000000066 Note: (Dong |rr2ee0pp1#l1c)carinteeddestshheeenssceee HDT, data provided in figure 7), ,LBWG response (9, 65*, 179", & 254*%); ~ rel spleen (8, 35*, 39*, 53*%) & thymus (14, 38*, WOA EL/ZOAEL~E~ cc5oe2ll*ll,ss&uubb5p9op*po%ulp)atwaiotlns:sa(;(stCCpDiDleA4on-i-nc1sC0,D21407,2/*7C,,D8 | rg dg] O. 00006 l/O. mg/kg-d] 00060 52*, & 73*%; DP - 16, 31", 49*, & 62*%; DN - 7, 22*, 32*, & 46*%; CD8 ~ - 5, 12, 34*, & 66*%; B220 ~ - 5, 9, 23*, & 33*%); ,[thymic CD4/CD8 O. 00146 mg/kg-d cell subpopulations (CD4 - 21,29, 41 *, & 56*%; DP - 23, 39*, 47*, & 61*%; DN - 13, 23, 34, & 45*%; CD8~ - 8, 23*, 36*, & 44*%) )36.9 ug/mL staffs signif ~,splenic & thymic cellularity (data provided in w/total I00 (3A, IOH, 3L).for compa rison purpos j(mmiraal i OAFZ i based) BMDL -based w/total UF 30 (3A, 1 OH) i0.000049 i (based on i BMDL ZSD effects, rl~e stu4v included an intermediate dose level (7 =m.~/kg total dos"0, coqfirming 5 mg&g as the ~otal dose LOA12L. 7bla! dose 1 mg//cg was a NOAbTL & supports a candidate Rfl) (f ~0.000006 mg/~N-d figure 4); & ,~rel kidney ll!, 18", & [ PFC) Pgs auc| 1S Predicted AUC ugknL*h 16*%) wt; oem nd pA 3 BR BSAS GSPT Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy Et PFOS - 36 of 75 22447766.0000336 craveerases STATE_07438131 Study Description | Admin Dose |Effects) Observed a cach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete | spWEISSCTATNP20v5raoe2eAomiSeerm0ab.mThmbcorad0saAg6ien00Arbn,a0ndUe,C||||||||||AmMa S7PB S EOa5otqkH%fercsspotc uiegA imp.iR tnon adoht o =epe0efroBi0rN2Mr nd8Saa(7To sDR3F1Bmr ChemD Cw1)ibme or rseehn8aoepetantpsnid egrspeg0eeiionr8hefdod ramon N/sex/group, etc. Admin Dose (mg/kg!d) [average serum concerti 1080, 10700, 53200, 106000, & 260000 (Wambaugh et a12013) Average serum concentration Predicted AUC ug!mL-hri(60 d x 24 hr/d) .... 0.75, 7.4, 36.9, 73.6, & 180.6 Effect(s) Observed at each Serum Concentration (or Admin Dose) ~ 73.6 ug/mL - 1~ food consump; signif ,~serum corticosterone (data provided in figure 3); ~, splenic lymphocyte proliferalion index EPA states that the SRBC-specific IgM plaque forming cell (PFC) response showed a dosc-rclatcd dccrcasc with statistical significance at _> 0.083 mg/kgiday (7.4 ng/mL). ~tDH con&tcted BMD~,w modeling of jimctional parwn e ter qi ~PF(." was also modeled, based on NTP data link BMD/BMDL ~ s> of 2 7. 65,'7g. 0 ughnL. Study PODnE~ (mg/kg/d) (e.g. NOAEL~) /serum Candidate RfD mg/kg-d Reference (note limitations in comment filed) ug!mL Tors anon | mghed | GTEC8 TG a 1, 3, or 5 day Oral nek mpm gavage - Male Se Dy Rae SC ad Sprague-Dawley Rats hy Lhe dn 385 N=5 10 mg/kg-d 4,tT4 (-47-80%) & IT4 (,-60-82%) @ all time points ,b(--23%) tT3 @ day 5 ,bCholesterol @ day 3 & 5 epsom, Mpc sero Hcpatomcgaly, hcpatoccllulax hypertrophy, onl esos Caos & macrovesicular steatosis. Genes oa rod omonaee associated w/thyroid hormone release & osab ie > synthesis path,say included type 3 od DIOS hh ce he deiodinase DIO3, which catalyzes the mision oT tye | deo inactivation of T3 & .type 1 deiodinase DIO] heh bos psormonTs4 0 DIO1, which bioactivatcs prohonnonc T4 to 3 DIO1 rprson & Ds nisin 8 T3. DIO1 repression & Dio3 induction @ ansday 5. Ti ors ses lk Meter The authors su,ggesled a link between FOR RS hrs PI,OS; PPAR, ~ lhyroM hormone homeostasis based on work by Miller et al. (wiv& on Fond (200 l) who observed d, serum T4 and T3 os 1 ep proersonlotn leveL~ & ~" hepaticpro#ferationfo/lowing co i r Po8 Df stos Ss Ae PY Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FROST PFOS - 37 of 75 Vaan Moxtin et al WTS 2007 aci (US fry EPA 2016a) 22447766..00003377 sate orssensz STATE_07438132 Soy Dsrpion | iis |Ei)Obed cach Serum [Soy PO, UF Conte| Rr Study Description dort rote|(ARD Concatnion orAd Do) | (gg) "fe duration, route/ Ld ENOL) athe Hains in vehicle, species/ cs sng,| fee Comment) strain, age @dosing, Niropse. | armen formes N/sex/group, etc. TG Sma | p o aCoiodertm h spethoatsemn r sn iTtnSRceoTdthi drFPe sE4nAemhReTnrR Cm 3 Day Oral study Fria cree SATE ERA Hower Fw or Evaluating carrier Joe SEwnh m1emDe win vo sen protein binding im ds hn ine rome ft interference Fond: pros Female SpragueDav i thri seesne 1} r mede ED iA Dawley Rats Admin Dose (mg/kg!d) [(werage serum conceder 5 mg/kg-d x 3 Effect(s) Observed at each Serum Concentration (or Admin Dose) exposure to peroxisome prolij~.rators. Ihey also noted that PFOS exhibited similarities to compounds' that ind~tce xenobiotic metabolizing enzymes d~rou,@ PPAR), & constitutive androstane receptor (CAR). No changes to serum TSH m~d FT4 when checked by & ED-RIA However, FT4 was signif 4, when measured with two analog methods, chemiluminescence immunoassay & simple RIA. Authors suggest reference method ED-RIA be usedfor serum ft'4 Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum SOR [Tis IG a ar Cm Single Oral Dose So Elan Say Es Stu@ Evaluating mies oc | Mess| 01860 820.975 36h) Eran serum binding protein me |r TST athe - Female SpragueDR |r| Jinn br ba in os Dawley Rats Ey "int | REG UGTA RRNA athe TYE 5-15 Sb rnd |Pg uc |S Study duration 1 day 15 mg/kg Measuredofinal concentration 61.58 ug/mL @24 hr Predicted AUC ,ktT4 (24% ~2hr; 38% @ 6hr & 53% @ 24hr) ~I'tT4 (68% @2hr & 90% @6 hr) 4,tT3 & rT3 @24 hr only ,kserum & liver ~-sI but q" in urine & feces q'ME & UGT1A mRNA @24 hr; q'ME activity @24hr Candidate RfD mg/kg-d Reference (note limitations in comment filed) Chm~g etal 2007 aci(US EPA 2016a) Ch~aag et al 2008 aci (US EPA 2016a) WSaamsaipa ug!mL*h 666 (Woanbaugh ct a12013) Average serum ThsTo aHDomieaisno CF TCTET lly ar00T Thyroid cross-foster ds | Shaan | 85 ne CTT dietary studyoon |SVEfos +| neo TT (04am) Pregnant Wistar Rats concentration Predicted AUC ug!m L-hr/( 1 d x 24 hr/d) 27, 75 ug/mL Doses not calculated and BW & :food CT, TC, & TT - ~,tT4 in offspring @PND21 & 35 (response in CT (71-75% of controls) & TT (63-64% of controls) Dooc r ndusm ion pe oss, Dr dct ost osAes py Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy os a PFOS - 38 of 75 Sra Yu et al 2009a Sin aci (US EPA Hien2016a) 22447766..00003388 erateerases STATE_07438133 Study Description|AdminDose |Effects) Observed acach Sram |Sindy POD | UF Candide| Reference Study Description durian, route | Ag | Concatraion orAdmin Dose aie "Dore duration, route/ hide specs 6 NoAFLw) mast | mtaionsin vehicle, species/ Sri, ve dosing| fre Comment ied) strain, age @dosing, Ne ete |somcon ramon N/sex/group, etc. Coed dur | compdon |p ser TCGOSTal Control diet or diet Coes 33mg |sopened | Soar containing 3.2 mg FrOSkgfood PFOS/kg food Pu crornsd Pups cross fostered Admin Dose (mg/kg!d) [(werage serum consump data not presented Thieme FOS ied 1 gh dgpon Wesson Thyroid hormone wor ps nyTEAS thBnd cs US ERA transport protein Tarn (TR) Th Bi transthyretin (TTR) ida is binding study Tours: EPAmtnhe 73 & Tabeahri Tested PFASs hemes copie is ods eonconcen3050 chemicals capabilib' romp wh 4 nt Bt r&er o for competing with T4 dapcig ormons over ei 04 t per820 & displacing hormone foe TR Hg aTG reo TT from human TTR Effect(s) Observed at each Serum Concentration (or Admin Dose) grps larger than TC (80-81% of controls) grp Study PODHEo (mg/kg/d) (e.g. NOAELn~) /serum PFOS raJaked 2nd highest in binding potency among PFASs tested. Binding potency ~-1/15 ofT4. EPA nows that +T3 & T4 obsem,ed in adult monkeys & rodents @ serum concen ~70-90 ugi)nL. But pregnant & neonatal rats' appear more sensiHve ~ t7V + appear @2040 ug/mL. But TBG O'ather than ~R) is the Candidate RfD mg/kg-d Reference (note limitations in comment filed) Weiss et al 2009 aci (US EPA 2016a) major thyroid hormone transporter m rats. Comments Simons Sr CR ROT 7 SPR el dS # Serum concentratio~s Serum concentration value are superior to external dose as a POD. Several studies measured serum concentrations at specific time imsEPA ered Kefoke UC Gert rt rh Co hd 4. Et COREE2 points. EPA performed PK modeling to calculate AUCs to determine an average sermn concentration for each data set. Average serum concentration l~s the oof rig th fot pont shot ra lor eo Tl 1 ROO wh Jr O d advantage of normalizing across the different exposure durations to generate a uniform metric for inter~ml dose in situations where the dosing durations varied as ns es meh pr 5 isSn ono os 1c oF + pod EPA Te 3 and serum measurements were taken immediately prior to sacrifice. Serum concentration dam listed are from publication or as reported in EPA Tables 4-3 a SEA oe through 4-8 (US EPA 2016a). IED maEpisDose cleby igi he vcssce coon 1)byhecasi Cl cons ca ols s fou 1 HED (Human Equivalent Dose) is calculated by multiplying the average serum concentration (ug/L) by the clearance rate. Clearance can be calculated from the mas Grn onJ 20 oa pn VO 0 2) 25 LAR 007 1571 00a] Abn rate of elinfination (derived from half-lili~) and the volume of distribution: Vd x (ln 2 + tl/2) - 0.23 L/kg bw x (0.693 + 1,971 day's) - 0.000081 L/kg bw/das.. merges in mn epssion dtds ~ Interspecies (animal to humm0 extrapolation denoted as A bts md sso Intmspecies variabilib, (variability witlfin human subpopulations - including life stages) denoted as H Dalabase uncertainty lhctor denoted as DB LOTaNON cumplLae LOAEL to NOAEL extrapolation denoted as L-Io-N Subronic-to-chronic extrapolation denoted as S-to-C Dr Docu for i dhs poe Df stFdRosOmSt sTinsAgeepk Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 39 of 75 22447766..00003399 sateonssenss STATE_07438134 anise Table 6-A2. RfD Derivation me --IE-- Critical study (source, date, rationale In this expedited review MDH has focused on key studies identified by EPA in the Dose Response Er Re Ta E, for the selection) Assessment of the Health Effects document (EPA 2016a) and has utilized the predicted average serum concentration as the preferred dose metric. The 2 generation study by Luebker et al 2005b was selected as the key study'. This study includes exposure over all life stages. MSoERe BMD/BMDL values have been generated by authors for several of the key studies. However, substantial a improvements have been made to the BMD software BMD modeling and therefore BMD modeling was also conducted by MDH when possible. Note: BMI) modeling results' were not reporwd (or utilized) in rE EPA 's 2016final document. Rationale for not using BMD modeling (the preferred approach) was not a a T) provided. 1)evelopmental endpoints were difJ}cult to mode! as suggested by t=7'A guidelines due to a iack Qf ind~vid~'al animaLqitter data for using the required nested models'. The non-nested results' are shown LE ER ./&r compa~qson pu~',~oses' on,~.v and do not represent true quantitative candidate po~n~s oJ'departure. Ct RA A summary of key studies (MDH has also included the 2002 study in monkeys) along with estimated average serum concentrations @the NOAEL/LOAEL or BM D/BMDL~ arc presented below a A SE T Study (duration) Effe{~ts Awerage Senlm Concentration (ug/mI NOAEL/LOAEL BMDL!BMD~'b Luebker et al 2005b 2 gcn study ~pup BW (F1 & F2) TT abicrata os | Ipwmon tng E TAT | es ADLAD Luebker et a12005a SpEe 1 gen study +gestation length .~pup BW 25/99~7 (F1) 6.26/25 (F2) ~i~;/)?//.~.~.~7.~].,>."/..~.~/>:.: 19.9/39.7 NA/19.9 A u~ao~" ~t3A ~DL.BA[I)_5) : 15/22~ (gestalion len~t0 13/19 mrButenhoff et a12009 DNT study Im]'motor activity & ,Hmbituation 10.4/34.6 a (pup BW P~ 5) [numerical data needed was unavailable ~H u~able to n~odel] NA en LL Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 40 of 75 sermon 2476.0040 ro STATE_07438135 i bmeetsin Thibodeaux el al & Lau et a12003 Developrnental study in rats ,hlmternal & pup BW ~pup survwal FT 17.6/35.1 ec in [N?)te: +T4 was Sie observed @NTO,4EL] Authors BMDL /BMD~: ir 2.814.1 (maternal BW)" | AST 1.0/4.3 (,bT4)~ 2.3/5.6 (fetal sternal defects)~ Sr 10.3/18.9 (pup survi~,al) ~ _,\IDH B3fDL/~BJ,ID fier 20.6/23.0 (nmtemal BW, ssonta emims 5.57/10.1 (materml IT4, BMR Sry, 20%) ffbr comparison pu~po~es Doug et a12009 Altered inunune 0.75/7.4 pamme|ers (minimal LOAEL) Bee SeSneaccaartceitaall J2o003 TiLieverreeiftfescttss ((M3s)) WE 16.5/64.6 Sa NA i ii | TERN 14 wk time-point within 2 ]'ALT & BUN a yr rat study Seacat et al 2002 ]'liver wt & hislopath; 38/157 MDH BA,IDL/BMD~o: Ci a | NE ie 6 month Monkey study ~BW; $T3 & TSH 24.7/29.0 (rel liver wt) rere Se NOTE: BMD/BMDL values reported by authms were for administered dose anti used older BMD softwaxe. MDH estimmed average serum concentration that corresponded to the BMf)iBMDL administered doses by using the relationship between the ete p Cr r ir average serum concentration and the NOAEI, or I,OAEI, administered dose which xvas consistent within a given study. See ESe R IIIS Admin dose to Serum Extrapol spreadshcvct, iVIDH conducted BMD modeling using most recent software a~d used predicted average serum concentration as the dose metric. TRARY he 5 1A isM Sil ~ MDH BMD/BMDL modeling reports can be found at \Oata3fb\ch~lLRA\COMMON\.Guidancc - WatcrYfox reviews- NL .o_.*_~ ~_I._e._Le_._~_.W_._i~_~0N!_F_ L~)~.~Z ,.x_.J 9._._d_~ !.*_~.. Cotct am dos: tc 205.82085p redpo BY sada do of hd Critical effect(s) and dose: OE C(OSNLtEserrFeenai Lohe5ti nreoerdheLoO52yR5Emig)mfoNmrmOehPepRdertdeEsoomFeopgAo 5DhooplsoEithaoe33dt-20E00aP0S3vvanale) (LOAEL~.:~)/BMD,{r~o) Luebker et al 2005a & 2005b - reported decreased pup BW @ an administered dose of 0.4 mgikg-d (LOAEL) and decreased pup survival @ an administered dose of 0.8 mgikg-d (only a 2-fold difference). The average serum concentration at the LOAEL for the 2 generation study (Luebker et al 2005b) was calculated by EPA to be 25 ugimL (or 25 mg/L). MDH conducted BMD modeling using EPA's predicted average sermn concentrations for the dose metric. Resulting BMDo5 values were 19.9 ugiml (F1) and 9.64 ug/mL (F2) for decreased pup BW on PND 7 (time-point of largest effec0. ito Dias Th NOME rt con vm tidds 0thd dts ss ri Point of Departure The NOAEL for the 2 generation study was an administered dose of 0.1 mgNg-d and the average serum ttt eos hteEFArab So 638m) MO snd concentration at this dose was calculated by EPA to be 6.26 ug/mL (or 6.26 mg!L). MDH conducted Da rasm ci pi ape.Do StSE AB Fol Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy ES PFOS - 41 of 75 24760001 2476.0041 erate arses STATE_07438136 (NOAELLc.LOAELws. BADmodeling wig EPA's precited rae sr encnratons othe dose tie Resin (NOAELHE>, LOAELHED, BDL) tNCBoODorRLiEoLrvooasurgiah24aowurFnge2 .b1heh0c5ommprh(oe1s)adde5g0r1o1uwpmi.Ohf(B3FN)TDBomrradilon.tsThpyohd OcBnNitcnoePnrteNsDstsrHwgompesr BMDL~..~) BMD modeling using EPA's predicted average sermn concentrations for the dose metric. Resulting BMDL05 values were 16.8 ug/ml (F1) and 5.91 ug/mL (F2) for decreased pup BW on PND 7. However, due to low survival in the two highest dose groups in the F 1 generation only two treatment groups were carried through to F2 which compromises the utility of BMD modeling. The modeling results support a NOAEL of 6.26 ug/mL. mn Euivalen Dose Th lovingsquaion is sed ocaluatnHEDfrom ths POD sum concen' Human Equivalem Dose "Adm HChEoDln(engVsel)o DPOiD..s. tbx(lLia1n2ehom.a nF6L) 0)23Lg 06931974)1- 0008 Lig Adjustment: The following equation is used to calculate an HED from the POD serum concentration-~: HED (mg/kg-d) - POD ................ x Clearance. Where Clearance = Vol of Distribution (L/kg) x (Ln2/human half-life) = 0.23 L/kg x (0.693/1971 d) = 0.000081 L/kg-d HED = 626mr 0000081 L=0i 081md pg HED = 6.26 mgiL x 0.000081 L/kg-d = 0.00051 mg/kg-d ncnVaal Fors. EVxnlaiepnencgiee:ss 310 SibLchoNoCrnohiEcniLiisca: NNAA oDnue.ss 3 Uncertainty/Variability Factors: Intcrspecics 3 Extrapolation: hatraspecies 10 Variability: LOAEL-to- NA NOAEL: Subchronic-to- NA chronic: Database: 3 Other: at 100 Total1: 100 FUIFiVVEF Comms Comments: Inspcis UFofS ppd 0aTd D fls rsand in theses ofhia information tothe h~terspecies UF of 3 applied to address TD differences mad in the absence ofchemical information to the Cony he def ueof 1fore Vb. Adin ecaeh ern contrary, the default value of 10 for Intraspecies Variability. Additional research regarding mmm braid. Dong5110 poe A NONELILOAEL ser nl 077 4 immunotoxicity is warrmated. Dong et a12009 reported a NOAEL/LOAEL serum level of 0.75/7.4 JL Te LONEL waseosin widirest mens mrkcr5. SRC IM pl: ggilnL. The LOAEL was associated with decreases in select immune markers (e.g., SRBC IgM plaque Forming vithsignif eres im phe mikes he ed dost ve1p (369 in) The forming cells) with significant decreases in multiple markers at the next dose level up (36.9 btg/mL). The LOAEL Som coschrofa74ipognm. Amaragtso crcl stds NOAEL um. LOAEL serum concentration of 7.4 gg/mL is similar in maguitudc to the critical study NOAEL serum Teel 626712) iescoos ending poet ima soppesion Inideo, cscs level (6.26 ~ag/L) and raises concerns regarding potential immune suppression. In addition, effects repr inDorc1 201 1hh ciacdceddr,po3LOrRFL 07421 30d rcportcd in Dong ct al 2011, which included an intermediate dose, support a LOAEL of 7.4 gg!L and a NOREoLf 2 Someitls a usted ssocision eee sr concernnd NOAEL of,~2 ggiL. Some epi studies have suggested an association between serum concentration and monn pr sh 3 od A as,Po. Sans et Conant immune paramctcrs such as decreased antigen levels, however, the associations havc not bccn consistent Son tes a pe es angpeg hath outcome acon) across studies and specific studies examining pathogenic health outcome (e.g., increase in infections) on lod fod cnt ors ors. Th sc TFmonogiphand psrv sone have failed to find significant correlations. The recent NTP monograph and peer review concluded that 1 eofd sppresedn ad sorsfo nlSs wandhsthhnn tls the evidence of suppressed antibody response from animal studies was high and that the human studies vie moderato of pstk FOS it wl pd ortion of rcension provide a moderate level of evidence that IPFOS is associated with suppression ofthe vaccination pons Epmogedesnetfc dt bc 3 nou deco acs aman A response. Epidemiological evidence to date do not indicate a fimctional decline in disease resistm~ce. A FCF of hahc pli 0 es Gos AAG an pn DB UF of 3 has been applied to address concerns regarding mmmne suppression3. MDH RID: 00051-01.00000081 me respocanmcdonicnng 26100-0061| MDH RfD: 0.00051/100 = 0.0000051 mg/kg-d [corresponding serum concentration 6~26/100=0.063 ug/mL] Commons Comments: Dr Docume for ie dcpo oeoD scads tin Aces pOKY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy FROST PFOS - 42 of 75 22447766..00004422 sate grssensy STATE_07438137 tn tt i it Total UF for derivation ofa HRL or HBV RfD is _< 3000 (RAA could be _< 3000 or > 3000) E t er n : US EPA 2016 Lifetime Health Advisory Evaluation CUSEPA 2016d): t IR tno me Predicted serum concentrations are converted into an oral equivalent dose by recognizing ttkat, at stead)" state, clearance from the body equals the dose to the Slbp am en body. Clearance (CL) can be calculated if the rate of elimination (derived from half-life) and the volume of distribution arc both known. EPA used Olscn ct al. BS (2007) calculated huluan half-life of 5.4 years and the Thompson et al. (2010) volume of distribution (Vd) of 0.23 L/kg body weight (bw) to determine a EE clearance of 0.000081 Likg bwiday using the followiug equation: estatcen henAn CL = Vd x (ln 2 + tkl) = 0.23 Likg bw x (0.693 + 1971 days) = 0.000081 L/kg bw/day tJq~ere : Hee Vd = 0.23 Likg In 2 = 0.693 EEsrt rine t~,4 = 1971 days (5.4 years x 365 days/year = 1971 days) ae Otfe Multiplying the derived average serum concentrations (in ggilnt) for the NOAELs and LOAELs by the clearance value predicts oral HEDs in lng/kgidW for fmm each corrcsponding scram measurement. The HED values am the predicted human oral exposures necessary to achieve scram concentrations equivalent to the BE Se NOAEL or LO~M~L in the animal toMci.ty studies using linear human kinetic information. [MDHNote: this is the same equation used in the MDH 2007 I evaluation to estimate HED values. Parameter values u.'ere identical, ~'ith the exception c~Vd which ~'as 0.2 Lg:g instead of 0.23 L/kg:] yO et 117 ; Imnmnotoxicit-y is an identified hazard of PFOA and PFOS exposure (as determined by NTP, 2016 aud in MDH' s identification as immune changes as a coSE a i Sts T