Document a4vdEoVadr0OvLnK0Q2q3rYBy

`IINCNoSnSTtTaRiRnUUsCCaTTsIIuOOmNNmSSarFFyOOoRRf aSSvTTaAAilFFaFFbleW WdOOaRtRaKKaSSnHHdEEoEnEgTToing staff analysis Data and Contains Data and analysisare subject to change a summary of available data and analysis are subject to change ongoing staff analysis Last Revised: 5/3/17 Last Revised: 5/3/17 PPeerrfflluuoorrooooccttaannooiicc AAcciidd Supplement to Original Review (completed on 12/07/2007) ReS-uEpvpalleumateinotntoFoOcruigseindaol nReKveiyewSt(ucdoimesplIedteendtiofnie1d2i/n07U/S20E07P)A Health Effects Support Re-Evaluation Focused on Health Effects Support Documents Released May Key Studies Identified in Documents Released May 2016 [IS EPA 2016 RRreeefferevttrooiooerriiggwiinnsaall-rreecFvviiioenewwamlwwpoPorFrlkkOssAehh\eetPeetFteO({Alldoo_cc2aa0ttee0dd7Raatte::v\Wi\DDeawat\taPa3Ff3bOM\eA\he~FHIiRRnaAAl\\CCNOoOvM M0V7M.IpOOdNNf)\GGuduieviddeaalnnoccpeeed-- iW Wnaat2t0ee0rr7i\TTfooo~xr `additional information reviews-completed\Final\PFOA\PFOA 2007Review\PFOA Final Nov07.pdf) developed in 2007 for additional information (CCAASS ## 333355--6677--11((ffrreeee aacciidd)) 5825-233633-551--66(66a--0m0m((oaaccniiidduffmlluusooarrliid,deeA))PFO) 3825-26-1 (ammonium salt, APFO) 335933 (slver sl) 22339955--0000-88 ((ppoottaassssiiuumm ssaalltt)) 333355.9-953--53((ssoidlvieurmssaallt)t) [Note: perfluorooctanoat3e3a5n-i9o5n-5do(essodnioutmhasavlet)a specific CAS number ] [Note: perfluorooctanoate anion does not have a specific CAS number.] Synonyms: PFOA Synonyms: PFOA IUPAC name (PubChem) IUPAC hame (PubChenO: 22,.22,.33,.33,,44,,44,,55, .55, ,6,66,,67,,7Z.78.,88,,88,-8p-epnetnatdadeeccaaffluluoorrooooccttaannooiicc aacciidd CChheemmicicaall FFoorrmmuluala:: CC88--HH--FF1155--0022 SSttrruuccttuurree HH Il Einitial Primary Re-Review NG e T00S0e6d |D92s0C1o6mpe Initial Primaw Re-Review | ((PPaarrttiiaall)) FFiinnaall PPrriilmnaarryy RRee--RReevviieeww | ((FFiinnaall)) FFiinnaall RRee--RReevviieeww [inital Sccondary Re-Review | AT Jame | mG Initial Secondary" Re-Review | (partis) Final Re-Review wens [1601s (partial) Final Re-Review (final) Final Secondary Re- (final) Final Secondary Re| Review Review Initial TeamRe Review Tox Team [9162016 | 103076 lnitial Team Re-Review | ((ppaarrttiiaall)) FFiinnaall RRee--RReevviieeww | inal Final Sccondary Re- i207 | 420i (final) Final Secondary ReReview Review JAJ Tox Team 7/22/2016 1111/777122001166 9/6/2016 11/9/2016 9/16/2016 11112/233//22001166 3/31/2017 9/5/2016 1111//0088//22001166 9/12/2016 11/16/2016 10/5/2016 1122/2222//22001166 4/2012017 Draft Draft Docu Document for- for review review and and discussion discussion ppuurrTppFoossOeeAss-oolny1l,y0.1DD92rarft document document docs does otnot onsite constitute Agcy Agency policy policy -- PFOA - 1 of 92 Exhibit 2475 22447755..00000011 SSTTAATTEE o707a433e8000044 Draft Draft Documens Document - for for review review and and discussion discussion ppuurpPpoFosOseeAss oo-ln2yl.y0. 9DD2rraafftt document document docs does not not constitte constitute Agency Agency policy policy PFOA - 2 of 92 22447755..00000022 SSTTAATTEE 0077443388000055. Current MDH Criteria: Acute nHRL (2009)* = Not iDerived (Insufficient Data) ** `SShhoorrtt--tteerrmm nnHHRRLL ((22000099))* -= NNoott DDeerriivveedd ((IInnssuuffffiicciieenntt DDaattaa))]|**** SSuubbcchhrroonniicc nn[HIRRLL((22000099))** == NNoottDDereirivveedd ((hIn~ssuuffffiicciieenntt DDaattaa))/[**** Chronic nHRL (2009)* = 0.3 ug/L (Development, Hepatic system, Imnmne system) * Values officially became HRLs (i.e., promnlgated into rule) in May 2009, however, the full review and values (as a~-IBVs) were finalized in Dec 2007. **Serum concentrations are the best dose-metric for extrapolating to hunmns. At the present time the i~fformation 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 cxists regarding toxicoldnetics in early life. Therefore, acute, short-total and subchronic HRLs were not derived. MDH Health-Based Guidance Evaluation Perfluorooctanoic acid (PFOA) is a synthetic, fully fluorinated, organic acid used in a variety of consumer products and in the production of fluoropolymers and generated as a degradation product of other perfluorinated compounds. PFOA is one of a large group of perfluoroalkyl substances (PFASs) that are used to make products more resistant to stains, grease, and water. Major U.S. manufacturers voluntarily agreed to phase out production of PFOA by the end of 2015. Because of strong carbon-fluorine bonds, PFOA is stable to metabolic and environmental degradation. Exposure to PFOA in the United States remains possible due to its legacy uses, existing and legacy uses on imported goods, degradation of precursors, and extremely high persistence in the environment and the human body. PFOA was selected for re-evaluation under the Contaminants of Emerging Concern (CEC) program because the US EPA recently published a new final Health Advisor (HA) (USEPA 2016b) along with a Health Effects Support Document (HESD) (USEPA 2016a) for PFOA which contain new information ,and more in-depth assessments (e.g., phannacokinetic modeling) of pre-existing studies. MDtt initiated a re-evaluation of the 2009 ttRL value to detemfine whether changes to this value are warranted. US EPA's published docmnents include a comprehensive review of the toxicological literature. This comprehensive review will not be duplicated in the re-evaluation. Rather, the re-evaluation will focus on the key studies identified in US EPA's risk response assessment. PFOA is a bioaccumulative chemical, with an average half-life of 2.3 years in humans. High, short-term exposures result in an internal body burden that can take several 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 bottle-fed and breast-fed infants as well as long-term exposures. Noncancer HBV = 0.035 ug/L (Developmental, Hepatic (liver), Immune, and Renal (kidney) systems) R~ (MDH 2017) Cancer cHBV = Not Applicable Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 3 of 92 22447755..00000033 STATE 07438006 Note: Table below is only a partial list andJbcuses on more recendy available gMdance values 00.0077uugg//LL |LiLfifeettiimmee ddrriinnkkiinngg ((UUSSEEPPAA22001166bb)) water health Based on RfD derived from a developmental tox study in mice advisory (HA) (reduced ossification of proximal phalanges & accelerated puberty in male pups), RSC of 0.2, mad lactating women intake rate (0.054 L!kg-d). HA is protective of short as well as lifetime exposure. A cancer-based value was also calculated (0.5 ug!L) but since it was greater than the noncancer value it was not used. [previous provisional HA was 0.4 ug/L (2009)] 0.4 ugiL Draft Groundwater Alaska (August 22, 2015) personal communication from Ted Wu to value Jimmy Seow. Based on US EPA 2014 draft toxicity values. 0.4 ugiL Drinking water guitdideelliinnee vvaalluuee Delaware Dept of Resources and Environmental Control aci ((UUSSEEPPAA 22001166bb)) 0.4 ugfL Provisional Illinois EPA aci (ASTSWMO 2015). Based on RfD from MDH. (Class I) Groundwater Rcmcdiation 2 ugiL Obj ectivc (Class II) 0.06 ugiL Drinking water Maine Department of Health and Human Services aci (ASTSWMO guideline value 2015) 0.42 ugiL Drinking water Michigan Department of Environmental Quality 2011 aci (USEPA guideline value 2016b) 0.04 ugiL Drinking water (New Jersey Department of Environmental Protection. 2007) guideline value Based on ~target' human blood level of 0.018 mg!mL, total UF of 100 (10A, 10H), DW-to-blood concentration factor of 100, and RSC of 0.2 0.014 Draft Health-based (New Jersey Drinking Water Quality Institute 2016) health-based ug/L MCL MCL recommendation is based on target human serum level of 0.0145 ugimL based on increase liver wt in mice. A total UF of 300 (10H, 3A, 10DB) was applied. A clearance factor of 0.00014 was applied, resulting in an RfD of 2 ngikg-d (or 0.000002 mg/kg-d). The draft MCL is based on the RfD, 2 L/70 kg-d intake rate and an RSC of 0.2. Recommendation was finalized in March 2017. NJ also calculated a cancer slope factor of 0.021 per mgikg-d based on increascd incidcnce oftcsticular tumors. The hcalth-bascd MCL based on cancer effects @1 in a million lifetime cancer risk level is a epee 2 ugiL 0.29 ug!L DDrriinnkkiinngg wwaatteerr guideline value Groundwater uscd as drinking water N0No.o0rr1tt4hh uCCgaa/rIr~ooll-iinnsaaamDDieivviaisssiiotohnneo&nfoW WnacatatenerrceQQruuavlaaillitutyye.aaccii ((UUnniitteedd SSttaatteess Environmental Protection Agency (EPA) - Office of Water 2016b) (TCEQ 2016) Based on RtO 0.000012 mg/kg-d 0.02 ug/L Drinking water Vermont Agency of Natural Resources aci (United States guideline value Enviro~maental Protection Agency (EPA) - Office of Water 2016b) 55/11199/22001166 8/22/2015 Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 4 of 92 22447755..00000044 STATE 07438007 eenaHFeeaallthh iinntteerriimm 5SuuggiLL | DDrriinnkkiinngg wwaatteerr qquuaalliittyy gguuiiddeelliinnee | (i(AAtupnsstJtrraallwiiaann HHheeeaaalllttthhh nPPsrrwootteegccotvti.iooannwPPernriisnniccriippoaanllmeCCnootmmfmaimctttitseteheee..eteesnnfDHloeecaalulttmhhe2n200t11s66/))pf| 662/2997/22001166 | as-interim-health-valuss-ahppe. pdf. .h...i~.t.p.....[/..~3y.~F~.h...e..`..a.~.t-..h.....As.~:g~v.au/~nvir~nm~nt/factsheets/D~cuments/p...f.. Based on TDI of0.0015 my/ke-d. as-i nterim-health-values-ahppc .pdf Based on TDI of 0.0015 mgikg-d S50ouugg/iLL | RRqeucacclrirectayattiigoounniaadlellwwianatetecrr 02uglL | qDDsucrrraiielnnietkkynii,innngggguwwivdaaatelteleuirrnee || (w(HHaetcaealrttthghuCCidaaennlaiadndea (22H00e11a66l0at))h SSCecarrnevaeednmiiann2gg0V1V6aabll)uu.ee Daarnnaddftddrrdaaofftct uppmrroeonpptoossieenddclddurrdiinenkdkiinngg 0.2 ugfL os(p2cr0roie1pe6onssaie)ndg&&Dvrailunkeing | cwcbaaaallsctceeuudrllaaogttuniioiodPnneoolOifnfaDea cc(Haaonnefcca0eel.rtrh0bb0Caa0ssae6endd2a5dvvaaamlla2uu/0eeok1oaf6f-bd33).00(DPuuegrgr/a/LkfL.tindsNNooceontuncamclaaenn2ncc0tee0rir4nvvcraalaulltuudseeetdudy) W Wp0ar1oat6pteeo6rrs)GeGuduiiDdderelilniinnkeeing TabahnnaedsdeccdTooDommInppowPosaOsisitDteec~oUUom_FFbooioffnfe022d.5500wrr0ieet6sshuu2ll5atti0inm.ngg2g/iiknRngaSa-CdTTaDD(nPIIdeoorkff10i.0n.5.s00100/e07t0000akl22g5520m-m0g4dg/ikrk0aggtd-ds.t.udy) (2016b) cTcfaiahlnleccauluTlilazaDteteIed wippnrraoos2pp0coo1oss7meeddb[pgginuruieeidvddeielwoliuininseteh.(.2aDD00o1o.c0c2)uuRmmDeSreniCntntsksaainarndrege1Wee.5axxLtppee/e7crc0ttGeekuddgittdoob-abendecteo Value 03 ug/L | Drinking Water |foff(ioDrnraanPPliiFFzsOeOhdAANiinwwnia2ass0st1r007y...77o[ufpgurte/yhLv]e]ioEunsvi(r2o0n1m0e)nDtr2in0k1i5n)g Water Guidance Value 0.3 ug/L (D(uaasrnneidddnfkggoirrnroogduurW nniddnakwwtieaanrttgeerr | B(B0D.aa0sas3eenddiLsiohoknneMdTT.iDDnIiISsitoornyfcf0eo.f00t.o0t0hx000e11pEmmrngg/voikikrefog-on-didf.m,Ple~`FnRReOtSSS2CsC',0'1Po5o)FffO0.A10.1,, aaannnddd PiinnFttaOakkSeeAraraatrteecooff water) used for drinking water) si0sicmi..m0i3lialaLadrrdikicCtgoOi-modlpnn.lpSoilifaiantnnchcceeeetcwwoioxittnhhpcraaoecfcnoiolmtempsropaosotfisPmiittFieoeOtnddSrrvii,nanPlkkuFiinenOggrAawwtaiaatontseedrrshPqqouFuauaOlllidiSttyyAbeccarrikritceteeprrtiiaa,, i<.1e.., WaadtdeitriognuiodfatnhceecfoonrcPenFtOraStiaonnd/liPmFiOt vSaAliuse0r.a1tiousg/sLh.ould be kept <1. Water guidance for PFOS and PFOSA is 0.1 ug/L 00.33 uugg/L | LpLriieffeceallouontniggonary valu prccautiona~ valuc PrPAecrcetaciuaotunitiVooannlaaurreyys. 01-06|PA(PPAcAAtViVoV)n) Values 2>00uu.6g1g-i-L01.56 | PAV10 PAV, >>01uw.g63l/-L51.05 | PAV3 PAV, S>01uw.ug5lg/-lL5l.L0 | PAV1 PAV, 05ugl 5.0 ugiL 0.5 ug/L | PPPAAAVVVoffoorr pregnant iiwnnoffaamnnettssn&& pregnant women | g((HFuiiecdaaallttnhhc.e23v00a00l66u))efDDorrriiannlkkliinnpggopW Wualatateterirovvnaasllguureeo--uplfiscfel(loofrnnoggmhhe2ea0al0ltt3hh)ttoolleerraabbllee agPPcuAAtiiVdVonass.nttcoPoellVeevrrAaaailbbuslleefeofffbroorrrcaaaollmmmppaaooxxspiiiumtmleauutmomiofnooPsffFg11Or00oAyuyrrpass,sn, d(33fPryyorrsOms,,S21| 0yy0Trrn3s,,)aoodrdriiitmimommne,eddiiniaattee |aaaascccctecioxooprrnedd.daaiPnntVccieeoAuoosfiflsttyhhfoeearsDDcproroiimsnnskkpiiiobnnslggiewW WaanqatdftePeirrFnsOOOorfrAdadriinaanansanndccfePei,nF,aeeOnffcfSfioo.arrltItnssreaaarsrdeeodutitrotoicoebbnsee,amminnaadddee,, ttalhheseveeelxlloospccetaaodllilcctieiiosrrcsucustumlhmyassntatasatnnhpcceoeesHsssPiaaVbll.llloeow(wah.,nedt0aolitnrrhees-dodbuufaaccsreeedaccspoorfmmiepncpoaaosnusitcititieeaolnppareererrysffollvuuuaorolcrruoeoescc)aaaorrnbbdfoonn 0.1 pall. levels ggiL. to less than the HPV (health-based precautionary value) of 0.1 T5007 1/5/2007 009ug 0.09 ugiL (E(SnSwvwieerddoeennnm))eLLniitvvss2mm01ee5d)de.ellssvveerrkkeett ((23001144))., cacii ((DDaanniisshh MMiinniissttqry~oofftthhee AEA`Ansmmavaiarxpxoirinemmmcaaaleulnttttioooll2ene0arr1ara5bybl)le.emellaeesvvueelrleoo,fft0h.e00.90l9ipgmiggt/iLLvawwlauases oddeefrriivv0.ee0dd9 uffgoo/rrLPPwFFOaOSsS,.further `cAaaopspnpptalliaiepemdrdienffcoaoartruettthidhoeendrassiuruynmm,koimofnfegsasewseavuvtereeennr, PtPhPFFeeAAfliSSlmussiouutrbbvossatctlaatunnaeccneeosssfuf0floo.f0uuo9nnnaddutgeiinn/L(PwFOaSs)f:urther cP(PoPeeFrnrBfftlaSlu)muo:oirrnhhPaeeetxsefaadlnnueedosrrusionulcklfftiobannnngaaottwieeca((taPePcrFiF:dHHP(xSePS)rFf):lO;uAPPo)eer:rorffcllPtuaueonorrrefoolbsbuuuuolttrfaaoonnhneeeaptssteuualln(ffPoooiFnncaOattaSeec)i;d a(((PPcPiFFFdBHH(pSpPA)AF;))P;P;AePP)ree.frldufllouurooorrcoothlaienexoxaiacnnooaiicccidaacc(iPiddFO((PPAFF)HH;XxPAAe)r),f;lauannoddroPPheeerrpfftllauunooorroiocppeeannctitadannoiocic: acid (PFPeA). DDrraafftt DDooccuummeennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuurpPpoFosOseeAss oo-lnSylo.yf. 9DDr2raafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 5 of 92 22447755..00000055 SSTTAATTEE 0077443388000088. 0.3 ugiL Health Value (United Kingdom. Drinking Water lnspectorate 2007) LLeevveell 11 ==00..33 uugg//LL ((ccoonnssuulltt llooccaall hheeaalltthh pprrooffeesssisoinoanlasl&&s mmoonniittoorr DW) Level 2 = 10 ugiL (Level I + put measures in place to reduce to below 10 ug/L) Lcvcl 3 = 90 ug/L (Lcvcl 1 + 2 + takc action to rcducc cxposurc wii 7 days) pT Type of Review | (Yearof focuses eee on more recenztj, released [Refetro the General HRL EndNote Library] Obtained 0.00002 mgikg-d ~ (2016) (USEPA 2016a) 5/49/2016 Heal~ Effects Suppo~ Document for Pe~uorooctanoic Acid (PFOA) 0.00002 mg/kg-d Dra~ inte~ediate (ATSDR 2015) 9/15/2015 M~ ~p ://w~.atsdr. cdc .g~/~_~.f!~_~p_~.~:_p_~ Dra~ Toxicological Profile for PerfluoroNkyls. (Dra~ M~s wcrc derived based on non-hum~ pinnate stu@ Toxicological (it was felt that extrapolating from the rodent studies Review 2015) incuwed too much unce~ainty). BMDL10 for liver weight (Butenhoffet al 2002 study in lnonkeys) used to generate a HED POD of 0.00154 mg!kg-d Total UF 90 (3A, 10H, 2 DB) resulted in inte~ediate M~ of 0.00002 mgikg-d 0.000006 mgikg-d (Prevention. 2014) Based on POD of 0.0018 mgNg-d (geometric mean of 6 HEDs for liver effects) and tmal UF of 300 (3A, 10H, 000.0000000115533 mmyg/ikkgg--dd Nte~ediate ~ ~0~) ((MMiicchhiiggaann DDeepparatmmeenntt ooff EEnnvviirroonnmmeennttaall QQuualailittyy 22001111)) Based on LOAEL of 3 mgikg-d (monkey study by ButeN~offet al 2002). Adjusted for differences in half- litE = 0.046 lngikg-d. Divided by 3,000 total UF (3A, 10H, 10L, 10S) 0.000002 mg/kg-d DraR ~ (New Jersey Drinking Water Quality Institute 2016) draR target human serum level of 0.0145 ug/mL based on increase liver ,~ in mice. A total UF of 300 (10H, 3A, a1p0pDliBcd),wraessualptpinligedin. aAncRleEaDraonfce2 fnagc/tkogr-dof(0or.000.0010400w0a2s applicd, resulting in an ~D of 2 ngikg-d (or 0.000002 mmgg//kkgg--dd)). NJ also calculated a cancer slope factor of 0.021 per 0.021 per tng/kg-d Draft CSF mgNg-d based on increased incidence of testicular rumors. 0.0015 mg/kg-d Interim TDI (Australian Health Protection Principal CommiRee 2016) 6/29/2016 [adoptcd 2008 EFSA TDI] `hhitttpp:://iwAwwwwwh.ehaelatlthhn.nsswwg.ogvo.va.wa/ue/ncynivrioronmnemnte/nftaifc~ttsshheeecttss/~Doo cuments/pt~s-interim-healfl~-values-ah ppc. pdf Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 6 of 92 22447755..00000068 STATE 07438009 0.000025 mgikg-d Draft TDI 0.0001 mgikg-d | TDI 0.0015 mgikg-d TDI (Health Canada 2016a) Screening Value and draft proposed drinking water guideline (Health Canada Iolo Eagh, shh oti 2016b). Draft document included calculation of a cancer b`baasseedd TTDDII ooff0.00.00033 mmgg//kkgg--dd ((rreessuullttiinngg iinn DDWW gguuiiddaannccee level of 30 ug/L), which was less conservative than the noncancer TDI. Noncancer value based on POD~,~,) of 0.000625 mg/kg-d (Perkins et al 2004 rat study) and composite UF of 25 resulting in a TDI of 0.000025 mmgg//kkgg--dd.. DDooccutmmeaennttss aarree eexxppeecctteeddttoobbee ffiinnaalliizzeedd iinn 22001177.. 6/30/2016 [The previous Drinking Water Guidance Value of 0.7 uugg//LL ((HHeeaalltthh CCaannaaddaa 22001100)) wwaass bbaasseedd oonn HHEEDD ooff 0.000077 mg!kg-d (based on monkey study by Butenhoff BL ok 3 ee ao pill et al 2002 and serum level of 77 ug/mL @LOAEL)]. (Danish Ministry of the Environment 2015) Based on BMDL10 of 0.456 mg/kg-d from Palazzolo et al 90 day rat study. Converted to HED of 0.003 mgikg-d by -142 factor for TK, UFA 3 and UFH of 10. (EFSA 2008) Administered dose NOAEL of 0.06 mgikgd (subchronic study in rats) and administered dose BMDL10 from a number of rat and mouse studies of 0.3 0.7 mg/kg-d. Admin dose BMDL10 value of 0.3 mg/kg-d was selected and an overall UF of 200 (10A, 10H, & 2 to compensate for uncertainties related to internal dose kinetics) resulted in a TDI of 0.0015 mgikg-d. 6/2/2 016 1/14/2009 :. :~w~: -a-i~.,~-Ti]=~-~ -fi~..~ ~ ~ ? , ~ ~ ~ ~ Toxlcokinetlcs: Source: (USEPA 2016a) (See Chapter 2 for additional information) and (USEPA 2016b) as well as MDH 2007 review worksheet. NOTE: Toxicokineiw prqfiles and the underlying mechanism.for half-life d~fferences across species/L,enders are not completely understood, although many q/'the d~]&~nces appear to be related to elimination kinetics and bctors that control membrane uwnsport. 7b date, three trans~ortJbmilws appear to play a role in absorption, distribu#on, and excretion: o~2ganic anion transporters (OATsg, otkganic anion transporting polypeptides Apion. Ariotsnrr shin nd dl spisonn, ails and (()AlTOs), and multidrug resismnce-associatedprotein~ Absorption: Absorption data are available for oral, inhalation, and dermal exposure in laboratory, animals, and extensive data are available from humans demonstrating the presence of PFOA in serum. PFOA is moderately soluble in aqueous solutions and oleophobic (i.e., minimally soluble in body lipids), movcmcnt across the apical and basal mcmbranc surfaces of the lung, gastrointcstinal tract, and skin involves transporters or mechanisms other than simple diffusion across the lipid bilayer. As discussed above, them are throe transport families that appear to play a role (i.e., OATs, OATPs, and MRPs) in enterocytes in uptake of PFOA. Together they ftmction in the uptake of organic anions from gastrointestinal contents and transport of those anions into the portal blood supply. Based on animal data, PFOA is well absorbed following oral exposure, with several studies Oe is reporting >90% total absorbed. An inhalation study in rats resulted in measurable serum concentrations following repeated exposure demonstrating absorption of PFOA, however percent Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 7 of 92 22447755..00000077 STATE 07438010 a"aTbbhsseoorrrppetstiiuolotnnswwoaasfsnnnoovtittrrreeoppoporertrteecddu..taTTnhheeeorrueesiiasbeesvvoiirddpeetnnioccnee ttshhaattt PPuFFodOOfAAiPFiiessOaasAbbssootrrhbbreeoddugffhoollrlalotowwaiinnndgghddueemrrmmaanallseekxxipnpooshsuaurvreee.. bbTeeheeennrrereespupooltrrstteeoddfbbinyy vFFialarssoaannpooereecttuaatlaln22e00o00u55saaannbddsossruupggtggieoesnsttsootnunldlyyieaas ossmmfaPallFllpOpooArrttitihoornnou((11g..h4444ra_=t+ a11n..d1133h%%u)m)ooaf.fntthshkeeinttoothtaaallve hAAuFFmPPaOOnaasppkpiplnliicaeddftpprecnn4ec8ttrrhaaottucerdsd.tthhTrrhooeuuggchhalrrcaauttlssakktieinnd aapnnerddmeaaannbeicglglilitiggyiibbclloceefaafmmiocoiuuennnttts((0w0..e00r44e883.2_05+.00.011%%)1)31ppecxnnec1tt0rraattcedd cdhceeeunrnmtmtiiaammnleetsttekoerxriinsscippatefeytrreshrhtoo4uuu8drryh((obemyurarhs/Kh.)e)Tnamnhne~edddcy99a..l4(c4199u9l+a8t5e22)d..88ip6n6edxxrimc1a1e0t0a.e"7bdiccltmihrtyaiut'hcaiiponnpelrfaiaftictcaaaitenninddotnshhuouwmfmeaaarxnen~a3ssq.kk2uii5ne,,ourrees1ss.ppp5ea1ecscttxtieivvoe1el0fyl-y5.A. PAAFO `dcooeurumllddalpprrtooodxduuiccciee~ttoosxxtuiiccdiiyttyybyaattKhhiieggnhhnedddooyssee(ss1.985) indicated that application of an aqueous paste of APFO DDiissttrriibbuuttiioonn:: IpIttrohhtaaessinbbs.eeeePnnrosstuueggiggneesbsttieendddittnhhgaattinPPFpFOlOaAAsmccaiirrfccruuollaamtteecssyniinnomtthhoeelgbbuoosddyymobbynyknneooynnscc,oovavatalsle,enntatlnlyyd bbhiiunnmddaiinnnggs ttwooappsllacasvsmamlaauated via ipiPnnrFov~OtieitAtirrnoosa.mmddePeetrthodhtoeoadtidnsc-so-bnriacnate,td,nitnhhruguammtianianon,pn,lsaaasrnnmaddnagmmifoornonngmkkfersyco'ymppnlloa1amsstmoomala5g0pup0rrsoopmttpeeomiinn.nsskHcwwyeuesrmr,eearanaabtbsls,lecattrnooudmbbhiianunlddmbu99amn77is--n1w10(a00Hs%%ScoAvof)aftlcuthhaaeretrcidedvia t2tPhhFeceOollaAmarrmggaoeedssndtt eppcdooarrrattrtiieocornnooonoffcfheyttnhhdteerraoPPtpiFFohOnOosAAbiraaacnmmmgooaintnnegggrifttharholeesmppirrn1ootttteeohiienn5b0ccl0oooommpdppp,omonin.enecnHmltuussdmoiofanfnghhssuuhemomrruaatmnn- appanlllaadbssummmmaea.di.niSSu(eemHrr-uSucmAmha)aaicllnbaburufdmmaetiitdnny iiss aaascceciirddoussm,m, mttphhroyyonrrtoocixxaniirnnrieeineh((ruTTo4m4)f)a,,hnyhhsdeeammroneepd,,hiionrnbaootirrscggiaamsnnaaiilctcebriiuoiomannilssns,,.iaanAnntddhvessaorobimmleoeteoypopdhh,faairnrmmmcealcaauescduueitnurigtecimacsleahsnlos.t.rstAA-opapfpnptrdrhooexlxniliemmdbatiauuetmemlilyy-nc/66h0Pa0%iF%nOofoAafftttthyhee `csceoormummpplleepxxrosstuegingueisntghaauccmgoonanfnfooesrrammnasadttiirooatnntasalliscchahlaabnnuggmeeiiinnn. ttAhheepvrpaorroiteteetiyinnoaafssmaaereaesssuuulrlettmoofefntththsee oPPfFFtOhOeAAbaiblbninuddmiinninggiaPasFs OwweAellll. "iTTnhhveeibtbriionnuddsiiinnnggogofaf PPrdFFiOOoAlAigttooanhhdmu-mbniaannndiTTnTTgRRass((atthyh.yyrrooPiiFddOhhAoorrmdmeoomnnoeenstttrraranantssppeodorartht ipprrgoohtteeiibnni))ndhhiasnsgaalalsfsofoinbbieeteynnfoeervvaaTllTuuaaRtteedd wwwiniiilttvlhhitd9r9io44sp99ulsnaniymmnoglno,ola,nsrccapaaeduucisoisiflniiiggnc2aganbid55n-00bd%i%inndgiinnionhhigibbpiiarttsoiisotoaennyion.ofsfPTwTFi:4OthAbbiinniddtenihmnedgoctinetoolstnlttruhhagleetaerTdTmTTaRR.ha.iglIitthtalasblrsiwsnoediolisislngppaoosassfssifiniibbntlliheeteytthshfaaeottrr uPPTmFFTObORuAAt Title work has been done to investigate that will display nonspecific binding to proteins little work has been done to investigate that probability within the cellular probability. matrix as well as in the serum but `NNaoodmccilnliiinnsiitccraaalltissottnuuoddfiieeass aacrroecntaarvvoaaliillleadbblldeeotsthheaatot feexxPaaFmmOiAinn.eeddHottiiwssessuvueeerdd,iisssttrariimbbpuulttieiosonnciionnlhhlcuutmmeadannissn ffbboillollomowowniiinntggoring and eaepdpimiddieenmmiisiotorllaootgigoyynssottuufddaiieccssonpprtrrooovvliildeddee dddaaottsaae ssohhfooPwwiFinnOggAddiiHssttorriwibbueutvtiieoornn, of PFOA within the samples collected in of PFOA within the bodybiomonitoring body. and "tTThhhaeen hhiiinggfhheeemssattltetisis.sssuuOeetcchoeornnccteeinsntsrtuaertsiaowtniistoahanrarsee tuuessnuudaaellnllycyyiinnttothhaeecclliiuvvmeerur,l.LaLitiveveePrrFaaOccccAuummaurulealtathtiieoonkniidinnnemmyasal,leelssunissgsgg,rreehaaetateerrtr, t`afhanonadudnnnmdiumnsPsfcFcelmlOee.A,alppeillsnuu.sslOittvhhteheer,eterelsstutintseegssssu,iiennsbmmwaailotleheassnanaadtnneddkneiduudetntneee,rrcyuusyss,tioinbnuafftceecmomuanalmlelyesus.ll.aotPPweooPslsettF-x-mOcmlAoosrrittaenremebmrtasshittneuu,ddkiiieedssnieinnyshh,uulmmuanangnsss, hhhaaevvaee.rt, fbund PFOA in livcr, lungs, bonc, and kidncys, but only low lcvcls in brain. DDPouusrrtiidnnegglippvrreeegrgnyma,nmcPcyF.yO, APPFFiOsOtAAraiinsssppfrererersseeednntt0iinnoftthfhseeppprlilaanccgeetnnhttraaoaaunngddh aalmaacnntinaoitotitioiccn fiilnudaiddioinnsebb-oortethhlaaatnneiidmmmaaallnssnaaennrdd hhuummaannss,. Post-deliveu, PFOA is transferred to offspring through lactation in a dose-related manner. MM (DKDaHrHrNNmoaotntees2s:0:0PP7u)ubblilinidcciaacttaiiotoennssthbbayyt ((lCCevaaertliisooninn22h 001155)),u , c((KoKiirmm mdb22l00o11a 1o~)d,),se(gn LrLiiuunm2200a11r11)e,),ty((pFFicrraoolmlmymm~ee9220001%10o0)).f, amaanntddernal css(oeKenrracuuremrnmmtccraoaontnnicc2oeen0nnst0.tr7raa)Ottiiinnooednnisscsataautnndeddythll(eeaFvvtreellloessmvieimnnles'bbri2rnee0aa1hss0utt)mmmaaililnlskkocaaomrrreeedat~sbivulpcoriaoceldadl/i~lysy'eer~r~u5u3mm%% oacoorfenfcmmteayantptteiercrraanntlaaillyolns~ssee9rir0unu%mmmootfhmeraslearnnadl bicbronreenfaacisesnttnffteterddhaatiiinnnoffnaiannsn.tttssh'Oeaanittre66msotmmtuhoodenynrtsh(s.ts,a)q'fofemtremr dedee2lli0vv1ee0r~)yy andalso and reported ~S-fold measured serum reported ~5-fold higher serum concentrations in concentrations in mothers and higher serum concentrations in infants than in their mothers. MMeettaabboolliissmm:: bPPoFFnOdOsAA. iiIsst sastltaasbbolleeisttroo mmeeetstaabbiooltlsioiccmteaatnnaaddbnoeelnntivvicirroboinnommterenantntasalflodrdmeeaggtrriaaoddnaa.ttiioonn bbeeccaauusseeooffssttrroonngg ccaarrbboonn--fflluuoorriinnee. bonds. It also is resistant to metabolic biotransformation. EElliimmiinnaattiioonn:: hEEaxxvccrereeittniiovoennsdtdiaagttaaataaerrdeetaahvveaaicilllaaibbmlileenafftooirronoororaafll ePexxFppOoosAsuurireen hiinnumhhauunmmsa,annsCsyaannnoddmlloaalbbgoourraasttoomrroyyn, kaaneniyimmsa,laslas.n. dSSeeavvteser.raalIlnsstthuuuddmiieeassn hffeeammvaealleienssv,,eeeslltiiimgmiainnteaadttiiotohnneppeaalttihmhwwinaayaytssioiinnnccollufuddPeeFppOrrAeeggninnaannhccuyym((accnoosrr,ddCbbyllonooooddm))oaalgnndudsllamaccttoaanttikiooennys((,bbrraeenaadssttrammtisli.lkk)I).n. human DDrraafftt DDooccuumlneennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuurpPpoFosOseeAss oo-ln8yl.y0.9DD2rraafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 8 of 92 22447755..00000088 STSTAATTEE 0077443388001111 Comments: hEEluliimmmaiinnnsaattaiioonnnd hhsaaollmff-e-liivlcaebssodrdiaiftfffoeerrry aaalmwnoiomnnagglssspppeeeccciiieeesss... TTIhhneefrroeeramarareetailaolsnsoofrssoiiggmnnihiffuiicmcaaannnttsggeednnodcdeserrnddoitfi,fffeaetrrteehnniccseetssimiinne, ehppxrurcoomrvveaiitdndoeesrysasuunhffdaffliifscc-oiileeminnvteetsdd.laaabtTtaaohrtteaoottoddrreeayttneesamrpnomilrimitnneaeerlstthshapeeepmmciaeapgsgn.neioIittnpauuflddoareerymoofaaftniiinonitntemerpf--oriiornnmtddaiinvvhtiiuddmruuoaaalllenaasi nndddorgeegensenanldndoeeetrx,rcdarditefifttffhieeoirrsneetnnoicmcfeeesPs,FiinnOA aeannxddcrpepotoosssrsyiibbhllyyalfitt-sslivbbieilslia.arTuyhleeiltimrmianninasapttioioortnneraasss awwpeeplllel.ar to play an important role in renal excretion of PFOA RRineecpplouordrtetdee:dd hhmaaollnff-lklieiffyeesiinn(hhVuuFmmaa3nn0ss21ttyyppdiaiccyasal)ll:lyyrrraatasnngg(eeMf/frrFoomm1 .522.33da--y3s3./.883.yy4eehaarorsus.r. sHH)aa:llaffn-ildivveemssicfferroom(mM/aaFnnii2mm7a.al1lss/15.6 dhdianaaycvysle)su.)d.eevTTdahhl:eeumaggtoeeenndnkddeteehyrresddii(iMmfffpfee/arFrceetn3onc0cfee/2dbb1eeevttdewwalyeeoseep)nnm; emmrnaaattlslaee(lMaaanng/ddFeoff1een1mm.a5aglledeenadrryaaesttr/ss3dii.is4sfnnfhooeotrtuessrnesec)eee;nnsaiiinnnndmmrlianictcisece.ae. nSS(deMevvfe/oeFrruaan2lld7ss.ttt1uhu/ad1dtii5ee.Pss6FOA ahppallta4vasesmwmeeaaevkaccsolo.unnaccteIeetnndattrprtaphateteiiaooirnmnsssptwwhaaecettrreemoaf33td35u-er-6v6a5et5-li-ofofoponlmloddfehhtniihtgagehhl teearrrgaeiinnnsopmmnoaragltleeefsnsedtathethruaarnndeisiifnnfrfeefreesempmnaocanlelseesissbialnatetra>f>otsr5$ atwwhneeedegekfekosnsoudonfedfraadtgghieeafftbbePuurtFteOnnnocoAtet aitinomt e4ehllowiirmmemiieonnknaasatt.iilooItncnoaoonpctcprcceouualrrrsss betwen the ages of3 that maturation ofthe between the ages of 3 and 5 weeks in the transport features and 5 weeks in the female rat responsible female rat andfor ,and appears tobe related the gender difference appears to be related to hormonal control. dDDooossseeeslloeefvv0eel.l aa1l0ls,oo3ii3mmp&paacc1tt0ee0xxcmcryree/ttikiogonen.d. RRfioirggdd3eednnaycestt.aallT((h22e0011ur55i))neaervvyaalluuleaavtteeeldds uuartriin3na3arUyanlldeve1e0ls0voomfeyfP/PkFlFgOO-sAAd wffeoorlllleooww5i0inn0gg. `da(anoends,de33s,,s2o2a0ft0(0u0)rt,taiit1mmi0eoes,nso33ggfrre&reaeastt1oee0rrrp0ttthihmaoanngn)/.akattgA-s11d00afmmogcrg/o/3knkesgd-e-addqysususe.ugnTggcehgesee,tsuhtiiarnnilgngFa-ttiihThfaetflteottvhhreeelrrcseeoanisttsi3aan3tuthaohrnrueesdsshhl1ooo0llw0dd-mdllioimgmsi/eikttgeoo-xnndporrweseseusoorrerrepp5twti0iooo0unnld b(beee.lglo.o,nnsggaeetrur rttahhtaainonnffooorrfssriiennsggollreeptooirronssh)h.oorArtt-s-tteaerrmcmonhhsiigegqhhu--ddeoonssceee,eexhxpapolosfs-ulurierfeess.f.or continuous low-dose exposure would SSSteeuvvdeeirreaasllhssattuvueddiieeessxaeemvvaialnluueaadttiitnnhgge ttohrhegraornolileecooafnfittrorananntssrppaoonrrsttpeeorrrssteiinrnstthh(eeOkAkiiTddSnn)eeyvlottcuuabbtuueldleessinhhtaahvveeebpebreeoenxnimccaoolnnddpuoucrcttteiedod.n.ofMMtooshstet ddsinteeussadccbieesennosddrhipinatnvgigoettnuuebbaxuunaldleme.d.iinOOsetAAdriTTbtShustaeiaroo3neer.gffaoIontnuminctddhaeniinKnioioodntntehhtyere.arrnttstiisphsseosuyureetessarraasess(rOwweeseAlpllolTn,assa)nindbdlolwweceaefrtroeeerddddiieinsslcicthuvueessrsspyeeorddofxeeoaairrmrlgliaiaeelnrrpiffocoorrratinttohihnoeeinirsor,frroothlleee iiwinnenclcallbulsaduosidnrirpgneataigaobnsllaoararrggpneetdinnoduunismomtbfrbieabernruitooiofofnmnmse,defhid~rcioctahmatetitioohkennidssgnlffeorryomo,memtrhuttehlhyeearassreefeirrluturrmematsepii.nnottnTooshittebhhleeterkKafiionddsrnnpdeeoyerytlitetvuruebsbruuayllreeoe fffpooaorrrretgeixxaccncurlriecaetrtiailooynnniaoansss, awiimlmebppluolomrairttsnaa)nrn,ettawiibnnhsieoecxxrcphcrtriemeotatniikooeonnsfooafmfnuPPiocFFnhOOs AoAffrobbimteeccuaatnhuuaesvsaeegiliilottambbbiliennerddufssloatroorefssmiuulotrrrvffaaaatccelee. ssTdouohfrefissnteergarrmnugslmnpoompprerrtooretutreelsiiannarssref((ippplataarrrrattttiiiicccouunu.lllaaarrOrlltlyyyher ttaerrlsabainnusssmtppaooinnrrct)te,ee-rr~avfsFahsanoimclchiiilialmetiseadkbbeeeplslriioemetvveueeicddnhsttooo(MfbbRieePt siiun)nnv.vaoovllHavvoieelwaddebinilnneerrrfeeo,nnratalrhleeeemyxxcochrvraeeavttleiioodnnnuortaairrnbeegetteghhneleoeOOmvAaAelTrTuuPaPltsaserdaafnni1lddtsrattehthxieetoennmn.umsliOtlvtitiedhdlreryuurgga.s the OATSfortheir role in renal excretion, resistance-associated proteins (MRPs). However, the OATs for their role in renal excretion. they have not been evaluated as extensively as dKKanntooewwrleleegddaargdeeiaanbgbootuuhtet ssgppeeenccidifefiirccsOOpAaAcTiT,f,icOOlAAiTmTPiP,n,aaatnniddonMMaRRtPePsttriranannasstppsoorrittneedrrissciianntetthhteehaKktiifddennmeeayyleiissreeavvtosolplvovisinnsgg.e.sSSstatuunddiieess ttoo adahccaatttviieevvereaenssgccaeecrfrrdfveiettncootgrryyothnmmeeeeglcciehhmnaaidnnneiairstsmismopntethhcraaiatfttiemcmsaealillnieemrrraiatanstt.sastddMioooanlmnerooattstepepsoxossishnseoesrrssas.mt.soSSnineeedxxsihhc(aoo.2trr.em,mtoohtnnaeetessstfoewwsmteeearrrleeonaarella)sstosoapooppbboesssacesrerrtvsvoseeddalt0lo edhdseaetcvcrrreaeedaaaislsoleele)ttfhahfeepecpppterraoeernssee0ennlcciimeencioonrffeaaOOtisAoAenTTtShrsaetiientnrsatthinhnseeprorrareettnnseaa.rllsM.bbaaaslseoollsaaettexerrhaalol rmmmeeommnbebrsraan(neee.sgs.,wwhtheisillteeosffteeemmroaalnleee)sseaexxpphheooarrrmmtooonneess ((ee..gg., estradiol) appear to increase the transporters. tMMouudccehhtewwromorirknkerrewemhmaeaitinhnsesrttooitbbsee drdeoolnneeevattnooteetxxopplhlauaiminnantthsh.ee ggSeeinmniddleearrriddtiiiffeffseerraeernn:ccpeeosssbbsieebttwlweeebeeenncammuaasleletaahnneddoffenemmgaahllaeelfrraaitssfaanniddn thhroauunmdmgeaaetnonessfrmhssauiunlggfegg-ecwlssithtvsseesttthhhiaeantrthtithtuheeimsyyarmnmeilieeggvphhiattndbebtemctoimmoholourormgeeyalliniskkstee.udttShihieeemsmmislaaualrgleeigtierresaastttiattnhrhgeaannpa ottvhshaeseriibffaebeleimmlaibaltelyeecarriauantt.s.tehTTethhhueecnrrcleboiosinsugnahdbbarrflofro-aaalcdidtfeionin oaroafnfndPPgFceFoOOonAAsfehqiianunlefssn-eletirlrvuyuemmsiiononrrfhuiinnuncmhthiuuaomnnm.aaennpGeittdrnraeeanmtnssiippcooolrvortatgrccyiaaapstpatiaubobdinislileiitistineessshuugrremegsseanusnlltttiiniOnngAggTaffrSrvooamamrniaggdbeeniOnleiAetttyTiiccPinvvSaatrhariireaa:ttuidioneonbnssoscruiiinnnbdssetidfrnruiaccnctttuuairoreenss view by Zar etal. and consequemly in review by Zafr et al. (2008). function. (2008). Genetic variations in human OATs and OATPs are described in a MMWhDDoHHw'esrEEeaascstotnMMneeetctrtrooedPP0FF.CC3 bbciiooomnmomoniniitatootrfeiinndgg pppurrbooljjieecccttwassatamemrpplsleeuddppalssuu(bbNsseeetl:osooffnpp2ee0oo1p6p)ll.e lvTivriiennaggtmiinennttthheeoEEaeassmttoMMveeettrrPooFgrCeisgiowonins who were connected to a contaminated public water supply (Nelson 2016). Treatment to remove PFCs was DDrraafftt DDooccuumlneennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuurpPpoFosOseeAss oo-ln9yl..y0.1DD9r2raafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 9 of 92 22447755..00000099 STSTAATTEE 0077443388001122 `a2ad0dd0de:edd ttootthhce PPWWSSaannddvvoollutmnttececrr ppaarrtitciipcainptasnhhtaasd bblloooodd lleevveellss mmeeaassuurreeddaatttthhrreeee ttimnec ppooiinnttss:: 22000088,, 22001100aanndd 222200000108148:0-111..429.9 uuugg~l/iLLLgggeseo0o mmmeeeaaannn (((CCC1I1911.227.99--1177:1.33.31),;);959955*p%el~prpceeerncterinltecile46e68007nuuuggtgiL.i((r(rlaaannnegggeee110...669--411111770u.ugg5l/Luy)gh) 201455 uggeo mean (C1 4.-6.64) 95 percentile 26 gL (range <LO--D47 ug) 2010 - 11.2 ugiL geo mean (CI 9.7 - 13.1); 95'l~percentile 48.7 ugiL (range 0.94 - 110.5 ugiL) 2014 - 5.5 ug/L geo mean (CI 4.6 - 6.4); 95~: percentile 26 ugiL (range <LOD - 47 ug/L) NNhieeswtworOOicaaakklddeaaxllpeeorsreeussiridedeenonttssth((eNNc=-o11n35t66a)m)iwwneaertreeedaallwssaootessarammhppelileerddsiiennr2u200m114s4.a.mSSpiilnneccseemtthaheeysseebienindrdievipviridedusuaealnlstsadtdiiidvdennoootftnhhoaanvv-ee whw2ai0ast1tteo4errrieecxxa1p8lpogoessxueurporeoesss:mu: ereanto the contaminated ug/L (C1 1.6-2.0); water their serum samples may 95 percentile$ug/L (range be representative 0.17-8.1), of non- 2014 - 1.8 geo mean ugiL (CI 1.6-2.0); 951h percentile 5 ugiL (range 0.17-8.1). `PPceeorrmsspooannraaleldccoo0rmmmEuannsutinciMaceatttiirooonn2ww0i1itt4hh eDDeeelaasnnnn(aaanSSdcchhteehrrerr2ee:0: 1FF1DD-LL20ss1tt2uuddNyyHidnAidNiccEaeSteddvellolow)we.err lleevveellss iinn tthhiiss ppooppuullaattiioonn compared to East Metro 2014 levels (and the 2011-2012 NHANES levels). NCNhHHeAmAiNNcEaElSSsbb(iiCoommDoConin2ti0too0rr9ii)nnggdindacalatuadT-edThheexepCCoDsDCu'rCse'sdFFaoouurrfttohhr NNPaaFttiOiooAnnaafllrRRoemepp2oor0rtt0oonntoHH2uu0mm0a4anncoEElxxlpopocotsseuudrreebytfooNEEHnnAvvNiirmEoSlnu.mneenPmtFaaOllA `swCweahavsseedrmdaeelitcteeuaccpltstdeea(ddtCeiDinsnCa0a 2hhti0ihgg0ehh9b)ppleienrerccsceluneTdtnaehtgdeaeoegmoxfoefpstotthhseeucrggeeeennndetearrtaaaullpfdUoUa.r.tSSPe..FwppOaoopsApuurlflearaltoteiimoaosnn2e.d0SS0iii3nnncc2teeo01ht2h70aa(0t4CttiiDmcnCoee,l,l2e0tthc1hte7ee)dCC: DDbyCCNhHHaassAiiNssssEuuSeed.dPFOA several updates to the tables. The most recent update was released in 2017(CDC 2017): Geometric mean g/L. (957% C1) and 95" Percentile ug/L (957% C1) from 1999 through 2014were: 2G11099e090o399m--2-e02t020r4i00c:00m:03:e.5$a9.2n5211(ug6((/445L.7472(.29--2555'77~.74)'%4a))naCadnIn)ddan119.1d1890.9(9(157(0m41900-P-1.e193r3-.c1.5e31)n).5tui)lgeul~ugjlLiL (95h% CI) from 1999 through 2014 were: 2222000000007535-2--2220000006800::46::334312..999(522 (4((334..6480583--.1444..242-72))) 42aaa0nnndddd299.1106.1180.330)((((8785..84890000----11110444...1515)))) 2222000010001979220--1202210020010:580::433...(100277 2((1428..0811139--.433..236546))) aaaannn-ndddd779.25..565.00068((2(685..29(060022.--06919.0..77.)40109)))) 22001115-22001142: :129.084(1(.19756-22.1.24)2)anadnd$55.768(4(56.00.26-67.74)9) 2013-2014:1.94 (1.76-2.14) and 5.57 (4.60-6.27) "T1Ta9ak9k9eennanttoodggee2t0thh1e2er.r,, OtthhveeerddaatthtaesscuuogguggreesssettottfhhtaatthPPFFsOuOdAAs.ccoohnnecceeenncttroramatetiitoornnissciimnnehhauunmmcaoannncessneetrruruammtiiionnntthhoeefUUP.FS,O. Addeeccilliinuneeddabbneettwsweceeeunnm dd$1e1e9c6c98rr9eegaaassLneed.dd2ff0Drro1uomr2mi. n55Og.22v1t1ehri~ustghgteiiLmc0teoouhr2se.e02r.80eo8 fbuBtt"ghsgie.Lbsaeatennunddd.ytt,hheemtha99ej55ogtrhheoeppmdeerurecccteretninictotiimnlleeeiccnaoonennncccveoeninnrrctaoretamnitetioronnatntdiadoelencciroresefaasPssFoeeOddnAffsrroiobmnymht11uh.19me.9uagn~/tgsLie.Lrut1mo0 manufctures as well 5.68 ~L. During this manufacturers as well 2: phase-outofproductofiCo-n5 compounds in th United Sates. time, there has been a major reduction in environmental emissions by as a phase-out of production of C-8 compounds in the United States. the TTSooouxxriiccceoo:ddyy(nnUaaSmmEiciPcsAs::20163) (See Chapter2foradditional information) and (USEPA 2016b) as well as MDH 2007 reviews SWoorukrschee:e(tUSEPA 2016a) (See Chapter 2 for additional information) and (USEPA 2016b) as well as MDH 2007 review worksheet. Mode/Mechanism ModeI/nMfooeofrcfmhAAaactcntitiiiosoomnnn Information: NSNioonnnccceaaPnnccFeeOrrAEEffiffseecmctetssta--bolically stable it is the toxicity ofthe parent compound that isofconcern. Since PFOA is metabolically stable it is the toxicity of the parent compound that is of concern. iHiHnucumrmeaaannseeedppliiiddveeemmrieioonllzooyggmyyesdd,aattdaaerrceerppeooarrstteaadsssvsoaoccciciaaittniiaootnnissonbbeerttewswpeeoeennnsePP,FFtOOhAyAroeeixxdppodoisssuuorrreedeaarnnsdd, hhpiirggehhgnccahhonolylee-ssittenerdrooullc,,ed hehinyyxcpapremeerriattnseeeennddssiilwooivnnoeraarnnkeddenzrppayrrstemeeePeccsFlla,aOmmdApepscsipriaera,oa,dsaaeunncdddtviccaoaancnncccpienelrraa(tnt(iettoessnsta,tiriccehuusilplgaaohrrna-aesnnexd,dpotkkhsiiuyddrrnnoceeiydcy).o)d.miEEmspoupirnidddieeetrmmysi,ioopplolroopeggugylynaasstnttiuucoddynii-eenissnadrucaed pppeorxropoauddmluuacicnttteiiiodoonnnwipponllraatknnhteteriisUnnnattithhtPeeeFdUUOnnSiAtitateetpeddrso,SSdttEaauuttcreetossipo(ienic,.e.p.a,ltanthndhetesA,sCCai88ahcciogohhhoo-errxtt),p,oaasnnuddremmeceommmbbemerrussonoiftfytthhpeeopggeuenlnaeetrriaoalln near a population in the United States, Europe, and Asia. mFFuoolrrtiPPpFFlOOeAAs,p,eoocrriaaells aainnniicmmlaualdl issnttguuddmiioeensskooefsfysshh,ooarrtt-tst,eeramrndssuumbibcccehh.rrooTnnhiieccsaaennddstccudhhirreoosnniirccepddouurrtraatdtiieoovnnelaaorrepemaaevvnaatiiallalabbellfeefeiincnts, mllDiievvuveelerrtilpaaonlnepddmskeKpinieddtcnnaieeelyysefittonfoexxciclicutcisidttioyyn.b,gsiimcmmrmmvouenudnkneeeiyneesaff,fnfereiaccmtttsass,,l, saaannnidddncmcclaauicnndecec.eedrTreh((cllreiivesveaeersr,s,ettdtueedsssittueiircscvuuirllveaaarprl,,o,raadtnnedddleappvyaaenenlcdocrpreeeamytaeiteicomc)p).a.elneifnfgecatns,d Dcvclopmcntal cffccts obscrvcd in animals includc dccrcascd survival, dclaycd cyc opcning and DDrraafftt DDooccuumlneennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOsseAess-ool1nyl0.y0.1DD9rr2aafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 10 of 92 22447755..00001100 SSTTAATTEE 0077443388001133 rlreeaddnuudcceedddevoosesslsioiffpiimccaeatntiitoo,nn,, sskkeelleettaall ddeeffeeccttss,, aallteerreedd ttiinmtiinnggooff oonn--sseettooffppuubebretrtyy,, aanndd aalltteerreedd lmnaammmlanraryy gland development. tBBheeeccabauiuossteerooafnfisitftssomiinmmapptaiacoctntooofnndccieetllallruulylaarrcrroenesccteeipptttuooerrnsstsaa,nnddinpptrreoorttmeeieindnsis,a,tPPeFFmOOetAAabppooloisstsseeesss,sseeassntdthheeotaahbbeiirlliixtteyynottoboiioimtmippca:acctt tccPhhhPeeeAmbmRiioictpcaralaastnblhbsyswfyoaaarymllstteaebrrtyiiinongingneeconrnfezzdayysimemitneeagraaytccrtctaiionvvnisitctsiirteeiistsputaaeinnnoddntsot,trfriaannmntissetpproomorcrtehtdokKniiiadnntereetitiaimcclss.e.atanPPbdFFoOpOlieAtAersoii,xssiakksnnnodomoawowltnnhlet0iropixaadeccmnttiieovvtbaaaittobeeotilcism, StaPsectPertrAoiovlRla,,taipaonnanddtohbfbwiimllaeeaynsaaccybiiyddgibbeniincooerssscyyannistntihhnPeegsPsiAitssrRaGaann-nsdndcurrrilepeltttiiinonmooinllceolm,nfeetmhtaaoibbtwoooelclvihiessormmn,dggireeinnandelesis.ac.natBBdaatpsshceaertddoixooinnaslottsrmroaananclssacclnrirpiiappicdtttiioimovnnacaatltleabtohelism, `CAR, FXR. and PXRand metabolic activites linkedtothese nuclear activation of many genes in PPARcz-null mice, however, indicate fl~at CAR, FXK and PXR and metabolic activities linked to these nuclear rrieteccaeelpsptotoorcrsas.n. activate Cancer Effects - UneUCdanndvecererirEEEPoPfdAAff'ec'csseatrsGGcu-nuiiniddoecegllieinnneeiessc ffpoootrrenCCtaairarlcc"iinnoofggoreennPFRROiiAsskk. AAEsspssieedssessmmmieeonnlttog((UyUSSsEtEuPPdAiAcs2200de00m53oaan)),sttthrheearrteeeiisasn""ssaususggoggceeissatttiiivvoeen ogcofevfnsisdeeercrranuulcmmcpoPPopFufFlOcOaatAAricoiwwnni.iottghhTcwkkniioiddcnncpeehoyyrtocaannnnitddciatbtleei"ssottfaiiocscrusualPlaayFrrsOottuufAmm.PooErFrspsOiaaAdmmcmosounnipoggploohhrgiitgyghhaspllytyoueedsxxiicpptsooesdseecfddminmmodeniesmnmtgbrbaefterocrrssoainotfsfaattsbhhiseeloictiyattioon bgbheaeelnttfeuuirmmafoleorpriiionggpeefunneilimaccatiliionennooa.nntTeeswooiorsr mcmvheoorrrroyeensioochrrggboaaironnsoatsssoostfafsymmsaaploloeefssPrriaaFtbtsOsl,,eAiitnnhcscaulltupudcdpiaionrnrgcgtittanhhopeegoellsiinivviteeicvrr,,eptotefetissenttnedetssii,n,agaalnnfiddonrppfaiaetnnsmccararlebeaeialsihs.tya. -s[(TtTnohhoeet adequately been tested. No cancer bioassaysare available in other species.] half-life in,female rats' is very short so it is possible that carcinogenic potential adequately been tested. No cancer bioassays are available in other species. ~ in female has not DDrraafftt DDooccuummeennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOsseAess-oon1nlyl1y.0.1DD9rr2aafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 11 of 92 22447755..00001111 STSTAATTEE 0077443388001144 Sopplcment to Original Review Completoedn 12103007. Supplement to Original Review- Completed on 12/10/2007. Table AL Study Summary of Key Suis Consideredfo RID Decision Table 6-A1. Study Summary of Key Studies Considered for RfD Derivation Sources: (USEPA 20062 es Section 31 red33 DH a fpsvgsed od] Sources: (USEPA 2016a) [See Section 3.1] [reviewed by 2~DH epi sm[f no suggesCed edi/~J Epdmioloy sofa fcsoc f PROA ivbesconducted re ofpec psin Epidemiology studies of effects ofPFOA have been conducted in three types of populmions: + hers toin hs ems plats roan owing PFOA (serum concent ae of 00102 cas ard 14 ind). workers exposed in chemical plants producing or using PFOA (-~serum concentration range of 0.010 > 2.0 (means around 1 4 gg/mL), 2 Wihcuposr ommamic om ra Wit Viton vt Spann ale saintioenr apred ofmrs 3 high-exposure communities (i.e., an area in West Virginia and Ohio that experienced water contmniuation over a period of more than 20 Seay srsoncreion ge 0010-0 100 gon). nd years) (,-serum concentration range 0.010-0.100 pgimL), and + enrl populon sds wih backround exponen consti age blo LOD <0010 int). general population studies with background exposures (-serum concentration range below. LOD to < 0.010 btg/mL). cu moder oi coreltons ncn PFOA ad PFOS re fc sen incl papas (0), the orion owe te West Although moderate-to-high correlations between PFOA and PFOS are often seen in general populations (r > 0.5), the correlation is lower in the West Virgin 3nd Oh hap ae -0) I alain ad sybian esl Fon hs sts. 5 npr 10 conser ilie Virginia and Ohio high-exposure area (r-0.3). In evaluating and synthesizing results from these studies, it is important to consider differences in the upon ang wnsl wationahd e expsts a nh I 70, TERE 0 eT)ob ok exposure range within the study population and the exposure level within the referent group, as differences (or inconsistencies) can be expected pening he haeof expo spore contsmd he cp ngs compoby ro sn sdb, th pil chs of depending on the shape of the exposure-response curve and the exposure range encompassed by different studies. In addition, the optimal choice of Conn met 0.5. laor epd) pe on cicne br xd skh cos scned odBd an exposure metric (e.g., cumulative or a time-specific) depends on the specific outcome being examined. Health outcomes assessed include blood pid nd ces chemi ols, hd cc,Abs. IN Foch ts 3nd Ft 3dBelo $700ehPsores. SEr lipid and clinical chemistry- profiles, thyroid effects, diabetes, immune function, birth and fetal and developmental growth measures, and cancer. Som ts Serum #pids The scion cen PFOA ad scum yidsasbc xamind insv sin dif polation: Cross. sctioslad longus The association between PFOA and serum lipids has been examined in several studies in different populations. Cross-sectional and longitudinal Studies captions tingnsd high Sporcom (he C1 HClrcstu popu)Selly Osened psi studies in occupational settings and in the high-exposure community (the C8 Health Project study population) generally observed positive Stains bo enn PRON an chlerl (TC) abs sd chen od 1-14 Sy ekof i 1c cmnee associations between serum PFOA and total cholesterol (TC) in adults and children (aged 1-< 18 yrs); most of these effect estimates were Sita nan Ahoogh ns 0h ll a pte con fhSls xa eof IF poi gh statistically significant. Although exceptions to this pattern are present (e.g., some of the analyses examining incidence of self-reported high hla ta oa oon, the eeFAT menta oust SH Soc wei se rsof LDs L, Das ot cholesterol based on medication use, the results are relatively consistent and robust. Similar associations were seen in analyses of LDL, bm were not Sco i HDL Th: ge ofpou i cccorl es se (nh ars vii een 044 13 mb), admc se cs seen with HDL. The range of exposure in occupational studies is large (with means vaodng between 0.4 and > 12 btg/mL), and the mean serum levels oe C3 popiion es wes ond 01% mL. Poinssaioas een sr PEON 3nd TC (1. nrc 1d nl with ring in the C8 population studies were around 0.08 ~tg/mL. Positive associations betaveen serum PFOA and TC (i.e., increasing lipid level