Document Yj8154q5DyQmrV1Ydmk0m8QKN

329 ff AR226- 1077 DRAFT HAZARD ASSESSMENT OF PERFLUOROOCTANOIC ACID AND ITS SALTS OfUf.iSc.eEonfvPiorlolnumtieonntaPlrePvreontteicotnioannAdgTeonxciycs Risk Assessment Division February 20, 2002 es0e0i PREFACE. aTshsiosciisataedprweiltihmienxaproysausrseetsosmpeenrtfloufortohoecptoatneonitciaalcihdaz(aPrFdsOAt)o haunmdaints hsaelatls.th aTnhde tmhaejoernivtiyroofnmtehent itnocxliucdoelsogayrienvfioerwmaotfiothneisstfuodrieasmtmhoatnwieurmepaevrafilluaabrloeoacstaonfoJiuclayc2i0d0(1APFO). This assessment A two-generation reproductive available in the spring of 2002. toxicity Effects studyof APFO were observed is in currently being conducted and a two-generation reproductive will be toxicity Study oaf important troeldaettedercmoimnpeowuhnedt,heprersfilmuiolraoroecftfaencetssualrfeonoabtsee.rveTdh.e resultsof the APFO study will be 000002 `Table of Contents Executive Summary 10 Chemical Identity LI Physicochemical Properties 10 ProdofuPFcOAtandiitsoSalnts 21 Usesof PFOA and its Salts 22 Environmental Fate 22.1 Photolysis 222 Volatility 223 Biodegradation 224 Hydrolysis 225 Bioaccumulation 226 Soil Adsorption 23 Environmental Exposure 23.1 Combustion 232 DischtaorWagteer 233 DischtaorLagned 234 Environmental Monitoring 24 30 Human Biomonitoring Human Health Hazards 3.1. Metaanbd Poharlmacoikinsetimcs 3.01 Half-life in Humans 3.1.2 Absorption Studies in Animals 3.13 DistributionStudies in Animals 3.14 Metabolism Studies in Animals 3.15 Elimination Studies in Animals 32 EpidemiologyStudies 32.1 Mortality Study 322 HormoneStudy 323 Cholesterol Study 32.4 Study onEpisodes of Care (Morbidity) 33 AcuteToxStiudicesiinAntimayls 33.1 Oral Studies 332 InhalationStudies 333 DermalStudies 334 Eye Iritation Studies 33.5 Skin InitationStudies 34 Mutagenicity Studies 35 36 SDuebvcehlroopnmiecntTaolxTiocixtiyciSttyuSdtieusdiiensAniinmAalnsi.mals 37 CarcinoSgtuedinesiincAniitmayls 1 6 6 8 10 nn n n 12 12 13 4 1 in in Is is 16 20 20 20 21 2 2 2 El 2 2 3s 36 38 38 38 39 39 3 39 40 a8 52 000003 3.7.0 Cancer Bioassays 52 3.72 ModeofAction Studies 5 37.2.1 Liver Tumors 53 3.7.2.2 Leydig Cell Tumors 54 3.7.2.3 Mammary Gland Tumors 55 3.7.2.4 Pancreatic Tumors 55 40 Hazards to the Environment 55 41 Introduction 55 42 Acute Toxicity to Freshwater Species. 57 50 References 62 ANNEX I - Robust Summaries 7 000004 Introduction EXECUTIVE SUMMARY Perfluorooctanoic acid (PFOA) and its salts are fully fluorinated organic compounds that can be produced synthetically or through the degradation or metabolismofother fluorochemical pprroodcuecstssi.ngPaFidOsAinisthperipmraordiulcytuisonedofasfaluroeraocptoivleymienrtseramneddifatleu.owrhoiclleaiststsoamlatesnradsreinusotehdearssurfactant uses. In recent years, less than 600 metric tons per year of PFOA and its sas have been manufactured in the United States or imported. Mostofthe toxicology studies have been conducted with the ammonium salt ofperfluorooctanoic acid, whichi referred to as APFO in this report, Environmental Fate and Effects PFOA is persistent in the environment. It has very low volatility and vapor pressure. It does not hydrolyze. photolyze or biodegrade under environmental conditions. Several wildlife species have been sampled around the world to determine levels of PFOA, PFOA has rarely been found in fish sampled from the U.S. certain European countries, the North Pacific Ocean and Antarctic locations, or in fish-ating bird samplescollected from the US. including Midway atol, the Baltic and Mediterranean Seas, and Japanese and Korean coasts. PFOA was found in a few mink livers from Massachusetaist a concentration range of <18 to 108 ng/g, dry w.. but not found in mink from Louisiana, South Carolin and llinois. PFOA concentrations in river otter livers from Washington and Oregon States were less than the quantification limitof 36 m/e, wet wt. PFOA was not detected at quantifiable concentrations in oysters collected in the Chesapeake Bay and Gulfof Mexico ofthe U.S. coast The concentrations of PFOA in surface water, sediments, clams, and fish collected from two locations upstream and five locations downstream of the 3M manufacturing facility at Decatur AL have been determined. Of the five downstream sampling locations, the two closest o the facility had PFOA surface water concentrations significantly greater than the two upstream sites (means of 1900ug/L and 1024 ug/L): the nearest three locations had sediment concentrations significantly greater than the upstream sites (wet wt. means 1855 ug/ke, 892 ug'ke, 238 ugg). "The average fish whole body PFOA concentration for the two upstream locations was 11.7 ug/kg (wet wi). while that for the five downstream locations was 106.4 ugk. The average PFOA concentration in clams at the two upstream locations was 4.38 ug, while the average for the five downstream locations was 8.42 ugk Based on available data, APFO does not appear to bioaccumulate in fish. In a study of fathead `minnows. the calculated BCF for APFO was 1.5 1 000005 Several species were tested to assess the acute oxicity of APFO; these included the fathead minnow (Pimephales promelas). bluegill sunfish (Lepomis machrochirus), water flea (Daphnia magna), and a green algae (Selenasirum capricornutum). Comparisons of the different studies are problematic for several reasons. The studies were conducted with different test substances. Generally the ammonium salt or the tetrabutylammonium salt was tested. Purityofthe test material is a major concern and was not sufficiently characterized in these tess. In some tests it appeared that 100% test chemical was used. for others a chemical of lesser purity (approximately 2710 85%) was used. Water. a solvent (isopropanol) or a combination of both was used in other tests. for no obvious stated reason. Finally, only nominal test chemical concentrations were reported; the actual concentrations were not reported. . Twelve tests were conducted with fathead minnows: 96-h LCS0 values (based on morality) ranged from 70 to $43 mg/L. is unclear why this fange i s0 wide. Assuming these studies are vtawloida.caunted vdauleuetso tfohre blliumeigtialtliosnusnfdiisshcuaslsseodianbdoicvaet,etlhoewsetotxoixciictiyty(v9a6l-u1eLsCiSnd0i5coafte4l2o0w,toaxincdit5y.69The mL). Nine acute tests were conducted with daphnids and 48-h ECS0 values (based on immobilization) ranged from 39 10 >1000 mg/L. The lower values are indicativeof moderate toxicity. bu the wide range makes interpretation difficult. Seven tests were conducted with green algae: 96-h ECS0 values (based on growih rate, cell density.cell counts, and dry weights) ranged from 1.2 10 >666 mg/L (the ErS0 cell density value of 1.000 mg/L. is excluded from this discussion). The lower value indicates high to moderate toxicity. based on the acute criteria. The lower value would also be indicative of moderate toxicity. based on the chronic moderate criterion (0.110 mg/L). A 14-d ECS0 value of 43 mg/L. based on cell counts, for green algae was also calculated in one study. This is indicative of low chronic toxicity, based on the chronic criterion (10 mg/L). Green algae appeared to be the most sensitive test species in the 44% APFO test sample, daphnids were the next most sensitive, and fathead minnows were the least sensitive: fuman Health Effects and Biomonitoring. Little information is available concerning the pharmacokinoeftAiPFcOs in humans. A preliminary studyofretired workers suggests simply that the serum half-life is between | and 3.5 years. These data provide evidenceofthe potential bioaccumulate PFOA in humans. In addition. this study provides preliminary evidence that the serum hal life may be longer in females than in males. Animal studies have shown thas APFQ is well absorbed following oral and inhalation exposure. and 10: lesser extent following dermal exposure. In ats and dogs. there are major gender differences in the distribution and elimination of APFO. APFO distributes primarily to the liver, 000008 plasina, and Kidney, and to a lesser extent, other tissues of the body including the testis and vary. It does not partition to the lipid fraction or adipose tissue. APFO binds to macromolecules in the tissues listed above. APFO is not metabolized and there s evidence of `tehnetfereomhaelpeatriact,cwirhciulleattihoen uorfinteheancdomfpeocuensda.rc bTohtehumraijneorisrtohuetemsaojforexrcoruetteioonf oefxcArPeFtOion ionfmAaPlFeOrasi.n In female ras. the half-ife is 24 h in the serum and 60 h in the liver; in male rats the hal life is 105 1 in the serum and 210 h in the liver. In beagle dogs, the plasma halFlfe is 254 h in females and 507 h in males. In ats, the elimination hal life is one day in females and 15 days in males Female ratsappear to have a secretory mechanism that rapidly eliminates APFO: this scerctory mechanism i either lacking or relatively inactive in males. Other studies in rats have shown that ptersetgonsatnecroynedoexneorttsapapneianrhiobictohrayngefefetchte ornarereofnealliemxicnreattiioonnofinArPatFs.O.ThHeogremnodnearldicfhfaenregnecse.during observed in rats and dogs has not been observed in primates and humans There are limited data on PFOA serum levels in workers and the general population. Occupational data from plants in the U.S. and Belgium that manufacture or use PFOA indicate hat mean serum levels in workers range from 0.84 10 6.4 ppm. The highest level reported in a worker in 1997 was 81.3 ppm. In non-occupational populations, serum PFOA levels were much lower. In both pooled blood bank samples and in individual samples i both adults and children, mean PFOA levels ranged from 3 to 17 ppb. The highest scrum PFOA level reported was in a sample from a child (56 ppb). Epidemiological studies on the effects of PFOA in humans have been conducted on workers. Two mortality studies. us well us studies examining effects on the liver, pancreas, endocrine system, and lipid metabolism, have been conducted to dae. In addition, a morbidity study was also recently submitted. A retrospective cohort mortality study demonstrated a weak association with PFOA exposure mtahonerdtsaptlruiodtsyyt:aathseocwlaeennvcgeetrrh.,otfAheemsrtpealstuoilsyttsmicecanaltlnyniosnticgrbneieafsidecidar.netctaTlshysicoscorimeapstuailrotnewdwaabssencooabtussoeebrvstheeedrevixenppoirnsousrtreaetcceaectnatcgnuocpreidrcaste to were modified in the update. In a morbidity study. workers with the highest PFOA exposures for the longest durations sought care more often for prostate cancer treatment than workers with Tower exposures Alenvoetlsh:erhoswteuvdeyrr,epnoornteeodfatnheinocrtehaesrehionremsotnraediloelvellesvealnsalinyzweodrkienrdiscwatietdh atnhey haidgvheersstePefFfOecAts.seSroumme of the same employees who participated in the hormone study also were included in a study of cvhaollueecsyasntdokPinFiOnA(.CCTKh)e oltevheelrsaivnaielmapblloeyesetsu.dy eNxoampoisnietdivcehaoslsesotceiraotlioannwdaosthneortesderbuemtwceoemnpoCnCeKats in workers. Theredid not appear to be any significantdifferences among workers ofdifferent exposure levels, except among obese workers (aspartate amino transferase and alanine amino transferase). However, PFOA was not measured directly, but indirectly as otal serum fluorine. 3 000007 "PTFheOrAe asreermuamnlyevleilmsitgarteiaotnesr 0thatnhe1s0e sptpumd.iesT,hebruetfmoorse,t anloltoafbltyhetsheersemsaulltlsnmuumsbtebreofinwtoerrpkreertsedwith carefully. aInndac2u5t0e-t5o0x0icmitayksetudfioersFienmaalneism,alasn,dt<he10or0a0l mLDeSkO vfaolrumeaslfeoranCIdD fveamtaslweeWriest>a5r0r0atms.g/Tkhgerfeorwmaasles innormaobrbtiatlsiwtyasfodleltoewrimnigneindha0labteiognreeaxtpeorsuthraeno2f01080.6mem/gk/gL.. fAorPoFnOe hisouarpirnimraatsr.y oTchueladreirimtaalntLDinS0 rabbits. while the data regarding potential skin ritancy are conflicting. tAePstFeOd eiisthneort wmiutthagoerniwci.thoAutPFmOamdmiadlnioatniancdtuicveatmiuotn.atiAoPnFiOn either S. did not typhimurium or E. coli induce chromosomal when 1a0becryrtaottiooxniscicnovnicternotriantihounms.anAlPymFpOhoweaysietseswtehdetnwitcesetefdorwiittshabainlditwyittohoiuntdumceetacbhorloimcoascotmiavaltion up aabbeerrrraattiioonnss ainndCpHoOlycpelloildiynivnibnoot.hInthteheprfeirssetnacsesaayn.dAaPbsFeOncienodfucmeedtabbootlhiccharctoimvoastioomna.lIn the sacetciovantdioans.saHyo,wneovesrig,niwfhiceanntteisntcerdeawsietshimnectharboolmiocsoacmtailvataiboenr,raAtiPoFnsOwienrdeucoebdsesrivgenidfiwciatnhtouitncreases ainsscahyrionmCos:oHma10lT.a,bemrroautsieonesmabnrdyoin fpioblryopblloaisdtys.anAdPiFntOhewais vnievgoatmiovuesienamiccerlol nturcalnesufsoramsastayi.on TSiuvbecrhirsotnhiecpsrtiumdairesy tinarreaettsoarngdanmiacnedwtihtaht m28alasndar9e0-fduraymsoorfeesxepnossituirvee htahavne fdeemmaolness.traDtieedtatrhyat the eTxyppoersturroepthoyAiPn FfOemfaolr r9a0tsdaatys10r0e0suplpedmi(n76s.i5gnimfgi/ckagnt/dianyc)reaansdesininmlailveerrwaetsigathtdoasnedshaespaltoowcealslu1l0a0r ppm (5 mg/day). Analyses ofserum and liver levels of APFO showed a marked gender edixfpfoesruernecetothdaotsaecsocofun3t0s mfoerktihgeddaiyffoerrehnicgeheinr sreenssuilttiveidtyi.n dIenath,90l-ipdiadydsetpluedtyiwonitihnrthheesaudsremnoanlkse,ys, aynpdocleylmlpuhlanroidyeos.ftUhnelbiokneeromdaernrtoswt.udainesd,maondaelryasetse oaftrtohpehyseorfuhmeanldymlipvheorildevfeollslidcildesniont trheevesaplleaen eexnpdoesrudriefofferreantscetoin30m0onpkpemysA,PbFutOt(h1e4.2samapnlde 1s6i.z1e wmga/skvge/rdyaysmfaolrlm(aNl=e2s).andChfreomnailcesd,ietary arensdpelcitvievrelleys)iofnosr i2nymeaalressraensdulefedmailneis.ncrIenasaedddiitvieonr,atnedstkiicudlnaerymwaesisgehstsw,erheemoabtsoelrovgeicdailnemfafelcetssat m30y0kgpdpamy)a,ndtohvealroiwaenswtbduolsaerthesytpeedr.plasia was observed in females afer exposure to 30 ppm (1.6 Prenatal developmental toxicity studies in rats resulted in death and reduced body weight in devaimdsenecxepoosfeddevteoloorpamlednotsaelstoofxi1c0it0ymagf/krg/ordaalyeoxrpobsyurinehtaoladtoisoenstoas25himggh/ams'1A50PFmOg./kTg/hdearye,wwahsilneo idnehvaellaotpimoennetxaplostuoxriecittoy2s5tumdgy/tmh'erreeswualtsead siingnriefdiuccaentd ifentcarleabsoedyinwsekieglhettsa.l vIanriaatriaobnbsitaofrearlexposure 4 000008 to 50 mg/kg/day APFO, There was no evidenceofmaternal toxicity at 50 mg/kg/day, the highest dose tested Areptrwood-ugcetnievreattiooxincirteyprsotduudcytiovfePtFoOxiScistyhoswtueddyhiisgchurmroernttallyitbyeoinfg cF1onpduupcsteadt.dosAestwaos-lgeonwearsat1i.o6n migke/day. The results of the APFO study will be important to determine whethera similar effect is observed. Carcinogenicity studies in Sprague-Dawley (CD) rats show that APFO isweaklycarcinogenic, inducing Leydigcell adenomas in the male rats and mammary fibroadenomas in the females following dietary exposure to 300 ppm fo2r years (equivalent to 14.2 mg/kg/day in males and 16.1 mg/kg/day in females). The compound (at 300 ppm) hasalso been reported to be carcinogenic toward the liver and pancreasofmale CD ras. "The mechanism(s) of APEO tumorigenesis is not clearly understood. Available data indicate that the inductionof tumors by APFO is due to a non-genotoxic mechanism, involving activation of receptors and perturbationsofthe endocrine system. The liver carcinogenicity/toxicity of APFO appear to be related to induction of peroxisome proliferation following binding to the peroxisome proliferation activation receptor a (PPAR a) in the liver. Available data suggest that ttohehionrdmuocntailoniomfbLaelyadnicegcreelslulttiunmgorfsro(mLCacTt)ivaantidonmaofmtmhaerPyPgAlRanad neoplasms by APFO and inductionof the may be duc cytochrome P450 enzyme, aromatase. Preliminary data suggest that the pancreatic acinar cell tumors are related to an increase in serum level ofthe growth factor, cholecystokinin. As the mechaofncaircisnomgensic action of APFO have not been fully elucidated. it is assumed that the tumors induced in rats are relevant to humans. Review of available mechanistic data of other drugs and chemicals that induce LCT in animals has led a workshop panel to conclude that all but two modesofinduction of the luteinizing hormone (LH). "dopamine agonism" and "GnRH agonism'", are considered {0 be relevant to humans. and that the possibilty of induction of Leydig cell adenoma in humans by specific agents with other modes ofaction cannot be ruled out despite the arity of LCT in humans. Al presen, there is no evidence that the induction of LCT by APFO is via the "dopamine agonism'" or "GnRH agonism" mode of action. It is recognized that there are quantitative differences in certain biological parameters between rats and humans. However, the principal cell control mechanisms appear similar. and the difference in carcinogenic response is probably quantitative. As binding to the PPARa appears to be the critical event leading to hormonal imbalance and APFO tumorigenesis, and the level of PPARa. in human livers is lower than that in rodent liver, it appears that humans may be less sensitive than rodents in the development of LCT, mammary gland tumors. or liver neoplasms. s 000009 1.0 Chemical Identity Chemical Name: Perfluorooctanoic Acid Molecular formula: C8 H IS 02 Structural formula: F-CF2-CF2-CF2-CF2-CF2-CE2-CF2-C(=0)-X, "The free acid and some common derivatives have the following CAS numbers: The perfluorooctanoate anion does not have specific CAS number. Free Acid (X= OMM =H) [335671] Ammonium Salt Sodium Salt Potassium Salt Silver Salt (X=OM+M=NId) ((XX== OOMM==: MM==KN)a) (X=0M#:M= Ag) [3825-26-1] [[323359-59-50-05]8] [335.933] Acid Fluoride X=F) [3566-0] Methyl Ester Ethyl Ester (x=cu3) (X= CH2-CH3) 076:27.2] [3108-245] Synonyms: 1-Octanoic acid, 22.3.3.4,4.5.5.6.6.7.7.888-pentadecafluoroPFOA 1.1 Physicochemical Properties For this report, perfluorooctanoic acid is consistently referred to as PFOA. Mostofthe toxicology studies have been conducted with the ammonium saltofperfluorooetanoic acid, which will be referred to as APFO in this report. PFOA is a completely fluorinated organic acid. The typical structure has a lincar chain ofeight carbon atoms produced by the ielomerization of tetrafluorocthylene. The physical chemical properties noted below are for the fee acid, unless otherwise sated. The data for the fee acid, pentadecafluorooctanoic acid [335-67-1).i the most complete. The reported vapor pressure of 10 mm Hg appears high. but is consistent with other perfluorinated compounds with similar boiling points. The fre acid is expected to completely dissociate in water. vDaeptoerrmpirneastsiuorneooff t=he | vxap1o0rEp-r5es(s3uMre EonfvAiPrFoOnmenistaplroLbalbeomraattiocr.y,Fo1r99A3P)FsOe,mtshetroeocelnotwlyforrepaorted `material that sublimes as the ammonium salt. This study measured the water solubility of APFO 10 be> 10%. 