Sor, y critical effec0, however, the lack of dose response and indications of immune system deficits in functional responses to pathogenic challeuges in even highly exposed cohorts, tmmpers quantitative inclusion of the effects observed in epi studies in deriving a reference dose (RtD). The presence of nmltiple perfinorinatcd rT compounds in human serum worldwide hampers the ability to determine the toxicity from a single chemical. However, "the epidemiological lilerature provides a ee Le oo er ep clear indication tlmt the additivit-y of PFAS is strongly' associated with inmmnosuppression. Coupled with these obser,:ations in human studies, alterations in i aulmal immune fnnction in response to sheep red blood cells has been shown "to occur in replicated studies (e.g., Dong, 2009, Dong, 2011) at serum TI concentrations near the point of departure for the critical study. Therefore, MDH will include a 3-fold database uncertai~W factor. MDH's current practice of FE R E el STR Ty SeEte comparing drinking water values to a composite hazard index of PFOA, PFOS, PFHxS, PFBA, and PFBS is well-justified and confers additional health protection bc~mfits in the context of risk management, and underlies the choice for a 3-fold DBUF versus using a higher uncertainty factor. comers sy CRITICAL/IKEY STUDY SUMMARY PRCritical Study(s): Luebker et al 2005b fn (from EPA, 2016) EE nn 2 Generation Reproductive Study- Rats PEA +een CIC tcp mtn Doses: A two-generation reproductive study was conducted in Crl:CD(SD)IGS VAF rats with five groups of 35 rats/sexigroup administered 0, 0.1, mm 0.4, 1.6, or 3.2 mg/kg/day of PFOS by gavage for 6 weeks prior to and during mating (Luebker et al. 2005b). Treatment in males PE EE I continued through the cohabitation interval, ,and females were treated throughout gestation, parturition, and lactation. i J ee aF prarB y ottTTsRcn Effects: FO: In the F0 generation male rats, mortality, clinical signs, and mating/fertility parameters were unaffected. During pre-mating, ne decreases in terminal body weight, body weight gain, and food consumption occurred at 1.6 and 3.2 mg/kg/day in males. The only effect te et Eema Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 43 of 75 no 2476.0043 ae rons STATE_07438138 on eightofthe nan ltl wiag fsan chon ie abst wghofbs inl sls (ih Fl nd prosin on weight ofthe organs evaluated was a significant reduction in the absolute weight ofthe seminal vesicles (with fluid) and prostate in rerd32 mA Fc Frara, here Wee 20 dhs dn ft 0 he prac pres nrales adlninistered 3.2 mg/kgiday. In the F0 generation female rats, there were no deaths and no effects on the reproductive parameters mesure bhdams coe00dID, 10a ho ledHodnr rly ToFOdamdimtrd= mgd od measured in both dams sacrificed on GD l0 and those allowed to deliver naturally. The F0 dams admini~ered _> 0.4 mg/kg/day had Tocalzedlose dunn rcmaig. estonia, a 3dca mb weighand ood onsumpicn. localized alopecia during pro-mating, gestation, and lactation, and a decrease in body weight and food consumption. Fi Generar Te serpupiiaoin was significa duced 163 m3ghgddo, hrfnly e001 Fl Generation: The F1 generation pup viability was significantly reduced at 1.6 and 3.2 mgikgiday, therefore only the 0.1 and 0.4 mah os rou rs ami th com Enron Tweo-Te F1 she Goss velr od, 01,010 4megda mg/kgiday dose groups were carried imo the second generation. Twenty-five FI rats/so,dose were administered 0, 0.1, or 0.4 mg/kgiday TPFOS by aa ae bing natn on posal dy (PND)2snd contig unl arc On tse vas ded 3 of PFOS by oral gavage beginning at weaning on post-natal day (PND) 22 and continuing until sacrifice. One rat/so,litter was tested in a PAS vanspri 1 4 dysof adg oo. SCV Wa cat 3 ar ld nar PND T0 On PND 2, passive avoidance paradigm at 24 days of age and one rat/sex/litter was evaluated in a water-filled M-maze on PND 70. On PND 28, Fone wre rato frag psc a. PND 54 slswerecx forprepil eparon On PND 0, ats weesignd females were evaluated for vaginal patency and on PND 34 males were examined for preputial separation. On PND 90, rats were assigned Wi cachdoe group tocision,adanc ond preg. the Fleweehowdnau. The FI genesnal ras within each dose group to cohabitation, mad once confimaed pregnant, the females were housed individually. The F 1 generation male rats Nee esdahrmong Prope, ad vada dened 0FOscraion ALFl enraion males wre aimeda were sacrificed after mating, necropsied, and evaluated as described in the F0 generation. All F 1 generation females were allowed to intandwes enon sdepon LD 3. deliver and were sacrificed ~d necropsied on LD 21. Mora oscnuhIrofspridng ofdonsafin | 02m3 ei At 16 ghey ocr 26h4e o0pewfes ford Mortality occurred in the FI offspring of dams administered 1.6 or 3.2 mg/kg/day. At 1.6 mg/kg/day, over 26% of the pups were found ad ocDean At 35mg, 450th pps wc fod cag LD 1 th 10%did LD2 The dom th dead between LDs 2 and 4. At 3.2 mg!kg/day, 45% of the pups wcrc found dead on LD 1, with 100% dead by LD 2. The dams dosed with mpd sho hd nat mcr Shp and NI A Wa 3 mgd30d 647 1 og 3.2 mg/kg/day also had a significant increase in stillborn pups and the viability index was 0% at 3.2 mg/kg/day and 66% at 1.6 mg/kg/day. To conex wk 04745 AA, A 3 mgd, THE Wer BC Es Ganeg 3nd merof The lactation index was 946% at 1.6 mg/kgiday. At 3.2 mg!kg!day, there were significant decreases in gestation length and number of plaation he nd edocs 1 a 7. Scrot s Po lO sa GSS hs Bhs implantation sites, and reductions in litter size. Statistically-significant decreases in pup body weight were also observed at the two highest oss sons ene cet pps 32 hey cloded mpocts on acai 1, hh ur [5] pops10 rg doses. Additional adverse effects in pups at 3.2 mg/kgiday included impacts on lactation (i.e., high number [~ 75%] of pups not nursing Sot vag milk pect Hooch), EEA sn oF hom Pap,gh dr ofmtr oO and not having milk present in the stomach), an increased incidence of stillborn pups, and a high incidence of maternal cannibalization of wep the pups. Inthe Fl gcc offpn, pops admits 3 mggocou alybi xaon LD | de tih gh moe rt. Alisbc In the FI generation offspring, pups administered 3.2 mg/kg/day could only be evaluated on LD 1 due to the high mortality. All viable pup fot he 6 hee 1o0phd mc (p< 005or 1) dead penn. pm ns, ok gh dar pups from the 1.6 mg/kgiday group had significantly (p < 0.05 or 0.01) delayed eye opening, pinna unfolding, surface righting, mad air ing ag cao, No dee <1 hed ne dinar is <4 ORGS Se 3h 3s ot Cd righting during lactation. No delays were observed in rats administered doses _< 0.4 mg/kg/day. Sexual maturation was not affected in the 1am mgaprops ac caning Th sus omthe passe avon(Sng 34 ysof) od warmaze 0.1 and 0.4 mg/kgiday groups after weaning. The results from the passive avoidance (beginning at 24 days of age) and water maze tests (OSE 70 af 56for movin fc showed 5doe cdlich onFes nd meron (beginning at 70 days of age) for neurobehavioral effects showed no dose-related effects on learning and memory. Sins FI gncationgp ibility was signal sac inde 162d 32 mgAdy dos oops, oy te 013d 0.4 phy dos: Since F 1 generation pup viability was significantly reduced iu tile 1.6 aud 3.2 mg/kg/day dose groups, only the O. 1 and 0.4 mgikg/day dose a_i gan, groups were carried into the second generation. 2Genera1rpsc ial isa no lcd siofmnorasl. Food cnsumpiwoans sms dered i Flmes,bs !,2 Generation -F 1 parental animals displayed no clinical signs or mortality. Food consmnption was traaasiently decreased in F 1 males, but va ofc nF ton Reprod prorat as affect Fda All Fene pops were src it was not affected in F1 females. Reproductive performance was unaffected in the F1 dams. All F2 generation pups were sacrificed, oxciandoampineeda,nLD21 presided oth FI gion pups iFgen pe Rineanspo necropsied, and examined on LD 21 as previously described for the FI generation pups. In the F2 generation pups, decreases in mean pup di wer Ghrs ed301 m/o o4D 0807. 1550 PpBo 8 We slr 10 Gl by LD 11 Topp body weights were observed at 0.1 mgikg/day on LDs 4 and 7, but mean pup body weights were similar to controls by LD 14. The pups in 18201 hei group duped gna dss ibody wightonLDS 7-143 LD 21 bd wghts eine ow a the 0.4 mg!kgiday group displayed significant decreases in body weight on LDs 7-14; after LD 21, body weights rclnained lower than Soto, bts sca SEA.No hr ested ts netobec controls, but were not statistically-significant. No other treatment-related effects were observed. Dr Docume for ie dcpo oeoD scatds tin Aces pOKY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy FROST PFOS - 44 of 75 22447766..00004444. stateorssenss STATE_07438139 FO NLOOAAEELL=0=.01.4mmpagdd. bedon dsinsbody weight ssn F0 NOAEL = 0.1 mgNg-d LOAEL = 0.4 lng/]~g-d, based on decreases in body weight gain FI NO=A0.EmpiLgd F1 NOAEL = 0.4 mgikg-d LOAEL~ 1 miebseontein dase spp ily, pup cit md sia LOAEL = 1.6 mg/kgiday based on the significant decrease in the pup viability, pup weight, and survival F2 NOAEL=0. mpg F2 NOAEL = 0.1 mgikg-d LO~0N.4 ELey, bdonthe aes ni es pf p body night LOAEL - 0.4 mg/kg/day, based on the significant decreases in mean pup body weight Conciiel Co-critical Sudy: Study(s): Developmental study in Pregnant Spraguc-Dawlcv Rats (Thibodcaux ct al 2003) Goa F516 eseSpgsDo rt were aed 0.1.3.3. 0 10h PEOS in 05 Tc20ediy by ogo uri Goups of 9-16 pregnant Sprague-Dawley rats were administered 0, 1, 2, 3, 5, or 10 mg/kg PFOS in 0.5% Tween-20 daily by gavage during Eeuaton] dys (GD) 30 Naar a sr soncranons: 14 55,700.33 & 149.4 ug EPA mocked memes rn gcstational days (GDs) 2-20. Measured final serum concentrations: 19.69, 44.33, 70.62, 79.39, & 189.4 ug/mL. EPA modeled average serum Eoncmion 176 351,216.17, 175 ng. Rot wrcutbaadGoD0 31and anscotamisn concentration = 17.6, 35.1, 52.6, 879, and 175 ug/mL Rats were euthanizcd on GD 21 and uterine contents examined. Nirah wih. foc consmpioan krcmurpiwoins gran dra(1 001) i don pendentmsec > 2 Maternal body weight, food consumption and water consumption were significantly decreased (p < 0.0001 ) in a dose-dependent manner at R 2 moe LAC nighwta motcedthe red a.Scrchert showed infidels (kes of 1ccompared mgikg Liver weight was not affected in the treated rats. Serum chemistry showed significant decreases in cholesterol (decrease of 14% compared oil)an hgh Sedo eatsof compre col) 10 mks Som ous 1 T3 wee gms doce to controls) and triglycerides (decrease of 34% compared to controls) at 1 () mg/kg. Serum thyroxine (T4) ~d T3 were significantly decreased in etdrt hencompre cool, hover edb Foon cn TSH wan cbc. The muomf pblaetsorns or ns ts all treated rats when compared to controls, however, a feedback response on TSH was not observed The number of implantations or live fetuses at {ema ot afcby smn Ts a 3 ras1 tl ih,and bthdfs ch CI Rt, pldich 00 term was not affected by treatlnent. There was a decrease in fetal weight, and birth defects such as cleft palate, ventricular septal defect, and egetofthe gh ram er Sarl3 10 EAE. ot HAS ns EE enlargement ofthe right atrium were observed at 10 mgikg, bnt the litter incidence rates were not given. `Conductedinorderto caninethepostalimpactof ner Developmental study in Pregnant Sprague-Dawley Rats (Lau et Conducted in order to examine the post-natal impact of in zttero expos 0 POS. al. 2003 - - companion exposure to PEOS. study to the one Se by Thibodeaux et al. -2003 above) On GI 33 dre n moms rsofparen dams admmsared 10 gh do, the stsbecamepl, nc, ad ora On GD 22, dams were monitored for signs of parturition. In dams administered l0 tug,g/day, the neonates became pale, inactive, and moribund in30-60 mieof s sd ded. nS mgaconte an morstr i12nsd, wth vis hn he st within 30-60 minutes of birth and all died. In 5 mgikg/day danas, the neonates became moribund after 8-12 hours, with 95% dying within the first 24s S07 id moray was cbr us amid mgd Pps Fro dae cstod wih no ld At 24 hours. A 50% fetal mortality was observed iu dmns administered 3 mg/kgiday. Pups from dams treated with 2 mgikgiday still had significaut {aicreie.ss ds dr | AY were i cos No ris wreOrd ne wth hh increases in mortality, but those from dams administered 1 mgikg/day were similar to coutrols. No differences were obse~wed in liver weight in the conte. Popbod wht wi snarls esd bums aired 2 gn phe <005) ds 1 5cpg neonates. Pup body weight was siginficantly decreased in dams administered R 2 mgikgiday. A siguificant (p < 0.05) delay in eye opening was cial h me die he pop.btniece ant of puberty nsorc tk dos. 04PND 2 erofa btn4. observed at the same dose in the pups, but no differences in onset of pubeity were observed at that dose. On PND 2, serum levels of both total T4 nTd 4wir re r sgnfly 1 he etd ops,bt OT ond10 vl sr hoseof co ols mes No and free T4 were decreased significantly in all the treated groups, but total T4 recovered to levels similar to those of controls by weaning. No hmges wesober 0 eam Tor TSH. Chin tna cis mh Tonal Ios, hich mie dod sa, ak changes were observed in serum T3 or TSH. Choline acetyltransferase activity in the prefrontal lobe, which is sensitive to thyroid status, was Shi eed pops, ky he ppc wast. si5dnot err an. srg defence Bcd oh slightly reduced in rat pups, but activity in the hippocampus was not. T-maze testing did not demonstrate any learning deficiencies. Based on the dings. olor LONE 2 mais PROSfrmort, 5eied bok nigh nd3 non 1-6 5 35 penbs findings, the developmental LOAEL is 2 mgikgiday PFOS for mortality, decreased bo@ weight, and a significant 1-day delay in eye opening; the NOREL | mgdo.Thesors cat3 eMDdL ford svn of02 mh NOAEL is 1 mg/kgiday. The authors calculated a BMDL5 for a 6 day survival of 7.02 mgikg/day. Dr Docume for ie dcpo oeoD scaFdRsOtSiT n Aces pOKY Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOS - 45 of 75 22447766..00004455 state grssereo STATE_07438140 DussopnnlGsSn CLCISDIGSVATRate Lush ct 20050 Developmental Gavage Study Crl:CD(SD)IGS VAF Rats - Luebker et al 2005a Rm (a2rt p)eso ksprosmain oh D4 Adm Srp cool. 20mg deny wer don GORY Animals (n=-20/dose) were exposed 6 weeks prior to mating through LD4. Additional 8/grp in control, 1.6 & 2.0 mgikg-d only were sac'd on GD20 or meme Dot ou 3.0.3: 03. 0.1311 20mhgg. Ser onwe smtps es win. FAmaedrieedn for assessment. Dose groups: 0, 0.4, 0.8, 1.0, 1.2, 1.6, & 2.0 mg?kg-d. Serum concentrations were not measured, however, EPA modelled average serum Coenvass 159,397.19, 95. 71 ad 3 Tug. concentrations were 19.9, 39.7, 49.6, 59.5, 79.4, and 992 ug/mL. Nm Eas Nomar,oeurd sd ao ct erasdeed parame (por i. mploation, se) ise Maternal Effects: No mortalib~ occurred oJad no effects were observed in reproductive parameters (corpora lutea, implantations, fetuses/litter) in those as ein Coto. noe 0p nnd onLD.5. rah do ge eosh cnn 3 rr05 he Orel dams receiving C-sections. In the group sacrificed on LD 5, a significant decrease in gestation lenglh was observed at doses > 0.8 mg/kg. Overall mndy wei o hedams eedhg 5 kBcn 10d mg ro dot dm absolute body weights of the dams were reduced slightly (5%-7% of that [br the controls) in the 1.6 and 2.0 mg/kg/day group dams during Sean: charsgh ht nrAA, rc ody veh hang wt gcere (p10 or 001) drs gestation; the changes, although slight, were statistically significant. Body weight change was significantly reduced (p < 0.05 or 0.01) during remain oka eysd dun cn 3 mg Fad comps owed <i ved ih cadisanne. premating at 2 mg/kg/day and during lactation at _> 0.8 rag&g/day. Food eonstmaption showed a decreasing trend ~vith increasing dose during main. aio nd can Fda mad dint Td plapir ns cr:stan nn. ns rs pre-mating, gestation ~Jad lactation. For dams allowed to deliver, the fertili~ index, implantations per delivered litter, gestation index, live births, pwee e nr cned cooldo. Ft oe ronsFo ert vm ho rl Ob and delivered pups/litter were similar between treated aJad control dams. Flat dose-response for decreased serum cholesterol was observed in re me 1B 250 50 300 & 0, p00w)i rome eb er ap05 ha treated animals (16"*, 24**, 25**, 23**, 27'*, & 23%**, **=p<0.01) with increased relative liver weight reported >0.8 mg/kg-d. Delo Els Olin bly vadeisoddri 0 mp nd vas asic ypc 2nd 20 mp Th ily nds Developmental Effects: Offspring viability was decreased starting at 0.8 mg/kg and was statistically significant at 1.6 and 2.0 mg/kg. The viabili~ indices te 370 BR Wo 1335 a7 1h 0 18 1013.16 30mg. pe petot wri, were 97.3%, 97.6%, 93.1%, 88.8%, 81.7%, 49.3%, and 17.1% at 0, 0.4, 0.8, 1.0, 1.2, 1.6, and 20 mg/kg, respectively. Lipids, glucose utilization, dbo nr mra hi en or vad ina Compe Goro. n Sc a Pop WY Was BET and thyroid hormones were similar or slightly different for treated animals compared to controls. In all treated groups, pup body weight at birth SRD Svat gman hn kf on do le nd ns fePpt. i dntsd ltd md on PND 5 was significantly less than that of controls. In one male and one female pup at 2.0 mg/kg/day, the heart aJad thyroid were collected and medmarioa. No oe <5 ound Whe oS cm exmnined microscopically. No lesions were found when compared to the controls. BNTuGraissSmsinff0g0m DNT Gava.~e Study (Butenhoff et a12009) Fema Sr DisRte (rewes one GD04sPND 20.0.1, 0, 10 mpyi. Messed src dio stn Female Sprague-Dawle3, Rats (25/dose) were exposed GD 0 to PND 20 to 0, 0.1, 0.3, or 1.0 mg/kg/day. Measured final sermn levels during Gestation: 1720 20 ag md Gntl 16198 850.4% bn. EPA mold neg tenn emerson Coton3 60 420 1.72, 6.245, or 26.63 ugimL and Gestation + Postnatal: 3.16, 8.98 & 30.48 ug/mL. EPA modeled average serum concentrations: Gestation - 2, 6.0, and 20 Com an Gotan PND... 10, 347 vgn. Open rors ugh P72 ug/mL and Gestation+PND - 3.5, 10.5, and 34.7 ug/mL. Offspring monitored through PND72. Nin Ect gh btpos ssa sigan ies nh wight Maternal Effects: slight but not statistically significant decrease in body weight gain Devon Es No reinetbiod Fact 4s cred sn staal haabnry asscsns promson NDS, 1,21, 3.45. Developmental Effects: No treatment related effects were observed on functional observational battery assessments performed on PNDs 4, 1 l, 21, 35, 45, 26Nic fying rdo at ano 13 i 1) hdst i 15) mrs mor S01. 31 AD and 60. Male offspring from dmns administered 0.3 and 1.0 mg/kg/day had statistically-significant (p < 0.05) increases in motor activity on PND tui ss arAdD15.3ar1 Nolinb ns nea l he 03h mks ce 10 17, but this was not observed on PND 13, 21 or 61. No effect on habituation was observed in the 0.1 and 0.3 mg/kg/day males or in the 1.0 mgd fm On PND 1, mkt 5 mgshowed lkofbaton vbrdbo sgn (5019) scremd sii mg/kg/day females. On PND 17, males at 1.0 mg,&g/day showed a lack of habituation as evidenced by significantly (p < 0.05) increased acdvity toh Semetlof 163, 31-24m6 ls Th al bso rps ott he hhh counts for the seqnential time intervals of 16-30, 31-45, and 46-60 minutes. The normal habituation response is tbr motor activi,t,ty to be highest Ohh lFr n rchtormr nd 4 ug A RIEfh at ct 0 oh when the animals are first exposed to a new enviromnent and to decline during later exposures to the same environment as they have learned hati ott The werte bo emake 0 sot rl Eeof Bl mn1h Nesssh sl what to expect. There were no effects in males or females on acoustic startle reflexes or in the Biel swimming maze trials. Mean absolute and RE ht ey re wh db retnh lh) es Btn he on dd Sl relative (to bo@ weight) brain weight and brain measurements (length, width) were similar between the control and treated animals. Lon DecShe pChemn11e201n2) Lung Development Study (Chert et al 2012) Sprgoc DaonRes (Nopwre exude GDI21 0.0.1, or 2mh. Ofspein wes scifi at PND21. iss Sprague-Dawley Rats (N-6 offspringigrp) were exposed from GD 1-21 to 0, 0. l, or 2 mg!kg/day. Offspring were sacrificed at PND21. Measured rn oncmvetoponndsb | 3nd 17S gmk. EPA dled <r um conto. 