with increasing PFOA) er chro mst othe eneral poplin Ss ch cps 50000-0007 yo. The erprsoif osuln for these: PFOA) were observed in most ofthe general population studies at mean exposure levels of 0.002-0.007 gg/mL. The interpretation of results for these chr] popu ties mse, Foner by the moder og or ons (Spam 0) 4d sla newesc ox PEON 0 general population studies is limited, however, by the moderately strong correlations (Spearman r > 0.6) and similarity in results seen for PFOS and FFOA. Adil. mio of C ties dt pear fo oe soirfor oe pctof tn rm i PFOA. Additionally, many ofthe C8 studies do not appear to have controlled for the impact of diet on serum lipids. Ive daeand oon Liver disease and liverfunction Fo hhof laos bts FON and vr discs abl, but the C Hell Pt did ct bir sitions with hepa, Few studies ofthe relationship bet~veen PFOA and liver disease are available, but the C8 Health Project did not observe associations with hepatitis, Fa ner cs,or ter ceof Ice GLa 10h ioc fPRO Exposa Incr mes (Cured ru, pon ison nce fatty liver disease, or other types of liver disease. In the studies of PFOA exposure and liver enzymes (measured in serum), positive ,associations were Son The el tsccuo pans ic rove cnc of a toch ih rca m sr AST. ALT, 2nd GT, ih he mst seen. The results ofthe occupational studies provide evidence of an association with increases in serum AST, ALT, and GGT, with the most Comitteefor ALT. Te toons we ao ig an gh dep nthe cova the mack nding IMI. i of gd consistent results seen for ALT. The associations were not large and might depend on the covariates in the models, including BMI, use of lipid rl Duce fr i smi pos iy. Dt cdost comin AR Poy Draft Document - for review a~ discussion purposes o@. Draft doculnent does not constitute Agency policy Ton "Wats PFOA - 12 of 92 2247755..00001122 statearsssors STATE_07438015 ovenmidshcc endes Twopoplars Fs ood gos vr Toor lowering medications, and triglycerides. Two population-based studies of highly exposed residents in contanfinated regions near a fluorochemical {nd Wot Vig bn ted sotwoih er cms xd he er fh wnhfs porcro of rn en rm industry in West Virginia have evaluated associations with liver enzymes, and the larger of the two studies reported associations of increasing serum InALTannGGT kel wih mrin en PON oncom Acost cos nasofdi ohah NHANES, epee of In ALT and In GGT levels with increasing serum PFOA concentrations. A cross sectional analysis of data from the NHANES, representative ofthe US nto popalaton aofound ssccision wi PONcomcction i aceasns sran ALT41GGT nls. Sein iba ns U.S. national population, also found associations with in PFOA concentration with increasing serum ALT and in GGT levels. Serum bilirubin was {any sawiih drum PFOA n heocuptional suis. U siopedexpose spose pi orm ir v3 hi srvd non inversely associated with serum PFOA in the occupational studies. A U-shaped exposure-response pattern for serum bilirubin was observed among 10 pticips 0h C3 Hea Rc. ih gh cali he 15S50 aons ped occupaho]ts. uel an soonof the participants in the C8 Health Project, which might explain the inverse associations reported for occupational cohorts. Overall, an association of Sem PEONcanciowin ceaons ner vtof LT 5dGGT ha bs some oid nestor gh exo serum PFOA concentration with elevations in serum levels of ALT and GGT has been consistently obselwed in occupational, highly exposed sida communi, and the US gers oplsion. Th soaion3s wot ren mage, dtpte of PON act residential communities, and the US. general population. The associations are not large in magnitude, but indicate the potential of PFOA to affect ne mon liver function. Inman cin [t1~lmune j~,lnction -Avoisions betweenprs, chidbod, or fut PRON epost ad ikof nfo cases a kc ofae: pecs) hve ct Associations between prenatal, childhood, or adult PFOA exposure and risk of infectious diseases (as a marker of immune suppression) have not coment ec, bough hr wa son ation occ Ocaby Boe1r sian ch fel chen bt not rk been consistently seen, although there was some indication of effect modification by gender (i.e., associations seen in female children but not in male hide The shivs eGsened actioneisn tlio hdr PEON enh 2nd aint spot sire bods children). Three staadies have examined associations between maternal and!or child serum PFOA levels and vaccine response (measured by antibody Tekh in hide (ci 0004 ug) ad mls ca 002 gi),Thehd adulswaspara hgh<posrs commuC ai levels) in children (meaan 0.004 ugimL) and in adults (mean 0.032 ugimL). The study in adults was part of the high-exposure community C8 Health Prot A diced nod spots onofeheh. lina Ss sed Arupc che he Vwc as sc wT casi es Project. A reduced antibody response to one of the three influenza strains tested after subjects received the flu vaccine was seen with increasing levels of PFOA thes ls was nto wilh PES. Th hdc chides wescodced mE poplin Noma nd nh Ft of serum PFOA; these results were not seen with PFOS. The studies in children were conducted in general populations in Norway and in the Faroe ands Decavans pis oa PFOA vl wa cs i,t nl 0mrt 5c th ord PEASY Islands. Decreased vaccine response in relation to PFOA levels was seen in these studies, but similar results also were seen with correlated PFASs Gapros) (e.g., PFOS). Noe: NTP ce compet sf rosa (NP 20166) sami he imma asadith posso PFanOdPRAOS. per /Note: NTP recently completed a drali monograph (NTP 2016a) regarding the immunotoxici& associated with e~qoosure to PFOA and !'I,OX A peer iw meting wan bekd us 1 014 Thepreeedfhon review mee~ng was held July 19, 2016. The panel agreed that: "TaSivem re oi r spprc esinof anh spss. romeerm and sts and non sesofPFOA sppoan The scient~c evMencejbr suppression oj'lhe amibody responsej?om experimental animal studies and human studies ~fPF()A support a handmoder ow fhe. esac Mgh and moderate level QfevMence, respectively. + Morne ve ofr m xaraail sesfor eased persed ones. onlo eeof evdeinn 3(oderate level qfevMence ~n experimental animal studiesjbr increased hypersensitiv~&-relaled outcomes, and low level qfevidence in mn Noel ogodr rona hoef deence or cie n dne ee one dco humans. [;Note draft mo~ograph kadproposed high level ofeWdencefor experimental anm~als butfol!owing peer review d~scussion this chordmore] was changed to mode~Jte.] The ts moms oshdon to016m (NT 2s 016) 7~e drq[~ monog~vph wasftna!ized in September 2016 ~VT'P 20I 6a) Thyroid - Th bests provi sport on sociation besePROA expos ad cinco preof thvyoidedns worn child Three large studies provide support for an association between PFOA exposure and incidence or prevalence of thyroid disease in ~vonren or children bk pont (mean 007% 173 ng/mL htt nc In ion. soctans eins PEONandTSH wer sen rept with background exposure (mean 0.026 - 0.123 ug/mL), but not in men. In addition, associations between PFOA and TSH were seen in pregnant omc wa TH sn abi cota, srl ul aiaber nound ec POA sd T5118 pcphohacdak ben gored females with anti-TPO antibodies, ha contrast, generally null associations were found between PFOA and TStt in people who had not been diagnosed wih das with thyroid disease. Diabetes - Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA- 13 of 92 2247755..00001133 statearsssore STATE_07438016 octane Gerdbv an FON vcs 3p 1 hts midenc lm Behr vores popes wl i cm No associations were observed between serum PFOA levels and type II diabetes incidence rate in general or worker populations with mean serum PFOA 3100 0913-011 ml. PFOA wat oteo ih mi of ar bl de in alts sls, Hower, os Sc PFOA up to 0.0913-0.113 gg/mL. PFOA was not associated with measures of metabolic syndrome in adolescents or adults. However, one study Tod tad frdevoid dates es ith can cn PFOA (ead preconceopf 0t0i0o3n1 mL. found an increased risk for developing gestational diabetes in females with mean serum PFOA (measured preconception) of 0.00394 gg/mL. Fort, reson adit comes Fertility, pregnancy, and birth oulcomes Thre rmccapsions xposo cr popusti caminin rncted persiosnnd primis lion 0 PRON There are no occupational exposure or general population studies examining pregnancy-related hypertension and preeclampsia in relation to PFOA xpos Theoldor vl conFor he ighupon CHa Rt ih ppl. Sve di. ans Hn engi exposure. The only data available come from the high-exposure C8 Health Prqiect study population. Several studies, using different designs and pours meas, a aminfs come hs popuThs i Pores Ear cmeand can slain(ox exposure measures, have examined that ontcome in this population. There is a progressively greater refinement and reduction in misclassification (or pons ad ome among hi1cs.Eachohhc rovesc o oofl onacs tion btn PFOA pst3nd1 cxposurc and outcome) among this set of studics. Each ofthc studies provides some evidence of mr association between PFOA cxposurc and risk of amas -ed Perino psc (001002 sgt) wihe hod ob ings From thology rong ods pregnancy-induced hypertension or prccclampsia (0.01 - 0.02 ug/mL), with the most robust findings from the methodologically strongest study. The scion toe PFOA ad birth weght was cine ners suis Most tics sed PFOA singmat Wood spc The association between PFOA and birth weight was examined in numerous studies. Most studies measured PFOA using maternal blood samples ken inthe sod i rescoond bnlood ls: Si oo. ih post C3 crt opiates 4 2 oc.Socios taken in the second or third trimester or in cord blood samples. Studies on the high-exposure C8 community population did not observe associations een FROan cbtight aon rm rhehe kof low thwg ag (ington Bhs In contrast. excl sof between PFOA and either birth weight among term births or the risk of low birth weight among all (singleton) births. In contrast, several analyses of rd popuban escAREASsvoiaion nc PFOA ec th weg whic As hd tS Sl SPURS A ct general populations indicate a negative association between PFOA levels and birth weight, while others did not attain statistical significance. A metansf maf eesis found 3manu ight dcof 195 (455CI 39)pe ach ot ut (gL) crsm lcm analysis of many ofthese studies fotmd a mean birth weight reduction of 19 g (95% CI: -30, -9) per each one unit (ng!mL) increase in maternal or Cod ru PFOA enh abic used tht GE ca pact Bh gt Amcacon PPRsenlafiodnhsat co cord seruln PFOA levels. It has been suggested that GFR can impact birth weight. A recta-analysis based on PBPK simulations fotmd that some of 1h scion repos bine PEON 3nd bh ghtSl10 GYR24h hsscl escnon couldbe cna1937510h (05% the association reported between PFOA mad birth weight is attributable to GFR mad that the actual association could be closer to a 7-g reduction (95% 35) Veer (2019)shoved hit, ls ih on GIR,tesa crs chs osu PHOA sdowerbith ws. Whi CI: -8, -6). Vetoer et al. (2015) showed that, in individuals with low GFR, there arc increased levels of seruln PFOA and lower birth weights. While {hess om. ety n cofth obeaadsaenbtwecsPEONsndbs gh 64to: Poot ptf ow GFR. th there is some uncertainty in the interpretation ofthe observed association between PFOA and birth weight given the potential impact of low GFR, the Sle aman fdcis ha the svi ete PFOA exposurean ih weightfore sce plan cat be lod ut. In available information indicates that the association between PFOA exposure and birth weight for the general population cannot be ruled out. In man hoe GER (hh nls es hh E133 80t1PaFdI fH Ich Bs WAY do 103 humans with low GFR (which includes t~males with pregnancy-induced hypertension or preeclampsia), the impact on body weight is likely due to a Combotion ft oo GFRand th rn POX combination ofthe low GFR and the serum PFOA. Two sis exained dvsoofpeprt i eee i lionxepos l1 PFas OcaAsed duh arocodbod Two studies examined development of puberty in females in relation to prenatal exposure to PFOA as measured through maternal or cord blood Samples in ll fpr sort comucicd i Enand. Th os fs sis concnlk cates or post samples in follow-up of pregnancy cohorts conducted in England. The results of these two studies are conflicting, with no association (or possible aon of usenh ss with hie PFO) nl 503 er chs cy wih Bhar PEO fs sod sch. Amber indication of an earlier menarche seen with higher PFOA) in one study, and a later menarche seen with higher PFOA in the second study. Another od amid PEO exposmeasSonn hh Acoft purl ts, An asain bth 4c 35 t Pichon study examined PFOA exposure measured concurrently with the assessment of pubertal status. An association between later age at menarche and Hii PFOA ees vas cbr. btemcpeaton o i din 1completed bh pal fstof pba on: epsre omit higher PFOA levels was observed, but the interpretation ofthis finding is complicated by the potential effect of puberty on the exposure biomarker eis. vee coma, levels (i.e., reverse causality). Statics ound psi asosiation ik ADHD chide he igh exposed community ad he ener popalson Nooder behavior Studies found a positive association with ADHD in children in the highly exposed community and the general population. No other behavior Cadport hd wor aoe wihmar PFOA cls lrppcLied doh ssa coro wcen hight PRO endpoints in children were associated with maternal PFOA levels in either population. Limited data suggest a correlation between higher PFOA Teel C002 in) nf and dcs r fdr and i, usa 5 croff PFOA cn mae Fry dps 0005 levels (>0.02 gg/mL) in females and decreases in fecundity and fertility, but there are no clear effects of PFOA on male fertility endpoints (0.0035 00S pnt) 0.005 gg/mL). SincePoe oncom C8 Science Panel conclusions Dr Ducumsr for ew scipoosni. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 14 of 92 2247755..00001144 statearessorr STATE_07438017 Rf CFFla Prot, 5 CS SnesFe sdpdemiologicl 0 lr vail hr 355 probs Fk een FOX As part ofthe C8 Health Project, the C8 Science Panel used epidemiological and other data available to them to assess probable links between PFOA por and dace. Anes mda by te CF Sen Pa] wid hrc serum PFO CAoarsms, hich nes Groped Bid on exposure and disease. Analyses conducted by the C8 Science Panel used historical serum PFOA estimates over time, which were developed based on mated akeofonddihg tr. Thpa cochat hpoeke ok tod cn PFOA cost ad rte os, estimated intake of contaminated drinking water. The panel concluded that a probable link existed between PFOA exposure and ulcerative colitis, eh choleradoseedparenSng rod dee. high cholesterol, pregnancy-induced hypertension, and thyroid disease. ThCe Sine Pane foun proleFlkBwess PRON xpos ndlie ther confining br ecottatsomma,ns: The C8 Science Panel found no probable link between PFOA exposure and multiple other conditions, including birth defects, other autoimmune des (5. hemo ahr, aps, | Gee, chsdies MS). pe 1 dbs, gh Hood pss Soy acy dss. diseases (e.g., rheumatoid arthritis, lupus, type 1 diabetes, Crolm's disease, MS), Upe II diabetes, high blood pressure, corona~" arte~ disease, {neousdst. nce das, Pam's ds, oso, prods opmens dsorr ndec..ADHD, arn mis infectious disease, liver disease, Parkinson's disease, osteoarthritis, neurodevelopmental disorders in children (e.g., ADHD, learning disabilities), carnoragreh. Shoe Ms ds, sk, COPD, 20 prkrth low ith weight miscarriage or stillbirth, chronic kidney disease, stroke, asthma or COPD, and preterm birth or low birth weight. Edensof aics frofe PEO imidmilogy stoi isa sofc dey aod scolar camer.Thess cnr oe lively Evidence of carcinogenic effects of PFOA in epidemiology studies is based on studies of kidney and testicular cancer. These cancers have relatively Mh Scar salesof 7sfoRds,oerandoPfor scr ner (no Nal C er os [NCI Sreonct high 5-year survival rates of 73% for kidney cancer and 95% for testicular cancer (based on National Cancer Institute [NCI] Surveillance, Fide. and FadRes dsfo 2005111) Ths sesfo xan coer ce a: pc nfl opss of ace The Epidemiology, and End Results data for 2005-2011). Thus studies that examine cancer incidence are particularly useful for these types of cancer. The hp commit ic0 veh deefor ube srof chain ck pend of Sst Tk. 8h Fon 0% high-exposure conununity studies also have the advantage for testicular cancer of including the age period of greatest risk, as the median age at mots 1.3 verTsoncapone Mtn2a Wsott Vrmsdo ot Brat cisof Bcscao ters, btach of diagnosis is 33 years. The two occupational cohorts in Minnesota and West Virginia do not support an increased risk of these cancers, but each of hemi td ball asofcb dhs dmc 2s. Too bs secant mbes oh C1 ct FreesshowedPs: them is limited by a small number of observed deaths and incident cases. Two studies involving members of the C8 Health Project showed a positive Sacimionnon PFOA ech (mean stcast of) 024 pm3b koe and rcscnc Toe rc ove decus lod association between PFOA levels (mean at enrolhnent of 0.024 ~tgilnL) and kidney and testicular cancers. There is some overlap in the cases included cs ss None of So Po hcl x o oFKear Cnr Ot oho wer oud 0 $8 in these studies. None ofthe general population studies examined kidney or testicular c~mcer, but no associations were found in the general Poinion bmnmeansera PEON eves0)00ygmL. ad cool brea, proto, dir, o Inca A pao C3 Heath population between mean serum PFOA levels up to 0.0866 ggimL and colorectal, breast, prostate, bladder, or liver cancer. As part of the C8 Health Prohte C,H Sent Pe cohl t potdable hk ete incon PFO cxporarsa scad ldo snr Prqj ect, the C8 Science Panel concluded that a probable link existed between PFOA exposure mad testicular and kidney cancer. grof odpue p clogssdcpniobogst ically evteh vmeiod nsforcasbod on 4sof A group of independent toxicologists and epidelniologists critically reviewed the epidemiological evidence for cancer based on 18 studies of xpaelcxposr oPFOAsnd sci poison con wiorwlbh Coupons o FOS.The pt wa ed bn SVL the occupational exposure to PFOA and general population exposure with or without co-exposure to PFOS. The project was funded by 3M, but the Cmpaay waas nidi he rep ofsprrval oof te eprtThe hor ved hepublischs eeddo he sd ds, company was not involved in the preparation or approval of the report. The authors evaluated the published studies based on the study design, Sites. nn sme. ok amet, coil or connisenesg.bis Th followed ts Bradon Hil gienste subjects, exposure assessment, outcome assessment, control for confounding, and sources of bias. They followed the Bradford Hill guidelines on the Sensoanaes ose, pans. an logic ren in rxhhiCionclugsion Th ound ac ofcomin ens strength of the association, consistency, plausibility, and biological gradient in reaching their conclusion. They found a lack of concordance between Cony poss nd esCxpTi oko nsgas he hn hors fohre Bel pops.Ths dpa Bas ros colnmunity exposures and occupational exposures one or two magnitudes higher than those for the general population. The discrepant findings across hppa nrGabHoA du to ane, Sofoanding. adore (Chino 301) the study populations were described as likely due to chance, confounding, and/or bias (Chang et al. 2014). PFO i Bosccumulaine compoundam the ost spprepristedosemerc regaofrdurdtisonds averse sera concern". PFOA is a bioaccumulative compound and the most appropriate dose-metric regardless of duration is average serum concentration% Thcreore 8 ingle stay sunary 4b roidedblow athe th ne ble fr Exhduo. Th orcsof leSI Focc5 Therefore a single study summary tame is provided below rather than one table for each duration. The contents ofthe table below focuses Kx dps sees re Es 1h US EPA Hal Advisors (HA) 3nd Heath Efcs Sport Document (HESD) Rls on the key endpoints mad studies largely identified in the US EPA Health Advisory (l-k&) and Health Effects Support Documem (HESD) Released Ni 207 For ada wires Esra MDI previousaesenont eof siclabrsom 2007. Te ses lod in LPA + May 2016. For additional infornaation regarding MDH's previous assessment refer to review worksheet from 2007. "II~e studies included in EPA's HENDdd HEwere diced by PA prohenoes cue and medesc cpionofh he os cc propofePrFOsAasnd HESD and HE were determined by EPA to provide the most current and comprehensive description ofthe to~cological properties ofPFOA mad he mk poss Bm huh di eke. ro hes sd, ott rece sce ts nhs or ln (15, dra the ri sk it poses to humans through drinki ng water. From these studies, those that presented serum data mnenable fbr modeling (i.e., determination HED wre elfocrdoseirspodnse arash: sng st of ide ed becof hue seede vedo 30d cise of HEDs) were selected *br dose-response analysis. The resulting subset of studies is lirnited because of the need to have dose and species-specific Sun a fr mde pt 45 n5el xpose drofoust cgi chev lcs sa1 cd Sas rofclons OPA Bo serum values ti)r model input, as well as exposure duratious of sufl]cieut length to achieve values near to steady-state projections or applicable to Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA- 15 of 92 2247755..00001155 starearessore STATE_07438018 nope cndpois wih sim consqens lning em xpos The pharmacinccl mold ves seen loss developmental endpoints with lit)time consequences following short4erm exposures. The pharl~3acokinetically modeled average serum values ork Sd ic3 ecto amapcshod oft hd espe 10 tPFOR sh. Ad]bos Fb bs from the animal studies are restricted to the anmial species selected for their low-dose response to oral PFOA intake. Additional studies have been Ialodd on NIDH i ey ped forion snl onpors of ert incl uded by MDH i f they provided in:formation on additional endpomts of interest. EPA dpe rmbt mk] dopedby Var2015)ialna se nmsosn cos wi * EPA used a peer-reviewed pharn~acokinetic model developed by (Wambaugh 2013) to calc~flate lhe average serum concentrations associated with the CoinsNORELL a LOAELS hgo iles, es ncofe FO (ot ml ed Gmc HED ci candidal,e NOAELs and LOAELs from the toxicological daI~base. Average serum levels of PFOA from ~t~c model were used 1~) determine the HED associated Nh NORTE 2d OAT Ranta (307et 51he Ann 3 (1) ot ot Shall Tan with tim study NOAEL a~d LOAEL. Wambaugh et al. (2013) used a model based on ~lm A~derse~ et a]. (2006) concept ~hat saturable fermi msog~fion is pons or she Rl o re A. FEof RO 0%SO PA F 1g 0s responsible fbr the long serum hN~=lives seen in hunmns and animals. A nnique i~at~c of the ptmrmacokinefic approach i~ the use of a single model fbr lira throe a tode rm PFOR Sl le eoft pt Fords, eo] ond FO LO A species and reliance on the serum PFOA level as the measure of exposure. For each species, the nmdel acconmmda{ed the appropriate to~coMnefic variables l~r ok se hc conor oe = rm es cwd ah Td rec ds the species/strain. The pkm~cokmetic anab.sis *i~cili~ted exmm~u~tion Ibr co~istency in fl~e average serum valnes associated with effect and no-effect doses oesrl PON es. Pomrehn dt oF from the anna1PFOA studies. A no~erarcNcal model for parameter vanes was assnmed wherein a si@e mm~efic value represeNed Nl individuals of the nrsm Sm Bo eR. roGr sn tof Ss ne Farvss same species, gender, and strain. Body weight, tl~e number of doses, m~d nmg~tude of rite doses were the otfly parameters tlmt varied. SidDipion Study Description dNoiradrooe du ration, route/ - ||| Adm Die Admin Dose ([e0m (mg~kg/d) || Faned ica)rOtbseernvepd otnahhrHsEDdsl | SahksP)OD Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODrlrD (mg/kg/d)~ UF~ Candidate RiD Retrce Reference aoamtinise) (note limitations SNervinrammtptdes,| vehicle, species/ strain, age at dosing, coer [ave serum concenl# ermcocel" mg/kg-d in comment filed) (hANen/siEeomx/ngSErdoPuiAep,sNetOcN. EpL seodrLOiNEnLSeroalhe cimood)edicbios,b+s(rWanbeiamgh 20c15h) of PkFOlfohe wrogkcauhoeunscnbtsio,n2sdasrsoewdswi0h CmoinsrrheeHeE0D00s01achtsebdvuidl)h.e dsNOAedELONLEL.Th HEDisltdvingalr POD lipid stint hm 20Goose Sy 0.1.7 Toor 37 FOF mo ST 2-Gen Garage Study Spm Davie Ra |Stl mre Sprague-Dm~-ley Rats ciao PL |Past|Makes FoF io) (F0 30/sev'dose; F1 heim ie Ara [Sse ti 21761, | Na 60isex/grp) P-doed0uks | Conumrosaonrsare| CrHlE5pan,2sdTcI pwanthy | EPAxNOAEL F0 - dosed 10 wks porting wt [6 Bugatti prior to mating & until EOshermang F | mesos | operoneon] ssoumit [300 sac (M after mating; F Saws | snmemorc | 10] gm [BW (7 1,8 30 p001)| EPALOALL [GA after weaning) Su dren st [106 mek | mea bo odcompan. | bcd JU | 10 Stndy duration 84 pti were STG T02 | LOTTO Toc Tria | 100) days (FO M) Finer wnaknhteas |=1711hea ers mecp nisn & &ipas. iins ohfe| ey F1 - in utero, ion & rows | cwiiengt | _| SSooyf setsoden 108 lactation, & through 0, 1,3, 10 or30 Sexually mature PTs have very short half-life. As a re.sult serum measured f!~al 10 & 30 mg&g-d were 0.37 & 1.02 ug/mL) and more episodic. As a result uli#& qf deve h)pmen F0 - Females: no effects F0 - Males >_ 45.9 ug/mL - q" rel liv wt (Ms - 21,47, 61, & 84%, p<0.01): ~" rel kidney wt (Ms 16-117, 22-23, 21-22, 23-27%, p<0 01)# [Note: hL~tological assessment does not appear lo have been conducWd] ~ 101.2 ngknL - + BW (7, 12, & 26%, p<0.01); ]" mean rel to bw food consumption (Ms105,110 & 118% of controls) > 171.1 ugknL - Tthickaaess & prominence of the zona glomerulosa & vacuolation in the cells of the adrenal cortex (Ms 2/10 & 7/'10) F0 & F1 (adul0 Ms NA EPA NOAEL 45.9 ug!mL EPA LOAEL based on ~bBW & ~" rel kidney 300 (3A, 10H, IOL) EPA Dr Duce or ewad dso poss lO os conc si Ase Draft Documem - for review a~Kl discussion purposes only. Draft documem does not constitute Agency oEPoA o i 0.00002 ~EPA poypolicy PFOA - 16 of 92 Tor (Butenhoff oymdi 2004a) aa~d act frei EPA 2016a ep bcos #[EPA indicates ho ny ws &at q"/adn<v wts werdoe at lower doses [cori can be regarded [msi as adaptive oon response to ger transport Sim challenge, overs however no pro supporting 2247755..00001166 statearsssoro STATE_07438019 StyDecrpion | AdiDe EF) Obccr HEDdia e vt |Sin POD | FF | Cie| Reece Study Description durin rte | hd) | ad cart me ponned ng Woo bios duration, route/ Sacer | Ines mad | hewn Ho) vehicle, species/ ne dvi.|onl [-- strain, age at dosing, Nem N/sex/group, etc. moms od | dene| 20 ns 16 dyf Sdn |NONELLOE la mating for Ms & omnis | imd iene mm dma gn | LuNA 0o00 pr weaning for Fs. Sn mon 16 wks fri Ew) Study duration 16 wks Sha10 |aiFeo Sal noma Rargon (M) (112 days); 10 NCE van | Umeda | Lo odeomanion (ol wks (F) (70 da)s) 2 -beugh 0n2P|T PNwSMtdnehasi=iiVoLoaem,oio INnAaU11,C30| |0||||| "yFVFosOmSooti EoieMeocbsnihrnGs1revgim3vve6iim0 t:nn5o(amrtReAgivRmnlrt1osoaom.nv0ly)oenecr|||| Fi 1SNsoOc6oaEsia h0m wyAoDw0ntnLel30((MDy||lcoEoomnnpmosse F2 - through PND22 Admin Dose (m~k~d) [ave ser[ull concerti# Effect(s) Observed at each HED dose level and earliest time point obse~wed studies in rats are limited 204.4 ug/mL - sac of 1M @day 45 duc to adverse clinical signs; clinical signs in other Ms including dehydration, urinestained abdonfinal fur, & ungroomed coat; ~ absol food consumption @91% of controls) Predicted AUC ug/mL*h 92500, 204000, 345000, & 412000 mg/L-h (EPA 2016a Table 4-3) IDH B~gfD modeling: FO M B W @te~w#nation (Bk/IDL/BMD) 75. 6/8 Z 2 ug/mL (B~o) lowest value but modeling ident{fied as "questionable ". FO M rel right kidney wt @ termina#on (BAlm) 6.56/16.0 ug/mL FO M tel #vet wt @ termina~on ~MR~o) models unusable or questionable (lowest vahws ] 6. 5~20. 4 ug~mL) Avcousscun | 1 pup mene Franti] | 0 ox Average serum Comms | ghd vm pp wir (5. | NONELLOAE concentration = ried MAU |)m sol shin. | Lo predicted M AUC WALSH | intd on mo(nene | SORT 022 ug/mL-hr/(84 d x a" Re Tan gy meted) 24 hr/d) F1 - pups !remember F rats very short t/:J Highest dose grp - -,~mean pup wt/litter (~8- 9.5%) J" mortal@~ shortly after weaning; delayed sexual maturation (Ms ave 3.7 days & Fs ave 1.7 days longer) Study PODH~D (m~k~/d)~ UF2 i Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) [NOAEL!LOAE L~m> NA/0.0064 mg/kg-d] rationale was provided] F0 Males 6.56 (F0) ug/mL Ms MDH BMDL 16.0 (F0) ug!mL Ms MDH BMD based on "[' rel kidncy wt 30 i 0.00003 l (3A, i MDH MDH i compa~qso i n purposes [F0 NOAEL/LOAE 0.00092/0.0022 mg/kg-d] stout [PL solr 45.9 ugknL or ZSDual BW emisions6. | Fioms 101.2 mi IRI al elena, | 17 171.1 ms =10( noRaFR3pctomesasi0ooNimrswnvmenIpesaakAdsr1rai yoo3)efo:RtrilseembeTamponoac)llnwrct11ue||||| mbEEu0PPno4BAhAsErnNaLoeSOOftAbAenLEpsLLt 204.4 F1 - adult offspring >_ 45.9 ugknL - 4 BW (Ms @termination 6, 6, 11, & 22%); " absol & tel (Ms 20, 40, 53, & 76%) liver wts (Ms); ]" tel kidney wt (Ms - 11-13, 18-19, 17, & 16-17%) >_ 101.2 ugknL - discolored axeas in liver (Ms 6/'60, 10/60, & 9/60), diffuse hepatocellular hypertrophy & scattered incidence of focal-to-multifocal necrosis & inflammation in liver (Ms); ~, absol & rel pituita~ wt (no histological changes) F1 pups 171.1 ug/mI_, EPA NOAEL 204.4 ug/mL EPA LOAEL based on ,bpup BW& T number of dead pups 0 mcsr n poo rs ot As Draft Document - for review a~l discussion purposes only. Draft document does not constitute Agency policy PFOA - 17 of 92 2247755..00001177 state orasuzo STATE_07438020 StdDocipion | Adm Die Study Description Gurnion roe | duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn strain, age at dosing, Rtn N/sex/group, etc. Admin Dose (m~kF_Jd) [ave serHlll concen]# | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Effect(s) Observed at each HED dose level | and cat i pn held (mwa RI | (mc bins and earliest time point observed VT ayn sood lbt | rOn Hcoc" mee| nSvmeknt) > 171.1 ug/mL - ~, absol tbod intake but rel = Connsont 100 itsven food consump signif ]" (Ms) hd monfl ated | shor 204.4 ug/mL - ~" incidence of urine-stained min fr do don |LF mn abdominal fur, abdominal distention; Rm aired hypertrophy & vacuolation of the zona Donocas gs land 1o 10. | mck glomcrsulosa of the adrenal gland (7/10); kr ty (Ay BWIWG Fs) |boe motor activ@" (Ms); ~, BW!BWG (Fs) tg haben | meted | a5 during cohabitation; T ave number of Sos s(3435d4is7h | elope estrous stages (5.4 vs 4.7 per 21 days) but ronfur han ondnib | upon further evaluation fbund not to be nto signif different Study PODH~I) (m~kR/d)~ [ Sel%lnl concerti~I *MDH notes" Ihat gwen the very short halflife in female rats this animal model may not be adequaW to assess developmental toxicl~' Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) 0Dmonofab Ms. MDII BII/ID modeling ofadu# F1 A4ales: FIA Ger( m i 993111 FI MBW@te~mation (BMR~o) 90.0/1!1 mt ming ened ug:~mL but mode#ng identified as Guess Questionab#. FEA yt @ rm n F1 M rel right kidney wt @ termination Ti 1975S end ants (B~o) !9. 7/~5.3 u,~/mL FIA rt omit (Ry ai| WBN F1 M rel #ver wt @ te~vnina#on (B~4R~o) all "wmsnie metas 19718 | NoxEtPAAone models unusable (lowest values ]6. 9/2 {. F2 204.4 ug/mL/NA EPA ug/mL) F2Pap merrts ver sat) | te MDH F2 Pups [remember F rats' vety short t~] TOLT&171 wmol riPND |o40% 101.2 & 171.1 ug/mL - ']" mortali~~ PND1 but dpcsnshi EPA fond independent stats analysis by EPA found odes nes. no differences btwn grps. ek pop er lt min there Note: pups were killed at weaning, therejbre mnft med nwt! post-weaning effects observed m F1 were not NOAEL/LOAE L *see MDH note abo~ od Reported details of rei male repro orgox~ Bio omsone histology from above Srstudy evaluated oomof ie sn ern No evidence of altered testicular and sperm mets nian Fos wing gp structure & function trt F0 rats w/mean grp mmc repo 1rn. St serum concen of up to ~45 gg/mL. Significant oi in id le (05 dose-related ~" in seminal vesicle wt (p<0.05) oEPaAn York et al 2010 aci EPA 2016a Do Domne dionpp ny Ds nA AS ky Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 18 of 92 275.0018 2475.0018 stateoresanzt STATE_07438021 Std Docipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD| UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ rm, su eds, [Src rn coc" strain, age at dosing, Neiman N/sex/group, etc. Admin Dose (m~k~d) [ave SelHlll concert]# edge Tnal oesonmToderirFcyomiiparyaootr ronle cd oosnosfr. Neurodevelopmental ac open bbe mo nh dietary study ER ter moby In cn C57BL!6~q3kl re ini ts M ofpverssgn pregnant mice on ore ane p= DUT & Fol wet 6/grp Expect GDI oo Sonam sa p D0i 10hn Exposed GD1 to end arn Cour pngdug es ur of of pregnancy. hetero " The behavior of the msdn es weaned offspring ~vas de TidMapnwee signers analyzed in somo cain Sin (00) oncor enbt ak locomotor, circadian iy dvs Ph ofdn 1 rhhd hed 2 activit.v, elevated plus aeod ed BARN Funan hdsaris maze, and forced att einpersp00)dr ola pi swim tests at 5-8 kara sc Coiohm trapep cins se as fhe weeks of age. Muscle prayrion ringoro od ffe strength and motor Combaiontes id ay rth op bs coordination tests Semen d Comptott Ft lftof were given at 3-4 ers etS5tnomcortstnsdcbtroroabnse4ps3codslrnflenuntydisedn.rcraebaponesdr & mons of agc. 0 or 0.3 Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD UF2 (m~k~/d)~ [ Sel%lnl concert]# wi & w/o fluid in F1 Ms, but fcrtilib~ of trt Ms in all generations comparable to the controls. Locomotor activity, anxiet.--related behavior, depression-like behavior, or muscle strength were not altered in offspring. In circadian activity, tests, M offspring were significantly more active (p = 0.013) & F offspring were significantly less active (p - 0.036) than control offspring during the first hour of the test. Trted M offspring were significantly more active (p<0.05) thala controls from the dark phase of day 1 through the dark phase day 2. Both M & F trt offspring had signifless inactive periods (p<0.05) during the light phase compaxed to their respective controls. In the accelerating rotarod test, trted F offspring e~fibited 4, fall latency over the four trials compared to control Fs, but no eff}ct of trt was observed in M offspring. Authors concluded that prenatal exposure to 0.3 rag&g/day resulted m gender-related postnatal alterations in off!~pring behm,ior & motor fraction at 3 4 marts qf age. PSprGDCiagmeornoremtnioCtepnsGDtD.adnn1Mst1in7sd|D|||r3nSMOo0aDcm5oTun10mod5a7T n1l,o| | r Sr ewhaCSodoiohnmldmd1e.eknsd,Tt7]0od1.o3ic04s9p.)8oetNs1oaserp:hlivse.coioD mAgpa0ireel7d n7|||dosEErPPc SAArLNNcuOoAOAngAEsELiL. Ay Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency Comte|eerence i Candidate RI | (mc bins ~ RfD mee| nSvmen kt) mg/kg-d Reference (note limitations in comment filed) One Onishchenko et SEs al 2011 aci EPA Soe 2016a Com es (='otTcet71s ; mater small nmnber of mfr animah" Jbr pe neurological cen ot assessment, not Ga ier clear Caioristfr controlledfat; meehown mice were housed me us 3-4/cage this mms can impact rr) behm,ioz and sre single close g~T party prohibits fitH ee dose response on evalua#on. oy [mtmFriiernaatspati1ee42 Gmotman poly policy PFOA - 19 of 92 2247755..00001198 stateoressozz STATE_07438022 i [ T | |SE Study Description - duration, route/ Admin Dose (m~k~d) Effect(s) Observed at each HED dose level and earliest time point obse~wed [1Study PODHED (m~k~/d)~ [. OC ie UF2 Candidate Reference i CpRfD (note limitations vssterhatiicnl,era,aggsapeeeaactitidedosons/ siinn,gg,, | concen) [ave serHHl concen]# NNi/sseevx//ggrrooaupp., eettcc.. nanny mSgt/kgd-d bo-- bifo E rehen tnPS O [| R r e Ar l SE SEC Tr r n r e ST Hai R rad|S je tin ra 13621, |A ToiTahod) |[ygTnaatlsA.eselBh gtr: HLBS io a eEianETeTetSHEiA r iEmf[aNeSaem fp e rE A-- ehiieko E nren s rmmm esans =re wl me Trane ProncmingBY: PNos=tvmstdinggBrW ep EBcoepmmne' vgtel ri &shaoensegatonoaflfl deeivneceps | 74VOMEL TFhoeasmrmiemfdstteGocalfrlldDdoaFsiamecepnrpcoio7mnm3t l8of.942 | | EPA tyLOAF Loboman a =. SSEhima, SE wr Rs quzumLy Luso GA. | 000002 po-------------------------- Draft Document - for review al~l discussion purposes olfly. Draft document does not constitute Agency policy [pEes: | ienocvoemumeeeentt ifieleed)) PFOA - 20 of 92 22447755..00002200 sagen Te : STATE_07438023 Sorin | Aa Study Description Te || duration, route/ S mas ,|e vehicle, species/ Admin Dose (m~k~d) [ave serHHl i EO ObvrEeDsdow Effect(s) Observed at each HED dose level and earliest time point obse~wed [Sy FOF Study PODHED UF2 m_st (m~k~/d)~ Col Candidate i | RfD -- mg/kg-d strain, age at dosing, N/sex/group, etc. concen]# [serulll coF!cen]# be Nsnauaeut m oSroTa esg ramept eu netdoess1s 4 [Sa EeSh|Emapna statisticaluntforfetal effcts, neonatal i en I) mh bEa aEE hw eee tiivrvee rome postnatalsurvival (sullbirths &nconstal mortalty); deleayeoypeenidng spraocciptal bone thors DLA, or Tari 109250 GA, | MDH Jou, a Srua Hbeedimumnbs 18 smo R e R e Se TE T InrS ,e R :e E iR A mn t em saamnmSsa elm3ypeTahs,etrom To Developmental reach |b | emtdymah Se garage study - ICR am S Ae AR hh etRN mice 0, 1, 5, or 10 mg/kg-d Maternal >_1 (admin dose) - ]'rel maternal liver (35", 115", & 185**%) & kidney (16"*, 14.5", & 27**%) wt; hepatic hypertrophy; renal cells in outer medullar & proximal tubule MaternalNA NOAEL Draft Document - for review a~l discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 21 of 92 re Reference tna (note limitations |i, in comment filed) fGpraetor oins a i Es a pra Sasa N Tho e (YaJlia 2010) and aci EPA 2016a arson 2475.0021 Erp-- STATE_07438024 Std Docipion | Adm Die Study Description Gurnion roe | duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn strain, age at dosing, Nethrmpte N/sex/group, etc. Doctor Dosed on GD0-17 (mst N59. (prenatal study, N-5-9 dmdams/grp) DontGD0-18 Dosed GD0-18 (mh 5 (posmatal study, N-5 di) dams/grp) Admin Dose (m~k~d) [ave serufll eoneen]# Pucscct Pups only assessed eth until PND4 | Ei) Obra achHED snl | Suh POD| UF Effect(s) Observed at each HED dose level | and cat i pn held (mwa and earliest time point obse~wed Study POD~D UF2 (m~k~/d)~ rn coc" [sertlnl COl]cen]# er gh berniaces| Lage were slightly hypertrophic (no incidcnce sore pom: BUN 075,| minds) data or dose-response data); ]" BUN (27.8", IEA co 26. zor do | LONEL 25.4 & 20.5 vs control 22.6 - no cle~ dose Tope) & pounfosdo response) & phosphorus (no clear dose oper) response) 28 oe nad (1208 >_5 (admin dose) - ~,matemal BW (12" & TR bl mt ner we. ol 17**%); ]'absol maternal liver wt, ;total rmpin 1 33053 pol scram protein (15 * & 22**%) & globulin EESO ASTotL He, (22** & 32**%); ~'AST (311 & 813**%), ALT (08 3 &ALPO2E ALT (150 & 372**%), & ALP (32 & 96 abana 8 15%) 296**%); ; albumin (11 & 15*%), raha (478 3275) ogholids triglycerides (47 & 82**%), phospholipids (RTTC)wa 30re8ay (10 & 33*%), TC (8 & 32*%),& free fatty ie 1 acids (34 & 44*%); 0m GOT oct rin 10 (admha dose) - ,~ GGT; delayed parturition w/~58% of all pups born stillborn ,and th arin 3 be death occtming w!i 6 hrs of birth in 1 mg/kg-d (admin dose) LO AEL CoRmIte|| (emercebnciens i Candidate ~ RfD mee| nSvmeknt) mg/kg-d Reference (note limitations in comment filed) Doma [0510035 Developmental Gresun | mpisd Garage Studyrun CB ie Pregnant CD-1 Mice io(N-10/grp) 0,2, 10or25 mg/kg -d remaining pups. Decent Deviopmenat Developmental ime give a in 0500| Thad >_5 (admin dose) - ,blive fetal birth wt (9.5** & ST I BY Beg|| Comino) 28**%); lpup BW (8** & 29**%); ~ ion NDI (1440 05) NOAEL survival on PND4 (84.4** & 0**%); Tieseh mam.rch oe q'incidence cleft sternum, reduced Phd osis&eniedopnin| Sus phalanges ossification, & delayed eruption ri 0s Sei pds | admin) of incisors [all starts signif at next dose ji) o(nWOdanpnpntaah level up] Developmental 1 mg/kg-d (admin dose) NOAEL 5 mg/kg-d (admin dose) LOAEL based on -,b pup BW & survival |23 adnde) pli de >--2 (admin dose) ;placental ~, T incidence pon ded ss 105. of resorption & dead fetuses; postopom a 5 31&S06481 implantation loss 8.83, 30.98 & 55.41% So cot prt compared to 3.87% in controls; parietal & NA NOAEL SSeErOa (Suh 2011) and aci EPA 2016a Treated GD11-16 Do Domne dionpp a Dt ConA AS ky S-TGC & GlyT cell fi~equency in the Draft Document - for review a~l discussion purposes tufty. Draft document does not constitute Agency policy PFOA - 22 of 92 2247755..00002222 sateoressazs STATE_07438025 StyDecrpion | AdiDe EF) Obccr HEDdia e vt |Sin POD | FF Study Description dorvion ron |ke | md aio pot omc ng duration, route/ Sacer | Ines vehicle, species/ ne dvi.|onl [-- strain, age at dosing, Nem. N/sex/group, etc. Dams vera Pc ont Wh es | TogAgd Dams wcrc sac'd on fr sFT2d 1FRS5otoorD0dhmkaa oleoiamhrrnpmeh soiemagsmsnrtiomRoniepbgi)Deyinsc osdLdsnRnftm:dtDBoscm.ldaihbado mmoerYncet2o2ot9omp2es.br5achser ootifeipenvoe P|eLrcTONodaEnm-Lioib,nei)ds GD 16 Admin Dose (mg/kg/d) [ave serulll concen]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD UF2 (mg/kg/d)~ [s~runl concert]~+ placental junctional & labyrinth zones was ~ in dose dependent m,~xqner; >_10 (admin dose) - j, fctal wt & number of live fetuses; placentas displayed necrotic changes 25 (admm dose) - +maternal BW MDH BA41_) modeling: For 'compariso~ purposes only" since BMD mode#ng couM not be conducted because we do not hm,e fitll nested dafasei (which would require indiWducd cm~mal dam) Number q/'#ve,~tuses: a# model resuhs unusable. Fetal BW B~DL/BNID+ 2.2%~2.56 (admin dosO mg/lcg-d 2 mg/kg-d (admin dose) LOAEL based on 4"resorptions, placental effects & fetal death Taseed OOO S00 Go) Gr | 001 wed Targeted Dogme art ero famine GDR il | (am G2) Developmental for UPD a 0S uhedt | EPANONEL Garage Studyme C3 is Tepe mins SIND Pregnant CD-1 Mice NE ons 203 aman LOL WOLS Clots | 03mga N=17-21 dams/dose Sido D1 ATOR THDwow ns | (smd) Animals dosed GD1I HTD.dere 1 ntot(PND| EFALONEL 17 0, 0.01, 0.1, 0.3, or 1 fom sms. w bSaodooa TIC Focused assessment of indi "Trmcmciomsicioonps (TEN ws|HFD ds liver effects. Gh Feast oi tocon d des son Only F pups assessed rtm nerscumon ADS | lon after weaning. pooh ni lo&d mie hi mics| Spo ub) Impact of high fat diet oven ho ofeonse potion Wh (HFD) was also sm permithepamioonknaas assessed BIDS tgs e bdk badd On PND35 offspring Ve planion BED stride were placed on HFD etree] mealot med tear. with 60% kcal% fat or >_ 0.01 (admin dose) - T chronic active per/portal inflammation @PND21 (still observed @PND91 in >0.3 mg/kg-d); q'hepatocellular hypertrophy @PND91 <_ 0.3 (admin dose) - LDL, HDL & TC levels in PFOA + HFD were lower than controls + HFD; dose related T tel liver wt (@PND 21) *Transmission electron microscopy (TEM) was only conducted on control & high dose grps. TEM of liver sections on PND91 showed cellular damage & mitochondrial abnormalities w/no evidence of peroxisome proliferation. W/i hypertrophied hepatocytes, m itochondria were q" in number but also e~fibited altered morphologies suggestive of q' &/'or uncontrolled fission & fusion reactions. 0.01 mg,q~g-d (adm dose) EPA NOAEL 0.3 mg/kg-d (adm dose) EPA LOAEL based on @PND91 in HFD ~J~imals (gestational lactational exposure only) 0 mr sn poo rs os As Draft Document - for review al~ discussion purposes olfly. Draft document does not constitute Agency | CWieo| oReebcieos i Candidate ~ RfD had| Smet) mg/kg-d Reference (note limitations in comment filed) (SERCA 2e (Quist 2015) ~d aci EPA 2016a policy PFOA - 23 of 92 24750028 2475.0023 state orasuzs STATE_07438026 | Re Study Description To [| duration, route/ Sp vehicle, species/ | strain, age at dosing, N/sex/group, etc. i control diet with 10% a Fme o Fnr e kca1% fat (1 pup from 7-10 dams/dose grp). EfaearEssy RS E E e E, After 6 wks animals Admin Dose (m~k~d) concen]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Authors state: findings confirm that developmenta! exposures to PFOA reduce allerations in choleslerol biosynthesis cmdfi~tly ao Study PODdeD on i | o, f (m~k~/d)~ UF2 Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) [sertlnl concerti# were returned to acM metabolism, and demonstrate that those EC E E E P E o f a r E n E a L E T R E T Ae L.L E T . Purina 5001 diet. responses may vary when anima~" are challenged with a high-Jal diet..., al PND 9i, when PFOA ls only detected at a low, residual level in the serum, these mice exhibited a dosedependent increase in hepatocelhdar t~vpertrophy. Ullrastructura! examina#on confirms that the h)gaertrophy was ~ot due to peroxisome prol@ra#on or SER induc#on as wouM be expected with PP~As or enz),ne inducers, respectively. Rather,/~werWophied cells contain increased numbetw of dividing and prol{/~raling mitochon&ia either as lhe result qfimpaired mitochon&ia/fmction o,~ possibly, a mitochon&qal &ff}ct due lo &velopmental PFOA exposure. re Te wg 4 wk gavage study in TI | | rr oe BALB/C or C57BL/6 HR SE mre | WE female weanling mice a N- 5!grp Ce (ms, | BOE om Garaged 5d/wk for 4 & | EES EErTERRmE E |||| A EoiEe wks 0, 1,5 or 10 mg/kg-d 5 d/wk Time adjusted: 0, 0.71, 3.6 or 7.1 mg/kg-d BALB/C mice: >_ 1 (adm dose) -~absol & rel liver wt; ;absol & rel uterine wt; delayed vaginal opening (VO) VO did not occur at 5 or 10 mg/kg-d (adm dose) > 5 (adm dose) - lmammar?.' gland development (.