1 was noted in an earlier study that concentrationsof20 g/L. "gelled" (3M 000010 cCaolmcpulaantye.d v1a9l7u9e),.-0T.9h,emipagrhttitniootn bcoeefafciccuireanttewdauserteoptohretemdetinhothdesucsecdarl(yHsatnusdcihesaondf5L.eoA1n9o7t9)h.er The formation of an make determination oefmullosgiPfiedidffliacuyletr. between the octanol and water surface interface would `The available physicochemical properties for the PFOA free acid are: MW: 414 (Beilstein, 1975) MP: 45-50 C (Beilstein, 1975) BP: 159- 192C/ 736 mm Hg (Beilstein, 1975) VP: 10 mm Hg @ 25 C (approx.) (Exfluor MSDS) Sol. - Water: 3.4 g/L. (telomeric [mp = 34 C ref. 0.01 - 0.02 mol/L ~4 - g/L) (MSDS from Merck, Fischer, and Chinameilan Intemet sites) PKa: 2.5 (USEPA AR-226 473) PH (1&/L): 2.6 (MSDS Merck) Due to the surface-active properties of PFOA, and the test protocol for the OECD method. PFOA is anticipated to form multiple layers in octanol/water, much like those observed for PFOS. Therefore. an n-octanolwater partition coefficient cannotbedetermined. Water solubility has been reported for PFOA, but it is unclear whether these values are foar microdispersion of micelles. rather than true solubility. Several reports note that PFOA salts self-associate as micelles at higher concentrations. (Simister, 1992; Calfours. 1985; Edwards, 1997). In aqueous solutions, micelles partition between the air/ water interface on the surface. Decompositionofdifferent salts produces perfluoroheptene (loss of metal fluoride and carbon dioxide). This occurs at 320C for the sodium salt and at 250-290C (Beilstein 1975). The ammonium salt sublimes at 130C (USEPA AR-226 473) "The physicochemical properties of PFOA and its derivatives are summarized in Table 1 000011 sTsen|mpmm[or Jomo]m Compound|CASREG[we| wr| [riccoF[3aseas [| ic| |1 [5C2F0FFsOoerme foee [erI nomee] S2E|| [RECOM[7335-671|55C| 189C[Tommilg|34g || I PFOA is manufactured by two major alternative processes: 1) the Simons Electro-Chemical Fluorination (ECF) process or 2) the telomerization process. P E EI E TTo E Ee im a Perfluorination oceurs when all the carbon-hydrogen bonds are replaced with carbon-fluorine e T T RE y E S EAL T MpSeu,. Separatereactor (3M Company, 2000b). Si In the telomerization process, tetrafluoroethylene is reacted with other fluorine-bearing Er te `mixturesofperfluorinated compounds with even carbon numbers (Renner, 2001), HI mee 3M Company is the largest manufacturer and impoorftPFeOrA and its salts in the United States. : These figures may overstate the total production volumeofPFOA since the vast majority of 000012 PFOA is consumed in the manufacture ofthe ammonium or sodium salts. More precise production volumes of PFOA and the ammonium and sodium salis have been reported to USEPA by 3M, but have been claimed as TSCA confidential business information, preventing disclosure in this report. Industry participants have characterized 3M as the dominant global producer of PFOA-related chemicals, manufacturing approximately 85 percent or moreoftotal worldwide volumesof the ammonium saltof PFOA (FMG, 2001). USEPA has not located information that would contradict this claim. Current production volume information for manufacturers other than 3M has not been provided by industry, nor is it available in USEPA's Chemical Update System (which contains information on non-polymeric organic chemicals manufactured in the United States or imported in volumes above 4,525 kg). Furthermore, there is no information on the otal cumulative production volumes of PFOA since initial commercialization. Since 1985, USEPA has received a totalofapproximately 25 notifications for PFOA-related chemicals that were not previously on the TSCA Chemical Inventory. Most of these: notifications were from companies other than 3M. In most cases, the notifications qualified for the Low Volume Exemption for new chemicals witha production volume fess than 10 metric: tons per year. In termsof on-going production, 3M has not committed publicly 10 a complete phase-out of PFOA and PFOA-related chemicals as it has for PFOS and PFOS-related chemicals. However. 3M has indicated that it is phasing out certain FLUORAD Brand specialty materials that contain PFOA and is salts such as FC-26, FC-118 and FC-143, FX-1001 and others (3M Company. 2000), Aside from the United States, OECD Member countries that reportedly have production capacity include France, Germany. laly, and Japan. There may also be some production in non-OECD countries such as China. Following are companies that may manufacture PFOA and its salts (3M Company, 20000 Directory of World Chemical Producers. 1998; Dynax, 2000; Renner, 2001; SEMI, 2001): OECD + + 3M Company (United States) DuPont (United States) ++ EPxCfRluoInre.Re(sUenairtcehd CStoartpeosr)ation (United States) + Atofina (France) ++ CCliabraiaSnptec(iGaelrtmyaCnhye)micals (Germany) + + DHoyencehosnt (AGketiremnagneyse)llschaft (Germany) o 000013 + EniChem Synthesis Sp.A. Miteni SpA. (italy) (italy) Asahi Glass (Japan) + Daikin (Japan) ++ DTaoihnkiepmpoPnro(dJuapcatns)Corporation (Japan) Non-OECD + Chenguang Research Instituteofthe Chemical Industry (China) + Shanhai 3F New Materials Co. Lid. (China) 21 Uses of PFOA and its Salts PFOA is used mainly as a chemical intermediate, and its salt are used in emulsifier and surfactant applications. According to 3M, the vast majority of PFOA is consumed to make the ammonium or sodium salts. 3M also uses PFOA as reactive intermediate in the industrial synthesis ofa fluoroscrylic: ester. The fluoroacrylic ester is used in an indusirial coating application (3M Company, 20004) "The salts of PFOA have additional uses. mostly in surfactant and emulsifier applications. These include the following: Processing aid in the industrial synthesis of fluoropolymers and fluoroelastomers such as cpoolnystuemtrearfiuusoerso(ct3hMylCenoempanadnyp.ol2y0v0i0nsy:liDduePnoenftl,uo2r0i0d0e;wiDtahiakinv,ar2i0e0t1y)o.findustrial and anPodstf-lpuoolryomeelraisztaotmieornspprroicoersstoinfguratihdesr iinndtuhsetrsitaalbiplriozcateisosnionfg s(u3sMpeCnosmiponasnyof, f2l0u00o2r)o.polymers + Processing aidforfuctory-applied fluoropolymer coatings on fabrics. metal surfaces, and fabricated or molded parts (3M Company. 2000a). + Extraction agent in ion-pair reversed-phased liquid chromatography (Petri. 1999) Based on the physicochemical properties of the salts of PFOA, they may also have other related surfactant or emulsifier uses as a photographic chemical or in the manufacture of electronic components such as semiconductors. These same properties may lead industry to explore PFOA as a replacement chemical for PFOS in other applications in which PFOA is not currently used. 0 000014 22 Environmental Fate 2.2.1 Photolysis Direct photolysisof APFO was examined in two separate studies (Todd, 1979; Hatfield, 2001) and photodegradation was not observed in either study. In the Todd (1979) study. a solution of 50 mg/l APFO in 2.8 litersofdistilled water was exposed to simulated sunlight at 22:2 C. Spectral energy was characterized from 290-600 nim with a max output at ~360 nm. Direct photolysisofthe test substance was not detected. However, the author noted that sample purity was not properly characterized which may have contributed to experimental error. In the Hatfield (2001) study, both direct and indirect photolysis were examined utilizing techniques based on EPA and OECD guidance documents. To determine the potentialfordirect photolysis. APFO was dissolved in pH 7 buffered water and exposed to simulated sunlight (Serano, 1999; Nubbe, 1995). For indirect photolysis, APFO was dissolved in 3 separate. matrices and exposed to simulated sunlight forperiods of ime from 69.5 to 164 hours. These exposures tested how each matrix would affect the photodegradation of APFO. One matrix was a pH 7 buffered aqueous solution containing H202 asa well-characterized source of OH radicals (Ogata, 1983; Lunak, 1992). This tested the propensityofAPFO to undergo indirect photolysis. The second matrix contained Fe203 in water that has been shown to generate hydroxy! radicals via a Fenton-type reaction in the presence of natural and artificial sunlight (Kachanova, 1973; Behar. 1966). The third matrix contained a standard solutionof humic material. Neither direct nor indirect photolysisofAPFO was observed based on loss ofstarting material. Predicted degradation products were not detected above their limits of quantitation. There was no. conclusive evidenocef direct or indirect photolysis whose rates of degradation are highly dependent on the experimental conditions. Using the iron oxide (F203) photoinitiator matrix model, the APFO half-life was estimated to be greater than 349 days. 222 Volatility Impinger studies were performed to examine the volatilityof APFO and PFOS. Solutions of APFO or PFOS containing ammonium acetate in water/I-propanol (50:50) or phase transfer agents, e.g. n-alkyldimethylbenzylammonium chloride (3M Environmental Laboratory, 1993) were blown with 280 litersofairat a flow rate of| Limin. (3M Environmental Laboratory, 1993). The results indicate there is some lossof APFO and PFOS, but most ofthe solutions retained over 80% or more of the fluorochemicals. The average retention was 92% for both APFO and POS. This indicates that there is loss from the solutions. However, some of the solutions, particularly the n-alkyldimethylbenzylammonium chloride solution, appearto retain all the fluorochemicals. These results were reviewed by Dr. Edwin Tucker ofthe Chemistry Dept. at the University of Oklahoma (3M Environmental Laboratory, 1993). He concluded that " 000015 tihteiisrvveerryyulnoliwkevlaypotrhatprtehsseusreesf.luoHreocshuegmgiecsatlesdwtehraet aremmoorveedplbayusibbulbeblmiencghaainritshmrofuogrhlowsastefrrodmucthteo solution phase is concentration of the surfactants in foam and loss from the bubbled solutions as foam or micro-droples. In the second part of the experiment, air was passed over the fluorochemicals and bubbled through a train of impingers containing the ammonium acetate solution. 1 was expected that if any fluorochemicals were presen in theair they would be transferred and retained by the ammonium acetate solution. However, no fluorochemicals were present in either the first or second impinger. 10 E07. The report concludes that the vapor pressure ofboth compounds is less than According to these experiments, APFO and PFOS (potassium sal) have very low volatility and vapor pressure. Quantitative conclusions regarding ratesofvolatilization from water or Henry's Law constant are not possible. However, APFO and PFOS are capableoftransport out of water. Also. the lossof the luorochemicals may have been as the free acids, not the salt forms. APFO sublimes at 130 C (see Physicochemical Properties Section 1.1). There is no information on the validity ofthe test method for determining volatility ofthe test substance. The study also lacks characterization of the purity ofthe test substance. 2.2.3 Biodegradation Using an acclimated sludge inoculum, the biodegradation ofAPFO was investigated usinag shake culture study modeled after the Soap and Detergent Association's presumptive test for pdergersaednacteoiofna(nRyeinmeert.ab1o9l7i8c).proBdoutchtsthoivn-elratyheer aconudrsliequoidf2ch1r/2ommaotnotghrsapihndyicdaitdinngotthdaettePcFt OthAe docs dnoetgrraedadeidlyinuancdteirvgatoedbisolduedgrgaedaitnioocnu.luImna(PaecleatAendalsyttuidcya,l,2.2604015).me/TLesAt PflFasOkswwaesrneotprmeepaasruerdaubsliyng. aamHiPneLrCa/lMsaSlDtssmyesdteimu.m,Se| vmerLalmeotthhearnoslt,udaineds c5o0nmduLctseedttbleedtwsleuednge.197A7n-a1l9y8si7sawlsaosdciodnndoutcotbesderwviet.h APFO biodegradation using what probably were standard COD and BOD methods, however, the emxeptehroidmsenutsaeldpirnottohceosles)stourditehserweerweeeriethienrdiincsautfifoincsioefntalyhidgehscdreigbreede(oif.expneordiemsecnritpatlioenrroorf. The r1e9s8u0l:ts3wMereC,omthpearnefyo.re1,9d8e5be:mePdacuenrAenlailaybtliecably. t1h9e97s)u.bmitter (3M Company, 1977: 3M Company, 2.2.4 Hydrolysis The 3M Environmental Laboratory (20012) performed astudy of the hydrolysis of PFOA. The study procedures were based on EPA's OPPTS Guideline Document 835.2110 (EPA 1998); although the procedures do not fulfill all the requirementsofthe guideline. they were more than 2 000016 adequate for these studies. Results were based on the abserved concentrationsof PFOA in buffered aqueous solutions asa function of time. The chosen analytical technique was high performance liquid chromatography with mass spectrometry detection (HPLC/MS). During the study, samples were prepared and examined at six different pH levels from 1.5 to 11.0 over a period of 109 days. Experiments were performed at 0C and the results extrapolated to 25C. Data from two ofthe pH levels (3.0 and 1) failed to meet the data quality objective and were rejected. Also rejected were the data obtained for pH 1.5 because ion pairing. led to artificially low concentrations for all the incubation periods. The results for the remaining pH levels (5.0. 7.0, and 9.0) indicated no clear dependenceofthe degradation rate of PFOA on PHI. From the data pooled over the three pH levels, it was estimated that the hydrolytic half-life of PFOA at 25C is greater than 92 years, with the most likely value of 235 years. From the mean value and precisionof PFOA concentrations, it was estimated the hydrolytic half-life of PFOA to be greater than 97 years 2.25 Bioaccumulation "To determine the potential for bioaccumulation, Fathead minnows were exposed to 25 mg/l APFO for 13 days (Howell et al., 1995). After 13 days exposure, the fish were then removed from APFO contaminated water and analyzed for depuration over 15 days. After 192 and 312 hours exposure to APFO contaminated water, the average concentrationof APFO in fish tissue was 44.7 and 46.7 pga wet weight (ww). respectively. At this point, APFO appeared to reach steady state. Twenty-four hours after being transferred to clean water, the concentration of APFO decreased to 19.9 ug/g ww and by 96 hours post-exposur, the concentration had decreased to approximately pug/ wi and remained relatively constant until est termination at 360 hours. The calculated BCF for APFO was 1.8. It should be noted that questions have been raised about ths study regarding the analytical techniques, high-test chemical concentration, and short test duration. Vraspir (1979) conducted a study to determine ifbluegill sunfish bioaccumulate fluorochemicals from the 3M Decatur plant. Two lotsof30 fish were used. One lot was exposed to Decatur plant effluent for 21 days and the other to river water onlyfor23 days. Exposed fish, both living and dead, as wel as the control fish were homogenized and analyzed for fluorochemicals by GC, TLC. and GC/MS. There were no detectable amounts of APFO in the ethyl acetate or toluene extracts of the tissues. No fuorochemicals were detected in the river water exposed fish. However, interpretation of this study is problematic for several reasons. Effluent concentrations ofsubject fluorochemiials were not characterized and the specific protocol for exposure of the. fish was not found. There was also no information on analysis of the Tennessee River water or effluent used in the study. Additionally, it was not known ifthere was any opportunity for the depuration of the fish prior to sacrifice. No explanation was attempted as to what was the cause i 000017 of the twelve dead fish in the effluent-exposed group. The study also did not differentiate: between the bioaccumulation of the test compound and the sorption onto the surficeofthe fish. 2.2.6 Soil Adsorption "The adsorption-desorption of APFO was studied in 25 mi solutions of 14C-labeled APFO in distilled water with 5 Brill sandy loam soil for 24 hours at a temperature of 16-19 C. The study reported a Kd of 0.21 and a Koc of 14 indicating that PFOA has high mobility in Brill sandy loam soil (Welsh 1978). The Koc value. however, is questionable due to the lack of accurate information on thepurity of the 14C-labeled test substance (Boyd 1993.0). Moody and Field (1999) conducted sampling and analysisof samples taken from groundwater | 10.3 meters below the soil surfuce in close proximity (0 two fire-raining areas with a history of aqueous film forming foam use. Perfluorooctanoic acid was detected at maximum concentrations ranging from 116 to 6750 ug/L at the two sites many years afier its use at those sites had been discontinued. These results suggest that APFO may have the potential to migrate * through soils to relatively shallow groundwater where it persists. 23 Environmental Exposure 23.1 Combustion For 1997. 3M estimated 1950 pounds of PFOA-compound (PFOA and related salts) stack releases at ts Cottage Grove MN location and another 4500 Ibs. from Cottage Grove incinerated offsite (3M Company. 2000.6). In 1998. 70% ofthe fuoride-containing wastes at 3M's Decatur location were incinerated off-site; incineration is now the primary disposal method for these materials (3M Company, 2000a.b). For 1999, DuPont estimated stack releases of 24,000 Ibs. APFO at its Washington Works WY location, plus another 16.000 Ibs. from Washington Works incinerated offsite (DuPont, 2000). Canadian research has stated that the thermolysis of fluoropolymers, ., Teflon, Kel-F, can liberate small quantitiesofpolycarboxylic acids, which include PFOA (Ellis et al., 2001). This information was insufficient to estimate potential yields 232 Discharge to Water By analogy to PFOS, PFOA discharged to water may remain there, become adsorbed to particulate matter and sediment, and/or be assimilated by organisms. For 1999. 3M estimated PFOA-compound water releasesof<30.000 Ibs. at its DecatAuLr location. and <15.000 Ibs. at its Cottage Grove MN location (3M Company. 