1 90md 35S nl. Lg os serum concentrations were reported to be 1.7 and 47.5 ug/mL. EPA modeled average serum concentrations: 1.9 and 38.5 ug/mL. Lung tissue was aioe maofovk at aan tapas poten ad amc oily, Ths adn) oop of 1 nso ted assessed for lnarkers of oxidative stress and cytoplasmic protein and exalnined histologically. Three additional groups of 10 rats/dose were treated Sireshoveand tof dettkoed sl ND5 as described above and the number of deaths/litter recorded until PND 4. Bod weight fhpup wadressed (20% PND)sdpospuptmarsist (y PND) was nc sig (p <00 3nd 001 Body weight of the pups was decreased (~20% @ PND21) and postnatal pup lnortality (by PND 3) was increased significantly (p < 0.05 and 0.01, open)a 20mao, when compardo he cont in:o reared fiWenreCoernsed 2101 maids Pos pp. respectively) at 2.0 mg/kg/day, when compared to the control litters. No treatment-related findings were observed at 0.1 mg/kg/day. Postnatal pup mori ntscontol. 0.1, 354 20 pha group on PND was approxima 1 3 an 3% pes. Hipage changes mortality in the control, 0.1, and 2.0 mgikgiday groups on PND 3 was appro~mately 4%, 3%, and 23%, respectively. Histopathological changes Dr Docume for i dcpo o oh Dh scatdc toAGS n PRY Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy FROSET PFOS - 46 of 75 22447766..00004466 statearsserer STATE_07438141 bsrvedin pup ange 20 ghd on PND.Oinloded kd hla hmong dicen nhaspam, and xsl lng observed in pup lungs at 2.0 mg/kg/day on PND 0 included marked alveolar hemorrhage, thickened interalveolar septum, and focal lung Comision On PND21h as se hd hcl hmedicen spun. a aio, cl on. Noesspi cl consolidation. On PND 21, the lungs also had alveolar hemorrhage, thickened septum, and inflanrmatory cell infiltration. Numerous apoptotic cells ee cht. arate makes aoc nh xa S555 3k oud mop on he 3OgHg Gams. ~vere observed. An increase in biomarkers associated with oxidative stress was found in pups from the 2.0mg/kg/day dams. 2d Disa St inAd RteCunt2008) 28 day Dietary Smdv in Adult Rats (Curran et al 2008) Sprgec DivioR 1Snr immer0.220,0, or 100mg dc. Adidoses swor salclsiebde 014015. Sprague Dawley Rats (15/sex/dose) were administered 0, 2, 20, 50, or 100 mg/kg diet. Administered doses were calculated to be 0.14/0.15, TS3T5,32173 7.6.0758 (MV) mahi Sen coesiions emia wer messed fob 0051. 13 4315.1, 20 933153, and 1.33/1.43, 3.21/3.73, 6.34/7.58 (M/F) mg/kg!day. Serum concentrations at termination were measured to be 0.95/1.5, 13.45/15.4, 20.93/31.93, and 2088132 vgn EPA meld ergssr concentrations wos 375.2405 4 6347, and 113 TARTS sgn. 29.88/43.2 ug/mL. EPA modeled average serum concentrations were 2.7/3.7, 25.9/35.4, 62.6/92.4, and 123 7/187.5 ug/mL. Thr wre no amet std diffs bsrodi hematologyandwinspater Sse signin(9 < 009)drs in There were no treatment-related differences observed in hematology and urinalysis parameters. Statistically-significant (p < 0.05) decreases in Do eiht and fod Common tsobseed h l nd erlis ared $07g PROS dit. Food Soasumpion csoe body weight and food consumption were observed in the males and females administered > 50 mg PFOS/kg diet. Food consumption was also Susy deed in mdlu s wel Fenn he 20mgPOSS dere. No rcs Sond Press Asano vee statistically decreased in males during week 3 oftreatment in the 20 mg PFOS/kg diet group. No differences in blood pressure measurements were rad rtohgrsoups. Deformdeabhlee od ldclr. ri ofteas ncnr gn one fn ah lc observed across the groups. Deformability index values in red blood cells over a range of shear stress levels ~vere significantly lower in both males Semin pon, 100 POS ht. li0cn ml Aloe 3d in Ie ws Wee SOCAN SP si and females exposed to 100 mg PFOS!kg diet, relative to controls. Absolute and relative liver weights were statistically-significantly increased in {0c and fm rat 20mg PRON dt. Relate cr ight vas is sical cease th mgPROSkg dt ke the male and female rats at R 20 mg PFOS/kg diet. Relative liver weight was also statistically increased in the 2 mg PFOS/kg diet females. topsites Suswer heed nh er fhe Pes tod wih mg PFOSAg dctan dod raompcriapy ad 31 Histopathological changes were observed in the liver ofthe males treated with _> 50 mg PFOSikg diet and included hcpatocytc hypertrophy and an Span ros in copa Rosa nach ph a pS:homogsny mh, nlni 1-50 apparent increase in cytoplasmic homogeneity. Increased hcpatoc.vtc hypertrophy and cytoplasmic homogeneity in the females was seen at R 50 me PROS dc Av th igh doc.te sr nofol ud bi nd olBrin ct ceed Spf Sem ces mg PFOS/kg diet. At the high doses, the serum levels of conjugated bilirubin and total bilirubin were increased significantly. Serum cholesterol cnt dered for ls a fale a= 501g PFO Rgdit Ser and T3 ss or idred es nd Kis was significantly decreased for males and females at ~ 50 mg PFOS/kg diet. Serum T4 and T3 levels ~.ere also decreased in males and females, TX vlbing ty gant deciot 20mg PFOSAE a heh corm0 she om onl with T4 levels being statistically-significantly decreased at > 20 mg PFOS!kg diet, when compared to the control levels. `Sng dossal catingsym sisibiginSpgsDil ot(Cling 1312008 Single dose study evaluating serum protein binding in Sprague-Dawley Rats (Chang et al 2008) Fins SpragueDale Rs 51 en hems are dos or 13g PEO. Mesto fs cnconsi tsiid snl ws Female Sprague-Dawley Rats (5-15) were given a single dose of 0 or 15 mgikg PFOS. Measured final serum concentration in treated anhnals was 1 SSugl 12 br. LPA modeled veg sr concenison was 27% gil. 61.58 ug/mL @24 hr. EPA modeled average serum concentration ~vas 27.75 ug/mL. SerumTTdecreed signin (5 < 019) compared cotfse hows ceofa247), hous (ras of 3575),ad 24 hours. Serum TT4 decreased significantly (p < 0.05) compared to controls after 2 hours (decrease of 24%), 6 hours (decrease of 38%), mad 24 hours Gets f$57, The 3 30d 1 ondeascc gnc he 2homporti,k FF wa sad hai 7d (decrease of 53%). The TT3 and rT3 only decreased significantly at the 24-hour tilne-point, while FT4 was increased significantly at 2 and Shor (657 ad 1 cvcot rpc) bor comin mao fFcml 1h 2 hut eepot 6 hours (68% and 90% over control, respectively) before becoming similar to that of controls at the 24-hour time-point. nthe second tof sd, Sprago Dawl sweet ncn witht 3 C4 (rls = Sionoc 1 C4 rls = In the second part ofthe study, Sprague-Dawley rats w-ere injected intravenously with either 9.3 gCi (females; n - 5!group) or 11 gCi (males; n rp) of 114Followedby le sl doeof hr ico 13m posi PFOSRAbn. Atth codfhe 34 buhesrl,s wre 4/group) of 125I-T4 followed by a single oral dose of either vehicle or 15 mg potassium PFOSikg bw. At the end of the 24 hours, the animals were Kidder nd ct sales ete StrTHcecaion va dnd 54 is FOS uted os nd fs coped killed and liver and serum samples collected. Serum TT4 concentration was decreased by 55% in the PFOS treated males and females co~npared to Cons Thr waso derream L251 etd er Ler 131 abuts Gsesedb 40s a 04 lsad ol controls. There was also a decrease in serum 125I in the treated males. Liver 125I radioactivity decreased by 40% mad 30% in males and females, esinel. Cote ie and os 25 bu ied hls AMheIos2E01 TS ces os ofONTO respectively, but the urine and feces 125I radioactivity increased, with the males exhibiting the most activity. This indicates a loss of thyroid Tomer me --, hormones and increased turnover. Reso suettht rl PROSadnstsion sis i ric sed se: vali fhboos, nrssd mons ofT, Results suggest that oral PFOS administration results in a transiently increased tissue availability of thyroid hormones, increased turnover ofT4, and duction in TT4, bu PROS distri osoo da 3 ps tidstoar he pola pian 10d as and a reduction in TT4, but PFOS administration does not induce a typical h.~y)othyroid state or alter the h}~pothalamic-pituita~,-thyroid axis. Dr Docume for ie dcpo oeoD scaFdRsOtSiT n Aces pOKY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 47 of 75 22447766..00004477 stateorsserez STATE_07438142 Dison)Gags sud ossand pdhrs (Ll 201). Developmental Gavage study - glucose and lipid homeostatis (Lv et al 2013) Ti potof sampnd abl pos io PEON hos ad hd bcs offing as cad, Groupsof6 print. The impact of gestadonal and lactational exposure to PFOS on glucose and lipid homeostasis in offspring was investigated. Groups of 6 pregnant SPF Wn thwre gcd o 0.0.01 ka iced 105% Ton2 om GID010 FD 20 Aer rth. pp ner src SPF Wistar rats were given doses of(), 0.5, or 1.5 mg/kg/day dissolved in 0.5% Tvveen 20 from GD 0 to PND 20. After birth, pups were sexed, daly cid nd rsotro ut herird pps per Hlad fl) Pp weciredginhedson PDS, randomly selected and cross-fostered to insure there were equal pups per litter (5 male and 5 female). Pup weights were determined on PNDs 0, 5, T0154 21Semand ce mpl ersi lito st AI 3nd31 oma ucthri of ap.Th Frappis entc 10, 15, and 21. Serum and liver san~ples were also collected at PND 0 and 21 from an unspecified number of pups. The remaining pups were ninfr 19 veka cans befor flac. Bodspl cre lie 104 5 chs ar cin ad xd maintained for 19 weeks after weaning before finn sacrifice. Blood sanaples were collected at 10 and 15 weeks after weaning and examined for tin sum rigs a choles. ad foog d aos. cose okast nsadmired ara 1 houroemigh st. fasting serum triglycerides, total cholesterol, and fasting blood glucose. A glucose tolerance test was administered after a 16-hour overnight fast. herpeevalus add eh ul. eap dap, ne, nd gral SEH. pasate aco r,t cumulation Other parameters evaluated included serum insulin, leptin, and adiponectin, and gonadal fat weight, pancreatic beta cell area, fat accumulation in {heirsmoos hoa i dhsad on sin, ods htof pps oiddas vssignals ce (p< the liver as monitored through oil red and hematoxylin and eosin staining. Body weight of pups from treated dams was significantly reduced (p < 1) ir drought cin, and pertonl cok 5psn doe Hd mre 1Es ls asOn 1 0.05) at birth, throughout lactation, and persisted until week 8 post-weaning. A dose-related increase in glucose intolerance was observed at 10 wks posinugp on sd ns i sical SETSaad 3 15 ghia AL 1S necks pe fom the 05mAdy weeks post-weaning in pups from treated dams with statistical significance attained at 1.5 mg/kg/day. At 15 weeks, pups from the 0.5 mg!kg/day ns dian cdhose taka, wl For igh 5 pps We aed tk hd taSt ABC Age 0 15 dams had significantly increased glucose intolerance, while that for high-dose pups was increased but did not attain statistical significance. At 18 ks at wena, pps Fmnes 1 gEho tac Se Al lie ne ad eo A weeks after weaning, pups from dams given 1.5 mgikg/day had siga~ificant increases in serum insulin, insulin resistance index, and serum leptin. Sm sponse a gry dersFp on lh sed 100 con ih hf col Al Sc, pps Hor Serum adiponectin was significantly decreased in pups from both treated groups compared with that of controls. At sacrifice, pups from both Red oop hl gC Se AID Ph. Sd S07 13 1h EF E-ons SS treated groups had a significant increase in epigonadal fat pad weight, and fat accumulation ~vas observed in the liver of high-dose animals. 2 year Dietary Study in Sprague-Dawlev Rats (Thomford 2002, Butenhof et al 2012) - mga Dai CF CD (SENG BR. rt v.10 0p ire dred ving FOS onsiin dit frp 010 wks.Fiposc pe oercp Sprague-Dawley Crl:CD (SD)IGS BR, rats (n - 40 70) were dosed using a PFOS containing diet for tap to 105 weeks. Five per sex per dose group oct and wicks Trament subd indseed bod igh wih castdIH Wik boPTr R were sacrificed at 4 and 14 weeks. Treatment resulted in decreased body weight, with increased liver weight with hepatocellular hypertrophy. Corespniag PROSdoes wes 0.002,005%,025, nd 0954mh: pectic, for isad 0 0029, 110,029, 1 751 mg Corresponding PFOS doses were 0, 0.024, 0.098, 0.24, and 0.984 mg/&g/day, respectively, for males and 0, 0.029, 0.120, 0.299, 1.251 mgikgiday, pecan, fo frais Fn mc heSd 100 Wr BE ng eck 320d ce pls wce andor ochninl respectively, for females. Five animals/sex in the treated groups were sacrificed during week 53 and liver samples were obtained for mitochondrial tm, epstoclio prlraion te,addrofe palonCOR rss cy. Incr NS 3 oErd activity, hepatocellular proliferation rate, and deterlnination of pahnitoyl-CoA omdase activity; liver weight was recorded. Tochad eu bratifroALnT 353 Necks wer Soret wilh hos 1 Gok moos gmc (<0) rss The clinical serum observations for ALT at 53 weeks were consistent with those at 14 weeks in demonstrating significant (p < 0.05) increases for he ghdose mesbt les A week 27. ALT ws res figsmals,but etSa Sasa gcc. For hls the high dose males but not females. At week 27, ALT was increased for high-dose males, but did not attain statistical significance. For males at Shem 0.2.5, 0d 0p sro, ALT vot wer 4 +4, 675 53.90575,41-53. n53d+$4 TUL. reseech. To re 53 weeks in the 0, 0.5, 2, 5, and 20 ppln groups, ALT values were 54 + 66, 62 + 52, 40 ~ 7.5, 44 ~+ 8.3, and 83 + 84 IU/L, respectively. The large SD were he itcf hls no sm)1 schof hecot 3 0 ois nd als 20pe ro Thssome SDs were the result ofhigh values in one animal in each of the control and 0.5 ppm groups and two animals in the 20 ppm group. Thus, some oi ob smi fo nc Tage Esl cum ha hi AST vs Wate nt Sd fr FBGsx Ser ld auimals may be more sensitive to liver damage as a result of exposure than others. AST levels were not increased for either sex. Serum blood urea tone (BwaUsNa)l p<010%) mass 20 pf als an rales a Sok 14 27. 4d 32d 1 py sand omisct. nitrogen (BUN) was significantly (p < 0.05) increased at 20 ppm for males m~d females at weeks 14, 27, and 53 and in 5 ppm males emd females at 370035 wks Th nes nthe 2pp thou hd scr (p< 009) tess i BUN 5 wks. At stifles pp3. 27 and 53 weeks. The males in the 2 ppm group also had a significant (p _< 0.05) increase in BUN at 53 weeks. At sacrifice, males at 2 ppm had a cn(p< 00) crs nhprcknrocltoorp. nh me nd fsa20. pe. her wreSEA(F< significant (p < 0.05) increase in hepatocellular centrilobular hypertrophy. In the males and females at 5 and 20 ppm, there were significant (p < 0 ncecco penghy. eosconic bios grams rales ny. ndcro plo 0.05) increases in centrilobular hypertrophy, centrilobular eosinophilic hepatocytic granules (females only), and centrilobular hepatocytic cain (le ar) AL bh Bs, Bae was 43a rie 0 mofb nalsit Sle ll pe erst bh vacuolation (males only). At the high dose, there was a significant increase in the number of animals with single cell hepatic necrosis in both end bl 3 wk males and females at 53 weeks. LoSd GageSusnF Soap DisRas(instal200) 1 to 5 day Gavage Study in Female Sprague-Da~vlev Rats (Martin et al 2007) 10mPROS a nitltmr il po age Desi(01 1, oSdys byol sagead deinmspdcofhPOeS 10 mg PFOSikg was administered to adult male Sprague-Dawley rats (n = 5) for 1, 3, or 5 days by oral garage and determined the impact of PFOS on mone ee Pollo ay, +n 3d Gv dot, ignders (p< 00) seed atl T4 dhe of 17-01) on hormone levels. Following a 1 -day, 3-day, and 5-day dose, a significant decrease (p < 0.05) was observed in total T4 (~ decrease of 47-80%) nde 4dof6r -200 Tot5 wa nis manycssad ae dy esse of 239, PROS tment sod and free T4 (~ decrease of 60-82%). The total T3 was only significantly deceased after day 5 (decrease of~ 23%). PFOS treatment caused Dm Documse fr inAd hcuion Po oh Dh At ASAGESPRY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy Trost PFOS - 48 of 75 22447766..00004488 sateorssenss STATE_07438143 Instore, epoca peop and manstossGenes sistedwih he fyi mons lsc ndsns es hepatomegaly, hepatocellular hypertrophy, and macrovesicular steatosis. Genes associated with the thyroid hormone release and synthesis ley lad pe dtd DIOS. wih cats he ncn o13and pe | diode DIDI hich eines proomons T4 pathway included type 3 deiodinase DIO3, which catalyzes the inactivation ofT3 and type 1 deiodinase DIO1, which deiodinates prohonnone T4 obras5 rset ih PROS cmd gman(p01) DIO epesionsd Ds chon cndiy to bioactivate T3. Treatment with PFOS caused significant (p < 0.05) DIO 1 repression and Die3 induction only on day 5. Developmental Study in Mice prenatal assessment (Thibodeaux et al 2003) and postnatal assessment (Lau et al 2003) Spr decopmeal suds wihPFS wa promod hc. Grofo0-c29CeD.1ms wes mms 0.1.5, 015,020 A two-part developmental study with PFOS was performed in mice. Groups of 20-29 CD-1 mice were administered 0, 1, 5, 10, 15, or 20 mou PFOS du GDS | 17. Serumconeniations wes hk pred. EFAmodeled eras som coments 31. 1,218,261, mg/kg/day PFOS during GDs 1 17. Serum concentrations were not reported. EPA modeled average serum concentrations: 33.1, 141, 218,260, 9 il and 289 ugimL. Neral bs weigh gin wa sgl dees 20mgd. Food sd waesonsioenrs otafdby se. PROS Maternal body weight gain was significantly decreased at 20 mg/kgiday. Food and water consumption were not affected by treatment. PFOS rent ried (115) Thr wight ddoseept mchermic T4 wa ered 1.3 sdeepron mcr GD 6 treatment increased (p < 0.05) the liver weight in a dose-dependent manner in the mice. T4 was decreased in a dose-dependent manner on GD 6 i scl fence (09) stand foro 30 gy arp, vl oT 1d TSH wre not flocibdy eament A gain with statistical significance (p < 0.05) attained for the 20 mgikg!day group; levels ofT3 and TSH were not affected by treatment. A significant {aces posphoost wa Red Saal SESS 20 AE. 20 ke iE (009 wrod oe increase in post-implantation loss was observed in animals administered 20 mg/kg/day, and reduced fetal ~veight (p < 0.05) was observed from mn 1015 md ouput oha Fl, cnr Ret,4 HSoF EAR SA dams in the 10 and 15 mg/kg/day groups. Birth defects such as cleft palate, vcntficnlar scptal defect, and enlargement of the right atrium wcrc eddno Home observed at doses _> 10 mgikg ost moss pups fomdas ist 15or20my dd st sui fr 24 hours afc Fils eect moray vas obsaf 10 Most mouse pups from dams administered 15 or 20 mg/kg/day did not survive for 24 hours after birth. Fifty percent mortality was observed at 10 mE Soretof ppt nh|3nd mo td am a srcml,A SRI (DRO rc In i In mg/kg/day. Survival of pups in the 1 and 5 mg/kg/day treated dams was similar to controls. A significant (p < 0.0001) increase in absolute liver Nght was chicod 2 mga A gmc de 1 5c opewnsiobnegn No oor esment hted ceerec abctdon weight was observed at >_ 5 mg!kg/day. A significant delay in eye opening was observed. No dose- or treatment-related effects were observed on TTS md Tenhtpope T4, T3, and TStt levels in the pups. Asnes ne 20 gheydoe group er om pl, wes, descendal did iin hoofbsi 10mga, 45% All neonates in the 20 mgikgiday dose group were born pale, weak, and inactive, and all died within a few' hours of birth. At 10 mg/kgiday, 45% then or rit2 bos Suv oh | he ap as mirfo ofcools Neon nigWih SEAT Ered of those bona died within 24 hours. Survival of the 1 mg/kg/day group was similar to that of controls. Neonatal weight was significantly decreased 1200kdy In he esfromdans sed wih 2 kv ee We re mbes ofl pls (0 S00), sem des at 10 and 20 mg!kgiday. In the fetuses froln dams treated with 20 mgikg/day, there were large numbers of cleft palates (98.56%), sternal defects 10 dedohn ofages (5725, wavy 1s (1073s dscea (07) nd cued us 6547) Somadees (100%), delayed ossification of phalanges (57.23%), wavy ribs (84.09%), spina bifida occulta (100%), and CUlWed fetus (68.47%). Similar defects NeCsr nee ods rsd eh 10 ecpt 3 ower ee: Hiopatholoss camshowed ht less were observed in the fetuses from dams treated with 10 lngikgiday except at a lower incidence. Histopathological exam showed that all fetuses amido I 13 ondas sd ih20h ne hsand hd eo res tlfo srs canal ono examined ou GD 18 from dams treated with 20 mg!kg were alive and had normal lung structures but mild to severe intracranial dilatatiou of the land ses Neonates fronios20 mh sds hd mg actos (pro compete colo oe lu o 3 beof te a) blood vessels. Neonates from the 20 mg/kg treated dmns had fetal lung atelectasis (partial or complete collapse of the lung or a lobe of the lung) ieicofaihoead acral ca dias when xaned hiipabelosly Tes nics onch fh w,ith reduction of alveolar space and intmcranial blood vessel dilatation when examined histopathologically. Three neonates from each of the five mad wih 10mg cr vt, n27dhd si 0 lcmand 37hid snr io ofbs bre lod evel dams treated with 10 mg/kg were examined, and 27% had slight lung atelectasis and 87% had mild to severe dilatation of the brain blood vessel. 