~ duetal length, number of temfinal buds, stimulated terminal ducts, BrdU revealed signif lower number of proliferating cells) 10 (adm dose) - +BW BALB/C mice: NA/1 mg/kg-d (adm dose) EPA NOAELiLOAE L based on delayed VO, T liver wt & ~uterine ~ Ffeoneir Yang et al 2009 aci EPA 2016a mt nf terete Draft Document - for review a~l discussion purposes tufty. Draft document does not constitute Agency policy PFOA - 24 of 92 Branch 2475.0024 ---- STATE_07438027 i | i | io Ob eS Ge SFyO | FT Study Description Te || ivres we duration, route/ fre vehicle, species/ | Sa mcm strain, age at dosing, okey ComoiSC pyToa am;Rmme t tetAmRmnorr EtseSiesyto||||| shSaorhenthatsaob.us N/sex/group, etc. Admin Dose (m~k~d) [ave serHnl concen]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD (m~kg/d)+ UF2 [seriull eOl"lCen]# C57BL!6 mice: >_ 1 (adm dose) q'absol & rel liver wt; ]'absol & rel uterine wt but signif +@10 mg/kg-d) > 5 (adm dose) - stilnulatoo~ effect on mammmy gland development; delayed VO (VO did not occur at 10 mg/kg-d (adm dose)) 10 (adm dose) - J~BW; inhibition of mammao, gland development C5 7BL/6 miec: NA/1 mg/kg-d (adm dose) EPA NOAELiLOAE L based on ~" liver & uterine wts era ST Developmental TT Ct|tent| i te fo | Garage Study- CD-1 han | Si |e Pregnant Mice EL, | RpmS |S [E SRTA | Study 1: 28-48/grp BT,|Set | fa GDI-17 & pups were Senn |AE Zo cross fostered. No | MAer | su fey pups remained with Em Le their original birth = | S S--emor -- ne || TEROVIst NrGio|Ri mother Study 1 0, 3, or 5 on GD 117 Pups cross fostered resulting in 7 trt grps: C, 3U, 5U, 3L, 5L, 3U+L, & 5U+L ~'~ FHITI were measured at Study 1 Cross-fostering study to determine if posmatal BW deficits, neonatal lethality, & develop delays were the result of gestational exposure, lactational exposure, or a combination of gestational & lactational exposure Maternal 77.9 ug/mL - Tliver +vt; delayed lactational morphology 94.2 ug/mL - q'BW/k3WG, ~" whole litter loss Study 1 ~Iatern~d NA EPA NOAEL 77.9 ug/mL EPA LOAEL based on ~'absol & rel maternal liver wt Cope| i Candidate ~ RfD -- mg/kg-d Study duration 18 weaning ~ also in Fpups @ 6 & 9 52 po Dengan wks ofage pics | S [Ei TA I |Camoe Predicted AUC SaAtu |d[SLod ivoire sxe | oe ug/mL*h Rel liver ~ "[" & reduced mamma~- gland development (~PND63 (F) in all exposed offspring Developmental NA EPA NOAEL 33700 & 40700 77.9 ug/mL - ,l, pup BW (M/F pup U 4/8 & 77.9 ug/ml_, mg/L-h (EPA FNGTIHA) | oping & bod hieprow (U & Ur | Badon 2016a Table 4-3) AE 2Tgrodtuepsbhh eedpeGA | o|a eSe Average serum concen tration redid AUC La Gays rene be ai| L aB, predicted AUC 13/15%, U+L- 15/21 & 21/25%); ,beye opening & body hair growth (U & U+L); "['liver wt in all trt grps (25 46%); 94.2 ug/mL - ,~pup birth BW; +posmatal survival (U+L); +eye opening & body hair growth (U & U+L) EPA LOAEL based on delayed eye opening & hair growth, ~'rel liver wt, ,I, BW, delayed [ar----------r---------- Draft Document - for review al~ discussion purposes tufty. Draft document does not constitute Agency policy PFOA - 25 of 92 [i Reference (note limitations in comment filed) re (Wolf 2007) Ts White et al 2009 RETTHS aci EPA 2016a rss 2475.0025 ere ress STATE_07438028 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmen kt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman 9LfT:i3oeAwresIl R |P|heOl RseewHcemadlmildadimcoyvwrstoSehmf apepppBusmDcem mqeopncdpdsm raxsdpiioensno ||| dkNmLieOafgvAmeEaNmlLsAoLpTgOmLAed7)En)||| 3GoOoA0xy.N|| aEvPons N/sex/group, etc. Admin Dose (mg/kg/d) [ave serHlll concert]# ug/mL-hr/(18 d x 24 hr/d)7Z9 ug/mL 94.2 Effect(s) Observed at each HED dose level and earliest time point observed q'Rel liver ratios in pups exposed lactationally @serum levels ~ 15 ughnL; in pups exposed in utero 65-70 ug/mL. MDH did not attempt B~D modeling due to the small number of dose grps ~md lack of nested data (which wouM require individual animal data). Study POD~so (mg/kg/d)~ i UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) [serunl co11cen]~I mamma~+ glared development (F) [NOAEL!LOAE LI n,:D NA/0.0109 mg/kg-d] 300 (3A, 10H, 10L) EPA [0.00004 i EPa shan [sua so? smis2 Study 2: 12-14/grp ReEqt [0505 Dim 1081 Fp rps an D2.|Matra Restricted Exposure sob corr Niameyid lpm abn a Study Subduion [121 | sada vas map 0 Feo| EPANOAEL Study duration 12 wn PDbBreGGGtcmeAGIWFSroODinosiBDeIIrciovlscaGSntAIudnAIairtah?TTnng(ciIISn1tiNfNAeAaee2o-CUUtE1IT4CnCi12onax| | ))re||||||||||pfio|eysmmRLSraowsaBsEwsReaasEemG rSil"Ter0G1mDdoo7liPpdyvdosBlndodaIiypeterfcbpm greonpeeRNso( Ti|dmoeeE imnpDtdEoxssoaOtegpSnerfTea poehtM niolspiosi dsCododeccDsocesadeIfonoon eisdnl SGxfmwo0iDds1ipmdiep7Pa7od aopdh.:FmfbBCvtG1QmeocpsO7s oe D dWnAde0o7nosehsrknisweeha7ip1eDnnm dedo0doGInees.c1sDGo1s7sII07l.||||d||o[t[IDiTsEbEEnb9o$nauPPPc 7vvasAAAn9mcsacNidLLcWueOo&mGwO2legnNAAehshEEE.!aLLLe Ay poly (GOT-17) Study 2 0 or5 GD7-17 (~=12/14) C D10-17 GD13-17 (N-12) GD15-17 (N=12) Measured final SeFHI71 concentration GD 7-~ 7:24.8 ug/mL Predicted AUC ug/mL*h 25400 mg/L-h (EPA 2016a Table 4-3) Average sertlm concentration = predicted AUC ug/mL-hr/(12 d x 24 lu'/d)= 8Z9 ng/mL Study 2 Dams & 1 M & 1 F pup necropsied on PND22. Mamma~~ gland development in F offspring assessed at various interval up to 18 months of age. BW of 1 pup/sex/dose weighed weekly from PND29-245. =~laternal "I'BWG in dmns exposed GD 7-17 or 10-17; q' liv wt all grps except GD 15-17. Qualitatively mammary glands fbr trt dams appeoxed immature comp~xed to controls. Control dams nursing offspring exposed to PFOA in utero also had delayed lactational morphology presnm ably the result of exposure to the control dam from maternal grooming of in utcro exposed offspring. Pups ,~birth BW (Ms) in dams dosed GD7-17 or 10- 17. By PND78 M offspring BW had recovered. Offspmag of dams dosed GD 1317 weighed significantly more on PND 161. Rel liver wl q" in all grps. Eye opening & body hair growth delayed in pups expos GD7-17 & 10-17 Stud,/2 Maternal NA EPA NOAEL 87.9 ug!mL EPA LOAEL based on "]'matemal rel liver wts Developmental NA EPA NOAEL 87.9 ug/mL EPA LOAEL based on delayed eye opening & hair growth, ~'rel Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 26 of 92 22447755..00002268 stateoressazo STATE_07438029 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmen kt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman N/sex/group, etc. Time DU Tw SamCN oS RmHnoavetnkoyenroaa dnongt&tocuua lismbmepgdcfoam cearpac ooogokemsc,dpofe y torrpaaemup daoehrinPrgeosN1hDcrtmsne st oearrT8gnsT,udiO2E5ns)E|||||||mLI(SNhianO4cmereANdaEdiNiALsAeJLDpplAOInAW)EdE|||0Ol1Au1.), | oEPmAom (=a MammaD7 aopmenngvage |Foffprnas| 20190 S55&0 97070 p00 | EPANOAEL, fry development gavage Sao Coen mired| ded a shen dno ie study - CD-1 Proms [GoD tr | pup) 6TNDII& 2 amen Laut Pregnant Mice Boob bin & [inco9m% | ckpmendtasitschonodocrs: | EVA LONEL Blood, liver, brain, & a ims | 07| nedimnagd. PADI 15128 16 | bcd Hoar 4th & 5th mammaD' ids wercolocd[rind INDI | 53 or el] frei glands were collected fenton | (uae) | 21] Ir NDI UF 17268 |mama pid from femalc pups. Sob dion 18 | 3T2iSsvinnte||7 dApTmnoFdugmaGnmDn pSend || SGcOiIon Study duration 18 am 5. eronPNBIL 2218VF4) days Bm [Epa mootne NoAELLOAE GDI-17 (13/grp) Coligrpscso |semvalu 03 | MDH IMDMingmig pm ce. | Lo NADODIT 6 offspnng!grp sac on NDT Ih | mpg 114 | For orien apes be romel | mead) PNDs 7, 14, 21, 28, Den WCo3bWwoseIEoertdeerernVamanednCseoicsTwaicaarmaiicDleletonteaoCrneanD.fsneod||||||| |KvBn vedDl4lasuCrma0moia7raen7ne,smi1,co. lho4dO G in1edmemdtrniiin u bdmcthoohteerd nerra n ednqm(oedts)cnoionn s hnbcvveheclececn' 42, 63, & 84 Admin Dose (m~k~d) [ave serHlll concen]# 0, 0.3, 1.0, or 3.0 F of/sT~ring serum CO!TCeR. tlq~asHped on PND7(ear#est time poin0 4.9& 1 l. 02~, & 20. 7 ug/mL & PND14 (peak #veh9 4.535, !6.95, ~ 26. 525 ug/mL EPA modeled ave serum value @0.3 mg/kg-d was 124 ug/mL (Table 4- 8). Values for other doses not reported. Using the ave sermn concen calculated for pregnant CD-1 from Lau et al & Wolf et al the ave serum concen for 1 & 3 mg/kg-d Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD (m~k~/d)~ i UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) [serunl COl]cen]# MammaD" gland development scores (ductal elongation & branching, appearance of TEBs) signif ,1, in all exposed grps @PND29 & 32. Mmnma~/tissues not scored at 18 mons of age due to lack of protocol for mature aafimals, however, d~xk loci (composition m~known) in manamary tissue occurred at higher frequency in exposed mfimals. >_ 0.3 [12.4 ug!mI,] - ]" rel liver wt PND7 (M/F: 26"/19", 59'/38", & 97*/76*%, p50.05); delayed mammary gland development (F pups) @PND14 & 21 (however, developmental scores did not show doserelated trend - e.g., PND21: 1.9, 1.3, & 1.6 vs 3.4 for controls) >1 - "~ tel liver wt PND14 (M/F: 17126" & 41"/58*%); delayed mamma~" gland development (F pups) @PND7 to 84 } rel liver wt PND14, 21 & 28 (M&F) MDH BMD ~ode#ng using serum concen: Fbr 'c'o~:~,)arison purposes only 'since optimal BMD mode#rig could not be conducWd because we do not have rid[ nested da~aset (which would req~m'e indivMual m#mcd BMR+o%- a# model results either questionable or unusable. Ques#onable result w/h)west AIC O. 779/7.61 ug/mL BMR+sD - a# model results either ques#onable or unusab#. Queslionable result w/lowest AIC 0.994/!.98 ug/mL liver wt, ,I, BW (M), delayed mamma~" gland development (F) [NOAEL/LOAE L~mD NA/0.0123 mg&g-d] NA EPA NOAEL 12.4 ug!mL EPA LOAEL based on Tli~,er wt & delayed manunary gland development @eND14 [NOAEL/LOAE L~+:~)NA/0.0017 mg/kg-d] 300 (3A, 10H, IOL) EPA ii 0.00004 EPA (Macon 2011) and aci EPA 2016a Do Dont Draft Document -redioppnny for review a~Kl discussion purposes tufty. De ConA AS Draft document does not constitute Agency kypolicy PFOA - 27 of 92 2247755..00002277 stateoressaso STATE_07438030 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman o Tigae. N/sex/group, etc. Admin Dose (m~kF_Jd) [ave serHnl concen]# would bc 38 & 77.8 ug/mL Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODHI~D (m~kR/d)~ Stdro dn [0100101010 | 2001 ss sen deme mgt |NAO!muh Study duration 8 days fey FCioeSmo5noene0Dtpnnaiygm1o1s331vi050e5e2e35m5sd5||||||MoR0CPCrFeS0BR1TOmroAooteiAD1rnHmwnDnDmScsLaLic 3omreoro n)sCatgmo0nhetkibetpIeoos1s06etiieapas5r nseGNnn5onn3e5.hnmei0g5E80sdn1o maivmsh3e sb34lro nond0iod0lfrS0ae0ofvPem3rm5Teaa3clDo|)d7n wEsmercLCoP5aTo 19.icsOsom 4t3cUnmiTNn7eBi8mvtSR0ddncumrsdD01dntduaiNe7erAe0bop5yoonse5o)mr vr7Prrdsr3dEhmnsaopyelnft.3Loios)synmsDemrega.l|||||||mbpp oNodOLopesanAOdhokFaegENn asoLvbnEAdIenavLoOneiiYAd)emEd 6D 10-17 (3-5/grp) 0, 0.01, 0.1 or 1.0 F q,ffi'pring serum concert, measured on PNDI (earlwst time pomt) 0.0226 (control), 0.2845. 2.3035, ~ 16.3055 ug/mL > 0.01 - staffs signif decrease in qualitative developmental scores @PND21 for mammary gland (2.2, 1.8 & 1.6 vs 3.3 in controls). Quantitative scores only statis signif @ highest dose >_ 0.1 - staffs signif decrease in number of temfinal end buds (TEB) 1 - Tliver ~vts Using the serum concentrations reported on 15D 1 (Post 2012) ca/culated BMDL/BMDo~ serum concentrations of O 024770. 0257 ug+mL .!br ~ qua#taaw" mammmT gland development score @PDN21 & 0.0229/0.0251 ug,mL for ~ 7~s @PND21. MDH modeling usinx PND! serum concen: For 'comparis'on purposes only 'since optimal BMD mode#rig couM not be cona~cted because we do not hove f!~# nested dataset (which would req~ire individuM animal a'a~aO 0.0836/0.379 ug/mL f!:r ~ # TEBs @PND2!: BMDL/BMD~s~ O. 0836/0.3 79 ug:)nL (lowest BMDL) O. lN~0. 685 t@)nL (viable alwrna/e) NA/0.01 mg/kgd (adm dose) EPA NOAELiLOAE L based on qualitative mamma~ gland development score LOAEL of 1 mg/kg-d (adm dose) based only on quantitative SCOI'e ised | FTN 01 | Weeden fn)GAD w= Multigenerational Ci Su e C01 |(Nar SON | Po Com0m0 court Spo | GPANOAEL. Garage Study - CD-1 i TmppaGor.| 007 maidrss md 5 Mice Eomptinet [17 ro DI SG Smad | 1medod Examination of frp Ficom 000 sod DOO313 | i) extended consequence rsd mamman | P000a8rt| Tg:mydead DIV2745% | EPALOAEL of altered mammary midncopment | Vimphad | Sic ioois ms gland development. P0~a - 0 (N 10), 1 (N 12), or 5 (N 11) mg/kg-d GD1 17. POI~ - 0 (N 7) or 1 (N 10) mg/kg-d A4emured serum levels ug/mL) (iLPND22 : PO: Control 0.0040; control t 5ppb DW 0.0748; 1 mg/~g-d 655g; ! mg.kg-d 5 ppb DW 4. 772; & 5 rag&g-d26.98 ug/mL. pups: control O. 0006: control D W O. 02~3; 1 mg/kg-d 2. 4438; 1 mg/kg-d + D W 2. 7439; & 5 mg/kg-d lO. 045 ug/mL NA EPA NOAEL 1 mg/kg-d (adm dose) EPA LOAEL Do Dont dioppnny Cm Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute UFUF~ ASAgency CoRmIte|| e(emrcebnciens i Candidate ~ RfD mee| nSvmeknt) mg/kg-d Reference (note limitations in comment filed) ky Siie us SomcomnratrresaS iceofl,r policy (White 2011)and act EPA 2016 Also see study summary of Albrecht el a! below m Other Studies seclion PFOA - 28 of 92 22447755..00002288 stateoresanst STATE_07438031 A -------------- Study Description - Admin Dose Effect(s) Observed at each HED dose level Study PODdeD UF2 Candidate Reference me a |e i lf duration, route/ (m~k~d) and earliest time point obse~wed (m~k~/d)~ ~ RfD (note limitations Eola J vehicle, species/ [ave serulll mg/kg-d in comment filed) Wo, [E mer strain, age at dosing, concert]# [sernnl concert]~+ Er N/sex/group, etc. EE Cm TTT a TE Mammary gland GDI-17 + 5 ppb F} clams: control O. 002; control + D W O. 0869; based on which evaluated SIs |itoms oman |i i whole-mounts were in DW starting 1 mg/Lg-dO.O093; 1 mggcg-dO.1733, & 5 delayed role ofPPARa Ene (ahd |r Fe Se scored on a GD7 for duration mg/lcg-d O. 013 7 ug/mL mammary gland using PPARa- REET Cl IE EE develop~nental scale Eur (LEH |mipiia ot, trons (FTL [a (quantitative of stu@. F1 females & F2 F2 pups: control O. 0004; control D W O. 0266; 1 mg~X'g-d O. 0046; 1 mg/kg-d + D W O. 0285; develop in dams dnring lactation hum~mized mice. (only 0 & 3 EET [or | TREAT Fr measut~+x, as in study continued to & 5 mg/kg-d O. O076' ug/mL mg/kg-d trt grps) Te (SE, Eien above, do not c~pear receive DW until Mammary gland EERE | | eared pa to have been end of study >_ 0 + 5 ppb DW & 1 mg/kg-d (admin dose) - ductal length ~ HEE [SE mae Eo) conducted) (except during F 1 ,bmammary gland score in dams & F1 Wrminal buds' [ir fi breeding & early pups @all assessment time points & F2 were quan@ed ren [ER | pi pre Lactational challenge roped NT r= substudy - dmns were gestation). So 5 'dose' grps : (PND42 only) 1 mg/kg-d (admin dose, gestation) - ~'F2 BW ~.e., gd not use quaBtative BE |B Sippingpn22 pe separated from CEI pn Sirs, offspring for 3 hr on rea BE Fs: PND l0 (peak of feu Er lactation) & then mmneyy,|| | = returned to litter & fle | seine pei, [A allowed to nurse for B= eLmHGi TdiIErSit"|||||| |e n E E TRym tE et t e ctR e n eo pfiE[frp-- Srarieeeeoindsm 30rain. * O, & 4,mammary developmental score . 0 ~ D W(~O. 054 @PND63 (but no effect in other dose grps) 1 & 5 mg/kg-d (gestation expo) - q'rel liver wt gestation 8- F1 pups O. !05 ~g/day 5 mg/kg-d (admin dose) - ]'prenatal loss, + lactation), number of live offspring & postnatal i mg~g-d survival in P0a; F1 exposed in utero had (gest only) significantly fewer implants; ~ F1 BW 1 mg/~g-d @ND42 [gesmtion) F2 control females exhibited unusually low ~DW mammary gland scores & developmental (37 ~ 0.051 delays in trt grps relative to controls were not statis signif. gestation & 37 ~ 0.30 F1 maternal lactational challenge - no ug/d~v significaaat effects on milk produced in 30 rain deve lopmen~l scorO. No sign~ dif~rence m either paramewr was observed btwn control & trt grps. In addition, expression of PIL~Ra target genes that modulate lipid membo#sm was ~ in both wild-&pe & humanized mice coincident wh,|S BE lactation), & = Fits 5 mgA~g-d | E e Eh=rnBee irr ir,g EEEEFesoEEs (gestation) or in time to initiate. Authors: Despite striking morphological abnorma#ties in lactating glands no clear evidence of diminished nutritional support provided by dams as measured by F2 B W was u(T #ver wt & microscopic [esions. Neonatal mortaBty was observed only in wild%vpe of~pring Ey Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 29 of 92 ---- 2475.0029 smn STATE_07438032 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Admin Dose (m~k~d) [ave serHfll conceu]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD UF2 (m~kdd)+ [serunl concert]~+ Nethrmpe N/sex/group, etc. Mamma Disp |0.00101038|COLmis iv Mammary Develop 0, 0.01, 0.1, 0.3 & CD-1 miec - CD-1 Mice Gover | mgd sen | <0 amsid si m)y Ni Gavage study- - 1 mg/kg-d admin >_ 0.01 (adm dose) - ,~qualitative mammoxy NA Fadia |GDLiTw inci con 4D 03 2, | EPANOAEL Female CD-1 & GD 1-17 via gland develop score @PND35 (2.3, 2.2, EPA NOAEL CRN |e SE TieT li C57BL6 Mice gavage 2.3, & 1.9 vs 3.1 in controls) but mite dope GPNDSE, | 001 med inconsistent dose-response @PND56; 0.01 ~ngfkg-d Golcxmmmsionof|Sesmmesed | ms sont prognrls ino Goal - exaanination of Serunl measured nonstatis signif "[ progesterone levels (adm dose) mag | BENDIS | 201 indo ata momma ond | EFALOAEL mammary gland (ii~PND 21, 35 & >_ 0.1 (adm dose) - ;qualitative mammaD, gland EPA LOAEL choca Sco hopes GND 35.208 1730| bedon development 56 in CD-1 develop score @PND21 (2.3, 2.0 & 1.7 vs based on Senin eos | And 25 Cony dined senskivity across And 2.9 in controls) delayed acme |PND @61 or | sk do) ely wt GENDYI (129) |mammarygd mouse strains. Ducts cms eB PDR &33 cho Due to space PND21 & 61 for C57BL/6 1 (adm dose) - ~,rel liv wt @PND21 (12%); +net BW ~!PND21 & 35 mammary gland development sions suds was nos limitations study was i?~!PND56 condi tock. | Md se |CB acon conducted in 3 blocks. Measured serum C57BL!6 mice - (gestational SCO a [lh nd) | 03odor ainmammarygod| pons se) 4-8 CD-1 littcrs/trt levels (ug/mL) >_ 0.3 (adm dose) - ;qualitative mammary gland exposure only) bk pity cigs NDR 38130035. block reported develop score @PND21 (1.8 & 1.8 vs 2.9 55 bi|CENDRL eros| neon snd PDO218173023 3-7 C57BL/6 litters/trt Bod np 53 | mol block (~PND21 (earliest dmep~ but ~22 in controls) and PND61 (2.1 & 1.7 vs 2.8 in controls) Expomsl. |do ofr ot Endpts measured: clc~w after/a~ t WONG, bts [pone | tors cmos BW/BWG, Absol!rel exposure): Authors notes: C57BL6 Mice Tort | Cotas | TER ed mitochon | 0 mgd liver wt; neonatal CD-i - 0.0748, TEBs, lateral & longitudinal branching & 0.1 mg!kg-d hy nm |04573.09008 | cond rch vere 1108 | (amon) develop; serum 0.4573, 0.9048, & seconda~;v branching were all ~ w/~ PFOA (adm dose) Candi Siiunl | ewing mamic rghohd | EPANOABL estradiol & prone 7:8 5 ntc o hesonn t ics progesterone (P); & 3.119 ug~)nL dose, resulting in a much smaller gland. By PND 35, in addition to the growth defects' EPA NOAEL ns mann | CALE iv dod, PFOA cameodose | 03 med qualitative mmnmary C57BL/6 already described, PFOA caused a delc~ in the 0.3 mg/kg-d Sddechg on |00741,0271 | tin ndrid n ter Gna) gland develop scores 0.0261, 0.2471, ../burth and.[!fih glands growing together. (adm dose) sors 3 i CALONEL 0.8913, & 2.14167 EPA LOAEL Subsdion 17 Sorngisbsothelefdlrs | bad Study duration 17 ug/mL Scoring is based on the level qf development based on dns comcitps etetbeedon | lyst days compared to controls & maybe based on delayed Cer fsoto scons itn| mem gd entirely d~ferent criteria that can still result in mammary- gland trsores ro ram. pen similar scores across strains. development pe @PND61 CO mome pero ne mre einer: | Genononst CD-] mouse appear to be more sensitive re: (gestafional cronmamarydein Toe cs| poesu) effects on mammary development. 7his is #/cely exposure only) enohlr & arcing a reflection ofthe higher & longer circulating tilC1 me, We a ort PPOA levels in CD-] mice. We suggest that it Do Dont redioppnui Dt ConA AS Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency CoRmIte|| (emercebnciens i Candidate ~ RfD mee| nSvmen kt) mg/kg-d Reference (note limitations in comment filed) air) (Tucker 2015) Saar ,and act EPA me 2016a Pray res PregnanQv rates nen Tv in CD-I were rth > 60% but much ir (Tn lower (~27%) in pret C57BL/6 mice kypolicy PFOA - 30 of 92 22447755..00003300 sateoressass STATE_07438033 StdDocipion | Adm Die Study Description Gurnion roe | duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn strain, age at dosing, Neiman N/sex/group, etc. Admin Dose (m~k~d) [ave serHlll concen]# | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Effect(s) Observed at each HED dose level | and cat i pn held r(mnwcaoc" i mReIe|| (nmScvbmeinnkst) and earliest time point observed Study PODdeD (m~k~/d)~ [serulll concerti# UF2 Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) rth tenn FOS cocina is lhe peak serum PFOA concenlradon that regulates lhese @cts, which ma3~ har,e abet aw ea occurred between b~rth & w/i the f!~'t two Sk rer hrese PHO vd weeks c(life),rather them the serum PFOA level i nef coat, Beis fs at the #me qfievalua#on. Based stu@ ~[fects reand oot fh evan re here and in Macon et al (~+H gesta#on or late Seon dogsocd lic orebcs gestation dosing) obse+wed {ffec!.s' are likely the erancapo, loved result ofin utero exposure, jbIlowed by Carbhoc fno he ipa hrm exacerbation ofef~ctfrom ~be exposure during lacta#on. Te EFPRRG | COT 00001, CDT Tue in Latency & PPARc~ NOExasionof [03.1.8 Smis: | 1 fmdon) Mec bt sisi)| do) MOA Evaluation of Tune Deopmen | 4 iaie humm: cl | EPANONEL Tulnor Development Reig ner pero (sated bt sng rem Resulting from Devchrm [SV 0.01, | CemedoenCntt) | Sneed ain Developmental (mtd asin, [03,006.81 Ts & FUo R Bi r | do) (gestation & lactation; dirty dod | med [py EpALONEL dams directly dosed rms rmGDI. Shed londow) ion {wad orn) | usdon le via gavage from GD1pion |v2.0, |e ipsi cm ax1i08 | clergy 17; pup lactation omens [005085 | Smid Cismoni exposure presumed Wohin | med nscld pern pmes | omseins due to long t in om Expos poi FONdcpcova | Soon dams) Exposure BIST. pa bonn (gari d gn | pours CD-1, SV-129WT & SUIS PPARGKO. iSomrl2 HOT, 17% srrn)d SV-129 PPAR~KO Ni TAR i eA d) Mice. pro coi dhPPAR, Anhnals were from separate experiments via iio) published at Hines et S30 Abbas 1S WT al 2009 & Abbott et al 20 Connie Barty (67 2007. 01217 mse con)md SPOS ci CD-1 21-37 female olson lion oon rom cont tt |mph bo offspringigrp [ti-om ko Son) 40 need] 12-14 dams/group & 6 CD-I: 0, 0.01, 0.1, 0.3, 1, & 5 mg/kgd SV-129: 0, 0.1, 0.3, 0.6, & 1 mg/kg -d SV-129KO: 0, 0.1, 0.3, 1, & 3 mg/kg-d CD-I: >_1 (adm dose) - "]'severity (but not incidence) chronic active inflammation; "Ito cell hypertrophy (sign trend but statis sign ti-om controls only at highest dose (5 mg/kg) 14% controls & 3%/27%/19%/29%/81% treated); 5 mg/kg-d (adm dose) - sign T trend for oval cell hyperplasia (3.5% controls vs. 14% @ 5 mg/kg-d) In addition to lto cell hypertrophy, mice exposed to PFOA developed ccntrilobulax hepatocUte hypertrophy (sign trend & sign from controls @ HDT; 17% (controls) and 17%/35 %/35 %/10%/81% in treated groups) - indicating that a PPARc~-independent mechanism was responsible. 129/Sv Wild-Type: Centrilobular hepatocyte hypertrophy" (60% (controls) ~x~d 50%/100%/50%/88% in treated (not sign from controls up to 1 mg/kg-d- but sign ]" severity) @ _> 0.3 mg/kg-d) 1 IngNg-d (adm dose) EPA NOAEL 5 mgNg-d (adm dose) EPA LOAEL based on "Ito cell hypertrophy @18 months from gcstational & lactational exposure T EAsG (Filgo 2015) aci EPA 2016a Do Dont redioppna Dt ConA AS ky dam/group @ HDT] Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 31 of 92 22447755..00003311 sateoressase STATE_07438034 | Re ao Study Description To [| i of duration, route/ Sp |, vehicle, species/ | on strain, age at dosing, EE N/sex/group, etc. BET TE Only- 6-10 female ee ERIEen offspring/dose grp for En a SV-129 grps [from 5SEE Ei 9 dams/group[. Admin Dose (mg/k~d) [ave sel-uHl eoncen]# bprtns R Ea ea ry ine Dosing duration 38 days and female Pe Le offspring cvalnatcd @ 18 months Effect(s) Observed at each HED dose level and earliest time point observed Study PODdeD (mg/k~dd)+ [ Sel%lnl concert[~I UF2 Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) 129/Sv PPARa-Knock-Out: Centrilobular hepatocyte hypertrophy (sign trend: 17% (controls) and 0/10%/11%/44% in treated); sign + Ito cell hypertrophy; sign T trend for hematopoietic cell proliferation (33% controls & 10%/80%/67%/78% treated); sign "~ bile duct hyperplasia @ 3 mg/kg-d; and sign ~ trend for bile duct hyaline droplet accumulation re ty ct Authors state that this study was NOT designed re id as a caxciuogenesis study but was desigued as a EEE result of liver tumors found in PPARc~ knocka out mice in a previous study. Difficult to draw ry conclusions regardh+g the carcinogenicity of ERPFOA based on the data collected because of Fd the small number of animals evaluated in both ety studies of SV-129 mice & the lack of PFOA EERE exposure between PND 21& 18 months tbr all u Sn h dose groups. Similar to Butenhoff et al 2012 lack of dosc-rcsponsc for total livcr tumors, EEalthough the four hepatocellular adenomas seen at 0.3 mg/kg/day in CD-1 mice were signif FRET, greater (p<0.05) than the control. Tumor types Eb varied across the dose groups. The authors also reported on preneoplastic basophilic, and SE Reosinophilic loci were observed in the CD-1 TE mice but did not show a response to dose. Ee An interesting histological finding in both the Emi CD-1 and SV-129 mice was a trend for "l" Ito cell atrophy& lesion severity across the doses. pam Ito cells accumulate fat in the liver sinusoids EERIE this observation provides additional support for a hepatic steatosis as a condition of concern i following developmental PFOA exposure. mtetms Peete Draft Document - for review al~l discussion purposes only. Draft document does not constitute Agency policy PFOA - 32 of 92 rrrssess 2475.0032 non STATE_07438035 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman TTcoSeEPCSPhmhIoiueooaOuslTnrlppNlgrmtsTcwspohoCoomoaedbdsDsspietcnahgpsmweoyneiososlco l2noooemwbdcmfraroorirplletmronbSiEKao htgrdtea3toabsiodnhcocspheemchr wddscplr1ecoiihsociPwheasensroPonsntethoA&eti.temoR& N/sex/group, etc. Admin Dose (mg/kg/d) [ave serulll concen]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD UF2 (mg/kg/d)~ [sernnl concert]# There was an 5" in severity with dose :for the lto cell fat deposits for all but the high-dose group. The Ito cell lesion was present in the SV-129 mice, but was not associated with tumors. CD-1 mice had a significant 5" in Ito cell hypertrophy at 5 mg/kg/day compared to controls, but there was a lack of dose-response. The authors concluded that liver damage from PFOA exposure occurring early in development is not totally linked to PPAR-a & could progress as animals aged w/o continued dosing, thus compromising liver function & possibly leading to tumor development. Te Gage S| period 07 [202 a do) Tp othe | 0Zmeied 14 day Gavage StudySSG) | a mesons. imi - Adult Male Crl:CD fy met 22 mao) Tab sr. EANOAL BR Rats fo Fin: rome ani. optic (l 5/~rp) Foc demi roamssityspt fore BV | 2a(an Focus - determine impo FOR sncabot a impact of PFOA on any 20s oy LB (pac cooslh | EPA LOAEL aromatase activity" Solsdun 14 ss hnaedrovnes Study duration 14 ks add days Tad Guests [0775 Sara | Th stoneisa an |eSApmgd 14 day Garage stu@ Nik Kain do Svc ertobet nsar| (am do) - Male Klunming me pilosa hebdoo.oty uber mice Tokeorae Coup ofbeemus ln dicion | NOAEL/ 8 wks ofage Gps ws Saemshe scaell, mcpmenetalnem || "LoOnXELpebat 6/grp tbr testes wts Sporcher erm pedi.Th vey oh sir|cot rile and 4/grp for other a p NIDAo hime parel ewsnssol mTphencin || SNOADF,2c&uBAsX assays 0, 0-pair-fed, 0.2, 2, 20, & 40 mg/kg -d 0, 2.5, 5 or 10 >_0.2 (adm dose) - "]'protein yield of hepatic microsomes, >2 (adm dose) - ~absol & rel liver wt; "['hepatic aromatase activity, total hepatic aromatase activity- adjusted for liver & BW effects; serum estradiol >20 (adm dose) - 4/BW (pair-fed controls also had ,I, BW) There was no effect on rel testes wl at any dose. Some effects were observed on tcsficular morphology at the lowest dose, including alrophy of the seminiferous tubules, depletion of spermatogonial cells, detachment of germ cells from the seminiferous epithelium, & sperm production. The severity of the testicular morphological changes 5` w/dose. The 5" in MDA & hydrogen peroxide accompmfied by 0.2 mg/kg-d (adm dose) EPA NOAEL 2 mg/kg-d (adm dose) EPA LOAEL based on ~ liver wt, serum estradiol & hepatic aromatase NA/2.5 mg!kg-d (adm dose) Author NOAEL! LOAEL based on 4,sperm count, testicular SOD, catalase, NRF2 & BAX Dr Duce for ew ad dso pos ls. Dos c cons AS Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency CoRmIte|| (emercebnciens i Candidate ~ RfD mee| nSvmeknt) mg/kg-d Reference (note limitations in comment filed) Tia Liu et al 1996 pr(~I]SO se~ Foner reproductive ans tes hormone studies erom in Other Study Seton ew) See#on below) EcFA tslie r Liu et al 2015 aci EPA 2016a poypolicy PFOA - 33 of 92 22447755..00003333 sateoressase STATE_07438036 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Nethrmapte N/sex/group, etc. vienscleo ie SOD 8 cin mylene | sionnd Evaluated effects on et md pms (CATstv & NRE pes me | TADA testes and epididymis Admin Dose (m~k~d) [ave serHlll concen]# inGomes [SbT STeGJ1SooupiLn5eegholDoi)slieTvnL ineiagc0bncnoSosenehmedtO byseone&cimsnCkonedasANFrahRNfTsdoF,D tRowicEPmppilwdiinsodsp)ssnmernclsee(sassnrcmaeshsshinssiooneoccrpminldscoen ||||||S| LdaepSoRu2EsimoiP8iiddpmnAlL5rieeooeNOogmmonsngOArcugsneEAttotsLLaneuaLtdS Taam 28 day Gavage Stud3,Di adie [0438 seen |TES when of bcbodtsar | 1348 mpd EAs - 14 day old Male BALBL Nie {Gdnmoc sid | om oe) BALBL/c Mice Sy Pasa fd rt ber those ictal 34/grp Su: Bute 5 ramfern taro | NOAELLOAE ol emer Study 1: Evaluate te st Lior Tei dr testiculax effects of FTO niHid feted GerSe: PFOA on the blood hens NofdLAiriaoEriSLiooreLmnrOnns)Ad.E fcsmawisoidioan:mmriesfstoonlte testes barrier Study 1 0, 1.25, 5 or 20 Effect(s) Observed at each HED dose level and earliest time point obse~wed the -1, in SOD & cam/t/he acyltransfcrase (CAT) activity & NRF2 expression indicate that oxidative stress played a major role in the observed toxici~T. NRF2 plays an important role as a messenger that upregulates genes involved in response to oxidative stress. @LDT (2.5 mg/kg-d adm dose) statis sign ,bsperm count (clear dose response based on Fig 3), ,b SOD & CAT activity (clear dose response based on Fig 4), and statis sign 4,folding change in NRF2 expression (clear dose response based on Fig 5) Study1~: > 1.25 - weakening of the blood testes barrier (dose-dependent manner) as indicated by passage of red fluorescent dye > 5 - q'tumor necrosis factor actin protein Study PODdeD (m~k~/d)~ [serunl eOl"lcen]~ expression and "I'MDA, hydrogen peroxide 2.5/5 mg/kg-d (adm dose) EPA NOAEL/ LOAEL based on ,b sperm count, changes in testicular morphology, evidence of q" free radical oxidation Study 1: 1.25/5 mg/kg-d (adm dose) Author NOAEL/LOAE L for blood testes b~xrier NA/1.25 mg/kgd (adm dose) Author NOAEL/LOAE L for protein biomarkers of cellular i Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) Lu et al 2015 aci EPA2016a Also see Lt et al 2011 summarized below under Other Studies re: assessment q/ wild, null and humanized PPAR mice and [esticu/ar toxicity. intcrcommunica t/on Do Dont fr dioponony De Cnt Draft Document - for review a~Kl discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 34 of 92 22447755..00003344 stateoressasy STATE_07438037 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Netimapte N/sex/group, etc. Sum Fates [Su Suh Swi Study 2: Impact on mri ders umberof mc mses pertmsemd. Nn male fertiliDT Snidatus primfies oma move (0-0 01):| EPANOAEL 6-8 wks of age Tow Tots opp ort (03207 |Smhad a 15igrp Admin Dose (mg/k !d) [ave serHul concen]# Study 2 0 or5 Solsdun 28 A E15 p ow oS pn) | EPATONEL Study duration 28 a hVCiarcdenoipnne& days Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODHED [serunl coF!cen]# Study 2: ,~ number of mated females per trt male and pregnant females per trt male mouse (p<0.001); ,Lnumber of pups per litter (10.20.72 vs 11.890.54, but not statis sign); ,,average htter weight (16.171.63 vs 19.950.80, p<0.05) Study 2 NA EPA NOAEL 5 mg/kg-d (adm dose) EPA LOAEL based on ,b fertili~T & ,bpup birth TCimiSnoes a i[02i.0s30 408 |es27 adln mdoeowln)CoA pint | "med 1() day hmnune ded [loomed Co (m ofprs on. mos dietary study EN pin) NONFLLONE C57BL/6 Mice Dictconcn0001, S2 i Sim d0 os ikvn nesSd ms | Lpiika& Diet concen 0.001, aes oar 00k 0.003, 0.01, 0.02 & a 0.05% 0, 2, 6, 2121, 4121 & 100 mg/kg-d >_2 (adm dose) -?lauroyl-CoA & palmitoylCoA (measures of pcroxisomc proliferation) >_20 (adm dose) - ~,spleen & thymus wts >40 (adm dose) -'[liver wts ~6/21) mg/kg-d (adm dose) NOAEL/LOAE L for spleen & fl~ymus TnDW edy [0.094 158 575, | 2202 inlnwtSL ned | 552i Immune DW study Nau Fle 7518 030 st SEIS dsp) daa. | EPANOAEL' Adult Female CUNY | mise Rostoney C57BL/6N Mice Duserponsduds aoa sl 106 S318 | Glu Dose-response studies Wow Stamps |"0% ed Spm poten | EPALONEL 16igrp Stldoin 15 |porwoynrorons | C(o0ndd) [iMProdpmcItSomSmBtEs | a[pbnd.eoM Study duration 15 ans ay fa Shall (1 song 0G 2%0 | doe, Ti day's Now Doerporse | doing NANA | ahd,IGrooms 14 hs | (05 dovepoke Note: Dose-response ny wird | TONNE | A SEapt m boobs | oy study is summarized reSc icstor [or [260ml | dnDTrpwems so isnd | &phenat here. ,See publication Jo he ie i ane fi)r i~f!) on the single liGomi |Pods AUC | 25 sol4 eelg 10308 | close (30 mg/kg-cD nos [vom matpsdon (73 | anhbody ,~Tnlhesis na 0Dwi n liPD BnW on) I--NOAELLOAE| 0oa study. 0, 0.94, 1.88, 3.75, 7.5, 15, or 30 mg/kg -d k4easmz'd fina! SeFUFt7 concentrations @d<v }pos~- dosing: NA,NA, 74.9, 8Z2, !28.1, or 162.6 ug/mL Predicted AUC ug/mL*h 7300,13800, 22400,30500, _>_. 20.2 ug/ml, - "[ rel liver wt (51-70% one day post trt & 45-61% 15 days post trt) (data not shown) >--61.9 ug!lnL - ,~ absol & rel (16', 18, 31", & 40*%, * p<0.05) spleen wt post dosing (PD) day 1 (by PD day 15 return to ~conlrol); ,~IgM response to SRBC challenge (7-11%, increasing to 29% @ highest dose), IgG response was T@ this dose level & 84.4 ug/mL but not higher doses, DTH response were not signif altered. ~: 84.4 ug!mL - ,~ absol & tel (rel - 10, 30*, & 49*%) thymus wt post dosing (PD) day I (by PD day 15 return to ~control) >_ 111 ug/mL - ;BW 38.2 ng/mL EPA NOAEL# 61.9 ug!mL EPA LOAEL based on -1- IgM (1 day postdose), q'lgG (15 days postdose), ~b absol & rel spleen wt (1 day postdose) [NOAEL/LOAE LHED 300 (3A, ra Duce or ewad dso poss ly D hc os consi Asay Draft Document - for review a~Kl discussion purposes tufty. Draft document does not constitute Agency PFOA - 35 of 92 CoRmIte|| (emercebnciens i Candidate ~ RfD mee| nSvmen kt) mg/kg-d Reference (note limitations in comment filed) a To (Yang 2001) and SERA aci EPA 2016a | ooo: i 0.00002 mni EPA poypolicy ewion (DeWitt 2008) aie mad aci EPA Er 2016a No: mh #Note. altkougk ame mies changes in liver vee ahr wt were observed aiD7ePA at the LDT EPA dors ths did not use this Cieraseh g~ct as the basis forsionsy Jbr selection qf hertkeir Nos soars NOAkZ/LOAkZ 22447755..00003355 sateoressass STATE_07438038 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmen kt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman 01LG0O0hTE5e04030)|| d1th5rs5BgMD6l10 SoOWs(e|trr BiOO1ST0|9E1S0 N/sex/group, etc. Admin Dose (mg/kg/d) [ave serHul concen]# 40100, & 56000 mg/L-h (EPA 2016a Table 4-3) Aves | R(MIDDHE bBdio e735w0sstiradr Average serum Coanranone | mtcomprav one 5455 concentration = puentyyil peter predicted AUC Wmiaelsax ug/mL-hr/(15 d x Bhar | Ma mcn snc de asons 24 hr/d) .... Brn | eedifone 20,2 ugimL 38.2 as61.9 Effect(s) Observed at each HED dose level and earliest time point obse~wed 155 ug/mL - 16 to 15% BW (Figure 2A) Authors BMD modeling oflgTP! serum titers B=LIDL/B=~VlD tsD }. 75,/3.06 mg/~g-d. /MDH based on dose:ave serum ratio estimated corresponding serum levels: ~34/53 ug ,)n L] MDH unable to model since data ~s only reported m figure. Study PODdeD (mg/kg/d)~ UF2 [Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) 0.0053/0.0087 mg/kg-d] 10H,I 10s) EPA 84~4 TomatGoay [0.070 T1509 ol de 74 en COR Nr hnmunotox 21 day Diao inked [DG E731 | hams NOAEL DW study - 4 wk old NcicRee | med 21703 a fo) ctnkin in Male ICR Mice 111 155 0, 0.49, 2.64, 1/.63 & 47.21 mg/kg -d ion pTeait o CDIebpmsm4o i3m8 | Ltmn td n=10/group 021008 250ms 1e00% mmicsCDImICDeS npoptustions:|| COONbmLdbCoDtR 0, 2, 10, 50 & 250 mg PION 1721 TFHo Sr0(imaeoaimerymi,kdemedt m&cCoEnem)oDpe,&x:esleecsypihii mfrofnaoek :peshorpafi.mps rrsok(oa sgoa5itm3&obtd1iens,0ns s7vplcnpslhls&e:. hes PFOA/L >0.49 (adm dose) - 50%+ in splenic CD8+ lymphocUtcs >_17.63 (adm dose) - q" interlcukin-l[3 in spleen;/l'c-myc expression in th3anus; "l" splenic CD4+ lymphoc)tes 943 & 106%); +thymic CD4+CDS+ popnlations; T rel spleen wt (28%); ~" rel thymus wt (46%) 47.21 (adm dose) spleen: enlargement w/maxked hyperplasia of the white pulp & ~" cellular density of the lymphoid follicles, q' tumor necrosis factor-a, interleukin-1 [3, interleukin-6 & c-myc expression; thymus: +cortex & medulla thickness & densely axranged cortex lymphoid cells, 110% q'thymic CD8+ lymphocy~es; "~ rel spleen wt (53%); "[ rel thymus wt (53%) NA NOAEL 0.49 mg/kg-d (adm dose) LOAEL based CD4- and CD8+ splenocytes SExeTsam Son et al 2009 aci EPA 2016a Do Domne dionpp ui Dns A AS ky Draft Document - for review a~l discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 36 of 92 22447755..00003366 stateoressaso STATE_07438039 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Nethrmpte N/sex/group, etc. mio 34 DW |S | Su Sb ews Immunotox 15 d DW uly PEAR | dpe) Sor | 75 omdose) thm iWT ott| 7350mpAsd amir study PPARa Sn Tense | mpAs gh do md me evaluation. Female FEARAKO mh | Ince SKC | 30 Sh doe 0 inWTai: rc) EY PPAR~KO and CBT dn a WT. IMU WT EKO | NONELLOAE C57BL!6-Tae WT Sob dion 14 honv Study duration 14 fae mhtSnToeuiibpdcso2a)sdr0e1-ssn09t4,a|||otc2en[suo1sruit5ut mrt2eoadmeiceh sddhoswseec)hmt ro1snircgefsfomias spbgomneotsnopronpmnnoz0en4ss.esr||||oiSjsNpmLlOoepmiiAueinseE"pEcRsdLdeydunEnLg(oCidOFneiA.AmnERt days Admin Dose (m~kF_Jd) [ave serHul concen]# Study 1 (T-cell depend) 0, 7.5 or 30 mg/kg-d Injected w/SRBC day 11 Study 2 (T-cell indepen) 0, 0.94, 1.88, 3.75 & 7.5 lng/kg-d Injected w/dinitrophenyl ficol day 11 Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODHED (m~k~/d)~ i UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) [serunl concert]~+ Study 1 : 7.5 (adm dose) - ,~rel thymus wt in WT (but not at highest dose) 30 (admin dose) - ,~BW in WT mice; +rel spleen wt in WT; ,HgM bolh WT & KO Study 2: >1.88 (admin dose) - ,Lantibody respon (9.4 - l 0.7%) Authors looked at changes" m lymphocyte populalions & saw no dose-depend changes, concluding that bot/~ sets' ofantigen responses were due to ch~mges in ce#uiar function rather than ~vmphocytotoxici(v. Study 1 : 7.5/30 mg&g-d (adm dose) EPA NOAEL/LOAE L based on + sheep RBC IgM response (PPAR KO mice) Study 2: 0.94/1.88 mg&g-d (adm dose) EPA NOAEL/LOAE L based on Tcell independent response (DcWitt 2015) ~d aci EPA 2016a ( Sdn Dr mg e[0.210 0820 [ 209 -Telinerwi 07) Na Sem0i8sx1 21 day Drinking WarSu ICR |mgPRON | 2264 Thus ALT (7%) EPANOARL EF Bolan Water Study - ICR meme 2763. TBC, Tpnma ST.rey male mice xem 0mBe0t.ea2d6i1 |71eoppcisirfntocseoydoicp]sewworoopclrokrxicippsohnrion.olc|snmrpmoooinro,npnmiumngi |||hNLpia0Eo()dh4iar9AodmenmTdALoLeOfonTieo)dNern N = 10 0, 2, 10, 50 & 250 mg PFOA!L 0, 0.49, 2.64, 17.63 or 47.21 mg/kg-d >_ 0.49 - ~'rel liver wt (27%) >_ 2.64 - ~'plasma ALT (50%) >_17.63 - ;BWG, ~'plasma AST, enloxged hepatocytes w/acidophilic cytoplasm & presence of eosinophils, + tumor necrosis factor-c~ expression 47.21 - +food & water consumption, ~ interleukin-[~ expression, ]'transforming growth factor-[3 expression NA EPA NOAEL 0.49 mg/kg-d (adm dose) EPA LOAEL based on ~'liver wt NOAEL/LOAE L for ~ ALT 0.49/'2.64 mg/kg-d (adm dose) Son et al 2(108 aci EPA 2016a Do Domne dionpp ny Ds nA AS ky Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 37 of 92 22447755..00003377 stateorsssnio STATE_07438040 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Netirmapce N/sex/group, etc. omCosi Suds [0.55720 posi fodcommie. NA 28 day Gavagc Study Nike Spon bea char b kosd,| EPANOAEL Male SpragueDm rae Tcl nde be.eg Dawley rats We 20SSCr e il Foamoinlnadoioglni.rnssoreti poskohneiec,eot r pancrtbpaosclin isistegmmoptsihvoooafo edntlnbree&s.ssfc||||| poSE cEavsPordAeLyoe iOniAEsL lOi rp Admin Dose (m~k~d) [ave serHnl concert]# 0, 5 or 20 Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODH~D UF2 (mg/k~/d)~ [sernnl conCell]# >_ 5 - h?ypoactivi|y, ~b food consumption, cachexia, & lethargy by 3rd week of study; '~ visceral index (i.e., hepatic, renal, gonad wt/BW) used to evaluate hyperplasia, swelling, or atrophy; hepatic hypertrophy, fatty degeneration, & acidophilic lesions as well as angiectasis (gross dilation) & congestion in the hepatic sinusoid or central vein; pulmonmy congestion & focal or diffuse thickened epithelial walls. 20 - scnsitiviD- to external stimuli; turbidness & swelling in the epithelium of the proximal convoluted tubule NA EPA NOAEL 5 mg/kg-d (adm dose) EPA LOAEL based on q" visceral indices & liver & pulmona~ lesions dyGases [0.051005|203 Ti omiroe sops os ne| 03 med 29 day Garage Studyter nin mid hel aod - Male CD-1 mice ni Met sl bitin 8 | A NOALL 2O/g~p Linc pron BOaS3 70 I,inear PFOA nd ahSRBC SIT vert el 10 8 | mgd aam I~iected with SRBC ian SER 103 8 ey| do) on day 24 Sb dion 9 E6b5,050n7 m s8w$s55w0l 8 (106,|haEdPoATnONsELl Study duration 29 bs 2110eSsS T[ mTprhodBomsoWmHatasl.sr nesiG0n(l.D1odv19eelB(ml2i lias5Le0c5ocmmahd0i0oog 2mucilung(8cwhmsst061scp,saeo05neG4)ri1dn00om9)srs1,2soin80(:ioom01hd2cn5o0eOs94pod|a e39eis&0s8dn,.l|||| i|pWcclelhepnsrcotioshs,nsewe days 0, 0.3, 1, 10, or 30 > 0.3 - Tincidence of microscopic lesion in the liver including mild hepatocellular h?q~ertrophy; T absol (25, 84*, 240*, & 230*%, p<0.05) & tel (33, 179*, 292*, 317*%) livcr wt; ; absol (1, 11, 44*, & 56*%) & rel (3, 14", 35*, & 45*%) spleen & absol (10, 2, 50*, & 50*%) & rel (10, 6, 66*, & 39*%) thymus wts. > 1 - ,~ HDL (29*, 39*, & 56*%); moderate-tosevere hypertrophy & individual cell necrosis (11/20, 20/20, 19/20 vs. 0/19 in controls); liver focal necrosis (3/20, 4/20, 7/19 vs. 0/19 in controls) > 10 - ,[BW; ~neutrophils and monocs~es & ; eosinophils; ~'serum corticosterone; ~ total serum cholesterol (TC) (31" & 49*%) & triglycerides (53* & 68*%), + hcpatoecllular mitotic figures, fatty changes, & bile duct hyperplasia; ;spleen & thymus cell counts, minimal-to-severe lymphoid depletion/atrophy of the thymus, 0.3 mg/kg-d (adm dose) EPA NOAEL 1 mg,&g-d (adm dose) EPA LOAEL based on " absol & rel liver wt, w/moderate- severe hypertrophy w/single cell & focal necrosis, 4,rel spleen wt Dr Duce for ew ad dso pos ls. Ddos c consi Asay Draft Document - for review a~Kl discussion purposes only. Draft document does not constitute Agency Comte|eerence Candidate RI | (mc bins ~ RfD mee| nSvmeknt) mg/kg-d Reference (note limitations in comment filed) C amies Cui ct al 2009 aci EPA 2016a poly omcprpFn mmnodmO0RiimoiaTeeroohetavwienrSmedwSic rmrmrdihidriisdnecosaetrhekrrsdeuotrnrss policy (Loveless 2008) and aci EPA 2016a RE: serum - - see Tan et al 2013 stu@ under Other Studies below which examined whetlTer dtetaqv fat content is an important variable. Only 1 dose level O mg/kg-d) was used. Study indicated that PFOA intensified damage to liver tissues when PFOA - 38 of 92 22447755..00003388 stateorssanes STATE_07438041 Std Docipion | Adm Die | Ei) Obra achHED snl | Suh POD| UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman SP rcNT$ooerttv1:sioSni3meeo ospogrTtg1arda5oeoordsfCdtceOErTsR2r8ct Ae.T4ln sH2nbpareo0mnroce1t cnasvtic)od,noDfosssiceefdreeretSedR(sC!CBOneOCRRYeaT) raawinehttncryidoeerr N/sex/group, etc. Admin Dose (m~k~d) [ave serHnl concen]# Effect(s) Observed at each HED dose level and earliest time point obse~wed Study PODdeD (m~k~/d)~ i UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) [serunl concert]# ,HgM titcrs; ]'scram corticosteronc (CORT) levels Note: negative correIaiion btwn serum CORT & I,~ was found Au&o~w hypothesized that portion of thymic response was" due lo physiological stress. However, De Wi~t et al 2009 investigated this hypothesis (see p<ges 3118 to 3-119 ofkT>A 2016a) & found that stress-related CORTproduction did not hm,e a mqior impact on IgM response to the SRBC inocuiation. given m the presence of a high f!~t diet TaCres TREE 0 | Tega oh Tardoew 29 day Garage Study pm 0 adiper | de) dwn - Male CD rats ai G68161 70 Eon. | EPANOAEL Er 20/grp Lew rior HDL 1 2 1 len, Linear PFOA Ammer dos HDL learG5 21026 8 3%), | 10mehsd Animals received dose RBC mda Shenton (3530 8 30), | (amd) of SRBC on day 23 0, (I.3, 1, 10, or 30 Study drnion 9 finane ord bps hAaLdON Study duration 29 bs 130-0mRTodTieHrrWnoeBoNnpGnoh&eebmmopr&rioegyi&: || nIMTnaeeemrdt11 day's >0.3 - T absol (9, 30*, 63*, & 42*%, *p<0.05) & tel (10, 35, 83*, or 91*%, p<0.05) liver wt; .~total (36*, 31", 19, & 16%) & nonHDL (43*, 38*, 15, & 13%) cholesterol, HDL cholesterol (25*, 21", 25*, & 21%), & triglycerides (31", 25, 32*, & 34*%); lninilmnn to mild hepatocelkdar hypertrophy >_10 - ~BW/BWG, hcmatocrit & hcmoglobh~; moderate hepatocellular hypertrophy & focal necrosis; 30 - ]" reticnlocutes & hematopoiesis 1 mgNg-d (adm dose) EPA NOAEL 10 mgNg-d (adm dose) EPA LOAEL based on ~'absol & tel liver wt & histological changes (Loveless 2008) and aci EPA 2016a No drs olshe & occll. No differences in total spleen & thymoc?le cell opm is ro camofe hms. & organ wts, microscopic exam of thymus, mh dcrppc oh mesenteric lymph nodes or poplutcal lymph EO SN the en 1 cont nodes, or IgM titers bem~een trt & control Toe Dan 000506% 191 | ST Gag~Trlinerst aw(15k15 | S337 Sgt|3 [100004|Goris300) 13 week Dietary SukMGR [ot [Ry wie [GA for [ash Study - Male ChRCh Do Dont redPn}hi epCsoo nipxppan onruati sD bes3e | NOt NLCAoOAnEAL |AS0) k|cpyomeprse|ie CD Rats 0, 0.06, 0.64, 1.94 or 6.5 >_31.6 ug/mL - T rel liver wt @wk 4 (13, 45, & 70%) & 13 (4.5, 19, & 56%) w/hepatocellular hypertrophy; "~ hepatic pahnitoyl CoA oxidase activig~ @ wk 4 3.=/.~ 1 ~6 ug/mL Author NOAEL/LOAEL 30 (3A, 10H) i~ [0.000015] I MDH, .for i compariso i npurposes Draft Document - for review a~Kl discussion purposes tufty. Draft document does not constitute Agency policy (Perkins 2004) and aci EPA 2016a PFOA - 39 of 92 22447755..00003399 stateoressosz STATE_07438042 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Nethrmpe N/sex/group, etc. TINO | Mma | 75% 90 563% p08vss | NORELAOAE Noi: be4 0, 1, 10,30 or 100 pr(1555) | rn Sol 500 pfcomn,d?| ce fo amc ppm (45-55/group) oom p(TIrGRe | I LAieT re a PpE ee pr ti 2 control grps plowdpdi | inl 765sin."hacpln] Co ovis ain ps nonpak-fed and pairI iy aT Beh OTRO | 316 fed Ripoca iri | meatatc | Bow RITE 19) mitt | EPANOARL 15/grp sac @ 4, 7 & orn vgn |wach {ih copra 13 wk of trt. 10/grp ia Bisa | 0 ion. er Sr sac @ 13 wks & 8-wk oes ped | Lat, 8356000| 40S gm {BW SB1C| EPALONEL recove~T period Sly duion0 | meLa To4k3)| toegncdooltcmonnpe[edB)Goodil ||b1 lcrstb Study duration 90 ans CrWFASobnnrroclaangenaiieAobiLsdoCns| | | Soweomwlr 4taShviiamonmeb|sp8s3ioo(winscmtFosvwand ||| WpcSs iaomehowmesnowaptslsoye||)3OE0hA, | 0E0n0013 days Admin Dose (m~k~d) [avc serufll concen]# Measured fina! concentrations." 