2002.0). For 1999, DuPont estimated the " 000018 following APFO water Ts.: Spruance VA, 150 releases per location: Washington Works WV, Ibs.; Chambers Works NJ, 9500 Ibs. (DuPont, 55.000 2000). lbs; Parlin NJ, 300 WDuoProknstWmVe:as0u.r5e5d2 aungd/lmfordoemlead1t9h9e9 fdorlilnokwiinngg wAaPteFrOsacmonpcleentorbaitaiionnesd afrtosm sGitEes:PlWaasstihcisngton ainmmaevdeiraatgeelyandnouwanlsPtrFeOaAm coonnctehnetOrhatiioonRiovfer0..42M3odueg/lLe.dwi1t9h9A6PAFPFOOc-ocnocemnptorautnidonrselleiakesleystiondeixccaeteedd 1 ug C1 about 50% of the time during the year, and likely to exceed 10 ug APFO/L about 22% of the time during the year. 233 Discharge to Land 3M reported that Tocation ended in land treatmentofsludse mid-1998; less than 500 from wastewater ireatment at their Decatur AL Ibs. were disposed to land at that ste in 1997. Sludge MfrNomftahcieliDteycsatsuerntsitteo aisnnionwdutsrtainaslpolarntdefdiltlo(a3nMofCfosimtpealnaynd.fi2l0;00sal.u0d)g.e fDruoPmon3tM'(s20C0o0t)taegsteiGmratoevde 3,900 Ibs. of APFO sludge landfilled on site in 1999 a thir Chambers Works NJ fcility. DuPont estimated 2,600 Ibs. APFO transferred offsite to.a hazardous waste landfil from their Washington Works WV facility rPreioer olpanedrfaitlilsonosperreasutletdedbyinDgurPoounntd'-saWnadshsuirnfgatcoenwaWtoerrkcsonWceVntfraactiliiotny.s oAfvAerPagOe msuornfiatcoerewdataetr concentrations for two landfills a maximum concentrationof 33 were ug/L. 1392 ug/L and 18.5 ug/L, respectively. A third in the permitted outfall. Average groundwater landfill had concentrations for two landfils were 2537 ug/L and 8.83 ug/L, respectively.A third landfill had a maximum groundwater concentration of 15 ug/L (DuPont, 2000). dDruiPnoknitngawlsaoterrepwoerltlesdofthtehefoLlluobweicnkg PAuPblFiOc SceornvciecnetrDaitsitornisc,t,mdeoawsnusrterdeJaamnoufarDyu2P0o0n0t,'sinWtahsrheiengton Works WV site: 0.8 ug/L. 0.44 ug/L. and 0.313 ug/L (DuPont, 2000). As of August 2000, the LwautbeerckatPDuubPloicntS'esrvWiacsehDiinsgttriocnt (WLoPrSkDs)farceiploitryt,edanAdP0F.2O.0c.o5n.ceanntdra0.t1iopnpsboifn t0.h2eptphbreien dLrPiSnkDinwgells (LPSD. 2000). 2.3.4 Environmental Monitoring 3efMMucnMtu,latnid-ClianydsSitlludlyearcehpaotretesdamopnlePsFtOaAkecnoincesnixtrcaittiioesns(3fMr,om20w0a1t2e)r., Fsoluudrgeo,fsethdeimceintite,s POTW m(DaencuaftaucrtuArLi,ngMoorbiilndeusAtLr,ialCoulseumobfufsluGoAro,chPeemniscaaclso;latFoL)owfetrhee "cistuipepsl(yC"lecvietelsantdhaTtNh,avPeort St. is 000019 Lucie FL) were "control"cities that do not have significant fluorochemical activities. Across all cities, POTW effluent concentrations ranged from 0.040 to 2.42 ppb. The POTW sludge (dry wt)range was non-detect to 244 ppb: the drinking water range was non-detect to 0.029 ppb the landfill leachate range was non-detect to 48.1 ppb the surface water range was non-detect to 0.083; the sediment range was non-detect to 1.75 ppb (dry wt.); and the quiet water range was non-detect to0.097 ppb. The "control" cities samples generally inhabited the lower end of the above ranges, except for the POTW effluent and sludge findings for Cleveland, which were intermediate in their ranges. Giesy reported that PFOA was rarely found in fish and fish-cating water birds. Fish were sampled from the U.S... certain European counties, the North Pacific Ocean, and Antarctic locations (Giesy, 2001a). Fish-cating bird samples were collceted from the U.S., including. Midway atoll. the Baltic and Mediterranean Seas, Japanese and Korean coasts (Giesy, 2001b) Giesy reported on PFOA in mink and river otter livers from the U.S. (Giesy, 2001c). PFOA was found ina few mink livers from Massachusetts at a concentration range of <18 to 108 ng/g, dry w., but not found in mink from Louisiana. South Carolina and Hinois. PFOA concentrations in river otter livers from Washington and Oregon States were less than the quantification limit of 36 ng/g. wet wi. Giesy reported that PFOA was not detected at quantifiable concentrations in oysters collected in the Chesapeake Bay and Gulf of Mexicoofthe U.S. coast (Giesy, 20014). Giesy reported on the concentrations of PFOA in surface water, sediments, clams, and fish collected from locations upstream and downstream of the 3M facility at Decatur AL (Giesy, 2001). OF the five downstream sampling locations. the two closest to the 3M facility had PFOA surface water concentrations significantly greater than the two upstream sites (means of 1900u/L and 1024 ug/L, vs. 0.008 (est) and 0.028 ug/L); the ncarcst three locations had sediment concentrations significantly greater than the upstream sites (wet wi. means 1855 ug/kg, 892 uke, 238 ugg vs. 0.08(est.) and 0.09(est.)). Clam and fish samples were collected at two. locations, one upstream and one downstream ofthe 3M facility. "The average fish whole body PFOA concentration for the upstream location was 11.7 ug/kg (wet wt.), while that for the downstream location was 106.4 ug/kg. The average PFOA concentration in clams at the upstream location was 4.38 ug/k: that for the downstream location was 8.42 ug/ke. 2.4 Human Biomonitoring Table 1 provides serum PFOA levels The highest levels reported to date in in both occupational cohorts and in the general population. the general population are similar to some of the lowest 16 000020 dleivseclusssiendwboerlkoewr.s exposed to PFOA occupationally. The data are currently limited to those p3eMrfhluaosroifnfaetreeddcovomlpuonutanrdysmseidnicceal19s7u6r.veiSlelrauncmePtFo OwoArkleerveslsathpalvaentbsetehnatmperaosduurceedoarndusreeported Sbiinocmeon1i9t9o3,rinPgrifoorrtPoFtOhiAs thiamvee, obneleyntroetpalorotregdanfiorc3flpuloarnitne: wCaosttmaegaesuGrreodv.e,TMhiennreessuolttas;ofDecatur, aAlltahbouagmhanaotndalAlnotfwtehrep,plBaenltgioufmf,ereSdursuvrevielillalnacneceyeianrsalinocflutdheese19y9e3a,rs.199T5h,e1919979,8 1d9a9t8a,raenpodrt2e0d00, ifnoraltlheofDtehceatoutrheprlasnatmpclonisnigstpeorfiaodrsafnodroamllsoafmtphlepolfaenmtsp.loyees; however, volunteers participated sMienacen 1s9e9r3.umWPoFrOkeArsleavteltshehaCvoettiangcereGarsoevdeslpilgahnttl,ywahebroethPtFhOeACoetxtpaogseuGrresovaereahnidghDeescta,thuarvpelatnhtes whiagshe6s.t4PpFpOmA(rsaenrguem=l0e.v1els.-- $1T.h3eplpamte)st(sOalmspelneetwala.s i1n99189)9.7,Oannldyt7h4e emmepalnoyseeersumpaPrFtiOciApalteevdelin the 1997 surveillance. The total number of employees working at the plant was not reported. SAetrtuhme PDeFcOatAurlepvlealntw,a2s631o.7f8 p5p0m0.emTphliosyeweasspsalritgihtcliypahtiegdheinr2t0ha0n0 t(hOelsmeenaentainl,19290801()1..54Tphpem)m.ean e1s0t2a0b0l0is,hedebmyplthoey3esMhEaxdposseurruemGlueivdeleslignreeaCtoemrmhiattnee5.ppCme,llthoepeBriaotloorgsichaaldLtihmeitlaVrgaelsuteincrease in SSceortuemhgPaFrOdAtebaemtw(e12e.n7019p9p8m)a.ndT2h0e00m.eaTnhelehvielghfeosrthleeverleswtaosf tinhae mcehmebmiecrasloofpetrheateoraomnwtahse 5.06 hpaptmt(hrisanigsedu5e-9topipnmc)r.easOetdhePrFjOoAb cpartoedguocrtiieosndaitdtnhoetDeexchaibtiutrspulcanhtableagrigneniinncgreianse1.993.M reports HSaevreumdePcrFeOaAsedlesvleilgshtaltytsheinAceni1w9e9r5p(pOllasnetnheatvale. b2e0e0n1l)o.werPtarhtainciatpaDteiconatiunrmoerdiCcoatltasguervGeriolvlaen,ceanadt "tThheeAmnetawnersperpluamntPwFaOsAthleevheligwheasst0i.t8h4a,danevderthbeeheinghienst20s0e0ru(m25l8evveollurnetpeoerrtsedouwtasof73.4040 pwoprmk.ers). Three employees had levels greater than 5 ppin. f3luMoroScpheecmiiaclatly rMeastcearricahls(BMuainludfiancgt2u3r6i)n.gcDoinvdiuscitoendlavboolruanttoarriyesb.iwohmeornieteomrpinlgoyoefe4s5peemrpfloorymees in 2000 (Olsen ct al., 2001). The mean PFOA serum level was 0.106 ppm (range 0.008-- 0.668 ppm. oDnaltyaaovnaiPlaFbOleAolnevsemlasllinctohheorgtesn.erTalhepompeualantisoenruamrePvFerOyAlilmeivteelds. arTehmeyucahrelvoewreyrrienctehnet gaennderaarlc population than in workers exposed (0 PFOA. " 000021 CPooomlpeadnbyl,oo1d99s9a3m,pl1e99s9bf)r.omTUh.eS.hibglhoeosdt bpaonoklsedinsdaimcpatleemreepaonrtPedFOwaAsl2ev2elpspobf. 3Satomp1l7esppwber(e3M collected in 1998 may be present in and the 1999. U.S. These general data provide a very preliminary population. However, it cannot viewof the be assumed PFOA levels that that these levels rareeprreespernetsaetnitvaetoifvetohfetUh.eS.U.pSo.puploaptuiloant.i2o)n mfoarnsyeovferatlherebalsooonds:ban1k)sblooroigdindaolnloyrscoanrteacntoetdnfeocressarily apcotsusailbllye biencelnusainoanlyiznetdhefosrtuPdFyOdAe,clainnde4d)tonoparottihceirpadtaet,a3s)uocnhlyasaasgmea,lslexn,uomrbeotrhoefr dseammoplgersaphhaivce information are available on the donors 2P0r0e1li)m.inaBrlyodoadtasaomnpliendsivfirdoumal65b2loUo.dS.saamdpulltesblhoaovde droencoernst,lyagbeesen20r-e6p9o,rtweedr(eOlosbetnaicntedalf, r2o0m01sbix, CAhmaerrliotctaen, NReCd; CBroosstsonb,loMoAd;baPnokrtslalnodc,atOeRd,in:andLoHsagAenrgsetloewsn.,CMAD:.MinTnheeapmoleiasn/Sst.eruPmaulP,FMONA;level wBalsoo5d.6sapmppbl.esThferormanUg.eS.wachsil<dlroewnehralviemiatlsofo bqueaenntiatnaatliyozne(dLfLorOsQe=rum19P2FOoAr.2.1A1)staom5p2.l3e opfpb5.99 children, revealed ages 2-12 years old. a mean PFOA serum participating in a levelof5.6 ppb. study of group The range was A streptococcal <LLOQ to 56.1 infections, ppb. The LLOQ rweassid1i.n9g2ionr223.8s8t.atesT.heTshaemspalmepslweesriencbooltlhecotfetdhefsreomsteuqduiaelsnwuemrbeearnsoalfyzmeadluesainndg hfiegmha-lperecshsiulrder.en alriequoindlcyhrpormealtiomgirnaarpyhya/nedlehcatvreosnportacyotmapnldeetmedmqausaslistpyeacstsruormaentcrey p(rHocPeLdCur/eEs.SMSMS). These data eItnala.n,ot2h0e0r1)s.tudyT,hitrhteyP-oFnOeAdocnoonrcesnatmrpaltieosnwwearse oabntaaliynzeedd finrohmum1a6nmasleeras aanndd l1i5vefresmaamlpelseosv(eOrlasnen a1v8e-rmaognethagpeeroifotdhefrmoamlethdeonInotresmwataison5a0lyIenasrtsit(utSeDfo1r5.t6h,erAadnvgaen5c-e6m9e)natnodfthMeedaivceriangee(aHgAeM)of. thTehe hfeemmaolrerhdaogneor(sn w=as16o45ry5e2ar%s).(SmDo)to18r.5v.ehriacnlgeea1c3c-i7d4e)n.t T(hn e= c7auosres23o%f)d.eahtehadwetrreauimnatr(ancr=an4iaolr 31934)%.),Bbortahinsetrumuomra(nnd =liv2erorti6s%s)ue.wderrueg oobvtearidnoesdef(rno=m 21 3ordo3n%or)s:an7d droenspoirrsatcoornytrairrbeustted(nli=ve|r otrissue olinvleyr asnadmpl1 edsoncoornsciosntterdibouft1e0d gseorfutmisosnuley.. SSaemrpluemssawmeprleefsrwozeerneaotbAtaiMnedafnrdosmhi5pmpledoffbrloozeond;to 3M qTouranatniatlaytsiisv.elySaasmspalyeesd wuesrinegeHxtPrLacCte-dEuSsMinSgMaSn afonnd-peaviarliunagteedxtvrearcstuisonapnruonceexdturraectaenddcwurevree, eExxttreancstiivoen mpartorciexdusrpei.keSsetruudimesvawleurees fpoerrfPoFrOmeAdrtaonegveadlufartoemt<heLprOeQci(s<io3n.0a)nd 7a.c0cunrga/cmyLo.f the S"AesrsuummiPnFgOtAhelmeviedlpowianst 3v.a1luneg/bemtLwweietnhzaergoeoamnedtrLiOcQmesaenroumf2v.a5lunegf/omrL.samNpolelsiv<eLrOtoQ,setrhuemmean ations were provided because more than 90% of the individual liver samples were <LOQ. oScecruupmatPioFnOalAelxepvoeslsurien tcoorPpForOaAtessthaofufladnndotmhaanvaegeorcscuartraed3.MweprleanrtepinorStt.edP(au3lM, MCionmnpeasnotya., 1w9h9e9ar)e. " 000022 Four mean offor31theesmepelmopyleeosyeheasd wsaesru1m2.P5 FppObA. levels greater than the detection limit of 10 ppb. The `Table I. SERUM PFOA LEVELS IN HUMAN POPULATIONS `Gecuptional Exposures (ppm Plant `Arithmetic Mean MGeeaomnetric | 95% Confidence | Interval Cottage Grove Plant 1997 (n = 74) 64 01-813 . | 1995 (n =80) 1993(n= 111) 68 50 00-1141 00-800 . | - Decatur Plant 2000 (n =263) 178 0041270 [113 099-130 1998 (n = 126) 154 1997 (n = 84) 157 002-676 {090 not reported | + 02-112 * 1995 (n = 90) 146 | not reported | + - 2000 (n= 258) 084 11995(n=93) LIS 001-704 [033 000-132 |* 027-040 : | 2Bu0il0d(0inn=g4253)6 0.106 0.008 0.668|lo0.o053s | 00370076 `General Population Exposures (ppb) -- Source [AritMehanmetic| Range [po|~ oHCoolomedm,edrsc19ia9am9lpsoluercses of ~ 3 ] in in = 35 lots) Blood Banks (n= 15), 1998 ~340-680 donors. 17 2-2 Individual samples American Red Cross blood banks. 2000 56 427-523 C(h0il-d6r5en2,) 1995 56 427-561 | n= 599) 3M Corporate managers/sial NR SE p----| St.Paul. MN, 1998 12500 not reported (0-31 "Geometric mean and 95% confidence intervals were not included in the reports, ~#+++PoFnOlA4ydeetmepcltoeydeiensabwoeurte a17b3oovfetthheepdoeotlecetdiosnamlpilmietsobfut10qupapnbt.ifiable in only 2 000023 3.0 Human Health Hazards 3.1. Metabolism and Pharmacokinetics 3.1.1 Half-life in Humans In order to determine the halF-life of PFOA, a group of retirees (n = 20) volunteered to participate in a S-year half-life study in which scrum samples will be drawn every 6 months (Burris ct al., 2000). The only other data available on the half-life of PFOA is from a 1980 study in which it was estimated to be approximately | year; however, this analysis was based on total organic fluorine in blood serum. Twenty-seven retirees, age 55 to 74 years, PFOA levels in this group rangedfrom0.1 volunteered to 3.1 ppm. to participate in this Moosftthe retirees half-life study. were employed at tvhaeriDeedcagtreuart,lyAlaamboanmgatphleanptarftiocriapanntasv.eraTgheeofav2e8raygeearlse.ngTthheofntuimmbeebreotfwyeeeanrsrestiinrceemernettiarnedmetnhte startof the study was 30 months (2.5 years) but ranged from 5 10 130 months (~ 5 to 10 years). There were 3 collection periods during which serum PFOA samples were collected and analyzed: November 1998, June 1999. and November 1999. Cottage Grove employees, where PFOA exposure was much higher, have only participated in 2 sampling periods; therfore, they were not included in this analysis. Half-lives were calculated using a one-compartment model. A log-linearrelationship (slope = c"oknes2t.a3n0t3w))aswadsetuesremdinteod,esutsiimnagtethteherehlalatiolinfseh.ipsT:hie:ha=lf0-.l6i9f3e/wkaa.s cOanllcuylattheodseafrteetrirtehees ewlhimoinfiatttihoen linear one compartmental model ( $ 0.6) for PFOA were included in the analyses. 113 data points were not available for any of the subjects and if therewas a lack of fit 10 the model, that retiree was not included in the analysis. Twenty participants met these requirements. The `median serum half-life of PFOA was 344 days, with a range of 109 to 1308 days. The two highest half-life calculations were for the 2 female retirees who participated in this study (654 and was 1308 quite days). 1t should be noted that large (0.1 - 3.1 ppm). It was thedifference not specifically in PFOA stated in serum levels between retirees the report; however, based on a statement in the report, it is assumed that the 2 female retirees did not have the highest PFOA serum levels. tFhoarnmtohsetofifrstt.heThpearretfiocripea,nttshendoattiandcildudneodt iinttthheeamnaoldyeslisa,ntdhethseeycownedremeeaxcsluurdeemd.entAlwtahsouhigghhtehris. `may justify not including those participants in the analysis, it is an indication of the many limitationsofthe data. was associated with the It is stated in serum PFOA the report that neither half-life calculations; age nor numofbmoentrhs however, ths statement is retired not saunpdptohreterdelwaittihonashniypdbaettawienetnhenurempboertr.ofInyaedadristeioxnp,osneodiinnditvhieduwaolrkdpatlaacweeraendprPoFviOdAedleivnetlhsearnedport half-life were excluded. Also, elimination of PFOA occurs via urine and feces; however, these 20 000024 Smuegagseusrteemdebnytsthweerpreelnoitmicnoalrlyecrteesdu.ltsThreerpeofrotreed,hierceanrneoptrebseednetatserrmuieneedliwmhineatthieornthhaelFha-liff-eliffreom the ubondkyn.ownFi.nally, the effetof continued non-occupational, low-level exposure on the halElife is "oTthepdraotvaidpereasnenetleidmianbaotvieonprratoe.vidIaneavdedrityitono,ugthheessetdiamtaatedoofntohtepprloavsimdae ahanly-iifnefoormfaPtFiOonA.aboIuttdotehse. GSitsattreimbeunttiotnhaotftPiFmeOAbeitnwetheenbroedtyi.remWeintthaonudt ethnetriyndiinvtoidtuhaelsdtautdayodFoscusppnootrtaifnfgecitnfthoerhmaatliolni,fethe ocaclccuuplaattiioonnalisehxipgohsluyrseusopeacftf,ecOtnPeFwOoAulsdereuxmpelcetvealsg.e. Slienncgethtohfeseexpdoastaurwee,raenndottipmreocvliadpesdcdinstihnece rBealplo-rltifaeondfsPinFcOeAonilyb3etdwaeteanpo|inatnsdh3a.v5eyebaeresn. caTlhceusleatdeadtatoprdaotvei,deneevicdaennocneolfy teshteimpaotteentthiaatl tthoe bioaccumulate PFOA in humans. In addition. these preliminary data suggest that gender plays a role in the hal life. 3.1.2 Absorption Studies in Animals dAePrFmaOliesxwpeolsluraeb.soIrnberdatsf,oalnloawvienrgaogreaolfan7d49inuhgaloarti3o7n %exopfotshueref,lauonrdinteoainltehseseardemxitneinsttefroeldlodwoinsge, awqauseroeucsovsoelruetdioinn cthoentuariinniengwi2thmign,4P.5FOhrAa)ft(eOrpPhaOugAadnodsSein(gbeyr,st1o9m80a)c.h iTnhteubqatuiaonnti2tymolfonfoannionic Tuorine recovered in the urine increased to 61%ofthe dose at hr 76% at 24 hr, and 89% a1 96 i. Amfatleer raatssi,nagtleleoarsatl9d3o%soefotfh"eCt-oPtaFl OcAar(bmeoan1n-4dwoases, a1b1s.o0rbmegd/kaet)24in hsooulrusti(oGnitbosognroaunpdsoJfothhnrsoene. 1979). The half-life for elimination of total carbon-14 from plasma was 4.8 days. F1o.l8loowir$n4gmAgP/Fm3O)hceoandc-eonntlryatiinohnasloaftioonrgeaxnpoofsluuroeriidnemianltehebraltsoo(6dhsrhoyw,ed3 adadyoss/ewrkelfaotri2onwshkip10wi0t,h tinhietitaelnltehveelxspoosfu1r0e8peprpiomd.inthraetsmetraenatoerdgaatno8f4lumogr/idme3b(lKoeondnleedveylsetwaelr,e119356p).pm,Im4m7edpipamt,elayndaft1e0r8 ppm in the 1. 8, and 84 mms dose groups. dSousbeesh)rowniitch edietrhmearl0,A2P0F,O20t0r,eoatrm2e0nt00inmrga/tskeanrdesrualbtbeidtsin(e1l0eavpaptleidcabtliooonds,orgdaonsoefsl.uo2reinset ldeavyesl,s which increased in a dose-related manner (Kennedy, 1985). aObMsaolrplteiyonaonfdPEFbObiAnsin(1m9a8l1e)acnodndfuecmtaeldeararbbaintgse. fiPnFdiOnAg s(t1u0d0ymwgh/ikcgh. i1n0d0i0camtegs/ksgig,niafnidca2n0t0d0ermal Wihgi/ckhe winersealtihneenslfuirtreyd) wwiatshaapppllaisctdictocoalplparr,oxainmdattheelytr4u0nk%owafsthwerasphpaevdedwtirtuhnkimopfterhveioaunsimpallasst,ic 2 000025 sheeting. The exposure period was 24 hr. days/week over 14 days. Mortality was 100% (4/4) in the 2000 mg/kg group, 75% (3/4) in the 1000 mg/kg group and 0% (0/4) in the 100 mg/ke group In the past, Chemolite workers have been exposed to large dermal doosfPeFOsA. I appears twhoartkedresr.maUlpeoxnporseucroegnmiatiyonhatvheatpPlaFyOeAd acosuilgndifbiecaanbtsororlbeedindtehremaalblsyo,rpwtoironkopfraPctFiOceAs iwnertheese. changed and engineering controls were adopted that reduced dermal exposures (Gilliland, 1992). A butyl ammonium saltofperfluorooctanoate i the formoftrated fabric and as a liquid formulation was applied dermally to rabbits (Johnson, 1995). Liver samples were analyzed at 28 days post dose for total organic fluorine. The results from treated animals were the same as control values. All otal organic values were below the practical quantitation limit. Serum levels were also below the practical quantitation limitsofthe analysis for samples collected at day | and 2 after administrationof the mixture or the treated fabric. From the pharmacokinetic study (Johnson, 1995) it would be unlikely that any extent of absorption could have been detected in this study. 