0d Inport Syn ie (Dog 13 200% 60 day ImmunotoMcitv Study in Mice (Dong ct al 2009) Inorietmeve chro ees fmol, dl msl CSiTce (B10La) er litre 0.0005, 00830417, 0333 1d In order to observe chronic effects ofimmunotoxicity, adult male C57BL/6 mice (10/group) were administered 0, 0.008, 0.083, 0.417, 0.833, and 2083 mh PFOS wih2%Tus801dood alrday by Mage or 6doe Msiurd a suconecuaions 067,715, 2.083 mg/kgiday PFOS with 2% Tween 80 in de-ionized water daily by gavage for 60 days. Measured final serum concentrations 0.674, 7.132, 3163816512o0r 11067 vm EPA mlshrgeseecontains 07.74.36, 736.8 1006 sym 21.638, 65.426, or 120.67 ug/mL. EPA modeled average serum concentrations 0.75, 7.4, 36.9, 73.6, & 180.6 ugimL Niimic ted wih 0.17mgd ad snc oerbd Night compared deco cs, 5 vol3 git At sacrifice, mice treated with _> 0.417 mgikgiday had significantly lower body weight compared to the control mice, as well as significant crs ne, hmsan ne washFood comatose a decrdn c 033n3d 0 mop Ler wight decreases in spleen, thymus and kidney weight. Food consumption in the study was decreased in mice at 0.833 and 2.083 mg/kg/day. Liver weight Na rsed gna ml dn rope corre como 170128 onto). S21 017, 57520 135.407 S01 3.175021 was increased significantly in all dose groups compared to controls, 5.17 0.12 g (control), 5.21 0.17 g, 5.78 0.13 g, 6.67 0.11 g, 8.17 0.21 Da Docume fr i 4dhie Pp oh rh idst AS AGES PRY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy FROST PFOS - 49 of 75 22447766..00004499 sateorsserss STATE_07438144 5.300 11.47.0125. optic Ser concosons was decd in mie a he woBigherdss. As in he shores sd, yian g, and 11.47 0.12 g, respectively. Serum corticosterone was decreased in mice at the two higher doses. As in the shorter-term study, thymic and Sem Cllr a eased 1 doe pnded hndrsGs een 0417 mi The splenic cellularity was decreased in a dose-dependent trend, with significant decreases observed in mice receiving R 0.417 mgikg/day. The DCDmarcelaprorned opandhem heatsdemoted rtseor f ol2 Bcll CDUCDY CD4/CD8 marker analysis performed on splenic and thymic lymphocytes demonstrated that the numbers ofT cell and B cell CD4/CD8 ubpopulons weedered ari 310-117 mg PTOSKG en. Spec NK cl sis was red gnc compafo ans subpopulations were decreased starting at 0.417 mg PFOS/kg/day. Splenic NK cell activity was increased significantly compared to controls G+ 195 nh mic 3 0083 gh ay (3.43 +1147 ihsinifcnmaskd reas 033 mga (002 = 21a7nd020)83 (31.14 1.93%) in the mice at 0.083 mgikgiday (45.43 4.74%) with significant nrarked decreases at 0.833 mgikg/day (20.28 2.51%) and 2.083 mga (1567 125) TheSRBCspecie IM logsForming ll respons shdoos wstedeeeds wih shoSg Fianc mgikg/day (15.67 - 1.52%). The SRBC-specific IgM plaque forming cell response showed a dose-related decrease with statistical significance at OTSA and hie 0.083 mg/kgiday and higher. DI iscopmmguam l ocSitsoMisi (itt al 20:08) Developmental Immunotoxicity Study in Mice (Keil et al 2008) PegCETBLION ome(rleCi HR)mic rs stdih FOSto cals devclopers rman n hist Pregnant C57BU6N females (bred with male C3HJq-leJ mice) were treated with PFOS to evaluate developmental immunity in their inbred BGCIFY affpring Thefevls (10e1re a2stpro. 1 1,1 Sm of PFS 0STosen20 gavedi angio B6C3F1 offspring. The females (10 12/group) were administered 0, 0.1, 1, or 5 mgikg of PFOS in 0.5% Tween-20 by gavage daily on gestation oy GD) 117. ups eid wih th a forpromi 3 sks th immanctoniey ssonspefod 4and 3 nck. One le days (GDs) 1 17. Pups remained with the dam for approximately 3 weeks with immunotoxicity evaluations performed at 4 and 8 weeks. One male ndoe forewescsc omhe raed HioF 6c a Rl up) for in Fh ONY PURPA. PRC and one female were selected from the retained litters (total of 6 male and 6 female pups) for testing ofthe inkmunotoxicity parameters; positive Cote wars nodfor oh controls ~verc included for each assay. NK ol activi was ot asd nay pup 4 chsod. A wshs, host, NK lc was spss inmls std wih 1nd NK cell activity was not altered in any pups at 4 weeks old. At 8 weeks, however, NK cell activity was suppressed in males treated with 1 and 5 meg (126 33 19 ders compas contol echa)n lesa 3 mo (3 1%comps com) Th mg/kg/day (42.5% and 32.1% decreases compared to controls, respectively) and in females at 5 mg/kg/day (35.1%, compared to controls). The Wapeomicngl espn for SRBCI proche nysects wack nd sk gna, pPcsed me 5 plaque-forming cell response for SRBC IgM production by B cells was only assessed at 8 weeks and was significantly suppressed in the 5 med aks (570m cll wat hardhs aks. Th ol sinc Hees TIO AAOTRGPeRs wOi R 21% mg/kg/day males (53%); no effect was observed in the females. The only significant differences in lymphocyte immunophenotypes was a 21% is nbc per f B12, ls nek Flesh Smg roa cpr10 contctoslt cher decrease in absolute numbers of B220+ cells in 4-week-old females in the 5 mg!kg/day group compared to controls; this effect was not observed at ks To lor cmtchum wae 25%dcr in D3 and 254Gres CD moses a hea mle at Boneh 8 weeks. The other significant change was a 25% decrease in CD3+ and 28% decrease in CD4+ thymocytes at 5 mgikg/day in males at the 8-week xan unc sponses ie proc) 0 LPS 3 err gme by Ferosmacrophages nr nok fick wihtimes evaluation. Functional responses (nitrite production) to LPS and interferon-ganwna by peritoneal macrophages were not affected with treatment in 2Sone mc ot sd 4 ek) the 8-week-old mice (not evaluated at 4 weeks). 21 day Immune Challenge Study in Mice (Guruge et al 2009) - 30S ig PEOS 00.00. or D035 mek: pecticwa)s alinstretdo 30 male ACSF is or21 dyo sadthnn cond 0, 5, or 25 ggikg PFOS (0, 0.005, or 0.025 mgikg, respectively) was administered to 30 female B6C3F1 mice/group for 21 days and then exposed en ml 10pl orm ts (3 Lfphpcred se) cesA 1ssupession Mc wee Goeol them mtranasally to 100 plaque fomaing units (pfu; in 30 gL of phosphate buffered saline) influenza A virus suspension. Mice were obsela~ed for 20doe pn lion Ter wa at at car i oc orra cis slo. tn nr Ads. 3nd ot): cat i: 20 days past inoculation.There was not a significant change in body or organ weights (spleen, thymus, liver, kidney, and lung) of the treated mice Compare comils Saa wasan dca cs ght S1 SHE 0 pnts. Sole compared to the controls. Survival rate was significantly decreased in the mice at the highest dose group after viral exposure. Survival rate in the at ody 20 aw 474 sas 75 hdr 0p. mice on day 20 was 46% in the controls and 17% in the high-dose group. 26 week Capsule Study in Cynomolgus Monkeys (Seacat et al 2002) - PROSam0i5psbc ti6o iosn31,01 075 gg& exo 003mgd Msrsd sum PFOS administered in a capsule by gastric inmbation to 6ise,~dose at 0, 0.15 or 0.75 mgikg-d & 4!se~dose - 0.03 mgikg-d. Measured serum Coemaons (MF) S315. 52 0665, 173171 wn. EPA oddsvescmcomet 17,3803 196 um. concentrations: (M/F) 15.8/13.2, 82.6/66.8, 173/171 ugimL. EPA modeled average serum concentration 7.7, 38.0 and 156.6 ugimL. omdor il cbibiddcrchoos (UF 230724, 310, & 630/19 -p 01 3 HDL. sho(lF3e302s5, 24567 Low dose animals exhibited decreased cholesterol (M/F 28"*/24, 3/19, & 68**N9%**, **p<0.01) and HDL cholesterol (M/F 33"*/25, 24/36"*, TRG 0 01) Mid dose aml cited incre ner nigbhs (tLFs 41&2 S173 9008%1)6 (MIF 123/17 8 & 79**/63%**, **p<0.01). Mid dose animals exhibited increase liver weights (abs (rVFF 4/12 & 55/47%*, *p<0.05) & rel (M/F 12.5/17 & PIT p03a el chins ram yd mons ls (rsdT(WF 1222 8 15/551 45-an0dmr0a1dT)SH 69*/61%*, *p<0.05) as well as changes in serum thyroid hormone levels (decreased T3 (MiF 12/22 & 48**/33%**, **p<0.01) and increased TSH UF 51508 16025 "p-010) Two of 07 mgrmais die oedid odo 15 wsond6 orod nd ws (M/F 151/30 & 160*/82%, *p<0.05). Two ofthe 0.75 mg/kg/day males died; one died on day 155 and one was found moribund and was `Scricd andy 179. Theminke kd hd UOT ee0t er Ei RUT ofpaar amnion casof sacrificed on day 179. The monkey that died had pulmonal3, necrosis and severe acute recurrences of pulmonary inflammation as its cause of aDome iAd hciPTO oh Dh ktdg tAS GE POY Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy ToS PFOS - 50 of 75 22447766..00005500 sateorssenss STATE_07438145 dah. Tospcassf ofthe moribund sion ws ot bled. Rows, then his sls vrs ss of rai l death. The specific cause ofthe modbund condition was not established, however, the clinical chemistl3j results were suggestive ofhyperkalemia. ONrll mambo weg i wa cat 90 0) e073 ph oymls nd Fels (5 -57 an + 5, pect) Overall mean body weight gain was significantly (p _< 0.05) less in the 0.75 mgikgiday males and females (lost 8 8% and 4 5%, respectively) Se retment hs predfo rs (aed 14 11%. especialy) Two igh dosmalsadn hh-dors mle sd after the treatment when compared to controls (gained 14 11% and 5 5%, respectively). Two high dose males and one high-dose female had mod cr 18 xSa ET. 1an 0 bred: hgh-dseml thd rig dh Allfoalsad31 les mottled livers on gross examination at sacrifice; this was also obselwed in the high-dose male that died during the study. All females and 3/4 males Shc ghd hadc sPpe s prT at the high-dose had centrilobular or diffuse hepatocellular hypertrophy. Dr Docume for ie dcpo oeoD scaFRdOsSTtin Aces pOKY Draft Document - for review and discussion purposes only-. Draft document does not constitute Agency policy PFOS - 51 of 75 22447766..00005811 sateorsserss STATE_07438146 `TTaabbllee 66--AA33,. CCoo--cc`rrCtlrtiilctciaacllalEEfLfffeeOccttAss ESSuu=Lmmmm|2aa5rryum. serum concentration @LOAELfrom Lucker et al 2008 Critical LOAEL = 25 ug/mL serum concentration @LOAEL from Luebker et al 2005b N[WNOiOeTnTEEa:p:pNrNoooptraailallltsesttuutddhseieeossrh~aaalvvdeeosmmeeevaasspurureerddeioocdrteccdaaallvccued/raaatlgeeedd ssseeerrruuummm cccooonnnccceeennr~trrraaa~tnoioonnnss~ rdrWeeellhnaaetttniifooaynnpsmsphhgri~oppwpfhjobreirtahvtveeaarrrtiihhooeuuesosfrssaetirlrcaadtiinonssss/.er~es'pwppseo'cepritecrsees'didddiiucunrwrasatditoeia~ov.ns~essrawwwgahaesiscssthe~etdrsueidd~d0toncooaatnsscasseivsnt~teriicnntt~on abaidevveleenrort~awa{gg~jee,4,mss0egcrgrtw~iihmmnetcc.hooennarccpeetphnnrtetorrexaafittfiimeoocannttsellirkeyeepllo1yyro5ot-eccfdccouulir~rdr'fosee~fddutaadhtiteexssseeewrrruhuumimmcbhcceoodnnnicccdeehrnnmtotrartoarhi~kaoovannebssoaaviteoo|rr SSttuuddyy ((ssooEuufrrccfeeecaatnnsdd oddbaastteee)r)vaaennddd:|| ib*"nSeSstltuo,udwdifeies,.s~wo4w0iitutlhhgbmEElyPPsAAo(umampoeopwdsrdeoewlxe#ihemeiddadctaaehvvOeew~rreaaIr,g~qeee5-dJssOeerMruuemomfcctoohnnnehccyeseennxirtti~urrwmaatte~piboooennlnssacdiaahrnmeegappfrrrrkeeossameebnnottthveeeedd.] Effects observed: fdciilroosstsLeeifwvos"ltplprhorewedEdeixidccettbleeyddissseteeurndauttimem0s.ccwooJhnnIicccReehAnniwtCrreaaOr#teMoo~nnMdrrOeeenNllata~G#teiuoodndnssbahhyriipepcssxet((r-sasepeeWoarrltaeeell#eernvvgaaTJnnohtxtowwrmooerrvtkkhsisehhsee-eett cwoimthpilnettheed LF2incaellfiPleEOaSt OE:P~A1t2~0~1,GCHOA3~P[EOONNGAuiddam~bwoe r- e~2T~oteSr~e,TroxurmeEvire1wassp- | comldeted'J~nal 4~FOS~l{PA 20 l (~tA PFOS Admi)ose T)~A'erumlixtrap.xlsx ] RRaatts1s.-- Developmental study in Pregnant Sprsguc-Dailey Rats (GD2 1. 1t0D@o1-e-7GGv.eD6Dl2ou21pg1m)/)me((lnTT.thhailifbba~oodtddumeedaayduuoixsnetePat|rlaemlgn22ea00n00dt33]S&&~r~L-aLagMawuautete-etaDralnala~22ll00e00fy33e)R):cattss-(GLD(2T4 @17f((.M6eMcDuDtgHHsh~B-BLMM{sD[Dta:ezdr0,mn~a=dlo11d0s0e.e.f11e1uuctmggs//gmm&ilLk)g)l~o&&w] - Maternal effects - +tT4 FT4T4by GDT. Developmental FT4 by GD7. Developmental @3355e=1.1ff2e3uucggtuis/mgm-Ll~)s[a.taeddrmnDneaddvlooedssleeeofpe22cmmmtesngg&tikadgll-o]dw][-T-p--_-u4+ pMMaBatWteemr&naall sBBuW rWvi((vMaMlDD&HH BMD BMD 2. Deve=ddleeo2llpa3amyyueeegnddht~eaeayylLee)s;toouDppdeeyennviieinnnloCggpmCeSntDal )- +Rpautps BW & survival & (6 wkprtiomaotirng hrs 2. DLLWDe1Dv49)e)9lo((pLLumugus/eebmrb~lhkt.eearrl[teasttdauamldlyd22o00ms00e55C0a0f).)l4:CmDy/(SkgD-)d]Ra-tsM (6 wk prior to mating aternal |serum th~a @19ccc.lhh9eooalulreegsdst/mtoeersLroelo.[rl.aedDDsmpeeovvndeesolelsooeappnm0mde.4neotmnnaltgyla/lk--s-ge~-epdnpuluwp-pitMBBhW Waotn/e/eBrBnoWWfatlGGw~o&&semrLe+utfTmIh'H4odbbsuutt ~noo ucbuselseeedand.re. ld[[ouMMsdeDDedrHHeaNsNspoootctnoee-sssec:raddinecdcaerloe]nalcsyedser[fle~4n4eo~ob,bitsashee~r~sne'eeddoeiifnnthwdthioiss sywill methods stt@~ wi# nor not @@393.97bd.ue7riauuntggci//lommunldL.(esd[ataaaddtsmmsscioddgo-oncssireefit00ibc..u83atlmm]oggnk/ykeg-1-7%ddd]]i--fM Mfarateteernrnntaaltlh--anL+egceoensstttraaottlioso)nn. 3. Gavad,ifgummeraamtDteicoNrmnnaTal(lssBtBtauWtWdisyddusiruingirSninngpigfrgbaegugsettusaetoat-ntiDilooyannw,1,l,er?7y%teelRldallitifivsfveee(rrreGwwnDtttO.,t-hP~NDc2o0nt)rols), G((3BBa4uuratt7geee~nuohDfoNfgfeTTt sata[tllua22dd00ym009i9dn))osSepr|~muye-kDyadw]le-yDReavteslo(GpmDe0n-tPaNl Def2f0ec)ts @34o~`.b7mmsoueotrgtovoharrntLianocctn[tiaidvvdaiimvttyey.dwwoi[sitteMhhD1|~HmhhgNaa/bobkitigtet-uusdaa]ttEii-oPonDnAeoodvnneePlPioNNpfDmDie1e!7n7datbbauulLtteOfnnAfooeEttcLtoosttbhh-aeerrsed oooS nnbshtehrsiavst annetdindodpenpnoodmdy mpnao.yti:sn.!~t/.M ~ ahtshDeehH22e00N~b1oa14steiddssr:aoc~tEiPhHHAeEEiSSdcrDtDeanfEEtl~PPRtiAAeDdssaeMelLelDcOtcHAedtIitLehhidisbsased study and endpoint as deefteecrsm]ined that sty determined that stuc~v vasthe was of suficient quay to basis ~/ltte draft R[D, O]su~ciem quali to MlI~sDstt Hoobbsseerrvveedd 44.. GG(aCavhraeanggceetLaLluunn2gg01dd2ee)vveellooppmmeenntt ssttuuddyy iinn SSpprraagguuee--DDaawwlleeyy RRaattss ((GGDD11--2211)) (@@C33h55ea.ns85uehugtig/as/mltmol2pL.0a1t[[2aha)dodlmmogddioocssaeel 22chmmagne/gkegsk-di[n --pu+lpppuulppunBBgWsW && ssuurrvviivvaallaass wweellll 55.. 224882dd3aaa7ysy hdduiiigsec/ttamomrlpy.yat(sshttFuouddl[oyyagdiiinncmadSSloppscrrhaeagagu0unee.g--e1DDs5aaiwwnmlleepeyukypaRR-alautdtssn-]g((1sC C2ru%a~nfeeelttaaTll 22r0000w%8e)), @>3h(H,9oo72w~.euv4vgeehvur~eg,ar,/Lhmh(iilFsstt)ooor[llaooadggdimimccaiadllnoccsdhheomas~n~e(gg)e.oe1ssf5nnmoo3t.tg73ssikeemgeey~-ndkun] ndi-tli]l1t2tww%o od~odrsoesl elillveeevvreel~lss.nu,pp DafDraft DDooccuummeennt t- ffoorr rreevviiewaanndd ddi~ssccuussssiioonn pptr~poessess noNl7.(y9.02DDS.r4arf~5uttg2dd:0moo1ccLuu7m5oernatdddmooeisns ot conse dese o~' 3,73 not constitute AR oly rn~kg-d] Agency policy PFOS - 52 of 75 22447766..00005522 SSTTAATTEE 0077443388114477 G@22l55iv.99e7/3r3w55t44.((wMV/I/hFFi))stuuogglh/olm~glLic[[aaalddcmmhaddnoogsseees,-~11etmmcg.g/sikkegge-n-dd]a]t--ne11x22t/22d22o%s%e~Tle'reeevllels 6. Singululieppvde((ro-~s2w2e--tff.sootwlluddd/yhhhiiicsggvthhoaeellrour))ag;;tiic[~naTTgl44Sceh((MraMun//mFgFep88sr,22ote/14et4ci88.n%b%si)e)nedninagt nienxStpdroasgeuleevels DDS@ai2anw1wgl.llee7eyy5doRRusaaetgtsss.t((uCCdhh[yaaaenndvggmacledutto:~saalelti2n21g00500s88me)y)ru/mkg-pdr]ote- iTn b4in&diLnTg3inasSpweralgluaes- 1114 @27.75 ugimL [adm dose 15 mgikg-d] - +tT4 &tT3 as well as ~'fT4 RRaatt ssttuuddiiaee.ss - DeessWttiimDmaaNtteeTddsssteeunrd,ytuimnicncoopnrrctecegennntatrnraatttiWiooinnssstar Rats (GDI - PND21) a. (D(@WW0Wa.a8nnDggmNeeeTtt/aaklsltgu22d0d01y1a55di))nmpdroesgena(nbta Wistar sed on Rats (GDI - Butenhoffct PND21) al 200-9 @0.S8sliienmnvcceegles/ddkwoogoss-iudinnlaggddwwimakaessdlovvysiieaabe(DDblWWaosweeiidnnrssotttneehaaaBddnoBuouftfetgngeahaovorhaafoggffeeeftattahhnleed2ss0ee0rr9uumm- ttulhehgveerre/eelmsffbolwrr)ee--oubbDleeedllvoolewiwlkoetthplhymeeebccneoot--laccolrrwiiteteifccrfaaetllhctabbsneen-nBcc"huhwmtmaetaanerrhrkkoomfofaffza~4ne4d00escape mullaaagttrieemgnniccLnyy)a/(l-MaMDLnDe)dHHveENNloPotiApnemsec:se:onne@ tafsfliceectdfstfeeaarc~ihtesttedhh-iissr?ewddsooapsstoeeenrsllemeevva1eez0llewbweee'esrrace.eape b. GavaNNmgOOaerAAgnEEienLuLa.rloEEadffefnfeevdccetEtlssoPpwwAim~lelcllnonntnoaostltidbbseeetruiiednyndccltiuhlndeuperdrdeeeasagspdsnoaccnnoost--eccSrrtpoiitri~abccgeaaullae][ b. GDD@a>aaw0vwl.aleg1eyey&nRRea0aut.tssr6o((mdGGegDDvk2e2a-l-o-11pd22m))ae((dnZZmteeanndlggossteeuettda(aylbl ai22ns00e1p1d11re)o)gnnaBnutt sSnphroafgFucetal @>0c22.h100a00n&99geee0sss.itt6nssmeernrgmuu/knmmgbll-eedevrvaeeGldlssFmllAiikkdPeeollscyyee<l<(lbs44,a00smeuudRgnNohn.nAL)Be)ux--pterEEenffshffseeoiccfottfnsse,t eatlc. e[c1fh3Mf4aeDnDtgHHses1NN0oiotnfetuesnns:uc:tmssiiiobggnennariilffGieicfFcafaAnenccPcteescooiesrrllusrrn,eecllmlaaetrRaiiorNo.nnAssNhhoiieptpxolpoifrsfethtsehesdesiseoae.ns, etc. . HPTc~crrf2fiii8tn'icccdtaasallyIe~ogf{.[af/'ieevmc.acttcgssteiaaottsntttahuhlidissy@ttiimmcnetea.s.d]]u~lstumnaclleearS.prNaogtuleisDteadwlaesy c. HR@Ra0aPtt.Tss5((2L&L8oodpp1aee.y0zz--mgDDgauu/rvvakagaall-edecstttauaadlldmy2200di11no44sa))edu(lbtamseadleonSpCruargruaenDctawalle2y008 @0.e5eLssHt&t ssaee1nrr.du0ummtmellsgeetivvokesegltl-ssedrlloiainkdkeeemll(yylda<<ots44de00o(suubegga-/sr/meemdsLpL)oo-)nn-sCerre)eup,proo&rrarttnee|ddetF|,~saSlscHe2rrt0uua0mm8ll dLdmoosHasekesasaan)adss.wtewesl[etollMlsataDsesHrohhiniNssoetttooe(llsfoo:laggitivccdeaaorllysccehhs-ramaeannslggpleeossnnuisnnme)btt,eeess&rtteeo"ss[f F@@aS>n>iH_11maalt sall ppLmieefgrrf/dcdktoogsss-eeodn)rg./rmp~pa/llaale)nnHddreccNpooronnotccedeuser:ct~ntvsiservrreeyeggosaarmrgrdadailnil~nsnggwussemttiuubg@dehsrsddoeehsfsaiaigvgnneni.m.baeelsn trrW,ee~ipplfeolocrrntttsoeedodniiinnnmclooauttlhdheeeerrrasesstpturucdoodid-ewscusrcitbbiiuvuctetalaaotterfmgmfaieunccctshhawthheiitggihghihhseertrrsiddhmooaessve|ee llbeevveeeellnss.. dd.. GG`WlliuuscctWooasrsileeRlan8&t:osltli(iippnGiicdDdlOuHhdo-omemPeNaoeDsos2tscta0oas)-siciss(riLDtDyiecevacvetlealellooffpp2e0cGG1taa3avr)taatggheeissstttiuumddeyy.]iinn W@@00i.s.ts55atrmmResg/eaikrktsgug-m-(ddGcDaaodnd0gmm-eiPninnNtrddDaoot2ssi0eeo)n((s(bb=Laa<vss4ee0eddtuooaglnn/2BBm0uul1tt3)ee-)nn[hhoBoffWffcet&t aallgl22u00c00o90se . 2yrdtetiosocltlteesarreraarynuncmcseetcuiindonynoociffenffnssSptpprrrariitaninogggnues<-D4a0wulgeyimRLa)t - s +BW & glucose (Thomford 2002, e. 2BB@0uuy.0ttr9ee8dn1ai0heh.ot1ao2frffcye(TttsaMtaulldF22y00)11in22m))Sparagdue-aDdamwdleoyseR(abtsas(eTdhoonmSfeoardca2t0e0t2, @0.aa0hlli9s228t00/o000l.33o1g2eiecst(atMlsse/ecFrrhu)ualmmnnggcce!oosknngcic-nedenlnatirdtvaemrtriao&dtnosis<[o<es4n4e(s00brauuusggme/idmmgLolL.un))coS--seeacat et @@00..2h2204i4s2/0t00o.202lo399g99cisc((taMVlsI/ccFFrh))uammmngggcke/oksgngc-ie-nddntliaarvdadetmmri &ddooss+eese((rbbuaamsseeddgoolunncSoSeseaeaccaatt ons <40 ug/L) - eett macroscopic & al 2003 cst scrum ]'macroscopic & hhciolssnttcooemmnootrrrappthihooolnlosogg<il4cc0aalluffgii/nmnddiLinn)gg-ss iinn lliivveerr `DDrraafftt DDooccuummeenntt- ffoorr rreevviieeww aanndd ddiissccuussssiioonn pptuur'ppoosseess nolnylB.yR. ODDSrra-af5ftt3dd.oo0cc1uu7mm5eenntt ddooeess nnoott consti constitute AAggeenrcey ppoolliiccyy PFOS - 53 of 75 22447766..00005533 SSTTAATTEE 0077443388114488 T11(1M0toa5r5inddaaeyytaoolrraa2ll0gg0aa7vr)aaggee ssttuuddyy iinn ffeemmaallee SSpprraagguuee--DDaawwlleeyy RRaattss c@(@oMn11ca0e0rntmtminrggaek/tktgigao--lndds2l0aai0ddk7mem)lyddoo<sse4e0((bbuaassgeedd)oonn-CC[hh1aaTnn4gg&ecttIaaTll42200&00T883sseerruumm concentrations likely <40 ugimL) - J,tT4 & fT4 &iT3 MMiicc7ee. - Developmental study in Pregnant CD-1 Mice (GDI-GDIT) 7. D(@(TT3ehb3vii.ebb1loooddpueegmaa/uuemmsxl.aeetltaaasdlltum22d00yd00o33isne&&P1rLLemaganuynaheentgttaadCll]D2200--10033DM))e:viceelo(pGmDen1t-GalDe1f7f)ect-s 8. @dd2e8e3llda3aay.y1yeeddourgeea/yylmeeILoomppm[eaeundnnimionntggdooxseGa1vmagge/kgSt-du]dy- Developmental in B6CSF1Mice effects- (Peden 8. A2`@8A2dd0ada,mam0yss8oee3trtagaalll/k22nm00mL0088u)[)n2o0t.o0x01G7amragg/eksS-tdudaydmindBos6eC]3F~1suMppirciess(Pioendeonf- @@>>10SS.0R8R8BBu3CCgugrr/eeimmsspplLoonns[[s>ee0,0,..00001177 mgikg-d adnr dose] - suppression 0.166 mg/kgadm dose] - Thymic of Tell, @>1dNN.o8KKscueacglelielmlvleLaalccstt[i~i0vv.~ii0ttly0yu1&&g7 m-llyly0sso.1noso6soto6mmcmeeongaas!cciktstigitvv-eiditntytya/[wdMimMtDhDdHooHtsNheNe]oort-teesss~t::u'tdhe@ iyfefmsceciactsssTaea-ttlcelll, adaussosesccdeoo1nnl0eccveeierdrlennsnsst<irrfe~ey~glcuaaorgr-dd/ei~inrnLiggcnddaoalatteiacfofrreneecppsoiorsarttteiinnntgtgh.w.isiTTtthhhieemosseeteh|.eeeffrffeescctuttssdiwwiel sillannsoowttbebleel 99.. 