7.1, 41, 70, 138 ug/m L Predicted AUC ug/mL*h 7230, 69100, 168000, & 326000 mg/L-h (EPA 2016a Table 4-3) Average serum concentration = predicted AUC ug/mL-hr/(90 d x 24 hr/d) 3.3 ug/mL Effect(s) Observed at each HED dose level and earliest time point obse~wed (75", 200* & 363*#%, *p<0.05 vs ad lib controls, #p<0.05 pair-fed controls), @wk7 (128,3~=7*, 671 ,#o+~), & @13 wk (25, 75#, & 113*#%) 76.9 ug/mL - + hepatic pahnitoyl CoA oxidase activity @ wk 7 through 13 (357 & 671% @ wk7, 75 & 113% @ wk 13); mild to slight coagulativc nccrosis in livcr (control to hi dose: 0/45, 1/45, 0/45, 2/45, & 3/44) 149.3 ug/mL - ,~ BW (~8%)/BWG (M4-17%) vs nonpair fed controls [BWG was still 4,at end of recover, period); + food consumption in wk 1 & 2 (M8%, w/~5% ave over 13 wks); indication of elevated estradiol ~ wk 4 (veD- few animals asscsscd) Study PODdeD (m~kdd)+ [seruul COlqCen]~ i Candidate ~ RfD mg/kg-d Reference (note limitations in comment filed) [NOAEL/LOAE LI~D 0. 00045/0. 0044 mg/kg-d] 31.6 EPA NOAEL Nole: Table 4 very few animals assessed for eslradol levels" at many time points' 76.9 ug!mL EPA LOAEL based on ~" absol & tel liver wt w!hepatocellulox hypertrophy accomp~xfied by slight (not stats signif) ]" heptatic coagulativc 30 (3A, 10H) EPA i 0.00015 i EPA 31.6 76.9 is orELLONE 149.3 necrosis [NOAELiLOAE dyGv Sid [0.3.10 30a 00|25-Gle res. rc ydox |iNbA4DnI 90 day Gavage Study Rh monks lod end hl phosphaselevdls | mgd a - Rhesus monkey. PONDS rata abtmrstmt =) PFOA in 0.5% Nikos? oak epics hes (0 ErANOARL Methocel7 for 7 d/wk Tic 10 mt mm SOP tb (N = 2/scx/group) Nose yw Chins bel ers (nr wo Note: very small er finals xpi monilogichges | WAL an number ofanimals Sob dortase 230momdernr e nsoe rss a"nlys BcYhm.gecin |E|PAL$0) Study duration 90 : hrc. RBC, o days 0, 3, 10, 30 or 100 >_ 3- GI upset (dia~hea, frothy emesis); doserelated trend ~ alkaline phosphatase levels; ~' pituitaxy wt but not accompanied by morphological changes (M) 10- 1 anorexic animal; ~" SGPT; 4, absol heart & brain wts & 4, rel liver wt (F) but not accompanied by morphological chm~ges >_ 30 - "~ mortality* (3 animals); ~, BW; moderate to severe ,~activ@~; changes in hematological values (e.g., ~, RBC, [tb, 0.0044/0.0108 mg/kg-d] NA (M)/3 (F) mg/kg-d (adm dose) EPA NOAEL 3 (M)/10 (F) lng/kg-d (adnl dose) EPA LOAEL based on Dr Duce for ewad dso pos al. Doc dos consi AS poy Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy God 7% Goldenthal 1978 (epbisied (unpublished So study) PFOA - 40 of 92 22447755..00004800 stateoreseoss STATE_07438043 A Study Description me a duration, route/ E E TR oEl[a EEF vehicle, species/ Admin Dose (m~k~d) [ave seruul strain, age at dosing, concen]# N/sex/group, etc. -------------- Effect(s) Observed at each HED dose level |e i J lf and earliest time point obse~wed Study PODdeD (m~k~/d)~ UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comment filed) ST mJeEr Hct, J" prothrombm time); ~, SGOT; ~" | En cholesterol, total protein & albumin; slight SIE dp van Tr to moderate hypocellularity ofbone E aae marrow; moderate atrophy of lymphoid pituitao, wt (M) & heart & brah~ follicles in the spleen 100 - 100% mortality* between wk 2-5, with clinical signs beginnhlg in wk 1 SRT *all animals that died had marked diffuse lipid pedepletion in the adrenal glands --E-- To -- 26 Week Oral Capsule EC Ee| Tate|| Study - Male BENE on |SET FOry on|SRE Cynomolgus Monkeys nr TIE| oe| [ 6/group, except 3 EE rian | EBERT | ath| mg/kg-d had 4/group ree (taepeosns| EE Lrey || ESae|| |[ie Study duration 26 pImmi i oFa eoeSrrnE,eL||||| [ S f W W B nHSLiEMr rh r S EE gOEo ai rRhe a n Gn t]res| EMen |(BBD, weeks (182 days) 0, 3, 10 or 30/20 >_ 87.0 ug/mL - ]" absolute & relative liver (dose was ~, from weight (20, 27, 60*%, *p<0.01); evidence 30 to 20 at day 22) of mitochondrial proliferation in livers; 1 death (cause undetermined); ]" triglycerides Measured steady (@wk5 - 16, 73*, & 145*%; wkl0 - 37, slate serum 77*, & 56%; wkl4 41,120", & 148%; concen (BuWnhoff wk27 - 16, 64, & 109*%) *p<_0.05); ,~ tT4 2004b):81~40, 9950, & 156i 03 ug/mL Autho~ state that steaa)~-xtate appears to hm,e been attend u+~ ~4-6 wks oJ dosing. ((@wk5 - 15, 37.5*, & 22%; wkl0 - 24, 35*, & 30*%; wkl4 - 16, 31", & 11%; wk27 33*, 29*, & 32*%), ~- fT4 ((@wk5 -8, 32*, & 23*%; wkl0 - 9, 27*, & 27%; wkl4 - 11, 29, & 10%; wk27 - 33, 38*, & 42*%); tT3 & IT3 was also 4,but dose response was not consistent. 162.5 ug/mL - J" mortality (only 2 tolerated dose for duration of treatment) dose was Predicted AUC ug/mL*h 380000, 553000, decreased to 20 mg/kg-d after 12days; ,~ BW; marked to moderate ~'serum enzyme concentrations (e.g., ALT); && 771100000000mmge/Lh-h | s3y~,I #v-to-brraaiinnwwttrraottiooBBMMDDLL-..... 33..99mmgg/~'gR-edd (EPA a4-d3) 2016a Table |ATSD(cRor(redsopfon2d0i1n5g)se[raubmsolcovneer. w2t3 ug/mL) A TSDR (draft 2015) ~[ absol liver wt B~DB~VIDL m 22. 01/!5.53 ug/mL NA EPA NOAEL 87.0 ug/mL EPA LOAEL based on Tabsol & rel liver wt (hepatocellular hypertrophy) [LOAEL HED ~0.012 mg/kg- ~ comt)ariso [ n pmT)oses i LOAkZ i HED i based i0.000041 [ IfBa4DL [based i o.oooo7 Era Draft Document - for review a~ discussion purposes tufty. Draft document does not constitute Agency policy Thomford 2(!01; (Butenhoff 2002) and act EPA 20126a PFOA - 41 of 92 -- 2475.0041 --_-- STATE_07438044 StdDocipion | Adm Die | Ei) Obachr HEDsa nl | Suh POD | UF Comte|eerence Study Description Gurnionroe | |andcat i pn held (mwa RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman rN mVBiaoaeduRswae nlAUeC| |||1RnIM4dnOaisHEmWmemtEBrri5DidDnksemgms5sisAIwB5ADnLiDlUeEeSBRtB BuMDeeDnD,.. 4 otc2v5e54s3W.s d87 21sD9ow3)s3 N/sex/group, etc. Admin Dose (m~kF_Jd) [ave serHlll concen]# Effect(s) Observed at each HED dose level and earliest time point observed Study PODHI~D (m~k~/d)~ Avcragc serum concentration predicted AUC ug/mL-hr/(182 d x 24 hr/d) 87.0 ug/mL 126.6 162.5 (HED=O. 00154 mgJkg-d)," Trel liver wt B,~ID/BMDLlo 53. 04,76.31 ug/mL MDH BMD modeling: Absol liv wt BMDLd3MD~o 24. U33.2 ug/mL Rel liver wt BMDL /B3/ID~o questionable modeBng results 38. 8~4. 7 ug/mL ([owest AIC) & 29.3/39. 2 ug~mL (h)west B~DL) 7?iglycerides B3JDL/BMDzsr) 29.3/45. 9 ug/mL .~4 all models unusable i UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comlnent filed) Tr DySek WFO TTT odo ACT WaT| TST) Se 2 year DietmT Study Groth [acts2ian 2821c7otsils p00). | mph adn 197 poled Crl:CDBR Rats Stevie mest SAoSmTEp A06& TAiLmFo(n6 AR4i20ncns|| EPAdNoOA)EL. Ftliatny 50/sex/dose Dianthes 0.300 | Adal STE corlo nT Bante DietaD" levels 0, 30 or stopp SrTiampiprss|||14miS2oBuI oomSpE cT1monap6nedi)anodonciib a)onRo.pmcndmcandogtobamysompolaE nen(o)Gnsa0bgr)U).o,tp e:F1o mesat1gcTc2oJTc8nec3os(epnIturoee m(nNNoinnMsw3cscnci3GacHste01ehn8oe,ol o nvhoc7n&ennraaseogti4Sls1alo,a8ihmh6vinra e3c5nb5ie%2h1snnrLess%n:|||||||||||mb1Nnm1mOoNEa4pU3OiAeP2hngPs1sTphWA1p)6Lar6NLade1Gr1dOOy ieeD)yNrDA(aoavUoUETdUEFE.mmLnsGF)L)) 300 ppm M/F 0/0, 1.3/1.6, or 14.2/16.1 mg/kg-d Add'l grp of 15/sex for 0 & 300ppm evaluated @ lyr interiln sac >1.3/1.6 (adm dose) - TALT(e.g., M @12 mons 132" & 217*% vs control levels, *p<0.05), AST (e.g., M @ 12 mons 57* & 68*% vs control levels) & ALP (e.g., M @ 12 mons 21 & 57*% vs control levels) from 3 to 18 months, but only at 24 mons in high dose grp (M); testicular vascular mineralization (6 & 18*% vs 0% in controls) 14.2/16.1 (adm dose) - +BW/BWG, slight ,~ in food consumption, ]`survival rate (likely due to lower BW); ]'incidence liver lesions: cystoid degeneration (M - 14 or 56*% vs 8% in controls); hepatocellular hypertrophy (M/F: 12/2 or 80*/16*% vs 0% in controls); lnononuclear cell infiltrate (M-64 & 96*% vs 74% in controls); Tincidcnce lung lesions: alveolar macrophages (M: 32 & 62*% vs 20% in controls), hemorrhage (M: 28 & 44*% vs 20% in controls); ]'incidence ovarian lesions: tubular h~perplasia (l 4* & 32*% vs 0% in controls); ]'incidence testicular 1.3/1.6 (M/F) lng/kg-d (adm dose) EPA NOAEL 14.2/16.1 (M/F) mg/kg-d (adm dose) EPA LOAEL based on ,,BWG (M/F), lesions in liver, testes, & lungs (M) NA!1.6 (M/F) mg/kg-d (adm dose) MDH NOAEL 1.3/16.1 (M/F) mg/kg-d (adm dose) MDH LOAEL Dr Dum or ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~Kl discussion purposes o~fly. Draft document does not constitute Agency policy Sibinski et al 1987 published as (Butonhoff 2012) and aci EPA 2016a PFOA - 42 of 92 2247755..00000422 sateorssenes STATE_07438045 Std Docipion | Adm Die | Ei) Obra achHED snl | Suh POD| UF Study Description Gurnion roe | | and cat i pn held (mwa duration, route/ Sides | [neon vehicle, species/ Sirius,| ncn rn coc" strain, age at dosing, Neiman emicsmsl,mlnio6n 15% N/sex/group, etc. Admin Dose (m~k~d) [ave serHfll concen]# Effect(s) Observed at each HED dose level and earliest time point observed Study PODdeD UF2 (mg/k~/d)~ [seFtlnl COlleen]# lesions: vasculax mineralization (6 & 18*% vs 0% in controls). Neoplos fings Neoplaslicfindings: Ns er epoca conn 2.8 Males: liver hepatocellular carcinoma 2 & Tks tmsom: Lev 10% vs 6% in controls; Leydig cell me 8 Te noe adenomas 4 & 14*% vs 0% in controls Tevamids revi [4% was indicated to be within notcos cons & EPS historical controls' by authors & EPA 50] TroCoolsma 2016]; Thyroid C-cell adenoma 4 & Foon cones 9% vs 0% in controls Fone many god sds82 Females: mamma~- gland fibroadenoma 42 Ns Thomsofnl & 48*% vs 22% in controls [all trabtew a mfr considered to be within the norm for Eyre Aecvatin background varialion. Re-evaluation Jo satssi iennfor found no statis s~gnifd~ference for a .fibroadenoma, adenocarcinoma, total Repressor otmast benign neoplasms, or total malignant pio neoplasm~J [Ncoptac Anding ae ccd furtherin [Neoplastic findings are discussed further in ae oto Table 7-A below] Trick Ow empha|T56 H, TnTTrw wr 2 yr Mechanistic ny GHD| rm ic vision svislices | NOAEL dietary study - Crl:CD BRN Ra | comsenteren3| we TacsLv ce peta BR Male Rats pre) monapiod] | (Hemming Tre | 16 mghed (156/grp) ionaposs | moh nachomawnn | (amine) (follow-up to study Shove) SonesNo sgt ais nem LOARL above) BerSoopem SeoCnrtSn mroencpnc cib1,51S461r83F1S68a9w12s2 0 or 300 ppm 0 or 13.6 mg/kg-d Interim sac conducted evew 3 months up to 21 lnonths 13.6 (adm dose) - +BW, ]rel liver wts & hepatic [~-oxidation activity; ~absol testes wts. ]'incidence Leydig cell hyperplasia (46% vs 14% in controls); }pancreatic acinar cell hyperplasia (39% vs 18% in controls). No signif difference in sen~m testosterone or prolactin. Scram FSH was signif ~@6 mouths & LH @ 6 & 18 months. Serum estradiol ~'@1,3,6,9,& 12 months. NA NOAEL 13.6 mg/kg-d (adm dose) LOAEL CoRmIte|| (emercebnciens i Candidate ~ RfD mee| nSvmeknt) mg/kg-d Reference (note limitations in comment filed) TeEwrremeor Biegel et al 2001 aci EPA 2016a Neoplastic findings : Do Domne dionpp ui Ds nA AS ky Draft Document - for review a~ discussion purposes only. Draft documem does not constitute Agency policy PFOA - 43 of 92 2247755..00008433 stateorsssoss STATE_07438046 Std Docipion | Adm Die | Ei) Obra achHED snl | Suh POD| UF Comte|eerence Study Description Gurnion roe | | and cat i pn held (mwa i RI | (mc bins duration, route/ Sides | [neon mee| nSvmeknt) vehicle, species/ Admin Dose (m~kF_Jd) [ave serHul Effect(s) Observed at each HED dose level and earliest time point observed Study PODHED (m~kR/d)~ UF2 Candidate Reference ~ RfD (note limitations mg/kg-d in comlnent filed) Sirius,| ncn rn coc" strain, age at dosing, concen]# Neiman N/sex/group, etc. inroads) Liver adcnomas 3% (ad libitum controls), 2 par cal 15% 1% (pair-fed controls) & 13% Lodi demon 1 nt ils Leydig cell adenomas - 11% in trt anilnals Smtbpd come compared to 3% in pair-fed controls & ma bmcrt 0% in ad libitum controls. Comments: o Se r Com s rl89 SFO See rn Son + Serum concentrations --Sermn concentration value are superior to external dose as a POD. Several studies measured serum concentrations at specific tflnc pot EPA PR koic ALC dtm i ge <1 cn od 1. oc eh points. EPA pcrlbrmcd PK modeling to calculate AUCs to dctcmfinc an avcragc scram concentration for cach data set. Average serum conccntmtion has the ee of migos htt vp oi Se AT oT)ot Bs Ah dg a hd advantage of normalizing across the different exposure durations to gcnemm a uniform metric Ibr internal dose in situations where the dosi~g durations varied encwa en ch p10 He.Se careds PABof 5 pts EFAToles 1 and serum measurements were "taken immediately prior to sacrifice, Serum concentration dam listed are from publication or as reported in EPA Tables 4-3 onan ORE through 4-8 (USEPA 2016a) ED man ieDos celeb iin he ngsr conctntion (51)by cae te Clconba scelr eb e ~ HED (Human Equivalem Dose) is calculated by multiplying the average serum concentration (ug/L) by the clearance rate. Clearance can be calctflated from rise cn Get omn NAnh vofSint VON 130.17 LAB (109 $540 ONLASPl rate of elimination (derived from half-life) and the volume of distribution: Vd x (ln 2 + t~i) - 0.17 L!kgbw x (0.693 + 839.5 days) - 0.00014 L!kg bwiday. peas nate ba Soon Gooed 53 : Interspecies (animal to hunmn) extrapolation denoted as A Is ay LRSai a ppaocinngsBe ge)dened 1 Intraspecies variability &afiabili~" within human subpoptflafions - including life stages) denoted as H Des wn rend8 Database uncertain~ factor denoted as DB LONNONEL cuppindermoLdiaos LOAEL to NOAEL extrapolation denoted as L-to-N ShSpindd S400 Subrolfic-to-chrordc extrapolation denoted as S-to-C Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~ discussion purposes o~fly. Draft document does not constitute Agency policy PFOA - 44 of 92 2247755..00008444 stateoreseoss STATE_07438047 cs me Table 6-A2. RfD Derivation mm Critical study (source, date, rationale for the selection) E EyE ie In this expedited review NIDH has focused on key studies identified by EPA in the Dose Response Assessment of the Health Effects document (EPA 2016a) and has utilized the predicted average serum concentration as the preferred dose metric. EPA selected Lan et al 2006 as their critical study (EPA 2016a). S i oe e BMD/BMDL values have been generated by authors of some of the key studies, lit should be noted that a le best practices have changed over time and substantial improvements have been made to the BMD software BMD modeling. Therefore, BMD modeling was also conducted by MDH when possible (e.g., I N E e data needed was available) and when appropriate (e.g., sufficient number of dose groups). Note: BMD E modeling results were not reported (or utilized) in EPA's 2016 final document. Rationale for not using TET BMD modeling (the preferred approach) was not provided. A summa1T of key studies (e.g., Table 4-8 w/ additional studies selected by MDH) along with estimated average serum concentrations @the NOAEL/LOAEL or BMD/BMDL arc presented below fw -- Study (duration) Effects Average Serum Concentration (ug/mL) DeWitt et a12008 - Mice hmnune toxicity r Eese m e Perkins et a12004 - M Rats Subchronic study RSEw Fi EGn| EL Lau et al 2006 - F Mice ,bIgM response to SRBC [>45% ?rel liverwt additional hepatic butno (ISS~SS~d] e ~'liver wt wihypertroplV q'liver wt & necrosis delayed ossification NOAEL/LOAEL 38.2/61.9 [~/20.2] 3.0131.6 31.6/77.4 NA/38 BMDL/BMD"'~ Authors BMR~sr) 34/53~' EosEes Authors B3/IRo_s Developmental accelerated puberty 33/4U pup BW ~'maternal liver wt [but no addaional hepa#c tunable to ntodel accel puberly inverse Wolf et a12007 F Mice Developmental GD 1-17 Macon et a12011 - F Mice Ee Developmenlal GDI-17 Butenhoff et al 2002 Monkeys EL Fe 26 wk stud}' endpts assessedj~ +pup BW 4/mammaD~ gland development q" absol liver wt ~1" rel liver wt a NA/77.9 NA/12.4 (q~mlilalive scorn) NA/87 A a 7'SI)R (drcgt) BMR~o 15.53/22. Ol ~triglycerides 24.1/33.2 (abso0 DDrarfatftDDooccuummeennet --ffoorrrreevviieewwaan~dddiissccuussssiioonnppuurrppoosseessoonnyly.. DDrraaftddooccuummeennttddoocessnntotccoonnstistuete AAggeeanccyyppoobleicyy PFOA - 45 of 92 -- 2475.0045 . ---- STATE_07438048 NOM ced vr sermon ope oth ENDLadi dosby win "~ MDH estinmted average serum concentration that corresponded to the BMD/131VIDL adnfinistered doses by using np boc ne rn oman rd LOREsichdo Ss lhe relationship between the average scram conccnlration and the LOAEL administered dose. See relevant td iin AdindooSr talSl worksheet witNn ...A....d...n-~.i.~L..d-9..~..c.`..L~....~-e..r...u.AL..E.:.%!~#..~..~-~..~t~Lc.`..a....d..~-~.ke...eJ.; NIDA makinmon ono es BSAACONN ibs Wiss u MDH BNID/13MDL modeling reports can be found at )!~......a..t.iL3..~5-e..1.).`.~:~-..R.....A-~\..C.....~...1}.`...~.....~...~.....N..):-G..1~.i...d~a.~..:..~A~.~L\~ aso Fa POAEID dln reviews-complctcd~Final\Pl::OA\BMD Modeling. n icsS erecpoins n he20 do le C11 ose Seu ~ Loveless et al 2008 did assess additional hepatic endpoints inthe 29 day male CD-I mouse study. Serum coro wr gota nd et og A gk ns rt concemratimts were not reported. Increased relative liver wt along with Nstological changes (e.g., necrosis) were pod tani doo EAL hm sd LONEL DEE 5 0 04 RE reported at admin dose of I mgikg-d, which is similar to the admin dose LOAEL in DeWitt et al 2008 (0.94 mg/kgimate mores d) and Lau et al 2006 (1 mg!kg-d). (Coect)tndadns Auth LDT (1mk veserum conctration 3 gn) Lat 1 008 pred rsd 49%) Critical effect(s) and dose: (LONELL</BMD). ps{rSmCTS0leuoehp0ebpipo7morpnq7supeeusgdltnmdmosrosnnvrteciciws)tlmloeaatiogspnnfpoghrmoeietonltrcmtfnanasopPdlolPmasSans.l.iTeaorunntfhlr,dfeidsabsens Btdg,nrt.EIdGshPDolaeeryLt(rninIccc oafIoanhdowMhooSdicfiLtIhedpueiDliepc.rwo ]aBea1dna5V4.d1dP0d7rm(cPsdodooageSveuh rtt parS1hsossrai4h uas)nhpldstdbrTampanwoodoiincdneLsrshgvcoadaeentolci)ms(Oos,enrnta.odf (LOAELr~:~iBMD~ar~r_~) At the LDT (1 mgikg-d, ~ave serum concentration 38 ugimL) Lau et al 2006 reported increased (> 49%) maternal liver weights and in offspring, delayed ossification in proximal phalanges and calvaria (but dose-response was not consistent), trend for decreased pup BW (dose group statis signifat >_ 3 mgikg-d (or 77.8 ug/mL); authors calculated BMDL/BMD05 of 0.86/1.07 mg/kg-d adm dose), and accelerated preputial separation in males. The later observation (accelerated PPS) is surprising for two reasons - 1) all other developmental parameters are consistent with delayed development and 2) inverse doseresponse (greatest effect is obselwed at the lowest dose level and decreases with increasing dose). Subsequent developmental studies by EPA (in which Lau was a co-author) did not report evaluation of male pups for tinting of PPS, therefore, there are no studies in mice which can be used to verif~v or contradict this effect. Nsconctsand fervcstigtoFros is ss ese sorry be epondowe alive Macon et al and other investigators from this same research laboratory have reported lower qualitative Sorodee nrg evlopen 03 gg dda (1 40) WAR ons scores for delwed mammaW gland development at 0.3 mg/kg-d adm dose (12.4 ug/mL) which is lower {han h ccd POD (1 mgd dm i ic. 3 agin. cr) However, lations ung rs than thc sclcctcd POD (1 mg/kg-d adm in micc, 38 ug/mL in scram). However, cvaluations using more Qn easof meaasr ld deep hve clpred gn ts a hher quantitative measures of mammaD, gland development have only reported significant effects at higher hills Indien, acon chlkngs wad conducted by Wht 1 2011 did ot diy dose levels. In addition, lactational challenge study conducted by V~,~hitc ct al 2011 did not idcnti~ uncios mpcn Thro, scant wla be 5 bs ct functional impairment. Therefore, this endpoint will not be used as a critical effect. Poof Departure EP's priced ves su concern theLDTLOAEL (1 hws cls 38 Point ofDeparture (NOAELL LONEecL gmt terme) (NOAEL~mD, LOAELH~D, BLL) BMDLm~:r)) EPA's predicted average serum concentration at the LDT LOAEL (1 mgikg-d) was calculated to be 38 ug/mL (or mg/L) Homan Equine Dose The llowingcaution sd cust sn HED foe thPODscrconcent Human Equivalent Dose "Adnan OHhEeDee(Votom DPOig D.na )Cl) maens IE) 017 LAG 04530395.) 001 Lig Adjustrnent: The following equation is used to calculate an HED from the POD semln concentration2: HED 0ngikg-d) = POD~,,............... x Clearance. Where Clearance = Vol of Distribution (Likg) x (Ln2ihmnan hall-life) = 0.17 Likg x (0.693/839.5 d) = 0.00014 L/kg-d HED = 38 mgx 0.001 Lid 00053most HED = 38 mg/L x 0.00014 L/kg-d = 0.0053 mg/kg-d Dr Dum for ew ad dso poss i. Ddos c cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 46 of 92 2247755..00008468 stateorsssnio STATE_07438049 Unccsiny Vaabl Foos. ExnIVrnaocginiensn: 310 So NGiOoNoaEaaL 3 Domuebruc 3 Uncertainty/Variability Factors: Interspecies 3 Extrapolation: lntraspecies 10 Variability: LOAEL-to- 3 NOAEL: Subchronic-to- chronic: Database: 3 Other: Tol 300 Total1: 300 UVFComments:BIocCSTnhiwieosoanfsdsrTmaeoecUnFodcnolefeptphostse2lnoLsiOfco nNcEILorsnfna otooLstcDmtFaiTLiedt dODRAd:sSih.fif4s sVho0ecmsamcUehrceFnloonheW31tibtw1rhasu0hwee1oc3xno,fncchhmoopihnmectsswi1pci3r.fosD0ioc8BmnndUiiPFooleF]nStRAd3oDDcfBhorUtFh UF/VF Comments: Interspecies UF of 3 applied to address TD differences, in the absence of chemical information to the contra~, the default value of 10 for Intraspecies Variability. With the exception accelerated PPS the effects obse~azed at the ILOAEL were mild. An L-to-N UF of 3 was used, along with a DB UF of 3 for the lack of an acceptable 2 generation study. [Note: the serum concentration corresponding to the RiD below is -l O0-fold lower than the LDT LOAElJ f!~om Macon et a! (0.13 ug/mL w~ 12. 4 ug/mL/. A DB UF for immunotoxicity concerns was not added at this time.~ NDI RID: 00053300-0000018mgd corrodingserum concentration $330 4.13 MDH RfD: 0.0053/300 = 0.000018 mg/kg-d [corresponding serum concentration 38/300 = 0.13 ug/mL] Commas Comments: To UFfrderivaoftaiHoLn o HNRID i 3000 RANckbe < 00.01.) Total UF for derivation ofa HRL or HBV Raft) is _< 3000 (RAA could be _< 3000 or > 3000) USEPA 16iim HohdnEonUSEPA 01 z US EPA 2016 Lifetime Health Advisory Evaluation (USEPA 2016d): TC rd Conon oC i un doseby capin cdsk, hodn cul doe The predicted senun concentrations are converted into an oral equivalent dose by recog~fizing that, at stead)' state, clearance from the body equals the dose to the Sy C(l 1)caece lon ft cide he l om o O GR o AP OLR 100 body. Clearance (CL) can be calculated if the rale of elimination (derived from half-life) and the volume of distribution are both known. Olsen et al. (2007) Cn l ogv o iscv Bret R010 vib 136 nedo nr calculaled truman half-life of 3.8 years in an occupationally exposed cohort. Bartcll et al (2010) determined a value of 2.3 years based on the decline in serum Oi nan er Br op a e I n a he Wokpt igon WA FFAch he levels among members of the generN population exposed via drinking water in the area near the DuPont Works plant in Washin~on, WV. EPA chose to use the half-life from Bartell et al (2010) because it is the most relevant scenario. Thompson et al. (2010) gives a volume of distribution (Vd) of 0.17 Likg body weight i es to ieVo 194LE rm mk Bt 194Th ro oslle 8 is (bw), which is siufilar to the Vd of 0.198 Likg determined for monkeys in Butenhoff et a12004. These two factors (half-life and Vd) are used to determine a CeO LAE i i lowon clearance of 0.00014 Likg bwiday using the following equation: LeVin 2 09-0h1s7b x03 095m 001 Ligbt CL = Vd x (ln 2 + t~i) = 0.17 L/kg bw x (0.693 + 839.5 days) = 0.00014 L/~cg bw/day Wkere: Wire Vd = O. 17 Likg In 2 = 0.693 A ms 23 yn es ams a3 tli~ - 839.5 days (2.3 years x 365 days/year - 839.5 days) lg hdc nccorningr)b NOWEL LOAF AID, or IDL,by co ospic cs 0s Multiplying the derived average serum concentrations (in ~tgimL) tbr the NOAEL, LOAEL, BMD, or BMDL by the clearance value predicts oral HEDs in ERE 0h renin ih men Th HED hs ed an Epos i At rn orion mgikgiday for each corresponding serum measurement. The HED values are the predicted human oral exposures necessary to achieve serum concentrations SieNOVEL or LOAEL te amosksing Home momo 131 h onee arndt equivalem to the NOAEL or LOAEL in the ani~nal toxicity studies using linear human kinetic information. [MDH Note: this is ~ke same equation used in tke SS itn mt HE et Pom sk 97 by SAD wr 403 8 mood 198 19 3 13 MDH 2007 evaluation m estimate HED values. Parameter values used m 2007 ~v A4DH were: [')t (~0.2 L/kg insmad (0.17 L/kg and ha[:~=liji~ of 1387 d~vs (3.8 rn sf d dns] yr.s? instead of839.5 da.vsff Dr Dos or insn cin pes. D ems sms As poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 47 of 92 22447755.0.00477 stateoressoso STATE_07438050 While monois nid baof PdFOA ad PFOS xpos 1s dtrmind by NTP 2016 and in DH's icatiosns 3 While immunotoxicity is an identified hazard of PFOA and PFOS exposure (as determined by NTP, 2016 and in MDH's identification as mn hin3 gbeelfes). he ac of do pos 4nd ck of cleitof oan: i Jes bn cto pons imnmne changes as a co-critical effect), the lack of dose response and lack of clear indication of immune system deficits in functional responses to ohogencclus cca gly c\posed obo. hampers quanti inclusionofects porn tlc dering3 pathogenic challenges in even highly exposed cohorts, hampers quantitative inclusion ofthese effects reported in epi studies in deriving a Teensdos (RID. MDH icomme 105 ator hssa TASTIS TAR MORNE btbdo Tn valle reference dose (RfD). MDH will continue to closely monitor the scientific literature regarding inrnmnotoxicity, but based on currently available Gs Hcl formehe DB UFfo PFOA his. Ths iy by D20t 0dn, t a NOAEL for mn: data it is difficult to justify further increasing the DB UF for PFOA at this time. The study by DeWitt, 2008 demonstrated a NOAEL for immune hans tthe cul ct LONEL,Rarer porns MDI cio ro3t 105 DB UF Th spdemsloic raspode cst changes at the critical effect LOAEL, further supporting MDH's decision to not add to the DB UF. The epidemiological literature provides a clear Indicuion teaii fPEAS i tong ced with mmucsprssion MDH' cur prac of mp dr vate as indication that the additivity of PFAS is strongly associated with immunosuppression. MDH's current practice of comparing drinking water values eacombanpd nod otfPFeO. PROS. PIS, PEA. ad PES wifiand cons ans oth protctonbei to a composite hazard index of PFOA, PFOS, PFHxS, PFBA, and PFBS is well-justified and confers additional health protection benefits in the Coos mansscmen: context of risk management. CRITICALKEY STUDY SUMMARY CRITICAL/KEY STUDY SUMMARY Criicarswiyo Critical Study(s): Developmental Gavage Study in CD-1 Pregnant Mice (Lau et al 2006 aci USEPA, 2016a) Dues Dekgn: Diciopmanl iit sdof PFOA va conduit vals thsfics of PEON opraand postsdeclopn in Doses & Design: Developmental toxicity study of PFOA was conducted to evaluate the effects of PFOA on prenatal and postnatal development in pringexposeddunn prepare Grogs rng9-15 Ud regal CO-1 mic wre gen. 1... 10,20.30d 10 meh PFOA offspring exposed during pregnancy. Groups averaging 9-45 timed-pregnant CD-1 mice were given 0, 1, 3, 5, 10, 20, and 40 mgikg PFOA Si orl gvon GD 1 17 Das wer ddd 0 0 up daily by oral gavage on GDs 1 17. Dams were divided into two groups. rough dams er sacioinGdD 1andsndrwsot matt nd fs cxaisstiocn.s tercnraweilgh cminsoofdns Group# 1 - danas were sacrificed on GD 18 and underwent maternal and fetal examinations (e.g., maternal liver weight, examination ofthe Ermidtru for mumof ibn o adden nd esoptions) Nil PONsrconnie assed incl in gravid uterus for numbers of live and dead fetuses and resorptions). Maternal PFOA serum concentrations were assessed (levels in the es werocxmined Live tcrsghd nd Si 1 nld 15s peop, nd eaad sera xan fetuses were not exmnined). Live fetuses were weighed and subjected to external gross necropsy and skeletal and visceral examinations. Group 30 atom doeofPFOA was admireodn GD 18.Dams wessllowd giv bithcn GD 19 Ths di following Group#2 - an additional dose of PFOA was administered on GD 18. Dams were allowed to give birth on GD 19. The day following rari vo eked FD)| Ton fron, condoof born, daof m fins gwes sco Th sim parturition was designated as PND 1. Time of parturition, condition of newborns, and number oflivc offspring were recorded The number Tepp inoch Wirap bod gh wer efor Fs 4dys ae thsd hn corpondig emai era Ee of live pups in each litter and pnp body weight were noted for the first 4 days after birth and then at corresponding intervals thereafter. Eye nnn wa end Pegg at PU 1 Pups wer anal PD 5 and parte Gods. Th pos sv ats wi opening was recorded bcginning at PND 12. Pups were weaned on PND 23 and separated by gender. The time to sexual maturity was cine by monnvain opsand props gam begininogn PND 24 To foe pps pr sede per Wr nee determined by monitoring vaginal opening and preputial separation beginning on PND 24. Two to four pups per gender per litter were dont Siteforobrvaoftpootrnal ml onth, a devon Fea Shen watGosia d og randomly sclcctcd for observation of postnatal survival, grmv~h, and development. Estrous cyclici~ was determined daily by vaginal toy Arwen, das ee arlced ad he Cotofhets ved fo PLEO SE. Prt mot at cytology. After weaning, dams were sacrificed and the contents of the uteri examined for implantation sites. Postnatal survival was Cadbd oeamberof platos oehdsom calculated based on the number of implantations for each dam. Ect Mr Siofgtnensd oie wee cbr lenin expose 0 PFOA ding pregnasey Sst sgn: dosed Effects: AIaternal - Signs of maternal toxicity were observed following exposure to PFOA during pregnancy. Statistically significant dose-related {ncn p00) ml nt htns ced4dot cl (4,77 85 1% 135& 159% coped tocol) AIT increases (p < 0.05) in maternal liver weight were observed at all dose levels (49, 77, 89, 118, 132, & 159% compared to controls). !MDH Noes: Hoc camer ot ne do espe1 ec consid], Dos date css rl woghgit Notes: Histological assessment ofthe liver does not appear to have been conducted/. Dose-related decreases in rnaternal weight gain rg gray ers od PSN Eda, wih A GM (1 09) 5 0 3 and amg dose during pregnancy were observed beginmng at 5 mg/kg/day, with statistical significance (p < 0.05) seen in the 20- and 40-1ngNgiday dose Eup. Th maof ptlsateion Sede asComprconl ms SC CN BE 0200) lk groups. The number of ilnplantations in treated lnice was comparable to control mice. Statistically significant increases (p _< 0.05) in fullDr Duco for ewsn dco poss i. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 48 of 92 2247755..00008488 stateoresaust STATE_07438051 Kr sorption wr prca doosf mh hme sof rnc hs dos rayof 4 hs litter resorptions were reported at doses of_> 5 mg/kg/day, with complete loss of pregnancies at the highest dose group of 40 mg/kg/day. SIEh til Sen cs 0 51a emg orer cbn 105d 0 ERE Slight, but statistically significant, increases (p < 0.05) in the average time to parturition were observed at 10 and 20 mgikgiday. Nini NOAEL KA Maternal NOAEL = NA Nitcmil LOAFL~ | mpgd (LDT) dn cad ns weight Maternal LOAEL = 1 mgikg-d (LDT), based on increased liver weight Deopmenal Developmental Grou ot examin) A20 sdosion (0.0)in vs tl body wight tm as por 20mg A stil Group #1 (ibtal examinalion) - A 20% reduction (p _< 0.05) in live fetal body weight at term was reported at 20 mg/kg/day. A statistically Sica ces pl ssasoburod he 20mgyds ou Oca (i of sfeoe frproi significant increase in prenatal loss was obseI~ed in the 20-mg/kg/day dose group. Ossification (number of sites) of the forelimb proximal ints sg end dos cp ms Ocof a spol nts ey phalanges was significantly reduced at all doses except 5 mg!kg. Ossification of hindlimb proximal phalanges was significantly reduced at dor cenSt mu. Redd ston (p<08) clar was o ned 1520 dhe all doses except 3 and 5 mg/kg. Reduced ossification (p < 0.05) ofthe calvaria and enlarged fontanel was observed at 1, 3, and 20 mg/kg nd 10me nh prt Bos SAS SEN TEAS 00 0) mr hh dl dT nk ened and at > 10 mgikg in the supraoccipital bone. Statistically significant increases (p < 0.05) in minor limb and tail defects were observed in fore the try the fetuses at doses > 5 mg/kg/day. Grou posamano) ns <0 in ih3d ssl mor or ceisnpossts suis cre Grottp#2 (posmatal examination) - Increases (p _< 0.05) in stillbirths and neonatal mortality (or decreases in postnmal survival) were mci doe Aly, ih sacha.30 ts nt 1 10 EAH GeSTS Acs observed at doses _> 5 mgikg/day, with as much as a 30% increase in these effects sccn in the 10- and 20-mg/kg/day dose groups. At doses mht: 2nd Sh han (weg dons 35-35 00ish9id,e Tt an _> 3 mgikgiday, a trend in growth retardation (body weight reductions of 25-30%; p _< 0.05), was observed in the neonates at weaning. ody he wt cont Kay 6 woofsfor ale ony 1 Wkofs ln cdfor rsa hoch night Body weights were at control levels by 6 weeks of age for females and by 13 weeks of age for malcs. A trend for increasing body weight Com: ren ha coaoGo ) 1 Ss dnl Re 13 chs 8 al odwih 1 2 EAS3 48 (~6-10% greater than controls) was observed in animals dosed with 5 mgikg at 13 weeks and in animals dosed with 1 and 3 mgikg at 48 weeks. Dtincsay post rohan dcop ao wer fetedby nfm da (p00) nc cin tdoes = Deficits in early postnatal growth and development also were manifested by significant delays (p _< 0.05) in eye opening at doses _> 5 mh Shh ee 009m a pegan mt o ts erGhd 0mA ele Com, mgikgiday. Slight delays (p < 0.05) in vaginal opening and in time to estrous were observed at 20 mg!kgiday in females; in contrast, Enns eels(7 005) olar ci sna cw rep bon eae doctr significant accelerations (p _< 0.05) in sexual naaturation were observed in males, with prepntial separation occurring 4 days earlier than Coote Tangy dosed2. i tt e31HE0 5 vt HEAdn $0 3 controls at the 1-mg/kg/day dose and 2-3 days earlier in the 3-10-mg/kg/day dose groups, but the 20-mg/kg/day dose group was only Sabidelved comp cools slightly delayed compared to controls. Dogme NOXEL WA Developmemal NOAEL = NA Dvopaial LONEL ~ 1 mh (LD), basedcn odonification and cs pb despised for Developmemal LOAEL = 1 mg/kg-d (LDT), based on delayed ossification mad accelerated pubertal developmem as well as trend for sd poy wa decreased pup body weight Actonconducted BMD moll. Vales or he bencdhs (BADferal eclopcolcdpos (BMDs nd Authors conducted BMD modeling: Values for the benchmark dose (BMD for the ~natemal and developmeutal endpoints (BMDs and BADE) we ce BMDL~) were calculated: ---- BND. GE) ENDLhE Endpoint BMD~ (mg/kg-d) BMDL~ (mg/kg-d) [Premsmmtworn[en sa Decreased maternal weight gain 6.76 3.58 [cred ml semen [oa[en] Increased maternal liver weight at term 0.20 0.17 Neonatal mortality (determined by survival 2.84 1.09 [o2 em Tm ] ] to weaning) EF ---------- Delayed eye opening 2.64 2.10 Dr Dos or insn cin pes. D ems sms As poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 49 of 92 2247755..00008499 state orasesz STATE_07438052 raion aposalpoh & Tor Alterations in postnatal growth & 1.07 0.86 dvopmen mddecreed pu bods development a~ad decreased pup body Reduced weight at Reduced ages weaning phalangeal sstsion ossification g<E]1 a<1 Corin Sunt: Co-critical Study(s): Suc ith measusrrEePdA dled sumconcmation Studies with measured or EPA modelled serum concentrations - GenGassSts inKas(ts 12008) 2 Gen Garage Study in Rats (Butenhoffet al 2004) 3Gonranon Gage StyIn Syogoe DowieyRs Ben10t0) 2-Generation Garage Study in Sprague-Dawley Rats (Butenhqffet a12004a) FC groupsof as (10 cdeton) wesadmis FFON b aa sds 0.1.3. 10, amd 30 mah. Avshod sis ws Five groups of rats (30 gendedgroup) were administered PFOA by garage at doses of 0, 1, 3, 10, and 30 mgikgiday. At scheduled sacrifices were he ompietionofthe cba pid in FO le tssnd cation dy (LD)22 Fee ras. Rapidclnaionf Frle as after completion ofthe cohabitation period in F0 male rats and on lactation day (LD) 22 in F0 female rats. Rapid elimination in female rats Senos he a of MleFO Mare ot surcomaion: NA, NA. 51.45 ugh. EPA mold mers us compromises the utilit~ of results. Males F0 - Measured final serum concentration: NA, NA, 51.5, & 45.3 ug/mL. EPA modelled average serum Sonoma 459,112. 71.1 & 200g. Ets trod LDT ae comkred ori os ocrst es concen concentrations 45.9, 101.2, 171.1, & 204.4 ugimL. Effects observed at LDT are considered co-critical as they occur at serum concentrations that Siro he cil sh LONEL stm concsnaton (35 mL) Foals mre live Int weighGs1 17.6. &37 001) are similar to the critical study LOAEL serum concentration (~38 ug/mL): F0 males - increased relative liver weights (21, 47, 61, & 84%, p<0.0 l) Sa creed esi ne weg (1617 2.23, 2122. 327% 0.01) Fl sl mle drs td weiht emai 6,6, as well as increased relative kidney weights (16-17, 22-23, 21-22, 23-27%, p<0.01). F 1 adult males - decreased body weight at termination (6, 6, TLR 225. ad ai ce wegh(t2e0.10,5.& 761)30d elt dos weighs (1-13 1-19 17, 16.170), Fosamy of 11, & 22%), increased relative liver weights (20, 40, 53, & 76%) and relative kidney weights (11-13, 18-19, 17, & 16-17%). For summary of afc cuntitis nlsTable 6A ho. effects observed at other dose levels see Table 6-A1 above. amar DsclopmeralGas Sasin Mis (Maansa201) Mamma~~ Developmental Garage Study in iMice (Macon et al 2011) COT mcwas gagdod th 035 0.030 mgPROfNrmRGSD 110 GD17arith 0,001, 01,354 10mg PFOloAsGD 1010 Cd-1 mice were gavage-dosed with 0, 0.3, 1.0, or 3.0 mg PFOA!kg from GD 1 to GD 17 or with 0, 0.01, 0.1, and 1.0 mg PFOA/kg from GD 10 to GD 17 nh ull stan purine (Sy 1)(GD 1-17), lpg were src of PADS 7, 4 21 3.42.633nd Bnd he bt GD 17. In the fidl gestation experiment (Study # 1) (GD 1-17), offspring were sacrificed on PNDs 7, 14, 21, 28, 42, 63, and 84, and in the half esi xerinn (Ss #2(GD 10-17) fm fring wesscied on PND 1.4.7, 14.30 21. gestation experiment (Study #2) (GDs 10 17), female offspring were sacrificed on PNDs 1, 4, 7, 14, and 21. Sty #1 (GDI-17) sr conenions wes mandin lsofpnigan PND? castepoi) 95, 1.026.820 afl& P.DL Study # 1 (GD 1-17) serum concentrations were measured in female offspnng on PND7 (earliest time point) 4.98, 11.026, & 20.7 ug/mL & PND 14 oak ev 55 1698, 2 S25 ug. EPA malone sr lo 403 maha das 124 gl.(Table 45, Ve oordocs (peak levels) 4.535, 16.95, & 26.525 ug/mL. EPA modeled ave serum value @0.3 mgikg-d was 12.4 ug!mL (Table 4-8). Values for other doses Rt pred. Usa he av ser conecalcu or pegaCD.| omLa Wal tl he ve rmcoon or 13mgs not reported. Using the ave serum concen calculated for pregnant CD-1 from Lau et al & Wolf et al the ave serum concen for 1 & 3 mg/kg-d R53 b 77Suml. FIsood selon nd mde up re ones conc heyocr binsr would be 38 & 77.8 ug/mL. Effects obseneed at the low and mid dose groups are considered co-critical as they occur at or below serum Ciocraiontsr lah ros st LONELsrsconc(n35 mL) Ione dose readpp in Ir weight concentrations that are similar to the critical study LOAEL serum concentration (~38 ug/mL): @ lmve dose - increased pup relative liver weight SIND (WF 209, SMS 977. e008) nd dvdmamma lind dvSogmcns (Fue) STAD& 21 (rower on PND7 (M/F: 26"/19", 59"/38", & 97*176*%, p<0.05) m~d delwcd mammary gland development (F pups) @PNDI4 & 21 (however, Elo sseedp idotm honsk latr e a PNDEL 15. 13. 12fo c. orr) mid dos - mrss on cr developmental scores did not show dose-related trend - e.g., PND21 : 1.9, 1.3, & 1.6 vs 3.4 for controls). @ mid dose -increased relative liver eh on DLS (MIF T36 41a5d0ay4m0ar)y god denclopmen Fp) PND? 4 weight on PNDI4 (M/F: 17126" & 41 *158*%) and delayed mammaW gland development (F pups) @PND7 to 84 Std #2 (GDI17) Gags aad dos 00, 0.1& | meg son Sn era wisely ioncorrangde lows dos - Study #2 (GD 10-17) Gavage @adm dose 0.01, 0.1 & 1 mg/kg-d/based on Study # 1 serum levels likely within co-critical rang(] - @lowest dose Sica Sot ders 1 qn deslopmenal sets PND2!fomam Gd (2.15 & 161333 in contol) mddose statistically significant decrease in qualitative developmental scores ~sa~PND21 for mammaD gland (2.2, 1.8 & 1.6 vs 3.3 in controls). @mid dose - Dr Dum Draft Document for- for ew ad review a~ dso discussion poss purposes ls.only. Ddos c cons Ay Draft document does not constitute Agency polypolicy PFOA - 50 of 92 22447755..00005800 sateoressoss STATE_07438053 nEilslossipogrsaamnnddcrermessidntmamigofh.iFnosalcdydso.f Citgh odbsesn- sisi alossie gvaln e5 Tsase n6-q4uSoanie : mam statistically significant decrease in number oftemlinal end buds. @ high dose - statistically significant decrease in quantitative mamma~3" development scores and increased liver weights. For summary of effects observed at other dose levels see Table 6-A1 above. Immune DrinkingWtSt nMise (OW 208) Inmaune Drinking Water Study in Mice (DeWitt et al 2008) To of hs poms ere ded- ropoef 6 msl CSTRLIGN mics weegiven 0.3.75, 7:5. 15 ad30mgPRONRgisy nhs Two studies of dose-response were included - groups of 16 female C57BL/6N mice were given 0, 3.75, 7.5, 15, and 30 mg PFOAikgiday in the ing tor 5doe arin Tn exer I hs cond experdo,c wrt 0,091, 55,7, 3nd 7 mg PRONsGy drinking water for 15 days during the first experiment. In the second experiment, the doses were 0, 0.94, 1.88, 3.75, and 7.5 mg PFOAikg/day minitred for 1 dy i the ching tr. Th: immunclogicl shtzstionad pods mooring i Weve1ha sd te administered for 15 days in the drinking water. The immunological sensitization and postdose monitoring were identical to that used in the ondoing 5SE CSR. NatTA Se Sonos 44 Ips sng NA, NA. 74.43: 128, or 143.6 constant dosing versus recover?.' experiment. Measured final serum concentrations @day lpost-dosing: NA, NA, 74.9, 87.2, 128.1, or 162.6 iil EPA model cre sum Soncotaion 203 352,619,544 114m 155 gm Efct chinhe ocr in dos 70039 ugimL. EPA modelled average serum concentration: 20.2, 38.2, 61.9, 84.4, 111 and 155 ugimL. Effects observed at the lower two dose groups are Coe oc] ovr blosrSonenrohnst sro is sc LONELsr sanction 3% considered co-critical as they occur at or below serum concentrations that are similar to the critical study LOAEL serum concentration (~38 ai) 0303 gm coed eons Ter nigh 510 cuda pst met & 5.61% 13 dys pos sme], Bowen,dt ns ct ugimL): @20.2 ug/mL increased relative liver weight (51-70% one day post treatment & 45-61% 15 days post treatment), however, data was not Shon ih pubcaton 519 aml Gssaech sluts 4nd En 53500 WEposgt ohs (PD)dy 1 Poy 1 etude shown within publication. @61.9 ug/mL decreased absolute and relative spleen weight post dosing (PD) day 1 (by PD day 15 returned to control Keel)(1 15, 31 & 40%, 0 0, decreased 9M resfoSpRBoCcalnlinsgs (111%. casio 29hig%hest dos).ad creased levels) (16', 18, 31', & 40* %, * p<0.05), decreased IgM response to SRBC challenge (7-11%, increasing to 29% @) highest dose), and increased 0G pone a his os vl 854.4 nlbot ot ihr des. Aor BMD 53 sl.fodeissd 5M sms. Forsma of IgG response @ this dose level & 84.4 ug/mL but not higher doses. Author BMD~sD = 53 ugimL for decreased IgM serum titers. For summary of Ss Cot hrdos nl Tae 6A) Sho effects observed at other dose levels see Table 6-A1 above. 13 Week Dietary Study in Rats (Perkins ct al 2004) NileCHrRt(3D58 por group wor aimmscrdcocenrions of 1, 10,50 3nd 100pom PFOA or 15 weeks.These doses cq Male ChR-CD mrs (45-55 per group) were administered concentrations of 1, 10, 30, and 100 ppm PFOA for 13 weeks. These doses are equivalent 100106, 1 54 3nd 6 Shp Thre were hocml rope Rr fof os rpamd ae od ane 1p fore 1399 to 0.06, 0.64, 1.94, and 6.50 mg/kg/day. There were two control groups--a nonpair-fed control group and a pair-fed control group for the 100-ppm {ow roy bos the eld sured fo) scm omens 1 41.70. 3nd 155 vg. FPAmodllod nce seu dose group); both were fed the basal diet. Measured final serum concentrations: 7.1, 41, 70, and 138 ugimL EPA modelled average serum ncaa 33 51,75 and 1. ug. Ets oud oh or tds 00p5 Gok Smahe ou concentrations: 3.3, 31.6, 76.9, and 149.3 ugimL. Effects observed at the lower two dose groups are considered co-critical as they occur at or Rio sum concann r as hc ctl suds LONELseconser 3 vgn). 151 60g. red la: below serum concentrations that are similar to the critical study LOAEL serum concentration (~38 ugimL): @31.6 ug/mL - increased relative Incr igh ak (15 45,8 10. 13 (05 19,8 360 hepstoclus bperaopysd incised ep mics Con vase semis liver weights @wk 4 (13, 45, & 70%) & 13 (4.5, 19, & 56%) w/hepatocellular hypertrophy and increased hepatic pahnitoyl CoA oxidase activity 038473 200 650. p08 vs. contol, 0.05parfd cnr, NA(IZ T3570 67120) & 130k (25,757 (gt) ~vk 4 (75*, 200* & 363*#%, *p<0.05 vs ad lib controls, #p<0.05 pair-fed controls), @wk7 (128,357', 671 *#%), & @ 13 wk (25, 75#, & T1370) prosesofney cnby md ot onescons peadss cl (24d her Fo summa of 113*#%). Progression of liver toxicity is seen by mild to slight coagulative necrosis at next dose level up (~2.4-fold higher). For summary of cts chictrdos onl 3 6A) Shr effects observed at other dose levels see Table 6-A 1 above. 26 Wek Ol Cape Sy in Mikes (Thomond 2001 adBaba2002 26 Week Oral Capsule Study in Monkeys (Thomford 2001 and Butenhoffet al 2002 Nile Crom moskev 1-4e0r dn6) vcradmired PFOAb rl apecoming 0.31, 3020 mg fx26 wks Male cynomolgus monkeys (n - 4 or 6 per dose) were administered PFOA by oral capsule containing 0, 3, 10, or 30/20 mg/kg/day for 26 weeks @ucnofTc al 2007), Doofisinns he Mdm ds rap cid sc 12 dvsand drs 020mggd when iedco (Butenhoffet al. 2002). Dosing of animals in the 30-mg;&giday dose group ceased after 12 days and decreased to 20 mgikgiday ~,hen reinstated on 1 22 bcofmor od consumo.decdbch wight a drs fs srl slssae sunsoon(Buco00l45l) day 22 because of low :food consumption, decreased body weight, and decreased :feces. Measured steady state serum concen (Butenhoff 2004b) Wr porto: B10, 59140. 