3.1.3 Distribution Studies in Animals PFOA distributes primarily to the liver, plasma, and Kidney, and t0.a lesser extent, other tissues ofthe body. It does not partition to the lipid fraction or adipose tissue, but does bind to macromolecules in the tissues. There is eviodfeneternohecpateic circulation of the compound. Major sex-related differences in the disposition of PFOA have been observed. Serum and liver concentrations of PFOA were determined in rhesus monkeys in a 90 day oral toxicity study (Griith and Long, 1980). In monkeys at the 3 mg/kg/day dose. mean serum PFOA was 30 ppm in males and 58 ppm in females. At the same dose, males had 3 ppm and females 7 ppm in liver samples. At 10 mg/kg/day doses, male monkeys had a mean serum PFOA of63 ppm and females 75 ppm. Liver levels were 9 and 10 ppm for males and females. respectively. Ophaug and Singer (1980) measured ionic fluoride and total fluorine i the serum of female rats following the administration of PFOA by stomach intubation (2 mlofan aqueous solution containing 2 mg PFOA). Serum from rats 4. hr after the administration of PFOA had a nonionic fluorine level 13.6 ppm and virtually allof this was bound to components in the scrum and not ultrafilierable. Despite the large increase in nonionic fluorine in the serum, the ionic fluoride level remained very low (0.03 ppm). Prior o intubation of PFOA. the ionic and nonionic fluorine levels in serum were 0.032 and 0.07 ppm, respectively. The nonionic fluorine: level in the serum decreased to [1.2 ppm at hr. 0.35 ppm at 24 hr. and 0.08 ppm at 96 hr. The acluetahroerds cfornocmltuhdeestehrautm.PFOA is rapidly absorbed from the gastrointestinal tract and rapidly 000026 Twenty-four hours after oral administration of APFO (2 mg APFO in 2 mi aqueous solution by stomach intubation), female rats had a mean serum nonionic fluorine level of0.35 ppm. while male rats had a mean serum nonionic fluorine levelof44.0 ppm (Hanhijarvi etal. 1982). APFO was bound to a similar extent in the plasmaofmale and female rats (97.5% bound). In male and female rats administered 14C-PFOA in propylene glycol/water (9.4 umolkg, i.p.). the concentration of 14C-PFOA-derived radioactivity in the blood was higher and climinated mmaolree rsalso,wltyheinlimvearlehsad(1t1h/e2h=i9gdhaeysst,PmFaOleAscvosn4cehnrt,rafteimoanle(s2,17V%aonfddeonsHeeautve2lhre,t2al%.,o1f9d91o)s.e Iant 2t8h.e days) followed by the plasma and kidney. Far lower PFOA concentrations were found in the heart, testis, fa, and gastrocnemius muscle. In females at 2 br post dose, the highest concentrations of PFOA were found in the plasma followed by the kidney, liver and ovaries in that order. The average t172 for elimination of PFOA from the liver in male rats was 11 days compared to an average of9 days for extrahepatic tissues. In females, the average t1/2 for tissue elimination was approximately 3 hr Vanden Heuvel etal. (1991) investigated the disposition of PFOA in perfused malera ivr. Aupmporlotxoitmala)tewlays 1ex1t%roacftetdhebycutmhuelalitvievredduroisnegaof f"iCrs-PpaFssO.A Iinnfaudsdietdi(o0n.,0t8heumcoulm/ulmaitnixve4p8ermcienn,t3o.f84 PFOA extracted by the liver at 2 min (33%) was substantially greater than that seen afier 48 min (119%) indicating that first-pass hepatic uptake of PFOA may be saturable. Yinen etal. (1990) studied the difference between male and female Wistar ats in the distribution and accumulation of PFOA after a single and subchronic administration. The single dose of PFOA (50 mg/kg in propylene glycol-water mixture, 1:1. vol. 0.25 ml/ 00g) was administered intraperitoneally to 10 week old rats (20 male, 20 female). Subchronic administrationof PFOA consistedof3. 10. and 30 mg/kg/day by gavage (in 0.9% NaCl, 0.5 ml/100g) to newly weaned ats (18 male, I8 female). Afier the single dose. samples were collected for PFOA determination 12, 24-168 (at 24 h intervals), 244 and 336 hours after the administration, and in the subchronic test on the 28th day. The serum was collected by cardiac puncture; after decapitation the brain and at necropsy samples from the liver, kidney. lung, spleen. ovary, testis. and adipose tissue were collected and frozen. The biological half-life of PFOA in the serum and tissues was determined from the linear relationship between time and PFOA concentration in the semilogarithmic plot. In the single-dose study. concentration of PFOA in the serum and tissues was higher in males than females a alltime periods. Twelve hours after the administration of PFOA about 10%ofthe dose was found in the serum of females, whereas about 40% was in the serumof males. After 14 days about 3.5%ofthe dose. remained in the serum. In females, PFOA concentration in the serum, liver, and kidney occurred ninina dtihsecfoenmtailneusouasndfamshailoens,,irnedsipcecattiivneglyd.istiInnctthpehafseemsa.lesT,hae hhaallff--lliiffeeoifn 6th0ehsewrausmeswtaimsat2e4danidn t1h0e5 liver during the first week. In the males. the half-life in iver was 210 h. Although PFOA was retained by the liver, it was not found in the lipid fraction. In the kidney, thehal life was 145 h and 130 hin females and males. respectively. In the spleen, the half-life was 73 hand 170 hin 000027 females and males, respectively. PFOA was also found in brain tissue. PFOA was not detectable in adipose tissue. In the subchronic study. samples taken on the 28th day indicated significantly higher PFOA concentrations in the serum and tissuesof males versus females in al three dose levels. After subchronic, as well a single-dose administration, PFOA was mainly distributed in the serumofrats. High concentrations of PFOA were also found in the liver, Kmiadlneesy,exahnibditleudn,groefspmeaclteisvealyn.dsfeermaulmesc.oncAetnttrhaethiiognhs odofs1e3.l9ev2elan(d3051m.g6/5kgu/gd/amyl),.lfiveemrales and concentrationsof6.64 and 49.77 ug/g, kidney concentrations of 12.54 and 39.81 ug/g, spleen concentrations of 1.59 and 4.10 ugg, lung concentratioofns 0.75 and 23.71 ug/g. and brain c7o.n2c2eungtlrea.tioAnssiognfifi0c.0a4n4tapnodsi0t.i7v1e0courg/rge.latTihoneeoxviasrteydcboenttawieneendth1e.1a6dumgi/ngisatnedretdhedotsesetasncdontthaeined concentration of PFOA in the liver, Kidney. spleen, and lung of females. On the contrary, no Significant correlation between the administered dose and the concentration of PFOA was observed in the males, as 10 mg/kg/day produced higher PFOA concentrations in the serum and organs than 30 mykg/day. However, in males, the concentration in the spleen. tests, and brain correlated positively with the concentration in the serum. `Vanden Heuvel et al. 1992) demonstrated that PFOA covalently binds to proteins in the liver, plasma, and testes of ats in vivo. Carbon-14-labeled PFOA was administered to six-week old ale Harlan Sprague-Dawley rats in propylene glycol/water (1:1, iv: | mike) at a doseof9.4 umolke, ip. No time-dependent changes in either absolute or relative concentrations of covalently bound PFOA-derived 14C were found ai 2 h. 1 an4d days post-treatment. Covalently bound PFOA was representedby 0.1 10 0.3% ofthe tissue 14C content. The absolute concentration ofcovalently bound PFOA was significantly higher in the plasma than in the liver. "The testes had the highest relative concentration of PFOA-derived radioactivity covalently bound. In in vitro tests. covalent binding of 14C-PFOA 10 a constant concentrationofalbumin o(f8 uPMF)OAintcorehaesmeodgilnoabilnineianrviftarsohiwoanswdiitmhiinnicsrheeadsibnygtPheFOadAdictoinocnenotfrcaytisotne.ineThbuetcnoovtalmeentthiboinnidnien,g suggesting that protein sulfhydryl groups may be involved Hanhijarvi et al. (1987) compared the disposition of PEOA between male and female Wistar rats daunriimnaglssuatbc0h,r3o.ni1c0,aadnmidni3s0trmagt/iokne.(iPnF0O.A9%wNaasCald,m0i.5mn1is0te0regd )byfgoarv2a8gecotno4se8cuntievwelyda-ywse.anUerdine wblaosodcowllaesctceodlloencttehdev7itahcaanrddi2a8ctphundcatyuorfe.theAtsteuadcyh (ddoisseculsesveeld,btehleowm)e.anAtPFthOeAencdoonfcetnhterasttiuodnys,in the plasma of plasma PFOA the male rats were concentrations for significantly higher than those the male ras were 48.6+-26.5 of the ug/ml female (dosed rats. at 3 mgT/hkeg)m.ea83n.1-- 24.7 ug/ml (10 mg/kg), and 53.4+-11.2 ug/ml (30 mg/kg). The corresponding figures for female ats were 2.43+-5.96 ug/ml. 11.3+-8.59 ug/ml, and 9.06+-8.50 ug/ml in the same order. The. PFOA concentrations in the plasma ofthe male animals suggested that the binding sites of PFOA nay become saturated at the chronic daily dose level of 30 mg/kg. Although the plasma PFOA concentrations ware significantly higher in the male rats no significant histopathological differences between the sexes were observed at necropsy. u 000028 The disposition of PFOA was studied in male Wistar ats after castration and estradiol administration as well as in intact males and females (Ylinen ct al.. 1989). The male rats (N=20) were castrated at the ageof 28 aysand afte $ weeks were used inthe tests. Hal ofthe operated and 10 intact males were administered estradiol valerate subeutancously 500 uglkg. epvuencrtyursee.coAntdtdhaeyednudroifngth1e4tdesaty(s9b6efhro)r.etthheectoensc.enBtlroaotdiosnaomfplPeFsOwAerien ctohlelsecetreudmobfyicnatradicatc.males was considerably higher (17-40 times) than in the serum ofother groups. There was no statistically significant difference in the serum concentrations between the other groups. PFOA was similarly bound to the proteins in the serum of males and females. Johnson etal. (1984) investigated the effectof feeding cholestyramine to ats on th fecal Climination of APFO. Since APFO exists as an anion at physiologic pH, it would be expected to c2)omwpelreexadwmiitnhicshtoelreesdtayrmammoinneiuinmvi1v4oC.-peTrefnluMoarloeocCthaanrolaetse R(i2v.1ermCgD/mr)atdsis(s12olwveeedkisn o0l.d,9%30N0a-C3l42as single intravenous dose (2 mifat, average APFO dose 13 mgkg). Five rats were given 4% cholestyramine in fecd. Urine and feces samples were collected at intervals for 14 days. at which time the animals were sacrificed and liver samples were collected. At 14 days post dose. the mean percentage of APFO dose eliminated in the fecesof cholestyramine treatedrats (43.25 5.5) was 9.8-fold the mean percentageof dose eliminated in feces by untreated ras (4.4+-1.0). Excretion in urine was 41% for trated rais and 67% for untreated rats. Carbon-14 present in the liver represented 12.1+-2.1 ug cq/g and 22.3+-6.2 ug eq' in treated and untreated rats, respectively (4% and 8%of dose, respectively). In plasma, the levels were 5.11.7 ug eq/ml awnedre141..78++--60..57 ug ug cq/ml eq/ml ianndtr4e.at2e+d-2a.n4duugnterqe/amtledinrattrs,atreedspeacntdivuelnyt.reaItnedrerdasb,loreosdpeccetlilv,eltyh.e lTehveels high concentration of 14C-APFO in live at 2 weeks afer dosing and the fact that cholestyramine treatment enhances fecal elimination of carbon-14 nearly 10-fold suggests that there is enterohepatic circulationof APFO. "The disposition of PFOA (tetrabutyl ammonium salt perfluorooctaancoiid)c in female rabbits ahansd b2e4emnyr/ekpeoratnedd (aJpophenasroend, n1o99r5m4a).thIrnoduigvihdouuatltrhaebsbittusdywe(rtheegainviemnalinrtersatveendoaustdhoes4e0s matg/0k.g4., 16, dose level died within minutes ofdosing). Serum samples were analyzed for total organic uorine at 2, 4. 6. 8. 12. 24, and 48 hours post dose. A1 2 hrs, serum organic fluorine levels in the 0,4, 16. and 24 mg/k dosed rabbits were 1.25 ppm, 4.09 ppm, 14.9 ppm and 41.0 ppm, rdeestpeeccttaibvleelya.t 4T8hehrr.e wTahseabiaopliogdicdaelcrheaalsFeifineswearsumonletvheeloofrdtoetraol fo4rghaonurisc. flTuhoreinteotwalitohrgiamnei,c nonfluorine in whole liver at 48 hr post dose for control animals4, me/ke. 16 mg/kg, and 24 mgke. intravenous doses were 20 ug, 43 ug, 66 ug, and 54 ug 3.1.4 Metabolism Studies in Animals FVaCn-dPeFnOHAeu(v9.e4l uetmaol.lk(g1,99i1.)..invPeosotliegdatdeadiltyheuriinnveisvoammpelteasbo(0l-i4smdaoyfsPpFoOstA-trienartamsenatd)mainndisbtielreed 5 000029 extracts analyzed by HPLC containeda single radioactive peak eluting identically to the parent compound. Tissues were taken from ras treated 4, 14, and 28 days previously with 14C-PFOA to determine the presence of PFOA-containing lipid conjugates. Only the parent compound was present in at tissues; no PFOA-containing hybrid lipids were detected. Fluoride concentrations in plasma and urinebefore and after PFOA treatment were unchanged, indicating that PFOA does not undergo defluorination in vivo. `fOoplhloawuignganodraSliandgmeirni(s1t9r8a0t)ioanlsooffPouFnOdAntoocfheamnaglee irnatsi.oniYclifnlueonricdteall.ev(e1l98in9)thfeosunedrunmooerviurdiennece of phase [I metabolism of PFOA following a single intraperotoneal PFOA dose (50 mg/kg) in male and female rats. 3.1.5 Elimination Studies in Animals The urine is the major routeof excretion of PFOA in the female rat, while the urine and feces arc both major routesofexcretion of PFOA in male rats (Vanden Heuvel etal. 1991). Male and female rats were administered ""C-PFOA in propylene glycol/wa(t9e.4r umol'kg, i.p.). Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91%ofthe dose being excreted inthe first 24 hr, while male rats excreted only 6%of the dose in that time period. Negligible radioactivity was recovered in the feces of female rats. In male rats during the 28-day colleetion period the cumulative excretion of PFOA-derived 14C in urine and feces was 36.4% and 35.1%, respectively. The female rat retained less than 10% ofthe administered dose afer 24 i, while the male rats retained 30%ofthe administered dose afer 28 days. The whole-body elimination half-life in females was less than one day, and in males it was 15 days. In renalligated rats injected ip. with 14C-PFOA. approximately 0.3% ofthe PFOA-derived radioactivity was excreted in the bileafter 6 hr (Vanden Heuvel etal, 1991). No sex-related difference in the biliary excretion of PFOA was observed when the kidneys were ligated Johnson and Gibson (1980) observed a sex difference in extent and rateof excretion of total carbon1-4 between male and female rats afer a single iv dose (mean dose: female, 16.7 mg/kg: male 13.1 mg/kg) of 14C-PFOA. Female rats excreted essentially all of the dose via urine in 24. hours while at the same time period male ras excreted only 20 percent of the dose; male rats excreted 83% via urine and 5.4% via feces by 36 days post dose. No radioactivity was detected in tissues of female rats at 17 days post dose: male rats had 2.8%of the dose in liver and 1.1% in plasma at 36 days post dose with lower levels (< 0.5% of the dose) in other organs. Ophaug and Singer (1980) investigated the metabolic fate of PFOA in female Holtzman rats. Animals weighing approximately 250 g were administered by stomach intubation 2 mlof an aqueous solution containing 2 mg PFOA. The animals were then placed in metabolism cages and provided rat chow and tap water for 4.5, 8, 24, or 52.5 hr. In addition, four ras were placed in metabolism cages and fed a low fluoride (<0.5 ppm) diet and distilled water for a period of 96 hi. At the endofthe experimental period the urine, feces and serum were collected. Within 4.5 hrafter PFOA dose, an average of 749 ug or 37%ofthe fluorine in the administered dose was 2 000030 recovered in the urine. The quantity of nonionic fluorine recovered in the urine increased to 61% of the dose at 8 hr, 76% at 24 hr, and 89% at 96 hr. Urinary excretion of ionic fluoride in the PFOA dosed animals was not significantly different than that ofthe control animals. Fecal excretionof nonionic fluorine was4.5%ofthe administered dose at 52.5 hr and 14.3% at 96 hr. "The urine from undosed animals contained no detectable nonionic fluorine. "The urinary excretion of APFO in rats was investigated by Hanhijarvi et al. (1982). Four male and six female Holtsman rats were administered 2 mg APFO in 2 ml aqueous solution by stomach intubation. Seven female rats were administered 2 mi distilled water as controls. The animals were then placed in metabolism cages with rat chow and tap water. Urine was collected until animals were sacrificed at 24 h by cardiac puncture. Serum was collected. lonic fluoride: and total fluorine contentofserum and urine was determined, and nonionic fluorine was caleulated as the difference. For clearance studies of APFO and inulin, the rats were: anesthetized with Inactin. The femoral artery was cannulated for continuous infusion of 5% `mannitol in isotonic saline and the femoral artery was cannulated for drawing blood samples. "The urinary bladder was also cannulated for serial collectionsof urine. Intravenous priming. dosesof $.2-5.6 mg [1-14C] ammonium perfluoroactanoate (sp act 0.5 uCi/mg) and 8.5 ug ritated inulin (methoxy-311, sp act 114 uCi/me) were given to each animal. The radiolabled inulin and APFO in 5% mannitol in isotonic saline was then infused at a rate of 0.21 m/min. An additional 0.42-0.63 mg/hr 14C-APFO and 9.6 ug/hr tritiated inulin was infused during the experiments. When the urine and serum collections for the clearance study were complete, probenecid was administered (65-68 me/ke, ip) and additional clearance tests were performed. In the cumulative excretion study. rats were dosed iv with a mixoftraduiolrabeeled APFO (1020%) and unlabeled APFO (80-90%). Five percent mannitol in isotonic saline was infused at a rate of 0.081 mi/min and urine specimens were collected over 30-min intervals. The effect of probenecid was assessed by administering 65-68 mg/kg ip at least 30 min prior to the administration of APFO. Twenty-four hours after oral administration of APFO, female rats had excreted 76+-2.7%ofthe dose in the urine and had a mean serum nonionic fluorine level of 0.35+-0.11 ppm, while male rats had excreted only 9.2+-3.5% of the dose and had a mean serum nonionic fluorine levelof44.0+-1.7 ppm. APFO was bound to a similar exten in the plasma of male and female rats (97.5+-0.25% bound). The clearance studies demonstrated major differences between the sexes in rats. The APFO clearance in female rats was several times ureater than the inulin clearance. Administrationofprobenecid, which strongly inhibit the renal active secretionof organic acids, reduced APFO/inulin clearance ratio in females from 14.5 to 0.46. APFO clearance was reduced from 5.8 t0 0.11 ml/min/ 100g. Net APFO excretion was reduced from 4.6 10 0.13 ug/min/100g. In male rats. however, the APFO/inulin clearance ratio and the net excretion of APFO were virtually unaffected by probenecid. In the males, APFO clearance was 0.17 mlmin/ 100g, APFO/inulin clearance ratio was 0.22. and net APFO excretion was 0.17 ug/min/mg. In the cumulative excretion studies. female rats excreted 76%ofthe APFO dose, whill males excreted only 7.8%ofthe dose over a 7-hr period. Probenecid administration modified the cumulative excretion curve for males only slightly. However, in females probenecid markedly reduced PFO climination to 11.8%. It is concluded that the female rat possesses an active secretory mechanism which rapidly eliminates APFO from the body. This 000031 stocxeirceittoyryofmAecPhFaOniisnmmaislelarcaktsi.ng or is relatively inactive in male rats and accounts for the greater Hanhijarvi et al. (1987) compared the urinary elimination of PFOA between male and female Wistar rats during subchronic administration. PFOA was administered by gavage to 48 newlywUerianneedwaasnicmoalllescatted0.o3n,t1h0e,7atnhda3n0d m28g1/thkgda(yionf0t.h9e%sNtaudCyl., 0A.t5mtihe/1e0n0dgo)ftfohre28stcuodny.sebcluotoidvewdaasys. collected via cardiac puncture. At necropsy, tissue specimens for histopathologic