66@00>7ddua.aysy4eIduImmtgommuiu/dnneoLontttiooj[jxx0..,0GG8c3aoamv-rgcaarkggieetei-cssadttuluddaeyfydt'mc((ioDDtnooadnntoggtshceeit]ts-aatllim2200er0e.0]l99))liver wt, splenic @@>>37NN.64KK7uccgueeg/lml/llmLlaacct[t[i0ivv0.0i.itt84yy31,,7m~|mSSgR/RgkBEg/C-Cddssappdaeemcdcimiiffniiinccdodi1|ogsesMM]e]- ]" - tel liver [BWG & wt, Tsplenic | relative spleen&, thymus @>36.7 ughnL [0.417 spleen, & thymus wis, Ispleni&c thymic cellularity mg/kg-d admin dose] - ,~BWG & ; relative wts, ~splenic & thymic cellularity MMoouussee sstaut. ddy2--8mmdeeaaayssuguarrveeaddg((eaattsttteuerdrmymiinInaaCttRiiooannd))ulssteerrmuuamlmeccooMnniccceeennt(trrQaaittuiioocnnt al 2013) a. 2@@822.d.55aymmgyg/a/vkkaagg--edd are reported in asaFtdidumgmduyrddeIooCss7.eeR(-(assdeScruerurlumttmmolccaioolnneccceeMlenlntictvrreaaactt(uiiQooolnniiuz@ @eatttteieamorlmmni2i&n0na1at3tii)oonn addareneerrdaarenenvgpgieoedmrmeteenendcntetionofoffcdFiceigesllurlurlelpaaty7yiee.)rorssn-,,o]f+e'Sbpelepiroidtdooiidlddi-yycemmesaltalllevsssappcbeeuarrromrmliiezccraee.ltlill[occnMooDu&unnHtt NacNoonotndtecesees:nv:tiItdrtaesitnsicddoei~nfosffififccrduaoi[lstmr1tuoF0paiatcgicocucurnureoarat7fewbbllulyoyteoescdsto-tnitiecmmesaatntetteesrabssteaeirrrourunimesmr.ap~pIeDaHr io cbbsoeeindcccleleoosnsseteirnattootmoiooirncresss.lfiiirgtoghimtsllyiFkeeiegxxluyccreeteeehded7s44be00urtuuuggcmo/mmcnioLc.ne,cnbbetanarstaserteiaddotoniosnonnaoospttaphhreeeerrar to `MgsgtrDureedHaaitteeessrrtittanhfhafmahnniacttdehheeictobbineescnnlecickrhhenmmlsyaarrtrehkkgejfabsorrerdriccunoomg--ccsriciiotcyincacalel.qn.utIIarnlnaitaatiydcoldndaisittn~oadonrn,e, MmmeeItt)hhHooddsootlaloofgfgihieeassd uucssoeenddc(ee(.erg.ng.s., use offormalin regarding study use ofjbrmalin as a fsa). qualiO, and as a.fixative). TThheessee eef[f[eeccttss wwiillll nnoott bbee iinncclluuddeeddaass ccoo--ccrritiiciaclaatlt tthhiiss ttiimmee..]| MMoouussee sstbu.ediseDse--veeelsotipmsmaenttetdaslsieerIruummmmmcuocnaoncnGecatnevtnartregaaettiisdootnnussdy CSTBLAGN Mice b. (@D(GG)cDDvIcml-l-go11p77/)m)kc((gKnKeteaaiilldl cmletmtdmaalolu2s2n00(00Gb88aa))sraedgeo study n Lau C57BL/6N Mice et al 2003 est serum cMc@ooo1nnfccfemesnnpgttrr/rkaiagtntii-godonnassd~~m<<44d00osuuegg/i(mmblaL.s)e)d-- Suppressed NK on Lau et al 2003 Suppressed NK aaeccstttiisvveiitrtyuymiinn c.. M2221100odd9faa)fyyspiirmimnmmguunnee cchhaalllleennggee ssttuuddyy iinn BB66CC33FF11 ((GGuurruuggee eettaall 20@0.000.90D2)2o55ngmmycg/t/kkaelg--eddstaasddemmruddmoossceeon((cbbeaanssteerddatooinnonPPsee<dde4n0e-Anug-d/amAmld.s)caet-mtasall && Dong et al est serum concentrations <40 ugimL) - `DDrraafftt DDooccuummeenntt- ffoorr rreevviieeww aanndd ddiissccuussssiioonn pptuur'ppoosseess nolnylB.yR. ODDSrra-af5ftt3ddo0oc1cuu7mm5eenntt ddooeess nnoott consti constitute AAggeenrcey ppoolliiccyy PFOS - 54 of 75 22447766..00005544 SSTTAATTEE 0077443388114499 Influenza A. ~Lssuurrvviivvaall iinn t(rrtt aanniimmaallss wwhheenn cchhaalllleennggeedd wwiitthh Influenza A. Monkeys Monkeys 10. 26 wk Capsule sd in Cynomolgus Monkeys (Scacat ta 2002) 10. 26 week Capsule study :in Cynomolgus Monkeys (Seacat et al 2002) @@177..77 uugg/m/LL [[00..0033 mmgg/ikkgg--dd aaddmm ddoossee]] ----- ,|~HHDDLL cchhoolleesstteerrooll ((FF)) bbuutt not clear dose response until ext dose level up. not clear dose response until next dose level up. @@3388 uugg/i mmlL. [[00..1155 mmgg//kkgg--dd aaddmm ddoossee]] -- ,[~HHDI)LL cchhoolleesstteerrooll ((FF)),, ]r'reell Tivr wt (MDH BMD, = 20 gin) liver wt (MDH BMDI, = 29 ug!mL) CorCritcal Effects: | RatsSWD:eehtsivcsilttolypomgwieitnchiaalalbci(heamantagielosnd)ceh,faenHcgtesep.satpniuccph(oBelrWe)s,trsodalectereelass()e1dc.igTgluhhctorsoe toClE)erance, Co-Critical Effects: Rats: Developmental (sternal defects, lpup BW, decreased glucose tolerance, cchhaannggeess iinn lluunngg ddeevveellooppmmenetn,t, |lssmur~vi'ivvaall,, ddeellaayyeedd eeyyee ooppeenniinngg,, ~Tmmoottoorr activity with ,~habituation), Hepatic (liver) systcm ('~v~eight w/histological changes, changes in cholesterol levels), Thyroid (E) ((+Immaatteermnaall && ppuupp t(TT44)) DDM"MeiesicSvcceeel::lRooppBmmeeCnnttaarlles((dpdoeenllasayey,eeddNyeKycecloolppeeannicinntgg)s),,.IImm|mmpuuennenssyysasnttedemmth((yiimmmummsuuwnneeeigsshuutpppp&rreessssiioonn callanty) - e g., SRBC cellularity) respouse, NK cell activiU, ~ spleen and thymus weight & MMHooonnpkkeseyyss(:iver) stom (changes in cholestrol. | lative lvoe eight Hepatic (liver) system (changes in cholesterol, ]" relative liver weight) Teal ttealth ndponis Endpoints: Cea Critical Fp~ Endpoints- DDeevveellooppmmeennttaall ((ppupp bbooddyy weight x~,eight) CsCyoosr-tCtemrii,ctiTachalyl rEEonnidddpp(ooEni)nitss ~ - Developmental, Developmental, Hepa Hepatic (ven (liver) yim, system, Immune Immune system, Thyroid (E) iB.mmNaonno-lcaongcie,rdEefvfeelcopt-mseHnetaallt.hrSetparondduacrtdisvSetnaetuutreotHoexailctihty:Effects, Specialty Study Summary(e.g., endocrine, [evNNaoolttueea:tA&ioccnoowmmhppillceethteereeevlviaaellduuaauttpiiooonnn oEffPttAhhee tt~ze:x~iicdcaollgoiagciecasalslmiteeernraatttuuarrneedwwkaeass nnsoout dccoonnidddueucnctttieefddi,.caAMtiIDDonIII(cEcooPnnAddu2uc0ctt1ee6dd0aa)|.ffooccuusseedd r-re- ~'ah~ation ~h~ch relied upon EPA ~s" hazard a.~sessment and k~v study ~dent~fication (EPA 2016a)o] Endocrine Eos Endocrine Effects Teed Tested: YoYes Observed: Y YNeuesmserous human epidemiological studies have valued thyroid NhhPoouOrmmmnScoornnoReeuesslleuehvlvuetelmslssafaanrnnoddcmlp/ootirdrhcttshmheyyirrosootliiodddgiddiccisiascelhaesastvseuediinipnersaaossvhssiaoodvcceieidaaettliivoioamnnliutwiaettidethhdsusstpheepryroururmomtidfor aPainnsFkOsasoSfsco.oricRaoieatdstiiiuoolnnnts.dfSSrettorrcmooennntggheceerrysaeaossssrstpooucosdisaiaeittsiooihnnnassvawweneeptrrre-oTvffoPioduOuennadddnltiiininmbppoitdoaeippdeuussllau(itpaioopmnnoass~rkaaftteorr for autoimmune thyroid disease) risk for iodine deficiency or positive for autommmne thyroid disease). anti-TPO antibodies (a marker Studics in laboratory anihmacareplortsed deceased serum Studies in laboratou animals havc reported dccrcascd serum dhyrod evs, in particular, tyros (14) in offspring and adult thyroid levels, in particular, thyroxin (T4)in offspring and adult FS ------ Draft Document - for review and discussion pro'poses only. Draft document does not constitute Agency policy FOS 550175 PFOS - 55 of 75 22447766..00005555 SSTTAATTEE 0077443388115500 hInmlnmulnoolgoigiec Bles Effects DDeevveellooppmmeennttaall EEffffeeccttss RReepprroodduuccttiivvee EEffffeeccttss "aCnhiaamnnaglesiasafitmneeoxxatppaoollssuuasrrneedllfeervveeeellssTsasiimhlaiavlaetr biinneemmnaagignnidittuueddeentoaotstthahieecccforr-ii<titiirccieaatllcdceaflefcectt. eCeffhffeeaccnttgsseaasnniddn TTtohhtyyarlrooaiindddhhfaarsseebbeeTee4nn hiiaddveeennttibiffeiieeednd as an Additivty Endpoint identified as a co-critical as an Additivity Endpoint. |TTcsotcds: id| Ves Yes ObOsbeserlv~e,edd: Yes Y AbAeetffsewewweehhnuuimmmaamnnuneeoppsiiuddpeeplmnriieoosllosogigyoynssttmuueddaiiseeussrhheaasvveeaneedvvaaslleuuraauttmeeddPaaFssOssSoo.cciiaaHttoiiowonenssver, obnnfoeoitwncclfleeeeeaacrnrtiaaiossmusssoomccduiiiaansttoeiiosaounsnpssepwwreeersreseiorreneppmoorretteaedsdubbreeesttwwaeeneednnssseeerrurumummPPPFFFOOOSSS. Haannoddwrreaavtteeessr, of infectious disease. sSSettvuueddriiaeclssiiinnmmlluaabnbooorlraaottgoori~ycaanmneiiammsauallrsseshhaa(vv5ee,sshhsoouwwpnnprttehhsaasttioPPnFFoOOfSSSeeRxxBppooCssuurrreeespaalolttneesrress `asaeennxvddpe/oorosarrulrnnieaamttluumerrvaauellnlkskoiilslloillgeemriricclcaeemrllletoaaacscttutihirveveiitsPtyy)O(.)De...gSS.oo,TmmhsueeepoopIfrfmtetmhshseueisnsoeeeneeSoffyfffeesSccttRtessBomocChccacursuerrsbapaetotennse eiiddxeepnnottisiffuiireeedd laaessveaalnns AAsdidmddiiitltavivriitttoyytHhHeeeaaPlltOthhDEE.nnTddphpoeoiiInnmttmaannuddneaa database System has database been auudnncdcererertstaasiinntthtyye nffaeaccettdoorrfohhraassadbbdeeieteinnoniinanlccootrreppstooirrnaagt.teedd iinnttoo tthhee RRIfDD ddeerriivvaattiioonn ttoo address the need for additional testing. Tested: ObOsbesrervveedd: Yer Yes Yes Y HHbeueutsmmwaeanenneepppriidedenemamaiiloollPooggFyyOSssttusuddeiireeussmhhaalevvveeelsssuuaggnggdeesltseotdwaeearndnbaaisrstsshooccwiieaaittgiiohonnt owen, this association has not been consistent. between prenatal PFOS serum levels and lower birth however, this association has not been consistent. weight, sSSettnuusddiiiteeissveccoodnnedvdueuclctoteepddmeiinnntllaaalbbooerfrfaaettcootrrsyy. aaDnneiicmmraaellasssehhdaa~vpveuipiddbeennotdtiiyffiieewddeissgeehvvteerraall `sataehppenppseebiaaatirsrvssiestotoodfebbtveeheaealommRpooemnfneeggrnttethahneelceemmfofDoseostctstsess.eeannDnssediitcticrvieoevaresrefeefffdseepccpottunsspdaaibnnndodg,d,syiicnnwrppueaamitrgt,,hfftoorrmmss `tcrheocepnoocbreatnnseictdsraecothinfoattnnhogeroeffRsacceotiofnneniemrceeoaenmlnrc.enerAADepollrisiomemdiiuattcenetdddivnnceuoumrdrmeebvbseepreloooorfnfpdmssitnteuugnddtiiseeeassrnuhdhmaacveheaaanllgsseoo.s in erefennopelerolrggorytwyeidmmnegcethetaaaxbbnpoogollseiisussrmimen((dmceu..garg,li.c,gngglreludupcecrovoosedsleeuocllpeteimvvveeeelnlsstd,,cllvAiipdcpidilddoitpmmimeoetnctaaanbbltooaellfniifsdsemmcct))hs.angcs in fiilnoenvlccellloluus~d.dviiinnnggg iiennxccprroeeasaussereedd dppuuurppinddgeeaadttehhv,, ewwleoerpreemooebbnsst.eerrAvvdeeddditaaittohhniiagglhheeefrrfeeecxxtppso,ossuurree levels. Tested: ObOsbesrervveedd: Yes Yes Yes aY AAsessssommcaialallltinnounmubbeetmrwoeobfefhnhueupmrmearacnnoneecppeiipddteeimmoiniooslleoorggyuymsstPtuuFddOiieeSss hahanavdveegrereesptpaootrrittoeenddaalann d`adsisieaasrbboueecmttieeaPsstiFoaaOnnnddSbeppctrroweengcgeennenaantnnrpccaryyteiciiononndndsucuoeccepefddtiohh0nyy.p0pse1ee2rrr-ttu0ee.mnn0ss1iiP7ooFunnOgiiiSnnmLpap.noopdpTuuhlglaeeatrstiiteoaontnhissaosnwwaiailtsthho. dsbeeeeecreunrnmeassosoPemmFdeeOfeSeervvtciiidoldieentnnyc,cceeenhtooorfawfateasioessnsorosc,cioiacaftotii0noo.c0nnes1sm2bbs-ee0to.tw0vw1eeer7enntuhsgseee/mrpruouLmsms.PiTPbFFlhOiOeStrSyeahtannahdsda.atlhsios is due to reverse causation have been raised decreased fertihty, however, concerns over the is due m reverse causation have been raised possibility that this `DDrraafftt DDooccuummeenntt- ffoorr rreevviieeww aanndd ddiissccuussssiioonn pptuur'ppoosseess nolnylB.yR. ODDSrra-af5ftt6dd.oo0cc1uu7mm5eenntt ddooeess nnoott consti constitute AAggeenrcey ppoolliiccyy PFOS - 56 of 75 22447766..00005566 SSTTAATTEE 0077443388115511 NNeeuurroottooxxiciciittyy EEffffeeccttss Tested: OObbsseernveedd: SSSettnusudiditeiisveeiisnnenaladbpboooriarnattto,orUywiaatnhmimdmaealclrsseaddsooesnmooittniimnnaddliicceraateteeprthhoadatut cfEetrirtvileiibo.r"giissannnoott3a twsweeeesniigtsghiehttsitsv-s,eb, addereeniccderrpeedoaaiisssneertdud,pweetppiiioitdhndiaidddseyaecmnxraeaplalossssepupsreeri:rnmmlcmocovaouelunesnthrt,,eiapganhrnodeddrtuehvctieaidvviedenetnchoceoerogsoeaffncbballuoosooiddn--g tdpdereesovvttceeelsloc-obippavmmreerenionetfttraahldleittssoorexxuiipcecftiiifttoeyycnt((ssas.eteesexaabpbooovsveue)r),e. Therefor, he RID wouldbe levels higher than those causing Therefore, the RfD would be protective of these effects. VesYes | yes Y DDbeeeeevsvneellcoooppnmmdeuencntttaealdl nnieenuulrraoobttooorxxaiticcoiirttyyy aaannniddmaaalddsuu.llttInnneceuruerraoosttoeodxsmiicociitoyyrssttauucddtiiieevssithhyaavvaeend dsbdeeeescectrnraeetaacissooeennddadluhhacaatnbbediidttulaianattciiltooaannbtoooirfofamntmoaeralyxleepoaofonsffiufmsrsppearrliasint.nggIlnewwvcaeralsessarsrseeeppdioommrrtteioeddtloo[frtabohallerlclootiwwrviiiinnttgyge.sa!nd eagerffeeffsetecantticaononndmdaplhhaaaasnvvsdebeldebaeecbemynnttiiiohnnenccallDulueddeveexeddplaooacpssoum-crecoenr-ticaatrtililteicAcvadaeldlliseetffsvfficeimtctstiys.la. ErTTnthdhoepetosshieeenteec.ffrffiectcitctssal aRRmreeeesmsuueolnlrttcssyoffmrironopmmaasnsssittemuudaddlibisecyssetuxuhpsseiionnsDggeedwwvadeatlutoeerrprimmmnaeadznzeteeavleteesAlstotdsspdmffioeotirnrvtllieotcyararmEnaisinnnadggdpuoaalinnntddts. have vielded inconsistent resultsoreffets onlyat higher dose levels memory in animals exposed during development or as adults have yielded inconsistent results or effects only at higher dose levels. NOOtOthTheEerr:SStThtueudfdioileelsso/EEwfifffneegccstttssu/dCioesnhsaiCdovneseirbdaeerteaitoninonissncluded ecause activationofPPARahbaeesn sedas rationfoawlhey effects observed in rodent are ot applcoahbumlancs. NOTE: Thefollowing studies have been included observed in rodent are not applicable to hnmans~ because activation of PPARahas been used us ratiomde fi)r why q,ff#ets PPPPAARR AAccttiivviitty-y- ((UUSS EEPPAA 220011663a)) iISnntuVVdiiitterrsoohave been conducted inorder to determine if PFOS activates PPARs. The PPARS are members ofthe nuclear RhhSeootsurrmpdmoiooennsnseeeha1rrveeecceeenbppdettoooergnr esscnuuooppneuedrsruffaaacnmmteiddilleyyixonoofogf erlldinggeaoarnundtsdo--aladcicetgttiaievnvrdaamstteeianddnedttrirafaaPnrn:ssFccaOrrsiiSsppotticiaoiocnnattivffeaaadccttetwoosirrstsP.h.PTTlAihhpReeisdssee.mTeffathacacettbooPorrlPssiAccsaaRmnn,s aeaalnlrtteeeerrrmgggyeoelnnhnoeebmeeeerxxosppsrotreeafssstssihiiseoo,nnnauiinnncdlear hcrceeeasllvlpeoddisniffpsffeeeecrriteeofnnitcetiinaartdtoiiolooengns.e. ndTTouhhrueeisnttaghhnrrddeeeeeveexttyyloppogeepessmn,,eoPPnuPtPsAAalRisRgcaw~,ne, ld4[l3s3/~a,a,noodnrr a17t,r,heaaerraaeesdseeuolnnctcciaoo(tddTeeaedddkawbbcyiysthddaiinlffidpffeeidArreebmnnbtteoggttaeebnn2coe0sls0,i,7s)elen.xx,pprerenessessregeddy in many issues, and homeostasis, and in many tissues, and have specific roles during development as well as in the adult (Takacs and Abbott 2007). able 3:21, Summary of PEAS Transactivation of Mouse and Human PPARs, 16, 1d1 e w e Prroosx . Foosx ros E3"D0E inpelt Zowoat xa p oe LOEe C low caonesco0n0str: ov cscs) ch he as compared t~ ~l:e ~egati~,~ control {[p < 0.05) ANa NNNaaa nics icc ~NA = a~ ac~P~ted W WPoPloAFlcRfteqatlaa|cl.ti((v22i00ty0088c))otuteelssdtteebdde PPiFFnAdASuS,c,ediinniccnlluutdrdaiinnnsggiePPnFFtOlOySS,r,attnoosfddeeectteetrremmdiiCnnOeeS~w-h,h1eetcthheelelrr ammsosoauuysss.ee aaTnnhdderhheuusmmulaatnns were: LPNNPOOOAEEERCCC~---a966c000tivymguimotmyoollcl o(((u4mm8lodo.u4usbsepee))/:i;nm22d00u)cmge(mdomoolinlus((terhha)uun:mmsa3iaen0nn))ptlmyotlra(nhsfuemcatne)d COS-1 cell assays. The results were: C20max - 94 ymol (mouse): 262 mol. (human) LOEC - 90 gmol (48.4 ggimL) (mouse); 30 gmol C20max - 94 ~tmol (mouse); 262 gmol. (human) (htmaan) `Draft Draft Documen--t Document - fofor evi review and and discussion discussion purposs ptu'poses oonnlylPy. .ODDSaraf-ft7ddo0occ7uumm5eenntt does does not not conte constitute Agency Agency policy policy PFOS - 57 of 75 22447766..00005577 SSTTAATTEE 0077443388115522 oZZfhhaahnnuggmaeetntala.Pl.P((A220R011.44))AeeuxxtmahmonirinnseecddottnhhceeluddidirreeedccttthbbaiitnnddPiiFnnAggSppsrrooippneedrruttciieeessdooifsfrPPuFpFtOOiSSonaaonnflddioopttihhdeerrhPoPFmEAeASoSsstuussaiisnanggindstthheeinllfiiglgaaanmnddmabbtiiinnoddniinnbggy ddtoohemmaaiinn coPPaPfPrAhbAuoRnmR~s,a)pp.naaPPtthFhPOwwASaaRyydyaia.ssspAwwlameyelhel odaalsrsstttlhhcheoesnPPtcrPPlouAAndRgRee~dsaxttpphaaaactttthhiwPwvaFayatA.yi.oSnAAspmmionotodnenunggcceytthhdeeisttrhhurrpeeteeiommneeommfbbelierprsisdoofhfotthmheeosssuutllaffsooinnsaatateendffaaimmnifilllayymttemesstaieetdidon((44,b6,y6,,thaanendd 8 carbons), PFOS displayed the strongest activation potency. IIMnnarVVtiiivvnooet-al, (2007) administered PFOS to male Sprague-Dawley rasby oral gavage at dosesof 0 or 10 mg/kg/day oMffoonrragr11et,i,nn33,e,esootarrasl5s5. o(ccc2ooi0nna0sts7eeecd)cuuawttdiiivtlvnheeindfdaiaasytytsyes..raecdPPiFFdPOOFhSSOomSeeexoxthsohitibabmisititaeesledd. ppSPeepFrrroaOoxgSiiussweoo-ammDseeapwpporrlooeorlylliiyffreeacrrtoasarttobroeryr-l-aaoactcrettaidilvvgawatiateetrddahgrrpeeeeccraeeotppxtdtiooorsrsoeaamslleppohhpfaar0oaalggoioorfnen1iri0sastttlo--nlriigskk/eeikngce/tffdhfcaeeecyttss gccoolnlororbgbeaeallnlaetggsieeonnaneestseeooxxcPppirarPeteessAdssiRiwoonniatghppoaanfttiattesttetrynmtssarceaaainndtddmheiinonntmdd.iieccoEaaxsttpteearddseiwwsss.eeiaPaokkFnOmmoaSfattHwcchhMaeesGss-pwwoCioitotrhhlAyhheercppeoadarturtoeoctlttoaoaxtxseieicdciwitwtayyistrrheesllipaagettnereiodfdi~scssaiognitnmlgayetunuprpearrosaetlgainfunuedldrawratweteoeaedrka,ssk.ainndthe cholestrol correlation cholesterol tbboiiooPss}Py~nAattRhheaessiaissgwownaaissstddtoorwewnanrtmreegegunultl.aattEeexddpiirnnesaasimmoanannonnfeerHr MssuugGggg-eeCsstotiiAnnggreaadmmuecectcahhsaeannwiissamms distinct from significantly distinct from utthphereegssttuaatltiainntses.d. ,TThahneeydy aallssoo nnaonotdteecddotnthhsaattittPPutFFiOOveSSaecnx~dhuriobbsiitttcaedndessirimmeicilelaaprtritotiricc(ssCttAooRc)c.oommppoouunnddss tthhaat iinndduucsc xxecnnoobbiioottiicc mmeettaabboolliizziinngg ecnnzzyymmecss tthhrroouugghh PPPPAARR and constitntive androstane receptor (CAR). `W eWxapanrneggsseetitaolan.l.c((h22a00n11g00e))sddioonsspeeuddpaasllbwbiiennrooeW Weixsisattmaairrnffeeedmmaaollnee ParaNitsDs :wwiit1thh.7,33..a22nmmdgg35.PPFOSOiSaSnk/ikfggicddainicetttefffrrfooemcmtsGGwDDer11et0oobwwseeearanvnieindnggon((PPgNNeDnDcs2211)).. GGeennee aieinnxnvvpdoorplelvseseesrddiooxiinninscnnoheemauuenrrgoopearacsoctltiiiinvvfeeeprulaliptigosgarawn-naddec--rtrreieevcceaeextppeatdtmoorrrineiicennedttpeetorroaanrccttP(iioNoPnnPD,,AsccRaa)1ll,ccs7iiiu,gumnamanlssdiiingg3gnn5.aa.lliSinnigggnppiaafittchhawwnaatyyessf,,feccceetllsl communication th cell were observed on genes communication, the cell ccyycclele., ,and peroxisome proliferator-activated receptor (PPAR) signaling. IeIntnalaa. 44--2ww0e1ec2ek)k ssGttruuodduyypiisnnorrfaast3s,0, ttmhhaeelhheeeppSapatrtiiaccgeeuffeff-eeDcctatsswlooeffyPPFFrOaOtSsS,,wW WerYYe-1-a14d4m.,i66n44i88staaennrddedpphchieetnnhooebrbaar2br0bitiptaapllm((PPPBBF))OSww,eerr:1e0cc0oopmmpppmaarrPeeddOS((E,Ellcc5oo0mmbbee: pepextpphmamilb. iW W2t0sYY1t-21h1)e4.4,c,G66o44rm8o8b,u,ipoonsrer od55f00e300f0fppempcptmmasloePPfBBSWpiiYrnn-agtt1hhu4eee.-dd6Dii4ceat3twaaalddenydlliibrPbaiBitt,utsumwmbeeffhoroearrvcaeiidinttmhgheei2rrnsi11sa,,te7c7r,,oemoodrbrei22in88theddedaaryyps2se.0.rpoTTxphhimeesossPttmuFueddOyypSrsso, hlh1ioof0wwe0reeapddtpottmrhhaaatPtnFdPPOFFOOSS,S.50 ppPe.hhX'deeRann.iobobibtasarrtbhbieittaacllo--lmiikkbeeineeenndzzyyemfmfeeeciitnsnddouucfceVerr.~. 'T~T-hh1ee4,dd6aa4tt3aa suggested that POS and PB, behaving as suggested that PFOS may activate not only PPAR, but also a combined peroxisome proliferator and may activate not only PPARa, bm also CCAARR aanndd PXR. wTTiooladas-sstseyespsses aPPnPPdAAPRRPiinnAvvRoollvkvenemomceenkntotuiitnn (ddeKevvOee)lloomppimmce.enntAtaasll etehffeffeerccettsssuooltffsPPfFFrOOoSmS,,tAhAebbbwboiotltttde-etytapalel 22a00n00d99KbbOrreeddpummpasallweeeaarnneddsffiememimlaaallree, t11h22e99S5au11t/ihSSovvrihmn. wcaccooitnnlidccv-llatuutydidpoeeenddattnhhdaattPPPPFFAOOSRS-a-iiknnndduoucccekeddounntee(ooKnnaOatta)allmllieecttehh.aallAiittsyy tahanneddreddseulelatyselfdreoeyamyeeotyhopepeeenwniiildnndgg-tywwpeeerreeannndoottKddOeeppepenundpdesennxtt~ooernne the PPARa, silnilar, the the PPARc~ author activation. SQQtaauzzdiyi eetitanald.li.c((a22t00ed0099t0ah)a)ttteteshsteteeddimtthmheeuenfeofffmeeocctdtssuolofaft00,i,o00n..00w00a55s%%p,,aorotrria00ll..0y022d%%epPPeFnFdOOeSSntoonnonwwiPillddP--ttAyypRpeeaaacnntdidvPaPtPPiAAoRnRac-~n-unlulll 112299//SS+v mmiiccee.. TThhee study indicated that the immunomodulation was partially dependent on PPARa activation. CoCrhhaa1nn0ggmeegss/ikinng/ggdeeannyee eefxoxrpprr7eesdsssaiiyoosnn(wwReoersreeeneexxctaammali.inn2ee0dd1i0in)n.wwSiiltdlu-ddt?y-]~tfeiyananpdnidedngPPsPPsAAuRgRag~=exsn-tunlutllhlamtmiticcheeeraaeddammrieniniPissPttAeerrReeaddvPiPnFFdOOpSSenbbdyyeggnaatvveaafggfeeecaattts00i,,n33, nnnoueurlclle1ls0mmsamiirccigeel/kytthghaaa/tdtraaayllessofofooorlcc7cceuudorcarfymiPtsn Pwwi(RiAiloloRddsn--ettnyyappceeettiamvmali.ticcie2eo.0n..1TT0hhT)u.ush,sSe,tursseodosmymuleeftoisnofadflittnshhogeesslvuisvpeupegrorgrceetffsffttechtchottssasetiintfnhrtetohhrmeee wowatiriehlldedPr--PttsyyAtppuReedciaae~nns-iiimnmthadaaleltspsieaannrdrdeiecnnnaootttetefPfeFcOtsSin exposure results in metabolic changes both linkedto andindependent of, PPAR. necessarily a reflection of PPARc~ activation. The results also support those from other exposure results in metabolic changes both linked to, mad independent of, PPAR-a. studies that indicate PFOS PTToFoxxOCCSaaswstatsAAstssessaatyyessd ---in 1,087assaysand was active in 175. Soomftehe data from the ToxCast assayssuchas the ioPinnnFttleOeyrrSaaoccb~ttsivioeaonsrnsvsteewwsdititeathhld cPPionPPnAcA1e,RR0nt8aar7nnaatddsisCCoanAAyssRRgarssnauudtppepwprooartrstthaatthncheettivheeeoxxsppieenercrii1amm7ue5sen.intntSaagollneddayaetatotoaatofffvtooihrreeiPPtdFFya,OOtaaSStfrraaionnbmddutPPtihFFneOgOATAt.ho.exIIConn uaccstaatsscaeesosssmawwtyheohseerPsreeuFcOeehffSffaeesrctattssthhewweererhreean ttohhneelyccysot~bootstoeoxrxivciecidittyyatiisscolleonsscssencceetrrrtataatiiinon.n. s greater than those causing cytotoxicity, attributing the outcome to PFOS rather than FFEosouturroddgieiffnffeeRrreencntetpeetssottrrroIogg-een(n rEreeScceReppIttoorrre((lEaEtSSeRRd,))saaussgssgaaeyyssstrireenppgootrrhttaeetddPaaFccttOiivSvhaatatiisootnnhffeoolllaloboiwwliiintnyggtPPoFFiOOndSSuttcrreeeaaEttSmmReIen.ntt,,PaalFlllOoofSwfwahnihticacghhonwwieezrreeed the aEannsddtrrrooogggeeennn Rrreecccceecppptttooorrr((1AA-RR)(E.).SAARll1tth-h)oourucgslhhatttchdhe,erresuiigssgnneoostddiniirrgeecctthtaccteelPlllFuulOlaaSrr echy?atsootttohoncxiicacibittyiylivtvyaalltuoueeinttooducccoocmmpEpaSraerRe,1, .PPPFFFOOOSSSrraaattnAAtaRRgoaannnizttaeagdgootnnhiicssmm `DDrraafftt DDooccuummeenntt- ffoorr rreveieiw aanndd ddiissccuussssiioonn ppruor'ppoosseess nolnylB.yR. ODDSrra-af5ftt8dd0oo1ccuu7mm5eenntt ddooeess nnoolt ccoonnstsittutie AAggeenrcey ppoolliiccyy PFOS - 58 of 75 22447766..00005588 SSTTAATTEE 0077443388115533 hooiccgcchuuerrrrreetddhaaatnt lliooswwreeerrspcceoocnntccieevnenttrcraaettliioosnnpssecttihhfaainnccttyhheetommtoiixnniicinimmtuymm ccyst~oottooxxiicciittyy vvaalluuee.. TThhyyrrooiidd rreecceeppttoorr ((TTRR)) aannttaaggoonniissmm AACCS500 wwaass higher than its respective cell specific cytotoxicity. cPPhFFeOOmSSokaaiccnttiievvaalttieegddanaadvv(aaCrriiXeetCtyyLo)offg1g0ee,nnCeesXsCrrLeellSaa,tteeddcottloolaiimgmemmnunutonytpooetxoIixciaicltitpyyhaiinn(ttChhOeeLTT3ooAxx)(CC,aasistnttddcaratltacabubakasisene.