564105 uml. EPAmold vas crus Concenaons 70 136.6, nd 62 viol. The sum were reported to be 814-40, 994-50, & 1564-103 ugimL. EPA modelled average serum concentrations: 87.0, 126.6, and 162.5 ugimL. The serum Soocimraion se LDTexchecercsl gs. Honenhre LDT ass LONEL BMD dln end BND.for mrs concentration at the LDT exceeds the co-critical range. However, the LDT was a LOAEL. BMD modeling identified BMD~o for increased Shs ne igh 0b 352 sl. ad BID fo ghcee 9sm Forsuman oltre lde os nlr s xe Tbe absolute liver weight to be 33.2 ugimL and BMD~s~:) for triglycerides 45.9 ugimL. For summap of effects observed at other dose levels see Table 6-A1 above. Dr Duco for ewsn dco poss i. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 51 of 92 22447755..00005811 sateoressoss STATE_07438054 Sueswithout esr ormodell scrumconcemtons Studies without measured or modelled serum concentrations 2xDicar StudsinasSis sl1957sod uffsta 2012) 2 yr Dietary Smdv in Rats (Sibinski et al 1987 and Butenhoffet al 2012) Sprague Dane (CCDBR) 4po edn er To descain 0.30, ad 30 po PFOA (0.15. 142mpg formals. Sprague-Dawley (Crl:CD BR) rats (50 per gender) were fed diets containing 0, 30, and 300 ppm PFOA (0, 1.3, and 14.2 mg/kg!day for males; 0, 16,30 16.1 mtgfor res). Groupsof 1 adore ends wer or 00pm PFOA and absted he yt crn 1.6, and 16.1 mg/kgiday for females). Groups of 15 additional rats per gender were fed 0 or 300 ppm PFOA and evaluated at the l-year interim cc sated ormodel sr oan bons a ot ab Homer edoort ches ects od LDT would bs sacrifice. Measured or modelled serum concentrations are not available. However, based on other rat studies effects observed at the LDT would be Winsor age 01 mhd- nersed ALT i mls(8.12 mos 132 217us co%nd nls p09) AST. @ 12 within the co-critical range: @1.3 mg/kg-d- increased ALT in males (e.g., @12 mons 132' & 217*% vs control levels, *p<0.05), AST (e.g., @ 12 monk $7 84S vs corr vey & ALP 130900 1 $7553orn no 14 mrt olst24 ns i gh mons 57* & 68*% vs control levels) & ALP (e.g., @ 12 mons 21 & 57*% vs control levels) from 3 to 18 months, but only at 24 mons in high os ps wll3subrule 6 & 152150% col). For sy of ofc ioc hr dos 152 dose grp as well as testicular vascular mineralization (6 & 18*% vs 0% in controls). For summary of effects observed at other dose levels see THEA shove Table 6-A 1 above. Dussomonsl Gage GIA-17r 13) Sn CR Mi Yb 1312010 Developmemal Garage (GD0-17 or 18) Study in ICR Mice (Yahia et al 2010) Pg IRmic n= or 10a)wor gedos wa) 15nd10mgPRON from GO O17or0-15.Ths dsdss from Pregnant ICR mice (n = 5 per group) were garage-dosed with 0, 1, 5, and l0 mg PFOA/kg/day from GDs 0-17 or 0-18. The dams dosed from GD O-17 ersneeonGdD 1, dhe ei hlmerge was cased Dindosedfon GDS 01 were allowedio ge bhand GDs 0-17 were sacrificed on GD 18, and the fetal skeletal morphology was evaluated. Dams dosed from GDs 0-18 were allowed to give birth and hefgger erproceed or patbgiol aan cbse for do for nil moral. Mearoermodel cus their offspring were either processed for pathological examination or observed for 4 days for neonatal mortality. Measured or modelled serum Cioran.ot val Howe econ orthc fs ocd DT ould be nN he <r ne mrs concentrations arc not available. However, based on other rat studies effects observed at the LDT would be within the co-critical range: increased li mer Tr ig (35,155 185th pens sro, acs srcams ls (AST ALT AnLdchP anges relative maternal liver weight (35*, 115*, & 185**%) with hepatic hypertrophy. Increased liver enzyme levels (AST, ALT, ALP) and changes in Ince were repaid he ethighestdoe el dict progorf Inicr ovient crowed ea ide Cig (16 145% & triglyceride were reported at the ne~ highest dose level indicating a progression of liver toxicity. Increased relative kidney ~veight (16"*, 14.5', & 750% weights Author poi hat el ls nur cla & pesmal ul wre hl prog (mcr. omens die 27**%) weights. Authors reported that renal cells in outer medullar & proximal tubule were slightly hypertrophic (however, no incidence data or score da wereprado nd acdBUN (735 254 & 2015 comrl 2) phosphors posh th ss do prs. dose-response data were provided) and increased BUN (27.8*, 25.4 & 20.5 vs control 22.6) & phosphorus - - both with no clear dose response. For summary of choc cbsred tier os nl 5TH 6A) shin. For summary of effects observed at other dose levels see Table 6-A1 above. Liver Developmental Garage Study in Mice (Quist et a12015) regan CDLI hot (V-1-1dao) wae gaged wih, 0010.1, 0, | gdong GDI-17. On PND3S ofp erlcd on Pregnant CD-1 Mice (N=17-21 dams/dose) were garage-dosed with 0, 0.01, 0. l, 0.3, or 1 mg/kg-d on GD1-17. On PND35 offspring were placed on HEDwih 60,ei fo codctwth 17 elFo pup 7-10sdom s 7)Np meld en concenanon HFD with 60% kcal% fat or comrol diet with 10% kcal% fat (1 pup from 7-10 danas/dose grp). Measured or modelled serum concentrations are octal However keg oe hac uc theafc sed hsdoes oul be whe ch oc Fe ened not available. However, based on other studies in mice the effects obseta.~ed at these doses would be within the co-critical range: increased patellar peop PND owe LDL HDLadhesives, and nese ens Ine night hepatocellular hypertrophy @PND91, lower LDL, HDL and triglyceride levels, mad increased relative liver weight. 4 Weck Ge Su inNis (Vagsta 2009) 4 Week Gavage Study in Mice (Yang et al 2009) 21nd Female BALB me(5 pr rou) wer gigs wilh 0.1. and10mgPFONR ly For dayper we or 4 neck0s 21-day-old female BALB/c mice (5 per group) were gavage-dosed with 0, 1, 5, and 10 mg PFOAikgiday for 5 days per week for 4 weeks to min th slof peerus PFO expos a pttaia hd declan 13 od fle CoTBL0mis er sh determine the effects ofperipubertal PFOA exposure on puberty and inammary gland development. 21-day-old female C57BL/6 mice were also sd nh amemot 3nd cinhfofPs RON0 rs sand elope 0 vag spe Messedormold us dosed in the same manner and examined the effects of PFOA on mammary gland development and vaginal opening. Measured or modelled serum Coocmrukrocnost lal. Honus bac 0tre ce STs Sd2 LDT dD iheSores ms concentrations are not available, iHowever, based on other studies in mice the effects observed at the LDT would be within the co-critical range: ral BALD credabcand laine er Woh decreed boltsnd eae vie ighandtde.al age penn (VO) female BALBic - increased absolute and relative liver weight; decreased absolute and relative uterine weights, and delayed vaginal opening (VO) VO mtr or 10 hed CETBLI reso sits nd aie ner nigh2d read abl sd i ore weighs VO did not occur at 5 or 10 mg/kg-d. C57BL/6 - -increased absolute and relative liver weight and increased absolute and relative uterine weights. Forsuman of cts obved ieoe vrlstTab 6-0 hore For summary of effects observed at other dose levels see Table 6-A1 above. NIH Noe: eon rine wt pow drseton on ied 0 ht dos lo i or coimhtshc ses] ~IDH Nows: ejfect on u~er~ne wt ~s m opposing d~recdons and delayed VO at th~s dose level ~s not consistent with other smcl~es] Dr Duco for ewsn dco poss i. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 52 of 92 22447755..00005522 sateoressoss STATE_07438055 Nan Gland DoclopmsnSudinMiss CTs tal 201) Mammary Gland Development Study in Mice (Tucker et al 2015) Styofhe fectsof sonal posts o mary gd elon mesure a prepbst imepoinis. Doofx0,00s1, 01,03 ad Study ofthe effects ofgestational exposure on mamlnary gland development as measured at prepubertal time points. Doses of 0, 0.01, 0.1, 0.3, and Tada we bmn ted pagan CD-1ind CST oo geonGI 117Sra chord PND, 35 & 3 CD.1 1 mg/kg/day were administered to timed pregnant CD-1 and C57B1/6 mice by gavage on GD 1-17.Serum measured @PND 21, 35 & 56 in CD-1 and PND offorCSTR icasspin was sl 2 aveafr cuposrs. Honebcd heSos is fs mad PND21 & 61 for C57BL/6 - - but earliest time point was still -22 days after last exposure. However, based on other studies in mice the Shsciv theedsswou be wiki thc-cdrg CD.1 mic 4-001 mg 4 dcrsdcub mamasSas effects observed at these doses would be within the co-critical range: CD-1 mice - @>0.01 mg!kg-d decreased qualitative mamma~~ gland nlop sere ENDS (25, 22.23, 1913.31 in col bot ssdose.rs espons NDS edmoan cnt increas develop score @PND35 (2.3, 2.2, 2.3, & 1.9 vs 3.1 in controls) but inconsistent dose-response @PND56 and nonsignificant increase in progescme els 0. mph sed quan mama glands PND] (3,2&0 17552 incomo xd 1 mgd progesterone levels. @0.1 mgikg-d decreased qualitative mammaq~ gland score @PND21 (2.3, 2.0 & 1.7 vs 2.9 in controls), and @ 1 mg/kg-d eland eIncr igh PND! (12)3nd deed wt BW PND 38 CST mice 03moddecd une decreased relative liver weight @PND21 (12%) and decreased net BW @PND21 & 35. C57B1/6 mice @>0.3 mg/kg-d decreased qualitative manny gland dniopscors PND (15 1515 2 mcontol) nd PNDOI (21.8174 23 cot [MN Nokes Onan mammary gland develop score @PND21 (1.8 & 1.8 vs 2.9 in controls) and PND61 (2.1 & 1.7 vs 2.8 in controls), ffffDHNows: Quantitative Scoringrt cndvced querer hngale) mammary devlopmeial scares wil rel pon odenctofcoornal scoring ~ot conducted quantitative (rather than qualitative) mammary developmental scores w~ll be relied upon for identoqcat~on ofco-critical kn For summa of cts ot b eoe fssnabe 6A shove ~f'ects.] For summa~ of effects observed at other dose levels see Table 6-A1 above. 21DayDrinWaktsiSntgs in Mis(S1o .3120i02080) 21 Day Drinking Water Studies in Mice (Son ct al 2008 and 2009) S00 dy te ICR icN 10100) wer xpos idking Wat 00,049.24 171647321 mafogr 21 days. Mssdor 2008 study - male ICR 1nice (N = 10/group) were exposed via drinking water to 0, 0.49, 2.64, 17.63 or 47.21 mgikg-d for 21 days. Measured or malic snconecraho7ns kl. Hons, Wt on Ahrics ch Tohc swtdos vss eu modelled scram concentrations arc not available. However, based on other studies in mice the effects observed at the lowest two dose lcvcls would Eth coh) gt nea toe Incr night (700d rsdpenaALT(7) bc within the co-critical range: increased relative liver weight (27%) and increased plasma. ALT (50%). 2009 4 wk hd ml IC ms (ND rag) wee cxposl dkrg lr 0 ant 100,045, 264,176, 3804721 gh or 2009 study - 4 week old male ICR mice (N=10/group) were exposed via drinking water to equivalent to 0, 0.49, 2.64, 17.63, and 47.21 mg/kg for SFdystodtm if PPO ses T ymphocys pacand cline \pcion ne. Neoarmolrded cn cotenhons 21 days to determine if PFOA alters T lymphocyte phenotypes and c~okine expression in mice. Measured or modelled serum concentrations are ot alaeHome hosed on or cs 1 ac CcSrl 4h oe os nl old li Coc ge not available. However, based on other studies in mice the effects observed atthe lowest two dose levels would be within the co-critical range: 0dcr ploreCDV ghar 50% decrease in splenic CDS+ 15~phocytes. Forsumer ffs t tee doe lsTable 6-1 son. For summaq" of effects observed at other dose levels see Table 6-Al above. 230s GausSut nMis (slssta2008 29 Da~" Gavage Study in Mice (Loveless et al 2008) Ne C1 mee (prog wreadmired 0.0, 1.10, 301m nr ROA by orlsvat or 29dvs. es ce dled dscum Male CD-1 mice (20/group) were administered 0, 0.3, 1, 10, and 30 mg linear PFOAikg by oral gavage fbr 29 days. Measured or modelled serum Ciocmesiownts ot le However, cd aOht e ch GsOs 3 octx nc od wi concentrations are not available. However, based on other studies in lnice the effects observed at the lowest taro dose levels would be within the onde. 003 my rednesofmeso san he ner clo mk eps bro. crac co-critical range: @> 0.3 mgikg-d - increased incidence of microscopic lesion in the liver including mild hepatocellular hypertrophy, increased Sil (2.83 40% 30%, 0.sn0d t)ne (35,1757 93%, S170) ce weighs 0 | med drew HDL (5, 9% & absolute (25, 84*, 240*, & 230*%, p<0.05) and relative (33, 179", 292*, 317*%) liver weights. @> 1 mgikg-d - decreased HDL (29*, 39*, & 567) ma rcvrpet sto sg hacll ero (172,303, 1530.013 controne. Foca mcr (O20, 56* %), moderate-to-severe hypertrophy & individual hepatic cell necrosis (11/20, 20/20, 19/20 vs. 0/19 in controls), liver focal necrosis (3/20, 20.71v5s D9 coanmddsos)hs, (1,47 & 3672 30d lie (144 350 & 4500) sls cis. Fomamasof 4/20, 7/19 vs. 0/19 in controls), and decreased absolute (11, 44', & 56*%) and relative (14', 35', & 45*%) spleen weights. For summary of Tc curstilt doe enh Tale 61 Shs effects observed at other dose levels see Table 6-A 1 above. Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review al~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 53 of 92 22447755..00005833 sateoressoss STATE_07438056 `TTaabbllee 66--A433.. CCoo--ccrrilttilccaall EEffffeeccttCssrSiStuuimcmammlaaLrrOyy AELr=p | 38ugimL. serum concentration @LOAEL from Lau et al Critical LOAEL~IrD = 2006 based on EPA serum modeling. 38 ug/mL serum concentration @LOAEL 2006 based on EPA serum modeling from Lau et al Nc!NoOnOcTeEnTtE:r:aNtNioootntsac.ldll Wss~htuueddriieeassphhpaarvovpeermmieaeataessuutrhreeeddorooarrlccdaaollscceuullvaastteeEddPssAeerruumm ppcVrroaeenrddicioeiccu~ttsmeedsd"iaaartviaveoiemrnrsaa.ggsHepeeqs~cseiee~errsuaumdmpupccrrooaont~pciwreomennmtstrerwaaattthisioeonnuosrrreaeedlllaad1tt0~oisooaensmssvihhssi&tpEfifPonorAr dv~ernioyuisns~grawinh.es~t/hseperc~thees/~ef/ufrecc~tstior~es pwo~rstueisndedsmidaesssiswthiinch did nidoetnh~ajv.,einagvewrhaegtehesre~rhuem~c5o~n'cc~esnrterla~toirotendliinkelsytuodciecsurwrheidchardid nss(eoaer~prupuhmr~mowxcceioom~naacTvteceenerltnayrtgraae1t.5~isiooefnnrossuldmaaiot cooforrtnhbbceeeellnosotwerwrcum.~-m~6o6b00nenuulic~gkh/emmmllyaL.rokc:cuarbroevde.a]r (approximately 1.5-fi~M qf ~he serum benchmark above.] `Study (source and date):|*Siudies with EPA modelledaverage serum concentrations are presented. Study (source and date): f~o*i3srSrsest,ut',dfvfiiosdelpsllorwoewwd#eeihddcFtbheJyy~dsAssiteuumrdiouieedmsselcwwloehhndiciccaehhnvtewwrreaaer.tr~eeieoiinsddeeerrnenutltimaifftiiieceododnrbbs~hyycieeepmxsxttr(rraaastppieooolmrlaaetltaiiernnveggapfnfrrtrooemwmsoernhtkhtseeehdeet dwohsheinvstphereEdxicceteldfisfeerautmO-coHnReeAn\trCatOioM~MrOelNatGiounisdhiapnsc(es-eeWarteelervaTnot wreovrikeswhse-et wcEcfooifdmme~ppcilntleestttehtedoedVbEFqexincniaeanl!l'cdflPi~ulIFed;eOOadAAtaOs'E,E:cPP'oJAA--I<Rr22iA00i'11~c6aCGlHHOaAAMrePPMFtbO,oOOlNAdAie_GdAuA.diddmamD~Dowosesee-TTWooSaSteeerrru'~umTkEoxxxitrrraeapvi.p.e~wvTisss-x., Effects to be included as co-critical are bolded RRaattss1--13 week Dietary Study in CHR-CDRats (Pekin ct al 2004) @@12. 3~1`3.1w613e.i6u~ggh,uet/gem/@kmlwDL.kie[[ta4aadrd(mym1S3dd%otous)sdeeyan00.6i4d.n6m4wCgkmh/1Rgk3-/Ckg(gD]3-d.:R]5:a%t)iisnnacc(rrPceeecaarsoskeemiddnpsrraeeenltlaaiattbleiiv2vydee00llii4vv)eerr whahcyyetppiigeveirhrttttyrr.@ooMppwihhlkyyd4taaonn(1dds3lii%inngch)ctrraeecnaaodssaeegwdudklhha1ete3ippvaa(et4tii.ncc5e%ppcaa)rlloammcsiciiattoosotmyylnlpeCaCxntooiAedAdosoobexxyiilddeaavseslee up. 2 (a(2~-c-22tG.i.v4e4-in-tffeyoor.lladdMtihhioiilngdghhtGeeoarr)v)slaiggehtSctouadgyuliantiSvperangeucero-sDiaswaltenyexRattdsos(eBluetveenl hupofcft @2.45.a2a1l9-G2200eg00n/44em0raLa))tiaondmGadroasgee Study in Sprague-Dawley Rats (Butenhoffet | mgd): F&OF1 Malincereassed mr@ reaelll4aae5tts.ii)9vv.eeu[glliiiMvmveDerLrH(([~Na22od0t0me% %s:d))onsaaeonntdd1cmkikeiigdad!rnnikeefgyy-hdi((]>s:>t11Fo0l00% o%g&)i)cFwwale1eieiMggvhhaatltlsuseas((tbb-ioooittnnhhscFrwFOee0arasaeennddd FF11 cpmcoaonarndlaedumsuc)e.ct/t~teee'dvrdIshhLoro)eHwwpeeoNvrveotertrmeoosot:trhheneeorrtthssctatuluneddailireeisvs~etrtfhhhwaaiistttcdodholooanigingniecccsallu.uldde|eevaaaldduidatittiiiooonnnsaallwlIeivvreeerr parameters report more than liver wt changes.] RRaart ssattuuddii2ee9ss --daeeyssttGiiammvaaattgeeded ssSeetrurudumym cciononnMccaeenlmterraCattDiiooRnnass s (Loveless etal 2008) a. s@@20e9.0r3.du3amy&&leGv1|ealmvmsaygglkiiekekgeS-l-tdydudaayd6dm0minuddMgoossmaeelle([]bbC~aaDissneeRcddroaoetnsnas(BBLeuudottvleeeinnvlqeeorsffsfwefettteatnaallol22t2000000+48) snsseiieggrpnnuaitimffoiiccclaeaalvnnltetulluusnantlrtiiiklhleyl11py0e0r<mmtr6ogo0pikkhueygg.-d/dmaaaLsdd]mwm-elddilnooscaserse)e),da, esmmceirdinenlaiiimsvmeeuudrmmwtrt(tio0g(lmnmyiociltelddrides, hHrHeeDDspLpaL,otnosmacenea)ddll[unnlooMannrDtHhHDyDLpNLeotrccterhhsoo:olplehedssyutt,eeerraotosollwl((ahehclolkowoawfesvedcevlerecneanrorreodacocslelseedeaarrtrrddiegooslspsyoeecncsen.dcs, b. 2yrrrreeeDsppioporeortttneesdaderee)fy/fjM feecSctItst)suHdwwyiNilllolitnnneosCo:trbbd:eeuCeccDootBonnsRslRiadiacedktreesordfa(ecaSsdlsiebcacioron--sdcckorriisiteieictcraaaell!s]]p1o98n7s,e b. pp2@uu1ybb.rll3iiDsshmhiegeetdd/akraaygss-SdBBtuuuadttdeyemnnhidhnooofsCffeefYtl[:taCballaD2s2Be00d11R22o))RnaBtsut(Seinbiinosfekfti eatla2l0109487, i(@(anas1cssr.s3ueumammseeegdddikaaAtgt-LssdttTeeaaadddm(yy13ssd2tiao%)tesee))&[ssbeeAarrusSuemTmd lloee(nvv5eeB7ll%ssu)tlleiiiknnkeehmllyoaylf<fee6<st00aautul gg21/02mm0mLL4o]]nt--hs. increased ALT (132%) & AST (57%) in males at 12 months. DDrraafftt DDooccuummeenndt - ffoorr rreeviienw aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oSonl4l.0y.1DD9rr2aafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuuttee AAggeenrcey ppoolliiccyy PFOA - 54 of 92 22447755..00005844 SSTTAATTEE 0077443388005577 Tiver lesions observed af nowt dose levels up (which was 10- fold higher) Liver lesions fold higher) observed at next dose levels up (which was 10- M Miiccee1. - Mammary Developmental Gavage Study in CD-1 Mice (Macon et aSMaltl ua22dm00y11m11#)m)1 y(GDDe1v-e1l7o)pGmaevnatagleG@a1va2g.e4 Study & 38 in CD-1 g/m. [ Mice admdo (Macon et se 03 & | mmS5yt0gu/id/kkyg3e-d#8d]1a]%t(--G0ii.Dn3n/cc11rr-)e1ea7aass)needGdd1a4rrveeall(gaaet/tiivF@vee-1ll12ii7v.v/4ee2rr6&"wwt3t8aaatttug1PPv/sNmcNoDLnD7t[ra((odMMlm/s/FF)doa22sn66ed//110d99.e3&l&a&ye1d mhm5oa9aw/mm3em8vmae%rra,ryaytdddi0de.3vne/e1alt)ovpasnmheodewn1lt4abdbao(aoMssseee/-ddFproeo-nl1nmaq7qtu/eeua2dla6iltint'traaaetttntiivdvl)eevsissncccoooorfrneeftsssrpo((rlssiscc)noograreeenssxd,,pdoesleadyeidn utero however, utero. did not show a dose-related trend) in offspring exposed in S[SBttuausddeyyd##o22n((GSGtDDu1dI0y-01-1177))sGeGaravuvamaggleeeve@@lasadldimmkdeldoyossee<000..0u011g,,m0..1]0.1 &&- d1|ecmmrgee/akasged-dd q[quqbauulaaainslittetaiadtttiioavvtneeiSvmmetuaamdmmyamma#m1armrysayerrdduyeemsvgeelllleoaovpnpemdmldeseennlvtitkeesslclcyooorpr<eems6se@0@nautallglls/mdcdoooLsrse]eesss.-.odDDneleecyccrrer@eaehasaiessdgeedhd Nddqoooustseeae.sn.:tIIintnhaicctsrriteevoaaelssomeegdidacllmaiilvvmeeervraarwwlyuttasgtalaiallosnsnoodooofdbbeIssvveeeerrrvlvodeepdodmc@~sehhninigtgohthseceasosptrtpededsooasosreen.t.loy/[h~@MaIDvDheHiHgbheen Nhcceooopnntadedtusuic:ctctheepiddas.,troahhlmooowewgetievcevearerslr,e,avtrraeeslssueuularltltussinoffn~croooomnmfcleooinvttiehhrreearrdtsoisttoeuunsddsinieeaossstsrraoeepcpppiooaerrtatteraadltlowtteehrareaeddvdme been dose. 2 ohoIemffpmIaummtnigcge/pkkaDgg-rr-ddai]]nm..keitnegrsWaattesrersutmudcyoinncAednutrlattiFoenmsaalsesoCcSiaTtBedLwG/NadMmicdeose (h(0DDn2eme0WW.ui2ntitteut geeDttiraamilnlLk22i[00n000g.889)W )4 magtekrgs-tuddyad:inm Adult dose] Female C57BL/6N Mice - increased relliver wt li(@ (s~=t523e000d%.%2a))su~[gcioMDm-DeLHrHt[iN0Nco.oa9ttle4esbs:m:utgdd/alakittgvaae-rdwwaalaasrsdemnnaoodtdtyosssihhenoo]cwwl-nundiwnweidcitatrhhesiiannsAeppdduuabbtrieilcilvcailaiittivyioeonrn.w. NNt oott EEl@inns6dtd1epp.doo9iainnsuttg.ci]]om-lc.ri[ti3c.a7l5 but liver myke-d alrea@ included as Additivity adm dose] - decreased spleen wt, @ ddfoeer6ccd1rree.e9caarssueeegaddhsneIIgdLgMIM[g3rr.M7ee5sssppemoorngnuss/mkeegt(ti-o0edrSSsa]RdRmBBCCdo[[sAAeu]utt-hhoodrreBcBrMeMaDDs~e,sd~z s-=pl55e33enuuggw/immt,lL. for decreased lgM serum titers] MMiiccee ssttuuddiieessa. eessDtteiimvmeaalttoeepddm`e'aanvvteearrlaaggGeea'vssaeegrreuum(mGccDooUnn-cce1en7nttrroaarttii1oo8nn)ssStudy in ICR Mice a. (D(@YY1eaavhhemiileaao/cpektmteaa-leldn22taa00ld110mG0))adroasgee[b(aGsDed0-o1n7 or 18) Study in Lat etal 2006 ICR Mice serum l@,r~eeev1lveaelmtlssigvwweiokoluguil-lvdddelrlaii(kkdee3mOl5~y%dhb)oeeswe<e6[i6b0g0ahuusteggd(/mmwoilL~h]|eLp---aaiuitnnieccctrreaheaa1yssp2eee0ddr0t6mmrasoateptreehurrymnn)aawllith lclriihevvlaeeanrrtgieevenneszzyalyitmvmneeeerx(((tii3nnh5cci% rrgeehaa)esssweetddediAAgoSshSTetT,,l(ewAAvelLLlh)TT.e,p, IaAAntLLcicPrPe)h)ayaaspnneedddrtttrrrreiioglgapllythyiccyveee)rriiwddeeith Kiockduhitdnaennergeymyee(sd(1a1ut66lnl%%ea)xr) tw&wheeiipgiggrhhohetxtsssitm((dassolllsiigegthhutltbelluyvyleeccl)hhs.aalInninggghceetrliieynnahsrryeeepdnneaarlrlteccrleeoallptllhissviieicnnand pioinnruccotrreveeriaadmsseeedcdd-duBBltUUlhaeNNrr&ennfooopttrreeeoddxtbhbimeyysaeaaluufttteuhhcboorturssslebbwusuitltliglqqhunutaoalnyntthhiietyatptiaievttreeetrdror)eepsshuulilcttssannnoodtt b. pDreovveildoepdmentthaelrGefaovraegtehe(seGD~1ff1e-c1ts6)wiSltlundoyt bine CliDst-e1d)Mice: b. (D(@SSe2uuvhbemeletoetapalaml 22ed00n11taa11ld))mGadroasgee (GD11-16) Study in (LD) basedon Lau CD-1 et al Mice 2006 (p@(lGGa2DDcIemI-n-tg11a7/7lk))gwss-edeeirgrauhudmtmm, llieednvvoceeslrlsese'am(msLie~gDdghjTTittn)bbc[eiebda<esn66ec00edouuofgg~r/emmLsiaLo]ur]p-ettiddaoeelncc2rr&ee0daa0sse6eeaddd fetuses (post-implantation loss 8.8% vs 3 9%incontrols) placental weight, incrcascd incidence of rcsorption & dcad fetuses (post-implmatation loss 8.8% vs 3.9% in controls) DDrraafftt DDooccuummeennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrFppoOosAsee-ss5ool3nyl0.y.1DD9r2raafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 55 of 92 22447755..00005855 SSTTAATTEE 0077443388005588. cI~oN,nlIDsDiHHstNNeonotcteyess:w:itt0oh0ootmmhueecrhhsuutnnucceeesrr-ttaainnio&ntlrriees":tessdeaerusrmacoll-eevcveerl&isc&&al] . c. T(cTQaoaurnriggsseietsttteeeeddtnacDDlyee2vwv0eei1ltlh5oo)ppommtehenentrtaasltluGGdaiaevrsaaggeen(o(GGt DDliIs1-te-11d77)a)siinncoCC-DcD-r-i1t1icMMailic]cee S(@@Qe00ru..ui33smt&&leetv1|aellmmsg2g/0w/k1koe5gu-)-ldddlaaiddkmmelyddboosseee <[[6bb0aasseueddg/oomnnL]ELaa-uureeettpaaollr22t00e00d66 hahseseerppuwaaemtltoolclceeaevlslellculuselllaawlrruolhhuayylrdppdeelriarkttmerralooygppebhheyya<naa6dnn0ddmuiccgthh/omaacnnhLggo]eens-sdriirnineapttlrroiirggtlleyydcceerriiddeess i`aanasbbnuwntooeerrrlmlom.aalasilitctieieellssuiilnanrhhedeppaaamttooaccgyyetteaessndooffmoolfftffosscpphrroiinnnggdroolnnalllyy eexxppoosseedd 4d. 4i4Fnewwmueaeteeelkrkeo((.W55eadvn/wklik)n)gGGaMaviracaggeee(SSYtatuunddgyyeitinnalBBAA20LL0BB9/)iCC oorr CCS566BBLLI/S6 lF@@ee1v1melmmasglgel/!hW kiegk-e-ddae0naalldbidnymemg ddMoo6sis0ceeeu[bg(baYasmaseneidgdo.~oenntBaDDAl Le2eWB00/ii9tCt)ee~itiaanllcr22e00a0088sessdeerrluiumvmer whwleyitvpsseelwwrsit/lrddiokoopesshleeyy--.dtdoeepdpbeeeecnnr<ddee6ean0nstetudgiinn/umccerrrLeei]aanss-eeeBwiiinAnsLhh&deBeepp/alCatatoo-cyceieenlldlchurlvlleaaaagrrsiendalliver dohopepyepepnneieinnrngdtg,re.onCpCthS5iy7Tn,BcBdLrLee/cIa6rs-Ge-eaiiisnnencdchrretee~paataesstreeomddceellliwivlveteusrrl&awwritdshseywwlpai/eyddreootdssreevo--apghiyna&l idiinnneccoprrpeeepnaaossdeseedidnnuutgttieednrriciirnrneeeecat~wisiveostn.sis.n/--[~9hM[we1Dipl)HHlatn?Nooovcttbeetileslns:uc:llaeeurfdfeehfcaytsopoeencnroutu-tcrcteoerrrptitiihnnceyealww&itiiss enienffofftoeoctbp.te.poDDisneeiclnllaaguyyddeeeidddraeVVcsOtOio~con-snncoroitttwcciocoilnanlslsin]isosttteeinnnttcwwluiidtthhe oatshcero-sctruidtiiceasl~ other studws will will ee. NnNeoeuturbrooeddieenvvceelluloodppemmdeeannsttacalol -ddciireaittaricryyalss]ttuuddyy iinn CCS566BBLL pprreeggnnaanntt mmiiccee ((@OO0nni3isshhmceehh/eeknngkk-oodeeattdaalml 22d00o11s11e))-- gender specific changes in cac~,ini2rr(i~ccm0aa.a3ddlmiisaangnh/oaakccugttsi-ivdveiidtatyyd3..m-4~(pdMD eoDrsHeHca-NNgogoetete.ensns:do:etssrmcmslpaaeelallcrgigffrriocoluuctpphrassneiizzfgeefecs((6t6i/s,n:,3wrpe))r, e atccohonnenitrmtrcraohollyls!lepehdrdoeJfucbosirreu,.ddaainn3n-ddg4odopnonelslryyeo-cornanegeesept,trorneneoasattetmmcaelesennsatetrsggsirrmfooeluuintpptte.eervvEeaaffllffueuccaattttsseeddwwielrle nthoetrbeebyipdreenctluicfOiaendg dcoos-ec-rrietspcoa|nlse assessment. Effects will f. nSMMtouuultdlibtygiegeienindneerCenarDatt-itifi1iooeMnndiaalcalesGGac(aovvW-ahacggireiettei(c(GaGelDtD.Ia]Il--112770))11++)DDrriinnkkiinngg W Waatteerr >m>Sat00umdmmmyyagikr/nkgygC--Dgddl-gag1anadMvraadiggceeeeve++(lWo55phppmippteebbnetDDtsW acWlor-2e0dsd.1eec1cr)reeaasseedd qquuaalliittaattiivvee m`11 mmmaagmmg/m/mkkaegra--y~dd ggggllaaaavvnnaaddggeeddeeaavvddeemmlloopddpomomsseeeenn-t-dtedssccecorcorreeeraases&seseddiqqnucuaraleliiattsaaettidivlveeiver wt. m[MamDmHaNroytegsl:andduedetvoecloompbmiennatt isocnoorefsg&aviongcere&aseDdIlYiver wt. e/Ax4pDosHurNeo&tesm.edauseurtoemceonmtobifnsaetirounmocfognacveangtreat~ioin)sWpost- wexepaonsiunrge r&esumltesasiun rgermeeantunocfesretrauimntycroengcaerndtirangtiosnesrpumost- wclleeove-vecaelrlnsis.ti.niEcEgafflfrf,eeccstHtussolwtrrseeevippneoorrgr.ttreeeoddatthmineurnttshchieiusrtsesattuisun@dOyh,wwari,veillegllaanorsotdstienbbsgeesesinndeecritulhuumeddseeeddaass eccefrjoJfi-ektcccirttcisstaialacn]andld.wwiHliolllwbbeeeveuurs,seodetthtdooer#infsitfbuordrinimesiiddheeannttv~ief[iiaccsaastteiiosonsneoodfflcchooe--se &g. CcMMrDaia-tmmi1cmmaaala.rn]~dyyCGGSllTaannBddLSiDDeMevivecelleoopp(mmTeunectnkatealrl GGaavraaggee ((GGDD11--1177)) etal 2015) ssttuuddyy iinn C@@@D0000-.31011,&a,0n0.d|.11Cm,,g500/7.33kBe&&L~d61|aMmmdigmgckeikda(go-Ts-ddueacaidkdnemmCr dSedotTosaBseleL2Gii0nn1mCC5iD)Dc-e-11fmbmiasiccesedaoannndd Lauer al 2006 & Wht ct al 2007 th serum levels would @0.3 & 1 mg/kg-d adm dose in C57BL6 mice/based on Lau et al 2006 & FIq~ite et al 2007 the serum levels would lidlikekecelrlyeyabbseeed~2-q82u8.a, l22i99t.a, t33iv2e2&&ma44m22muuaggr/imynlL.gl&&anttdhheedrreeevJfebolrroeep<me<66n00tauulgg/smmcoLjr]e-s idinneocofrffesfaspspreirdningq,guaQQluiuataannttiitvitteaattmiivvaeemssmccooarrriiynngggl~wavanasds nndooettvcecolonondpudmcutecentdet.adl scores D"Drraafftt DDooccuummeennst f-oforr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeessSoon6nl.yly.0.1DD9rr2aafftt ddooccuummeenutt ddoocess nnoott ccoonnssttiittuuttee AAggeennccyy ppoolliiccyy PFOA - 56 of 92 22447755..00005866 SSTTAATTEE 0077443388005599 Am~a4DmDmHHarNNoyottdeeess:veqqluuoaaprnmiteiantartitaivlveescr(roaraethsrewriTtlhlaabneqqrueulaai#eltdaitpiavoe]n) for dmid1eaemnmnttm(gftaTc~cad;avntidooaennvdooemflfocdcpoooms--ceecrnriinttiaiccClaasDlceeIoffr.ffee~mcs,ctwtss.i|]il--libneccrreelaieesdeduproenl floirver wwh1iitsmstsoignnliookgofgiff-cfdsasplparrediimnnggvd((o11s2a2e%%inloaafCttiDPuPv-NNe1DrDam2d2o1i1ec)t)se [[-M niMoinDtDcaHHorpepNNaeonsoatetreedssto:theal vliveer alhbbtieeseeetnrnoelccodoognhnidecdupaucalcttteeievdcda.,pluahhaoorwtwaieoemvnveeerqtr,,felrrrioveessesursuldtessorffeurrsmoomncmoontoocatthepneeptrerssaattrueidtooisnehssarrveeeppoorrtt B2aaa1ssltssedooracceyiidaaIttheeneddmpauwwtniiaacodtDdmoaxdrdDaoormssieeentkoqeifrflsnupgpaWt0taoste1lreummrmggs/ct/k~uodgndy-cdienn4trawtikonosd Male h. 2II@C1C0RR.d4aMM9yiic&Icmee2.m((6SSuo4onnnomtteotaaxallDd22r00ina00k99d)i)nmgdW osate[rbsatsueddyoinn 4 wk old Male Deitearl 20S2@p00l008e.8n4si9secer&rCuumm2D.6Sll4eevvmleelylgssm/wpkwhogoo-uudcldydatdlekimkesledlyosbbeee [<b66a00seuudggoimmnLL1]])-e-Wddietetccerrteeaaalsseedd ii. (s11p55CleddnaSayyicTIlmCnBDmmLuSun+InoWolt6ytToom-nxFpeTDDhmrroaiaicnnlyckketiiennMsggiWW caetae(terDressWttuiuddtyy eiitnnalPPPP2A0A1RR5RG)KKoo & & 20SCSt0t5uu87ddBysyeL##r/226u-@@mT1a1.lc.e88W v88elmTmwkgFoieekum-gd-addlleiaakdMdemmliycdedbooe(ssDeee[6[W0bbaaiutsstgeeeddmtooiannl]2DD-0ee91W5-i)1int1t e%ert al al dm2dea0ecrc0rgr8eeiaasnsseaeerldudamaannndltteiicvbbleooeldsdayyrwdrroeeoussspMpeoonrlnsieekss.eep.lo/yMinvbsDleel)H<aH6NNs0ootuoteLes,s/::mobrrLsee[essr-ppvooe%nndss.1ee1%iiss 3 fme2.1efafcOrdtgcatsiysnwwaDilrilliallnnnokdoittncgbbleeeWaaiirntdcenolrusdecsetrdueeadsaypsoiccnnoosMr-ecatrwliitceaiacsIlanC.l.oR|]t observed Mice (Son etal j. 2220100O40d889a))y Drinking Water study in Male ICR Mice (Son et al 8 2.64 madadmdose [baonsDeelid eral 22'e~00l,0,0l08i8.4v9sseeer&rwruutm2m.6all4eenvvdmeellgsis/nwwkcogrou-eudlalddsaed#kdmpkeelldiayossbbemeea[<bAa66Ls00eTduuggo(/nmmaL2DL] ]e6-Wi-1niimtncgtcr/erehteaaaa-slsdee) kk. rel liver wt and increased plasma ALT (@2.64 mgikg-d). 22090d8a)y Gavage Study in Vale CD-1 Mic (Loveless etal 29 day Garage Study in Male CD-1 Mice (Loveless et al &2~00,00L3.a83n)c&&et11almm2gg0ik0/g6d-dseaarddummm ddleoovsseeels[[bblaiaksseeledydoonn6DD0egell~mittlee]t-aall 22000088 wii~nnicc[rr~deeueaacssereeteddaa1siine2cd0ni0dH6ecDnsLceie,roumofmdofmdmileeecrivrcaeorntlossesc-lcciotkopoepei-liycsce<lvii6evv0reeerrughllee/ysmspiioeLonrn]tss-r&&opllhiivyveer&r 1 w6iinntwdd,eiidvveeiikdcduruTeaaealsltsccieeecdlulllHnanreDeccoLrrxoo,issmciitssoyiidnGnearliivavvteaeerrg-,,teodd-SeestcceurrvdeeeyaarsseieendhdMyssplppelleereeternnowwpihtssy & 1. hh6@uu1wmmaemanenakiizzhTeeeeddsdtPPicPaPuAdlARamr(R~dtooMMxsieiciccei[etbya((LLsGieiadcerottaangalle2D2S00e1t1u1l1d))ty in Male etal 2008 & Lae eSe@tpt1aealr1mm22g00a!00bk66rgo-ssdemernrauaudmlmmilliedesvvoeesalle~snd[aabrrdaeeesceleirdkleeaoylsyne<Dd <6ete0W6stuui0gotgst/tmemeitr]Ioafnnfle-.20eiTn0ec8srrte&iacsdLueladaur aIlsecpdsseimiroomndnosssawweb)ene.roreer/mooMbbaDslsiHeetirrevvNseoetddaeansad:t ttdhhseeeucdrnneseeaxxsdtteodddeoostsseeerstaloeevsevteeelqlruouuenppset.((i55Tonmmessaagtriinckkudgel-addr swasuidulpmplppnodoorrottsssbeeht)h.iee~deenlnDeteiedfHdifefoNdoraro~ftsiue~rsrct:thhoseetr-urdrsstytiuudddi.y.ov.ced. asuHHeloroaww1eis0eveveserqir:uu,eyttshhtqieeoussaneelsieeta~eyfnfcbdtctss waccnooiannlllccyneesrorinntsssfboeiinneiccdvlleuuanddlitiuninfgaig:ei:dnggagrrsoohucuioppgs-hscilirzzyieetvaiacanranidldadbooulnneellyytsooopnsneeteurditmiymmaeqetuppoaoog#iiOennan,tnotqfdfcl akohnoroearrv@mmaool~nnuisaaafltlopepradarersavameametltueseatiretcsrin.asgl; ltthee:issgtatehbeslsyhkeviinsasctrioeiopaopabfatlmket wwsopaaessirmnnooadtttaouqagunea0ntnitic{feaienddd ldoinaridccekicavoaatftleeuraei(pfftieobbdraatsssiteena#igtnnis&eetiddcqoaautaltlanayt;sishhfaooibwcwssaestnaiaccocenccoeeopfpjis'tmapaebobcllliieeIfipip&rcroopdccaeeedtdsauurr(oeeIfo)s9:s;peaarnnmdd im. aaH[abbonenmokoroomrnamflaraieltlpiitoleiasert.stie.n]ngcy&stquudayontf{OCcDa-ti1onmqicfespgeecs(iOactotnyaplelsyofsperm m. Hexopromseodna(lGlDaIte-n17c)y(sHtuidnyesoftCaDl-120m09ice gestationally "raft Draft Documfoeroniet Document - for review and and discussion discussion ppuuPrrppFooOssAeeess-xoo$pln7yol.y0s.e1dDD9ir2(aaGfltDddooI-cc1uu7mm)een(ntHt ddinooeesss hot consuls et al 2009) not constitute ABSTEy Agency poy policy PFOA - 57 of 92 22447755.100005577 STSATTAETE 0077443388006600 001 ~ 03 mykgd adm dose [basedon Lar 1 01 3006 sws@eeeri0rug.u0mhm1t,ll-eesvve0eelr.ls3su' mmwwoolgueuipklltgddi-nlidiklkeaeelvdlyeymls<6ad6no00sdeuusgg[eb/mmrauslLme]]d-i-onisinnunlcLcirraneeuaalsseeeveetddlasbb/ao2otdd0yy0261- w33ra11etiiwwgoeheaeett,kk4sss2oeorfwufeamagegekle.es.opNNtfioonagslseettaav.tt[eiislsMsssDaiiHgngndniifNsfoeddtriieuffsmff:eerrietennhnseccueelsitiinunndlyffeaadvttee--stltosio--galletneaa2ann1n-d lraevtieol aotf4de2tawieleiknsroepfoargtei.n[gMisl)iHnaNdoetqeusa:ttehetostpurdo~vviddeesign and sflse~uevf/.fe~ilccoiiieenfnnsdttuelllyytiarnrioolcbbiaununsstrtvdeadparaotytraadtiunnneeegeetiddsoeefiddnasat1to0dieaanqsgsussseeatsstaesstsmmt,oeetptcaaribobrovoclialididcceiaiimnmppcaalccett,ss a(egeg-.,maitncshuilning,cainc.v)artyhecrlueefotroefit~hsetsinegefsfteacttuss,wiclilrcnaodtibaen cycle, aigdee-nmtaitfcihaeisndgc,o-ectcr.i)itchaelraetfotrheisthiemsee. eFffuerctthsewrisltlu~doy,t be replication and valdarion identified as co-critical at replication and validation arethis are needed. time. Further needed. [ study, M Moonnk1k.eeyys2s6--week Oral Capsule Study in Male Cynomolgus Monkeys 1. (2T6hwomeefkorOdra2l00C1ap&snBlueteSntuhdoyfFmetaMlal2e0C02y)nomolgus Monkeys e(~@Tvt)ih88do77emnuucfgogeo/rm/dfLLm2i0[[t0LoL1DcDh&TTon33Bdmmnritgeag/nlkhgpdo-rdfofleaaitdfdemamrladt2dio0oos0snee2]]i)n--liiinvneccrrr,eeaianssecerddelafisiveeedrr wwi,t, tteFrrvTiigi4gdllyeyAcncecTerreSiiddoDeefsRsm(((isttdtoaarcttaihsstsos2ini0ggd1nnr5iaaa)tlt BpnnMereoxxDlttiyfddoeoorsasfeeotirollefnevvaebienlsluolulpipv)a)e,,nra,adnnidneddclderelceaicrsvreeeeardassweeiddst(2TT244.0&&1 `uufaTggn4iidm.mBALLMTaaSnnDddD:R553.304f(.o0durt4rgarfuiitggm2limL0yc1.Le5.r)iMMBdDMeDsHHD4~3BBo.MM9fouDDrg]/ff'maoolbrr.saaobblMssaooDlnl dHlliivrveaeeltrrtlwwievtmtep33rt3.3s2w.2tutosgum/2go2!mdm.l0e1L.l arenldatBivMelDi~vse>r wttb,r t(rTi4gloyrceFTridweser4e5.u9nsuugc!cmesLs.fuMl.DMH DattHemNpottsest:o 74model crcehh2laaa-nntfiggovleeedsslhiwwiveegerrhreeewroottb,bhstsaTeenr4vrteohvdereafactdTto4-tthchwreeieLLircDDeaYTlunb((ssesuenecrrcucuiemmmssallfereuvvklee.lsl~e88rD 77uuumHggl~emmNvlLeo)l)toewwsfh.h3iiTcc94hh iiss uhu>ogm2/rzmlmfo.Lol,ndBBeh~MligreDDvheelmmrsootwdhceealrelnleiitnnhaggleswwcoaaosrs-ecwuprnoinstrsiuctucaeecd!ecsbensmesf~nurlcad.th.smDD(aeMercackrrretseeaiarnssueeemddi athlhleyyv2rre0ool0iod7d)f3b9ut wdhuononsfrJeomb)r.rtotuunTrnehaaetlrteeeevlfleyyolsroo"enn.wllyyearooentnhaeeilshshoiitggirhhmeepddoootshsreeeterlldeeeivivnseelilrnawwstausa'fssfOtitce~eiIsseatenertdtdi(nd(2o2et00taamml0gg2k/c0k0glg7ua-)dddbaenudtm: changes in T+ as dose). 7hereJbre, changes in T4 as ccaoot--tcchrriiistiitcciaamlle]] there is insuj]icient data to include `CCoo--CCrriittiiccaall EEffffeeccttss:: | IIhnynpccerrreetaarssoeepddhyll.iivvceeerrlwwleeinigegchhrttossswiwhs/i)hscitshotaolnloogggeisiccaailnl ctcrhhiaagnnlggyceeessri((de5e..ga.,nhdheecpphaaottlooeccseetllellruuolllaarrlevels. increased AST. ALT & ALP: increased kidney wt hypertrophy, cell necrosis) changes in triglyceride increased AST, ALT & ALP; increased kidney wt decreased splenic CDS+ and cholesterol levels, decreased splenic CDS+ lIdysemmvpephlhooocpcymytetencsts,a,lddec(cdcrercelaaassyceeddd smsppailmcoccmnnawrwtyt &&gdldeaccncdrredcaaessveceddloIlgpgMmMenrrtcessbppaoosnnessdec;;onaannqdduantitative dscsceceloovlrreuiillnnoaggrp,,mdhhaeeempnpaatatagtiliecc,(deemfefiffleaetccyottcesshdoafmonldlllaroomiwwalilinnnabggrnyoiinnmgiluuaattnleeidrrotodceeesxxv)pp.eoolossupurmreeeoonnntllbyya~-selldiivvoeernr wwqeueimigg~hhttsist.a,tive cellular damage, mitochondrial abnormalities). HHeeaalltthh EEnnddppooiinnttss::| CCarcrieitctiilcceaarllatEEenndddppporoieipnnutttssia~lDDseevsvepelloaopprmmeaentn&ttaiatlloe((nbbd,aasseefddoroodnnedcdereellaaaysyeeeddd oposussspiiffbiiccoaattdiioownne.,ight), HaHceecppacatlctiirccat((clidivveeprrr))cpssuyytssittaeelmmscparation, & trcnd [br dccrcascd pup body wcight), C`heCopo-a-CtCirrciittieccfaafllecEEtnsn)dd;ppHooeiipnnatsttis-~cDD(eievvveeerll)ooppsmmyesentntetmaa:ll I((mmmmaamummnmaeraswyysggtlleaamnn;dd addneedvveeRlleoonppammleenntt, h(k(ekipiddannteeiycy))efssfyyessctttesem)m; Hepatic (liver) system; Immune system; and Renal DDrraafftt DDooccuumlneennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOsseAess ooSlny8l.y0.1DD9rr2aaft ddooccuummeenntt ddooeess nnoott ccoonnssttiittuuttee AAggeenrcey ppoolliiccyy PFOA - 58 of 92 22447755..00005888 SSTTAATTEE 0077443388006611 A. Non-cancer Effects Health Standards Statunte HeoalthsEffects, Specialy Study Summary (c.g endocrine, Note: A comple evaluation ofthe otcoletcal irae was not condvcted MDH condictaeodcdre- ~Vote: A comt:de~e ev~/uatio~ q/'the to.ricological literature w~Ts ~ot co~ctucted MI)H coi~ducted ajbcused re- evaluation witchrefed upon EPA hard assessment ae ey sy emtfiaton (E74 20160) ewduatio~ which relied upo~ EPA 's hazc~rd assessment aml key study ide~(~k'ado.~ (E~A 20_16c0.] EEnnddooccrriinnee EEffffeeccttss Tested: YYeess ObOsbesrev~eedd: YYeess ((SSoouurrcceo,, iinn ppaar~t,, EEPPAA 220011663a)) Ta~~Thsyhyrsreorrcooeeiiiaalddtairreeogfefneffeebeecceppttitssi::ddweeemmeinioolPlooFggiOiccAaallexssttpuuoddsiiueerssepparronovdviididnecssiuudpeppnpocore~torfoporrreaavnnalence of atathdhsdyysiorrtoociiioiddant,iddoiiasnsseesbaaossecee~ivaiintneieffoneenmsmPaabFlleOeevAwdasdueeulxnltpsPooosFrurOrcceAhhi~kladddnredeninTn,,cSbbiHduuettnhnnacotevteoiinsnr spmmoraaellvbeeaessle.ennInnce of narsoedppdosoriitgtsioneeinddf,iiiacnnsapspnortreecaggisannstaaoioncntnitasfftebiomoeantawslleewsseenwwriiPtthFhfoOaaunAnntidi-m-TbTatPdPwOOTsSaaonHnnttiihbbPaooFdvdiOeieeAsas.l.saoHHnodobwweTeeeSvnveHerr.o,r dt~nhioyyarrsgooingiioddnsiehhfidooca~mwnioottnnhaeestssshoy((crTTioa44itdoioordrniTTsse3w3a)csiiernnc people found people who ha not been between PFOA ~d who have not been TSH or diagnosed with thyroid disease. aEE5ffffweclcttlss coohfPfaPrFaFcOOteAAriooznnedtthhtyyrhroooiiddshhooomrfm~PooRnnOeeSss.iinnRsaenndiuimcaealldsstoaatrraelggaeennnderrafalrllyey nTnoo4tt wafwsooelrwrdeeehlrsilepgpcohhoerartsreetaddhcatiinenmrtiaazhddeeuudlslttcarmsmuatahmllooelsoraevattossfaacPnnoFddmOemmsSopo. onnRnkkededeiyunsyacgasettodsstteeorrhtuaumlmRaDlene.dvvefellse>se> T3540000-- aHfHonooldndwtehhevveiegerhdr,,oesrtthehteherssaeeenspddthoooscnsesesssecwwrraeemlrreealtco~hvnecdlllocoiwowoerefrsssettsepddrooousnseemdssinottgeresasttltoeedTd~4wwciwitR~ihtfiiDnhn.PtthhFeeOssAtuuddyy m3d the dose-response emxapiosnusreuhnaskoewtn be exposure has yet to be Fully alate relationship of fully evaluated snd th howe serum total T4 and the lowest efictive dose with PFOA effective dose remains unknown. aOOnttdhheesrrteuednnyddoorccersriuinnlteeseeaffffreeccnttssobbeeenyytioornneddlytthhcyoynrrsooiiisddtehhnaat.vveeDnmeoosttrbbaeeseeenndwwetelellsl-t-soststuutddeirieeodnd,e, abmaunnatddd uiisnstnuuccdarrelyeayarsseeaesdduhceltisssgttrhaaaerdderiioonPlloFiitnOneAmnmltleairvleeeelyltrascstsotnhaaasnnniddsttemmhnioitcsc.eeeDwhhehmaciv~rceeehbabsoefeedonnmterrtesehptpooosrKttbeeaerdsdo,i,nse obfutthuesuRaIlDl.y a(tShecigRheeprrPoFduOcAtilveeveElfsftehcasnftohroasdediwthioicnhalfoimnf~orthmaetbioans)is of the ~. (See Reproductive Effects for additional information). Immunologie Efocs | Tostd Yes Immunologic Effects Tested: Yes Observed Observed: | YoAsesssocS(iSoaout~irocsnc,s, biinnetppwaasKre,,nEEpPPrAeAna22t00al11,663ac))hildhood, or adult PFOA exposure aA~Hnadsdvseoricinssiokkattoioboffeniiesnnnffbeececctottwinioeosuueissnsddtpiierssedeenaaasssteeassel(,(aacisshniaalsdmmphiaodaroekdme,riroolorfofkagiidimmneammlltuurPdnnFeeiOssAcuuppepprxrepessosssiiuoornne)) `hAAalslvttehehnoodnuuoeggtrhhb.ttehheaeensrreocsowwsnaatsssiisssotoeonmnmsteelysiiennsddneieiccniaantitniifooennapooifldefefemcffhfeieicocltltdormmgeionocdadbiluifftsiicto ucadtaiioteinsin.bt ombnyayle Cmgchaheitinlledddrerrneerannl())i..aeT~n.,dhrlaeroseesrohsscttiiuaudddtiiioeosnsseshhrsaauevvmeeenPeeiFxxnOaafmmAeiminnlaeeolddveeaacssshssaioonlcdcdiriaaevttnaiiocobncnuisstnbbneeeortttwewissenpeeomnnnsaele am((dmmuaeeltactassmsuuwarraleeddsanbbpdyay/rotaarnnocitfihbtbioholddedyhysiclegrehavl-meclssxP)pFoiiOnsnuAccrhheiilclleddvorremeelnmnsuaa~nnndiddtavayddauuclCtcl3tsis.n.HeTe~arhcelestphssottuPnurddsyocyjiiennt raatedersnedtldeutdsuccaweefdadesraapneatici~biovoddifynthgrreeesthshpipogonhfns-lseexvtopaoconcosinueneereoofactfotshhmemsttehuerrnneeietwyiifntCfh8lluiHennererzaealatssshtirtPnagriosnejselcts; otopefofspstsueeeldrrauutammifotenPPrsFFrOOieAncA.eN.iovT~rihnweogaytsshttueaudNnfidleoussnvtiiannhcccechhiiniFlledadrrrweoenenawsIwesslreeareenendscc.wooninDtddheuuciccrntteceearddesaeiisndninggvgeeanncleceerirvaanelells Tr Document for evo 0 casioprrcpeosuspprpuopolonnasssteiecosinionnsnlrriyeenllaaNDttiioolonn,rtatdooyoPPaFFncOdOuAAin the Faroe Islands. Decreased vaccine dleovceslsotwacsosnesnisinAthgers sptouldys, bu lcvcls was sccn in thcsc studics, but Dr~t Document - for review and discussion Fron $hoo3 p~oses oNy. Draft document does not constitute Agency policy PFOA - 59 of 92 22447755..00005599 STATE O7430062 STATE 07438062 Developmental Effects | Testd Developmental Effects Tested: Observed Observed: Csahimemriilacrarleessalunlstds aacllossouodwweneroreetbsseeeeentnrwwiibiltuhhteccdoorsrpreelcaeitefdidcappleleryfrlfurooarPinFtaOeteAdd chemicals and could not be attributed specifically to PFOA. StSehevyvemerruaasll waanneiimmiaallgssathtsudwdtieicelsssldddeeemmoconrnsesttarrsaatetedefffifcmetcmtsusnooennrtthehseepssoppnllseeeeennTaahnneddse fStehfityfemcdctsusLswwOweAeerEriegLhoo.btbsssTeeahrrsevvweeIddeamlalmtauSssneederrueumscmryeccsaootsnneeccdeesnintmitrsrmaattteuiiodnonenass5reisaisnmpioiAlnaadsrdeito.ovTtithhtheeysrceriiticcaal sEtnuddpyoiLnOt AbaEsLe.dTohnecIomrmtiucnaelsayfsfteecmtsis listed as an Additivity Endpoint based on co-critical effects. Yes Yes | "YoTeshser((SShooauuvrrcsbe,,eiiennnppanarrut,m, eEErPPoAAus22h001u16m63aa))n epidemiological sudics eTetxxehpaaeommrreiiinnchidiannvaggenPPbaFFesOeoOncAAinaoeutxxmippoeonorssobuuuerrsetwhaaeunnemddnaddPneeFvveeeOpllAioodppeammmneedninotbtlaiaolrlgtieohcffafweleccisgt.tshu.td.SSieooMsmmoeestssttuuddiieess uSrsetcdupodoioirnestdsedmomreaeantashsaiuursrrdseeoiddcmiPPaetFiFosOnOtAboouuertsstwiininegygecnmmoaPadttFeeObrnslAao!loadbbnllsdooaoombddpilrtssehaasm,mwppelSlieetgsshutttda.akiMkeeeonnonssiitnththehee iahssegigschoho-c-neiedsaxptpoioorossntuhusrirbreedeCCttw3r8iemcceonoemmsPtmemuFrnuOoinArtitiynyancppdooocprpidutulhlbaealtrtoiioobondinrhhstahaamvvweepeilnnegooshtt.tooSabbtsmuseedorrinvevgseeddotnertmhe icbaosinnrstttorhsacssitaoor,ttrhiotshnoesverbiriseasltkkwonofefleanlooswPFebbOiiorrAfttghhaowwneederiigegahihlttht epaarommpbooilnnrttgghiaaowllnllesi((gsniihgnntlgdaeliemttcoootnnna)s)gbbntieierrrtgtmhhasts..ivIIenn aocasostssnootscrctiaiaaastitt,iinoosnnsetvbbaeeesrtttawiwlceeaaeenlnnaslPPiygFsFneOiOsfAAiocfalInegocveeeen.llessrAaaalnnmddpeotibapit-ruathlhnastwwiloeyeinsigsgihhsitnto,,dfwwimchhaaiitlnleeeyaoootntfhheeegtrrahssetiddsvieiedd 9Sns)touutpddoairetstsacifafnocouhusnntaddutinaasitmmitceaea(lannnsgibgiinitrmithfLhicwwiaennecicirggeehh.attsAedremuidnceutttcaite-ioaornnnnaoaolfylf1so1i9rs9c8ogofr((m99d55a%ns%eyrCCouIIf:mt3-h30e0s,,e- SP9Pi)FFmpOuOleAAarteillaeeocvvnehsel,lss.1.t-HhuHoenwoiatewsvs(enoevcgrei/,rma,twLiwoh)hneienenncprllaeooatwwseeGGdiFFnbRRemtwwawtaaeessrnnaaaccPlccFoooOruuncnAtoteeradddndofsoerbrriuriinmtnhPPBBPPKK simulations, thc association reported bctwccn PFOA and birth `wweeiigghhtt iiss lleessss tthhaann tthhaatt ffoouunndd iinn tthheeiirr lmneettaa--aannaallyyssiissoofftthhee c{hpeirdeenaircliongcyredaastead aenvd sshoofwssehrau,m PniFnOdAivaindudailsowwetrhbirltohwwGeFigRh,ts epidelniology data and shows that, in individuals with low GFR, t"bThTihhreitirsshe ssgauurggehggieetnsscttcrssoettuahslaedthdabaleepoacvoroerilnttsiofoononfuoonfsftedrthehudeembaaPyssssFoooOccwiAiaattmaiioanonntdebblmoeeawttwlweeeGreebPnniRrPPthFuFOnwOdAeAeirgaahnntdds. hcbcoyoirnpntdehdirittwtiieoeonnnisgssihosstnuucccohhuaaldss procclampia and be confounded by preeclampsia and pregnancy induced low maternal GFR pregnancy-induced under hypertension. TTowoomceppaiiiddneemmliaiootllioooggniicctalol spstrtuuedndiaieetsasleeexxxmapmnoisinnaeerdds ddteoevvPeellFooppOtmneaAensnttomoeffapspuuubrbeeerdrttyy in in tCtfheharmrhoooauurlggeshhs, mimhnoaawrtteeeelvranmetairaol,onotrthocecooprrrreddeanbblalltsooaooolddfexsstpaahemomssppeullreteessotiionntPffuooFllOelloAsoww--aauursppsmcooeoffnafppslrurieercgegtndnianagnn.ccyy wSwcioeithtnhhornnwtioso,taahhssoshswooicgceihivaaeettriiro,oPnntFho(OeoArrr)aeasunpploootsssnssoeibbflstiehtueiindsnyeddiitncc~aavttodiiaoosnntutoodeffiareasnnmaeecrnaeaarrclriioecrnrhfemmliecesntneiaeanrnrgec,hhee "swcictnh whiigthhehrigPhFeOrAPFiOn Ath)e ianhoenressttuddsy and a later mcnarchc sccn with higher PFOA in the other study. AdAemmvoeolnnoggpmthheeentaaannliidmmeaalllassyttsuudd(icieegss.,, ddleeoccwrreeeraassbeeodddyppooswstetnniaagttahaltl gdgerrlooawwyttehhdlleeeaaxddeiinngg 0to oSdoeppepeveannerilianontgpgi.,mondde)eenllhtaaaayysleedbddeevvleawagngisoninba(saleel.groov.,pepedleno.niwinnTgegh,re,bsanoendddcyaawecccecteilglehefrtsao,triedmddetlpaphryreeeppbduuaettsiysaiellofthe {RsRheIfapDDnarataahnnteiddosnwwe)eerhrureamsoocbbboessneeecnrrevvnoeetbddrasaaettrivSoseenedrrcu.uomTmrhecceoossnnpeccoeeennfntfdterricaantttsiiotofonnosshrme~030tR0hA-e0Do-.bfloalsddishhoiiggfhhtheeerr than the serum concentration corresponding to the RfD. Dr Docunen frei nd dicusion puFrproosnes6on0l0:1D93r docu docs not consis Agerey poy Draft Doculnent - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 60 of 92 22447755..00006600 STATE 07430063, STATE 07438063 QdQueuavaellliitoaaptimveenstsccooorfriifnneggmaaalssesseeossfssfmmsepenrntitnffgooueuxnnpddoddseeelldaayiyneeddimmeaarmmammasraUyaggmllaaluneddvels jjtduuhessevtteRlslIloiDigp.ghmhtHletyonwthheioivggfehhfreeer,rmttMhahlaaDennHotthfhfheesapssdrecirncrmogunmnecxcceooprnnoncssceeenrdntetrgirnaaatrtuiidootiennnrgocctooahrmtereessisepprhuoormnndedilinennvggettloso otvvhfaaerraiiavRabebIirDillaii.tgtyyHe ioilnnweqnuqegauvtlaheiolrti,tafatMtmiivavDeemHssmcchaooarrridiynngcg.go.lnTTachnheederdnuuusssceertoesogfafarQqnduudiananngntiitthauaeitivvimneeohfmmebtereeeaarnsesmtuuirrnereassl eoednnfeddanvbbieuureddasdsgeiisnntleafftneeimgmsttaahilcleeaolpfpluymuppSassimgwwnmieefarieercyaaanlgltssloadoneaadlssassdeeyussacssetesddhaiiinngndhooennnrueedmosststbueueddrlyyeovaafennltsdde.rmTihneasle effets have been includeda co-riical identified statistically significant delays effects have been included as co-critical effects. at higher effects. dose levels. These dAAunnctaaddbddriaittniicoohnniaalnlgssttpuuaddtyyteeervnvasallauunaadtteetddhetthhaeebccioorlrrree1llaasttiuioopnnpobbreetttwwpeeueepnngmmraoamwmtmhmaray~ rough lactation No significant impacts duct branching patterns and the ability to through lactation. No significant impacts were found support pup were found. growth sDDeoorssueemss crreoesnsuuclelttniitnnrggatiinniossneercrnuommrrcceoosnncpceoennnttdrraiattntiioogonntsshe>>77R00I00-D-fforolelddsuhhliieggdhheeinrr ttdhheaacnnrettahhseeed neonaal survival serum concentration neonatal survival. corresponding to the RID resulted in decreased RReepprroodduuccttiivvee EEffffeeccttss Tested: OObbsseerrvveedd:: YesYes | YAYseeossr((iSScoosuurorcfcese,u, diinnicppasartr,it,nEEhPPeAAig22h00-11e66x0ap))osure C8 Health Project study `pApprooepspeguuralliaanettcsiioyoon-nfihhsnaatduvvudeecieerrsedeppinhooyrrtttpheeeeddrthaaeissgnssshooic-coeiinxaattpoiioorosnnpussrrebebeeecCttlw8waemeHepesnneiaaPPl.tFFhOOLPiAArmoicejtexxecppdtoossdstuauurtrdsaeyaanndd Sudpsgeurceegrgegenesaastsntecascycoi-roninrrferdeelucalcautentiiddooinnthyybbpeeaettnwrwdteeeeefnnnsoirohhtniigygohh.reerroprPPweFFeeOcOrlAAam,llepervvseeievalle.ssrLsiinneimfcfeaeimtumesadaallleedisstaytaaannhddas cbbdolceoccannrreaessfsuufeggesggceeitsnssttoefefeddcPsusiinFnndOccieeAtybboiiarrnntthdhmaaafenlnreddtillfliaetrcytati,alhitcitooywnteaenarvdraceprocc,tillnriiemtmivsiiennhroaasatteviinoeocnnabuerrsooeauunlstiestys.. hNNaoos denied clear effects of PFOA on male fertility endpoints have been identified. AAremmpoornnoggdutthcheetiaaovnnrieimmfaalrl ssittutuddiiepessa,,rttahheemrreeetwweaarissnsnnfooemeeaffflfeeecttraoosff PPHFFoOOwAAevooennr it s`rsechhpooomruuoplldaddrubbeceedtivnntoeoottmoeeadrdlftteehhrartaiatltiffsteeyommrpaaalolreetaharmearttesstephhreaascvviieeensvvfeeerIrmyyn"cahhrleieigagrhshaeteedsll.iiuimmHliionnwlaattteiivoroennr,rraiatttee ecrrexoespsmooorpsrpapetrtdicoidanotnstosaacnnmrdduaiilmncncccrorraenetacsasesoenerdtdrossatttlhiillcloibrnrissrtpthh>ess7c0iwwe0es-e,rfreeolnloocdbbrcshsaeiesrgrcvhvdeeerddfutiihlnnlappnlirrtteetheggrnnaasnncttrummmiiccee ceoxnpcoesnetdraattisoenrcumomceosnpcoenntdraitnitoognsth>e7R0I0D-.fold higher thaw the serum concentration corresponding to the RfD. wNNaoosreeevvpiidoderenntcceeedoofinfaaaldlttueelrrteeddmattelesesttriiccsuullaaerrxaapnnoddsessdppeetrrmmdosssttrreuusccttpuurrroeeduoofcriffnuugnnccstteiioronunm ccwcoooannscmcercenentpstrorapartttoiieoodnnnsisdnto>i>at33nd5h5u0ge0-lt-ffRmooIllDadd.lehhOiirgagnhthesecrresxttthuphdaoaynnsehttdhahesetossreecdrprouousmremtseccdpoorinnonccdceeurnnecttairnsraegtiidoosnnsepruemrm a{achbboennrrooremrsiumplaoainlltidtiiicsentssgudaatynnoddLthddOeeeAccRrEreefLDaa,ss.eeOhddonttweeeessvsttoetousrsdt,teyerMrohonDaneesaHratethpddaosoorstsceeodllneeicvvnececlmlrssesasssriimeemidgilalaasrrprdeitornmg ttothhhneeelyqcquruaaitatlilihcititayyglohosfetfruttddhhyoisssLsestOstuuAddyEyaLan,nddhooowtthheeevrressrt,tuuMddiiDeessHhhahavaees reported concerns reported thes effects regarding these effects only at higher doses. NNeeuurroottoovxiiciittyy EEffffeeccttss Tested: VYeess t(liimmiitedd)) Observed: YYeess ((SSoouurrccee,, iinn ppaarrtt,, EEPPAA 220011663a)) Draft Draft Document Document --fo- for view review and and discussion discussion ppuuPrrppFooOssAeess-6ool1nyl.y0. 