examination were collected from the controls and from the group receiving 30 mg/kg/day PFOA. On the seventh day of the study period, the female rats in lowest dose group (3 mg/kg/day) exhibited significantly greater urinary PFOA excretion than the males (3.12+-0.30 vs 1.50+-0.57 `mg/24hr/k). Unlike the female rats. on the 7th day of the study all three groupsofmale rats excreted significantly less PFOA than their daily dose of PFOA, which suggested that the males had not reached a steady state by seven days. On the 28th day. the males excreted an amount of PFOA equal to thir daily dose. Hanhijarvi et al. (1988) investigated the excretion kinetics of PFOA in the beagle dog. Six Taboratory bred beagle dogs (3 male. 3 female) were anesthetized with methoxyflurane and catheters were placed in both ureters after laparototomy and cystotomy. The animals were given an intravenous dose of 30 me/ke of PFOA followed by continuous infusion with $% mannitol Solution at 1.7 ml/min. Urine was collected at 10 minute intervals for 60 min. AS ml blood sample was collected in the middleofcach urine sampling period. Probenicid (30 mg/kg i.v.) was then administered. and urine and blood samples were again collected as before. Renal clearance of PFOA was calculated for the before and afier probenecid injection periods. Four additional dogs (2male, 2 female) were given 30 mg/kg PFOA intravenously. These dogs were kept in metabolism cages, and blood samples were collected intermittently for 30 days. From these dogs, plasma PFOA half-lives were determined. There was no difference between the renal clearancesof the male and female dogs either beforeorafter probenecid. Renal clearance rate was approximately 0.03 mi/min/ke. Probenecid significantly reduced the PFOA clearance in both sexes, indicating an active secretion mechanism for PFOA. The plasma halE-lives of PFOA were longer in the male dogs (473h and S41 h) than in the female dogs (202 h and 305 h). The urinary excretionofPFOA was studied in male Wistar rats aftr castration and estradiol administration as well as in intact males and females (Ylinen et al, 1989). The male rats (N=20) were castrated at the ageof28 days and after weeks were used in the tests, Half ofthe operated and 10 intact males were administered estradiol valerate subcutaneously 500 ug/kg every second day during 14 days before the test. Urine was collected in metabolism cages. during 96 hr afear single intraperotoneal PFOAdose (50 mgkg). Blood samples were collected by cardiac puncture. Castration and administration of estradiol 0 the male rats had a significant stimulatory effect on the urinary excretion of PFOA. During the first 24 hours. Female rats excreted 72+-5% (N=0) of the dose. whereas the intact males excreted only 9+-4% (N=6). After the estradiol reatment, both the inact and castrated males excreted PFOA in amounts similar to females (61-19% and 68-14%, respectively). The castrated males without = 000032 estradiol treatment excreted PFOA in urine faster than the intact males (50+-13%) but less than thefemales and the estrogen treated males. At the endofthe test (96 hi), the concentration of PFOA in the serum of intact males was considerably higher (17-40 times) than in the serum of other groups. There was no statistically significant difference in the serum concentrations between the other groups. PFOA was similarly bound by the proteins in the serumofmales and females. Vanden Heuvel et al. (1992a) investigated whether androgens or estrogens are involved in the marked sex-differences in the urinary excretionof PFOA. Castrationof males greatly increased (> 1-fold) the eliminationof "PFOA (9.4 umol/kg. .p.) in urine. demonstrating thata factor produced by the testsi responsible for the slow climination of PFOA in male rats. Castration plus 17B-cstradiol had no further effect on PFOA climination whereas castration plus tasesrtaotsstewriotnheirnetapcltacteesmtiesn.t Tathutsh,e ipnhymsailoelorgaisc,altelsetvoelstrereodnueceedxePrtFsOaAn ienlhiimbiintaotriyoneftfoecttheonsaremneallevel excretion of PFOA. In female rats, neither ovariectomy nor ovariectomy plus testosterone affected the urinary excretion of PFOA, demonstrating that the inhibitory effectoftestosterone on PFOA renal excretion is a male-specific response. Probenecid, which inhibits the renal transport system, decreased the high rate of PFOA renal excretion in castrated males but had no effect on male rats with intact tests Hormonal changes during pregnancy do not appear to caauchsanege in the ate of elimination ofcarbon-14 after oral administration of a single dose of ammonium "PFOA (Gibson and Johnson, 1983). ALS or9 days after conception. four pregnant rats and 2 nonpregnant female: rats were dosed (mean dose, 15 mg/kg) and individual urine samples were collected at 12, 24, 36. and 48 hours post dose and analyzed for carbon14- content. Essentially allofthe carbon-14 was climinated via urine within 24 hours for both groups ofats. Feedingofcholestyramine to rats enhanced the fecal elimination of APFO (Johnson etal (1984). Male rats were administered ammonium [14]perfluorooctanoate (2.1 mg/m) dissolved in 0.9% NaCl asa single intravenous dose (2 mira, average APFO dose 13 mukg). At 14 days post dose, the mean percentage of APFO dose eliminated in the feces of cholestyramine-treated ats (43.2+-5.5) was 9.8-fold the mean percentage of dose eliminated in feces by unireated rats (4441.0). Excretion in urine was 41% for treated rats and 67% for untreated rats. 3.2 Epidemiology Studies 32.1 Mortality Study A retrospective cohort mortality study was performed on employees at the Cottage Grove, Minnesota plant which produces APFO (Gilliland and Mandel, 1993). At his plant, APFO production was limited to the Chemical Division. The cohort consisted of workers who had been employed at the plant for at least 6 months between January 1947 and December 1983. Death certificatesofall of the workers were obtained to determine cause ofdeath. There was almost 2 000033 complete follow-up (99.5%) ofall of the study participants. The exposure status ofthe workers was categorized based on theirjob histories. IF they had been employed for at least 1 month in the Chemical Division. they were considered exposed. All others were considered to be not exposed to PFOA. The number of months employed in the Chemical Division provided the cumulative exposure measurements. OFthe 3537 (2788 men and 749 women) employees who apanrdti1c4i8paotfetdhien t3h4i8s smteundy,wo3r9k8e(d34in8tmheenChaenmdic5a0lwDoimveisni)onw,earneddtehceeraesfeodr.e, Ewleerveencoonfstihdeer5e0d women exposed to PFOA Standardized Mortality Ratios (SMR), adjusted for age, sex, and race were calculated and compared to U.S. and Minnesota white death rates for men. For women, only state rates were available. The SMRs for males were stratified for 3 latency periods (10, 15. and 20 years) and 3 periodsofdurationof employment (5. 10. and 20 years). For all female employees, the SMRs for all causes and for all cancers were less than I. The only elevated (although not significant) SMR was for lymphopoietic cancer, and was based on only 3 deaths. When exposure status was considered, SMR for all causes ofdeath and for all cancers were significantly lower than expected. based on the U.S. ates, for both the Chemical Division workers and the other employeesof the plant. In all male workers at the plant, the SMRs were close to | for mostofthe causes ofdeath when compared to both the U.S. and the Minnesota death rates. When latency and duration of employment were considered. there were no elevated SMRs. When employee deaths in the Chemical Division were compared to Minnesota death rates. the SMR for prostate cancer for workers in the Chemical Division was 2.03 (95% CI 55 -4.59). This was based on 4 deaths (1.97 expected). There was alsao statistically significant association with lengthof employment in the Chemical Division and prostate cancer mortality. Based on the reosfpuroplorttionsal hazard models, the relative isk foar 1-year increase in employment in the Chemical Division was 1.13 (95% CI 1.01 to 1.27). Tt rose t0 3.3 (95% C1 1.02 -10.6) for workers employed in the Chemical Division for 10 years when compared to the other employees in the plant. The SMR for workers not employed in the Chemical Division was less than expected for prostate cancer 58). An updateof this study was conducted (0 include the death experienceofemployees through 1997 (Alexander, 2001a). The cohort consisted of3992 workers. The eligibility requirement was increased to 1 yearof employment at the Cottage Grove plant, and the exposure categories were changed to be more specific. Workers were placed into 3 exposure groups based on job. history information: definite PFOA exposure (n = 492, jobs where cell generation, drying. shipping and packaging of PFOA occurred throughout the history ofthe plant): probable PFOA elxopwoesruorret(rnan=sie1n6t85e,xpootshuerrecsh)e:maincdalnodtiveixspioonsejdobtsowfhleuroeroecxhpeomiscuarlest(onP=FO18A15w,apsripmoasrsiilbylenobnut- with chemical division jobs). 0 000034 In this new cohort, 607 deaths were identified: 46 of these deaths were in the PFOA exposure group. 267 in the probable exposure group, and 294 in the non-exposed group. When all employees were compared to the state mortality rates, SMRs were less than | or only slightly higher for all of the causes ofdeath analyzed. Noneofthe SMRs were statistically significant at pF=ive05d.eatThhsewheirgeheosbtsSerMvRedr(e3p.o8r3teedxpweactsedf)o.r bladder cancer (SMR = 1.31, 95% C1 = 0.42 3.05). A few SMR were elevated for employees in the definite PFOA exposure group: 2 deaths from cpraonsctearteofctahnecelrar(gSeMinRte=sti1.n3e0)(.SMInRa=ddi1t.i6o7)n., e1 mfprloomyepaenscrienatthiecdceafnincietre(PSFMORA=ex1p.3o4s)u,raengdro| ufprom were 2.5 times more likely todic from cerebrovascular disease (5 deaths observed. 1.94 expected; 95% C1 = 0.84 6.03). In the probable exposure group. 3 SMRs should be noted: cancerof the tests and other male genital organs (SMR = 2.75, 95% C1 = 0.07 ~ 15.3); pancreatic cancer (SMR = 1.24, 95% CI = 0.45- 270); and malignant melanoma of the skin (SMR = 1.42,95% C1 = 0.17 -- 5.11). Only 1. 6, and 2 cases were observed. respectively. The SMR for prostate cancer in this group was 0.86 0=5). "There were no notable excesses in SMR in the non-exposed group, except for cancer of the bladder and other urinary organs. Four cases were observed and only 1.89 were expected (95% CI=0.58 5.40), Iuis difficult to interpret the results of the prostate cancer deaths between the frst study and the update because the exposure categories were modified in the update. Only I death was reported in the definite exposure group and 5 were observed in the probable exposure group. Allofthese deaths would have been placed in the chemical plant employees exposure group in the first study. The numobfyeearrs that these employees worked at the plant and/or were exposed to PFOA was not reported. This is important because even | prostate cancer death in the definite PFOA exposure group resulted in an clevated SMR for the group. Therefore, ifanyofthe. employees" exposures were misclassified. theresults ofthe analysis could be altered significantly. The excess mortality in cerebrovascular disease noted in employees in the definite exposure group was further analyzed based on numberofyearsof employment at the plant. Three of the 5 deaths occurred in workers who were employed in jobs with definite PFOA exposure for more than 5 years but < 10 years (SMR = 15.03,95%C1 = 3.02 43.91). The other 2 occurred in employees with less than 1 year ofdefinite exposure. The SMR was 6.9 (95% C1 = 1.39 -- 20.24) for employees with greater than 5 yearsofdefinite PFOA exposure. In order to confirm that the results regarding cerebrovascular disease were not an artifactofdeath certificate coding, regional mortality raes were used for the reference population. Theresults did not change. `When these deaths were further analyzed by cumulative exposure (time-weighted according to exposure category). workers with 27 years of exposure in probable PFOA expose jobs or those with 9 years ofdefinite PFOA exposure were 3.3 times more likely 10 dieof cerebrovascular St 000035 disease than the general population. A dose-response relationship was not observed with years of exposure. The slight excess in bladder cancer in the cohort as a whole should be noted, especially given the bladder cancer mortality experience at 3s Decatur plant, which produces mostly PFOS. Bladder cancer mortality was 4 times higher in workers with high PFOS exposure jobs at M's Decatur, Alabama plant than the genral population (SMR = 4.81, 95% C1 = 0.99 - 14.06) (Alexander, 2001b). Three deaths were reported, and allof them occurred in the high exposure group. Serum PFOA levels in workers are lower a the Decatur plant, where PFOA is used as an elastomer in luoropolymer production or is produced asa by-product, than at Cottage Grove: however, the manufacture of PFOA began at Decatur in 1999. Therefore, PFOA exposures will likely increase at this plant. It is not clear whether PFOA, PFOS or some other chemical may be responsible forthebladder cancer deaths observed at these plants; however, follow up should continue in an effort to shed somelighton this observation. Its difficult to compare the results of the fist and second mortality studies a the Cottage Grove. plan since the exposure categories were modified. Although the authors claim that the newer exposure categories are more accurate. it is still likely that exposure misclassification occurred. Without measured exposures (serum PFOA levels). it is difficult tojudge the reliability ofthe exposure categories that were defined. In the second study. the chemical plant employees were sub-divided into PFOA-exposed groups, and the film plant employees essentially remained in the "non-exposed group. This was an effort to more accurately classify exposures: however, these nen categories do not take into account duration of exposure or leonfemgplotymehnt. Another limitation to this study is that 17 death certificates were not located for deceased employees and therefore were not included in the study. The inclusion or exclusion ofthese deaths could preatly change the analyses for the cauofsdeeatsh that had a small number of cases. Follow up of worker mortality at Cottage Grove (and Decatur) needs to continue. Although there were more than 200 additional deaths included in this analysis, it is a small number and the cohort is sill relatively young. Given the resultsofstudies on fluorochemicals in both animals and humans. further analysis is warranted. 3.2.2 Hormone Study Endocrine effects have been associated with PFOA exposure in animals; therefore, 2 crosssectional studies were conducted on employeoefas plant producing PFOA (Olsen, etal. 1998). Medical surveillance, hormone testing and PFOA serum levels were obtained for volunteer workers in 1993 (n = 111) and 1995 (n = 80). Sixty-cight employees were common to both sampling periods. In 1993, the range of PFOA was 0-80 ppm (although 80 ppm was the limit of detection that year, so it could have been higher) and 0-115 ppm in 1995 using thermospray mass spectrophotometry assay. Eleven hormones were assayed from the serum samples. They were: cortisol. dehydroepiandrosterone sulfate (DHEAS), estradiol, FSH, 17 gammahydroxyprogesterone (17-HP), free testosterone, total testosterone, LH, prolactin, thyroidstimulating hormone (TSH) and sex hormone-binding globulin (SHBG) n 000036 Employees were placed into4 exposure categories based on their serum PFOA levels: 0-1 ppm, h1o-r<m1o0neppvma,lue1s0-i<ncl3u0depdp:m,mualtnidva>r3i0abplpem.regrSteastsiisotnicaalnamlyestihso,dAsNuOseVdAt,o caonmdpPaeraersPoFnOcAorrleelvaetlisonand coefficients. PFOA was not highly correlated with any of the hormones or with the following covariates: age. alcohol consumption, BMI, or cigarettes. Most of the employees had PFOA serum levels less tHhoawnev1e0rp,pmh.eseInle1v9e93l.s roannlgyed12freommplaopypereosxihmaadtesleyru1m0 plepvmelsto>ov1e0rpp11m4, papnmd. 