-.1TTahhleepssheea gg(eeInnLee-ss1)iin.nccplluulddaese::minogen acractechictcviemvapattotookorrirns((euPPbLLlfiAgAa)ma.)in,ldppyll(aagCssoXmmniCeinnLoCo)ggDee14nn00,aaCc(cttCXiiDvvCAaaLtt)ooS.rr, uuAcrrlooollkkloaiifnngaaetssnheee t(y(iPpPmLeLmAAuIUnIURoa)lRlpo.)gh, iavvcaa(asCslccOuuallLsaas3rraAccyea)s,lllwinaaeddtrchhereelscpsiueiookrnnfinomm-r1omolelaeedlccpubuhlylaeet(h((eIVvLVeC-ClnAcA0dMM,o)pr1,l)a,BsiaamonnSddiencttohkhge.ecnTTTNNhFeF vivrcseecnndciddfpooftrirocdrduilistddutbnnofooatdtmehhtiaalevyvreemgiaacnnceccx.vitaCtooltDtolov4xig0iceci(nitCteyyDAaA4cCtC0i)5vS.i0tfAyfololcreaovenfvetbhereciyyaitccmerelmilllbuttuyntypepoedelotuugottiiicllPiiazOzleeSdad..s.sGGaiyivvseewnncttrhhceepllciimrmtibittreemdd cccdygtobotytootxxhiiccciivttyyenrrdeeoffererrBeeninoccSeecvvcaakll.uuTeessheiitt is difficult to determine if all gene activity can be attributed to PFOS. cPPoFFnOOdSSucaatccettdiivvuaanttdeeeddrPPtPPhAAeRRTso,sx, CPPaXXsRRt,,pccrooongnsrstatiimtt.uuttiiPvveeOaaSddrrooisnsttdaaunnceeedrreetccheeepptDtooNrr A((CCsAAeRRq)u),,eanacnneddsrreefttoiirnnooPiiPccAaaRcciidadlrrpeehccaeepp(ttPooPrrA((RRR)AA,RR))peiinrnoaaxssisssaaoyysmse ppcroroonlldiiffueecrrtaaettdoorruhnhoodrremrmotohnneeeTrreoesxsppCooannsssteepeerloleegmmraeemnntt.ssP((FPPOPPRRSEE)i,n),daaunncddedPPtPPhAAe RRDNggaaAmmsmmeaaqu((ePPnPPcAAeRsRyf)o)raaPnnPddAaannRttaaagglpoonhniaizz(eePddPttAhheeRcPP0PP,AApRReYroxrreeisccoeepmpttoeorr.. iTTnhhdeeuoconenldlyyDPPNPPAAARRseaaqssusseaanyyceAAsCCfS5o00r tPthhXaattRwwaaatsscoaanbbcooevvneetrttahhteeioccneelslll--lssoppweeeccriifftiicchaccnyytttoohtetooxcxieiclcilit-tysypeAAcCiCfS5i0c0ewwyataosstoPPsPPicAAiRRtyy~ AaaCnntStaa0gg.oonnCiissAmm.R. aPPnFFdOOSRS.AR aainllpdphuhaaceaadnnttDaagNgooAnniisssmemquwweeenrrceeeasallfssooorooPbbXsseeRrrvvaeetddcobbunutct ennnootttraaatttiolleenvvseelllosswbeeellrootnwhattnhheethcceeelcllleslslpp-esecpcieiffciicicficccy~tcoyottmooxxtioiccxiititcyyitvvyaallAuueCess.5.0. CAR and RAR C. Duration Specific Health-based Water Criteria Derivation RelaHHtievenenrwyS'o'ssuLLrcaaewwCCCooonnnstsrttiaabnnuttt((iaoatrnmmm(3Rm/S3Cmim)lo)l)| PPFururereeshwwwaaattteeerrr::: 334..00.557xxx 1110009 || 3(3BMMasrreeedppooornrtt t11h99e99a99b3aosvcceiittweeaddtebbryysOOolEEubCCiDlDit23y00v00a22lues Fresh water: 4.7 x 10.9 aaa(Bnmnd,dasuuettdiillioiznziinntghgetthhaeebovvvaapepoowrr apptrreeersssssuourrlueebooiflf3it3.y.22v77alxxue11s00.9 atm. VVhat is the volatility~? Ts hore documentation to justify the use| A non-standard approach was uilized. See discussion below Is there documentation to justin the use ofan RSCother than the defauls?" of an RSC other than the defaults?2 No A non-standard approach was utilized. See discussion below. oma(25 TE7 sin asim, Low (5 TF TES a ml, odes (153 15.3 motor Th (TE 90 ma) Nonvolatile (<3 x 1E-7 alan m3/mol); Low (3 x 1E-7 to 1E-5 arm m3!mol); Moderate (1E-5 to 1E-3 atm m3/mol) or High (>lE-3 atm m3imol "Nam voltichon solider olay 1-5 or cutssbrt em. 0.2 for beh Non-volatile/low volatility/moderate volatility - 0.5 for acute/short-term, 0.2 for subchronicichronic High olay 02fo seu Ahort embebATo ro 3I tigh volatility - 0.2 tbr acute/short-term/subchronic/ctuonic RRFrSSoCCmaeevvanalaltuuiaaottniiaoolnnpfefrrrosopmmecEtEiPPveAA, (tU(heUSSdEEoPmPAiAna220n01t1664sd)o)ur(c(SeSeoeeefSSeheccuttmiioaonnn88e5.x5pfofoosrurrmmeootrroeePiiRnnOffoSorrmmisaaettxiipooennc))t::ed tobe from the die; indoor dFdAudursovstimt sfforraoromynma(tcciaHaorrAnpp)aeelttwsspaemasrnsadcdpaeoolctctthhuievleraret,sseotodhuuerurccsdeieosnsmgaallaisnsrooaenliiaststsaaionnvueiirmscmoeppuooorrrctfteaahnnucttmonssatoonruuirrebccuxeetpoioofosfnuee(rxxeppotoRossuuPrSoreFe,fO,C2eeS0ss)pp%iese,cceiiaxwalphllleiyycctffheoodrraltccolhhoiiblwlddesrrefefnron.or.moEEtPtPhhAeAer''sdsPiFHeHOtee;Saa.illnttdhhoor ieeAnxxdtppavookissesuuorarreeytess(oHofuuoArrrcc)leeawsscta((aset..gic,na.,gdlcudwusuoltsatm,t,eedddniiceutt(,s,0iaan.ii0grr5))a4ttoorLeimmlakaatgkikvdeee)(uus0ppocu88arl0c0c%e%ulcooaofftntetthhriaeebluRRitAffiDeoD.tn.im(EEeRPPSHAACA)nufssooeefrdd2P0aaFnn%OR,RSwSSoCChifocohff00.0a.07.l22lyoaawynns,ddfttoahhrneedo99tr0h0teehcrppoPeemrFrmccOeeennSntdtisill.ee tetihnhxaatpattoksiiettuaarrpapeptpelslyycfeot1nor0alrbbaioocotttsahhtissnhhgoorwtr-ottemermenn((1(i.0e.,..0,5ww4eeeLekkikssgtt-ood)mmtooonntcthhaslsc))usslcaceetennaaarriiloiofssetddiumurreiinnHggApprrfeeoggrnnPaannFccOyySaaonnddf 0lla.a0cc7ttaatt#iigoo/nnL,,,aaassnwwdeelrllelcaaossmttomo lelinifefdetsitmimee- exposure scenarios. MMThDDeHHRSRRCSSCCisAAapppppplrriooeaadccthho:account for all routesofexposure and allocates onlay portionof the RD to water ingestion wwTviahilttehuheRttshhSoeeCfrreteismhmeaaaipdinnupirilnianetggdipoptnooorrsttapiicoeoccnnoifauaillnclltoodcfceoaaftrtaeeuaddllltffrooRorruSnntCoeossnn--o(ww0fa.aet5t,xeerpr0.oee2s,xxuppraooesnsudaurner0eds.s,2,afloiilnrnocccllsauuhtdoedriisntnog-gtneiilnrynhmha,aallpsaauottibirotcoinnhornaaonnnoddifciit,nhngageeensRsdttfiicDoohnnrtooffnrriowocmma,tefrfooerosoidpnd.e.gceTtTsihhtveieeolny,) a(avrraMeeluDbbeaaHssseoe2dd0f0too8h)nne.ttdhhIueenrtammhtaiaegognncniaiststpuueeddcoeeioffoifPcfcFcdoOoneStnf,artruitiblbhtuemRtRiiSooSCnnCsoofc(tf0oth.hn5ece,ses0eep.t2oo,tnthhaeeenerrddeee0dxx.pp2tooosfbsouuerrreaesspshpotthlrhtiaa-tettedoorccmicc,unuarsrufddbruucrarhiimnnreoggwnottihrchek, arrreneelldceeovvcgaahnnnritotzneeixixncppg,ootrssehuuesrrpeeoencddtuguirvraaettliiyoo)nn (MDH 2008). In the case of PFOS, the RSC concept needed to be applied in a framework recognizing the long `DDrraafftt DDooccuummeenntt- ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppruor'ppoosseess nolnylB.yR. ODDSrraaf-ft5t 0dd.oo0cc1uu7mm5eenntt ddooeess nnoott consti constitute AAggeenrcey ppoolliiccyy PFOS - 59 of 75 22447766..00005599 SSTTAATTEE 0077443388115544 elimination half-life of PFOS, such that a person's sermn concentration at m~y given age is not only the result of his or her current or recent exposures within the duration of concern, but also from exposure from years past. Egeghy and Lorber (Egeghy PP and M Lorber 2011) examined the relative impact of non-water exposures using a two pronged approach: 1) based on scram concentrations reported in the 2003-04 National Health and Nutrition Examination Study (NI-L~NES) and 2) exposure media concentration data from multiple sources. For the second approach Egcghy and Lorbcr sclcctcd exposure media concentration data from multiple sourccs in thc litcraturc to estimated daily median and 95th percentile exposure intaxkes for young children and adults from dust, diet, water, and air. Because of the sparseness of media-specific data, the anthors deemed the resulting intake estimates adequate for screening-level intake assessment bnt subject to considerable tmcertainty. This uncertainty was greater for the upper percentile estimates than for the median values. MDH has chosen to use recent NHANES biomonitoring data (20132014) and East Metro new resident biomonitoring data (2014), to estimate upper-end non-water exposures (similar to ooppttiioonn 1| iinn EEggeegghhyy aanndd LLoorrbbeerr., 22001111)).. MDH uses the Exposure Decision Tree process as presented in EPA's Methodology for iDeriving Ambient Water Quality- Criteria for the Protection of Hurnm~ Health (US EPA 2000). The Decision Tree presents a series of decision points at which the quality and qua~tity of available exposure data are evaluated and at which the derivation of the RSC is ultimately steered toward one of several conclusions indicating an appropriate RSC. MDH has relied upon the percentage method, which is intended to reflect relative portions of other (non-water ingestion) routes of exposure and the likelihood for changing levels within those multiple sources. The relevant portions of the Exposure Decision Tree are presented below. I Identi~~ poptdation(s) of concern ~ .Identif.~ exp/orsuerele. va.. nt Are adequate data available to dcscribc central tendencies & highends for relevant exposure sources/pathwws? No Are there sufficient data, pl\ysicalichemical prepeW, fate & transport, &/or generalized information available to characterize the likelihood of exposure to relevant sources? Yes .IYes Tn Tu Are there significant known or potential uses/sources other tl~an the source of concern? [apApppoorrtiotnttihheeoRRifnDD iinncclluuddiinngg 8800%% Spprosch with ceiling & oor) ceiliwj20% floor using percentage approach (with ceiling & Iloor). Yes ~ SA | Is theresome inft ffoorn~ mnaattiioo~ nnaavvaiali7 laabbllee~ to Yes SC. | PPeerrffoorrmm aappppoorrttiioonnmmeenntt aass. Yes 8C.~ erization of exposure? described in Box 13, with a 50% ceiling/20% floor. Draft Document - for review and discussion ptu'poses only. Draft document does not constitute Agency policy PFOS - 60 of 75 22447766..00006600 STATE 07438155 The $0 percent ling within th Decision Tie i 0 case tat heHealt basd goal will b ow enough provide The 80 percent ceiling within the Decision Tree is to ensure that the health-based goal will be low enough to provide adequate protein for individuals whos oa sposrs due fon of he expose sources,highor an chy adequate protection for individuals whose total exposure is, due to any ofthe exposure sources, higher than currently Inte by th nalble da (US EPA 000). Thi ss hreass the marin offy 10 aesunt for posi indicated by the available data (US EPA 2000). This also increases the margin of safety to account for possible unknown souees ofpow. unknown sources of exposure. thas buen seknowdged that serum conceratons ath best measurs ofposs, Ths vals canb usd in It has bccn acknowlcdgcd that serum conccntrations arc the best measure ofcxposurc. These values can bc used in lace of he RD in he Dison Tee process Th scum concentration at the POD sclctod by MDI1 (ad EPA) i place ofthe RfD in the Decision Tree process. The semln concentration at the POD selected by IMDH (mad EPA) is 5% nmi. The scr onsentraton soccd wih h olinRIwhich ncomporotfad UF of 10,15 6.26 ~tghnL. The serum concentration associated wifl~ fl~e resulting RfD, which incorporated a total UF of 100, is C06 ai or 3 HEL). Echo Goo poms um mova genio see) dts or he, is 0.063 ~tg/mL (or 63 gg/L). Background (i.e., exposure from non-water ingestion routes) data for infants, the populationofconcen, are not vals however, given the ong I ie th biomonitoring resus fom the Esst population of concern, are not available, however, given the long half-life the biomonitoring results from the East Rio row rent) and NHANES cs 5 wed o provide insight to the maghiteds ofnoler POSS. Metro (new residents) and NHANES can be used to provide insight into the magnitude ofnon-water exposures. MDH' East tro PC biomonitoring proc smpld a subctofpeople iin nthe ast Vet sion who were MDH's East Metro PFC biomonitoring proj ect sampled a subset of people living in the iEast iMetro region who were Comnactadto contained public wate supply (Nelson 2016 Treatment emons PFCs was ddd10h pul connected to a contaminated public water supply (Nelson 2016). Treatment to remove PFCs was added to the public Sater syst (PIS) and olumietparicpsnt ad lod eels measured st rs im: pots: 2008, 2010 3nd 2014: w2200a00t8e8r--sy33s55t..e77mggeo(PooWlmneSea)annan((dCC1Ivo331.l14u.4nt-ee44r00p..5a5)r)tiugcggip/iLaLn((t9s955ht%hadppeebrrclcoeenontdtiillleeev11e00ls00 mpgggc/iaLLs.,urrrcaadnnggaeet t33h.22rc-c- 4t4i44m88cugpggo/iiLLn))ts: 2008, 2010 and 2014: 2010-249gan mean (C1221 280) lL (95 porentl 695 iL ane 16-234 pg) 2010 - 24.9 geo mean (CI 22.1 - 28.0) btg/L (95*~ percentile 69.5 gg/L, range 1.6 - 234 ~ag/L) 22001144 -- 1188..55 ggeeoo mmeeaann ((CC1I 1166..11 -- 2211..33)) pggg/iLL ((9955t%hppeerrcceentnilte7i70l0..e00 pbgtg//LL,, rraannggee 11 -- 118300 pbgtg/iLL)) As pat ofthe lst biomonitoring fort nev Oakdale residents (N=156) wre also sampled n 2014. Since these As part ofthe last biomonitoring effort new Oakdale residents (N=156) were also sampled in 2014. Since these india dno has Hori Exposure 0h Com le ht Sum Samples cn cnr individuals did not have historical exposure to the contaminated water their seruln samples can be considered rreperepsernetastiveeonoftfMMianitnnneisesovotetaa nnoonn--wwaatteerr eexxppoossuureress:: 77..22 ggeeoo mmeeaannpggg/iLL ((CC1I66..55--88..00));; 9955tu ppecrrccecnnttiillce 2211 pggg//LL ((rraannggee 0.34.30 These ewes an higher ha the NHANES 20133 geometric mean and wil he confides inal of 0.34-30). These levels arc higher than the NHANES 2013-14 geometric mean and within thc confidence interval of he55percent value (shownbelow but ars naicabl lowe han the Eat Vict population hat we the 95th percentile values (shown below) but are noticeably lower than the East Metro population that were Hepa omc wr. historically exposed to contaminated water. I"Icti1ims0pdiomdrpriooarptnasnttit0eo nn2oo0tt0ee3tt-hh0aa4ttt(thhheeeggseeennreeuramsloppoolppusullaawttiieoonnd((iNNIEH-LAseNcNEhESS)a)nssdecrrLuuommrblxeervle2sl0s1hh1a)aveTbbhene2n0d1d5eec-r1ce4arsdianegavoprevsoreviritdnimemgeet,,howwimittohhst33 t0o r4e-cfoenldt daadrop rseingcaerd2i0ng03`-o0c4k(gtrhoeusnedrusmerluevmelseeulsesd iintEhgeUgShygoanndrLsoorpbuelrt2i0o1n1s).. The 2013-14 data provide the most recent data regarding 'background' serum levels in the US general populations. Genera population (NHANES) serum eels ha bn deseing ver ime (CDC 2017) General population NHAN ES) serum levels have been decreasing over time (CDC 2017) 55% C1 ssl ssacr) Year Geometric Mean (gg/L) (95% CI) 50th Percentile (gg/L) (95% CI) 95th Percentile (gg/L) (95% CI) 1999- 2000 30.4 (27.1-33.9) 30.2 (27.8-33.9) 75.7 (58.1-97.5) 2003-2004 20.7 (19.2-22.3) 21.2 (19.8-22.4) 54.6 (44.0-66.56) 2005-2006 17.1 (16.0-18.2) 17.5 (16.8-18.6) 47.5 (42.7-56.8) 2007-2008 13.2 (12.2-14.2) 13.6 (12.8-14.7) 40.5 (35.4-47.4) 2009-2010 9.32 (8.13-10.7) 9.70 (8.50-10.8) 32.0 (22.6-48.5) 200201 2011-2012 2013-2014 190052) | S0@0570 | 83054220) 6.31 (5.84 - 6.82) 4.99 (4.50-5.52) 6.53 (5.99- 7.13) 5.20 (4.80-5.70) 21.7 (19.3 - 23.9) 18.5 (15.4-22.0) W Whhiillee(Sddacathateooacnntinenrfa2nf0ts1i2iss)snnatomt paavvliadlilaacbbhllieeldtthreehnreeianarerDeappluulbabslliccTtaetiixooannsssbrreeetggwaaerrdedniinngAguttghhueesssteeraunuldn Nleeoevvleelssmbiinneryyoo2uu0nn05gg.clhRiielrdporeer:nt:ed median (Schecter 2012) salnpled children in Dallas, Texas between August and Novelnber 2009. Reported median nYodursmofuag.mRePpFoOrSodsedriumacnoanned nmtavaitmiuwomnePsRO2Snsderu10m cnutle,nieashpoencstweelt,: 3.c7 3h0dk73.o3swgthan thr m~d maximum PFOS serum concemrations were: 2 and 10.6 ugiL, respectively, in children less than three + yr(TeeeWssapapreesc2ctot0iifvv1aae5gyl.yes., mRiinnpeccplhohdirlitdecerdheninmldooerlldeddineearrnttthaohnaadtnn mthhirragexsheitmyycueeamaarssrPooofFffOaaagSggeesebbriunuutmCtleassclsointhhfcaaeinnnatSsribaxxteiyoeeenaaesrrsnswDooeefrfecaa:eg.3me..b7earnd202037.3 ug/L, and N o vem be r (Wu 2015) sampled children two to eight years of age in California between December 2007 and November 22000099.. RReeppoorrtteedd ggeeoommetertriicc mmeeaann aanndd 9955*~ ppeerrcceennttiillee PPFFOOSS ssecrruumm ccoonncceennttrraattiioonnss wweerree:: 66..2288 aanndd 1133..11 uugg/!LL,, spectively respectively. Dra Document for vi an dcasion poss nl. Dr document dos ro consis Agee pokes Draft Document - for review and discussion pro'poses only. Draft document does not constitute Agency policy BOS ol ars PFOS - 61 of 75 22447766..00006611 STATEorsastse STATE 07438156 + a((HnHdaarr2rii0ss1220001177)t)hrreeeccBeeonnstttlloyynppauurbbelsli.isshhReeeddpossrertreuudmmgcceooonmncecetenrntitrrcaattmiioeonnassnniannssdixx90toote tpeenrycyaeenartriololelddPccFhhOiilSlddrrseeennrussamammcpoplnleecddenbbteerattwtwieeoeennns22w0e0r00e77: 62a0d 137 ug/L, respectively mad 2010 in the Boston area. Reported 6.2 and 13.7 ug/L, respectively. geometric mean and 90th percentile PFOS serum concentrations were: c"TTohhneessseeervddaaatttiaavsesuurppepppoorrertsetthnhteeautuissveeoesoffoufupppbpeaecrrk--geernnodduppneedrr"ecennniotilnlee-vvvaaatluleessinffgrreoosmtmiNoNnHHoAAuNNtEEsSSofaannpddotsthhueerEEeaasstt MMeettrroo nneeww rreessiiddeenntt aass conservative representatives of 'background' non-water ingestion routes of exposure. ("TTihhgeehaappeppnodor)rttisioeonrnmmuemennvttattloouewwafatrteeorrmiitnnhggeeessrtteiicooennntccaabnniobbmeeoncciaatllcocuurlilaanttgeedddabtbyya tfaarkkoiimnnggthaaeccEoeaiilslitinngMgeootff8r8o00n%%ewaannrddesssiuudbbetntrrtaasccottiirnnNggHaAccNoonEnsSsee.rrvvaaEttiiigvvheety ppp(heeerrirgccceheennntettinolodfef)vttshhaeeleruuessmsee,rruvuamamlsaucceoohnnficrcgeoehnmn-tetrrtnaahdtteiieoorsnnetciaaemssnassttooeccboiiiaaofttmeebddoacnwwkiitigtotrhhroittnuhhngeedd,RRaAfntDaDonfww-roovomuautllteddhrbebeeeExp5Sao0s0st.44uMruueeggs/t/rLLo.rn((o66em33wuturgge/h/LsL.iedxxewn00t3.sE8)a.)os.rtSSNuMubHebtttArrraaNoccttEriienSnsgg.idtEhheienegths99t55y(t2h1 puaUpgepr/Lcre/o)nxooitrirml2Lea20t0v1e1al33)ly-u-11eS4s40, NN%asHHofaAAthNNeigEEhSSs-ce((nr11du88m.e5sctouuingmgc//aeLLtn))etprpoarrfotoibddoaunucackcetgsearstaohuereenssRddiI,duDnuaaol(ln6-ss3weucrgrauu/tmemLr)cceaooxnnnpcdcoeeasnnputtprrreraastot,iixoofinrnmoaoomtffoetrulhogyeuhgn6lhe0lyw%yo33Ef00asughtgLeM/L,$e,t0rooo%rrcrlesiidnenvtsal(u2s1 a(a(5pp5p0p0r.r44oopxuurigimgaiLt)ae)t.ealGGynidivv5ece0onn%nstthiohseefttccehooncntnsssweecirrrtvvuhaamttbiiovcvseeonnSncaaCcttonuurtfrreetathooifeotfnthDheeeacticctashalileceouuRnllfaTaDtriiooe(n.n6,,3IssuecsgleehiccLortu)iilooadnnnbdooefafaanpnnoptrRRodSSxiCCtmhooaaftfch5Sley00%%6r0eff%sootrroswwofaattfhteeetrrhi8iisnn0gg%aeensascttlieiyooislnniinsiigssdovanloutc Saupppproorptriraaticsianngdtchoenaspipstocrnttiwonimthenbtooxf8wCatoefrthicngieDstcicoisniosnouTrrcecs. 