1DD9rr2aafftt document document dosdoes otnot consis constitute Agency Agency policy policy PFOA - 61 of 92 22447755..00006611 STSATTAETE 0077443388006644 eTifhhfeeetddsaa)ttaaofppeePrrttFaaOiinnAiinnagrg ttoolinnmeeiwutrreoodt,toobvxuiitccitdtyyo ((niointnccliunhddiiinncggatneneetuvhrreoopddreeesvsceellnoocppemmeoenfnttaall aeaEsfspsfsieoodccceitimsaa)ittoiioolofnonPsgsiFbbcOeeattlAwwseeateeruenndilPPeimsFFOiOhtaeAAvde,aanbfnduodatuandvdvoaarnnriiooeetttayysinsoodoffcoiciuoaatuttceticootonmhmeebseep.str.ewseeennce of mmEomaptatitodeerermnmaaliliolsslloeesrgruiuamcmnadlPPscFFtoOuOgdnAAiietsccioovhnneaccvaeeennitftrrolaauttsniiodoonnnsfsocaahnnaiddslsdffoiricnenieenamtmaoiogtoneotdrobrse6ktsaiwklnileldsles,n,1gg5rroossss mammgoooenntdtothhr7sssykooeirrallrbbss,eetata~nnwveddeeecpnnroebbgneenahhitataaivvvlieioPorarFaablOliolAoitrieeccxsoopoooorsrfdducirihnneai.alttdiiErooepnnnipdpaerrgomoebibdlolele6momagssnyiidnnst1ccu8hhdiiillcddsrreeonnf cwachgheieiallddkdrr7esetnnyateddiaesertrrsiiicvvaaeenldddasffprsrorooemcmniaatttthhaieelonNPNFHHbOeAAtANwNeEeEexSSnposaasennurddrueCCm.88EPpppFooiOdppueAulmlaawtitioiitolohonngsspyaofrosueutnnuntddadileas of sports of ADHD (Hoffman etal. 2010; tin etal. 2013) weak statistical association between serum PFOA with parental reports ofADHD (Hoffman et al. 2010; Stein et al. 2013). oIInnfffmooirrcmmaattfiieoodnn PffrFrooOmmAaantnihinrm-~oaaullgsshttouuuddtiieegssesiitsaaatllissooon qqhuuaiidttesdellitilmemicttteeaddb.l.eTTlhheeeveoolffsffssoppfrriinngg doPPeFfFpmOOrAeiAcseiiinnofenttdh-heiiPikrrFeObbrbrAaaeiihnntahssvriaaototurbbgiirhrottorhh.u.mtuLLgsooecccslooteammtoisootttnrooerrnhgaaatcdchttiidvwvieetittyrey,ec,tanaaobnntslxeiiaeellteytyve--rerreleldslaaotteefdd or or edCCxieiprprlccroaaerddsaisitaiaoonnrnyaa-lcibtvkeivehiiabtvyeihttoeearssvttpissoarrrte,etvveoeemraasmlleeudIdnstggcelehennddsesterorr-ec-rinreaegllltaahattreewdodeuddrpeiiffsfnfteeorirtenenanglcc,teeessrtehiidenn. wePPxeFFrpOOelAoA-rla-coestsoxsprpayoocstsbieeevddheammtvahailaolenersstpwwhaeetetirerreerenmmssp.ooerIrcneettiaahvcceettciisvovoneectaiaraonnllddsg,PProFFTuOOhpAeA-s-eoretextxsipunpolgots,sseeothddfeaffeenmmafanlleess vawvirioeor'rwoetsslhettusuisddnyyahcooetffivhhpeiirpptpehposaocnecaantmhmoeppfiaar5llr0esssyynpnnaedapcptttii1ivcc0e0ttrcruaoamnnnosstmlrmoiilPsssssF.iioTOonnhAeaainnrneddcsrnnueeelautussrreioitdtfeean in SngseppruooorwnnittttaahenngeeinrooouuthwssetsshpyynrnTeaahsppeetfnisiccceeccduuoarrtfrraee5nn0sttuegaaagnn~edddst1ha0aad0dn~aaetnnemdoeelqqfuuoPiriFvvaOoodccdAaailtliiniioIcmnnrpapealaaccssttetudoodnnies of potential neurological neurite growth. These potential neurological eee of PFOA. data suggest a need effects of PFOA. for additional studies of OOtthheerrSStutudidelde/sE/EffffeeccttssC!oCnosnisdiedrearattiioonnss S7T"taaunndeyettwaaal!sQ(20d01e13s3)i)gnaaeccdtl EEoPPdAAet22e00n11m66iaaneifdictary fat content could be an important variable influencing the impact ofPFOA odoSnnitutssdee(yrrRuwuFmmaDs)TliidpopeiirdsdaissghnGGiergrdhoo-utufoppastsdedootcffetsrsmce(vviFenenDne )oiof,rrdecwiieiigattahhDhtto~m4r-ofmawntiottcnhhoto-nhuot-teolnlPddt FcmmOoauaAlll,eed CfCboSe5rT7a3BBnwLLieIm/c6GkpNsNo.rmmtaTiinchctseevwwRaereFriraDeebslgpeirivvoieenvnnifldueceeiidtnthcee1irrn2aga%lltaihiqnqeuudiiidmdthepreeaagHucutlFlaoaDrrf atPFOA fat pdp(srrieoaotfvvfi(ildRdoceFwddeDr33)5a5o%n%rdaoocfhfottihhgmehcii-irrfla)cctaadllPooierFritiOcc(ssAHffFrwroDaoms)m, affwatd.tid.theTTdohh0erewffbaaittttsshhowwuedetirrceePtFsppOrrfiioAmmra,ar3rfiiocllyryk3mmsowonenoaeoutkunssn.aesTatvtuhuereraaRttthceFaddtD((moopallriiionvvvteeiadooielinld)e)doo1rr2%ppdooolla?ysn~udanonstfhasatetumuHrragaFtt/Dceddday t1b(o0syathfthfheeleommwPiRiceceOre.Aa. -nTTtdhhreecaoPtPrenFOdOoAigAlr).ottruPeepFasatOettdAheggwrrpooaruuseppvasisdowwdueeserdrdeeatoyffeebddoaathdd libitum, diets for libitum, and the control groups 3 weeks at a level that and the control groups were given maintained were given the amount a dose of 5 the amount consumed mg/kgiday consumed by the PFOA-treated groups the previous day. T"tiThshseeueff,auttbccuotonntnoetnttioneoflfnittvhhteeerwddieiceittgsshaatllooTnnheeerreeassduudliltteeiddoniinnossfiiggPnnFiiffOiicAcaannttot ddtiihffeffeeRrreFennDcceerssesiiunnlbbtoeodddyyinwwsieegiinggihhftitcaaannnddt ssiuuncbbrcceuuattsaaennseeioonuussbowwdhhyiitteeeiaagddhitipp,oossleeiver twawienseisdigughHeth,.Ft,bDAuAtLLrnTeTso,,utlAAitnLeLPdlP,iiv,neaardnnwddeceppirllgaaehsstma.msaiaTenhffrerctechaedffdaamttiatttyysiosaanoccfioiddbfssoP,,tFbbhOuutetApnniootdottiiitdnnhyeAmAaRSSlFTTaDoonrdrrebbssiiuulliiblrrtcueuubbditinnai.nn. cTTsoihhgueensiaawfddihcddiaiintttitoofinnnacoordffeePaPpsoFFesOOsitAAisnttTbooohbbdeooyttHhhwEttehDhiegeahRRlto,FFnlDDeiver adhdieniddpdannHtoootFtcDyrrteeesrsuehulstyulipiltnneterdddteerfifoniipnnhdiiytteii,cvvreeneaaaslleetteserrcaianttiiaotrohnnnedssoimiinnnafsvlslisvarieomrfmhhasbiitossottt,horoppyeaapttchihedoollilldoogyigynm.yf.aillWWzahtnheideonnnsuPPwbeFFcrOOueAtAaonbwwesaeoasrsuvsaaedddw.ddheeiTddthetteoofalttthvhdeeeedRRpFaoFDsmD,ita,s.giinnTeddhiiicecnaaHtttiihoFoennDssanaooilffomanles nehbbceeeriiponnasggtiosffced~daentthdhheeyiHHpneIfFrlDDtaromwwmpiahitttyhhi,oPPnnFFeOacOcrAAocsowiwmsap,asasanniiindneccdirrn,eefaalisasnemetddhmimmsaootrcoraeersyett,hchaaebnnlyl iiiinnnifttihdhleterdaRRrtiFoFopDDnl--twPPaFeFcrOOecAuAombuaasnlneiairmmtvaiealodlsns.,a,Tanahssdeisininldigdvniiceicafraittdeceadadmnbtbaylygyhheiiigignnhhcerethreraellseeaevvndeeillimssvaooelfrfs twinrneiicgcgrlrcyeoeacsseirseridiaddnieends,,tihbbneuuftltHannmoDotmt liacitvvoioenrrntoccalhhcooclcloeoesmsmttpepearraoornlleieododrr,offirnreteehtehffiaaRstttFtcyyaDsaacecci,ioddnbss.ty.roIlIinlnpttibhhduetdederepopcipidrdleieidtadysaymecmdcaaullwmiaatdduihilppatoothisseoeenatdtaiidsnsissdtuuieesossin,,gnaoadidffiiiPppcooaFccnOy.t~tAlyee cissnoiizcmeerpeawwarsaaeessdd liver fo bibPnooFcttrhOheAttahhseeewdaRRsiFFnaDDtdhdaaeenndHddtFHFoDFtDhDceoccnHootFrnnotDtlrooclblo.su.mt IInpnnoafftlrlmetadhnmemtmoaRattFtohoDre.ryyRNccFeeoDllldciiannoaffniitllrfttroorarlattitbiohuonent swwduaeabscserueootabbassenesdcrovewuersdithwiinhntihtttheheeeaaedeptpdiiiditdiisiodsdnyuy3emonsafalwlPaaFasddOiipApprooosscveeoitdmtieissdpss.auureeessdwwtohheenn PFOA was added to the HFD but not the RFD. No data for the subcutaneous white fat tissues was provided. DDrraafftt DDooccuumlneenntt fo- for sie review aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-6ool2nyl0.y.1DD9r2raafftt ddooccuummeenntt ddooess noott consis constitute AAggeennccyy ppoolliiccyy PFOA - 62 of 92 22447755..00006622 STSATTAETE 0077443388006655 The authors evaluated he hepatic expressoifon gene involved in he elatoifofan acid metabolis ig The authors evaluated the hepatic expression of 84 genes involved in the regulation of fatty acid metabolism using RTs ProfsPER Arts NPD andr PFOA ard thcapresso o 33 gens C15 Fo PFOA lone RT2 Profiler PCRArrays. HFD and/or PFOA altered the expression of 33 genes (> 1.5 fold). PFOA alone pried 15genes 1 Spand dowmreglid $15 ges with Ft sed and risen cabato, Eight fy upreNflated 13 genes (> 1.5) and downregulated 4 (> 1.5) genes with fatty acid and triglyceride catabolism. Eight fatty i sport ard ene was upratedb PFOA i one as donut Th tds demons he acid transport-related genes were upregulated by PFOA and one was downregulated. The study demonstrates the porns ofth ft Som of te dic 203 modafohe fos fPFOAt on he Hv in rl. Dama 10 he importance ofthe fat content ofthe diet as a modulator of the effects of PFOA on the liver in animals. Danmge to the ver aes was madhe postos ofte WFD liver tissues was intensified in the presence ofthe HFD Wolreal 2080 ac E24 20160 Wol!'et a! 2008a aci Et'A 2016a Toland apt fst wipe 2951/Simd minc-- -8prgroup) and PPAR ul mi (12984Se- To characterize hepatic effects wild-type 129S 1iSvhnJ mice (n - 7-8 per group) and PPARct-null nfice (129S4iSvJaePPARGmo m6por ron wer gasedosc wih. 15 or 10g PFOAor 50m Wacth 14633 a PPARmmlGonz/J, n = 6-8 per group) were gavage-dosed with 0, 1, 3, or 10 mg PFOA/kg or 50 mg Wyeth 14,643 (a PPARG sori ad dpe CD10 7 or row) wih, 1nd 10mg BEOARG 17 de The miss wre PPAR~ agonist) mad wild-type CD-1 (n = 7-8 per group) with 0, 1, and 10 mg PFOAikg for 7 days. The mice were est 34 hors Fo in the ot dein. rood wes collet for eum nde hor cr reve and sacrificed 24 hours following the last dosing. Blood was collected for serum, and the livers were removed and `wweeiigghheedd.. LLiivveerr sseeccttiioonnss wweerreessttaaiinneedd wwiitthh hheemmaattooxxyylliinn aanndd ecoossiinn ffoorr eexxaammiinnaattiioonn bbyy lliigghhtt mmiiccrroossccooppyy aanndd wwiitthh mag itfoerieson coon igseoP. Lie aShors wer HAD Press Fenopy OF uranyl acetate for transmission clcctron microscopy. Livcr scctions wcrc also processed for immunohistochcmistry of PCNA ieoeye pertoph and 1aculaion obs ed both Sn oF a:pe e, wereseigned 3 sco PCNA. Hepatocyte hypertrophy and vacuolation, obse~wed in both strains of wild-type mice, were assigned a score Pom 104 ch on vey ih bmg eons abe nd bins anh cops wih copa' from 0 to 4 based on severity, with 0 being no lesions observed and 4 being panlobular hypertrophy \~ith cytoplasmic Ceclaion Tat eons 1 PPAR were snc scone (0) bcd on ciopomic vaio sn vacuolation. Hepatic lesions in PPARa-null were assigned a score (0-4) based on c~oplasmic vacuolation as no Rpeophy was ahsed. hypertrophy was observed. Comparison valu, host sod lis Wool Jtonssgs, ad ging i ers Al Compared to control values, the absolute mad relative liver weights, lesion score, mad labeling index were significantly isiningccnrrieefaaissceeaddnt((lpyp<<i00n..c00r55e))aisinnedaa(ddpoo<ss0ee.--0dd5ee)ppeiennnddtehenenttwimmladan-nntneyeprreiinn12bb9ooStth1h/ssSttvrraIaiimnnJssoomfif cwweiilleddxttpyyoppseeemmdtiiocceeWeeyxxepptooshseedd14,tto6o4P3P.FFOOTAhAeaaabnnsddoaalllusstooewawenerdree significantly increased (p<0.05)in the wild-type 129S 1/SvlmJ mice exposed to Wyeth 14,643. The absolute and eB Ter weights ang ion eos wis agen eras (<5 05) in de eparden mamma all PFOA relative liver weights and lesion score were significantly increased (p_<0.05) in a dose-dependent manner in all PFOApon PPAR mice Th sling des was sian msc (00%) in PPARGnl mice cup 1 exposed PPARc~-null mice. The labeling index was significantly increased (p<0.05) in PPAR~z-null mice exposed to 0m PON Absoc and eine ner wei. sion score. and ing ew of PPAmuRl mice Epes0 10 mg PFOA/kg. Absolute and relative liver weights, lesion score, and labeling index of PPARa-null mice exposed to Welh 14643 wer no Gret rom contol vas. (es Tal 3-1 rom EPA 20166 bon) Wyeth 14,643 were no different from control values. (see Table 3-15 from EPA 2016a below) op | uVnarlew3o.15g.nHsep|atWiciipeetmsg1inmPikF|eOA.troesutmesoMince| agus Group Liver Weight (g) Relative Liver WeigM (%) ~R(l-type CD-1 Mice Le:sio~ Score gabeRng In(~ex I mg.;.k~...,:.da.v PFOA I0 mg,kglday PFOA Con~'o:l I mgikgiday PFOA Sommetirseaonnroonr|| 10 mg.:.k.~...,".d.a.v PFOA ~ ne14,643 I mg;kgiday PFOA 3 mg~:kgiday ?t:'OA I0 mgNgiday PFOA RT 2,26 :: 0.~"4" 3,48 ~ 0,54~ 6,5 ~ 0.5" 10.5 : 0,8" Wild {)])e 129S1iSvhna 0.87 ~ 0.08 1,22 ~ 022" ri0sso0nn || 2,20 =..0...a.a.. 3.3 ~ 0.4 1,6 m 0,T evirsionr 8,3 ~ 0,2* 02)2 0,08 Fri mse PPAR~ m~II Mire 3,4mor 2_g ~ 0 18~ 9.4 2 1 ~ 0.9 3,0 ~ 0* 0.3 ~ 0.5 2,0 ~ 0,0~ STiosroeyr 4,0 ~ 0,0~ JETS 0,7 ~ 0.5 7,7 ~ 30* 0.3 ~ 0.2 0,7 ~ 0.6 TToeoyr 2,4 ~ 0,9* [XE EeE r I.ct nes t A LU a AAA PY Draft Document - for review and discussion purposes only. Draft documeut does not constitute Agency policy TRonsisotoy PFOA - 63 of 92 22447755..00006633 STATEo7dssoes STATE 07438066 Ulsan wredons on ve scons om ide 12951 Sun ics and PARll ic, bi Ultrastructure evaluations were done on liver sections from wild-type 129S1/SvlmJ mice and PPARc~-null mice, bm oom Ce te oewar oxo tse Somer oF pe hm so not from CD-1 mice. There were the expected differences in the characteristics of hepatocytes from the control wildoe estoniBohahs PRO edamd oth MS whe me te PARA mis type mice when compared to both the PFOA-treated and Wyeth 14,643 wild-type mice. In the PPAR~-null mice, the i oe com nd och 15d lr sa bt eps of PEO dod as responses of the control and Wyeth 14,643-dosed animals were similar, but the response ofthe PFOA-dosed animals ddiiffffeerreedd.. ((ssecce TTaabbllee 33--1166 ffrroomm EEPPAA 22001166aa bbeellooww)) Table 3-16, Mouse Hepatocyte Ulrastructure After PFOA ar Wythe 14643 Treatment Table 3-16. Mouse Hepatocyte Ultrastructure After PFOA or ~,Vythe 14,643 Ireatment sommes | omen |Go oh| Fsivorsonion| somone | TSapne Mo~se:ire~ment Glycogen Gol~ii Roll~ ER Mitochondl~a Peroxisom~s Lipid-like Vacuoles EaT terrEoTn Roi pe Rom sos omeTnr ET Somered Wiid-~e:'PgOA er > (10 mgikg) Woop [Nepe [Nou ce Namo [Yomen [nr Wild-wc~Wycth Negative Negative [FPA Cont om J e|n[s Sed PPARc:-null/Control TAFRTO [Cimier Times TNonspne--orsed--[Noron" PP,~(c-nulFPFOA FE(10 rag&g) PAR {roman | Pomona |e PPARw-tmlFWyeth ~'onm~m~l Lhniied ~omme~l Nolr~nat: ~cmce ER No:mmaF scagcc ER Pro~nent Linfi~ed Nmnero~s Nmncmas Nume~o~s Not rc~or~ed Prommem Numero~s Numervus Numerous Ab:,;em Not tcpo~~ed Ab:sen~ Scattered Sca~c:rcd Sca~{ered Numerous' Sca~ered Ty Source: Wolf e~ ai, 2008a is spat PFOA and Wath 14,64 ved silly nthe ilps ti bt ies nthe PPAR: It is apparent that PFOA and Wyeth 14,643 behaved similarly in the wild-type strains but differently in the PPAR~zhepeaof FRsO deita FAR mics Sod oe Seog soto Gl de2nd null mice. The hepatoc~es of PFOA-dosed PPAR~-null mice exhibited lower glycogen content, Golgi bodies, and EE os associated rough ER than both the control and Wyeth 14.643 PPARa-null mice. In addition, the PFOA-dosed Fol me 1d amo ee mmmBond Ip 0 vaulc rosshok eves 0 igh PPAR~-null mice had numerous large nonmembrane-bound lipid-like vacuoles throughout the cytoplasm. At the high on 1 me dv rw crn ne ig nh ck tne wh Woche 0 Th dose (10 mgikgiday), there was an increase in the labeling index that was not observed with Wyeth 14,643. The a ee shen he sce of PRO ded PPARs cre cs authors concluded that the large lipid-like vacuoles in the hepatocytes of PFOA-dosed PPARc~-nnll mice were likely loon of PEA Uns Sonn of is le LORY i md con mcd aaabbcscsooullmuuttueelaaatnnioddnrrseelloaafttiiPvvFeelOilivAvee.rrUwwneediieggrhhttthamenacddohhneedppiataittoiinccsmmooorfrptphhhiosollsootgguydyycc,hhtaahnneggeLessO:;AnnoEoLNNOOwAaAsEE1LLmwwgaaisskgee/ssdttaaabbylliibssahhseeded.d. on increased NNakaa murakeettaala 1220000m 99aacctiuEEPPAAr220012a 66a0--- ee HOA pone Betwci and ba was estigted wig unanizedPARG The functional difference in PFOA response between mice mad humans was investigated using a humanized PPARct as ons me PPAR Fweder hh lof ono FPA Rep nh transgenic mouse strain (hPPARa). Humanized PPARct mice express a high level of human PPARct protein in the Ee Rad kre (uPA ce, PAA and IPPARS rate shed wih, liver. Male 8-week-old wildtype (mPPARu) mice, PPARct-null mice, and hPPARa mice were gavage-dosed with 0, nd 03 mh PRON 14 por op) fo3 eu nd snd 530 hour Folin hc Bs. 0. l, and 0.3 mg/kg/day PFOA (n = 4-6 per group) for 2 weeks and sacrificed 18-20 hours following the last dose. Blas codan endforhore ad lence oncenndAtLTomentss,. Lor Blood was collected and analyzed for triglyceride and cholesterol concentrations, and ALT measurements. Livers erode orf gh csant omen, hs patho ha. were collected and analyzed for triglyceride and cholesterol concentrations, plus histopathological changes. (see Tome om EPA hres bo) Table 3-17 from EPA 2016a below). Drmpines sr ntoDTS ATTY Draft Doculnent - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 64 of 92 22447755..00006644 srare_orisoet STATE 07438067 Table 17. Rel Response f AP AR. PAR, nd ARs nl Mie PFOA Table 3-17. Relative Response of hPPAR~,., mPPAR~., and PPAR~-null Mice to PFOA Farsmeer PAR wil ParaRlerer bPPAR,~ mPPARa PP~o re im iFE E Liver weigh~ ND r compared m cNmoi (0.3 ~ comFared to tom,rot (0.1 nwkg/:day) mg;kp:day} Te [i isiri Liver~body weigl~t rato >~) g compared D cm~troI (0.3 ND mgikg:day) Seppe {arid Hepa~oc:?~e l~}lyer~ophy b~ld [0.3 mg.kg;day) Mild (05 mg/k~id.ay} ND AE i ALT ND ND ND me J Plssma chole~lerol i compared m mPPA]{ r~ ND ND - {al~ doses) Tr C SptareaE sha san Ta [7 Live~ choles~eroI ; compmed k~ PP.~-nu[l ~ compared *o conuoI (0.3 ND @. 1, 0.3 mgikgidayL mykg~day) mPPAR{~ (0.3 ET wo 5 Plasn~ ~rigiycedde N~} ND ND bob SS SSTadR Ss aSa e Liver n~giyceride ~ compared m PPAR~HmI1 (0S mglkgiday) ~ compared ~o PPARu-n@i (0.1.0.3 mg<'kgiday; ? compmed to control (03 ~Wkgiday) ? comFared to nk~PAR~ @1I doses) Nole.s: TA R . ND=o difference, - To FPARG ic fad mh wldsps mis nh ti pls cr vs gia nerd nd The hPPARa mice differed from the wild-type mice in that flaeir plasma cholesterol was significantly increased m~d rts hl hs So ot AC do es their liver cholesterol and triglycerides significantly decreased at the highest dose. In addition, the increases in ns nd sr we so hho seo Hp i The PPAR mis absolute and relative liver weights were less than those observed in the wild-type mice. The PPAR~-null mice Fw tm A or a differed from the wild-type in that liver triglycerides were significantly increased. Under hs condtns fh sts hs NOAELILONEL or PPARs mis v0 103 mtg dy of FOR bn Under thc conditions ofthe study, the NOAELiLOAEL for mPPARc~ mice was 0.110.3 mgikgtday of PFOA bascd on inicnrcreeaasseedd lliivveerr wweeiigghhttaanndd iinnccrreeaasseedd lliivveerr ttrriiggllyycceerriiddee aanndd cchhoolleesstteerrooll ccoonncceenntrtraattiioonnss.. TThhee NNOOAAEELL ffoorr PPPPAARRa-an-nuullll ED Sohn GOD Ssh come ba ot gt vee td el he mtn mice was 0.3 mgikgiday (HDT) because the changes in absolute liver weight were not dose-related and the increase in ir wee as a yt Gn fm he coil Ts ROAEL fo bAPRam at son relative liver weight was not significantly different from the control. The NOAEL for hPPARc~ mice was also 0.3 PFOA Hoven mms tdsed aSamm pn ce mgikg/dav of PFOA. However, a nonsignificant but dose-related increase was observed in plasma cholesterol. cto 011s 604 ut Li et a! 2011 aci EPA 2016a hoa mows ad ha PPARa in POA dd snr its as vss, Wb. The involvement of mouse and human IPPARa in PFOA-induced testicular toxici~ was investigated. Wild-type, PEAR one PARE me 150m wr sc FOR ds Ena ds 10 1 PPAR~-null, and hmnanized PPARc, male 129iSv mice were given PFOA daily by gavage at doses of 0, l, and 5 iy or Sk Bs wh ad sl st cid tn ro, Ae md mg/kg/day for 6 weeks. Body weight and testis weight were not affected by treatment in any group. Absolute and Rema a pata ar eae sos Sawrndonts oo dg BE relative weights of the epididymis and seminal vesicle plus prostate gland were decreased only in high-dose wild-type PR om th HT ol Noo pe Som TOT re et 4 00 $5 mice compared to the wild-type controls. No effects on sperm count and motility were seen in any group. Sperm mine er bly mad nth tops of Es maed PARA, ti abnormalities were significantly increased in both treated groups of wild-type and humanized PPAR~ mice, but not in PEAR lt Fama atone Ils i ean owdo wine ics md the PPARct-null mice. Plasma testosterone levels were slightly decreased in low-dose wild-type lnice, and ssiiggnniiffiiccaannttllyy ddeeccrreeaasseedd iinn hhiigghh--ddoossee wwiillddttyyppee aanndd llooww-- aanndd hhiigghh--ddoossee hhuummaanniizzeedd PPPPAARRca~ mmiiccee ccoommppaarreedd ttoo tthhee go Teton hi ty ch doccd mnt me PPAR ms control groups. Testosterone levels were slightly reduced in a dose-related manner in the PPARa-null lnice, but me ava statistical significance was not attained. RNA ll forse gns ascites shod sis, npr, and soon mRNA levels for several genes associated with testicular cholesterol synthesis, transport, and testosterone inns i cared Lok FG.CoX mi, FIG Coke rt rrshred biosynthesis were examined. Levels HMG-CoA synthase, HMG-CoA reductase, and aromatase were not changed hr mer me Boa, Epaof Cogan a Gs Po (SRF HORSE a after treatment in any group. Expression of 65teroidogenic acute regulatory protein (which transports cholesterol into no A Ape me oh dt dn od PAR ce Gos mitochondria) was inhibitcd in ~vild-typc mice at thc high dosc and in humanized PPARct micc at both doscs; Cr oat mon PE, Dr dt otros A oo Draft Doculnent - for review and discussion purposes only. Draft document does not constitute Agency policy Le PFOA - 65 of 92 22447755..00006855 rare orsseoss STATE 07438068 ppseierdriieppchhheaeriraanllcbbleeennazzvooadgdieiaaezzneeppziiynnmeeerreewccaeesppdtteoocrrrlleeeavvseelel dwwaaisns bddoeetcchrreegaarssoeeuddpsooonnlflyywiiinnlhhdii-ggy~hp--eddoomssieecehh:uummcayantnioizczehedrdoPPmPePAPAR4cR3z0mmi1icc7;ea;-hccyy~dtorocochxhryrolomamseec/PPCA41S570-O 22dsie00dhellyycydaharssaoeeignwwecanalassesaiievnnahhwigiabbeisitteeednddezcyaarttmettaehhseeewdhhaiisiggnhhdbeddocootrshseeeatsriienendabbtioeondtthhbgorwwtoihilulddpg--srottoyyfupppeehsuaaonnmfddanwhhiiuuzlmdmea-datnyniPpizzePeemddAiPPRcPeP;mAiAccRyeR~.tommcDiheicrcceoer.m;eaaaennsPdde4d335ep~0x-3ph-1ryh7edyasrds-orhixoyoyxnsdyirsooetefrxroyo1ili7dads-eiC 17- hdpyaydelrhdmoyrioxdtxyroosyygtlstteeerrnraoaonisiseddfewddreeaahhssyyeddd(errCcooPrggeTeea)nnsaaewssdaeesinwwdaabessoctrtthheheeatrsooeenandltleyyidnccbghhoraatonnhuggpgeesrffoooouufupnhnsddoumfiinnawtntirrilezedaae-ttdetedydPpPPPeAPPaARAnR(dR~a-ahmni-nugicuhle-ll.ldoDmmiseciecece.hr.euaImInsnaenttdhhieeezxemmpdiirttePoosccPshhiAoooRnnndGdrorimfiaai,1,c7ecc1,3aa-mraninittdiinnee pSiSnaOOclmDlDuidlltieoonvvygeelltlarssabwwnnescofrremecraarrlsceeddsuu(eCccmceiPddnTiii)fnnewaarallolsuttsrdrceteauactbtrcueedldaesswwe,idilldadi-n-cttkybyoppofeethaaggnneddrromhhuuupcmmsealoanlnf,iiwzzoeerildddne-PPtcyPrPpoAteAiRcaRancdemmlilhicsce,igc..hw-HHediriossetstoeooppbhasautethhmroovlaleonodgigiziicecnadalhlPillgPeehAss-iiRodocnon~sssemoofwfiitcthlehdce,-atttenyssdpttecess,, iaPannnPcddAlRuhhGduu-immnnaguannlailibzzneemoddicrmePP.PaPAlTARhse(Re~mmmIini-ciimcefyee./.rkoNNgu/oosdtammuyoborudrppolhehsoseol,loowlgagaicisckcaatollhfeccghhaeaaurtnnmhggoeecrss'eslwwlseLe,rrOeoeAroonEbbessLceerrrfovvoteericddsiciignennlittlhsfh,ieecwtateneesstrtteee(sso<b0ffr.sroe0omrm5v)ePPdsFFpOiOneAArhmittgrraeheba-antdnioom~mseneenantltwiiiiinnlcds-.type dPePcArReacs~e-ndutlelsmtoisctee.rTonhee, a1n-md gse/kvger/dalaybidoocsheewmiacsalthaeltaettrtahtoiorn'ss LinOtAheELPPfAorRsaigannidfichaPnPt A(pR<a0.m0i5c)e,spbeurtmnaobninortmhealPitPieAsR, a- ndustuelaclltlirsemmtaiiciscceeae.ld. stTTiehghsneteiorrfseeitcewwarneoecrrneee.e,ddoaosnseed rrseeellvaaettereaddl ddbeeiccorrceehaaessmeessiciiannl testosterone in the PPARa-nul mics, but they did not achieve alterations in the PPAR(~ and hPPAR~ mice, but not in the PPARc~- testosterone in the PPAR(z-null mice, but they did not achieve MDH Note this study might statistical significance. ~lDH Notes Ibis stu@ might iinnddiiccaattee nneeeeddffoorrffuurrtthheerr ssttuuddy..v, hhoowweevveerr., ssttuuddyy qquuaalliitt~yv ccoonncceerrnn rreeggaarrddiinngg eeffffie,ccttss rwreeappsoornrtoteetddrieinnpohhrPltqeP~dA.ARRat~:y:peGGsroroofuuspppsseiirzzeemssattboonooorssmmmaaallliltffiooerrsaa(ddbeyeqqhuueaaattdee. ssappiee.rrmmmieedvv-aaslleuucaattitiioono.nnsseootrrc)tteewssettorosesttenerorootnnreeeeepvovaraltlueuadat.tiiootnnesss,t,ommsottoei#rloilinttyeydodanatltyaa eweinvvadaasillcunauaotattoetrrdoeeaapfdttoloorotnnweeedT,itbiimtmyueep--pepnist,o,onenffoosepcccetllresemaaorrnaddboconossoemer-brm-iernaseeplidostinpepssoreonf(fsbsootyerarth7eTe'aff&rdro,osmmteamoililo,wnwaml1tivo0de-hshsiiieggcchhl.t,ieowaanicc,.cceeeswtscses.oor)roewy.o,ebssrseeeexxrnoovorertgdgr.aaennptssoesaarttrreeeesda,aistsseteesonntopssiasi~tirevvireeownaes only noi qiqnuudaainnctat(ti/oiferdiboebfydyloiiwnnccTiiddbeenunccteenooorrseefsfveeevcretsriitotyynaacnnoddmnnbooitnt esstdtaatptiirssottisictcaaaltlellyy&eevvsaaelhmu~aaitnteeadd.l. vesicle wt. were observed, testes histopath was not AAMbablbbeoottatneedrt aafl!em22a00l00e77a1ac2ct9t 8EE1PP/AASv22I00m11J66aaand PPARa-null mice were used in studics to determine if PFOA-induced dddMeoevasveleeeldlooappfnmrmdeoemnfentGmtaalDalltteoo1.x~-1i1i2cci79ittSyyw1iwwitSahavss0l,mmme0Jed.dai1inaa,tdt0ee3Pdd,Pbb0Ayy6R,PPuPP1-AA.n3RR.ua(ll~.5,.mPP1ir0cr,eeeggawnnnaaednnrte2t 0u112s2me99gdSS11iP/n/FSSOsvvtAlulmkmdy)iJe/swwdiatiollydd.d--teyytHppeeeertmaeainrnnoddezPyPifPgPoAPAuRFRsaOc-~(An-Hun-EiulnTllld)mumliciiecctdteeerwwseaerlreesooorwraaellrllyye pdpbrroaoocsdedkduugccrfeeorddoumnbbdyyGammfDafatetci1itnn-e1ggd7wwsiwuilrliddvti-h-vttay0ylpp,.ee0T.aa1hnn,edd0H.PP3PPE,AA0TRR.6Glc,-iztn1-eun,rui3sll,lw5emm,raa1ell0ees,ssaacwwnridiittfhh2ic0wweidmilloddg-n-ttPyyPFppNOeeDAaanniIkddSgPPidPPaAAyRR. -H~n-euntluerlllozddyaagmmossuttsoo(ddHeeEtteeTrr)mmliiinntteeeirifsfgagelesnnocetwtiiccere background affected SUladval. The HET litters were sacrificed on PND 15. TrTehhseeorrreeptwwioaansssn)n,ooemefuffmfeebcettrooofffttrriemeapatltmamneetnnst,t ooonnrmmpauatpteerrwnneaaillghwwteeiaiggthhbttiroothrr.mmWaaittleedrm-natalylpwweeeidiggahhmttsggaeaixinnpo((seeexxdcclltuuodd2iinn0gg.6tthhmoogss/eekwwgi/ittdhhayffuuallnll-d-llitPtteePrrARa-null dcrdoeaansmmtorsrsopleestixx.oppnoAosss)Uee, ddSnuttomom-g_b>/>3e5krgmm/oggd/fa/kikymgg/p/iddnlawaayniyltshhd,aa-oddtryaappesusiipgdgnnawiimffeiisiccgaaahnnntttdllayyt2gbg0rirreemtaahgtt/.eekrWrgpp/ieelddrrac-cyteeynnipttnaeaggPdeePaoAlofnRfaslli-iettnxteueprlrolllsooedssdsasmtccosoo,_mm>p1p0a.a06rr0eem%ddgltoi/oktegttrhihdleeoairryssrraeenosscdppceeuPccrtPtriieAvvdeeR. a-null RecnRluoelanlltatriatoidvvluseel.ltliAifvvteee_mrr>a5wwleemeisigggdh/hkottsgwweidadaasswyissiiitngghnnwi>iffi3iilccdmaa-gnnt/tytlkplyyge/iiddnnaaccymrr.eesaasBsaeeonddddyii2nn0wwweimiillgdgdh-i-ktttyygipp/nedeawadaiyduliduln-ltttPyffPepeAmemaRaolflceef~sss-npddruooilslsneegdddabmwwoisimtt,ohh1f_20>d101a%mmmgsgl/i/ktktdgego/r/sddleaoadysyswaaionntcddhcuii1nnr.r0ePPdPP.AAR~R- nmm(mugga/ll/lkkeaggsd//)dudalaatynyfdewwmaPasasNlDessisigg7ndn-ioif1fsii0eccdaaannnwttldliyytPhrrNe_e>dDd3uumc2cee2gddi(k(f(gppe=m/<d<a00la..ey00s.55)).)BccoNoodommypdpwaiarefrfeiegeddhretttonoicncceooswnnwtitlrerdoor-lletyooopffbfefssspeoprrrfifivnsnepggdrbibbnooegdtdybweowwereneniigogPhhfPttdAaggRnaaaaii-nsnnduooolnnslPePdoNNfwDfDsipt99hr,,in111g0.00,,baaonndddy 2222 w(wimneeiwaiggilhelhtsdt)-aatannynddpdeccPooTniNntttDrerorolsl7eo-o1xfffpf0ssoppasrrneiidndnggPobNb2ooD0dd.6yy22wwmeey(ifi/gcghkmhtg./ta.dlaSScyusu.r)r.vviNbivvuaotallodwoifafffscppruuncoppntsscacfffrsrofoewmmcctbbrecidirrttoihhnbsttPocoPl~wwAeRceadaan-nbinicnnutgglwlwwccalainsstePsrssiiP.ggAnnSiiRfufiiraccv-aainnnvtutallllyyl owrrfeaefddssuupsccriieengddngi((fpbpi<o<c0ad0n.y.t00l55y)) ddbineeoccwmrreeiltaadoss-eetPyddPpA((epRp<<ali0-0t.tn.e00ur55ls))leffxdoopraromwwsiseilldddd-o-ttotsyye_ppd>ee0w.aa6inntmddh gHH3/EkEmgTTg//dkppaguuy.pp,ssbObubffotosrwmpnra1tiso0nngwwoibitllodadr-ftntfyoyeppcfeteewdddiaalimdmn-ssPtyPddpAooessReedcdda~m-wwnisiuttlhhsl hl1|iotwmtmegerg/dsik.kaggS/d/uddorasavyeyi-vraaaennllddwatffaeoosdrrstHHirgEEennTTidfippfcuouaprpuss.tly dbdineoellrdaanayvyteeooddfPeePevyAxeeeRoocopp~pee-ennniniunnilglgngdccawoomammspspadoarrobeessddeedrttovoweccdiootnhinttr3rtoomhllegooof/fkffffsgspsp.prrOriininfgngfgs((pbssriioiggnnmngiiffobiifccoaarPnnnPttlAloyyRfaddw-eenilllauadyyl-eetlyddpdaaeattmds1|a.mmmgAsg/tikskgwhg/eo/dadwanaeyiyd.n,gpap,<<d0r0o.e.0sl0ae55t)-)ir.,veelbbauulttietvdnneoortrwdedeinififdffgeehfrroteernnwccaees oissnfiiggfdnnsiapiffyriiicconaagfnntegtllyeyysetiiaonntpccierrocnenaaainslsclgeyddwe((appxs<<p0o0o.s.b00es55de))rtviionend3wwimiilnlgdd/t--hktteyeyippodcefafooysffpffrssippnrrgiinnbggonggaecssottaafttPiiooPnnAaalRlllyy~-ecnxxupplolossdecaddmttsoo. 20.1 mg/kg/day and At weaning, relative >0.1 mjkgiday and in PPAR-null liver weight was in PPARc~-null offspring gestationally exposed to 3 mgikgiday. t"ThThahete eaaxuupttrhheoosrrsssiccooononnccflluuPddePeddAtthRhaatisssuurrrevvqiiuvviaarlledoofffoPPrPPPAAFRROacA-~-n-iunlnulldluppcuueppdss paaonnsddtnddaeetaaatlthhlssetoohffalHHitEEy:TThppouuwppessvebbroo,rrncattroolyPPPPpArAeRRngca-zta-nnluulllleltddhaaallmintssy iiwnnaddsiiccaatteess tibihnunadtdteeopeptxeehnnpeddrreeemsnnestticooohnffaPnPoPiPfsAAPmRPRsaA~.m.RiDDgaeheiltslaaryayeleeqsdduoeiecryvoeneedtorofippobeeruntnPeii.FnngOg Aaann-ddinrrdeeuddcuueccdeeddpoppsootsnsttanntaaattlaalllewtwheeaiilggithhytt; gain appeared to be mediated by however, early prenatal lethality gain appeared to be mediated by PPwPPaAsARRu,, but other mechanisms might also contribute. DDrraafftt DDooccuummeennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOsseAess6oo6lny.l.y0.1DD9rr2aafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 66 of 92 22447755..00006866 SSTTAATTEE 0077443388006699 AdTiblorbecrfheutrcthhteererteaavl!al22u00a113t3e atahcceti d1,e2v~EPeAAl2o20p0m11e66na2tal effets potentially mediated by PPAR. groups of female wild-ype, PPAR enTniuuoltllhlf,,euraarntnshaddecrrPPiPePfviAAcaRRelud-aaho-thuneumGtmahDenanid1izezveee(ddlnomm=piimcc5ee-e8nwwtepaerelrreeefgggfrieivovcueetspnn)po00oraatennanddltli33aolwmmlyeggdmPP(e0FdFOgiiaAOvtee/dkAbgibroyotnnhPPaGGnADDdRssct~h11,e--ng11r77soaubcbrypyisfooirorcaafelldf,ggeamaavvlaaaoglgeneeg.w. wFiFileedtmmh-tayatlhpleeeesis,rwwPlePiertrAeeerRs a(-n 3-14), on PND 20. either sacrificed on GD = 8-14), on PND 20. 18 (n = 5-8 per group) or allowed to give birth and then sacrificed, along with their litters (n EuEtvveaarlliuunaaettwiioeoinnghootnn, GGnDDum1b188erssohhofowwieemddplnnaoontecaffttfEieoctntsssoopfefrPPFdFaOOmA,A oaadrdmmniuniinmsibstetrrraaottiifoornnsooonnrpmmtaiatoteenrrsnaapllerbboolddiyytewweieiniggdhhatt,m,sbbooofddyyanwwyeeiigggehhnttoggtamypnn.,, ggFrroaarvviidd uaaconntneiitrmmrioanallelsss.waaellBliloogodwhwytee,ddwntetuooilmgilhtbitetetorer,rfo, fttdhhiameemspaavvladcemurraraagigtneeiogddnalasayycptooaeftpfriaopdrnaa,trmuturt,hiroiettriinoonnnuumwwambasseorbssfolliipefgguhhrteptrllssyyorlblpaaotttiemoerpniiesnnrpPPeFFirOeOlAriA-t,tte-rtrpreueianapttdeebmddodnhhysuummowaefanianignizhzyteegdddeummnrioicictyeenpttelhha.aacnFtnaotiirninotnth,hee caaSunonrddnvtitrthvohaelels.oodnnBussreoeitdtonyogffwpPpeuNuipDgphseetyyo1ee-foo5dppwaeemannsisinnsdggiugwwrnieinefrrgieeclasasniictmmtlaiyiltliaarorrenbdb,ueetchttweewdeeneeiunnnnttatrhrbeeeeaarwtteieoddlfdpaa-nuntddpypscceobonoPntrtFrrnOoolApl -eggtrrroroliuuetptpaesser,dffopogrrurpaaollullbpogg,edenbnyouottwtyyneppoeigetssh.i.tnOOdtfuhfffressinpoprtgriihnlneaggrctation, senotypes. survival during genotypes. PNDs 1-5 was significantly reduced in the wild-type PFOA-treated group, but not in the other aMMnaitametearrlnnsaallolnliivvePerNr ~Devie2g0i.ghhttMwwaatassesmsiiaggnnilififiviccearannwttellyiygiihnntccrrweeaaassseenddotiinnattfhhfeeectttrreedaattoeendd PggrNroDuop2su0oofpifnaasltlllheggeePnnPooAttyRypp-eenssuoolnnl GGorDDP1P188AaRanandd-hiiunnmwwaiinlldid--ztteyydppee mamminiiciccemee..aalOOnsndnonGCGyDDPpNd11Da38l,,20mm0a.iatntMeewrmainatkaelilrntllyiaivlpveeelrrivassenaarmdmwpphlleueeimssgahffntrriowozmmeasdttrrnemeoiaacttteeea.ddffggEerrxcoopteuurdppesssosnssihhoPonoNowwfDeeddC2iiy0nnpcci2nrrebetaa1hss0eeeddaPnPeedAxxppRCrrycee~psss-s3niiaouollnnlo|oofwfrAeAPrcPceooAxaxR!lls~oii-nnhinuwwcmiirlleaddan--stiyyezppdeeedin all mttwhhirirlceedeee-aggyneepndneootCmbyiyp'cpepees:4s.a.elOO0xpnnirnePPswNNsiiDDlodn-22ot00yf,,pmmeCayaattpneer2drnnbhaa1lul0mlliwiavvaneesirrzusseaandmmcmphplailecenessg.effErdroxomimpnratterrlseesaagittoreeonddupoggsfrr:ooCuuayppnpssd2ssbehhx1oop0wrwaeeensdddsiiiCnonnccyorrpefe3aaCsaselyeddp1 3eewaxxeplprrreee| ssawsslaisioosonnoiinonfccfrrAAeeacacssooeexddx|1iiniinnnaallll three genotypes. wild-type mice; expression three geno~pes. of Cyp2b 10 was unchanged in all groups; and expression of C5~3al 1 was increased in all gM MrioiccurrpoosssccooonppiiGccDeevv1aa8lluuaaanttiidoonPnoNoftDf thh2ee0,mmwaaittteehrrnndaaellcrlliievvaeesrressdhhioonwwceiedddeccnecenenttrariinlldoobbsuuelvlaaerrrihhteeyppabatytoocPceeNllllDunll2aa0rr.hhOyypnpeerGrttDrroopp1hh8yy, tiinhneaalllllivPPeFrFOOlAeA-sti-ortrneesaatwteeeddre aggmrorroaardudpeephddoslaoaossngimmGciiaDllldd 1fiin8enattathhnueerdewwsPioiNllfddDt--httey2yplp0eei, vwmmeiriictchele,e,dsmemicioirnnneisiammdsaiealfdl-f-tetiorone--cdmmidisilellddnigchiientnlatythuhebedehhsteuuwvmmeeaearnninitiygzzeeebnddyotmmPyipNicceeDse.., 2aa0nn.ddOmmniinnGiimmDaall18iin,n ttthhheee nullliver null mice. The lesions were mice. The morphological features of the liver lesions differed slightly between genotypes. dRRaeemllsaat.tiivvOeenffeePttaaNllDll2iiv0vee,rr wwreeeliiaggthhitvteoolnnivGGerDDwe11i88gwwhatasswassiisggnniiinffciircceaaannsttelldyyoiinnnlccyrreeaaisnseepddupiinnsfffeerttuoussmeesstrffarrotoemmd ttwrrieelaadtte-edtdywwpieillddda--tmtysyp.pee FaaonnrddfehhtuuummsaeansnioizzneeddGD dH118au8,m.malTsinv.vieeOrzrnessdaaPmmNmpipDlcleee.2ss0ffE,rrxoropemrmlaetttsrirseveiaeaottenleiddovfeggrrrCoowyuuepppi2ssgbhss1hth0owo~wwavesaeddsiniiucnnnrccecrraehesaaaessndeegddeodneexlxfypporrilenelssopsswiuiioopnnnsgooffmrfoaAAmtcecomtorxaxe|lal taaePnndFddmOCCAiydypa-pddt4ymaaipllne00isdiitnanzmawwtsiii.lloddFn--ottiyrynppfaeeeltluaatnnsedrdseeon GD `hgtzreueenmnaootatetyndypipzdeeesasd,,mswwmhhsiicilhleeeo. weeEexxxpdpprriereenssscsssriiioeooannnsoeoofdffCeCCyxyppypr3pe32asablsli|11o0wnwawoasfassAiinunccncorrxcee!haa|assneeagddnediidnnCfhyhouupllmmioaawanlnii0nizzgeienddmwffaieetlteaadrll-ntalliyilvvpeePerr.F.mOiOOcAnne;PaPe&NNxnDpDirie22fsi00ss,,tirppaouuntiopponfliivviCneeyrraplss2laabtmmh1prp0elleeewssasffrroomm tiwirnniecclarrdteeetaadyssepeddedamiainnnsdaalslllhhouggewmenaneonodti~yzippneeecdssr:e;pauaaspnnesdd.d eeeTxxxhpppurrrseee,sssssesiiixooopnnnroeoofsffsiCCAoyycnppooS3xfaallPl|a1nPwwdAaaCsRsyiipntn4accrarrgeleeaa0tssegiendednwffeooislllldtlo-howtawytiipnnmeggomdmmuaialcttaeeet;rmeneaaxlllpiprPPieFdFsOsOmieoAAtnaaaobddmofmilCniiniyssipmst2trwrabaatlts0iioonwn aiinsn wihinnoiccwlrdrecen-ataeyssrcpe,ded tiainhnnebdbonohtetuohhnmwwataiianlldlidz-mtyeyodprptepcaulaapinntsddy. Thhwuuhammusasao,nnbieisxzzcepcrddrvemesmsdiiiccooeennlccoyoofiiinnPnccPwiiAiddlecRdnn-~tttwwytaipirtetghheofiitnfngsccperrrnceiaeansssgce.tddhallitivvmcerrowdweueiliaggthhett andlipid and mmlniicecrtraoobssoccoloipspimicc wlseiasosionnss;; however, the neonatal mortality was observed only in wild-type offspring. HHoorrm moonnee DDiissrruuppttiioonn ((EEPPAA 22001166aa-- SSeeccttiioonn 33..33..33)) TTMhahyryrtroioinidd:c:t al (2007)administered 20 mg PFOA to adult male Sprague-Dawley rats (n= 4 or 5) for 1. 3, or days bMbtyhyeaoorsrtrieaanlrl ugcgmtaavarwlaa.aggs(ee2a0aan0nna7ddl)yddazeedettdemerrnifmnofiriisnncteechddorclttedhhseet2e0iirlmnomplpa,gaccttPetFsootOfofsAPPteFiFrkOoOgnAAet,oooannFdThhu4ooltrrammmnodoannltceeotSlaleelpvvreTeal4ls,gs.u. acBBn-lDldooaootwoddtlawwclayaTs3sr.acctoosRllll(NeneccA=tteeed4dxtovvririaaa5ccct)aeafdrroddrfiiar1aco, m3pp,uuhnoneccrtt5luuirrdveeearyaasnsndd ttwwhoaxaeisscsiuuetyssr.ueedmdFffowoolralgsgoeewannineenagleeyxxazpper1rd-eedssfassoyii,roocnn3h-ppodrrlaooeyffs,iitlleiainrnnoggdl,,,5ggt-eeedsnnatoooymmstideioccrsoess.niigegan,naaIstFtiuuTgrrn4eeisasf,,incdaaannntddtotdppaealacttThrhe4wwa,aasayyenda(annptaao<llt0yya.ssl0eeTss)3ttw.ooaRddsNeetotAeebrrsmemexirintnvreeeadcaateimmndeescfcerhhoraamunnmiitsshcmhmeollooiefvfsetresrol dt((o~e4x.c,5iLrce-4iat57ys-27.e2d%F%)o(,)pl,l<ott0owo.tt0iaan5llg,TT4a41l((7-~~d0,[~a%8y8)33,%%f3)o-),d,laFlFyoT,Tw4ain((nad~~gL85830--0d%d%aa)y)y.,adaaonnnsddde,5ttooa-tdtasaalilygTTn3P3ifFi((cO~~a+A,n22t5d5do--se44ec88.r%%e)aP.)s.FeSOS(eeAprr<uut0mrm.e0tat5ete)ssmttweoonsasttsteewroroabonsnseeemrwwvaeasads ssiniiggtsnn0ieifhrfiuiceccmpaaannttchtlolhyytoolexeistceidrtoyl `drraeeenllcdaarttepeeaeddsreggodcexnni(oospmom<mi0iecc.0sps5rii,ogglnn~iaa-ft~etuur7rar0stes%is,o,)na.afsoslPwwleoPlewllAlianaRsgs ssnaiiug3gcnnl-daaetatauuryrrcerassengdffuool5rra-thhdeecadppyaagtPteooFncceeOclslAllwuuledlaarorreshheiy}.np~PdeprFuctcOrrteorAdopphbtyhry.yea,PthhmFyyOpeponAoctchthworolealcasctssmiltneccnarrttoo.cllhccGemmdeiinaat,eo,shhhyyaepspposoalolticiopiptaiiodtdxeceidmmciiitaay.,- and peroxDDirsraaofftmt DDeoopccruuommleiefnnesrta---tiffooonrr.rreePvvPiieAewwRaa~nnddnuddicisslcceuuassrssiirooennguppuluaPrrtppFeoodOsseAegsse6oonl7neyl0s.y.1wDD9er2rraaeffttindddooccuuucmmeedennbttyddooPceFssOnnoAott constitte Agency treatment. Genes constitute Agency policy associated policy PFOA - 67 of 92 22447755..00006677 SSTTAATTEE 0077443388007700 wDwiiiottlhh, tthhweehitthhcyyhrroodiieddiohhdooimrnamltooennseeprrreeollheeaoassreemoamnnaedd TssyynnttthhoeebssiiiossappctaaitthvhawwtacayyT3ii,nnccwllueudrdiienngagfDfDeiicoet33e,,d;wbvhyhiicPchhFOccAaa.ttaallTyyrzzeeeasstttmhheeenitinnwaaicctttiihvvaaPttiFiooOnnoAoffrTTe3s3u,,ltaaenndddin DssCiioggionnAilif,friiwcecdaahnunitctcllthyyasduueeppri(roeeidggnuivunlolaalattvteeeesdddpeeirxnxoppchrrhoeeorsslmsseiisoootnnneeroooTlff4DDbiitiooeos33byniaaotnnhaddecstddiiovoswa)wntewnrareTesg3gu,uslilwagatnteeierfddeicaeeaxfxnfppterlrceyetssesusdiipoorbnneygoouPfflFaiDODtielAoedl.1aT((npprd<<e0a0c.th.0m0o5l5)ee.)ns.ttEEewxrxopipltrhreebsPsissoFiisoOoynnnAotohfrefesHHsiuMsMltGweGa-ds-.in ddCooowwAnnrrreeegdguuulclaattateesedd in a mannerconsistent with PPAR agonists. (involved in cholesterol biosynthesis) was significantly in a manner consistent with PPAR?' agonists. upregulated and cholesterol biosynthesis was RRCeeopporrkooddeutt~caciltiivvee(1HH99oo2r)rmmogonanevseas:g:e-dosed male CDrats n = 15pergroup) for 14 days with 0, 1. 10,25, and 50 mg oPPCbFFosOOoeAkrA/vek!etkydga/lidi.dnaa(yr1ya9ttsto9.o2Aee)xxgaasamemvpiaianngreeaet-ttedhhoeecsoppenoodtsrssmosilibbaigliellriitoCyyuDptthhwaartaattsasannp(naeeinn=-ddfoo1ecc5drripintneoeertgrrheerelloaauStte0ped-)dmfmmyoe/rekcc1yhh4/aadnudaiaiysysmsmgrwmmouiiiptggh.hht0tB,eelx1xo,ppol1ldaa0ii,annn2dLL5e,etyyaedsdntiidiggc5ucc0leeallnrllaiaagnddteeennrosoimmtaaasls ofurlabuitssiddewrwwvaeesedrrdeeionccsooerlaldlltesew.ccittAteehddsa0aettpaannnreedacc5trreoo0pcpsomsyyngtfrfooPorlrFOghhArooo/rrumkmpgoo/nwndeeaasayannpafaaloliyyrr1s-sifi4essddiianntocycllsutuhaddeniinnd5ggc0htt-emaessltgtloo/eskstntgeeg/rrdeooadnnyeew,,gieetrsoshtturra1pad0di0oiBol,lllo,usoaoadnnfddahnLLudHH.mt.eaAsAntisccseheupoplaararirraoaitntneeitceggrrrsootiuutippalooff grc`aowotlonsinacawdedatooesttdrrdooaoppnisidnneda((hnwCCaiGltGyh)z)o0eordar nf22odrnm5ateg0esnnmtaaogllsootPxexFroooOnnneeeA/ikak/kgnggd11/dLhhaHooy.uurfrSoppcrrrrii1uoo4rmr dtofoarynnoseemaccrnrrooadtppsscsyhcyhat1alolleliinnengdndeguudeccdeewwttieitehtssthto1os0s1t0t0ee0rIrouoTnsnueesocchfoohCnnucGcemenantalrtnsraoatctihiwoooannsrssi.o.annBBialcllooyoozddedwwafasosr P, 1achydrosyprogesterone, and androstenedione. collcctcd and analyzcd for tcstostcronc and LH. Scrum P, 17a-hydroxyprogesterone, and androstenedione. from rats challenged with 100 Ius hCG also was analyzed for T"oTrhhgeeanrreelulaanttiitivveerellliiavvteeirrvewwweeeiiiggghhhtttaatwt a11s00,,s22i55g,n,iaafnnicddan55t00lymmdggecPPrFFeOaOsAAed/wk(gdp/ad<0ay.y0ww3)aassatss2iigg5nniaiffniidccaa3nnt0tllyymgiinncPcrrFeeOaaAssekeddg/((ppd<<a00.y.005c5)o)..mTTphahereeaadccccteeosstsshooorWsyesseexx wowsieregginiagginhfhtitucssaniniintntlrccyeooldnnatettrcirvoorlelearrwaastteess.di.gTaThhthetewherareeshllaiastgtiigihvveneesiftwwicedeaioinggshtehltytscsoodofmefcpttrahhereaeslldeiivdvteeor(r,p,t<aahcec0cc.p0eeas5siss)roo-arfrtyyo2dss5ceeoxxanntoodrrrogg5laa0nnmuungnitit,P, FaaOnnddAvvikeengntirtdraaallyppcrrooosmsttaapttaeerewwdeertroee those significantly decreased at the highest dose compared to the pair-fed control. SoSbeesrrueurmmveeedssttirrnaaddtiieooslltowwsatasesrsosiinggenniaiffniidccaaLnntHtllyybiienntccwrreeeeaansseetddheaattt>>ra11t00emmdggratPPsFFaOOnAAd//ckkoggntccrooolmmppaIanrretehddecttohoattlhhleeeccnoognntertroeolx.lp.eNNrioomeddniitff,ffeerrseecnnrccueemss wtweeesrrteeosterone owbassesrvigendifiincatnetsltoysdteercorneeasaendd(L<H0.b0e5t)wbeyentrthaetmtreenattewditrahts50anmdgcoPntFrolO~ AIn tahfeecrhcahlalelnlegnegeexwpietrhim1e0n0t,lusserhuCmG.tesNtoosterone ddwwieiaffrfsfeeesrreoiegnbnnsccieeefrssicviiaennndtttelaeyssfttedooresstctcereirertoaohnnseeeerdccchoo(anpnlc<lceee0nnn.tg0trer5.aa)ttiibIoonynnttwwhreeeeahrtremCGooe-bbn<sstheewarrvlvitleehdedn5iign0netmtdhhegerannPtaa,FllOooaxxnAood/nrnkeoeg-s-tccaehhfnaateelldllreiecnonhgngaeeelddlwernraaagsstes,s,iwaagnnnitiddhfinn1cooa0n0ddtiliIffyuffseerrrheeedCnnuccGceeessdNiinnaotLL5HH0 mg wPPtrFFeeOraOetAAeodk!bkersga,es,r.bbvuueTtdthnneaoofateuddtiriffheffoeiertrrhseeensnrccuecegshsgaeiilnsnlteccenoodgnnetcc.heeanIntnttrtrtahahteteiiooohnbnCssseGwwr-evecrerheedaooldlbebescsneregrerevvadeesdderdaiitnnssP,eParnoourdmr r11ot77esstacet~cnosh-ehtydeydirdorornonoeexxyywlpepravrsoeolggssseigtcstoneeurirflooidcnnaeebnebbtleedyttuwwreeeedteeuonncdcceeoodcnnrtatertraoo5sll0eaadmnnddg tccLrooeOnnaAvvteeeErdrLssriiaoowtnnsa.sooTff1h110e77maaagu--/thhhkyyogddrrsrbooasxxsuyyegpdpgrreooosnggteeeisdsnttectehrrroeaoatnnseetehdtetooloiaabvnnesddrerrrwoovesseittdegenhndeteeddcaiirnooednnaeesienaadcssrasaeearrrseueessmduullsttteeoosrftfuoiimsnntcecerrrseotearanassedeeiddloelsvseeelrerlusvuemmlcso,eeusslattdrrnaadbddeiitoohdlleulleNeevvtOeoelAlssd.E.eTLcTrhheweeaassed| mehg, LOAEL mg/kg. was 10 mgikg based on increased liver weight and increased serum estradiol levels, and the NOAEL was 1 BnBeiiceregoelplsteiatelda.l.on(1(d199a99y55))15gg.aaBvvlaaogsoeedddammnaadlleetCCesDDticrruaalttassrwwienetrreeersggtiaatvviaaalggeef~l<udtioodssewededrff:oorrco11l44leddcaatyyessd wwfioitrthhho00,,m00oppnaaeiirra-ffneeadld,y,soiosrr.2255LimmveggrPPsFaFmOOpAAle!kksggwaaennrdde ncsciooeglclnllreieofccpittceseaiddnetdfflooyorrniaannndacaalrlyyeysas1isi5sseo.dofB(fppploe<ero0rood.x0xmi5is)saodobmmtyeaasl2lt5ic[o3mux-ligoadxrPiadiFtnaitOteioAornsn/tkiaatgnniaddlwmmhflieuiccnirdroocwssoooemmmrpeaaallrcoeaaldrrlooetmmcoataetttdhaaessfeeoadraachcltotiiivrbvimiitttioiueensms.e.anaSSndeearrpuluaymmisri-seef.ssottLrrdaaicvddoieinoortllrswwaolmaasspatlse.s were TaTsceitegsistnvtiiiitfccyiuu,cllaaanarrtnliidynnttpieenerrscsrtrtoiictxtaiiiaassllcodffmllua(upliidd<[0ttoee.xs0sitt5odo)ssattbteeyirrooo2nnn5eeamccctooginvnciPcteFeynnOtwtrAreaatritkiieoognnswiwwghnaaiessfnisscciiaggonntnmilifyfpiiacciarancnnctdrtlleytyaosddteeehdccerr(eeapaad<ss0lee,iddb0i5((t)pup<m<i00n..a0P0n5F5d)O)Apaa-anntiddrr-emmfeaiidtccerrcdooossnrooatmmrsoaallclroaaamrtrspoo.ammartaeatdassete.o the pair-fed control ats. activity, and peroxisomal the pair-fed control rats. ~3-oxidation activity were significantly iucreased (p<0.05) in PFOA-treated rats compared to HHduiirnnieenssgeegttealas.lt.at(2(i2o00n0099c))oemexxpamamrnieindneetddottdhhueerirronoglleestshttihhraattadeeuxxlpptooyseusaruresrt.toeoTPiPmFFeOOdA-ApraaenngddnooavvnaatrriiCaaDnn-hh1oorrmmmiocoenneewssermmeiiggghhattvpaplglaaeyy-diionnsaaenndiimminaaltlssweeoxxbpplooossceekdds oodwnneurrGGienDDgdsosgse11es--dt11a7w7t,ii,otbbnhuutc0t o.nnmoo0tt.ptt0ahhr1ecer,rdccaat0.f1,ofitc0cdr3r.u.,rBiB1n,llgaooccnthkkde1i| raaamnndiigmumlaPatlFlyssOeAwwa/ercksrr.gec/Tdddiaomoysse.ecddd-Apwwtiriettbghhinr00ta.h,n,t11,p,Cu33,Dp, sa-a1nnwddemrS5iecmmepggowoPePlrFeeFdOgOAwaiAritkah,ggi,en-aacdnnaoddcshbebldlboolciconkkctk22waaaonnnbdiimlmodaoaclslksess: `wgseurerobrosueuepptdoaaofnnsfddeedrrmaawannliddtehoosmm0lf,lyyr0o.rr0meeddlc,iiass0ctt.rrh1iib,bduu0ott.se3eedd, ga1ar,mmoaoounnnpdgg(50tt,hnheea0g0dd1Paa,mFmOs0s.A((111,i0k00.gpp3iuu,dppa1ssy,p.paeAnerrdtllbi5ittitremetrhrg)),..PpOOFufOpfffAsss/ppwrkriiegnnr/gegdpawwoyeero)releewdwwaesewaaOinntehVedidnXaaettaal33cwhwweebaeelenokkiscsn,k,gaamonnardddtaadheosdeay aasfufttbeesrrewwteoeaafnnifiennmgg.a. lAAelslllfaaronnmiimmaealalsschwwederoreeseoobgbsrsoeerurvvpeedd(0u,unn0tti.i0ll1tt,hhe0eyy.1,rree0aa.c3ch,hee1dd, 18 monthsofage. and 5 mg PFOAikgiday) 18 months of age. was OVX at weaning or the day BBanoodddyythwwreoeiuiggghhhtto1of8fmooofffnfsstpphrrsiinnoggfabbgooerrnncttooomddpaaammrsesdeexxtppooocssoeenddtrttoool 5o5fmmfsggprPPiFFnOgOAbAo,/&dkyg wwaass ssiiggnniiffiiccaannttllyy ddeeccrreeaasseedd ((pp<<00..0055)) oonn PPNNDD weight. At weaning. the body weightofoffspr 1 | ing bom to dams and through born to dams 1ee8xxmppooossneetddhsttooof1| mgage mg cPPoFFmOOApA/akirkeggd/!dtdoaayycowwnaatrssossliioggnfnfiisffpiiccraiannntgtllyybodddeeyccrrweeaacssigeedhdt.