15Thienr1e99w5e.re onl4y employees in the >30 ppm PFOA group in 1993 and only $ in 1995. Therefore, itis likely that there was not enough power to deteet differences in eitherof the highest categories. The mean age of the employees in the highest exposure category was the lowest in both 1993 and 1995 (33.3 years and 38.2 years, respectively). Although not significantly different from the other categories, BMI was slightly higher in the highest PFOA category. Estradiol was highly correlated with BMI (r= 41, p< 001 in 1993, and r = 30, p< 01 in 1995). In 1995, all 5 employees with PFOA levels > 30 ppm had BMIs > 28, although this effect was not observed in 1993. Estradiol levels in the >30 ppm group in both years were 10% higher than the other PFOA groups; however, the difference was not statistically significant. The authors postulate that the study may not have been sensitive enough to detect an association between PFOA and estradiol because measured serum PFOA levels were likely below the eobmspelrovyaebelse ienfftehcits lsetvuedlys hsuagdgPesFtOedAisnearnuimmallevsetlusditheiss(h5i5gh.ppmThPeFyOalAsoinsutghgeeCstDthraatt).theOnhliygh3er estradiol levels in the highest exposure category could suggesta threshold relationship between PFOA and estradiol Free testosterone was highly correlated with age in both 1993 and 1995. "The authorsdid not report a negative association between PFOA serum levels and testosterone. There were no statistically significant trends noted for PFOA and either bound or free testosterone. However, 17-HP. a precursoroftestosterone, was highest in the >30 ppm PFOA group in both 1993 and 1995. In 1995, PFOA was significantly associated with 17-HP in regression models adjusted for possible confounders. However, the authors state tht this association was based on the results ofone employee (data were not provided in the report). There were no significant associations between PFOA and cortisol, DHEAS, FSH, LIL, and SHBG. "FTirhsetr,eaalrtehsoeuvgehratlhedreeswigenreis2susetsudtyhaytesahrosu(l1d9b9e3 naontded19w9h5e),ntehvealpuoaptuilnagtitohnesrweseurletsnoofttihnisdespteunddye.nt. Spairxttiyc-icpiagthetdaimnptlhoeyscteusdypairnti1c9i9p5a,tetdhiunsbroetdhucyienargs.theSepcoownedr,oftthehree swteurdey.31Thfeerweerweemrpelaolyseoevserwyhofew SeemcptlioonyaelesdeisnigcinothfetrhyeeasrtwudiythdoseesrunmotPaFlOloAw lfeovrealsnaglryesaitseorfttheamnpo1r0aplpimt.y Third, the crossof an association. Since tshoemhealbfi-olliofegiocfalPaFcOcAomimsoadtalteiasotn|tyoetahre, etfhfeecatusthoofrsPFsOugAg.estFotuhratth,it osnlpyososnieblseatmhpaltethwearse tmaakyenbefor n 000037 cach hormone for cachofthe study years. In order to get more accurate measurements for some. opfarttihceiphaontr.monFeifst,h,posoolmeedofbltohoed atsaskoecniaitniaonsshotrhtattwiemreepemreiaosdusrheodulidn thhaisvestbuedeynwuesreeddfoornecabcahsed on ttheestroesstuelrtosoneflaenvelesa.rliHcorwpeavpeerr,thtaottallisnekredumPoFrOgaAniwcitfhluionrcirneeawseadsemsteraasduiroledanidn tdheactrsetausdeyd instead of PFOA. makingitdifficult measurement error of some toofcotmhpeacroenftohuenrdeisnulgt.variFaibnlaelsl.y, there may have been some. In In 1997, voluntary medical surveillance this sampling period, cholecystokinin was again offered to employees (CCK) levels were analyzed in (Olsen, et al., 74 employees 19980). to determineif they were positively associated with serum PFOA levels. CCK levels were observed because research has suggested that pancreas acinar cell adenomas seen in rats exposed 10 PFOA may be the result of increased CCK levels. Seventeen of the subjects were common to all three sampling periods (1993, 1995. and 1997). The same statistical methods were used in this study period as used in 1993 and 1995. and the four PFOA exposure categories were also the "The mean PFOA serum level in employees participating in the 1997 study period was 6.4 ppm (range 0.1 - 81.3 ppm). The mean CCK value was 28.5 pg/ml (range 8.8 - 86.7 pg/ml). The hwiegrhees5t0C%ChKigvhaelruiens twheersee 2recpaotretgeodriiensthteha2n eixnptohseucraetecgatoergioersigersealetsesr than than 10 10 ppm. ppm The means (p= 06). nWehgeatnivaedjaussstaecdiaftoironpobteenttwieaelncoCnCfoKunadnedrsP,FmOuAlt;ivhaorwieavbelre,retghreedsastiaonwmeordeenlostiinndcilcuadteedd ianwtehaekreport The following explanations may indicate why this study failed to finda positive association between PFOA and CCK values: lis possible that the hepatocarcinogenic effectsofperoxisome proliferators in rodents do not act the The serum same biochemically in PFOA levels observed humans, in workers may have been (00 low to detect an effect. Effects in animals were observed at higher doses than mostof the serum levels found in CCwoKrkerrse.ceptors maybedifferent between rats and humans. Therefore, the monkey may be a more appropriate animal model to study the pancreatic effects of PFOA in humans, Theinvolvement ofCCK in the initiation or promotionofpancreatic cancer is controversial. Thsienceraatcimnaayr cneoltl bmealaingnaapnpcrioepsr.iaitnedmucoeddelbyincathrecisntougdeynosfipnanrcatrse,aatriecrcaarnecienrhiunmahnusm.ans, The same methodological issues that applied to the study in 1993 and 1995 apply to this portion ofthe study as well. 8 000038 323 Cholesterol Study aBnadseadltoenraatinoinmsalin tleisptiidngmewthaibcohlirsemp,oratecdrotshsa-tseacntiimoanlals.eoxcpcouspeadtitoonaPlFsOtAuddyewvaesloppehrfeopramteodmetgoaly dTeactleirym.in1e1i5fswiomriklearrsefwfeercetssatruediperdesteontdeitnewromirnkeerwsheetxhpeorsesdertoumPFPOFAO.A IanffaecPtEedOthAeiprrocdhuoclteistoenrol, elixppoopsroetdeitnos,PaFnOdAhefpraotmic1e9n8z5-y1m9e8s9(wGielrleilianndclaunddeMianntdheel.stu1d99y6().96F%orptayr-tciicgihptatwioonrkreatres). whSioxiwye-re ufinveexepmopsleodygereosupw.hoThietsheeremvoplluonyteeesrewderoer waesrseumaesdketdo 0havpaertliictilpeaoter,nwoePreFOinAcleuxdpeodsiunrethbeased on wthoerikrejrosbhdeasdcrPipFtOioAn.levHeolwsemvuecrh, wgrheeantersetrhuanm tlheeveglesnwerearlepaonpaullyazteiodn,.it wThaesrenfootreed,tihnastethaidsogfrjooubp of categories, total serum fluorine was used 10 classify workers into exposure groups. Tmoetaaslurseedr,umdufelutooritnhee wcoasst uosfaendaalsyzaisnugrotgheatseammpelaessu.reBlfoorodPFsOaAm.pleSserwuermePaFnaOlAyzweadsfonrototal Swearnusmamfilnuaorsiene(,SsGePrTu)m, gghaumammay!glouxatlaomnycettriacnstfrearnassaem(inGaGsTe).(ScGhOolTe)s,tersoelr,ulmogwl-udteanmsyi!typlyirpuovpircoteins c(aLtDeLg)o,riacnsodfhtiogtha-ldesnesriutym lfilpuooprrionteelienvsel(s:HD<L1).ppmAl,l o1f-t3hpepmp,ar>ti3ci-pa1n0tsppwme,re>1p0l.a-ce1d5 into five ppm, and > 15 phpma.olfTthhfee rwaonrgkeerofstfheel sinetroumthefl>uor1i-ne3 vpaplumescawtaesg.o0ry0, w2h6ilpep2m3(hmaedasne3r.u3mplpemv)e.ls<App1rpoxpimmaatnedly1'1 Had levels > 10 ppm. "uTnhievraeriwaetreeannaolyssiegnsiffiocracnhtoldeisftfeerroeln,ceLsDbLe,twaenednHeDxLp.osuIrnetcheatmeuglotriiveasriwahteenanaanlaylsiysz,edthuesrienwgas not a asilgcnoihfoilcacnotnassusmopctiiaotnio,nabgee,twBeMeIn,toatnadl sciegraurmettfelusomroinkeinagn.d cThhoelreestewreorlenoroLsDtaLtisatfiecarllaydjsuisgtniinfgicfaonrt dHiofwfeevreenrc,esinacmroeansgesthine eSxGpOosTuraendcaSteGgPoTrieoscocfurorteadlwsietrhuimncfrleuaosriinnge tfootralSGseOrTu,mSfGluPoTr,ineanldevGeGlsT.in obeseworkers (BMI = 35 kg). mSipnlcoeyPeeFsOA(egw.aslennogtthmoefaseumrpeldoydmireencttelxypaonsdurteh)e.r tihsenoreseuxlptossouftreheinsftourdmyatpiroonvipdreovliidmeidteodn the ienefonrmoabtsieornv.edThinetahuetsheoresmpsltoatyeeetsha;thnooweavdveerr,seit cilinnoitcaclloeaurtcthoamtetsheerleatheads tboeePnFfOoAlleoxwp-ouspuorfe have wfiordmeerfoermmpalnoyyeosf.theIneaxdpdoistuirone,ctahteegroarniegse,oifnrdeiscualttisngrevpaorritabeidliftoyr tinhethleivreersuelntsz.ymGeisvewnertehatfaiorllyy otonehasvaempsleveerwaalsstaamkpelnesfrtoamkeenacohveermptlimoeyeteo,enthsiusriestnhoetirsruerlpiraibsiliintgy.. 1I waolusoldwobuelmduhcahvemobreeenhelpful tihnotesreeswthinog wtoerceomorpiagrienatlhley trehsouulgthstofnotthetowoberkeexrpsowsehdofwoesrceeikfntohwernetwoebreeeaxnpyosdeifdfteorePncFeOsAam0ong x 000033 the employees participating in in these groups. the study than There were moreof those who worked in the "unexposed" employees PFOA production (1 =48). (n = 65) 3.2.4 Study on Episodes of Care (Morbidity) aInn o"redpeirsotdoegoafincaardedi"tainoanlalysiinsswigahst uinntdoerttheakeefnfeacttsthoef Dfelcuaotruorchpelmainctatloesxcproeseunrfeoronmowrobrikdeirtsy" health, outcomes that may be associated with long-term, high exposure to fluorochemicals. An "episode ofcare ias series of health care services provided from the startofa particular disease or ecomnpdliotyieoensu"nthielalstohluctliaoinmosrrreecsoorldustiuosnionfg CthlaitnipcraolbCleamr.e GErpoiusposde(sCoCfGc)arseofwtewarree.ideAnltlifiinepdatinient and uoustepdatiinetnhtevdisiiatgsnotsoihse,alttrheactamreentp,roavniddemras,napgreocmeednutroesf,oavnecril4la0r0ydsiesrevaisceess oarndcopnrdeistciroinpstiwoenrderugs racked. wEpoirskoeddesaotftchearDeecwaetruer apnlaanltyzfeodr aftorle6a5st2 1chyeemaircbaeltewmepelnoJyaeneusaraynd1.651999f3ilamndplDanetceemmpbleorye31e.s 1w9h98o, GBraosuepd Aoncwonosrikstheidsotforayllrefciolrmdsa,ndemcphleomyieceasl pwlearnet pwloarkceerds;intGordoiuffper1enhtacdoempmaprliosyoenesgrwohuposo:nly wwiotrhkehdigihnPciOtShFeretxhpeosfiulrmeso;r achnedmGircaolupplDanth;adGreomupploCyeceonsswishtoedwoofrkeemdplionyheiegshwehxpoowsuorreksedinitnhjeobs ccohnesmiidcearledpltaonthafvore 1l0ityleeaorrsnoor fmlouroeropcrhieormitcoatlheexopnosseutroef, wthheilsetucdhy.emiFciallmppllaanntteemmppllooyyeeeesswweerree assumed to have the highest exposures. nRautmiboesrosfowbesreerbvaesdedtooenxp3e'ctsedemeppilsooydeeesopfopcualraetiwoenreexcpaelrciuelnacteedusfionrgeaicndhirpelcantt.staEnxdapredcitzeadtion ptleacnhtn'isquoebss.erAverdattiooeoxfpetchetecdheemxipcearlipelnacnetw'sasobcsaelrcvueldatetdo etoxppercotveiddeexapererliaetnicvee rdiisvkidraetdiobyforthceacfihlm oefpciasordeetohfatcwareere(oRfREgrPeCa)t.est95in%terceosntfwiedernectehionsteerwvhailschwehraedcbaelecnulraetpeodrtfeordciancahniRmRaElPoCr. Episodes eipnivdolevmiinoglotghiectlhiytreoriadtugrleaonnd aPnFdOSlipainddmePtFaObAo:lislmi,vedriasnorddebrlsaoddferthecanlicveerr,aennddobcirliianreydtirascotr,dearnsd reproductive disorders. "tThheemoanlleyrienpcrroedauscetdirviesksyosfetpeimsaonddesforfotrhtehoevseercaolnldciattieognosryoofafpcrainocreirisntaenrdestbewneirgen fgorronwetohpsl(awshmischof tihneclouvdeerdalclacnacnecreorfctahteegmoarlyefroerparlold4ucctoimvpeasryisstoemn).groTuhpse.re Twhaes rainskirnactrieoawseads rgirsekaotfesetpiinsotdheesgfroorup o1f.e2m2p.l1oy)e.esIwnictrhetahseehriigshkesotf aenpdisloodnegsesitn elxonpgo-stuirmees, thoigfhl-ucorxapcohseumrieceamlpsl(oRyReeEspCals=o1w.a6,s9r5ep%orCt1ed cfoornfmiadleencreepirnotdeurvcatlivies vcaenrcyewrisd(eRfRoErPmCal=e9r.e7p,ro9d5u%ctiCv1e=ca1n.c1e-r4s5a8n)d. tIhtesshuobu-lcdatbeegnoortyoedftphraotstthaete 6 000040 cancer. Five episodesofcare were observed for reproductive cancers in chemical plant employees (1.8 expected).of which 4 were prostate cancers. One episode of prostate cancer was oexbcseesrsveidn ipnrofsitlamteplcaanntceermpmloortyaeleisty(3w.a4sexopbescetredv)e.d iTnhtihse fCiontdtianggesGhoruolvdebpelannottemdorbtealciatuysestaundy when there wer only 2 exposure categories (chemical plant employees and film plant employees). The update of the study sub-divided the chemical plant employees and did not confirm this finding when exposures were divided into definitely exposed and probably exposed employees. There was an increased riskof episodes for neoplasms of the gastrointestinal tract in the high exposure group (RREPC = 1.8, 95% C1 = 1.2-3.0) and the long-term employment, high exposure group (RREPC = 29, 95% CI = 1.75.2). Most of the episodes were attributable to benign colonic polyps. Similar numobfeepirsodses were reported in film and chemical plant employees. In the entire cohort, only 1 episoofcdaree was reported for liver cancer (0.6 expected) and | for bladder cancer (1.5 expected). Both occurred in film plant employees. Only 2 casesofcirthosis of the liver were observed (0.9 expected). both in the chemical plant. There was a greater isk of lower urinary tract infections in chemical plant employees, bu they were mostly due to recurring episodesofcare by thesame employees. I isdifficult to draw any conclusions about these observations. given the small numofbepiesodres reported. mChoermeicliaklelpylatontseeemkplcoaryeeefsoridnitshoerdheirgshofetxphoesubriel,iarlyontgr-acttertmhaenmtphleiorymcoeunnttegrrpoaurptswienrtehe2 f%iltmipmleasnt e(mRpRlEoPyeCe=s a2.n6d,9154%inCflil=m p1l.a2n-t5w.o5)r.kerEsi.ghtTeheenseupbi-scoadteesgoofrcieasrethwaerinefolubesnecrevdedthiisn ocbhseemrivcaatliopnlant were episodesof cholelithiasis with acute cholecystitis and cholelithiasis with chronic or unspecified cholecystitis. Most of the observed cases occurred in chemical plant employees. Risk ratiosofepisodesofcare for endocrine disorders, which included sub-categoriesof thyroid disease, diabetes, hyperlipidemia, and other endocrine or nutritional disorders, were not clevated in the comparison groups. Conditions which were not identified a priori but which excluded the null hypothesis in the 95% confidence interval for the high exposure, long-term employment group included: disordersofthe pancreas, cystitis, and lower urinary tract infections. "The results of this study only should be used for hypothesis generation. Although the episode of care design allowed fora direct comparison of workers with similar demographics but different exposures, there are many limitations to this design. The limitations include: 1)episodes of care are reported, not disease incidence, 2) the data are difficult to interpret because a large RREpC may not necessarily indicate high risk of incidenceofdisease. 3) manyof the risk ratios for episodesof care had very wide confidence intervals, thereby providing unstable results, 4) the analysis was limited to 6 years, 5) the wtlization of health care services may reflect local medical practice patterns, 6) individuals may be counted more than once in the database because they can wo 000041 be categorized under larger or smaller discase classifications. 7) episodesofcare may include the osnamleonign-dtievridmudailsasbeivleirtayl 9t)imtehse.a8n)alnyostisalml aeympbleoyfiemeistewdebrye tihneclsuodfetdwairnetuhesedda,tawbhaisce.h such may as those. misclassify episodes of care, 10) the software may assign 2 different diagnoses to the same episode, and |1) certain services, such as lab procedures may not have been reported in the database. 3.3 Acute Toxicity Studies in Animals 33.1 Oral Studies The acute oral toxicityofAPFO was tested in male and female rats in three studies. Death uocpcounrrneedcratopcsoync(eknitdrnaetyi,osnsto2m4a6c4h,mugt/ekrugs)(Iwnetremeato'blseRrevsedan(dGlDazeav, C1o9r9p7.),at193780)0. mAgb/nkogrm(hailghfeirndings. concentrations were not tested). Clinical signsoftoxicity observed in these three studies included the following: red-stained face, stained urogenital area, wet urogenital area, dhyepcoraecatsievditlyi,mhbutnocneh,edatpaoxsiat,urceo,msetaalggoepraecditgya,ila,nedxcheyspsoitvheesramliivcattiootn,oupclho.sis, piloerection. Itnatsonweersetu6d8y0(Imngt/ekragt'(l39R9es-- a1n1d57Demvg/Ckogrp9.5%19c7o8n)f,itdheencorealliLmiDt)SOforvamlauleess;fo4r3C0hamrgl/eksgRi(v2e9r5CD626 mlimiet) f9or5m%alceosnfainddenfceemalliemsi.t)Tfhoer freemmaaliensi:nagntdw5o4s0tumdgi/eskgpr(o3v8i9d--ed7L49DmSavkaelu9es5o%f(c1on)f>i5de0n0ce (mGya/zkae,1fo9r97m)a:leanCdr(:2C)D<(1S0D0)0BmRg/rkatgs,faonrdma2l5e0-a5n0d0fmemealke Sfhorerfmeamna-lWeiCsrtlar:CrDat(sS(D3)MBRCoramtpsany. 19760). 332 Inhalation Studies Tdohseealceuvteel ionfha1l3a.t6iomngt/oLxi(cniotymoinfaAl PcoFnOcenwtarsattieosnt)e.d ainndmaelxepoasnudrefedmuraalteiSonproafgounee-Dhaouwrl.eySiragtnss. aotfa Tsoaxlivcaittiyo,nd,ureixncge,ssainvde ulpactroim1a4tidoany,sdaefctreeratsheedeaxctpiovsiutry,e lpaebroiorde,d ibrnecaltuhdiendg,thgeasfpoilnlgo,wicnlgo:seexdceeysessi.ve mucoid nasal discharge, irregular breathing, red nasal discharge, yellow siainingof the anogenital fur, dry and moist rales, red material around the eyes. and body tremors. Upon Bneacsreodpsoyn, tlhuensgtduidsycorleosurlattsi,onthweatsesotbssuebrsvteadncienawahsignhoetrftahtaaln tnoorramtaslatiancniodmeinncealofexrpatossu(8r/e10). concentration of 18.6 mg/L and exposure durationofonehour (Bio/dynamics, Inc. 1979). * 00042 333 Dermal Studies The acute dermal toxicity ofAPFO was tested in male and female Hra(NZW)SPF rabbits, at a dose levelof 2000 mg/kg, anda 24-hour exposure period. All animals appeared normal and exhibited body weight gain throughout the study, with the exception of one male that lost weight during the first week. Dermal iriation consisted of sight to moderate erythema, edema, and atonia: slight desquamation: coriaceousness: and fssuring. No visible lesions were observed upon necropsy. The dermal LDSO in rabbits was determined to be greater than 2000 mg/kg (Gilaza, 1995). 334 Eye lrritation Studies "The eye irritation potential of APFO was tested in albino rabbits, at a dose level of0.1 gram. In twoofthree studies, APFO was determined to be a primary ocular iitant. In the studies in which APFO was found to be a primary ocular iitant, APFO was left in contact with the eye for 7 days. then rinsed, or not rinsed. Imitation scores varied during the observation period. Imitation scoresofthe conjunctivag, iris, and comea ranged from 2 4 in one study (Bioscarch, Inc. 1976) and from 2 10 in the other study (3M Company. 1976). In both studies, imitation remained evident for the durationofthe observation period (7-days post-cxposure). In the study iin which APFO was determined to be a non-iritant (Gabriel), the test substance was left in csocnatraecstwweirteh rtehpeoretyeedffoorr5coonrj3u0ncsteicovnadsir,riatnadtiotnhefnorthuep etyoe7s-wdaeyrse proisntse-de.xpIonsuthries,sstoudtyh,epaoustthiovr'es negative conclusion for ocular iritancy is problematic 335 Skin Irritation Studies The skin irritation potentialofAPFO was tested in albino rabbits in two studies, at a dose level 0F0.5 grams, under occluded test conditions. In one study (Riker Laboratories, Inc. 1983). APFO produced irreversible tissue damage in female rabbits, following a 3-minute, 1-hour, and 4-hour contact period. Moderate erythema and cdema, as well as chemical bum, eschar, and necrosis, were observed following all three contact periods. An endpoint was not achieved in this study du to extreme irritation following each contact period. In the second study (Gabriel), APFO was reported as a non-irritantofskin after an exposure period of 24 or 72 hours, based on primary irritation scores of zero. 3.4 Mutagenicity Studies APFO was tested twice (Lawlor, 1995; 1996) for its ability to induce mutation in the Salmonella E colifmammalian-microsome reverse mutation assay. The tests were performed both with and without metabolic activation. A single positive response seen at one dose level in S. ntoytphiinmduurceiummutTaAt1i5on37inwehitehnerteS.sttedypwhiitmhuorutiummetoarbEo.liccolaicwtihveantiotneswteadseniottherrewpriotdhucoirblwei.thoAuPtFO did mammalian activation. 000043 A`nPdFwOitdhiodutnomtetianbdoulcieccahcrtoimvaotsioomnaulpatboercryattoitoonxsici covnicrerontirnahtiuomnasn(Mluyrmlpi,ho1c9yt9e6s;wNhOeTnOtXes.te2d0w00i)t.h AnPthFeOfwiastsatsessatye,d AtwPiFceOfionrdiutsceabdilbiottyhtcohirnodmuocseocmharlomaobesrormaatlionasbearnrdatpioolnsypilnoCidHyOincbeloltshitnhevitro. Cphrersoemnocseoamnadlabasbeernrcaetoiofnsmewtearbeoloibcsearcvtievdatwiiont.houI t the second activation. aHsoswaey,venro,swighneinfictaenstteidnwciretahses in metabolic activation, APFO induced significant increases in chromosomal aberrations and in polyploidy (Muri, 1996b). eAmPbFrOyowafisbrtoebsltaestds.inaThceelcetlrlatnrsafnosrfmoartmiaotniaonndwcaystodteotxeircmitiyneadssaasybcootnhdcuocltoendyitnrCanHsfo1r0mTa;tiomnouansde Ttoecsitetdriannscfiotrhmerattihoencpooltoenntyiaol.r fTohcieraesswaaysmneotheovdisde(nGcaerorfyt&ranNseflosornm,at1i9o8n1a)t anyofthe dose levels. ASiPgnFiOficwaants itnecsrteedastewsiicnemiinctrhoenuicnlveiivoanmdouwsaes mciocnrsoidneurceldeunsegaastsaiyv.e uAnPdeFrOthdeidcnoont dinidtucoiefoatnnhyiss assay (Muri, 19960). 3.5 Subchronie Toxicity Studies in Animals nTcw.o(uMnepturbilciksahnedd 2M8ar-idaasy,f1e9e7di7nagnsdtuCdhireisswteoprheerpearnfdorMmaerdiaast,In1d9u7s7t)r.ialInBbioot-hTersatsLaanbodrmatiocreietsh,e liver was the target organ. In rats. males had more pronounced hepatotoxicity and histopathologic effects than females. Ifenmaal2e8s-dwaeyrestsutduydoiefdC(hMRe-tCrDic)kaalnbdinoMarraitsa,s,ei1g9h7t7)r.andAoftmelryraastssiwgenreed aglrloouwpesdoftofiavceclmiamlaetse afonrdafive w1e0,e0k00i,noirnd3i0v,i0d0ua0lpcpamgeAsPthFeOy tfhoren28redcaeyisv.edAstimtihlearbefgeiendncionngtaoifntihnegs0t,ud30y,th1e00a,ni30m0a,ls1a0v0e0,ra3g0e0d0, w8eiggrhtasmsanfdorfmoaoldecsoannsdum7p6tigornamwserfoerrfeecmoarldese.d w`eTehkelayn.imAanlismwaelrsethoabtsedrievdeddudraiilnyg atnhedsbtouddyy were eixncalmuidneeddafcoormgprloestsepeatxhaomliongayt,ioansowfegrreossusrvpiavtihnogloagnyimaanldsaatco2m8pdlaeytse. seIttoifsttiastseudesthaantdthoergsatundsy owregraenewxeaimgihntedt,hebnutsttahienesdpefcoirfhiislitsotpaisthnooltosguipcpleixeadm.inaLtiivoenr.s were weighed to determine relative Awelreanniomaplrsemianttuhree1d0e,a0t0h0saonrdot3h0e.r0c0l0i-nipcpaml sgirgonuspsofditoexdicbietfyorien tthhee eotnhdeorfgtrhouepsf.irstBwoedeky.weTihgehrte gsaiinnswweerreearlseoduocbesderivnetdheingrmoaulpess reexcpeoisveidngto1030000oprpmmoraendppmma.lesSlaingdhtferemdaulcetsiofnesd i1n0b0opdpym.weight Reduced food intake was observed in ats fed 1000 ppm or higher ina dose-related manner. "0 000044 Rmoerlea.tivGerloisvserpwaetihgohlotgsicwaelreexiancmredaisdednotinrmeavleaels tfreedat3m0enptp-rmeloartemdorefefeacntds ifnemkaildenseyfsedor30o0thperpm or oarngiamnaslsbefseidd3es00lipvperms,. aFnodcalmutlotimfuolctailfoocaldicfyftusoepleanslmaircgeemnelnatrgoefmheenptaotfochyetpeastowcaystensotweadsinnoatneidmainls fed 1000 ppm or higher. These effects were more pronounced in males (Merck and Marias. 