0it s8h0opuelrdcebnct.notcd that thc rcsults of this analysis do not support raising the apportionment of water ingestion sources to 80 percent. Cl DevelopNowCancer Water Guidance Value "TfTheheeommfooosvstteraappfppirrvooeppryreiiaaarttsee. ddCoorssieetemmreietatrrfiioccrffbooirroPPaFFcOOcSuSmiiusslssaeetrrueummcoccnootnnaccmeenintnrtaranatttiisoonnf,o.cPPuFFsOeOsSSoiinss laobbnigio-oataceccrcumumemxuuplloasatiutvreeescc,hheeHmmoiwciceaavll,e,rww,iitthhhigah.hhaallff:bslsirhfheeooarsotrt-ftt-eoferevmrderceefoxxipvpnoeosssyuuuerrmaeeaersss.ccmaaCunncrirrhteesgsruiuraallttfeoiinnrr ibvinniototelearumcnacmalulembboouofdldaygtiubbviuuerdrdcdoeeonnnnsastattmhphaoiantratabankkotesedfycoweacearuirsssgehttsotoolebnialimslmiiosnninagtta-hette.ea.rmoIInlndffeaaexnnrpttsosh,,siuwwkrhhieeseet.tnhhHeearornwdffooearrvdmmueulurtl,lsaa.h--iffgIeehndd, oorr biaanddrddediiaicttsaiitoto-fennes,,dPtPhcFFaoOtOnbSSseuccamrrsoetosfsaseesmsdiutthncheehg ppcgllaraaenccaeertnneetstruaavltaaonnliuddnmisissiegttnroraifannlcsisqfafenuertirrdeeeddxopnttooosaubbprrreeeeasras,sbttmomrideliyslkku.wl.teEiEnimmggphipitriribhiccaiaasglilhsddetarahttasaanrffruorolommdmecrttohnchechepiplnuudtbbrrlelaiintssihhaoeennddds liaiittdneueirlrantftasua.tnreIetns cinodmipcaatreesdthtoattbhericrasmtofteheedrinsg can result in significant exposures, resulting in higher serum concentrations in infants compared to their mothers. cSSeeorrnuumcmeccoonnntccerennatxtrrtavatitaiiootonnenss iccnaatnnakbbeee acctaaelc)luallnaedteddvoiflfutehmeeorrafatteedoiofsfterelilibimmutiiinnoaanttiiaoornen k((ddneeorrwiinvv.eeddTfrhreoommfohhlalaolflw-iflinf)ge,)e,qttuhhaeetiddooonssee(i((wswaoattueersred by EPA to caleulae HEDS) provides the simple relationship concentration x water intake rate) and volume of calculate HEDs) provides the simple relationship beneen dose and average serum concentration. distribution are known. The following equation (also between dose and average serum concentration. used by EPA to oe Sn) 182 erum concentration (48) x fhm m9 Serum Con,cen~ration x 1000 Dse(kkgg.ddaayy)= tearance Rate (jLt) tearnce ete (rks) Clearance Rate (~) hen: Where: Clearance Rate Volume ofDisiribution (Lk BY) x (Ln2 half. days) Clearance Rate t,2)lume ofDistribution (Ling BI/t9 x (LnZ/ha{i-I{i& daya9 andand Dose (ng kg dy)~ Water Dake Rate (kg BV dy) x Water Concentration (1) x (1 ms 1000 vg) Dose (mg&g - day) Water Infake Rate (Likg BI+5/day) x lk2~ter Concentration (ug~Z) x (~ rag,7 000 ug) "TThhiiss eeqquuaattiioonn ccaann bbee rreeaarrrraannggeedd ttoo ccaallccuullaattee ssecrruumm ccoonncceennttrraattiioonn bbaasseedd oonn ddoossee aanndd cclleeaarraannccee. seamen (18) (raLg) Wer concentration (48) : we clearance e Rate (1r 7-75) ) DafDraft DDooccuummeennt t- for for revireview and and ddiissccuussssiioonn pptrup'poosscess oonnlylPy. .ODDSria6tft2dd0oo1ccuu7mm5eenntt ddooess otnot consi constitute Age Agency ppoolliiccyy PFOS - 62 of 75 22447766..00006622 STSTAATTEE or07a4z3e8i1s5T7 cps sc cds ss pat a Two exposure scenarios were examined: 1) an infant fed with formula reconstituted with contaminated ~vater starting at birth and continuing ingestion of contaminated water through lit~; and 2) an infant exclusively breast-fed tbr 12 months, followed by drinking contaminated water. In both scenarios the si~nulated individuals began life with a pre- ry existing body burden through placental transfer. The serum concentration of the mother were calculated to be at steady state, using the equation presented above, at the time of delivery. Upper percentile intake rates were used for Te a wes the breastfed infant scenario and 95th percentile intake rates were used for water intake to simulate a reasonable a maximuln exposed (RNIE) individual. According to the 2016 Breastfeeding Report Card (CDC 2016) nearly 66 percent of mothers in Minnesota report breastfeeding at six months, with 31.4 percent exclusively breastfeeding. The percent breastfeeding dropped to 41% at Ee twelve months. MDH has selected an exclusive breastfeeding duration of one year for the breast-fed infant scenario. J -- A summary of the model parameters is presented in the table below. For details on the basis of each of the parameters aanndd tthhee sseelleeccttiioonnooff iinnppuutt vvaalluuce((ss)) ppllceaassce rrcfecrfttooetthhree BBaacckkggrroouunndd DDooccuummenetn:t: MMDDHH TTooxxiiccookkiinnccttiicc MMooddeell aanndd anil Derivation of Human Health-Based Water Guidance located at: O:\HRA\COMMON\Guid~ce - Water\Tox reviews- ._c__oj.__nj?1 eted\Final\PFOA\Ex.po Scenario Cal c\Fi n alTeamRevi e~ Material s\Backgr_._c_L.[_)._.~._a_._r_._c_:_h__~'.~._n_._a_i[ooo,TK Model .docx (MDH 2017b) Model Parameter Half-lifc (days) Volume of distribution (Vd) Vd Age Adjustment Factor (Vd AF) Clearance Rate (CR) Placental transfer factor Breastmilk transfer factor Water Intake (Likg-d) Breastmilk Intake (l,ikg-d) Body weight (kg) Value(s) 1971 days 0.23 L/kg Range from 2.1 @age 1-30 days to 1.2 @age 5 - 10 years. Value of 1 used for ages >10 years. 0.23 L/kg x (Ln 2/1971 days) = 0.000081 Likg-d 46% (% of maternal serum level) 1.3% (% of maternal serum level) 95tt~ percentile for Consumers Only (default intake rates used by MDH Table 3-1 & 3-3, EPA 201 l) Upper percentile (approximates 95'h percentile) for exclusively breastfed infants (Table 15-1, EPA 2011) Calculated from water and breastmilk intake tables listed above. i ri -- Tp ---------- Draft Document - for review and discussion ptu'poses only. Draft document does not constitute Agency policy PFOS - 63 of 75 ---- STATE 07438158 22447766..00006633 Veith Water Concentration Calculation Results: pJ Scenario # 1 - Formula jbrmula-fed fn/bnt r -- The water concentration that keeps the serum concentration attributable to drinking water (solid line below in Figure 1) below an RSC of US Lh approximately 50% (0.0.063 mgiL sermn x 0.5 = 0.0315 rag/L) throughout life is 0.060 ggiL. Because of the long half-life the serum Sr EE concentration curve is very flat, and even a small increment increase in the water concentration (0.061 gg/L) raises the serum concentration above BR the 50 percent threshold for nearly 9 years. i ---- Figure 1. Strictly formula-fed infant serum concentrations over a lifetime, based on 95th percentile water ingestion rate and an RSC of 50%. " --_------ ioze/ i - Scenario #2 - Breast-~'d Infant or A oa LE While a water concentration of 0.060 ~tgiL is protective of individuals directly exposed to contaminated water it is not sufficiently protective for nr infants who are exclusively breastfed for a year by mothers who have been chronically exposed to 0.060 i~giL in water. Under scenario #2 infant EB e e EA ra aa hs PFOS scram levels exceed the serum concentration at the reference dose for ncady 20 months and the 50% RSC threshold for nearly 18.5 years. See Figure 2. ses Page 64 of 75 seroauss 2476.0064 corse STATE_07438159 nFiiggduorreR2:2S.SSCeer0ummS0cc7on4ocenntwraitciornmscffooaorraanntn eecxxocclnluunssioivvfseellyyObbSrrDesRasEt-fedffoorr|1xye,ar, lobywwategesdion, followed by water ingestion, bonpd e based on upper/95th psc percentile mio ingestion irate and an RSC of 50% at a water concentration of 0.060 ggiL. essfed (Ups percentile nf PROS Serum ConcenatonsatWater ConcentrOa0Et0igo/nL Joufo Ee fom E E iE hs kT = Norrdetwoameacionsmceumtcontboe osws l0onD3UERTSCLsSsPoe07600630. = 051 mt) ois cui bt ros In order to maintain serum concentrations below an RSC threshold of 50% (0.063 x 0.5 = 0.0315 rag/L) for infants exclusively breast-fed for one year the water concentration must be lowered to 0.027 ggiL. See Figure 3. Prseserrs Page 65 of 75 22447766..00006855 saeonaseteo STATE_07438160 i. Sn ns sly os. slyva sn, dn le sn Figure 3. Serum concentrations for an exclusively breast-fed for 1 year, followed by water ingestion, based on uppeff95th percentile ingestion rate ft rete po es ocrm t]hfeirn PES Sram Concrtions Wate Coser 0017 af. and an RSC of 50% at a water concentration of 0.027 gg/L. L { amntn sens cn mcm ar ton 0231s contin ne sc ld Even a small incremental increase m the water concentration (0.028 pgiL) raises the senma concentration above the 50 percent threshold for more et en apcf t eBoo n SEOl than three months. Given the health endpoints of concern include developmental concerns and the duration of exceeding the 50% threshold bie on Be wo a FL mbt do rm 30 constitutes a subchronic period of time, the acceptable water concentration was set at 0.027 ggiL and not rounded to one significant digit. rctsars Page 66 of 75 246.0068 2476.0066 ene crs STATE_07438161 Cr Go| es|I eaSr e Cancer Study Description Com - duration, route, ee i] species/strain, age at pir dosin g, N/sex/group, early Fry life exposure?, etc. for ------ 2-yr dietary, study Rats Administered Dose (mg/kg-d) 0/0, Tumor Incidence Rate Per Tumor Site at Each Dose Level (by sex, stmistical significance) Scc Table 6-A1 above for nonearcinogcnic effects. Obcaweoemdnes4. 0, 0.5, 2, 5, or20 ppm in diet. Observations were made at 4, | 00980 120. 0.024/0.029, 0~098/0.120, | Neoplasacefece: NeopIastic [sr Study | [Th POD | EoFEsroE mgikg/d Slope Factor (mg/kg-d)4 Reference (note limitations in comment filed)*" (Tbomford ocrtt 2002) and (Butenhoff 14 and 53 weeks of treatment 0.24/0.299, or Males - 2012) 0.984/1.251 hepatocellular adenoma (Ms 0, 6, 6, 2, & 12% - positive trend) and aci (US (M!F) mg/kg-d thyroid follicular cell adenoma & carcinoma (10, 12, 10, 10, EPA 2016a) & 8.5%) Fe~r~des - A -- hepatocellular adenorm~ (0, 2, 2, 2, & 8*% - positive trend), 1 mn carcinolna in highest dose grp; thyroid follicular adenoma & carcinomas (0, 0, 0, 6* & 2%) & Hi Se C-cell adenoma & carcinoma (20, 14, 12, 16 & 8*To); mammau fibmadenoma/adenoma (38, 60*, 46, 52, & 25'0/;) aac & carcinomas (18, 24, 31, 22, & 23%) [high backgrd in controls] *Note: exposnre inclnded early life stages; maximnm/olemted dose level was not achieved; and time-lo-tumor (latency) informalion if available. I CrimvieEe Human Carclnogenicity Data: feo (USEPA 2016d): ty tm ae een ictus i cho mips Asin Several human epidemiology studies evaluated the association between PFOS and cancers including bladder, colon, and prostate (Alexander et en, al 2003; Alexander and Olsen 2007; Mandel and Johnson 1995). A large increase in mortally risk from bladder cancer was demonstrated, and a oe Fl subsequent study of bladder cancer incidence in the same cohort found rate ratios of 1.5 to 1.9 in the two highest cumulative exposure Fe RAL LE ree categories, compared to an internal referent population (Alexander et al. 2003; Alexander and Olsen 2007). The risk estimates lacked precision EE RE because the number of cases were limited. Smoking prevalence was higher in the bladder cancer cases, but the analysis did not control for SREnE e rm nr, smoking because data were missing for deceased workers, and therefore positive confounding by smoking is a possibility in this analysis. No elevated bladder cancer risk was observed in a nested case-control study in a Danish cohort with plasma PFOS concentrations at enrollment Page 67 of 75 no 2476.0067 aon STATE_07438162 etn 0001 and 0013 ml. (kent 009) Orstl ot eacanedsk orspilt, bs) nh between 0.001 and 0.0131 gg/mL (Eriksen et al. 2009). Other studies that evaluated cancer risk for specific sites (e.g., prostate, breast) in the emer popu ertone (Bone Jorg to 201,204. Fal. 2014 as 3018) general population were inconsistem (Bonefeld-Jorgensen et al. 201 l, 2014; Hardell et al. 2014; Innes et al. 2014). Amal Carcinogenicity Data: Animal Carcinogenicity Data: USEPA 20 (USEPA 2016d): sie chromcoer casi smalfs avssleFo POS (Tho20m0 Bfcorfd 2012) cred idenceof A single chronic cancer bioassay in animals is available for PFOS (Thomford 2002iButenhoff et al. 2012).5 Increased incidence of posure teal (12% he igh dose) and ler 84 hs High dosead combinedaenomasrinons nh hepatocellular adenomas in the male (12% at the high dose) and female rats (8% at the high dose) and combined adenomas!carcinomas in the ums (107 he igh do) wes ober, utet dplay clsoe ltd esos fn les nl, heeumalas nmin, females (10% at the high dose) were observed, but did not display a clear dose-related response. In males only, the serum alanine transaminase ALT ble wre cssa 1 2,50 53 wis At 103 46k es was iis 1csnolic Src fo 0d (ic (ALT) levels were increased at 14, 27, and 53 weeks. At 105 weeks there was an increase in eosinophilic clear cell foci, and cystic pics deation inms gen2. 45 20partspor lho PFOS Thomiord (202) erin vsofsaecl hepatocellular degeneration in males given 2, 5, and 20 parts per million PFOS. Thomford et al. (2002) identified low levels of single cell ross i doerugs (lsan Tors) ih fran ese cde3 he ighdo for les ndmls Thon nd necrosis in all dose groups (males and females) with a significant increase in incidence at the high dose for males and females. Thyroid and Imannd fnem elstd btdd ot Gos respons. Ma adrn r 3y 0 igh Rocks drs nA mamma~ gland tumors were also observed but did not exhibit dose response. Mamma137 gland tumors had a high background incidence in all oe rradshowed no png doe dose groups ,and showed no response to dose. Under EPA's Glinfor Casings Risk Assen (USEPA 2005s) thsis So Finen ofCore i Poni FOS Under EPA's Guidelines for Carcinogen Risk Assessment (USEPA 2005a), them is Stggestive Evidence Of'Carcinogenic Po~endal for PFOS. onl hrol oly a aimee sy ofPROS a, <rand hod rs (rst hcnoman ct eid bth In the only chronic oral toxicity and carcinogcnicity study of PFOS in m~s, liver and thyroid tumors (mostly adcnomas) were identified in both he Comtreal 1 1 ot ht mg don. Th ndsfor cr 1 al J ORS the controls and exposed animals at levels that did not show a direct relationship to dose. The evidence for cancer in animals was judged to be 10 edeSoper AeSoe ERT 10 dort SPO) too limited to support a quantitative cancer assessmem (i.e., no dose-response). Gensosicty Data Genotoxicity Data: SERA 201) (USEPA 2016d) INP snc sto nd2nArc cs, marlon 1 in ss, 4. ir ssfo hoon sherions, All genotoxicity studies including an Ames test, mmnmalian-microsome reverse lnutation assay, an in vitro assay for chromosomal aberrations, Emihotld BA syn ed eosmont wi an unscheduled DNA synthesis assay, and mouse micronucleus assay were negative. CraCancerStudy formsion ComerClasifcsion out 50). Cancer Classification (source & date): Sop ctorSous, Dtaf Decl. Slope Factor Source, Date of Developlnent: Sipe Factor Su Quy Slope Factor Study Quality: Dusen the ss oh Tovey Valu: Describe the Basis for the Toxicity Value: SupportingSut Description: Supporting Study Description: Sgsestve EviodfCeasnincose Pec (USEPA 20160) Suggestive Evidence of Carcinogenic Potential (USEPA 2016d) Not Appibie Not Applicable Not Applic Not Applicable Not Appcabl Not Applicable Inthe oly choi ol icy snd carcnagict sud of FOS int. ve and In the only chronic oral toxicity and carcinogenicity study of PFOS in rats, liver and id mors (mori coma ct kd bth hecons nd prc thyroid tumors (mostly adenomas) were identified in both the controls and exposed il sel hd ot sho ct ela dos. (Thomond 00) animals at levels that did not show a direct relationship to dose. (Thomford 2(/02) Tbll 01. The cineforcnc slwaJsd oetbo red 0 (Butenhoff 2012). The evidence for cancer in animals was judged to be too limited to rt GUaASERT (15. 10 Ge rp) support a quantitative cancer assesslnent (i.e., no dose-response). Page 68 of 75 22447766..00006688 sate orsseiss STATE_07438163 iofe Aton formations 1. Is there evidence of mutagenic mode of action or another mode of action expected to be linear at low doses? No. Sethe eden of aweolodie ovfaatirn. awsviolf necwet sdf normaion spporin avonboar ede 2. Is there evidence of a nonlinear mode of action (e.g., no evidence of linearity and sufficient information supporting a nonlinear mode pron of action)? USEPA 2016 5c Section 423 tr mor desi]. (USEPA 2016d) [See Section 4.2.3 for more details] Thmadeofcrim ci of FRO s otcel undead. Some a ond sed o valle tah ner orsosc in The mode of carcinogenic action of PFOS is not clearly understood. Some have concluded based on available data tha~ liver tumors observed in he Cbn om r on beatae uly he pacofPROS prpotrisonesed oa poh onsas of the cancer bioassays can be attributed mostly to the impact of PFOS on peroxisome proliferation based on a hypothesized lower sensitivity of an 1s MON. Sotarspeor: poet hit PPAR sons OAcouldbe responsi rceveda humans to this MOA. Some data support the hypothesis that PPARa agonism MOA could be responsible for observed liver tumors in animals. Sev ssKaedemos PFOS caine PPAR: bower, da pray Beinfor sed1lion Several studies have demonstrated that PFOS can activate PPARm however, dam arc generally lacking for increased cell proliferation. Sith cae n epi oll porto as deed 1 sobs sl (Scat3 00 oh snr bse (Toon Specifically, no increase in hepatic cell proliferation was detected in the subchronic study (Seacat et al. 2003) or the cancer bioassay (Thomford 200210 POS Limi ro vas psrs hessss bot sd or mon3 pis 1d. 1 30.20 abhor 2002) of PFOS. Limited necrosis was present in these studies, but did not demonstrate a response to dose. h~ addition, no subchronic or long,rTem Sis cad vinof peopfo nh ner term studies revealed evidence of preneoplastic loci in the liver. Strut soto ssssc ht PFOS int DNA civ compound, ih egsin ests rom five stoi, well 5 Short-term genotoxicity assays suggested that PFOS is not a DNA-reactive compound, with negative results from five in v~t~v studies, as well as Tom nin on aon mo from an in vivo bone marrow micmnucleus assay. eps MOSfo caring hve boo lors, nig mitochondrial Bogeannd stpaiccons elo Other possible MOAs for carcinogenicity have been explored, including mitochondrial biogenetics and gap junctional intercellular Commotion (G0) Thee a ot rs dnd MOS. dhs spore tne10 POS post hot i communication (GJIC). These are not clearly defined MOAs, and their importance relative to PFOS exposure is not certain. 3. Tethers idence ht the modeof ction nt reletovhuamannst? 3. Is there evidence that the mode of action is not relevant to humans? Rot Avs (NR) Not Available (NA) PT A---- 4. Is there evidence of life-stage sensitivity? WNA WAre therestructscure coreations avaiable? 5. Are there structure-activity correlations available? NA Isrometo-rout xteapolation sd? Nt apis 6. Is route-to-route extrapolation used? Not applicable Page 69 of 75 22447766..00006899 sateorsseiss STATE_07438164 Eeve CanerGdnVsl China iene Cans ilk 1013 (Comer Fain00s (Additional Lifetime Cancer Risk, 1 x 10 2) x (Conversion Factor,1000 u~m~) (SFx03 0128EAE an y+ (OF 3330SLigds 10+ OF 3 13000 LAkd 501170 [(SF x 10 x 0.125 L!kg-d x 2) + (SF x 3 x 0.04.~ L/kg-d x 14) + (SF x 1 x 0.041 L/kg-d x .~4)] ! 70 i SFcafs nsms h) ......wh~rel ~On~e~ S!OP~ fa~gr (per mg/kg-d) b [JoSmam p aocurssn ee | ~Enter in Slope Factor Ea =ug/L orOR (Ans iti Canc Rik, 10 CamcoFactor 000 gig) (Additional Lifetime Cancer Risk, 1 x 10 s) x (Conversion Factor,1000 u~m~) Slope Facto,per mh etme Adm Factor (fein take Rot.008 LA0E) (Slope Factor, per mg/kg-d) x (Lifetime Adjustment Factor) x (Lifetime Intake Rate, 0.044 L/kg-d) Ea =ug/L Comments: Not applicable Page 70 of 75 22447766..00007700 stare ones STATE_07438165 RReeffeerreenncceess CCoonnssuulltteedd DDuurriinngg RRee--RReevviieeww:: CAAhSSeTTmiSScWWaNlMsIOO(PF((2C20s01)15:5).).PeAArsfsslsooucociriaaottoiicootnnanoocffiSScttaAattceeidaann(ddPTTFeOerrArri)ittoo&rryyPSSeorolfliildduoW WraoasostctteeaMMneaanSnaualggfeeommneaetnnett(OOPfffFfiOicciSiaa)llss.I.nPfPeoerrrfmfllauutooirroiinnnaatteedd CPPaahppeeermr..icals (PFCs): Perfluorooctanoic Acid (PFOA) & Perfluorooctane Sulfonate (PFOS) Information AAPeTTrSfSlDDuRoRr.o.al((k22y00l11s5.5)".). ""AARgegeternnicceyyveffdoorrATTuogoxuxisicct SS1uu5b.bss2tt0aa1nn5cc,eessfraaonnmdd hDDiiitsspee:aa/ssfeewwRRoeewggiasisttstrrdyyr..eDDderr.aafgflotvTT/ootxoxixiccporololoofgigilicceaasl/l(PPprr2oo0ff0iillpeedfffoorr Perfluoroalkyls." Retrieved August 15, 2015, from http:/!www.atsdr.cdc.gov/toxprofiles/tp200.pdf. `AAsuuusistdtrraaanllciieaannonHHeehaaulltmthhanPPrrhooettaeelccttthiioornnefPPerrriinennccicippeaavllaClCouoemmsmimftoitrttepeeee,r,-ee.a. n((d2200p11o66l)).y.-f""leeunnoHeroaealalltkthhylSStstaauttbeesmmteaenntnc:te: sIInnfttoererruiimsmenniaanttiisooinnteaall iignnuvviedesastntigciaegtaiotoninohsinuinsnmAaAunusshttreraaallltiihaa.""refffreroromemnchhettttpvp:a:/l//uw/evwsewwfwo.rhhepeaealrltt-hhannnssdwwp. ggooolyvv-.faalwuu//oeernnovvaiilrrkooynnlmmseeunrbt~/stt/ffaaancccttesshsheefeeottrss/u/DsDeoocciunummseinetetnsts//ppftahss-iinntteerriimm--hheeaalltthh--vvaahl~ueess--aahh#_pp_p_._ec_._..p_p__ddf._f._. CBBhiijajllnaagnn,dd,,DSSI..,,EPPhCCreNNsmRRaeennn,sseeJnnL,, BEEuJJtePPniihecotteferfrm,maaHnn,M, AAGCCPEEriMMncaeasnss.s,, (JJ2WW011vv)aa.nn"ddPeeerrrfHHlouoooormron,a,lMMkyJlJ vvSaaunnlfEEornrkka,t,eKKsWWCauvvsaaenn DDAilijkjkky,,l SSCCChain LCLAePehnnOaggnEitg*hh,3--D-DDLeJeeppEieehdnnrdedeenesnnmCttaEHHnTe,epPpJaLatMtiiBicccuSSettetee*naahTttooooxsfsfiii,sscoHaalnnModdgGiHHcyayPplproiolnSlciciipepeniidn.dcee(emm2si0iaa1121MM3)(a.1ai)"in:nPlleyy2rf9bbl0uyy-o3IIrm0mop3apalakiiyrriilnnSgguLLlifioppnoopaprtreoostteeCiiannuPPsrerooAdduulckctytiilooCnn hiinanin APOE*3-Leiden CETP Mice." Toxicological Sciences 123(1): 290-303. BBstuuuttdeeynnhhwooiftfffh,, pJJo.,,tSaSsCCsiCCuhhmaannpgge,r,fGGluWWoroOOollcssteeannn,,ePPsJJulTTfhhooonmamftoefroidrnd..Sp((22r00a11g22u)).e. D""aCChwhrlrooennyiiccraddtsii.ee"ttaaTr~oy'xttioocxxoiiclcioittgyyyaa2nn9dd3ccaa1rr-cc1i5in.nooggeenniicciittyy study with potassium perfluorooctane sulfonate in Sprague Dawley rats." Toxicology 293:1-15. CCAanartriiioogunu,a,cRR,.,.,BBBLVVeeeByyirzraaencn.dd,,(AA201YY5a)a.mmaa"ddPaea,r,fAlAuoBBreecrrarrleekbbyiil,, DDaciZZdaal(lkkPooF,,A$AS)DDuulreraavnendlds,, aCCndPPpoorlolllfooinnlooe,,siPPnMMabarrreccahhsatannmddi,,lk1J,--CCmaLLteeebbmllaaannlcc,a, nIJd--PP cAchhnootrriddgnssaeecrr,uuBmm Loofef FFBrrieeznneccch.h (ww2o0o1mm5ee)n.n "aaPnneddrfttlhhueeoiirrronnaeelwkwbybolorarncnsisd."