((ppA<<t00.w.00e55a))nccinoogmm,pptaharreeeddbottodoyccoownntetrirgoolhl tooofffffssoppfrrfiinsnpggnbbnoogddyy DDrraafftt DDooccuummeennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrppFoosOseAess6oo8lny.l.y0.1DD9rr2aaftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuuttee AAggeennccyy ppoolliiccyy PFOA - 68 of 92 22447755..00006688 SSTTAATTEE 0077443388007711 wiwneetiaiggchtht.tc.oAAntrssoiilggnnbiioffiidccyaannwtteiiingnhcctrr,eeaawsseeas((ppo<<b00s..e00r55v))ediinn ibbnoonddtyyacwwteeimiggihhctte, dedxuupceottsooedmmotororee0.rr0aa1pp-0ii.dd3wweeimiggghhttPggFaaOiinnAaaffget/erdrwawyeeeekk 1100,, ccoommppaarreedd ftoo intact control body weight, was observed in intact mice exposed to 0.01-0.3 mg PFOA/kg/day. GGchllauulcclooessneegettaoolleerr1aa5nn-cc1ee6ttewessetticinknggssoshrhooawwtee1dd7nnmooonssttthaatstii.ssttAiicctaall2lly1y ssaiinggdnnii3ff1iiccaawnnetteddkiisffoffeferraeegnnecc.eessasiiinngbnbaiasfseeillciiannneetggillnuucccrooessaeseeoofirnrresesesprpoounnnsseelet1potiggnlluaucncoodssee dicininhfssauufllellieirnnnengllceeeevvaeewltlass1sww5ao-a1bss6sooe~bbrvsvseeeeerrdkvvsbeededotriiwnnaetiienn1nft7aatccmhtteommfniiatcchteetso.ee-Axxippctoao2nss1eerddaatnt1iod0oo003f.1.0i011nwteaaaecnnktddsc00oo..1n1ftamrmgoggle,aPPanFFdOsOAigi/AnnKt/igakfc/igtcd/aadgnyeat.ysti.naNNctrooieoassnsttaaealttiiisnestitxscipeacrolaulslymedssliiegagpnnnitiiiffmniiacclaaansnndttat 42. gwdweieesfefteeakkrtsseionoonfcfaealaglgweye.a.esNNxopoobosssseiiegrgdvnnieaiffdmiiiccbmaaenanttltwsddeiiaefftfnfe4etrr2heeennwccefeehetwkw-tsaaoss-olfocoaabgbnsesee.rrravvtSeeioeddroiiunnfmiffnoeotsooatddcrtaccdcooiononnlsstuulrlmoenvplpetaltinisoodwnnienbbrteeeattncwwoteetgeeenndsitiifannftttieaaorccntntatcclolobynnettetrrxwoolpel eoaansnneddidniitannamtctaatmcctctaolnstraotl4a2nd dgiininetftsaaftcceattrtieggoneencssaettslaaltiyaioomnenaoxalpnlllogyysteeehdxxeppagoonrssiomeeuddaplsaasnnaiaitmmt a14al82lssmwaaotenet11k88hssmmoooonffntahatghgsee.s.., SiETEexhrxpuepomobssouuedrrsyeetrttawoodeiiPPogFFlhOOtleoAAvfeaalnssstaawanncetraameddiuunlclottetdddiigdideffsnnetooratettnrrieteossbnuueallttltwiineenxebbnpoooddisnyyetdawwcetteioicggo1hhntmttrgol and ddPPiiFFffOfOfeeAArrkee/nenkcc/geed/ssdaaaiyynmwwbooanadsgsytsshwiiggeenniigigffrhiioctcuaapanntsmtlloyyatniign1n8cctrrhmeeeaaosgsneertddohus((pppos<<f00w.a.e00gr35ee).) Tcocboohsmmecpbpraoeardrdee.yddwttooeiaagddhuutllttofmmiiinccteeaceetxxmppooiscseeeddgettoosta11 tmimoggnaPPllFFyOOeAAxgp//kodgs/aeddya.yto. NN1 oomoogtthheerr differences in body weight among the groups were observed. "TpThhheeenaaouuttythhpooerrssscicononmnciclcleuu.ddeeAddttthhlaoawt dddeeovvsceelslo,oppimmnecenrntetaaaslleeedxxwppeoiosgsuhtru,etrtoieoncllorowewadsdoeosdseesssearanundmd hihniisgguhhlindd,oossacenssdooiffnPPcrFFeOOasAAedrresesseuurlluteemddliiennptddiiinffffweeerrreennett opofabhbt.sesneeiovrntvvcyeer1dde~iaeinsnseiadanddbuumlrltitocwmmein.ciceAfe.att., lAAoaUwtnhdidiggdohhesceddrsoeo,sasiesenesscdrttehhsaeepasleanednieimnmwawealeilsigsdghihdttsi,.spiplnlUacanyryedeeaeddsredddteehccserreeecraauossmneedddiitnwwiseoueinligsigonhh,fttatiinnnhdeeeaaisrnrtllcuyyrdeyaaa,nnsddethdlleaasttdeeeeruvlliiemffele,,olpdedpmeecetcirnrneetaaawssleeerdLdeOwwhAhiEitteeL dwfWaeaatv,sseil0n0o..c00pr11meaemmsnegtgdaPlPbFFrNoOOOwAA/An/kkEfsgaLtb,bwaaaassneesdddedsooetnncarbiielnniaccssrrheeeedadas.sseepddlewweeneiigwghhettiggghaatii.nnUaannndddeiirnntcchrreeeaacssoeendddssiteeirrouunmms oiinnfsstuuhlleiinnstaaunndddy,lletehpptteiinndellevevveeellolss.p.mNNoeo.ntal LOAEL ~MdtoleDDvaseHHsloeNspNsoomttmeeeesnst-ta-tablhtohNeleiOsscttAuuidEdmyypLdadecwestsaisisgg(nnees.aat2ann.bddillinlsesehvuveeledilln.oofvfaddreeyttaadiihlleiinn0rreefpapsootrritininngggstiiastuiisnn,aaddceeiqqruucaaatdWeiat1no0cppyrrclooevv,iiddaeege.ssuuffefftiiccc.ii)eenntthtlleyyrerrfooobbruuessttthddeaastteaaennfeeeeecdtdesedd will no be denifiad co-cricail this time. Further stud; replication and validation to assess metabolic impacts (e.g., insu#n vary due tofasting status, circadian cycle, age, will not be identified as co-critica! at this time. Further study, replication and validatio~ are needed]. etc.) therefore are needed.]. these effects B. Duration Specific Health-based Water Criteria Derivation EExxppoossuurree DDeecciissiioonn TTrreeeeJf?roomm ((UU..SX. EEnnvviirroonnmmeennttaall PPrrootteeccttiioonn AAggeennccyy ((EEPPAA)) 22000000)) uusseeddaass bbaassiiss jfborr RRSSCC sseelleeccttiioonn.. Relative Source Contribution (RSC) CC5 tHheernerdyo'scuLmaewnWtCaW htoihinoasnttsai0nstttJh(euaersmwvtoimllatt3ihmlieimtywuo~sloe)?||911.03e8s,x 10 ~- oxplaim I EpiSuite Is ofan RSC other than the defaults?" there docmnentation to justify the use of an RSC other than the defaults?2 omole (5 x TE-7 am n/m; Low G3 If yes, explain TET 1 TES am mmol):Moderate (TES to TE-S im mmoor Fgh CTE 323"NNNaaoroommnnn-v-rvmovaolm3oal/altomitililelole)lf(l)<loo3wwxvvo1olElaat-it7illiaitttyyra/mmomdo3ed/remraaottlee);vvLoololaatwtiilli(i3ttyyx-010.E.55-7ffotoorraa1ccEuu-i5tiesa/shthmoorrm-tt-3tee/rmrmno,tl)00.;2.2Mffooodrressruuabbteechh(rr1ooEnni-i5cc/ictcohhrro1oEIn~-ii3cc arm ra3/raol) or High (>lE- HHiigghhvvoollaaitiilitt-yy- 00..22foforr accuuttee/sshhoortr-tteremr/smusbcuhbroenhicvc/chohrrnooniniicc: RFRiSSnCdCineegvvsaallfuuraaottmiioosnntuffdrriocomsmoEEnPPpAAopu~lUa(StUiESoEPnPsAAi22n00t11h66ebb)U)ni~(tSSeeedee SSSeteaccttteiisoo.nnC88a..n66adffoao.rr mmanoodrreWeeiinsnfftooerrmmmaaEtutiirooonnp))e:: support the conclusion that Fddexiiienpetdotisissnugttrhhseeefrrmmooaumajtjoossr,rtuccsdoopnienetctsrriiiaobblnuulttypoororfptooourltstaooetttinaoasllnitsPPiFFivneOOtsAAhuebeepUxxopppnouoisltseauutdrrieeo,S,nttstay.ytpepisiEcc,aaPCllAllayynuawwsdiietatdhh, aaddnnrrdiinRnWkkSiiCnengsgotewwfranatte0eE.2rruaaanrnonddpd/te/oohresrudd9puu0psstotrpaatessrthciimeemnppctoioorlnntetcaalinnunttstaiaaodkdndediittrthaiioatoetnnaall feftoooxrrpbloloaatsccuhttraasetthiinronorggutw-wtetoose,mmrmeeesn(npice((.c00i..a0e0l5l5cy44kfLLso//rkktgsgoe-ddmn)o)sintttotiovhcecsaa)lslcucsuubcllpeaanottaeperuaailoallsitififdoeeutntirsmii.mneeEgHHPpAAAreufgfoonsreradnPPcFaFynOOaRAAnSdooCflfao0ct.f00a.0t077i.2oygng.ga//naLLds,, taawhnnedde90rrle*eshctclopoomemrmlmcieeefnnnetddiislsmeett-ihhneaatxttapkitotesaaurpprappetlelyy scenarios. to both short-term scenarios. (i.e., weeks to months) scenarios during pregnancy and lactation, as well as to lifetime-exposure DDrraafftt DDooccuumlneennst - ffoorr rreevviieeww aanndd ddiissccuussssiioonn ppuuPrrppFooOsseAess6oo9lny.l.y0.1DD9rr2aafftt ddooccuummeenntt ddoocess nnoott ccoonnssttiittuttee AAggeennccyy ppoolliiccyy PFOA - 69 of 92 22447755..00006699 STSTAATTEE 0077443388007722 MDH l~C;C Ap~roach : The RSC is applied to account for all routes of exposure and allocates only a portion of the RfD to ingestion of water, with the remaining portion allocated for non-water exposures, including inhalation and ingestion from food. The values of the duration specific default RSCs (0.5, 0.2, and 0.2 for short-term, subchronic, and chronic, respectively) are based on the magnitude of contribution of these other exposures that occur during the relevant exposure duration (MDH 2008). In the case of PFOA, the RSC concept needed to be applied in a froanework recognizing the long elimination half-limb such that a person's serum concentration at any givcn age is not only thc rcsult of his or her current or recent ex )osures ~vithin the duration of concern, but also froln exposure from years past. In order to examine the relative impact of non-;vater exposures, MDH reviewed the source studies reported in Egeghy and Lorber (Egeghy PP and M Lorber 2011). The sparseness of media-specific data results in highly uncertain estimates of intake rates. The framework proposed by Egeghy and Lorber also included use of serum concentrations reported in the 2003-2004 NHANES biomonitoring effort to estimate intakes. MDH decided to use the most recent NHANES biomonitoring data (2013-2014) and East Metro ncw resident biomonitoring data (2014) in a similar fashion to estimate current upper-end non-water exposures. MDH ntilizes the Exposure Decision Tree process as presented in EPA's Methodology for Deriving Ambient Water QQuuaalilittyy CCrriitteerriiaa ffoorr tthhee PPrrootteeccttiioonn ooff HHuummaann HHeeaalltthh ((UUSS EEPPAA 22000000).). TThhee DDeecciissiioonn TTrreeee pprreesseennttss aa sseerriieessoofdf edceicissiioonn points at which the quality and quantity 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 (MDH 2008). The relevant portions of the Exposure | [Decision Tree are presented below. Identify population(s) of concern I Identify relevant exposure source s/pathway s Are adequate data available to describe central tendencies & highends for relevant exposure sources/pathways? No Are there sufficient data, physical/chemical propet~y, fale & Iranspott, &/o r generalized information available to characterize the likelihood of exposure to relevant sources? = I. ~ Yes Are there significant known or potential uses/sources other than the source of 1153:. Apportion the RID including 0% Apportion the RID inclnding 80% ceiling/20% floor using percentage approach (with ceiling & floor). concern? I [ros some norman mae | Yee Yes V Yes Is there some information available to 1 Yes make a characterization of exposure? 8G.| Pefomappotionnnas 8 Perform apportiolunent as described in Box 13. with a 50% ceiling/20% floor. J Draft Document - for review and discussion purposes ~ only. Draft document does not constitute Agency policy PFOA - 70 of 92 22447755..00007700 STATE 07438073 The $0 erent cling within the Dison Tr i 0 cus that th el-based gos will be low rough 0 provide The 80 percent ceiling within the Decision Tree is to ensure that the health-based goal will be lo~v enough to provide adequate paeeion fo nda whose 0 posure i. duc foam offh expose sources. her han cyl adequate protection for individuals whose total exposure is, due to any ofthe exposure sources, higher than currently nied by he alledia (US EPA 2000. Ths lo erases the min ofets 0 secu forpose indicated by the available data (US EPA 2000). This also increases the margin of safety to account for possible uunnkknnoowwnn ssoouurrcceessooff eexxppoossuurree.. LN ------_-- It has been acknowledged that serum concentrations are the best measure of PFOA exposure. These values can be Lcd plc of th RID nh Deksion Ti rocks. Th scram Concnraton at he POD sled MDH and used in place ofthe RID in thc Decision Trcc process. The scrum conccntration at thc POD sclcctcd by MDH (and EEPPAA)) iiss 3388 p~gtg//mlnLL.. TThhee sseerruumm ccoonncceennttrraattiioonn aassssoocciiaatteedd wwiitthh tthhee rreessuullttiinngg RRFfDD., wwhhiicchh iinnccoorrppoorraatteedd aa ttoottaall UUFFooff 330000,, 6015 hl (or 130 1) Background (1. pore from non-ater nGetion ruts efcxposr) da for is 0.13 ~gimE (or 130 ~tg/L). Backgronnd (i.e., exposnre from noniwater ingestion routes of exposure) data for infinth population ofconcen, ie mot waa, however, en he ong IF he blomontong results rom infants, the population of concern, are not available, however, given the long half-life the biomonitoring results from th Ea Mr ne eds ad NHANES ca 5 eed o provid sighs i he magituds ofnsater the East Metro (new residents) and NI-LA_NES can be used to provide insight into the magnitude of non-water pos. exposures. MDH East Metro PEC biomonitoring prjot suspubselof pedopl ing nth East Moto gion who wer MDH's East Metro PFC biomonitoring project salnplcd a subsct ofpcople living in the East Metro region who wcrc Comeced 3 conaminacd publ war sop (Neon 2016) Teament to emove PFCs was added 10 te PS connected to a contaminated public water supply (Nelson 2016). Treatment to remove PFCs was added to the PWS nd vlna acing bond ves ageda hc me pot: 200%, 010 and 014 a22n00d008v8o--lu11n44.t.9e9euurggp//aLL~g*geiecooipmmaenetasannha((dCC1Ibl11o22o.d.9~9l-ev11e77.l.s33))m;;9e955a%tshnppreeedrreaectnttehilrene6et600tiiumuglg/eiLeLpo((irrnaatnsng:gee201106.86-.-2101111770)) m~d 2014: 222000111400--- 5111..125.2uugug/g/LiLLggegeoeoommmeeaeanann(((CCC1I14969.7-.-7-6.1143.13)),;.19);59%955"pt~eprpceeerncteinlretil2ec6448u8.ge./77Luugn(g/r/LaLn(tg(rreaaninLggeOel0D0..99e--44-4-7)111100..55)) 2014 - 5.5 ug/L geo mean (CI 4.6 - 6.4); 95th percentile 26 ugiL (range <LOD - 47) A Pa ofthe ot bomenioring effort me Oude residents (N-156) wor as sumpld in 2014, Sines hss As part ofthe last biomonitoring effort new Oakdale residents (N=156) were also sampled in 2014. Since these edad demo ies tones poms oo toatod viet ht sem sales be epreselaie of individuals did not have historical exposure to the contaminated water their serum samples may be representative of Tomar pote. 1 goo mem (C11 020 95 perch Sug (ane 0175 1 Theo vcs we vrs non-water exposures: 1.8 geo mean ugiE (CI 1.6-2.0); 95th percentile 5 ug/L (range 0.17-8.1). These levels are ve~aj tan 30-14 NHANES dot forthe pnt plc. similar to the 2013-14 NHANES data for the general public. Guna poplin (NHANES) biomaniorin dita dens thik sar lve ge be decreasing oer ne General population (NHANES) biomonitoring data demonstrate that serum levels have been decreasing over time (CDC 2017, The 2013-11 dota prove ths mt es dia ending. `background: srum vl th US ger (CDC 2017). The 2013-14 data provide the most recent data regarding 'background' serum levels in the US general Populi population. Year Geometric Mean (ug/L) 9~t~' Percentile (rig/L) (55.1 Gch (95% CI) (95% CI) 1999 - 2000 5.21 (4.72-5.74) 11.9 (10.9-13.5) 2003-2004 3.95 (3.65-4.27) 9.80 (7.40-14.1) ES000E:20T10 2005-2006 2007-2008 2009-2010 So es1330 3.92 (3,48-4.42) 4.12 (4.01-4.24) 3.07 (2.81-3.36) 750620970 11.3 (8.80-14.5) 9.60 (8.90-10.1) 7.50 (6.20-9.70) 2011-2012 2.08 (1.95-2.22) 5.68 (5.02-6.49) 2013-2014 1.94 (1.76-2.14) 5.57 (4.60-6.27) White data on ina is not alae her ar publications regain he scum ves in sun cir While data on infants is not available there are publications regarding the serum levels in young children: 2 Sihecter 2012 sampled chidron in Dil. Texas behwsen stand November 2000. Reported median (Schectcr 2012) sampled children in Dallas, Texas between August and November 2009. Reported median nda, PRON wrt Socnions were: nd 6g spacey, in sheep hr es and maximum PFOA serum concentrations were: 2 and 9.6 ug/L, respectively, in children less than three Sarsofape Reportad medion ind mama PFOA serum concentaons were 1 and 111 ap. years of age. Reported median and maximum PFOA serum concentrations were: 3.1 m~d 11.1 ug/L, ea nS olor rt eas of5 ok oot prot 2, respectively, in children older than three years of age bnt less than six years of age. ((WWuu 22001155)) ssaammpplleedd cchhiillddrreenn ttwwoo ttoo ceiigghhtt yyeeaarrss ooffaaggee iinn CCaalliiffoorrnniiaa bbeettwweeeenn DDeecceemmbbeerr 22000077 aanndd NNoovveemmbbeerr 22000099.. RReeppoorrtteedd ggeeoommetetrriicc mmeeaann aanndd 9955~ ppeerrcceennttiillee PPFFOOAA sseerruumm ccoonncceennttrraattiioonnss wweerree:: 44..4466 aanndd 77..44 uugg//LL., respectnaly respectively. + Hs 007) cen published serum concnttons nis oe ear old children sampled between 2007 aa(Hnnddar22r0i0s11020)0)1ii7nn)tthrheeecBBeonostslttyoonnpuaabrreleciaas..heRRdeeppsooerrrtuteemdd ggceoeoonmmceeetntrtrriiacctimmoeneasanninaannsiddx99to00t~teppneerrycceeeannrttiiollleedPPcFhFOiOldAAressnecrrsuaumnm~cpcoolenndccebennetttrwraatetiieoonnnss20ww0eer7ree:: 44..22aanndd 77..99 uugg/iLL., rreessppeeccttiivveellyy.. Dr Document fo vi nd islon iTprsoan Tal.oDth domed ot cosine Ages poli Draft Document - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 71 of 92 22447755..00007711 stare onsors STATE 07438074 These dat suppor the sc ofupper ernie ves fom NHANES andthe East Metron sidenta These data support the use ofupper-end percentile values fronl NItANES and the East Metro new resident as const ps of Sgro ar WES Fes ofAOS conservative representatives of 'background' non-water ingestion routes of exposure. The aporionent water nesion ca cll by kinlngg of 80% ad ubtings contin The apportionment to water ingestion can be calculated by taking a ceiling of 80% and subtracting a conservative (ih ond) sr vale fonts cent loaning data fom he 013-14 NHANES. Eg percentofths som (high end) serum value from the recent biomonimring data from the 2013-14 NHANES. Eighty percent ofthe serum concentration askocitod with he RID would be 101 ag. (130 up, 0.9) Subtracting he 95 percentile valu 36.8 concentration associated with the RfD would be 104 ug/L (130 ugiL x 0.8). Subtracting the 95t~ percentile values, as a hand estimate of background. on-walr cxpouISs, om he 3013-14 NHANES(57 ug/L roduc a dal high-end cstimatc of background, non-watcr cxposurcs, from the 2013-14 NHANES (5.57 ug!L) produces a residual `sseermrunm ccoonncceennttrraattiioonn ooffrroouugghhllyy 9988 uugg//LL., oorr aapppprrooxxiimmaatteellyy 7755%%ofotf thhee ssecrruumm ccoonncceennttrraattiioonn aatt tthhee RRffDD ((113300 uugg/fLL)).. Thi cletaion canbwed alta, song with th sin pos n Box AC of he Decision Te Sct This calculation can be used qualitatively, along with the ceiling proscribed in Box 8C ofthe Decision Tree to select 50a t%he RSCfo water meio. 50% as the RSC for water ingestion. ThJsRmst approprTiateEdoTs metTic oIrPEOTA is su consnttion, PFOA i a bicseumulatv hail, vith The most appropriate dose metric for PFOA is serum concentration. PFOA is a bioaccumulative chemical, with a hhaallff--lliiffeeooff 22 -- 33 yyeeaarrss.. CCrriitteerriiaa ffoorr bbiiooaaccccuummuullaattiivvee ccoonnttaammiinnaannttss ffooccuusseess oonn lloonngg--tteerrmm eexxppoossuurreess.. HHoowweevveerr,, hhiigghh,, order xposures ca ul mal od urd (take scto cahirn, nt, hth bold or short-term exposures can result in internal body burdens that take years to eliminate. Infants, whether bottle-fed or Seated com mach Tevou of Wd 0 et bos wight bas hander hiadiels. In breast-fed consume a much greater volume of liquid on a per body weight basis than older children and adults. In addin. PEON coe th placena and s rans to brasil. Epil da fom the publied rns addition, PFOA crosses the placenta and is transferred to breastmilk. Empirical data fi-om the published literature ato te regio a ool Se enon, onl her cmo8ons indicates that breastfeeding can result in significant exposures, result in higher serum concentrations in infants Compared thn mothers. compared to their mothers. Serum soncetstiocnasn be cleat fh rtof clinton derived rom WF), he dos ater Serum concentrations can be calculated ifthe rate of elimination (derived from half-life), the dose (water Concern wate kere) ad volume of dsabution ar known. The follwing Cation (as wed by EPA 0 concentration x water intake rate) and volume of distribution are known. The following equation (also used by EPA to lc HED) proves the mpl lation betwen dos an very scrum concottion calculate HEDs) provides the simple relationship between dose and average scrmn concentration. p(n (10g),) dmpoe m9 Serum Concentration x 1000 70)" Caprre (agsn) DSe(kg.d9-daay)y)=TT creaRr oeo (--m E--e ) e 9 Y: Wher Clearance 14,'here." Clearance RRaattee ~= VVoolluummee ooffDDiLsst'rtriibbuuttiioonn ((L1ikkgg BBWW)) xx ((LLnn22~hhaallfJ-'l-!i!ffee., dda~yyss)) aDose ng dy - Water Inake Rate (14g BWdy Water Concentration 1) 1 m/ 1000) Dose (my,ikg - day) Water Imake Rate (L/kg BW/day) x Water Concentration (ug/L) x (1 mgH O00 ug) This ution canbe eamanged to slelate sr concentration based on dos nd lean This equation can aren mnton (2 gL er crn) be rearranged to calculate serum concentration based oll dose mid clearance. L SerumConcentration(1 q) = Cearance Rater.og) ormrarceRoteloL y Clearance Rate(~--ffT~) Two supose semis were examined: 1 an nf od ith formula contd with contaminated war sarting Two exposure scenarios were examined: 1) an infant fed with formula reconstituted with contaminated water starting rh nd comm sion ofetait wale ron Han) a at vl bao or 13 at birth and continuing ingestion of contaminated water through life; and 2) an infant exclusively breast-fed for 12 Inonh, lowe by drinking contaminated arr In ot seer he Simul midleg i with rc months, followcd by drinking contaminatcd watcr. In both scenarios the simulatcd individuals began life with a pre- eexxiissttiinngg bbooddyy bbuurrddeenn tthhrroouugghh ppllaacceennttaall ttrraannssffeerr.. TThhee sseerruumm ccoonncceennttrraattiioonnoofftthhee lmnootthheerr wweerree ccaallccuullaatteedd ttoo bbee aatt ats se a ocurred oom. th nO dey: Lppes perocatl aks ios wows 56 steady state, using the equation presented above, at the time of delivery. Upper percentile intake rates werc used for ih bread an sri and Oh perce ak le wee whl 0 wer KS 1Sm 3 RIC the breastfed infant scenario and 95th percentile intake rates were used for water intake to simulate a reasonable mama exposed (RTE) mimi maximuln exposed (RME) individual. Orson or vie and aston ago al Dh rs et ote Ag oe Draft Doculnent - for review and discussion purposes only. Draft document does not constitute Agency policy Tororo PFOA - 72 of 92 22447755..00007722 STATE 7420075 STATE 07438075 According to the 2016 Breastfeeding Repo~ 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 twelve months. MDH has selected an exclusive breastfeeding duration of one year for the breast-fed infant scenario. A summaD" of the model parameters is presented in the table below. For details on the basis of each of the parameters and thc sclcction of input valuc(s) plcasc rct~r to thc Background Documcnt: MDH To~cokinctic Modcl and Derivation of tluman Health-Based Water Guidance located at: O: \ttRA\COMMON\Gnidance - Water\Tox reviews- (MDH 2017b) Model Parameter iHalf-life (days) Volume of distribution (Vd) Vd Age Adjustment Factor (Vd AF) Clearance Rate (CR) Placental transfer factor Breastmilk transfer factor Watcr Intakc (L/kg-d) Breastmilk Intake (Likg-d) Body weight (kg) 1S 840 days Value(s) 0.17 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. 0.17 Likg x (Ln 2/840 days) = 0.00014 I,ikg-d 87% (% of maternal serum level) 5.2% (% of maternal serum level) 95th pcrccntilc for Consumcrs Only (dcfanlt intakc ratcs uscd by MDH. Table 3-1 & 3-3, EPA 2011) Upper percentile (approximates 95th percentile) for exclusively breastfed infants (Table 15-1, EPA 2011) Calculated from ~vater and breastmilk intake tables listed above Draft Doculnent - for review and discussion purposes only. Draft document does not constitute Agency policy PFOA - 73 of 92 22447755..00007733 STATE 07438076 Water Concetenion Calclaton Ress Water Concentration Calculation Results: SF nro1 rmoednsos Scenario/~1 - Formula botde-ibd Infant Theatr concentra hor keepsth sr cocention ssl 0 drain wae Gold in cow in Figure1) losnRSCofS The water concentration that keeps the serum concentration attributable to drinking water (solid line below in Figure 1) below an RSC of 50% (01305 00Smg) ovghont 1015s (0.13 x 0.5 = 0.065 mg/L) throughout lifc is 0.15 ~tg/L. Figur 1 Excsivey formu fod fin sven onstsoctritoss, saa95 ose wangtsioners ad sa RSofSC74, Figure 1. Exclusively formula-fed infant serum concentrations over a lifetime, based on 95t~- percentile water ingestion rate and an RSC of 504. PFO Serum Concanation, Formula Fd Scare, 5th parcel nia rte, ter cre. 015ug. P.f:OA Ser~lm Co~cer~t~atio~s For-~x~u[a iFed Scer~ario, 95ti} perce~}ti[e ntake iate, water cos,c, 0,15 p~g/L of ~~ i _ Set ABe (ea~s) SB om 2oo ln, Scenario/i2 - Breast@din/ant Wie acto cometmion 015 Ls prtciveof vil rt cxpfooonsomentdd alr 0sft procs for While a water concentration of 0.15 ~tg/iL is protective of individuals directly exposed to contaminated water it is not sufficiently protective for in ho assy sadfr 57 By ter who an bn onal Pod. 01S Wg. wa. Undersat1an infants who are exclusively breastfed for a year by mothers who have been chronically exposed to 0.15 ~tgiL in water. Under scenario #2 infant BRON era clcco the sem concen te rene dsFor oer 45s dhe S07 RSC sol Fr cr coFt PFOA serum levels exceed the serum concentration at the reference dose for over 4 years and the 50% RSC threshold for over 9 years. See Figure ?2. Do Domne dionpp a Ds ConA AS ky Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 74 of 92 2247755..00007744 statearsssorr STATE_07438077 nFdueR2SSCcorfum0c7oncaeaironcooreanirexiclounsivoefly1b5aJsEtLd. r 1a, lowedby tegen, bsopps 95 esl nto ls Figure 2. Serum concemration for an exclusively breast-fed for 1 year, followed by water ingestion, based on upper/95th percemile ingestion rates and an RS C of 50% at a water concentration of 0.15 ~tgiL. PRO Serum Concentration, reat fd 12 man, Upper percentile intake rae, waterconcen 015 gl 5 I Sesto ~e (years) Sneetrhtwo eic ainseo r com cenbiehoe mnsereoln o0Da0n5Rt SEChkshSosldFoifsS0754 (01330-0065mg)fo fs xcasiely brs foc In order to maintain semln concentrations below an RSC threshold of 50% (0.13 x 0.5 = 0.065 mgiL) for infants exclusively breast-fed for one year the water concentration must be lowered to 0.035 ~tgiL. See Figure 3. Do Domne dionpp a Ds ConA AS ky Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 75 of 92 2247755..00007755 stateareseors STATE_07438078 Fue3. Scrum consemionfora excise bret fd for | rll by tr ingston, bse on pp 95 prt mstonas Figure 3. Serum concentrations for an exclusively breast-fed for 1 year, followed by water ingestion, based on upper/95th percentile ingestion rate nd RoSf7Ck ar concoef 0n3S pL. and an RSC of 50% at a water concentration of 0.035 ggiL. PFOA Serum Concenraton,Beast fos12 men, Upper percentile Intake rae, water concen 0035 g/t pr Enc ml ccm mrs in howaterconcetation (0036 gL) rshscm concesnvte he $0perce shold for Even a small incremental increase in the water concentration (0.036 ~g/iL) raises the serum concentration above the 50 percent threshold for Spr ok math ic.Ps dp oF oa He Gr Enc, AP wSemeNS LS appro~mately one month. Given the health endpoints of concern include developmental concerns, the acceptable water concentration was set at Swe adm ound 0 okspcoh 0.(),_ gg/L m~d not rounded to one significant digit. Do Domne dionpp ai Ds ConA AS ky Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 76 of 92 2247755..00007766 statearsssoro STATE_07438079 | 7A. Relevant Cancer StesSummary Tab Cancer Sid Docrpion |Adminbieed| Tamer nace Rat Per TumSoirc at EachDose Cancer Study Description Zion, ote, Dose Vere (bysnail senfane) - duration, route, pinnate) species/strain, age at ming,Nperonp, cary dosin g, N/sex/group, early Administered Dose (mff_!kg-d) Tumor Incidence Rate Per Tumor Site at Each Dose Level (by sex, statistical significance) Study POD mg/kg/d Shope [Refer Slope Far | (ve Factor (may | cfonmimeonnts in (mg/kg-d)-1 Reference (note limitations in comment life exposure?, etc. filed)* 2 year Dieta~ Stu@ - GicoBRRas Crl:CDBR Rats Stine 50/sex/dose Diy lnc, 300300 Dietmy levels 0, 30 or 300 Fyppm Sexually mature Ks' hm,e yt he veJT short ha~'-life ste restosf therejbre, the results of cancerbos cxprer cancer bioassay, except ctt Sinha suf/~cienl@ hiy~h doses, in emai as eo sd ./i,male rats is oflimited pry uti#ty in assessing carcinogenic potential. M/F 0/0, (13060 | fadieen y 1.3/1.6, or W261 | Neots: far 30. 00a] 14.2/16.1 mudd | Ms mg/kg-d Adfapor| TLieeyirsb cllap escaorcs mi4nmo8 152%. 0100%8 (Over Add'l grp of 15/sex for 0 & 00pm ts & 74 301] 300ppm |exsuod Thad Col shmana 0.48% evaluated | Give mer @lyr interim [a NFieBd frmelanrae ndororf,ooe droeewomaasb nm2 rl42l an& 4re5%nd ianf)ol sac See Table 6-A above for discussion of non-neoplastic findings. Neoplast~c findings: [control, 30, ~ 300 ppm] Males: Liver hepatocellul~x carcinoma 6, 2 & 10%; Leydig cell adenomas 0, 4 & 14*%, *p<0.05 [4% was indicated to be within hL~torica[ controls by authors & EPA 2016]; Thyroid C-cell adenoma 0, 4 & 9% Females: Mammmy gland fibroadenoma 22, 42 & 48*% [all considered to be within the norm for bac'kground variation. Re-evaluation found no starts s~gn~r d~rerence for fibroadenoma, adenocarcinoma, total benign neoplasms, or total ma#gnant neoplasms] Tech Gn [orTS6 | Nelo fb 2 yr Mechoxfistic dietary Suds CACDBR Male |mpid | Livesadnsme 196i pind coucinahb,t study - Crl:CD BR Male Kaw 156m) mma Comrie 5%, ml Rats (156/grp) (follow-up to study above) Oaroipmm owveoiaetns| cma oinnssswoansfL,coyhannigdecl1nl1s5pmimnr(tHeInsN1:4%in 0 or 300 ppm 0 or 13.6 mg/kg -d Interim sac conducted every 3 months upto 21 months Neoplastic findings: Liver adenomas - 1% in pair-fed controls, 3% in ad libitum controls and 13%, in trt animals Leydig cell adenomas - 3% in pair-fed controls, 0% in ad libitum controls, and 11% in trt animals. [Note: ]" incidence of Leydig cell hyperplasia (46% vs 14% in controls was observed)] NF eon Toy TH ge mm OA vw 1, dems(5) Note: describe if exposure included early life stages; nm.,dmnm tolerated dose level was not achieved; and time-to-tumor (latency) Sibinski ct al 1987published 1987 published as Buell as (Butenhoff 012amd 2012) and act Eka EPA 2016a Beer Biegel et al 2001 EPA 2001 act EPA ole 2016a oro i~fformafion if available. mf Doss fr evi sd dicsionpups nl. Dsdc octconn Age ply Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 77 of 92 22447755..00007777 STATE Gresecen STATE_07438080 OraCancereed Sy Summaries: Human Carcinogenicity Data Human Carclnogenicity Data: EPSot Soin 3.43 Synthesis ndEvaltion of Carini Ef. EPA 2016a - Section 3.4.2 Synthesls and Evaluation ofCarcinogenic Effects'. Evidence ofccna cesOf PFOA in pdcoloy sc bs pearl on sofcdnc adctu acerThos ann iEvidence of carcinogenic effects of PFOA in epidemiology studies is based primarily on studies of kidney and testicular cancer. These cancers Ka lines gh sl re (5. 2095201 cat iails 75% nd95spun. one esocaer ed have relatively high survival rates (e.g., 2005-2011 5-year SUlwival rates 73% and 95%, respectively, for kidney and testicular cancer based on NCH Sule Fpiemoloe and idReusda)Ths stoi ot exami caer cspricy well or vs psof NCI Surveillance, Epidemiology and End Results data). Thus studies that exanaine cancer incidence are particularly useful for these t3pes of Caer The besscommunity sicsho Rae he apa, oscarcant of cinai prod fis 2 he cancer. The high-exposure community studies also have the advantage, for testicular cancer, &including the age period of greatest risk, as the ian sc digo 3ca The cecal chor 1 in350s Wet iri (os cn pst in Rach ta 201 median age at diagnosis is 33 years. The two occupational cohorts in iMinnesota and West Virginia (most recently updated in Raleigh et al. 2014 xd Scnand an Woske 2012 ok appr an nad oofksscancers,but acofbhe ied 3sll uohed and Steenland and Woskie 2012) do not support an increased risk ofthese cancers, but each ofthese is limited by a small number of observed Esi Kidneycao ths, 6 cdo Linecnr cs,od cet scl nor as Raloigh 12 2014 11d cases (six kidney cancer deaths, 16 incident kidney cancer cases, and five incident testicular cancer eases in Raleigh et al. 2014; and 12 kidney Cmca deaths od tr incedh n Scns Wis 2013 Tw tubes ihn nor of CF HehPrt med cancer deaths and 1 testicular cancer death in Steenland and Woskie 2012). Two studies revolving members &the C8 Health Project showed a posi soso tn PFOA ees (cans clit 002 nil) ad does ad scrcanes (Bary tl 01% Vii to. positive association between PFOA levels (mean at enrolhnent 0.024 ggimL) and kidney and testicular cancers (Barcy et al. 2013; Vieira et al. S075 hrs om nea hecas hdhi lcs, goShon wis found 1h rl popula EMSER 2013); there is some overlap in the cases included in these studies. No associations were found in the general population between mean serum PFOA ela10 030 ml a colorec beas,proto, bdr and nercas Bonced Jorgen c3t 201. Eniocnc a 2009, PFOA levels up to 0.0866 ggimL and colorectal, breast, prostate, bladder, and liver cancer (Bonefeld-Jorgensen et al. 2014; Eriksen et al. 2009; Hard tal 2014 anc 2014) noof hne ses examined dco str acer Hardell et al. 2014; Innes et al. 2014); none of these studies examined kidney or testicular cancer. Avimal Carcinogenicity Dats Animal Carcinogenicity Data: EP 2b Secon 3.42 Synthesis ndEvelationofCrcinogEncic. EPA 2016a - Section 3.4.2 @nthesis and Evaluation ofCarcinogenic Effects. Tu snl cena si mcs thaPFON Expr co eo nradn (Bisel ta 2001),Leicol comBisg Two animal carcinogenicity studies indicate that PFOA exposure can lead to liver adenomas (Biegel et al. 2001), Leydig cell adenomas (Biegel US 00 Bacal 1a 201), 4 PACT (acc 01)1 male SpragueDewi ra. Lc enon 3 aba 0h Bs<1 ct al. 2001; Butcnhoffct al. 2012), and PACTs (Bicgcl ct al. 2001) in male Spraguc-Dawlcy rats. Liver adcnomas ~vcrc observed in the Bicgcl ct 5 ly (301)st rnc of 071 20mg. Th: enc cond sup was 2805+) Asaph 0 cr noms al study (2001) at an incidence of 10/76 (13%) at 20 mg/kgiday. The incidence in the control group was 2/80 (3%). Although no liver adcnomas rch in talc (201), cueemare knifed hemal cont, mal non oe 1p ERE). a ls were obse~ed in Butenhoff et al. (2012), carcinomas were identified in the male controls, males in the low-dose group (2 mg/kg/day), and male dei os the hosesro (3 mah)The dns fro om nr nt gnc itersa. bt he archos and female rats in the high-dose group (20 mgikgiday). The differences from control were not significant in either study, but the carcinoma {edenarmmg the kab3 (112 hd lc (1w0s 4a0t ho te amen he Ft] c31 Sy C200) incidence among the Butenhoff et al. (2012) high-dose males (10/50) was similar to that for the adenomas in the Biegel et al. study (2001) 107) Liver con ws ome th le and ewe te 1 3nd 2asonics (Bol. 2012 A rsd mcsof (10/76). Liver lesions were identified in the males and females at the l- and 2-year sacrifices (Butenhoffet al. 2012). An increased incidence of Bsheponcgtooscaydbp crt creda 20 moo Ah 2casacce, hepa sed degen diffuse hepatomegaloc~osis and hepatocelhdar necrosis occurred at 20 mg/kg/day. At the 2-year sacrifice, hepatic cystoid degeneration {chractonind by asof moemicrotst e rpron) asoben 5.1,3nd 504.8 ls of heconte, 3nd 20- (characterized by areas of multilocular microcysts in the liver parenchyma) was observed in 8, 14, and 56% in males ofthe control, 2-, and 20Ed os ro Eh Ta Aol leIe GR nd8 ihn 7(06 c0P 4Cr). mgikgiday dose groups, respectively. Hyperplastic nodules in male livers were increased in the high-dose group (6% versus 0% in control rats). Filet (2019) examined he crhefuns fic exposed ly dri gestsocation or ts when ey wee scr. Filgo et al. (2015) exanfined the livers ofthree strains of lnice exposed only during gestation/lactation tbr ttmaors when they were sacrificed at Tmo Liv ms wer Found cc dosSoup tor pcr 37d 4 iedr ss dil vieonfdss spss. The 18 months. Liver tumors were found in each dose group, but tUlnOr types varied and the data did not display any evidence of dose response. The imalrs vrs TomTn Te poetnd he, i pds soaus sepl] Ths, he a af ot equfor animals were survivors from two different projects and the number per dose group was small. Thus, the data are not adequate for determining itor PFOA 1 cata ce. Sh n eed r otosc NOTds ol arisen. ulcs oroof whether PFOA is a carcinogen in mice. [Study authors" noted that this study was ~VOT designed to ewduate carcinogenesis but was a result qi pris st por ns torson PAR eft ce. ls 408 coms ha 1 0orhst a previous study that reported liver tumors in PPARa-de/icient mice so this study was considered an initial mechanistic study to co~/irm that PROcn te pono ctviro PPAR pan PFOA can mediate hepatoloxic effbcts via non-PPARa pathwa~w',] Dr Duco for ewsn dco poss i. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 78 of 92 2247755..00007788 sateoresaoet STATE_07438081 Concho re Ineurs: Owl the ar reponse srs ne avalos us ossrr and rr demons ace. 'Conch~sions' re: liver tumors': Overall, the tumor re~7)onse observed in the avai&b!e studies was not strong and did not demonstrate a doseelders. Buel tol (30ndB1es3e )1 (3901) shes si htPEO potepnoe canendoon henow related response. ButenhoJfet al. (2012) and Biegel et al. (200]) studies suggest that PFOA is not a potent hepatic carcinogen based on the low nor ene fcr pein pen. [MDH ote vts 4 GutsHc. On pec xedbs ot 304 minor incidence and.finding ofhyperplastie nodules. [MI)H Notes: available data are quite limited. Only species examined has been rats and it ela hs Fasl Quek ste PEOuti ban odessis| is clear that female rats quickly excrete PFOA unlike humans or other animals.] Teil Leis col mors(LCTS) wor defi im bohde Btcbotfac.(2012) nd ie 1 200) ses The mor ces: Testicular Leydig cell tmnors (LCTS) were identified in both the Butenhoffet al. (2012) and Biegel et al. (2001) studies. The tmnor incidence SEGSI0), 350 1, 2nd 750.11) or he cool, 20 5d 2gdodos group. spreinls (RSMTCt S013 Ths Bgl was 0/50 (0%), 2/50 (4%), and 7/50 (14%) for the control, 2.0-, and 20-mg!kgiday dose groups, respectively (Butenhoffet al. 2012). The Biegel Sesh 3001) nchdedon os1p (0 MERGa) ut rcp wisM6 11)compre OW (0%) teconl Ep. et al. study (2001) included one dose group (20 mg/kg/day); the tumor incidence was 8/76 (11%) compared to 0/80 (0%) in the control group. LCTinion 20mh ay was combs bts hetwo tos (11804150) LCT incidence at 20 mgikgiday was comparable between the two studies (11 and 14%). Conchstons re: LCT: The ctioof LCnT byPFOA could ered a boolmechs ry PFOA eer nibs 'Conclusions' re: LCTs: The induction ofLCTs by PFOA couM be attributed to a hormonal mechanism whereby PFOA either inhibits' estore Moya dr owes sin i comer 0 cabo Bh rsd roseCy nc testosterone bioo~'nthesis and;or lowers testosterone by increasing its" conversion to estradiol through increased aromatase activity in the liver. othof es china pear be meshed PPARSew of he xa PFOA che poontrecofPOA ondecrad Both ofthese mechanisms appear to be mediated by PPARa. Several qfthe available PFOA studies support an impact 9fPFOA on decreased leone proton Stes comb by Cook andcoBlagelerl 1975 Cook. 172. efaf 199% foundhtmce testosterone production. Studies comlucted by Cook and colleagues (Biegel et al 1995: Cook et al. 1992; Liu et al. !996)Jbund that adult male Ton inden POA 3 inser14 hoddcr um canara and reed rl ee (ook1 199. rats administered P!,'OA by gavagefor 14 days had decreased serum testosterone and increased serum estradiol levels' (Cook et al. ! 992). Theeender conse coldwih ens hoe 113 hel 1. 301) These endocrine changes correlated with its potency to induce LCZs' (Biegel et al. 2001). Dutaae pot caren ficken o demas ho he ner es sep nepo MOA are eprs 1 PFOA asoll Data are not currently sufficient to demonstrate that the other key steps in the postulated~klOA are present in PFOA-treated animalsfollowing xpos hted10 pe form es are edad ode reof GH nd LH concer ihshe hors exposures that lead to tumorformation Studies are needed to demonstraW the increase ofGnRH and LH in concert with the changes in mo andae aa Thee verao bc of erred Penh coll rst edocs at coud cs Beg 1 aromamse and estradiol. There was a~o no indication ofincreased Leydig cell proliferation at the doses that caused adenomas in the Biegel et a (001) Tis ol esr eked odes 1emo store crcl Inc oto 1 a!. stud), (2001). Thus, additional research is needed to determine ~fthe hormone testosterone estradiol imbalance is a keyJi~ctor in eniofLoCT apv mriteaFnLO cpa. development ofLCTs as a result qfPFOA exposure. Pancreat sircll mrs (PACES) wee ols osvd ithe ge. sty UDI) The ide was 576 11% 7aden, | Pancreatic acinar cell tumors (PACTs) were only observed in the Biegel et al. study (2001). The incidence was 8/76 (11%; 7 adenolna, 1 Crin1omngsd)Nils2 nr ober heSom ml Ahh 00 PACTS wersvencd bn Bacabolf ct) 2012) carcinoma) at 20 mg!kg/day while none were observed in the control almnals. Although no PACTs were observed by Butenhoffet al. (2012), PareSm AB abcd 20d 20 4 mercer 14 (4) 3 (24, pcan whch eked dn pancreatic acinar hyperplasia was observed at 2 and 20 mg/kg/day at incidences of 2/34 (6%) and 1/43 (2%), respectively, which lacked dose espns. Reeof hm eputa ea kon in Bunt (012)smd Big] ca (201) sue theconclusion thor 20 response. Reexamination ofthe pancreatic lesions in Butenhoff et al. (2012) mad Biegel et al. (2001) resulted in the conclusion that 20 muda mse honof prooi sclcons th stds: Some et Bel 1.3 sy 200) hd mg/kgiday increased the incidence of proliferative acmar cell lesions in both studies. Some lesions in the Biegel et al. study (2001) had Prosssedo smn progressed to adenomas. Conchnions re: PACTS: Twposal MORs ve bospropos: 1. chine nBiece id fi ocompasiton hot ds 0 'Conclusions' re: PACTs: Two hypothetical MOAs have been proposed: 1) A change in the bile acidflow or composition that leads to hao, hy coi n rann e 1 CR cishock Ivresins nrffr of rorsprt cir 1s. cholestasis, thereby causing an increase in CCK activating afeedback loop resulting in proliferation ofthe secretory pancreatic acinar cells'. CK pepe ormsho rs he dotnet obP Sd os CCK is a peptide hormone that stimulates the digestion of/~tt andprotein, causes the increasedprochwtion ofhepatic bile, and stimulates Comhre ail beer, AV HED. pi hon. and change be comport re ors or Is segueof vs. contraction ofthe gay bladder. An HFD, trypsin inhibi#on, and changes in bile composition are proposed initiators'for this sequence ofevents. ; otrane fone pot 4 reat ac sollpenseoc di oi de fert and 2) Increased levels" oj'testosterone support the growth qfacinar cell. preneoplasticjbci, leading to the development ofcarcinomas. Theres mimo omarion ni eatonofsPhFOpA xpos oofi he proposr edMO Howenr ETA rots PEO pears 7here is minimal information on the relationship ofPFOA exposure to either ofthe proposedMOAs. [However, EPA notes: PFOA appears to pps omer roche oug1h eon of roned 56 ecru TITo. kodPO MOAfr suppress testosterone production fl~rough the induction oj'aromamse and to increase the estradiol. Therefore, the secondproposed MOA Jbr PACT:dos otcpu plyPOA PAC~s" does not appear to appO~ to Dr Dum for ew ad dso poss ls. Ddos c cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 79 of 92 275.0079 247510079 stateoressosz STATE_07438082 hs tl ig fom te knot ads (202) sss) omy esfnsle is Mowers 2 The initial findings from the Butenhoff et al. study (2012) were equivocal for mammary fibroadenomas in female rats. However, a nti fh ar 3G und lc ns bce me ukeofBrit rit ps ofhe reexamination of the tissues by a PWG found no statistically significant differences in the incidence of fibroadenomas or other neoplaslns ofthe Irnd n owe cor 0 td rt Bt F10 Th PG wl: dagnr ons ndered oF mammary, gland between control and treated animals (Hardisty et al. 2010). The PWG used the diagnostic criteria and nomenclature ofthe Soyof Tousloil Pabolheomg.t Lrhos Chr at De AOR oferdoc Society of Toxicological Pathologists for the reexamination. Under those criteria, there was an increase in the number of tumors docmnented in hol ru,oi raion cogil cat alr pT.To ston1a tofapsabe the control group, especially fibroadenomas originally classified as lobular hyperplasia. The reclassification led to a loss of significance when hr ih ed hl erecompa nr Sel the tumors in the treated animals were compared to tumors in the control animals. Ova tr pis an anon shows bindrl ts (nol. 2013)MraFe C10) mind Ovarian tubular hyperplasia and adenomas also were observed in female rats (Butenhoff et al. 2012). Mann and Frame (2004) reexamined the Nara ns pad c Ah hc om of Pt te Bg tid The an ors ovarian lesions using all updated nomenclature system, which resulted in some ofthe hyperplastic lesions being reclassified. The ovarian lesions adhri le ie le gas originally described as tubular hyperplasia or tubular adenomas were regarded as gonadal stromal hyperplasia and/or adenomas. After the hn, ee wie SoS Sre as et n Go me kB 0 We om reclassification, there were no statistically significant increases in hyperplasia (total number), adenomas, or hyperplasiw'adenoma combined in ropo oon treated groups compared to controls. Gonos Dua Genotoxicity Data: En Str3a1Siumna EPA 2016a Section 3.3.1 SummaD': PEON ben tor Goi in arity fr and is cys.Th dt om the i i tdi os nd hls PFOA has been tested for gcnotoxicity in a variety of in Wvo and in vitro assays. The data from the in vitro studies arc summari zcd in tbc table on below - Tess GaeewdyaONm Table 3-32. GenotoxM~' of PFOA .I~ !~Ttro Tors nb | WA Web cri era] c}-{~ 0]:: meuse CcH Fm~fl~m~ti,:m atanm. emi |=5 Clra | C,,I [ 10L. mmtse (?ytotoxicity NA [Crear n, menor | Jp [ I | | TA [ ..............5....3...7................................................................................................... Gan7 arid Ndson Gm<ry and Nclson + Lawbr 1995, 1996 ost = TT ee on| CHO celb Chrom~som~] A.be~rafions CLT -- en oe| CHO cells ~ P~JS'Pk~d3 Huma~a Iymphocy~es ~ Chro~msomal iain] : SN [ Abem~tions [ET re a Jomesmman] K-I C[tO ce!Is {3e~e a a =| "[A98, TA! he tas : | ....................................... MurIi t996h. 1996c ........................................................~ Mu~li . i99d=b~ .i9..9.6..c.... SaNto 2002 t'reire e~ aL 2008 PROM was cst in cl sormation sd cic sy cond in CHIU sscnr bbls The coll oration vas PFOA was tested in a cell transformation and cytotoxicity assay conducted in C3H10T~,~ mouse embryo fibroblasts. The cell transformation was mid ehco formation snd oe mnThr 2 of Farman 5oF Gt ch od determined as both colony transformation and foci transformation. There was no evidence of transformation at any of the dose levels tested in on ume rm hhoPAs oh hn rt contaAB Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 80 of 92 22447755..00008800 sarecress STATE_07438083 ier te colony or fo say methods PFOA ws sted is os iy nos oon fe Slsoncl E climamnalin- either the colony or loci assay methods. PFOA was tested twice for its ability to induce mutation in the Salmonella - E. coli/mammalianicrusomeensman sy The ere efomed hhnd ii abl cto. Asgl oie sposece microsome reverse mutation assay. The tests were performed both with and without metabolic activation. A single positive response seen in S. apmTATS3T hen ested hot ool enn a 1 pune PFO dot nds sion Gr phen typhimurium TA1537 when tested without metabolic activation was not reproducible. PFOA did not induce mutation in either S. typhimurium OE colwhenteed ihr withor whut cab con. PON nt leshompsnl sbratans iat poets whe or E. coli when tested either with or without metabolic activation. PFOA did not induce chromosomal aberrations in human lymphoc~es when Ct ihand do cabot conp10 cto onions. Sod (R03)reported sdPFOA did not nds os tation tested with and without metabolic activation up to cy.