1977) Imanlae2s8a-nddayfisvteudfyeomaflCehsarwleerse sRtiuvdeire-dC(DCharlibsitnoopmhiecrea,nedigMhatrirsaan,do19m7l7y).asAsfitgenredmgircoeuwpesroefaflilvoewed t3o00a,cc1l0i0m0a,te30f0o0r,d1a0y,0s00i,n oirnd3i0v,i0d0ua0lpcpamgeosftAhePyFtOhefnorre2c8eidvayesd.siAmitlatrhefbeegdinconnitnaginoifntgh0e, s3t0u,dy10t0h,e daaniilmyalasndavbeordaygewdei$g8htgsraamnsd ffooromdacloenssaunmdpt7i6ongrwaemrse froercofermdaeldesw.eekTlhye. anAinmiamlaslswetrheatodbiseedrvdeudring Ithhee ssttuuddyy winecrleudeexdamaicnoemdplfeotregreoxsasmipnatahtoiloongoyf, garsowsesrpeatshurovliovgiynganadniamraelpsreaste2n8tadtaiyvse.settiosftistsastueeds daentdeorrmgiannesrwelearteiveexoarmgiannedw,eibguhtttthheesnpesctiafiincedlifstorishinsottospuaptphloileodg.icLeixvaemrisnawteiroen.weighed to A`glroaupnidmiaeldswiinthtihne 21600d0a-ysppemxcaenpdt h|igmhaleer.grOonupesadniiemdalbeifnoreeacthheofetnhdoef30d.aaynd9.1T0h0e-pepntmirgero3u0p0s-ppm dPiFeOdAp.remAattu1re0l0y.ppmClsinoimcaelasniigmnaslwseerxehiobbisteerdvceydanionsmiiscoenedxapyosse1d0.taon1d0011popfmteasntidngh,igbhuetradppoesaersedo.f normal throughout muscularweakness the as wreelstloafstshiegnsstuodfy.cyaAnnoismiaslsaffteee9rdd3a0y0spopfmtreexahtimbeintt.ed Aronuigmhaelds ffuerd a1n0d00 ppm exhibitedsimilar effects after 6 days and those receiving 3000 ppm or greater doses exhibited effects after 4 days. iAnllmimciecefefded30A,P1F0O0, lost weight. or 300 ppm. RAedduocstei-orneslaitnedbopdayttweemigwhatsgsaeiennwienrethfeodlelporweesdsebdy weight losses. body weights. Rpaetlhaotliovgeiacnald aebxsaomliuntaetiloivnerofwkeiidgnhetyssweorreotihnecrreoarsgeadnsinbmesiicdeesfeldiv3e0rspips mnootrdmisocruessAedP.FOT.reGartomsesnt reenllaatregdecmheanntgaensd/woerrdeisocbosleorrvaetdioinn othfe1loirvemrsoarmoinvegralllobAesP.FOHitsrteoaptaetdhoalnoigmiaclsexianmcilnudaitnigon ofall '(pAaPnFOlotbruelaatredhympiecretrroepvheya)leadccdiofmfpuasneiceydtobpylafsomcialc teonlmaurltgiefmoecnatl ocfythoepplaatsomciyctevsatchurooleusghout the liver Degeneration and for necrosis of hepatocytes and focal bile duct proliferation were also noted in mice within all groups (Christopher and Marias, 1977). T(Ghorledeen9t0h-adla,y1s9u7b8c4h)r,oonnice twoaxsicciotyndsutcutdieedsihnarvheebsuesenmoconnkdeuyctsed(.GolOdennethwaals, c1o9n7d8ubc)taendditnhreattshird was conducted in malerats(Palazzolo, 1993). a 000045 3In.1t0h,e 3m0onokre1y00stmugd/y,keG/odladyenptehrafllu(o1r9o7o8cbia)naodimcinaciisdte(rFeCd-r1h4e3s)usinm0o.n5k%eyMset(h2o/cseexl/7grboyupg)avdaosgeesofofr07, abaysseidsvuepeoknftohre9w0edeakyls.y bAoldlydowesiegshtwse.reAgniivmeanlsinwaecroenostbasnetrvveodlutmweisceidnadiilvyidfuoarlgdeanielryaldopsheyssiwcearle appeprefaorramnecdedaunrdinbgethhaevicoorntarnold ppehrairomdacaontdomxoinctshilgnys.durGienngertahle spthuydsyicpaelrieoxda.miInnadtiviiodnusalwebroedy wpeeriigohdtsanwderaet r| eacnodrd3edmownetekhlsy.of Bthleoostduadyndfourrihneemastaomlpolgeys.wcelrieniccaolllcehcetmeidsotnrcyeadnudriurnignatlhyesicso.ntrol tMiosnsukeesyfsrowmeraenifmaasltesdtohavterwneirgehtsapcrriiofritcoedthate cthoelleenctdioofnotfhebsltouoddyaannddufrrinoemsaanmipmlaelss. thOartgdainesd and dhuisrtionpgatthhoelotgrye.atmHeinsttpoepraitohdolwoegryewwaesigpheerdf,oermxeadmionnedthefofroglrlooswsinpgatohroglaongsy farnodm saallmpmloensketaykseninfotrhe c{ownittrholcoarnodnatrryevaetsmseenlts)g,roduiposd:eandurme,nalisl,euamor,tja,ejbuonnuem,, bcreaicnu,me,scooplhoang,usr,ecetyuems,, kgiadlnlebylasd,dleirv,erh,ealrutng. Smkuisnc,lem)e,sesnptleereinc, playnmcprheanso,dper,osrteattreo/puhtarruysn,geiabljluynmctpihonno(dbeo,nemammarmraorwy),gslaalnidv.arnyergvlean(dw,itlhumbar stpoinngaule,courrdi,naprityuibtlaardyd,ers,tovmaagcihn,a,teisdteenst/iofvyairnigest,attthoyor,oiadn,dpaanryatthiysrsouieds,(st)hwyimtuhs,letsrioancsh.ea, tonsil, Awlelemko2n:kaellysaniinmathles 1w0e0r-emdye/akdg/bdyaywegerkou5p.s dSiiegdnsduarnidngsytmheptstoumdys.whTihcehffiirrssttdaepapteharoecdcudrurreidndguring wsuemesk. 1 swioncllluednedfaacneoarnexdieay,esf,rostlhiyghetmetso issevwehriecdhewcraesasseodmeatctiimveitsy,brproowsntrianticoonloarn,dpbaloedyfawceemabnlding. 7Tharnedetmhoentkweoysfefmraolmesthdeie3d0-dumrgi/nkge/wdeaeyksgr1o2upanddie1d3.duBreinggintnhiensgtuidnyw;eoenke4m,aallel dfoiucrdadnuirmianlgsweek sanhdowaetadxisal,igshwtotlolemnodfearca,teeyaensdasnodmevtulivmae,s-assewveelrleadsepcarlelaosreodfatcthieviftay.ce aOnndegmuomns.keByeghiandneimnegsiins week 6, two monkeys had black stools and one monkey had slight to moderate dehydration and ptosis of the eyelids. N`moymkogdnakye-ydsoisnethgero3uporoc1c0asmigo/nkagl/ldyahyagdrsooufptsstdoioeldsdourrimnogdetrhaetsetutdoy.marAkniemdadlisarirnhetah;e 3f-rothy e`amneosriesxiwcadsurailnsgo woceceaksi4o,nhalaldyanpoatleedainndthsiwsoglrloeunp.facOeneinmwoenekke7yainndthhead10blmagc/kksgt/odoalys gforrosuepvewraasl ays in week 12. The other animals in the 10-mg/kg/day groups did not show any unusual signs or symptoms. Cdohsaenggerosuipns.boMdoynwkeeiygshtfwreormetsheim3i0laarn0d t1h0e0cmogn/trkogl/sdafoyrgarnoiumpaslslofstrobmodthyew3eiagnhdt1a0ftmerg/wkege/kdaIy. `Atthe endofthe mg/day group study. (2.30 this loss was kg vs 3.78 ke statistically significant for the control). for the one surviving male in the 30- 2 000046 Htheem3ataonldog1y0 vmagl/ukegs/dataythgereounpdso.f Athte 310amngd/k3gm/doanyt,hsthoefsturrevaitvmienngtmwaelreehsaidmidleacrrfeoarsethdencuomnbtreorlsaonfd {eirmyetharoncdytaecst,ivdaetcerdeparseodthhreommobgilnobtiimne, dweecrreeaalsseodihnecmraetaosecdr.it,Thaensdeiinnccrreeaasseedspwleatreeleatsp.paPrreontthartom| bin `month but were much more marked at three months. F(1o1l7lovw3in8g9omnge/1m0o0ntmhioifnttrheeatcmoentnrto,lg).luTcohseeawuatshosrisognfiftihceanrtelpyoerlteavtattreidbuitne tthheis3t-omay/skigng/ldeayhiggrhoup vsarlouuepsfohramdlaelvee#l7s3o6f61w12h,o1h0a5d, aanvdal1u2e0o-fme1/311.00Tmhi.e oGtlhuercotshereleemveolnskienytshein1t0haen3d-m3g0/mkgg/rdkagyday rmoonutphsswoefrtere1a0t4meanntd, g1l2u2c-omseg/l1e0v0elmslw,erreesp8e1c,ti9v6e,ly8,,afatnrdo6n6e-mmgo/n1t0h0omftireianttmheentc.ontArtolt, h3,e10 and 30 my ke/day groups respectively. "iTnhtehree cwoanstraold)eactreoanseemionnatlhk,alsienheicphhopseprhsaisttaesdeilnevtehlesoinnetshuer3v0iv-imnggkmea/ldeay(3g6r0ovusp8(53165IUv/sL5i9n7thUe1 cmoonnttrhols)waetr3em7o5n3thasn.d A7l4k3alUiAnesphhoowsiphnagtaasdeoslee-vreelslantedthtere3n-datnodwa1r0dmdge/ckrge/adsaeydglrevoeulps.s at three ScoGntOrTol)leavnedlsiwnetrhee roendeuscuerdviivnitnhgem3a0l-emgat/k3g/mdoanythgsro(u8p8svast4o5ne1Um/o1nitnhth(e59covntsro2l9).1US/GPinTthweas c1le0vaitnedthiencboonttrhotl,he1100aanndd3300mmgg//kkgg//ddaayygdroouspesg,rroeusppesctative|lmy.onSiGOthTe lleevveellss iwnetrhee 1150,-3m4g,/akngd/d4a4y Cglreovuaptewderinetchoemopnaerasbulrevitvoitnhgemcaolnetrionlsthaet 330m-omn/tkhgs/(d3a4yvdsos31e gIrUoupin(t4h6e1cUo/n)trol) but were sill Cmheo/le1s0t0ermo)lainndthteotoalneprsoutreviinvainngd maallbeumiinnthien 3th0ismagn/ikmga/ldawyergeroruepduwcaeds.cTlootvaaltepdro(t2e4i0n vwsas1655.52 vs control level of 8.21 /100 ml and total albumin was 2.00 vs control level of 4.82 /100 mi. "There were no treatment related changes in urinalysis studies at any time period studied There Study were no or which mwaecrreosscacorpiifcicleedsiatontshenoetnedd oafttghreostsrenaetcmreonptsypoerfioadn. y animals which died during the "rTehleatfivoellwoewiignhgtcohfatnhgeesheianrtasbsionlufteemaalneds rferloatmivteheor1g0amnew/ekieg/hdtacyhagnrgoeuspwweerree dneoctreeda:saebds:oalbustoelautned bwreaiignhtwoefitghhteofpifteuimtaalreysinfrmaolmetshifsrsoammteheg3romugp/wkegr/edaaylsgordoeucprewaassedinacnredasreedl.atiTvheegrsoigunpifmiecaannce of these weight changes is difficult to assess, as they were not accompanied by morphologic changes. 000047 Ogrnoeupmahlaedamnadrtkweod dfiefmfaulseeslfipriodmdetphele3t0iomngi/nktgh/edaadyregnraolsu.p aAnlldmalallaensiamnadlsfefmraolmesthfer1o0m0tmheg/3k0g/adnady m1o0d0emraytkeea/tdraoyphgyrooufplsyamlpshoohiaddfsollilgihctletsoinmotdheersaptleeehny.poOcneellfuleamrailtey forfotmhethbeon3e0-mmagrkrgo/wdaayndgroup athnedlalylmapnhimnaodlessi.nNthoeo1t0he0r-mcgo/mkpgo/duanydgrreolautpedhaldesmioondserwaetreeastereonphiynoaft tthhee3l0y.mapnhdoi1d00fomlgl/icklge/sdiany groups. No treatment related lesions were seen in the orgofaaninmasls from the 3 and 10 mykg/day groups. DTohseeleveSlesroufmP(FpOpmA)in the serLuimvearnd(plpimve)r ar presenLtievderbetlotoawl.(ug) 0 Males Np Females 1 ~~ Males 00s Females 007 3300s08s6s N3D 7ND 04s 07 7 7 9 ND ND 10 30 ND ND 0 145 ND ns os 60 125 100 ND ND 00 325 Males Females 3s 250 350 ND ND 600 ND ND 750 5000 7500 4000 9000 6000 20000 I1n0,t3he0.fi1rs0t0,ra3t0s0t,udayn,dGo1l0d0e0npthpaml p(e1r9f7l8u5o)roaodcmtianniositceraceidd.CDTrhaetsse(5d/osseex/legvreoluspa)rdeiaeptaprryoxliemvaeltseloyf0, e7q6u.i4v7almeenktg0/d0a.5y6,in 1f.e7m2a,le5s..64, A1n7i.m9,alasndwe6r3e.5hmogu/skegd/idnadyiviindumaallleys,inawnidr0e.m74e,s2h.3c,a7g.e7s, a2n2d3h6adanfdree access to mortality. food and Detailed weaxtaemri.naAtniiomnaslswewreerpeeorbfsoerrmveedd twice once a daily forsigns of week. Individual toxicity and body weight for and food cSoanmspluemsptwieornewceorlleercteecdordduerdinwgeetkhelyprdeutresitngpetrhieopdreatnedstatan| datnrdea3tmmenot npertoifohdtshs.e Blood study and for urine hSheimpipteodlotgoythaendspcolnisnoicralfocrhaenmailsytsrisy,apnodolureidnasleysrius.m At week samples. 13, sex Organs and and group. tissucs frozen and from animals that wpeerrieodsawcerirfeicweediagthethde,eenxdamoifntehde sftorudgyroasnsdpfartohmoltowgoy afnedmaslaemsptlheast tdiaekdendufrorinhgistthoepattrheoaltomgeyn.t H1i0s0t0oppaptmhodloosgey gwraosuppse:rfborarimnedwiotnh tcheervfioclallocwoirndg,olrugmabnasrfsrpoimnarlatcsorfdr,opmetrhiephceornatlronle,rv1e0,0,ey3e0s0., and pIinteusietnatreyr,itchlyryomipdhwniotdhep,atrahtyhmyurso,idb,oanderewniatlhs,malurnrgo,whe(asrttewmiutmh),cosraolniavarryyvgelsasnedls,,samoarltla,instpelsetian,es (prdousotdateen,uumt,erjuesj,usnkuimn,(imlaeummm)acroylognl,anpda)n.craenays,tilsisvuere,(sk)iwdintehysg,rousrisnlaersyiobnlsa.ddLeirv,ertsestferso,movraartsiefsr.om tdhoese10graonudps30w-eprpemfrdoozseen garnodupssenwtetroetahlessopeoxnasomrinfeodr microscopically analysis. and liver samples from all a" 000048 TOhneesefedmeaaltehsinwtehree1n0o0t acnondsoidneerefdemtaolebeintrtehaet3me0n0t-rpeplmategdr.ouApllditehdedrurainnigmaclosllseucrtivoinvoefdbulnotoild. scheduled sacrifice. VTshe4r6e6wgasinathseigcnoinftircoalntgrreoduupc)t.ioFnoiondmceoannsubmopdtyiowneiwgahst rinedmuacleedsiinnmtahlees10i0n0t-hpep1m0g0r,o3u0p0(a3n6d2 1000-ppm groups, butthedifferences were not statistically significant eMrayltehsroicnyttehse a3t0,th1e0e0,nd3o0f0 tahnedt1re0a0t0m-epnptmpegrrioodu.psThhaed vsaiglnuiefsicwaenrtely7r.9e5d.uc7e.0d5.nu7m.b16e,rs6.o7f2, and 6.94 vinaltuheescconotmrpoal.re3d0,to10t0h,e3c0on0taronlds 1in00al0l-dpopsmeggrroouuppss,,rbeustpewcteirveelsyt.atiMstailcealslyhsaidgnriefdiuccanetdaltetuhkeoc3y0t0e ppm group only; 30. 100, 300 and leukocyte 1000 ppm values were 10.64, 8.88, groups, respectively. A 9.33. 9.35, 7.63, and similar phenomenon 8.06 in the control. was seen with 10, dhoesmeoglleoveblinonlvya.luHees,mowghilcohbiwnevraelrueedsucweedreat all, dose levels but were significant at 16.2, 14.7, 15.0, 15.4, 14.9, 13.1inthe the 10-ppm control, 10. 30, h1e0m0a.t3o0l0ogaincdal1p0a0r0ampeptmergsrooufpfse,mraelsepercattisveilny.theTshteudrye. was no similar effect upon the. wMhailcehs waterthees3t0at,is1t0i0c,al3ly00s,igannidfic1a0n0t0a-tpapllmbduotstehele1ve0l0s-hpapdmidnocsreealseevdelg.lRuecpoosertleedvegllsu(comsge/1l0e0velmsi), were 121, 120, 136, groups. respectively. 134, 143 B.U.N. and 135mg/100 mi for levels were elevated in the0, males 10, 30 at the 100, 300 100, 300, and and 1000 1000 ppm ppm dose rleevseplesc:timveelayn, cvaolmupeasraetd90tod1a6y.s2wmegr/e12000.4m,i2f3o.r9tahnedco3n5t.r1olsm.g/A1l0k0almiinefoprhtohsephtahrteaesedowsaesgerloeuvpast.ed tiihnrmeaelgersouipnst,here1s0p0e,ct3i0v0e,lya,ncdom1p0a0r0e-dpptom 1gr0o4upIsU; tfhoerltehveelcsonwterorles.14F7,em2a0l4esansdho2w12edIUn/oL sfiomritlhaer changes in biochemical measurements. aNelitthhoeurghmafleemsalneosrffreommalalelsgsrhoouwpesdshanoywetdreaathmiegnhterreflraetqeduecnhcaynogfeoscciunlutribnlaloyosdisinpathreamuertienresthan did males. aTnhiemaolnslyhagrdoesnslnaercgreodplsiyveorbsstehravtastihoonwewdasvanroytiendgidnemgarleeess oatftshuerf1a0ce0d0i-spcoplmordaotsieonle.veNl.eiTthheerse females from the 1000-ppm dose level nor males or females from the lower dose levels showed such effects. B1o0t0h0-apbspomlugtreouapnsdarneldatiinvoenleivefremwaelieghitnsthweer1e00si0g-npifpimcagnrtoluyp.inCcroemapsoeudndin-rmeallaetseidn ltihveer30l,es3i0on0sand tooccmuurlrteidfocinala,llvmearyleslriagthst-itno-tshleig1h0t0,hy3p0e0rtarnodph1y0o0f0h-epppamtogcryoutpess. iTnhceesnterilleosbiuolnasrctoonsmiisdtzeodonfalfocal regionsof the affected liver lobules. In some instances these lesions were accompanied by an as 0000439 ihnecpraetaoseeydteasmoanudntococfasyieolnlaollwyisihn-sbirnouwsnoipdialgmleinntinrgecselelmsb.lTinhgeliinpcoifduesnccien ainndtsheevceyrtitoyploafstmheoflesions was more pronounced among male rats at the 1000-ppm dietary level A`macloemsptahrainsoinntohfe tfheemasleersumisldeuveelstootfhPe FgeOnAdeirs sdihfofwernenbceeloiwn.elTihmienagtrieoatnearstdoxeimcointystorbasteerdvebdy itnhethe differences in serum PFOA levels. Dose PFOA in Serum (ppm) Males Females 0 0 10 21 N0D 30 34 100 36 01s ND 300 000 38 #9 025 065 ND = Not Determined. In the second group. doses orfat1,st1u0d,y,30P,aolraz1z0o0lop(p1m99(3a)ppardomxiinimsatteermedea4n5-c5o5mmpaoluenSdpcroangsuuem-pDtaiwolneyatrwatesepker13 of 0g.r0o5u.p0s.(4a7,no1n.p44a,ira-nfded4.c9o7ntmrogl/kggr/oduapy)anAdPaFcOonatrdolligbritouumpipnaitrh-efdeidcttofotrhe1310w0eepkps.m dTowseogcroonutpr)ol vgreoruepawlseoreexfpeodsebadsadlurdiinetg ftohratapneraidoddi.tioFnoalll8o-wuienegktshepo1s3t--wtreeeaktmeexnptosaunrdeopbesreirovde,d1f0oarnainmyalssigpnesrof r`Aelcloavneirmy.alsAlwletreestodbiseetrsvweedretwaiscseadyaeidlyanfdoervmaolrtuaaltietdy,fmoorrtiebstunmdaitteyr,iaalnhdogmeongeernaelictlyinaicnadl sstiagbnisliotyf tpoexriicoidty,. anBdotdhyenweoinghthtesdaweyroef nreeccrorodpesdy.onFeoobedfocroenseuxmppotsiuroenswbaesgarne,cowredeekdlwyedeukrliyngfotrhealltrdeoastmeednt Lfrorouaplls,ofitnhceluadniinmgatlhserneotnapianierd-ffoerdtchoentrreoclovgerroyuppshdaasielyofftohethsetupdayi.r-Afedtoatnailmoafls1,5aanndimtahlesn pweerekly droosuepd-wgerroeupsawcerriefiscaecdraifftiecred13fowleleokwisongf4,tr7e.aotrme1n3t wanedekfsololfotwrienagtm8enwte;ek1s0oafninmoanl-slrpeeartdmoesnted- Streerautmmesnatmapnldesfrcoolmlecatendimfarlosmpe1r0 daonsicmda-lsgrpoeurpddousreidn-ggrreocuopvaetrycawcehrsecahneadluylzeeddsafocrriefsitcreaddiuorli.ntgotal toexsitdoasstee,roanne,inlduitceaitnoirzoinfg pheorromxoinseosm,eapnrdolfiofrertaetsitomna,tweraisalanraelsiydzuecd. The from alesveecltoifonpoaflmliitvoery!thCatoAwas orbotaminaleldafnriommal$saantiemaaclhs spcehreddousleedd-sgarcoruifpicate ewaecrhe swcehiegdhueld:edbsraacirnif,iclei.ver,Tlhuengfso,lltoewsitnsg(oonreg)a.ns saenmiimnaalls vweesrieclpe,rpersoesrtvaeted,icnoa1g0u%lapthionsgphgaltaen-db,ufafnedreurdetfhorar.malTihneanfdolelxoawimnignetdissmuaecsroisnctohpeiscealslay:me eSxptienranlaclorsdu,rftahceeonafstahlecabvoidtyy,aanlldoprairfiacneass,althseicnruasneisa;ltchaevitthyo,ratchiecexatbedommailnsaulr,faacnedsopfetlvhiec bcarvaiitniaesnd a 000050 (aonnde)v.issceemrian;aalndvesailcsloe,exparmositnaeted,mciocargouslcaotpiicnaglgllya:nda,naynadbsureertvherda.leIsnioandsd,ibtriaoinn,,thlievefro,llluonwgisn,gtestes iJusnsguse.stweesrtes p(ronees)e,rvseedmiinnaglluvtesaircalled,eahnyddeprfoosrtealtee.ctron microscopic examination: brain, liver, cInomtphearaenadltyositsohefcotnhterdoaltaa,niamnailmsalisn itnhegrnoounppasierx-fpeodsegdro1u0p.1,wh10i,le30t.haenddat1a0f0rpopmmthAePpaFiOr-fweedre cCoonntsriodleraendimoalbsewheroemocgoemnpcaoruesd atnodanstiamballesuenxdpeorstehde (e0x1p0e0ripmpenmtaAlPcFoOn.ditAilolnst.estAdlilcatnsiwmearles Shuartviwvaesd staocsricfhiecdeudloend swaeceikfi4cd,uweittohstehveeerxecneeptcikosnoorfesonuenrealnaitmedationttrheeat1me0n0t.