*(PEEFnnvAviiArroo)nnlmmeveenenltts IIannnttdeermpnaratotiifooinlneaasll i88n44:b:r77e11a--s88t11m. ilk, maternal and CCDDCC ((22001166)),. CCeenntteerrss ffoorr DDiisseeaassee CCoonnttrrooll aanndd PPrreevveennttiioonn.. BBrreeaassttffeeeeddiinngg RReeppoorrtt CCaarrdd. CCExDDpCCos((u22r00e117t7)o)~ECCnevenintrteeorrnssmeffonortraDDliissCeehaaessmeeicCCaolonsnt.trrooUllpaadnnaddtePPdrreeTvvaeebnnltetiisoo,nnJ((aCCnDuDCaC)r.y). 2lF:0oo1uu7rr,tthhVoNNlaatutiimooennaaOllneRR.eeppoorrtt oonn HHuummaann Exposure to Environmental Chemicals. Updated Tables, Janua~, 2017, Volume One. CC"hEhvaaannlggu,,atSS.i,.o,BnBoCCf AAslelllreeunnm,, KKliLLpidAA,nntddhryreresos,i,dDD.JJanEEdhhrrheeesspmamtaainnc,,cRRlinFFiaacllavvloo,c,hAAemPPirrsootvverennicicehhnseerar,,ssGGocWWiatOOillossneennw,,itJJhLL sBBeuurttueenmnhhooffff.. ((22001166)).. Tpp"eoEerxrvfifallculuouoolarrotoogioooicccntataaolnnfeSesscseuuirleluffnmoocnneaalsittpe(eiSd((u,PPbtFFmhOiOytSrSto))eiddiinn,maccanyyndnnusoohcmmeropoilaplgtgtiuucsscmlminooinnckkaeleyycssheaamfftteiesrrtrooirreaasll iddnoosasisinsnoggcwwiaiitttihhonppoowttaiatsshssiisuuemrmuPmPFFOOSS.."" Toxicological Sciences (Submitted manuscript). iCCnhhdeeuncn,e,sT.o,T,xLLidZZahthaiavnnegg,,srJJe--qsqsYYauuneed,, aZZp--oqqptLLovvs,,isWWinXXitiaha,e, YYlu--njgWWoafanrn,a,tYYo--fyyf-LLsipi,,ri$Sn--gqq."XXuRu.e.p((r22o00d11u22c))t.i""vPPerreeTnnoaasttiaalcloPPlFoFgOOySS33ee:xxpp5oo3ss8uu-rr5ee45 induces oxidative stress and apoptosis in the lung of rat off-spring." Reproductive Toxicology 33: 538-545. DEDvaaannliiussahhtiMMoininnioissfttrrhyyeoaolftfhtthhheeazEEannrvvdiisrroaonnnmdmeepnnrtotp((o22s00a11l55))o..faPPeerhrfefllauluotohrroobaaallskkeyyldlaaqttueeaddlisstuuybbsscttraainntceceresis:o:nPPfFForOOdAAr,,inPPkFFiOnOgSSwaaatnneddr,PPFFsoOOiSlSAaA.n.d `Eggrvroaoulunundadtiwwoaantteeror.f. hEEennavvlitihrroohnnammzeaenrntdtaasllappnrrdoojjpeerccottpNNooso.a.l 11o666f65a5,,h22e00a11l15th5.. based quality criterion for drinking water, soil and DpDeoornnfggl.,uoGGr.o-.-HoH.c,t.,anYYe--sHHulZfZohhnaaanntgge,,eLLxpZZohsheuenrngeg,,oW Wn iLLmiimuuu,,nYYot--oHHxiJJciinni,,tyQQ--iCnCaHHdeue,l,t((22m00a00l99e)).C. S""7CChBhrLroo/nnSiiccmieecfffefee.cc"ttssAroocffhives of TpToeoxrxfilicucooollroooggoyyct88a33n::es88u00l55f-o-88n11a55te. exposure on immunotoxicity in adult male C57BL/5 mice." Archives of PPaaggee 7T11ooff 78 75 22447766..00007711 STSTAATTEE 0077443388116666 DpDeoornnfggl,,uoGGr.o.,,oMcMtaMMneLLsiuiuul,f,oDDnaWWteaan(ngPg,F,OLLS)ZZhhoeennngtg,h,eZZbFFalLLaiinaacnneggo,,fYYtHHypJJeiinn|,, a((n220d0111t1)y.)p.e""2SSuucbby-t-ccohhkriroonnneiiccineeaffdffeueclcttt ooCffSTBLG mice." ApAerrcrfhluivcoersohooofcfitTaTonovsexisciuecololfolosogngyayt8e85(5P: F11O22S3355)--o11n2244th44e. balance of type 1 and type 2 cytokine in adult C57BL6 mice." (EEPFEFSSOAAA)((22a00n00d88t))h.eEEiuurrsraoolpptese.aannSFcFiooeoondidifSSiaacffeeOttpyyinAAiuuotthnhooroirftityty.h.ePPPeearrnffelluluooornroooCccottnaatnnaeemssiuunllaffnootnnsaattiee ((tPPhFFeOOFSSo))o,,dppceehrarfilfnu.lour(ooQoruceotsaotnciooiincaanNaccioicdd E(EPFFFSSOAA-A-QQ)--a22n00d004t4h--e11i66r33s))a.lts. Scientific Opinion of the Panel on Contaminants in the Food chain. (Question No EEsuggleefoggnhhayyteP:PPPAaanncdodmMMparLLioosrrobbneeorrf((22e00s1t11i1)m)..at""eAAdnniaansstssaeekssesswmmieetnnhttvoaoflftuthehese ieenxxfppeoorsrsueudrreefoorfofAmAmemNrHeirAcicNaanEnssSttoodappteearrff*lluJuooourromoooacclttaaonnfeeExposure sSSuccliifeeonnnccaeeteaa:nnAdd EEcnonvmviirprooannrimmseoennnttaoalfl eEEspptiiimddeeammtieoidolloionggytay.k. e2211w.:it11h550v0-a-11l6u68e8.s. inferred from NHANES data." Journal of Exposure GFFerronozmmemmle-e,B,oHHr.o.,CviCcMzMeoonsyscc,hh,B, MMKolMMeotrozorkvoiovt,iztzW,, IIVAAolllbkbaea-l-AAl(lee2j0jaa1n0nd)d.rree,",PSSreBB-ooacenhhdmmePerors,,inMMatKaKliirrEaaxnnpoogoglsluuu,r, eFF tFFoaaPbbeeerrrf,l,I1uoHHraiannnnanitibebadall,, O0 `GCCoeomnmzppeool-uuBnnoddrsso((vPPicFFzCCes)ns).y.*", BEEnnKvvioirrlooenntzmmkeoenn,ttaWall SVSccoiileeknnecclee. (&&20TT]ee0cc)h.hnn"ooPllrooeg-gyyan44d44:P:77o11s22tn33a--t77a11l22E99.x.posure to Perfluorinated `GHGoeecrhrmsmaaaunnerMMliainnnidisksttrLre)y"iosof.f HHSeteaaaltltthehm.e((n22t000b06y6).)t.hAAessDssreeissnsskmmieennngttoWoafftPPeFrFOOcAoAmiiinnsttshhieeoddnrrii(nnTkkriiningngkwwwaaatsteesrreorofkfotthmhmeeiGGseserirmomnaa)nnof the `HGPGroeoercvrmhimssaaiannounMeMarillinaniEnisxsdttak~rlry"uoeaoiftsfi.HHoeSnaetaolatfltethhmPFaaettTnttthihbneeyDFFtreehiddeneekrDraialrnlignEEWknnaivvntiigerroroWnwnmmiaetteenhnrttctAAohegmgeeGmnnucciisyydseiJJouuSnnnuee(b2Ts21rt1i,an,nk22cw00e0s0a66sP/sierrereerfvvkliioussmoeerddmoJoJiuucsltslyyaion1nc133i),,co22af00c0t0ih6d6e,. (PP(PrFoFOvOiAsAi)o) naaannlddEPPveearrlffulluautooiroroonoococttfaaPnnFeeTSSuuilnlffDoonnraaitnteeki((nPPgFFW OOSSa))teaarsswEExixtahammpthlpeelesGs..uide Substances Perfluorooctanoic acid H"HaParrrreridissi,,ctMMo.r.,s, SSofLLPRReiriff-aaass-n-SdShhPiimomlaaynnf,,luAAorMMoaCClakalylalaffaSatut,,bXXstaYYneec,,eAA(MMPFAM MSoo)rraaP,,lTTasFFmW WaeCbeosbntsceteerrn,,tErEatOOikkoeennns,,iSSnKK6-SS1aag0giivYv.e. a((r2200O11l77d)). American Children * Environmental Science & Technology Advance Access: DOI: "Predictors of Per- and Polyfluoroalkyl Substance (PFAS) Plasma Concentrations in American Children." Environmental Science & Technology Advance Access: DOI: 6-10 Year Old 1100..11002211/iaaccss..eesstt.66bb0055881111 HHeeaalltthh CCaannaaddaa ((22001100)),. DDrriinnkkiinngg W Waatteerr GGuuiiddaannccee VVaalluuee PPeerrftlluuoorrooooccttaanneesusullffoonnaattee ((PPFFOOSS).). SuHHbeesaaltlttahhnCcCaeansnaad(daPa.F.A((S22)00.11"663a)).R.et""rHHieeeaavlletthdh MCCaaannyaad2da7a','ss2DD0r1ri6inn,kkifinnoggmWWaatteerr SSccrreeeenniinngg VVaalluueess ffoorr PPeerrfflluuoorrooallkkyyllaatteedd hhSutuutppb::s//t/assn33cd~ deosoccu(uPmmFeAnentStc)c.ll"oouuRdd.oeontrrggi/eidvdooecdcuuMmmeaenyntts2s7//2,277255066133688, 66fH/rHoemeaalltthh-C-Canaandaad-PaF-APFSA-SSc-rSecenrienegn-Vianlgu-esV-aFlaucte-SsSh-heeFeeat.cppdtdf:f.. CHHoeenaaslltuthhlaCCtaianonanaddaDa.o. c((u220m01e16n6bbt).)., ""fPPreeorrmfflluhuooprr:oooo/ccMtthaaennaeelStuShluyfclfoaonnnaaadtiteean((sPPFgFeOOScS)a)riihnneDaDrlirtinhn-kksiiynnsggtWeWam.tasetyersr..tDeDrmreaa-ftffoorrPPuubblliicc Cssaaonnnttseeul/cclaootnnisosuunllttDaattoiicoounnmss//pepneertr.f"flu,luoforroroomoocchttatantnpee:--/s/shuuellfafoolntnhaayttece/a/ddnooaccduuimmaenensnt.t-g-eecnn.gcg.d.hpphehpap.l.th-system-systeme- K"KEaaxrrprmmoasanun,r,eoAA.f.,, Pl|eEErrlriiuccossrooinn,n,aBBtevvdaaCnnhBBeamavivecelal,,lPPsOOthDDraoarurnngeehrruuLdad,c,taMMtioAAnu:unneeL,,evAAelGGslolyyfnnnMn,a, tScLhLieiggdnneeHllull,mGGanLLiiMnniddslstktrrooammn.d. (S(22e00r00u77m))..and aa"ETTxeepmmoppsouorrraealloTTfrrPeeennrddf,,lu11o99r9i9n66a--t22e00d0044C,,hiiennmSSiwcweaedldseentnh..r""ouEEgnnhvviiLrrooanncmtmaetneitnoantal:lLHHeeevaaleltltshh oPPfeeMrrssppaeteccchttiievvdeessH1u11m155:a:n2222M66--i2l2k3300a.n. d Serum and KKShiiimmn,,, $JSH.--KKL,e,eKK. TT(20LL1ee1ee),,. CC"SSDiKKsatarnniggb.,uLtLioTTnaoaoof,, pKKerKKfalanunnonaraonnc,,hKKemRRicKKailimsm,b, eCCtKKweKKeinimms,,erJJaSSaLLneedee,,miPPlSSk PPfaarrrokkm,, tYYhWWe sYYaomooeo,,mJJoYtYhHHeara,s, YYSS aaSnnhddinii,mmJpHplliiLccaaetteii.oon(n2ss0ff1oo1rr).pprr"eeDnnaiatstatarllibaaunntddioppnoososttfnnapatetaarllfleuexxopproooscsuhurereemss..i""caEElsnnvvbiierrtoownnemmeeennntstaaellraPPaoolnlllduuttmiiooinlnk11f55r9o9:m:116t6h99e--11s77a44m..e mothers LLaauu,, CC..., JJRR TThhiibbooddeeaauuxx,, RRGG HHaannssoonn,, JJMM RRooggeerrss,, BBEE GGrreeyy,, MMEE SSttaannttoonn,, JJLL BBuutteennhhoolfff,, LLAA SStteevveennssoonn. (T(22o00x0i03c3)o).l. o""gEEixcxpapolosSsucurireeenttocoeppsee7rr4ff:lluuo3or8ro2oo-oc3ct9at2nane ssuullffoonnaattee dduurriinngg pprreeggnnaannccyy iinn rraatt aanndd mmoouussee.. IIII: ppoossttnnaattaall eevvaalluuaattiioonn.."" Toxicological Sciences 74:382-392. Page T2007 Page 72 of 75 22447766..00007722 SSTTAATTEE 0077443388116677 eLLxiiuup,,osJJ,u.,rJJeLLoiif,, pYYerLLfiliuuu,,orHHinMMateCCdhhacanno,,mpYYoZZuhnhadaoos,, fZZorCCanaiei,w, bYYorWWnusu..."((2E200n11v11i)r.)o.n""mCCeoonmtmppaIanrtriiessmooanntiooonnnaggleess3t7t:aattiio1on2n0aa6nn-1dd2ll1aa2cc.ttaattiioonn exposure of perfluorinated compounds for newborns." Environment International 37:1206-1212. rLLeoocppeeepzzt-o-DDrosovcvaaalnl,,bSS.e,.,mR RodSSiafalilggeaadddobo,y, AAperLLfaalffuuueoenrntoteeo.~ct((a22n00e11s66u))l.f""oTTnahhteeeee(xxPppFrreOessSss)iiooinnn aoodffussleetvvemeraraalllerrreeapptrrsoo."dduuCcchtteiivmveeoshhpoohrremmrooennee155; 488- 497.receptors 497. can be modified by perfluorooctane sulfonate (PFOS) in adult male rats." Chemosphere 155: 488- rLLeuupeerbbokkdeeurrc,,tiDD.o,.n, MManTTd CCcraaosssees,,-fRRoGsGteYYroosrrtkku,,diJJeAAsoMMfopooeorrrefe,l,uKKoJrJoHHocaatnnassneeenns,,ulJJLfLoBBnuauttteeenn(hhoPofFffOf..S)((22i00n005r5bab)t)s..."""TTTowwxooi-c-ggeoenlneoergrayatt2ii1oo5nn: 126- 148.reproduction 148. and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats." Toxicology 215: 126- eLLxuupeeobbskkeuerrr,e, DDt.o.,,pRRerGGfluYYooorrrkok.o,ctKKaJJneHHsauanlnsfseoennna,,tJJeAA(MPMoFooOorr)ee,,inJJLLSpBBruuattgeenunheho-ofDffaf..wl(22e00y005r5)aat.)s. d""oNNseeeoo-nrnaeatstaapllonmmsoeorraatlanildittyybifforrcoohmmemiiinncuautlteerraoond ppehxhaparrommsauacrcoeoktkioinnepeietirifccluppoaarrroaamomecetttaeenrresss.""ulTTfoooxnxiaiccteooll(ooPggFyyOS2211)5.~:in: 149-169. Sprague-Dawley 149-169~ rats:dose-response and biochemical and LL"Gvvl,.uZZc,.o,sGGeLLian,i,dYLiLLpiii.,dCCHoYYmiiennoggs,t,JJasCCihhseenni,n, TCTAdhCuelhtnen,R,aJJt WWeIseii,I,mYYpaLiLirinne,,dYbyJJiiEaaannrggl.,y-YYLiWWfaeanEngxg,p, oBBsuSSrhheuu,,toBBPeXXruuf.,luSorXXouou.c.t((a22n00e11:33)).. "SSGuulllffuoocnnoaastteee..a""nEEdnnLvviiiprroiodnnmmHeeonntmtaaelloTTstooaxxsiiisccooilnlooAggyydu228l8t::R55a33t22--I55s442I2.m. paired by Early-Life Exposure to Perfluorooctane MMMaDDttHHer((o220f000P88)r).o.pMMoisinenndneeRssuooltteaasDDReeepplaaartrtitmmngeentntotoHofefaHHleteahaltltRhh.i.skSSttLaaittememimteesnntotfooGffrNNoeueenedddwaaanntdderRR.eeaassoonnaabblleenneessss ((SSOONNAARR)) iinn tthhee Matter of Proposed Rules Relating to Health Risk Limits of Groundwater. MHMuDDmHHan((MMEiqinunninevesasolotetnaatDDDeeoppesarerttmCmaeelnnctutlooafftiHHoeenaasllttihhn))t.o((D22e00r11i77v4aa)).t.io""nMoMDfDOHHraHHleeaaRlletthfheRRrieissnkkceAAsDssosesessesssmm(eeMnntatyMMe2et0th1h1oo,ddssrettvooisIInendccoo2rrp0po1or7ra)at.et"e: from hitp://swevw health state mn us/divs/ehyrisk/guidance/hedrefuide pdf. Human Equivalent Dose Calculations into Derivation of Oral Reference Doses from ..h..t..t-p...j..~:..h....e.:.a-[t..~.~.-s..t..`.a...t...e........m..1~:..t.~.s../..d...i.v.....s./....e..~..~/..~i.s...!~/..g~-d danceihedrefg.u__i_.d_._e_..p__.d__._f_. (May 20111, revi sed 2017)." aMMnDDdHHPF((MOMiAinnnanenesdsootltaas DDUesepepaarirnttmmteheenntDteoorffiHvHaeetaaillottnhh))o((f22H00u11m77bba))n BBHaaeccaklktgghrr-oobuuannsddedDDoWocacuutmmeernetGn:ut:iTdToaoxnxicicceookVkiainlneueetdsi.cc MMooddeell ffoorr PPFFOOSS and PFOA and Its Use in the Derivation of Human Health-based Water Guidance Values.. dNNaeetllassoobnna,,se.JId. ((o22n0011J66u))n.ePP9ee,rrss2oo0nn1aa5ll MCCeooemmtmimunnugincAiacgtaetinioodnna rraeenggdaarrMddaiitnneggriMMalDDsHHfoMrMtNNhe((AEEdaasvstitsMMoeretytrrooP)a)nPPeFFlCCtobbtiiohoemmoEonnnivititoorrroiinnnmggenpptrrooajjleecctt HdHeaeataallttbhhasTTerrdaaccokkniinnJggunaaenndd9,BB2ii0oo1mm5oonMnitietooerrtiiinnnggg PAPrrgooeggnrradamam.and Materials for the Advisoi-y Panel to the Environmental hhittptp :w//vwvwww.hheeaalltthh. ssttaattee,mmnn.uussdidiivvss/ihhppecdd/ittrraacckkiinnggippaanneell//2200115SJJuunneemmataeterriiaallss.ppddf. NNTTPP ((220011662a).). NNaattiioonnaall TTooxxiiccooccoollooggyy PPrrooggrraamm.. DDrraafftt SSyysstteemmaattiicc RReevviieeww- ooff IImmmmuunnoottooixciictityy AAssssoocciiaatteedd wwiitthh EExxppoossuurreettoo PPeerrfflluuoorrooooccttaannooiicc AAcciidd ((PPFFOOAA)) oorr PPeerrfflluuoorrooooccttaannee SSuullffoonnaattee ((PPFFOOSS).). NNExTTpPPos((uSSreeeppttteeommPbbeererfrl22u00o11r6o6)o)..ctNNaanatctiiioocnnaaAllciTTdooxxoiriccPooeccroofllloouggoyyroPPorrcootggarnraeammSuMMlofoonnnoaogtger.raapphh -- IImnmmuunnoottooixciciittyy AAssssoocciiaatteedd wwiitthh Exposure to Perfluorooctanoic Acid or Perfluorooctane Sulfonate. QaQiPiuuo,,teLLn,.t,iXXalZZhThaarangngeg,t, XfXorZZhPheaarnnfggl,,uoYroZZohhcatanangng,e,SJJulGGfuuo,,naMMteCC-hIhenendn,u,cZZedZZhhRaaennpgrg,o, dXXucW Wtaianvnegg,D, ySSs--fLLu,,nWWctaainnoggn.i((n22M00a11l33)e). MS"iSecreetr.too"llii CCeellll IIss TaTooPxxoiictceoonlltooigaailiccTaalalrSSgcecitieefnnoccreePsse11r33f5l5u((1o1)r):o: o22c22t99a-n-22e440S0..ulfonate-Induced Reproductive Dysfunction in Male Mice." RRPEIIOVVSM.M ((A2200p11r00o)p).os((aNNlaattfiiooornnawalaltIIennrssttqiitutuauttleeitffyoorrstPPauunbbdllaiirccdHsHeieanallatthchcaaonnrdddattnhhceeeEEwnnivvtiihrrootnhnemmeWennattt))eErEnnFvvriiarroomnnemmweoenrntktaallDirrriiessckktillviimem.iittsRseffpooorrrt 6P600F11O177S114.400A1131p/3r/2o200p11o01s0.a.l for water quality standards in accordance with the Water Framework Directive. Report PPaaggee 7330o1f7785 22447766..00007733 STSTAATTEE 0077443388116688 SSBcichhmeebccatteuermr,,.AA(,.,20NN12)MM.alail"ikPk-o-BlBayasfssls,u,orAAoMaMlkCCyalallaCafofaamtt,,pKoKuKKnadattsoo,,inJJAATeCCxoaolslaaccCiihnniool,,dTrTeLLn GGferenotnm,t,BLLirSSthHHytynhnaranon,u,gTThRR12HHaYarerrraiisrs,s, SofMMaAlagllelaa,," LL BEEnnivrvniibrrooannummmeenn(t2taa0ll1HH2e)e.aal"lttPhhoPPlyeefrrlssuppoeerccottaiivlvkeeyssl 11C2201o:)m: 55p99o00u--n559d94s4..in Texas Children from Birth through 12 Years of Age." SScchheerr DD,, PP.. CC.. ((22001166)).. PPeerrssoonnaall CCoommmumnuincaictaitoionn.. PPFFCCss iinn FFDDLL SSttuuddyy.. sSSteeuaadcciaaetts,, oAA.n,.,pPPeJJrfTlTuhhooormmofofocortrdda,n,eKKsJuJlHHfoaannnassteeenn,p,oGGtaWWssOOilulsmseensna,,ltMMTiTn cCCyaansseoe,m, oJJlLLgBuBusuttsmenonhnhokofeffyf..s.((22"000T02o2)x).i.c*"oSSluoubgbiccchharrloonnSiccctioetoxnixcceicistity6y8 2s2t44u99d--i22e66s44.o.n perfluorooctanesulfonate potassium salt in cynomolgus monkeys." Toxicological Sciences 68: cSSheearacocanati,t,c AAd.,i.,ePtPJaJryTTthhoooxmimfcofiotryrodd,f, pKKoJJtaHHsaasnnsiseuennm,,pL1eArAflCCulloeermmoeoencnt,,anSSeRRsuEElllfddorrniiaddtggeee,,inCCrRRatEsF"llccTooommxbbieec,,olJJLoL.gByBuu1tt8ee3nn:hhoo1fff1f,7,-((12230010033)). ""SSuubb-- chronic dietary toxicity of potassium perfluorooctanesulfonate in rats." Toxicolo&y 183:117-131. TPTrCCoEEtQeQc.t.i((v22e00C11o66n))c. e""nTTteerxxaatasisoCCnooLmmemvmieslissssii(ooPnnCLoosnn).EE"n,nvvfiirrrooonmnmmheeinnttptaasll:/QQu/uaslawil.tityyt.c.eqTT,eetxxeaaxssasRRigissokkv/RRreeedmdueucdctitiaiootnnioPPnrr/oorgrgrpra/amimmp((pTTeRRlRRsPPh)i)m--] Protective Concentration Levels (PCLs).", from https://www.tceq.texas.gov/remediation/trrp/trrppcls.html. C`TThhLiibabuo,odde(ea2au0ux0,,3)JJ..,"RRExGGpoHHsaaunnrsseoonnt,o, JpJMeMrfRRlouogogererorsos,c,tBBaEnEeGGsrureleyfy,o,nBBatDDe dBBuaarrribbneeege,,prJJHeHgnRRaiincchchayarrdidnss,,raJJtLLaBnBuduttemenonhuhosofeff.f,, 1:LLAmAatSSettreenvvaeelnnssaoonnnd,, C Lau, (2003). "Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and pprreennaattaall eevvaalluuaattiioonnss..""TToxoixciocloologgiiccaallSScciieenncceess 7744: :336699--338811. TTShuhloofmmofnofiorcrddA,,cPiP..d((P22o00t002a2)s).s.i1u10m044S--aWWlteeee(kkPFDDOiiSee;ttaaTrryy-6CC2hh9rr5oo)nniiincc RTTaotoxsxi.icciFittiyynaaalnnRddepCCoarartrc.ciinnVoooggleenunimicceiisttyyI-SSIttXuu.ddyCyowwviiatthnhcPPeeerrSfftlluuudooyrrooNoococttaannee. 66S33u22l9f9-o-1n18i83c3.A. cid Potassium Salt (PFOS; T-6295) in Rats. Final Report. Volumes I-IX Covance Study No. UURenngiiutteledadtKKiioinnngsgdd2oo0~m0n.0./D0D1rriinsnpkkeiicnniggfiW WcatatoteePrrFIIOnnssSppee(ccptteoorrrfaalttueeor((2o20o00c07t7)a).n.eGGsuuuiilddpaahnnoccneaetooenn) atthhneedW WPaFattOeerAr SS(uupppeprplflyylu((oWWroaaottceetrranQQouuiacalliiattcyyi))d) cRcooenngccueenlnatttriraoatntiisoonn2ss00iinn0/dd0rr1iinnskkpiienncggifwwiacatetteorr..PFOS (perfluorooctane sulphonate) and PFOA (perfluorooctanoic acid) UUAmSSbiEEePPnAAt ((W22a00t000e0)r),.QUUuaSSliEEtnynvvCiirrriootnnemmrieeanntotaarll tPPhrreoottPeerccotttiieoocnntiAAogngeeonnfccHyyu..mOOafffnfiiccHeeeoaolftfhWW.ataEetPreA.r.-8MM2e2et-thhBoo-dd0oo0l-loo0gg0yy4.ffooOrrcDDteeorrbiievvriinn2gg000 Ambient Water Quality Criteria for the Protection of Human Health. EPA-822-B-00-004. October 2000. aUUnSSd EEDPPevAAel((o220p01m11e1)n)..t.UU"SSfEErnonvmviirhrooinntmmpesen:nt/tacalfl uPPbrrooettpeeaccttgiiooovnninAAcgegeae/nnrcciyysk""/EErxexcppooorssduuirsreeplFFaaayccctftooirrnss?dHHeaainnddd2bbo3oo6ok2k.5.2OO.ffficeofoffRiReessceeaarercchh and Development." from https;//cfpub_epa_gov/ncea/ri sl~!recordis[~lay, cm ?dei d-236252. UUDoSScEEuPmPAeA.n.t((22f00o1r166P6c)e).r.fl""uUUoSSroEEonncvtviairrnooennSmmuelenfntotaanlaltPPerr(ootPteeFccOttSiio)on.n"AAggeReenntccryyie--vOOefdfflMi%caeeyooff19W W,ata2et0er1.r6.,HHefearalolttmhh EEffffeeccttss SSuuppppoorrtt hitps iw epa govsites/production'file/2016-05/documents/hesd_pfos._final-plain pdf Document for Perfluorooctane Sulfonate (PFOS)." Retrieved May 19, 2016, from ._h_.__t.tp s :iiw~ ep..~:.g.~..~{..s.i..t..e-~.&/.p....r...~.....d..t..~...c...tj...~....n.].~.~....e.~.&/...2..-()..1.~.~!).~../...d-...~..g~1N~.~1`~.~!1~.~.``~~.8~~~ n al @__a.j.__n.._:_p.__d__t.7. UUAdSSviEEsPPoAAr.y. ((f22o0r011P66e4dr)).f.lu""oUUrSSooEEcnntvavinirerooSnnummlefenontntaaaltlePP(rroPotFteeOccStt)iio.o"nn AARggeeetnnrcciyyev--edOOfMfffiaiccyee oo19ff,WW2at0ae1ter6r.,. fDDrrroiinnmkkiinngg W Waatteerr HHeeaalltthh hAhitdttpvpssis:Fo//Dw"wwfwor.eePppeaar.fgslouovo/rvsoitosecsit/aptnreoedSsuuc/ltfioponnra/tfeoile(dsP/uF22O00c11St66)-.-i"005o5iRddnooec/cturuimfemevineetndlst/sMeipIf~aoyfso_s1h9eh,ae2la0tlh1t_h6a,dafvrdiovsmiosroyr_yfifninala-l-ppllaaiinn.ppddff. `WMWaaMmmabrbataiuungg,hh,K, JJD.,,aRRs,WWJCSSeeDttezzWeerir,t, tAA,MMMPPSiitttrrruyunzzazzree,lllRoo,, JJJuLdLisiuuo,n, ,DDKMMARReHeioiffu,,cNNk,CCCKKllLeeaiiunns,stt(rr2ee0uu1ce3rr),,.NN"CDChohisinniggm,,erYYicWWaaannngcgh,,oNrNinSSgioippfeess,,in Mvvii,~v,Moo aaannrtddinim,nKvviiDttrroaosss,ttJuuCddiieDesseffWoorritppt,eerMrfflluSuotorrroyoonoaccrtta, anRnoaaJtuteedsaaonnndd, ppKeerArffllHuuooorruoocookcc,ttaaCnneeLssuaululff,oo(nn2aa0tt1ee.3."").TT"ooDxxioiccsooilmloogegitircciacallaSSncccihieeonnrccienessg 11o33f6~:m: 330088--332277. PPaaggee 7d4ooff 775 22447766..00007744 STSTAATTEE 0077443388116699 WWmaeatnnaggb,,olLLi.,,smYYdW Wiasatnnugrg,b,aYYnceLLsiiaainnnggB, ,AJJLLLBii,,/YcY mLLiiiuuc,,eJJthZZrhhoaaunngggh,, iAAnhZZihbhiaatnniggo,n, JoJfFFulu,o, wGGdJJeiinaasnniggt,,y ((l22i00p11o44p)r)..ot""ePPiFnFsOOeSSxciirnneddtuuiccoeendd*lliippiidd mSScceiiteeannbitoiffliiiccsmRReedppoiosrtrtutssrb44-a:n44c55e88s22.i.n BALBic mice through inhibition of low density lipoproteins excretion." WWuu,, XX,., DDHH BBeennnneetttt,, AAMM CCaallaaffaatt,, KK KKaattoo,, MM SSttrryynneerr,, EE AAnnddeerrsseenn,, RREE MMoorraann,, DDJJ TTaannccrreeddii,, NNSS TTuullvvee,, II HpHeoerprtutzlz-a-PPtiiiccoccniisooottfttooc,,hi((22l00d11r5e5)n)..a""nSSdeerarudumumltccsooninncceCenantltrirafatotriionoinnasso."offEppneevrriffrlluuoonormriiennnaatttaeeldd Rcceoosmmepaporoucunhndsd1s3(6(.PPFF2C6C)4)-2aa7mm3o.onnggseselleecctteedd populations of children and adults in California." Environmental Research 136: 264-273. PPaaggee 77580o1f7785 22447766..00007755 STSTAATTEE 0077443388117700