*otoxic concentrations. Sadhu (2002) reported that PFOA did not induce gene lnutation Nh td th or ut tab acon eK. neof CHO ol clr Mor (1956, 1996) sted PEO tc fr | when tested with or without metabolic activation in the K-1 line of CHO cells in culture. Mufti (1996b, 1996c) tested PFOA twice for its ability fondschomeson brain in CHO sells Inthefistsay. PFO nedbotchomasonal shraions nd pollo inbth to induce chromosolnal aberrations in CHO cells. In the first assay, PFOA induced both chromosomal aberrations and polyploidy in both the rene ad ac of o abl ciao nh ond ss 0 Sct rs 1 chros somlsbraon are Oecd hot presence and absence of metabolic activation. In the second assay, no significant increases in chromosomal aberrations were observed without Eon However, ahi sad wath cable anion, PFOA aed nan rcs n crocs erosas pelos activation. However, when tested with metabolic activation, PFOA induced significant increases in chromosomal aberrations and in polyploidy {Sr 1996)The csc wre src a 8 to Sncnttos (HSA 208) PFOduc pis masses sti, wihor ibs (Mudi 1996b). The effects were observed only at toxic concentrations (EFSA 2008). PFOA did not display mutagenic activity with or without Intl cation. mann as TAY, AIG. TAGS,or TAIG4 (Fer 13 2008. metabolic activation in S. typhimurium strains TA98, TA100, TA102, or TA104 (Freire et al. 2008). nvrdt saidston in Tale 3.32sho sist ht POA i cate Asingle poss stn. piri ws ct In Wtro data summarized above in Table 3-32 above suggest that PFOA is not a mutagen. A single positive result in S. typhimurium was not ere: by Tess chor das ot pte oder dic actioncts vere oudi CHOGals reproducible by the salne authors and was not replicated in other studies. Potential chromosomal effects were found in CHO cells at to~c prioritised concentrations, but not in human lymphocytcs. PFOA was etic hs vems ional ss PFOA didnot indus ay sift nrc in miro and ac PFOA was tested twice in the m Wvo mouse micronuclcus assay. PFOA did not induce any significant increases in micronuclci and was Comsed nai derhe combihsnacay (Mr, 199 1996) G 7h 3 (C01) ed AL cltodetteemrtmni considered negative under the conditions ofthis assay (Mufti 1995, 1996d). G Zhao et al. (2010) used AL cells to determine the nmtagenicity TPF tmmm cll, AL <1 3 bran trby rid oniing CHO-K| chroosons 0 5 opsof hn of PFOA to mammalian cells. AL cells are a human-hamster hybrid containing CHO-K1 chromosomes and a single copy of human Chamone 11 Th sooff honi croma or 1 ht coud fr pet fs el roepin CDS AL 100 chromosome 11. The significance of human chromosome 11 is that it encodes for expression of the human cell surface protein CD59. At 100 30 pl PFO A6L 3H a Sa, Gd ar rca or 1.3400 1d. CDTonn s Ete and 200 gmol PFOA, AL cell viability was significantly decreased after incubation for 1, 4, 8, and 16 days. CD59 mutation frequencies were {acre AL lsacs 16-day ncbaion ni 00 nl POA. Thr a0 crs lions ochon etnAL cos increased in AL cells after a 16-day incubation with 200 gmol PFOA. There was no increase in mutations in mitochondria-deficient AL cells Shir ban ah100or 200 ol FON after incubation with 100 or 200 ~.unol PFOA. Cota Cancer Soy Torin: Comes Clasico (sss &dw: Cancer Classification (sourec & date): Sipe FactorSure, Date of Dvclopment Slope Factor Source, Date of Development: Sop Factor Sud Ql: Slope Factor Study Quality: Underth EPA 2008cas guidlines, hs don forthe ings ofPEOA Under the EPA 2005 cancer guidelines, the evidence for the carcinogcnicity of PFOA is Comrade bce ol on: pcshi o aad fr he pons nd considered suggestive because only one species has been evaluated for lifetime exposures and mor responsccm rman ml (EFA 2016) the tumor responses occurred primarily in males*. (EPA 2016a) lB te rre o opi ors PFO *Note: unlike male rats, j~male rats rapidly excrew PFOA EPA2016 (Nhs deed casper ssdsp blow) EPA 2016 (NJ has also derived a cancer slope factor see description below) Too tls xis ome (Buteholft 2012)bas two ssn grosand ws condoon Two studies exist one (Butenhoffet a12012) has two treatment groups and was conducted on mal snd female ras. Hoe, ems spd xc PFOA Cnc bias dias. both male and female rats. However, female rots rapidly excrete PFOA. Cancer bioassay data is tale ter cis (3. mie) A ll ap sd Bice] 43 001) vas conde not available in other species (e.g., mice). A follow-up study (Biegel et al 2001) was conducted Dr Duco for ewsn dco poss i. Df ctdos cosineAS pbs Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 81 of 92 22447755..00008811 sateoressons STATE_07438084 ony in marsad lidnly ome smn rco ots ihe dose gp in only in male rats and utilized only one treatment group (equal to the highest dose grp in Buia 012 Butenhoff et al 2012). Dustthe Bass rhToy Valu: LPrTOaCBiC0raohji1ToLometcp)scn)cent.tdtFrtcahroLSoeTo(lCrnnn2hsaoTo0etrfsdqn22dhsesf0)aers0wpoaon1hpmtap)iot,aDcsoTcchcdihuBoqeowltuucecPametsAibcacdcCcalraeahTnonn tdnmiitseloofutcnrnmissda.so(knrn2rT abedn20e csid01edi1)la3ys(newS ssBeTh ehdaicrrriogPs GohcFcdmtroseOI adansr Adiodisilnse0r1ioh1esl5hCtto .sohphTsoepels(nVrsishavonigcvirisllnim, nshsdtraeemod1dfdolac.oo3.pssso0eet2Bealdwt0hlmro1eem9esiocenl.fBceTnabathonpchfhetolnC0acvsrtis0esoashdo2ofHeeyod4erf,drar0fsbhehseyeb.yt Describe the Basis forthe Toxicity Value: The increase in hepatocellular rumors did not show a direct relationship to dose in male rats and was not significantly elevated in either males or females at the high dose when compared to controls. There was a dose-related significant increase in LCTs in male rats in the Butenhoffet al. study (2012), which was confirmed by the high dose in the single-dose mechanistic study by Biegel et al. (2001). The PACT tumors, only detected in the single dose Biegel et al. study (2001), do not support quantification. Therefore, dose-response data are only available for the LCTs from one study, Butenhoff et al 2012. Two studies involving members of the C8 Health Proj ect showed a positive association between PFOA levels (mean at enrollment of 0.024 gg/mL) and kidney and testicular cancers (Bar~ et al. 2013; Vieira et al. 2013). Therefore, the data on LCTs from Butenhoff et al. (2012) were modeled to provide a perspective on the magnitude of the potential cancer risk as it compares with the level of protection provided by the RfD. hedos ssponss or te LCT sen Butts. 0012) ws old sing EPA's The dose-response for the LCTs from Butcnhoffct al. (2012) was modeled using EPA's BenchDo Soar: (BMD) Veron 3:1 The utes ctsmode cedth Benchmark Dose Software (BMDS) Version 2.3.1. The multistage cancer model predicted the deus inesnao enc woadoceu. Th Fs wsche own dose at which a 4% increase in tumor incidence would occur. The 4% was chosen as the low-end Fhe hired apo ge inh Boteal (01 eis. Boih fs300 of the observed response range within the Butenhoffet al. (2012) results. Both the first and ccd degre polynomialsGn tc] sof cic (ve ad A'S second degree polynomials gave identical goodness-of-fit criteria (p value and Akaike's niomanos Coanen ICH Information Criterion [AIC]). Ressfom Results frolll PA's EPA's dling modelingaarsesshhooswnn lo: below: Table 4-tl. MuLtistage Cancer M~del Dose Predicti~n Results for a 4% Increase . LCT Instone in LCT Incidence nb mig BDL sign BMD (m~,'~;g;day) BMDL (m~oikgiday) Toe First Degree Pol;,:~omial Fit 3.51 1.99 Sent Doe Pmt i Second Degree Poly~umial Fit 3.51 1.99 A[C- 62.6936 P - 0.2245 Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review al~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 82 of 92 22447755..00008822 sateoressoss STATE_07438085 0.2,5 0 ~15 0.1 ne Figure 4-1. BMD Model Results for LCTs (Butenhoff et al. 2012) Figure 4-1. BMD Modal Results tbr L(: I ,_ (Butenhoff et al. 2012} TheCSFfor PROSisdnd fomhe BDLDA of 19 mgd fr comrinhge ail Thc CSF for PFOS is dcrivcd from thc BMDL04 of 1.99 mgikg/day af~cr convcrting thc animal DL 3 HEDwing bh weights fn poner. Th HED iclaro oom: BMDL to a HED using body weights to the ~/; power. The HED is calculated as follows: HED = Anns) MDL anima oy weigh (humsbody weight tIED = Animal BMDL x (animal body weight)1/4 + (human body weight)1/4 HED= 199 mghyiy 037346)" + 104g|)= 19 mpix029 0 SS my ttED = 1.99 mg/kg/day x [(0.523 kg)1/4 + (70 kg)1/4] = |.99 mgikg/day x 0.29 = 0.58 mg!kgiday Where." 19 mga = INDL or LCTs 1.99 mgikgiday = BMDLo4 for LCTs on "oA 0.29 = DAF The Cis colette fo th BVIDLDS HED3 ons The CSF is calculated fronl the BMDL04 HED as follows CSF rom - BDL HED. CSF response + BMDL04HED CSF 004+055 mahgiay 007 mga CSF = 0.04 + 0.58 ~ng/kg/day = 0.07 (mg/kg/day)-1 he CFshou tb:wd a docs >0.5 may. he HEDcomsponding tePOD or The CSF should not be used at doses > 0.58 mg!kg/day, the HED corresponding to the POD for ioe oFLCT Following Hts xpos i PFOA. The Sheddscns: the 4% incidence of LCTs following lifetime exposure to PFOA. The observed dose-response Dr Duco Draft Document for- for ewsn review a~l dco discussion poss purposes i.only. DfDraft ctdos document does notcosineAS constitute Agency pbspolicy PFOA - 83 of 92 22447755..00008833 sateoressoss STATE_07438086 aicshidopoet ono: nay shoe ise, and th: cddose. rspons ods eee relationships do not continue linearly above this level, and the fitted dose-response models better Chaherdoseespanne forthe ght spouses characterize the dose-response for the higher exposures. MDH Nets: gintis son abou tsTK of PFOA uliztion fhe BVsling ot iMIXIt Notes: given what is known about the TK of PFOA utilization ofthe BW scaling default Spo in ppsdnd wold ol ug thease cnr Tk NF approach in inappropriate and would result in underestimating the associated cancer risk. NJ has denned coer soe xr do creed denof LCsT N) CoF 0001 er also derived a cancer slope factor based on increased incidence of LCI's. NJ CSF is 0.021 per uh sd do 2 Shbk| mgik-d admin dose in rats. See below.] Sin sem concenwtrtnoitvcinasl N)conducted MID dlwiin aniigd Since seam concentrations were not available NJ conducted BMD modeling using administered os ThGannndLogdogs models geSegaSld Sm ss 0h vcs dose. The Gamma and iLog-logistic models gave acceptable and similar results so the values `wr ncn NDLIBNIDS - 2364 2 mga Fora BRof Sthorspodosa were averaged: BMDLiBMDo5 - 2.36/4.23 mgikg-d. For a BMR of 5% this corresponds to a ierpin ope of 0021permake4 bmds: Tocomentthesinidsostessr0 cancer potency slope of 0.021 per mg/kg-d adm dose. To convert the administered dose in rats to SHED Nwth heTK (MAM) dina lersand ans 40ds? a HED NJ utilized the the TK (half-life) differences between male rats and humans: 840 days/7 {ys 120 Using his valets CS i ts comresponds 0 CSF hans oF 252 et gh days = 120. Using this value the CSF in rats corresponds to a CSF in humans of 2.52 per mg/kgS100 perp 40doa?do) d (0.021 per mg/kg-d x (840 days/7 days))] NOTE: MDH condctd BNDmodeling ing initrdods: Resa NOTE: MDH conducted BMD modeling using admmistercd dose. Results: Ug 47 am FE) BAIDU. 150%] mpd Using 4% (same as EPA) -BMDL/BMD~4 = 1 99/3.51 mg/kg-d Uiig So cm 2 I TATDLINDL 2404 41 mpd Using 5% (sane as NJ) - BMDI2BMD0~ --- 2.50/4.41 mgNg-d Vai (54BNIDLBID=.5 15906 meet Usmg 10% - BMDI ~iB MD~ ~ ---- 5.15/9.06 mgikg-d Resin CSF ~012 per mydmedost 1 ts Resulting CSF = 0.02 per mg.&g-d adm dose in rats. The dl ofBW scsi ost ppfor colin HEDS. Fheoldos scum ~II~e default of BW scaling is ~._o__t._._.a_12t2_.r_.o_.priate for calculating HEDs. lfthe oral dose to seam concnitionlioshipclued b LPA fomirandoe cl bss caPins con.centration relationship calculated by EPA for similar admin dose levels based on Perkins et 200431 sd1 staCoepond srs oncrraboose VDL ves of 1930 al ~2004)is used to estimate conespondmg serum concentrations fl~e BM DL values of 1.99 and 25k would orapond 0 eum cose oF 800308 9073 wml. Uni 2.5 mg/kg<l would correspond to serum co~centrations of 80.09 a~d 99.73 t~gimL. Using 200014 hee sumsencnitons would oespodto HEDof 0011 ad 0014 0.00014 C1 fl~ese sermn concentrations would correspond to an HED of ~0.011 and 0.014 need Ths eating CSF db op md ich: sb in maps 0 NJ m~ikg-d. The resulting CSF would be 3.6 per mgikg-d, which is similar in mag~itude to NJmd Ce HED cladwi Ralf rnc)o 2 per mead ot ems based value (HED calculated using halt~life dii%erences) of 2.5 per mgikg-d but significantly ihr das EPA'sBW cling bs alos of 007 pes had higtier tha~ EPA's BW-scaling based value of 0.07 per mgikg-d. "42ND conductedBNDmodelingandderind CSF based on LCT or comparison "~*~'MDH conducted BMD m odeling and derived a CSF based on LCT :for comparison purposesot MDH does not el ht theciting databases suiciet to supprt 3 purposes only. MDH does not feel that the existing database is sufficient to supporl a Qiiascerisevsmeent sc blowfdo ion raion quantitative cancer assessment (see below for additional rationale)~'~* `Suppor Std Dserption: dBascanifaosotEnPswAsceeesnsmPcFnansdOiocnnAhc-oTah hdndei+nas gskrfodrcacrssr:inhowneannr fporovnidemspeoorftfora Supporting Study Description: Basis for EPA cancer classification - The findings tbr cancer in humans provide support for an association between PFOA and kidney and testicular cancers; however, the number of independent studies examining each of these is limited. Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 84 of 92 22447755..00008844 sateoressoss STATE_07438087 hetsnesconducted in bortry sins, both i as spp psi ding rhe The two studies conducted in laboratow animals, both in rats, support a positive finding for the iyof PFOA ob mor con f or nos fms ttFei rs. DH ability of PFOA to be tumorigenic in one or more organs of male, but not female, vats. Pt. fom ran. ie mle is cod er sci, reply srs PLO)Tor 3 50 Notes: female rats', unlike male rats and other specles, rapidly excretes tq:OA.] There are no ringed om cen al spies Ther re somedash rove spon or carcinogenicity data from a second mfimal species. There are some data that provide support for he potest he PPARssgn MOA i whol or pari ke 10 achhoe the hypothesis that the PPARa agonism MOA is wholly or partially linked to each of the GhemnoraiedsThedes porta PARA MORfrth nchorsad sre observed tumor types. The data support a PPAR~ MOA for the liver tumors and thus are nhc of ek of ean 0 mans.PPARsctvsatiGoound plo 1k nh tr indicative of lack of relevance to humans. PPARa activation also could play a role in the other mr chiro,btmoreditospon modiesp i tspapoed MOA tumor types observed, but more data to support intermediate steps in the proposed MOAs are eed The tandts on PFOA re Kr eg, avs hr sme oven needed. The mutagenicity data on PFOA are largely negative, although there is some evidence for htogencs heprs of cos hati1nd YON concen for clastogenicity in the presence of microsomal activation and at cytotoxic concentrations. Ginthechemical and pss ropofePRsON icihne gct 15n Given the chemical and physical properties ofPFOA including the fact that it is not tbls, binds clrprim,and rics at nen ccasf horse metabolized, binds to cellular proteins, and carries a net negative electrostatic surface charge oe chute eft3 hh the rl oaf dct mechan PFOA ho he prc 0 the clastogenic effects are likely the result of an indirect mechanism. PFOA has the potential to cfr ihhe proocf DeNsA plicationbcassof pose bid propria interfere with the process of DNA replication because of its protein binding properties and the ht Won, rs, smi ond in,a 3. Pon rs he fact that histonc proteins, spcrminc and spcrmidinc, carry a net positive surface charge. Dpth mins nth dtfor te LCT and PACTS, ts U'. EPA Guin or Despite the limitations in the data for the LCTs and PACTs, under the U.S. EPA Guidelines for Caring Rik Assent (USEPA 2080) cr se doce ofcrcncgene Caminogen Risk Assessment (USEPA 2005a) them is sugges#ve evidence ofcarcinogenic okorfPFaOA i ha powndal of PFOA in humans. MDH Notes: the existing desta or asssingthecarcinogenic poenil ofPFOA is. ~13I:t Notes: the existing database for assessing the carcinogenic potential of PFOA is insufficientfor quantiatve asessment insufficient for quantitative assessment: ony dse vee sts . Onlytwo dose levels were assessed TITof male et i nd roe he sing dbs prides o The TK of female mrs is unique and therefore the exisdng database provides Kidda for | 0 mn 1g 7s (a) limited data for 1 sex (males) iu one species (rats)o + NoNOS)hvebea deni however, PFOA ct eto anda ~ No MOA(s) have been identified, however, PFOA is not genotoxic and a omona mochanter basbeensad3p MOR The MOA would hormonal mechanism has been suggested as a potential MOA. This MOA wo~fld Tk hve shold reponse 1addon, he oesposefrom orLCT. likely have a threshold response. In addition, the dose response from for LCT, 1h uly pts ht bil bs tos pont ra the only response th:~t can sufficiently be related to exposure, is nonlinear in {dap The rss 30 ps wih onic cond vss nation th shape. The response at 30 pprn is within historical control levels. In addition, the eons hod he hgest dost Ine (30 pn ted ge response obsm~,ed at the highest dose level (300 ppm) is limited in magnitude oy (14%). + Relevance ofLCT response i as0 hans. Thr we sevc phsiclogics Relevance of LCT response in rats to l'mmmas. There are several physiological rence enn isand manhot ct is oul nT differences between rats and hmnans that indicate rats would be significantly ork oti Leva cl monenes (Cook 199) (Sib 015) more sensitive to Leydig cell tumorigenesis (Cook 1999) (Steinbach 2015). Dr Dum for ew ad dso poss ls. D oc dos cons Ay poly Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 85 of 92 22447755..00008855 sateoressoss STATE_07438088 EE Te ERNEENT RRNTREEIEN 1.a threeviofdmuteagenniccoedeof ction or another ade ofaction expected be near ato des? 1. Is there evidence of mutagenic mode of action or another mode of action expected to be linear at low doses? No 2 ere denoef atsimdoof cin eww ssdeus of arty od sulfcint docation supposing. ones ede 2. Is there evidence of a nonliuear mode of action (e.g., no evidence of linearity and sufficieut iuformation supporting a nonlinear mode ofscion? of action)? E73 20700: Themodes afoxclosialsinaocogneofnPiEOcAss otclay wndersod However, altedt set otth EPA 20J 6a: The modes oftoxicological/carcinogenic action of PFOA are not clearly understood. However, available data suggest that file induction of unr hl de fo Borcghao nob bine recente, patfthsoadocnrine v, induction oftumors is likely due to nongenotoxic mechanism involving membrane receptor activation, perturbations ofthe endocrine system, no he reofDnNA his nd il din PFOA lacks difo sth ad diy DNA sbongh Shortt and/or the process of DNA replication and cell division. PFOA lacks the ability to react with and modify DNA, although its electrostatic oie oud Pt ic ih hos ie I 56 PS rs CRE properties would permit interaction with chromosomal histone proteins with a net positive surface charge. 3 Ion cence htthemoodfacteions nat eva0hunmants? 3. Is there evidence that the mode of action is not relevant to humans? Soe FAbasRbch ca a4pd ole MORfor er on This MOAhas bn shor fd tor mio chr Some. PPARa has been suggested as a possible MOA for liver tumors This MOA has been show to not lead to tumor formation (other liver ficsmay sil ocr homans. effects may still occur) in humans. 4 Tether cxdofeenstac sitivity? 4. Is there evidence of life-stage sensitivity? Ro cronopen psy loess a ct as igs No carcinogenic potency evaluations regarding early-life stages. S5. Avetherestructure sti Are there structure-activity coreations correlations aviale? available? No NoI tapicar bcrastoxtespc olation sed? 6. Is route-to-route extrapolation used? Not applicable E. DendopaCancerGuidance Vue Calculated forcomparison purposes only" SFx [(SF x 1030128 g (SF33n 50088Lg 19(O+F 3130.01 Lhd4891/70 Additional Lifetime Cancer Risk 1 x 10-~ x Conversion Factor 1000 u m l0 x 0.125 L!kg-d x 2) + (SF x 3 x 0.045 L/kg-d x 14) + (SF x I x 0.041 L/kg-d x 54)] / 70 *Calculated for 0mparism! purp0ses only* [JoesGugene og | SF* Cancer Guideline [ug!L] bf s om| 3.6 0.029 erin adr *Enter in Slope Factor Ca p--------y-- Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 86 of 92 22447755..00008868 sateoressoso STATE_07438089 enCaleulatedfRRooruconodmuepdantroi00ds0.05o3envugpdi/uiLlrposes only ***Ca|culated for comparison purposes only*** Comments. Comments: ibn th EPA Host Elects Doc(upagme4-e20)nstc. Ushe eEPA 00S cancersilos, he sree or th crc of Within the EPA Health Effects Document (page 4-20) it states: "Under the EPA 2005 cancer guidelines, the evidence /br the carcinogenicity oj FON mtr so oct iy ap pS ber est7at xterra PFOA is considered suggestive because only one species has been evaluatedjbr !~[k~ime exposures artd the tumor responses occurred primar@ in ler Dore nse cto are oly ale or he LT on eh, Hones. eoaes mab mobs of C3Heath Pt in males. Dose-response data are on~v awtilabiejbr the LCTs in one study. However, two studies involving members q!the C8 Health Project Showed ein ooo PFOA Tis meanat inf ond dey and scrccs (hart. 015: showed a positive associalion between PFOA levels (mean at enrolmenl qfO. 024 txg/ml,) and kidney and tesdcular cancers (Barry e~ al. 2013; Vier crd 2013 Tree. ie to on CTrsu enol et, 2013 wer mkt 1sprove erspeiveon he esis of 0 Vie#zt et al. 2013). ThereJbre, the data on LCTsfrom Butenhoff'et al. (20~ 2) were modeled to provide a perspec~ive on the magnitude q/'~he ssev rik c compart wihss fedofrset red te ED potential cancer risk as it compares with the level ofprotection provided by, the Rf!). " Ti angus iomiwitth our draiofn fco ompuin purposes ny"ac This language is consistent with our derivation of a 'for comparison purposes only' values. Nis paren of lh (DF 017 Minnesota iDepartment ofHealth (MDH) 2017) Do Domne dionpp nyDs nA AS ky Draft Document - for review a~ discussion purposes only. Draft document does not constitute Agency policy PFOA - 87 of 92 22447755..00008877 sateorsssoso STATE_07438090 RReessoouurrcceess CCoonnssuulltteedd DDuurriinngg RReevviieeww:: ACAhSSeTmTiSScWaWlMMsOO(PF((2C20s01)15.5).).PeAArsfsslsooucociriaaottoiicootnnanoocfficSSttaAattceeidaann(ddPTTeFerrOrriiAtt&oo)rryyPSSeorolfliildduoWWraoasostctteeaMMneaanSnaualggfeeommneaetnnett(OOPfffFfiOicciSia)allss.I.nPPfeoerrrfmfllauutooirroiinnnaatteedd PPCaahppeeermr..icals (PFCs): Perfluorooctanoic Acid (PFOA) & Perfluorooctane Sulfonate (PFOS) Information APAeTTrfSSlDDuoRRroa((l22k00y11l55s)..)." ""AARgegeternnicceyyvetfdborrATTuogoxuxisicct SS1uu5b,bss2tt0aa1nn5cc,eessfraaonnmdd hDDtiitsspee:aa/ssee/wRRweewggiasitststrrdyyr..eDDdrer.aaffttsoTTvoo/xtxioicxcopolrlooofggiiilcceaasll/iPPprr2oo0ff0iillpeedfffoorr Perfluoroalkyls." Retrieved August 15, 2015, from ..h...t...t.p...:...//.~'-....a...t...s...d-..r..~..c....d....c..:.g.~..~i./..t...~...~.p.g~..~.~...e~.s../...t.p..~..~....~...:R.d..t.~. AAguuusistdtraraanllciieaannonHHeehaaulltmthhanPPrrhooettaeelccttthiioornnefPPerrriinennccciipepaavllaCClouoemmsmimftoitrtetpeeee,r,-.e.an((d22001p16o6)l).y.-f""leeunnoHHreceaaallltkthhylSStstaauttbeesmmteaennntc:te: sIInnfottererriuimsmenniaanttiisooinnteaall ngvinevutseiedtsriatiigngmaca-tehtiieoooannnlssthhiiu-nnmvaAAaluunusstehtrsrae-alaalihilaatph..p""er.fferpfrodeofmrm.enhhcttettl~pv::ai/liu/wewwswwwfo.hhreeapaletlrth-h.annnssdwwp.ggoov. olyv.-afluua/oue/rneovnavilrikoroynnlmmesenutnbtsifftaaactncshtceseethssefeotsriDDuoscoeucimunemnsetitnset/spipffaass-- interim-health-values-ahppc.pdE: BBPuTuthteeonnmhhfooofffrf,d, .1J..,(GG20C0Co2os)sttaa",,ToCCxiEEcllicctooymombfbeeA,, mDDmFoFaanrrriraaurr,,mKKPeHHraafnnlsuseoenrn,o,oHHctIaIwnaoiaai,,teRRJiuJnnuMgnag.l,eGGCKKyenennonnmeeoddlyygJurJsr,, MPPoLLniikeeeddeyerrs,, aGGfOtOelrslsOeernna,,l PDDooTsshiinongmg fffooorrdr66. MM(2oo0nn0tt2hh)ss..""*TTToooxxxiicicciotolyloooggificcAaalml mSSccoiienenniuccmeess 69: 244-257. Perfluorooctanoate 69: 244-257. in Male Cynomolgus Monkeys after Oral BB`Tuuhttoeemnnfhhoorofdff.f,, J(J.,2,0GG04LL).KKee"nnPnnheeaddryymaJJcRRo,,kiPPnMMetiKKciinsndodefrePlfileitrteefrrl,,uPPorHHooLLciiteeaddneercr,a, tRRe JJiuunnnCggy,,nKKoJJmoHHlaagnnsusesenn,M,oGGnSSkeGGyoosrrmmaaTnno,,xiPPcEEolNNoogokikceearrl,, PPJJ Sciences 82: 394-406 Thomford. (2004b). "Pharmacokinetics Sciences 82: 394-406. of Perfluorooctanoate in Cynomolgus Monkeys." Toxicological oBBfuutateemnnhmhooofnfff,i, uJJ.,m, GGpLeL.rfKKleeunonnrnoeeoddcyytaJJnrrc.,,icSSRR(FPFrrFaammOeei,,)nJJCCthOOe''rCCaoorn"nnnoToror,x,iRRcoGGloYYgooryrkk.1.96((:2200900544-a1a)1).6.""TThhee rreepprroodduuccttiivvee ttooxxiiccoollooggyy of ammonium perfluorooctanoic (APFO) in the rat." Toxicology 196: 95-116. BBstuuuttdeeynnhhwoiotfffhf,J,pJo.,tSaSsCCsiCCuhhmaannpgeg.r,fGGluWWoroOOollcssteeannn,,ePPsJJulTTfhhooonmamftoeforidrnd..Sp((22r00a11g22u)).e. D""aCCwhhrlroeonnyiiccrdatids.e"iettaaTrroyyxtitoocxxoiilccoiittgyyyaa2nn9dd3.ccaa1rr-cc1i5in,nooggeenniicciittyy study with potassium perfluorooctane sulfonate in Sprague Dawley rats." Toxicology 293: 1-15. CCDDCC ((22001166)).. CCeenntteerrss ffoorr DDiisseeaassee CCoonnttrrooll aanndd PPrreevveennttiioonn.. BBrreeaassttffeeeeddiinngg RReeppoorrtt CCaarrdd.. ECxDDpCCos((u22r00e11t77o)).ECCnevenintrteoernrssmeffnootrraDDliissCeehaaessmeeicCCaolonsnt.trrooUllpaadnnaddtePPdrreeTvvaeebnnltetiisoo,nnJ((aCnCuDDaCCr)y). 2FF0oo1uu7rr,tthhVoNNlaatutiimooennaaOllneRR.eeppoorrtt oonn HHuummaann Exposure to Environmental Chemicals. Updated Tables, Janua~, 2017, Volume One. CTCuoomoookrk,i,JgJ.e.,GneGsRRisK:KiliiAnneefRfeeellvtteeirre,,wJJoFFfHHtaahrreddiPisshttyyys,,iRRolMMogySS,hhaaPrrappteeh,,olPPoMMgyDD, MFFoeoscsttheerar.n. i((s119m99s99,9)).a. n""dRRoRodedelenentvtLaLeneycyedditigog HCCauelmlllans * Critical RTeuvmioerwisgeinneTsiosx:iAcoRloegvyie2w9: o1f6t9h-e26P1h.ysiology, Pathology, Mechanisms, and Relevance to Humans." Critical Reviews in Toxicology 29:169-261. DDEvaaannliiussahhtiMMoinnioniisfsttrrhyyeoaolftfhtthhheeazEEannrvvdiisrroaonnnmdmeepnnrtotp((o22s00a11l55))o..faPPeerhrfefllauluotohrroobaaallskkeyyldlaaqtteueaddlisstuuybbsscttraainntceceresis:o:nPPfFForOOAdAr,,inPPkFFiOnOgSSwaaatnneddr,PPFFoOiOlSSAaAn.d Eggrrvooauulunnddatiwwoaantteeror.f. hEEennavvlitihrroohnnammzeeannrtdtaasllappnrrdoojjpeerccottpNNooso.a.l 11o66f665a5,,h22e00a11l5t5h.. based quality criterion for drinking water, soil and DIDemeWmWiutnittot,,mJJo.,d, uCClBBatCCioooppneelilaannnAddd,,uMMltJJCSSStt7rryyBnnLaa/rr,6, )RRWoWr CLLSuu7eebBbkkLee/,,6((N2200F008e8)m.)a. l""ePPeeMrriffclluueoorr"ooEoonccvttaiannrcooiniccmeAAncctiiaddl--IIHnneddauulccteehddPerspectives I11m1166m((55u))n:o66m444o4-d-66u55l0a0.t.ion in Adult C57BL/6J or C57BL/6N Female Mice." Environmental Health Perspectives DDreeesWWpiointtstt,eJ,sJ,.,i nWWmCCicW Weileillxliipaaommsses,,dNNtJoJ CCrreeeecchh,, RRWW LLuueebbkkee,, perfluorooctancic acid ((22001155).). : Role ""SSuupppprreessssiioonn of PPARa and ooff aannttiiggeenn--ssppeecciiffiicc aannttiibbooddyy T-and B-cell targeting." Joumal orfesIpmomnusensotinoxmicicoeloegxypo1s3e(d1):to3p8e-r4f5l.uorooctanoic acid: Role of PPARa and T- and B-cell targeting." Journal of Immunotoxicology 13(1): 38-45. DDrraafftt DDooccuummeenntt fo- for sie review aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oo8ln8yl.y..0DD1rr2aafftt ddooccuummeenntt ddooess otnot consis constitute AAggeennccyy ppoolliiccyy PFOA - 88 of 92 22447755..00008888 STATE 07438081 STATE 07438091 EE(PFFFSSOAAA)((22a00n00d88))t.heEEiuursrraooippsee.aannSFcFiooeoontddifSSiaacffeeOttpyyinAAuiutohtnhoorofirtityty.h.ePPPeearrnffelluluooorrnooooCccottnaatnnaeemssiuunllaffnootnnsaattieen((tPPhFFeOOFSSo))o,,dppecehrraffillunu.oorr(ooQoouccettsaatnnioooiincc Naacoci.idd EE(PFFFSSOAA-A-QQ)--2a2n00d004t4h--e11i66r33s))a.lts. Scientific Opinion of the Panel on Contaminants in the Food chain. (Question No EEsuggleefoggnhhayytePP: PPAaanncddomMMparLLioosrrobbeneorrf((e22s00t111i1)m).a. t""eAAdnniaansstssaeeksessswmmieetnnhttvooaffltuthheees eeixnxfppeoorssruuerdreefoorfofmAAmmNeHreirAiccNaanEnssSttodoappteaer.r"fflluJuoooruroomooacclttaaonnfeeExposure Ssucilfeonncaetea:nAd Ecnovmirpoanrimseonntaolf eEsptiidmeamtieodloignyta.ke21w. it1h50v-a1l6u8e.s inferred from NHANES data." J ournal of Exposure Science and Environmental Epidemiology. 21:150-168. F(FiPillFggOooA,,)AAi,.,nEEdMuMceQQduuisiLstit,,veMMrJJLHeHsooieenonenersrffioonfffTf,,wIAoME~StBBrrraiiixxn,,soGGfEEMKKiicissesslliiFnnoggl,,lSoSwEEinFFegennDttoeonvn.e.l((o22p00m115e5)n).t. a*"lPPeeErrxffpllouusoourrrooeooscc:ttaaPnnooPiiccAAARcciiIdds NN(PooFttORReAeqq)u-uiiirnreedddu..c""eTdTooLxxiiivccoeolrlooLggeiisccioPPnaastthhioonlloToggwyyo443S3::tra55i55n88s--5o566f88M. ice Following Developmental Exposures: PPARa Is GHGoeecrrhmmsaaaunnerMMliainnniidsskttrlr)ey"iosof.fHHeSatelaattlhteh.m.e((n22t000b06y6)).t. hAAessDssreeissnsskmmieennngttoWoafftPPeFrFOOcoAAmmiinnistthsheeioddnrriin(nTkkriiningngkwwwaaatsteesrroeforktfothhmeemiGGseserirmomnaa)nnof the HPGGreoeorrcvmmihsasaiannounMeMarillinaniEnisvdstatkrrlyyrueaooitsffi. HoHSneeotaaalftletthmhPEaaeTttnttthihbneeyDFFtreehiddeneekrDraiarlnlignEEkWnnivavnitigrreoorWnnmwmaietetennhrttctAAohegmgeGemnnucicisyydseiJJouuSnnnuee(bTs22tr11ia,n,nk22cw00e0s0a66sP/s/errereerfvvkliioussmoeerddmooJJiucusltslyyiaonn1o133i),,co22af00ct00ih6d6e. P((PrPoFFvOOisAAi)o) naaannlddEPPveearflffulluautooiroroonooccottfaaPnnFeeTSSuuilnlffDoonnraaitnteeki((nPPgFFOWOSSa))teaarsswEExixtahammpthlpeelesGs..uide Substances Perfluorooctanoic acid H"HPaarrretrdisis,,ctMMor..s, SSoIfL.PRReiriff-aaass-n-SdShhPiimomlaaynnf,,luAAorMMoaClCakalylalaffaSatut,,bXXstaYYneec,,eAA(MMPFAMMSoor)raaP,,lTTasFFmWaWeCebobstnstecerer,,ntEErOOaktkeienoni,,nnsSSKK6-SS1aag0giviYv.e.a((r2200O11l77d)). AA"1Pm0m.ere1red0rii2iccc1ata/onnarcsCCsho.hiefillsPddterr.ere6-nnb.a0"*n5EEd8n1nP1vvoiirlryoofnnlmmueoenrntotaaalllkySSclciiSeenunccbeesta&&ncTTeeec(cPhhFnnooAllSoog)gyyPlAAadsdmvvaaannCcceoenAAcceccncetesrsasst::ioDnOsIi:n 6-10 Year Old lO.1021/acs.est.6b05811 HHeeaalltthh CCaannaaddaa ((22001100),). DDrriinnkkiinngg W Waatteerr GGuuiiddaannccee VVaalluuee PPeerrfflluuoorrooooccttaannee ssuullffoonnaattee ((PPFFOOSS)). HHSeueabalslttthhanCCcaeansnaad(daPa.F.A((S22)00.11"66)a.)R.et""rHHieeeaavllettdhh MCCaaannyaadd2a7a','ss2DD0r1ri6inn,kkifinnrggomW Waatteerr SSccrreeeenniinngg VVaalluueess ffoorr PPeerrfflluuoorrooallkkyyllaatteedd hSiutbpsyt/asn3cdeosc(uPmFeAntSc).l"ouRd eotrrige/vdeodcuMmeanyts2/73, 725061368,6f/r1oemalth-Canada-PFAS-Sereening-Values-Faci-Sheet pdf: http :/is3. documentcloud.orgidocum entsi2756386iItealth-Canada-PFAS-Screenin g-Values-Fact- Sheet.pdf. HHDeoeacalulttmhheCCnaatnna.ad"daa.f.r((o22m0011hi66t)bp.)./h""cPPaeelrrtfflhluyuocoraronooaocdctitaaannnosiiccgeAAccciai/ddh(e(PaPlFFtOOh-AAs))ysiitnneDDm-rrsiiynnskktiiennmgge-WWsaatanetiere.r/. cPPouunbsbluliilcctaCCtooinonsnsusul/laaatctiiioodnne-DDrraafftt perfluorooctanoic-aciddocument-eng php. Document.." from http:/ihealthycanadians.gc.ca/health-system-systeme-santeiconsultationsiacide- perfluorooctanoic-acid!document-eng.php. L"LaEauiu,e,cCCt..s,,JoJRfRTPheTirhbfiolbudooedraeoauouxcxt,,anRRoGGicHHAaacnnissdoonnE,,xpMMoGsGurNNeaardroouttrssikknyy,g, PJJrMMegRRnoaogngeceryrss,i,nAAtBBheLLMiionnuddssstetrr.oo"mmT,,oMxMiJJcoSSlttorlgTyinncaarar.l. ((S22c00i00e66n)).c.es 9"E0f2f)ectSs1o0-f5P1e8r.fluorooctanoic Acid Exposure during Pregnancy in the Mouse." Toxi cological Sciences 90(2): 510-518. aLLonovdveelMleiesscsse,, ASS.d.,,mDDiniHHsootbbeaarnne,,dGGLiSSnyeykakeressA,, mSSmRRoFFnrriaamumeme,,PNNerEEflEEuvvoererorddoscs.t. a((n22o00a00t88e))..."""TEEovvxaialcluuoaaltotiigooinncaoolffttShhceeieIInmmcemmsuun1n0ee5(SS1y)y:sstte8em6m-9ii6nn.RRaattss. and Mice Administered Linear Ammonium Perfluorooctanoate." Toxicological Sciences 10~(1): 86-96. MMFeanactcooonnn.,, MM(2.0.,,11LL)R,R V"VPiirllellananantuuaeelvvaaP,,erKKflTTuaoatrtuuomomc--tGGainibbobibscs,,ARRciDDdZZEeexhhprr,o,sMMuJrJeSSittnrryyCnndaa-rr,1, JJMPPicSSet:taannLkkooo,w, -SSDSSoW WsheihtDiteee,v, eLLloHHpeelmlfefanannttat,,lSSEE FEEfefffneetccottnss. aa(nn2dd01II1nn)tt.eerr"nnPaalrleDDnoaostsaiimlmePette1rr3yf~l.u.""oTTroooxoxicictcaoolnlooogigiciccAaallciSSdcciEieexnnpccoeesssu11r2e222(i(n11))C.:d1-113344M--11i44c55e:. Low-Dose Developmental MMPeaariifnnleeuoCCreeonnottceetrrafnfooirrcDDAiicssieedaassieen CCDoronintntrrkooilln&g&WPParrteeevverennCttiiAoonSn..R((e22g00i11s44t).r).yMMNauaxmxiibmmeuurmm(FEErxexeppooAscsuiurdr)ee:GGu3u3ii5dd-ee6l7lii-nn1ee. ffoorr PMMeDDrfHHluo((r22o00o00c88t))a.nMMoiiicnnnnAeescsoiodttaainDDDeeprpaianrrkttmimneegnntWt ooaffteHHreeaCaltlAthh.S. RSStetaagttieesmtmreeynntNt ooufmf NNbeeeeerdd(Faarnnedde RRAeecaaisdsoo)n:naa3bb3ll5ee-nn6ee7ss-ss1.((SSOONNAARR)) iinn tthhee: MMatattteerrooffPPrrooppoosseedd RRuulleess RReellaattiinngg t(o0 HHeeaalltthh RRiisskk LLiimmiittss ooff GGrroouunnddwwataetre.r. DDrraafftt DDooccuumlneenntt ---ffoor rseviieew aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oo3nl9l.y..0DD1rr2aafftt ddooccuummeenntt ddooess nnoott ccoonnstsitiutse AAggeennccyy ppoolliiccyy PFOA - 89 of 92 22447755..00008899 STATE 07438082 STATE 07438092 MMMaDDttHHer((o22f0000P88r))o.pMMoisinenndneeRssuooltteaasDDReeepplaaartrtitmmngeennttot ooHfefaHHleteahaltlthRh.i.skSSttLaaittememimteesnonttfoofGfrNNoeeuenedddwaaanntdderRR.eeaassoonnaabblleenneessss ((SSOONNAARR)) iinn tthhee Matter of Proposed Rules Relating to Health Risk Limits of Groundwater. MMHuDDmHHan((MMEiqinunninevesasolotetnaatDDDeeoppasarerttmCmaeelnnctutoloafftiHHeoeanlastlthih)n).t.o((D22e00r1i17v7aa))t.io""nMoMDDfHHOrHHaeleaaRlletthfheRRrieisnskkceAAsDssosesessesssmm(eeMnnattyMMe2et0th1h1oo,ddssrettvooisIInencdcoo2rrp0po1or7arat)et"e. HffrrouommmahhnitttEpp:q:!/ui/wiwvwwavwlew.nhhteeDaallotthshe.sstCaatateelcmmunnla.utuisoidnssiv/isnietdoh!Diriesvrlicv/sggautui/iioddnaaennocchfeeOhi/heraedildrrResefefggfkueuirie/ddneec.ppeddD.f.oses (May 2011, revised 2017)." MManDDdHHPF((22O00A1177bab)n.)d. ((liMMsiUinnsnneeessioontttaahDDeeeDppeaarrrittmmveaenntttiooofffnHHHeeuaalmlttahh)n) BBHaaecacklktgghrr-oobuuannsddedDDoWocacuutmmeernetnG:ut:iTdToaoxnxicicceookVkiainnleuetetiiscc MMooddeell ffoorr PPFFOOSS and PFOA and Its Use in the Derivation of Human Health-based Water Guidance Values.. MPMeiriccfhhliiuggoaarnnooDDcteeappnaacrrittcmmaeecnnittdoo(ffPEEFnOnvAvi)irr.oonnmmeennttaall QQuuaalliittyy ((22001111)),. HHuummaann && WWililddlliiffee TTooxxiicciittyy SSuummmmarayry.. Perfluorooctanoic acid (PFOA). NdNaeetllassoobnna,,seJJ..d((o22n0011J66)u.)n.ePP9ee,rrss2oo0nn1aa5ll MCCeooemmtminunmngincAiacgtaetinioodnnarraeenggdaarrMddaiitnneggriMMalDDsHHfoMMrtNNhe((EAEadasvstit sMMoeretytrrooP)a)nPPeFElCCtobbtiiohoemmoEonnnivititoorrroiinnnmggenpptrrooajjleecctt HHhdieatepataalltwtbhhawsTTerredaaccokkhnieinanJglugtnahaennsdd9ta,tBBe2i.i0oom1mmn5o.onMunitsieto/oerdrtiiiinnnvgggsPAPrrhgopoegegndrrad/armamac.aknidngM/paatneerli/a2l0s1fSoJrutnheemaAtdevriisaolrsy Panel pdf to the Environmental http ://www.health.state.mn.us/divsihpcd/tracking/panel/2015Junematerials.pdf. NNDreeiwwnkJJieenrrgsseeWyyatDDeeerppaaartrttPmmeeennnnttsogofrfoEEvnnevviWirraootnnemmreenSntutapalpllPPyrrooCtteeoccmttipiooann.n.y((22000077).). MMeemmoroaranndduumm:: GGuuiiddaannccee ffoorr PPFFOOAA iinn Drinking Water at Pennsgrove Water Supply Company. NNDoeecwwumJJeeenrrtsse:eyy PDDerrriifnnlkkuiionnrggooW WcataattneeorricQQuAuaclaiilitdtyy(IPInnFssOitAittu)ut.tee.. ((22001177)).. HHeeaalltthh--bbaasseedd MMaaxxiimmuumm CCoonnttaammiinnaanntt LLeevveell SSuuppppoorrtt Document: Perfluorooctanoic Acid (PFOA). NwNiTTtPPh E((2x20p0o116s62ua)r).eNNtaaottiPiooenrnafallluTTooroxoxioiccctooaccnooollioocggyyAcPPirrdoogg(rrPaaFmm.O.ADD)rraoafrfttPSSeyrysfstlteeummoaratotioiccctRRaeneevviiSeeuwwlfoooffnaIItmnemm(uPnuFonOtoSot)xo.ixciciittyy AAssssoocciiaatteedd with Exposure to Perfluorooctanoic Acid (PFOA) or Perfluorooctane Sulfonate (PFOS). PAPeemrrmkkiionnnss,,iRuR.,m, JJPLLerBBfuultuteeonnrhohooofcfftf,,anGGoLaL.teKKe(enAnnnPeeFddOyy),, iMMnJJMPaPaallleaazzRzzaootllsoo,,* ((D22r00u004g4)).a.n*"d11C33h--WeWmeeieeckkalDDiTieeottxaariryycoTTloooxgxiyiccii2tt7yy(4SS):ttuudd36yy1-oo3ff78, Ammonium Periluorooctanoate (APFO) in Mal e Rats." Drug and Chemical Toxi cology 27(4): 361-378. PwPoaoststet,,rGGc.,o.,ntPPaDDmiCCnoaonhhtnn',, KKARRcrCCitooiocopapleerrr,e, v((i22e00w11o22)f)..re""cRReeevnvitieewlwi:t:erPPaeteurrrffell.uuoorrEoonoovccittraaonnncomiieccnaatccaiildd((RPPeFFsOeOaAAr))c,,haann116ee:mmee9r3rgg-i1inn17gg.ddrriinnkkiinngg water contaminant: A critical review of recent literature." Environmental Research 116: 93-117. MQQuiuitsiostct,,hoEEn..,d, rAAiJJalFFiiAlllggtooe,,raCCtAAionCCuuimnmmCmiDni-ng1gss,M, iGGcEEe KAKisissssosllciiinnaggt.,eMMd JwJiHHtohoeenPnreeernrhhaotofafflf,,ESSxEEpoFFseeunnrtteoonsn..to((22L00o115w5)).D. o""sHHeeesppaoatftiicc MPeritfolcuhooronodcrtiaalnoAiclteArcaitidon(PinFOCAD).-"I TMoxiciecoAlossgoicciaPtaetdhowliotghyP4r3e:na5t4a6l-E55x7p.osures to Low Doses of Perfluorooctanoic Acid (PFOA)." Toxicologic Pathology 43: 546-557. BSScichhmeecbctateeurr,m, AA(,,20NN12MM).aalli"iPkko--lBByaafslsssu,,orAAoaMMlkCCyalallaCafofaamtt,,pKoKuKKnadattsoo,,inJJAATeCCxoaolslaacCcihinniool,,dTrTeLLn GGferenontmt,,BLLiSrSthHHyytnhnaranon,u,gTThRR12HHaYarerrraiisrs,s, S$ofMMaAalgllela.a,", LI. BEnivrnibraounmment(2a0l1H2e).al"tPholPyefrlsupoercotailvkeysl 1C20o:m5p9o0u-n59d4s.in Texas Children from Birth through 12 Years of Age." Environmental Health Perspectives 120: 590-594. HSStteeaiinnbbmaaccihh,&,lTTH..a,,trRRdoRRy'nMMsaarIronondnpuposottt,,raJJFlFTHHoaarrdxdiisisttyyc,, ((o22S00il11x55)to.)h.EgdHHiuutyimmoa,nan.n RRMe.elleeB.vvaaRnnccDee HooaffrRRbioosddoeennn,ttGLLTeeyyJddoiihggnCCseoelnlll,TTJuuommhonrosrW.si. ley & HSoanms,iltIoncn. & Hardy's Industrial Toxicology, Sixth Edition. M. B. RD Harbison, GT Johnson,, John Wiley & Sons, Inc. Suh, C., NK Cho, CK Lee, CH Lee, DH Kim, JH Kim, BC Son, IT Lee, (2011). "Perfluorooctanoic acidiiaSnnnudddhuu,CccCeeeldd.,luiiNnlnaKhhriibbCEiintthiidoooon,ncCrooifKfnppoLlllaaeoccegee,nyntCt3aaH3ll7:ppLrreoo7ell-,aa1ccD5ttiiHnn--Kffaaimmmii,llyyJHhhooKrrmimmoo,nnBeeCaannSddoffnee,ttaaJllTggLrroeo~ewv,tth(h2rr0ee1tt1aar)rd.daa"ttPiioeonrnfliiunnommrioicoceec..t""anMMooiolcleeacccuuildlaa-rr and Cellular Endocrinology 337: 7-15. DDrraafftt DDooccuummeenntt fo- for sie review aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oo9nl0l.y0. 1DDr2raafftt ddooccuummeenntt ddooess otnot consis constitute AAggeennccyy ppoolliiccyy PFOA - 90 of 92 22447755..00009900 STATE 07438083 STATE 07438093 TCEQ. (2016), "Texas Commission on Environmental Quality. Texas Risk Reduction Program (TRRP) PTrCotEeQct.i(v2e0C1o6n)c.e"nTtreaxtaisoCn oLmevmelisssi(oPnCLosn)E."nvfirroomnmheintptasl:/Q/uwawl.ityt.ceTqetxeaxsasRsisokviRreemdeudcitaiotnioPnr/orgp/ratmrrp(pTeRlsRPhim) - Protective Concentration Levels (PCLs).", from https :/iwww.tceq.texas.goviremediationitrrp/trrppcls.html. seTTnuusccikkteeirr,v,eDDpu..,beMMrBtBalMMatacacroognen,t, iMMnJJCDSSt-trr1yynnaaanrr,d, S$CSDD7aaBggInn/iin6nomo,i,cEIe:fAAonlndldeoerwrsiseennng,, pSSeEEr:iFFnaeetnnattloonnp,e, r((f22l00u11o5r5)o)oc""tTTahhneeoimmcaaammcmimdaa(rrPyyFggOllAaan)ndd iiss aa eesxexpnpososistuuirvreee.."p"uRRbeeepprrtraoolddutuaccrtgtiievvteeinTTooCxxDiicc-1oolloaogngdyy $C5445::722B661--3i3666m.. ice following perinatal perfluorooctanoic acid (PFOA) URUenngiiuttleeaddtKiKoiinnnsggdd2oo0mm0.0./D0D1rriisnnpkkeiicnniggfiW WcatatoteePrrFIIOnnssSppee(ccptteoorrrfaalttueeor((2o20o00c07t7)a).n.eGGsuuuiilddpaahnnoccneeatooenn) atthnheedW WPaFattOeerAr SS(uupppepprlflyylu((oWWraoaottceetrranQQcuuiaacliliattcyyi))d) Rccooenngccueelnnatttriraoatntiisoonn2ss00iinn0/dd0rr1iinnskkpiienncggifwwicaattteeorr.PFOS (perfluorooctane sulphonate) and PFOA (perfluorooctanoic acid) AUUmSSbiEEePPnAAt ((W22a00t000e0)r)..QUUuaSSliEEtnnyvvCiirrriootnnemmreieanntftaoalrl tPPhrreoottPeerccotttiieoocnntiAAogngeoenfnccHyyu((mEEaPPAnA).)H.eaOOlftffhfii.cceeEoPofAf-WW8a2tae2ter-r.B.-MM0e0et-th0ho0od4do.ollooOggcytyoffbooerrrDD2ee0r0rii0vv.iinngg Ambient Water Quality Criteria for the Protection of Human Health. EPA-822-B-00-004. October 2000. UaUnSSdEEDPPevAAel((o220p01m11e1)n),.t.UU"SSfEErnnovmviihrroiotnnpmmse:en/nfttcaafllpuPPbrrootteecpcca. ttisiooonvn/AAncggeeeann/crciyysk""/EErxxepcpooorssduuirrseeplFFaaaycc.tctoofrirssn?HHdaeanindddb2bo3oo6ok2k.5.2OO.ffffiicceeooff RReesseeaarrcchh and Development." from https:i/cfpub.epa.gov/ncea/rislcirecordisplay.cfm?deid-236252. UDUoSScEEuPPmAAe..nt((220f01o16r68Pa)e)..rf""lUUuSoSrEoEonncvvtiiarrnoocnnimmceenAntctaialdl PP(rProoFttOeeAcc)ttii.oo"nn AARggeetenrnicceyyve--dOOfMfffaiiyccee 1oo9ff,WW2a0ta1et6er,r.. fHHreoeaamlltthh EEffffeeccttss SSuuppppoorrtt Dhhitottppcssu:m//iAwewnwwtowwfo.eerppPaae.rggfooluvvso/siriotteoessc//tpaprnrooodiducuccAtitcoiinod/ni(lflPieFlsOe/22sA00/1)1.66"--00R55d/edotorcicueumvemendetnsMt/spa/fpyofoa1_a9h, e2hs0eds1_d6f,ifnfiranolam-l-ppllaaiinn, ppddf. UAUdSSvEEiPsPAoA.r.y((f22o00r116P6beb)r.)f.l"u"UoUrSSooEEcnntvvaiinrroooinncmmAeecnnittdaall(PPPrFrooOttAee)cc.ttii"oonn RAAegtgereinneccvyyed-- OOMfafffyiiccee1o9o,ff2W W0a1ta6et,err.f.rDDormriinnkkiinngg W Waatteerr HHeeaalltthh hAidtpvsis/oAwrwyawforePpearfglouvosirtoeos/cptraondoucitcioAn/cfiidle(sP/2F0O16A-0)5."docRuemterinetvse/dpMfoaay_h1e9a, l2t0h1_6a,dfvroimsory_final-plain pdf https:/iwww.epa:gov/sites/production/files/2016-OS/documents/pfoa health_advi sory_final-pl ain.pdf. UAUdSSvEEiPPsAoA.r.y((f22o00r116P64ed)r.)f. l""uUUorSSooEEcnntvvaiinrreoonnSmmuleefnnottnaaalltePPrr(ooPtteeFccOttSiio)onn "AARggeeetnnrcciyyev--eOOdfMffiacefyoofi1f9W,Wact2ae0te1re6.r.,DDfrrriionnmkkiinngg W Waatteerr HHeeaalltthh hhAutdttppvssi:s//oiAwrwy5w,fv~o.vre.ePppeaarf~glgouvoosvrioistoietcset/sapinpreroodSduucultcfitoioonnnaft/ieflile(ePss/Fi22O001S16)6-.-"0055/Riddoeoctcruuimemevneentdtss/iMppffoaosys.___1h.9e.h,ael2at0lthh1_.6_a,_d.vfaridosvmoi rsoy_~fyi_nfainl-apl-lpalianin..ppddff.. WMWaaMmmabrbataiuungg,hhK,,J1D..,asRR,WWJCSSeDettezzWeeirr,t, tAA,MMMPPSiitttmrryuznzazzree,llloRl,oJ,JJuLdLisiuuo,n, ,DDKMMARReHeioiftu,;cNNk,CCCKKllLeeaiiunn,sstt(rr2ee0uu1ee3rr),,.NN"DCCohhsiiinnmgge,,trYicWWaaannnggc,,hNNoSSriiopipfeensis,,gn Mvv3ii0vv8Moo3aaa2nnr7tddinim, KvviiDttrroaosss,ttJuuCddiieDesseffWoorritppt,eerMrfflluuSootrr~oo'nooaccrtt,aannRooaaJtuteedsaaonnndd, ppKeerArffllHuuooorruoocookcct,taaCnneeLssuaululff,oo(nn2aa0tte1e.3."").TT"ooDxxioiccsooilmloogegitircciacallaSSncccihieeonnrccineessg 11o33f6~:ii:n 308-327. W WDhoihstietee,P, FSS.,.O,JAJPPESSxttpaaonnskkuoor,,eKKs aKKnaadttooM,,aAAmMMmaCCraayllaafGfalatta,,nEEdPPGHrHioinnweetssh,, SaSnEEdFFDeeinnfttfooennr,e,n((t22i00a11t1i1)o.)n. i""nGGeTeshstrtaaetteiiooGnneaalnleaarnnaddtiCCohnhrsrooonnfiiccCDLL-oo1ww-DMiocsee PFEOnvAirEonxmpeonstuarlesHaenadltMh aPemrmspaercytiGvelsan1d9(G8r)o:wt1h07a0n-d10D76if.ferentiation in Three Generations of CD-1 Mice." Environmental Health Perspectives 119(8): 1070-1076. WCWoSloflLf,a,uCC.,,.,BSSDEEAFFbeebnnotttootnn,,,(JJ2EE00S7S)cc.hhmm"iDidde,,veAAlMMopmCCeaalnlatafafaaltt,,TZZoxKKicuuikktllyeennoyyfiikPke,,rXXflAAuoBBrorroyycaatnnattn,o,JJicTThhAiicbbioodddeeianauutxxh,e, KKCDPP-DD1aasMs,,oSSuSSseW Whaifhttieteer,, CCCrSroosLsssa--uFF,oosBsttDeerrAaannbddboRRtetes,st(tr2rii0cc0tte7edd).GG"eDesstetaavtteiioloonnpaamll eEEnxxptpaosolusTrueorsex.s"i.c"itTyToooxxificPcooellroofglgiuicocaarlol oSSccctiiaeennnoccieecssA995c5(i(2d2)):i:n44t6h62e2-4C477D33-.1 Mouse after HWWeuru,t,zXX-,,P.i,DcDcHiHotBiBoee,nnn(ne2et0tt1t,5,)AA. MM"SCCeaarllauafmfaatct,,onKKceKKnatatrtooa,t, iMMonsSStotrrfyynnpeeerrr,,flEEuoAArnindndeaetrressdeennc,,oRRmpEEoMuMonordrasann(,,PDDFJCJ)TTaaanmnccorrenedgdii,,seNNleSSctTTeuudllvvee,I, Hppooepprutulzla-aPttiiioconcnissoootftfoc,chhi(i2lld0dr1ree5nn). aa"nnSdderaauddmuullttcssoiinnncCCeanaltlirifafito~irornnniisaa."o* fEEpnnevvriifrrlouonnommrienenantttaealdl RRceoesmseepaarorccuhhnd11s3366(:P: F226C644)--2a27m733.o.ng selected DDrraafftt DDooccuummeenntt fo- for sie review aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oo9ln1yl.y0.1DD9rr2aafftt ddooccuummeenntt ddooess otnot consis constitute AAggeennccyy ppoolliiccyy PFOA - 91 of 92 22447755..00009911 STATE 07438084 STATE 07438094 Y`pYeaarhhfiilaau,,oDrD.o,.d, cMMtaAAnoEEiIc1--aNNcaiasdssse(erPr,,FMMOAAA)bbeeedxdepelol-s-LLuaraietiif0,, CCprTTesgsuunkakunutbbaam,,iMMce YYoonosshrhieidpdara,o,duIIcSStaaittooon,,."S TTThsesuuddaa,, ((J2o2u0m0a1l1o00f)). T""oEExffiffceeocclttossgooifcfal SpSceciriefelnnuccossro33o55:ct55a22n77o--i5c533a33c.id (PFOA) exposure to pregnant mice on reproduction." The Journal of Toxicological YiYnaahnnigbg,i,tQiQo,.n, YoYfcXeXilieel,, pAAroMMlifEEerrriiakktssissooonnn,a,nBBdDDdeNNveeelllssooonpn,m,eJJnWtWiDDneePtPiheiyermrrireec,, a((n22d00001s1)p).l.en""iFFcuurarttthhreeorrpheeyvviiiddneednnuccceeedffoobrrytthhteeheiinpnvevorolovlxevimseeomnmeteonoftf ippnrroholilibiffieetirroaanttooror fppecere~flfllluupoorroroolcicftteaarnnaootiiioccnaaccaiindddiindnemmvieiccleoe..p""mBBeiinootccihhneemmthiiyccamallicPPhhaanarrdmmsaapccloeolnlooicggyyat66r2o2:p:1h1y1133i3n3--d11u11c44e00d..by the peroxisome DDrraafftt DDooccuummeenntt fo- for sie review aanndd ddiissccuussssiioonn ppuuPrrppFooOssAeess-oo9ln2yl.y0.1DD9rr2aafftt ddooccuummeenntt ddooess otnot consis constitute AAggeennccyy ppoolliiccyy PFOA - 92 of 92 22447755..00009922 STATE07438085 STATE 07438095