-ppTmwidcoes-edda-iglryoup eWxeaimgihntastwieornes sofeaelnlcaonmipmaarlesdwetorethuenpraeimra-rfkeadblceo.ntroAltg1r0o0upppdmu.risniggnwiaficckan1t arneddutchteionnosnpianibro-fdeyd croendturcotliognrsoiunpbdoudryinwgewigehetkssw1e-r1e3 a(pip.a..retnth.rouBghooduytwteriegathmtendta)t.a iDnutrhienogtrheecrodveorsye,d-hgorwoeuvpesr,wenroe cpaoimnp-afredabcloenttroolcogntrrooulps.duArting10w0epepkm,1 amnedasnigbnoidfyicawnetilgyhltogwaeirnsthwaenrtehesingnoifnipcaintreldy-hciognhterrolthgarnouthpe uhreinnognpwaeierk-sfed1-c13o.ntrAotl g1r0o.aunpdat30wepepkm,2.meTahnesbeoddiyffweeriegnhctesgaiinnbsowdeyrweesiigghntifgiaciannstlwyelroewenrotthan o2b1s0er0vepdpdmurdiunrigntghewereekcosve1 raynpder2ioodn.ly,Siwghniefniccaonmt pdairffeedretnocetsheinnofnopoadirc-ofnesducmopnttirooln gwreoruepsobnsoerved odtihfefrerseingcneisfiacmanotndgiftfheergerncoeuspsinfofrooadnycoofnstuhmephtioornmowneerseenvoatledu.ate`dThienrtehweesreerunmo. siLginkiefiwciasnet, serum nreaaltymseinsto.f tSetsattimsattiecarlilayl sriegsniidfuiceasnthohwigehdernoheipnactriecaspealimnissierryumCoAAPFoxOidlaesveelascotivveirtythweacsouorbsseerovfed apter3i0od-.anAdt11000 ppppmm,; shtoatwiesvteicra,lltyhsisigenfiffeicctanrtethuigmheedrtloevceolnstrooflhleepvaetliscbpyaltmhieteonydloCfothAeoxriedcaovseery cantiimvailys weexrpeosoebdse(r0v1e0d,a3t0,weaenkd $10o0nlpy.pm.MeAalnl deonszeydmegraocutpisvietxehsibwietreed hsiiggnhiefsitcadnutriinngcrweeaseeks8infor anbdsol1u3t.ecaonmdparreleadtiove tlhieveprawier-ifgehdtscoanntrdolhegpraotuopc.ellTuhlearahuytpheorrstrsoupgheyswteerdetohbasetrhveesed cathawnegeekssm4i,g7h.t obxeiadsassoeciaacttievditwyitwherpeeraolxsiosoobmseerpvroeldifaetrathtiisond,oessepelceivaellldyusriinncgetirneactrmaesntc.s iDnuhreipnatgicrepcaolvmeirtyo.yl CoA However, noneofthe ivereffects were observed. indicating that these treatment-related liver effects were reversible. "LTOheAreEfLoreo,fu1n0deprptmhe(0c.o4n7dimtgi/okngs/odfayth)isarsetuidnyd,icaatNeOdAbEaLsedoofn1.r0edpupctmio(n0s.0i5n mbgo/dkyg/wdeaiyg)htaannddabody weight gain, and on increases in absolute and relative iver weights with hepatocellular hypertrophy. a 000051 3.6 Developmental Toxicity Studies in Animals Three prenatal developmental toxicity studiesof APFO have been conducted, one inhalation and two oral studies. oTnhethfersrtesouflttshoesfae srtaundgiees-fwiansdianng sortauldyd,eavneluopppmeerntdaolsetolxeivceiltyofst1u5d0ymign/rkagts/d(aGoyrwtnaesr,se1t9f8o1)r.theBased 0de.f0i.n0i5t.iv1e5s,tu5d,yanindw1h5i0chmgf/ikvge/gdaryoAuPoFfp2Os2intidimset-ilmlaetdewdaSteprrabgyugea-vDaagweleoynrgaesstwaetiroenaddamyisni(sGtDer)e6dc1l5.inicDaolsess wieorfgetaodnxjiucissttye.d aIcncdoirvdiidnugaltboobdoydywewiegihgthts.weDraemrsecwoerrdeedmoonniGtoDre3d, 6o,n9G, D12,31-52,0afnodr 20. w"AenriemaelxsamwienreedsafcorritfihceenduomnbGerDof2c0obrypocrearviluctaela,dinsloucatmioobnfavenidabrtlheeaonvdarniocsn,-vuitaerbil,eafnedtucsoens.tennutmsber Soufbrjeescotrepdtitoonesxitteersn,aalngdronsusmbneecrroopfsyi.mplAapnptratoixoinmasitteesl.y oFneet-utsheisrdwaorfethweeifgethuesdesawnedrseexfiexdedanidn rBeomuaiinn'insgolfuettiuosnesawnedreexsaumbijneecdtefdortovisskceelreatlalabenxoarmmianlaittiioens ubsyinfgreacl-ihzaarnidnsreecdt.ioning. The wSeigihotsfgomanntGerDsna9l, t1o2x,iacintdy c1o5nastisttheedohifgsht-adtoissteigcraolluypsiogfni1f5i0camngt/rkegd/udcatyi.onsMienamnemaantemrantaelrnbaoldybody wSeatiigshtticoalnlyGsDign2i0ficcaonnt.tiOntuhetro sriegmnasoinflmoawteermtahlantocxoinctirtoylst,haatltohcocuurgrhetdheondliyffaetrethnecehwigahs-dnooste AgdrmoiunpisitncrlautdieodnoaftaAxiPaFaOndddueraitnhg ginesttharteieonradtiddanmost.apNpoeaorthteoraeffffeecctttshweeorvearriecpsorotredr.eproductive act 150 of the dams. my/kg/day for Under the maternal conditions of toxicity were the study, indicated. a NOAEL of$ mg/kg/day and a LOAEL of dAosseiggnirfoiucpanotfly1h5i0ghme/rkgin/cdiadye:ncheoiwnefveetrustehsiswistkehleotnael mviasrisaitnigonstaelsrocborcaccurwraesd oinbstehrevceodntartotlhseahnidghtthheeroetfhoerre twharseendootsceongsriodueprsed(attosibmeiltarreaitnmceindt-ernecleatbeudt.loNwoersitghnainfitchaenthidigfhf-edroesnecegsrobuept)waenedn treated annudmbceonrtorfolmgarloeuspasnwderfeemnaloetse,dtfootralotahnedrddeeavdelfoeptmuseenst.atlhepamreaamnetnerusmbtheart oifnrcelsuodrepdttihoen msietaesn, diemspclrainbteatdiaosn asivtaesr,iectoyrpoforaabnluotremaaalndmomrephaonlofgetiucsalweicghhatnsg.esLilkoecwailsizee,datofetthale alernesaoffintdhiengeminbirtyiaolnlyal tnhuecrleefuosr,ewnaost claotnesriddeetreedrmtionbee ttorebaetmaennt-arrteilfaatcetd.oftUhnedferreet-hehacnodndsietcitoinosnionfg ttheechsntuidqyu,eaanNdOAEL for developmental toxicity of 150 mg/kg/day (highest dose group) was indicated. BAasseecdoonnd otrhaelrepsruelntastaolf daervaenlgoep-mfeinntdianlgtsotxuicdiyt.yasntuudpypewrasdocsoenldeuvcetleodfi5n0rambebkitgs/(dGaoyrtwnears,s1e9t82f)o.r athdemidneifsintietrievde0s,tu1d.5y,i5n,wahnidch50fmouyr/kger/oudpasy oAfP1F8OpriengdniastnitllNedewwaZteeralbayndgaWvhaigteeornabgbeisttsawteiornedays a 000052 (piGtDui)ta6r-y18l.utePnriezginnganhcoyrmwoanseesitnaobrldiesrhetdoiinnedaucche osveuxluaatliloyn,maftoulrleowfeedmablyebayrtificivi.alinijnescteimoinnaotfion W2istdhay0.05 moflgeosftaptoioolne.d sAemcoennstcaonltledcotsede fvroolmummealoef|rabmbiitksg; twhaesdaadymionfisitnesreemdi.natIinodnivwiadusaldebsoigdnyated w3e2i9ghftosrwaebrneormmeaalsucrliendicoalnsGiDgns3., 6O,n9,GD12,291,5.th1e8,daoneds 2w9e.reTehuethdaoneiszewderaendobtsheerovveadrideasi,lyutoenruGsD npldacnoantteinotns esixteasm.inFeedtufsoerstwheerneumcxbaemroinfecdorfpororgarolsusteaab,nolirvmealaintdiedseaadndfeptluascese,driensaor3pt7ioCns and ivinsccuebraatloarnfdorskae2le4t-ahlouabrnsorumravliivtailecsh.eckA. blPouopdsswaemrpelesuwbasseqtuaeknetnlyfreoumthsainxidzeodesanprdioerxatomidnoesdinfgorand twheerneosnenGtDto 1t8heasnpdo2n9s;ora floirvearnaslaymspils.e wTahsistiankfeonrmfartoimonthweassamuneaavaniilmaabllseoant tGhDe t2i9.me Aolflthsiasmples SwiegingshotfgamiantoenmaGlDto6x-i9ciwtyheconnsciosmtpeadorfedsttaoticsotnitcraolllsy;sbigondiyfiwcaenitghttrangsaiiennstrreetduurcnteidontso cionnbtroodlylevels orenpGroDduc1t2i-2v9e,trAacdtmiconnitsetnrtastoifonothfe AdoPesF.ONdouriclnignigceasltaotrioonthdeirdtnroetatampepneta-rre1l0ataefdfescitgntshewoevraeries or reported. Under the conditions of the study. a NOAEL of 0 mg/kg/day. the highest dose tested. for maternal toxicity was indicated. Nmaolessignainfdicfaenmtaldeisf,fedreenacdesorwelirvee nfoettuesdesb,eatnwdeefnetaclonwterioglhstsa.ndLtirkeeawtiesdeg,rothueprse fwoerrtehenonusmigbneirfiocafnt dciofnfceerpetnicoens rinecpiodretnecde,foarbtohretinounrmabtee,roorf rtehseo2r4pt-ihoonuranmdoritmaplliatnytaitnicoindesnictces,ofcotrhepofreatulsuest.ea,Gtrhoess ndeecvreolpospymeanntdaslketloextiaclitvyisccoenrsailsteexdoamfinaadtoisoen-srewlearteeduinnrcermeaarskeabilnea.skTelheetaolnlvayrisaitginono,fextra ribs or m13e%igibd,aywi,th20st%atiastti1c.a5l msigg/nidfiacyan.ceaantdth1e6 h%igaht-0domsgehkggr/oduupy().38A% aattSt0imcga/lkyg/sdiagyn,if3ic0an%taitn5crease iSnig1n3if1icrainbcse-sopfuhriresd eofcfceucrtriesduinncetrhteaminids-idnoceseingrbootuhpotfhe$hmiggh/-kga/nddayl;owh-odwoesveerg,rotuhpes.bitohliosgeifcfaelct oThcecruerfroerdea,tutnhdeesratmhee croatnediatnidonwsaosfntohtessttautdiyst,icaalLlyOsAiEgnLififocrandtelvyedliofpfmereennttaflrtoomxiccointtyroolfs.0 mg/kg/day (highest dose group) was indicated Sctoanpsliessteedtaolf.a(n19i8n4ha)laaltsiooncoanndduacnteodraal dpeorvteiloonp,meeancthalwittohxitcwitoy tsrtiualdsyoorfeAxPpeFrOi.menTtsh.e sTthuedyfdiresstitginal wthaesstehceotnedratrtioall,ogtyhepodratmisonowfartehealsltouwdye.d itno wlhitiecrhatnhdetdhaempsupwserweerseacsraicfriicfeidcoednoGnDda21y: 35w-hpiolsetin partum Wo 000053 For rats the inhalation portionofthe per group exposed to APFO study, the two rials consisted of by whole-body vapor inhalation 12 pregnant Sprague-Dawley 0, 0.1, 1, 10, and 25 mg/m' 6 hfiorustrsa/nddays,eocnonGdDtri6a-l1s5,.resIpnectthievoerlayl, pwoerrteioandomfintihsetsetrueddy,02a5ndan1d0012mgS/pkrga/gduaey-DAaPwFleOyirnatcsofmorotilheby gbaasviasgaenodnwGheDn6-t1h5e.nFuormbootbfhmreaotuetreds foefmaadlmeisniwsatrsatbiroend,, tfheemyalweesrweerraenkmeadtewditohninanbraesc-dnienegddeadys bryoubposdy(swiexidgahtmsanpderasgsriogunpe)dwteorgeraodudpesdbytorcoatcathiotniailn order of that was rank._ Finally, pair-fed 0 the two additional 10 and 25 mg/m' soups. 2F1oratnhdeotbesreartovleodgydapiolrytifoonroafbntohremsatludcyli(ntirciaall osingen)s,. dOamnsGwDer2e1,wetiheghdeadmosnwGerDe s1a6c,ri9f.ice13d,by16, and Ctehrevriecaplroddiuscltoicvaetisotnataunsdoefxcaamcihnaendimfaorl awnaysgervoaslsuaatbendo.rmaTlhietioevsa,rileisv,eruwteeriugshtasndwecroentreenctosrwdeedreand Seixtaesm.inPeudpsfo(rlitvheeannudmdbeeardo)fwceorrepocrouanltuetde.a,wfeiiveghaenddadnedadsefxeetudseasn,dreesxoarmpitnioends faonrdexitmeprlnaanlt,ation veixsacmerianle,danfdorsvkieslceetraallaalltetreartaitoinosn.s Tashewehlelaadss mofaaclrlo-coanntdromliacnrdoshciogphi-cdoevsaelduagtrioounpoffetthueseesywees.re For trial rial one two, in which up (0 GD 21. Tthweodadmaysswbeerfeoraelltohweeedxptoecltietedr,datyheopfrpaorcteudruirteiowna,scatchhe dsaammewaassthhaotusfoerd in awneiignhdeivdidaunadl ecxagaem.inTehdefdoratcelionficpaalrtsuirgintsioonnwDaasysnot1e,7d.a1n4d,daensdig2n2atPeP.d DOany D1 aPyP.23DPaPmsallwedrae.ms wwearsesusabcsreiqfiuceendt.lyPuwpesigwheerdeacnodunitnesdp,ecwteeidghfoerd,adavnedrseexcalmiininceadl sfiorgnesxotnemDaalyaslt4e.ra7t.io1n4s,.anEdac2h2pPuP.p DTaheysey2e7saonfdt3h1e pPuPpsfowretrhee galasvoaegxeapmoirnteiodnoofntDhaeysstu1d5y.andPu1p7s PwPerfeorsatchreiifincheadlaotnionDapyor3t5ionPPanadndon examined for visceral and skeletal alterations. Inhalation Exposure "Trial One: "2T5remagtm/emn'tarneldactoendscilsitneidcaolfswiegntsaobfdommaetnesr,naclhrtooxmiocdiatcyrfyoorrtrihaelao,nech(riocmroarthoilnoogr)rohcecau,rraegdenaetr1a0l and uconnkceemntprtataipopneagrraonucpe,oanlnyd).leTthharregeyoiuntfoofur12dadmasmsatdtiheedednudroifngtthreeeaxtmpeonsturaet period (high25 mg/m' (on GD 12, s1i3g,naifnidca1n7t).diFfofoerdenccoenssuwmeprteinoontewdasbestiwgneiefnictarnetaltyedreadnudcepadiart-fbeodthg1ro0upasn.dS2i5gnmigfi/cma'n;t hroedwuecvteiro,nsnoin cboondcyenwteriagthitonwoenrley.alsLoikoebwsiesrev,edstaattitshtiecsaellcyonscigennitfriactainotnsi,ncwrietahsesstaitnismtiecaalnsiivgenrifwiecaingchetsatwtehreehsiegehn- amtattehrenhailght-oxciocnicteyntorfat| iaonndgr1o0upm.g/mU'n.derrestpheectciovnedliyt,iwonassoifntdhiecatsetdu.dy, a NOAEL and LOAEL for 000054 MNeoaenffefecttasl wbeordeyowbesiegrhvtesdwoenrethseigmnaiifnitcaenntalnycdeeocfrperaesegdnainn ctyheo2r5t-hmegi/nnc'idgernoceuopfsraensdorinpitohenscontrol sroup pair-fed ot reveal any t2r5eamtgm/emn't.-rlAatdeedtaeiflfeedctms;ichroowsceovpeirc visceral and in the control egyreouexpatmhiantawtaisonpoafirt-hfeofdet2u5ses did wmga/smo'b,searsvteadt.istUicnadlleyrstihgenicfoincdainttiionnesroefatsheed isntcuiddye,naceNoOfAfEetLuseasndwiLthOApaErtLialfloyr odsesvieflioedpmsetnetmaelbrac toxicity of 10 and 25 mg/m', respectively, was indicated. Trial Two: Ctlhionsiecadlesscirginbseodffomratreiranlaolnet.oxiMcaittyersneaeln batod1y0 waenidgh2t5 gmagin/dmurwienrgetsriemaitlmaerntinatty2p5e magnd/mi'ncwiadsencleessas dthaamnscdoniterdoldsu,rianlgthtoruegahtmtehnetdaitff2e5remngc/em'w.asNnootostthaetirsttirceaaltlymesnitgnriefliacatnetd.efIfnecatdsdiwteiroen,r2epoourtteod,f n1o2r twheerecoanndiytaidovnesrosfethefefescttusdyn,otaedNOfoAr EanLyoafntdhLeOmAeEasLurfeormemnattseomfalretporxoidcuitcytiovfe 1 paenrfdor1m0amncge/.m',Under respectively, were indicated. SpiugpnbsoodfydewevieglhotpmoenntDaalyto|xiPcPit(y6.i1n tghiast g2r5omupg/cmo'nsivss.te6d.o8fstianticsotntircoallsl)y.siOgnnifDicaanyt4sreadnucdt2io2nsPPi,n pup body weights continued atisticaly significant (Day to 4 remain PP: 9.7 lower g at 25 than controls, although the mg/m' vs.10.3 in controls: difference was not Day 22 PP: 49.0 g at 25 omfg/thme'pvusp.s5o0r.1wiitnhcoonpthrotlhsa).lmoNsocospiigcniefxiacamnitnaetffieocntsofwetrhee eryeepso.rteUdndfeorlltohweincgonedxitteironnasl oefxatmheinsattuidoy.n 2 NOAEL and LOAEL for developmental toxicity of 10.and 25 mg/m', respectively, were indicated. Oral Exposure "Trial One: TGhDree11o;uttwoofo2n5GdDams12)d.ieCdlidnuircailngsitgrnesaotmfenmtatoefm1a0l0tmogxi/ckigtyAiPn FthOe dduarmisngthgaetstdaiteidonwe(roenesidmeialtahrotno ttrheoasteedseaennimwailtsh cionhmaplaartieodnteoxpcoosnturroel.s. FNooodacdovnesrsuempstiignosnoafntdoxbiocdiytywweeirgehtnsowteedreforreadnuyceodfitnhe rLeipkreowdiuscet,ivneopsaigrnaimfeitcearnts dsiufcfheraesncmeasinbteetnwaenecnetorfeaptreedgannadnccyonotrroilncgirdoeunpcsewoefrreesnoortpteidonfso.r fetal weighs, or in the incidencesofmalformatiaonds variations; nor were ther any effects noted following microscopic examinationofthe eyes. 5 000055 Trial Two: `Similar `adverse oebfsfeecrtvsatoinonrsepfroordculcitniivcealpseirgfnosrwmearnecenootreidn for the anyof dams as the fetal in trial one. observations Likewise, no were noted. 3.7 Carcinogenicity Studies in Animals 37.1 Cancer Bioassays (T3hMe,ca1r9c8i7n)o.gIennitchipsostteundtyi,algorfouApPsFoOf 5h0asmableeenanidnveSsOtifgeamtaeldeiSnaprtawgou-ey-eDaarwlfeeeydi(nCgrs:tCuDdyBiRn)rartasts wpeerresefxedwedrieetsfecdon0t,aoirni3n0g00,pp30m oFrC3-01043papnmd EeCv-a1lu4a3tefdorattwtoheyoeanres-.yeGarrouinptseroifm 1s5acaridfdiictei.onTahleramtsean amcutkuaglitdeastyarftoirctlheecloonwsuamnpdtihoinghw-adso:semaglreosu,ps1,.3reasnpdect1i4v.e2lym.g/kg/day; females. 1.6 and 16.1 Tthheerfeemwaalse aradtossaes-rceolmapteadrededctroeatshee cinonbtroodlys;wethieghdtecgraeianseisn twheeremaslteatriasttsicaalnldy stoiganilfeiscsaenrtenxtetnhte, in chiognhs-udmopsteiognrowuapss aocftbuoatlhlyseixnecsr.eaTsheed (broadtyhewretihgahntdcechraenagseeds).areThterreaetwmeenrterneoladtiefdfseirnecnecefseiend tmhoertcaolnittryolb,eltowwese,natnhdehtirgeaht-eddosaendgruonutprseawteerdeg:romuaplse:. t7h0e%s,ur7v2iv%alanfadte8s8a%t;thfeemeanldeso.f5100%4,w4e8e%ksafnodr 5i8n9c%i.deTnhceesoinnlythcelicnoinctarlols,iglnowo-bsaenrdvehdigwha-sdoasedogsreo-urpelsawteedrei:nc4r%e,ase18in%aatnaxdia30in%.theSifgenmiaflicearnats; the decreases observed in in red the blood cell high-dose counts, hemoglobin male and female rats concentrations and hematocrit as compared to control values. values were Clinical C(hAeLmTi)s,trasypcarhtaantgeeasmiinndoitcraatnisvfeeorflasieve(rAtSoTx)icaitnydianlcklaulidneed pihncorsepahsaetsasien a(lAaPn)inienabmoitnhottrreaantsefdermaaslee rliovuerpasndfrkoimdn3e-y18wemiognhtthss,webrute onnoltyedininthbeothhighhi-gdho-sdeosmealmeasleata2n4dmfoenmtahlse. fatIsn.crSeiagsneisfiincarnetlantoivne- nienocpildaesntciecoflelsiivoenrs mwaesrseess,chnypperripmlaarsitliycinnotdhuelelsivaerndanfdoctie.stains;d tihnetreeswtiecruelarinmcarsesaseessiinntthheehigh- ddoifsfeusmealheepgartooumpe.galOotchyetrosliivse,r ctyosxitcoiedffdeecgtesneirnactliuodne,daosned-rpeolratatledmoinncorneuacsleseairn tcheleliinncfiidlternacteioonfin bdootshe mmaallees.andAfsetamtailsetitcarlelaytesdiggnriofuipcasn;t,thdeossee-irneclraetaesdesinwcerreeassetaitnistthiecailnlycisdiegnnciefiocfanotvainritahne htuibguhl-ar dhoypseerrploauspiaswwaassf0o%u,nd14i9n%f.eamnadle32r%as.: rtehsepeicntciivdeleyn.ce Boafstehdisolnestihoenseinttohxeiccoenftfreoctls,,ltohwe-,hiagnhddhoisgeh- Sdeelcercetaesdedinbtohdisyswteuidgyhatpgpaeianr,sitnochreaavseedrelaicvehredantdhekiMdanxeyimwueimghTtoslearnadtetdoxDiocistey (iMnTtDh)e.hemBaatsoeldogoincal `ianncdidheepnacteiocfsaytsatxeimas,(atchleinLiOcaAl EsiLgn)foarnmdaloevaarnidanfteumbaullearrahtyspiesr3pl0a0sipapm(.wh[iBcahseisdroenverisnicbrleea)s.esthien the LOAEL for female rats is 30 ppm.] 2 000056. oAftthtehe ltievrerm,intaesttiios,notfhyrtohieds,tauddrye,naalslainghdtmiancmrmeaasreyingltahnedsi,nceitdc.e)ncweaosfsveaernioiunstnheeotprleaatsemdsa(nitmuamlosr.s Amamloenrgatst,heain,d tohfemiancmrmeaasreyd fiincbirdoeandceensoomftaeisntibcoutlhagr (Lreyodoifgu)fecpmelalslaedreantsomwaesreinsttahteishtiicgahl-ldyose stiugmnoirfisc(anLtC(TP)<i0n.t0h5e)caosntcrooml,palroew-d atondthheicgohn-cduorsreenmtalceosntwroalss.0T%h,e4i%ncaindden1ce4o%f,trheespLecetyidvieglyc;eltlhe rTeshpeecitnicvreeaisnecsiadreencaelssoofstmataismtmicaarllyy sfiigbnriofiacdaenntoamsacionmtphaerfeedmatloethgerohuisptsorwiecarlec2o2nt%r,ol42in%ciadnednc4e8s%. (SLpCrTa.gu0e.-8D2a%w:lemyacmomnatrroyl rfaitbsruosaeddenionma17, c1a9r.c0i%no)goebnisceirtvyedstiundi1e,s3(40Chmaanlderaancdt a1l.,,321999f2e).malTehe t"opobnetaapnpcroouxsiimnactiedleync5e%of(cLiCtTediinn: 2C-lyeegagr eotlda.S.pr1a99g7u)e.-TDhaewrleefyorrea,tsunindeorthtehresctounddiietsiownassorfetphoirsted rsattusdya,ndAPmFaOmmias rcyarcfiinborgoeandiecnoinmaSspriangtuhee-fDeamwalleeyrartast.s, inducing Leydig cell tumors in the male fInouanfdotloloiwn-duupce2-lyievearr tduimetoarrsy asntdudpyan(c3r0e0atpipcma)ciinnamraclelel Stpurmaogrusei-nDaadwdlietyio(nCtDo)Lreaytsd,igAPceFllOtuwmaosrs; hAoPwFevOerh.asdeatlasiolsbeoenntshehoswtundytodpersoigmnotaendlitveurmocarricnicniodgeennceesiwseirnernoodtenrtespo(rAtbeddel(lCaotiofketetaall..,1919919:4) Nilsson etal. 1991), 3.7.2 Mode of Action Studies "SThhoertm-etcehramngiesnmostooxfitcoixtiycaoslsoagyiscaslucgagrecsitntohgaetniAcPaFcOtiiosnnooft Aa PDFNAO-rareeacntotivcelecaorlmypounudnedr;stiot oids.non- SmauctcagheanriocmyicnetsheceArmeevissitaeest(GursiifnfgitfhivaendstLaoinnsg,of19S8a0l)m.onAevlalialatbylpehidmautraiiunmd,icoarteinthaant atshesaiyndwuictthion ofmors by perturbations APFO ofthe is due to 2 endocrine snyosnte-mg.enotoxic mechanism. involving activation of receptors and 37.2.0 Liver Tumors p11ehraosxibseoemnewperlollidfoecrautmieonntiendthtehaltiAvePr FofOraistsaapnodtemnitcpee(ro.2x.i,sIokmeedapreotlailf,rat1o9r8,5;inPdausctionogr etal. p1r9o8l7i;feSroahtiloennieuxsisetstailn.ra1t9s92().KaAwassexh-iremlaateetdaldi1f9f8e9r)e.ncbeutinnottheininmdiucceti(oSnohoflelnivieurs epteralo.x.i1s9o9m2)e. Tdhepeenhdigehnetroinndtuhcetsioenxohfolrimveornepetreosxtoisstoemreonpero(lKiafweraasthioinmainemtaall.e r1a9t8s9w).asLsihkeowmnantoyboethsetrrongly pofepreorxoixsiomseomperoplrifoelriafteorrast,orAhPeFpaOtohcaasrcailnsoogbeeneensiss)hoiwnnrattos c(aTuaksaeghie,peattaolm.eg1a99l2y;(Caonoakr,ly19b9i4o)maanrdker "mTihceeto(tKaelintnyoedfy,the1s9e87d)a,taanadppienadruscetooxsiudgagteisvtetDhaNt Athedalimvaergetoixnicliitvyeraonfd rcaatrsc(iTnoagkeangiiciettyaol,f A19P91F),O may be related to induction ofperoxisome proliferation. Meanwhile, estrogen has been shown to a 000057 pirncormeoatsee hinepeasttorcoagrecnilneovgeelnscasfitserinArPatFsO(Yeaxgpeorsuarned(Ydaigsecru,sse1d98b0e;lCoaw)memraoynaoltsaolp,la1y98a2)r;olaenin hepatocarcinogenesis in fats. 3.7.2.2 Leydig Cell Tumors Ato lianrdguecenuLmebyedrigofcenllont-ugmeonrosto(xLiCcTc)oimnporautsn,dmsiocfed,iovredrosges.cheAmirceavlieswtorufcttuhreesavhaaivleabbleeninfroerpmoartteidon ognroLupCsTbainsdeudctoinonthieniramniomdaelssolfedacatiwoonr(kCslheogpgpeatneall,to19c9l7a)s.sifTyhtehecsoemcmoomnpotuhnedmse iinnttohseemveonde of arcotwiotnhfobrymdoisstrucptoimnpgotuhnedhsypiostthhaaltatmhiecs-epicuoimtpaoryu-ntdesstacfufleactr tahxeishaotrmvaorniaoluscopnotirnotlsotfhaLteryedsuilgtcienll itoncsrteiamsuilnagtitnhge stheeruprmodleuvcetlisonofolfutteesitnoisztienrgohneo,rmLoHnema(LyH)a.lsoItplhaaysabemeintopgoesntiuclartoelde tihnatthien Laedyddiitgi.on cgerlolws;tha-sstuismtuailnaetdinigncmreedaisaetoinrscisruccuhlaatsinIgGLF-H1,leTveGlsFa.ndlecuhkrootnriicensetsimaunldatviaornioofusLefryedeirgadciecllaslsbyc'an lead to LCT development (rev. in: Clegg etal. 1997). A`masleeriSepsorafgsuteu-dDiaeswlheayve(CbDe)enractosnedxupcotseeddtotoinAvPesFtOiga(tCeotohke emteaclh.a1n9i9s2m;oBfictguemloretfaolr.ma1t9i9o5n; iLniu ct aVLa.ri1o9u9s6)d.oseNolesvieglnsiffoircan1t4 idnacyrse.asHeosweinveLrH, wseerreumseaennditestthiecurlaasr alefveerlstorfeeasttmreandtioofl AwePrFeO at SthiagtnitfhiecaenltelvyaitnecdreesatsreaddiaonldletveesltsosmtaeryonceaulseveelLseywdeirgecseilglnhifyipcearnptllaysdieacarenadsetdu.morIt fwoarsmaptoisotnulbayted a(cTtiGngaa)s, awhmiicthogbeinndasntdootrheenehpaindceirnmgalgrgorwotwhthfafcatcotrorse(cEreGtFi)onr;etcheepttorraannsfdosrtmiimnuglagtreodwtcehllfactor epxropleirfiemraetnitosn,hfaovreisnshtoawncne,thhautsAbPFeOen dientcercetaesdedintLheeyldeivgelcseollfse(sTtreaedridosl ebtyal.i,nd1u9c9i0n)g. cyStuobcsehqruoemnet $k4n5o0wnXItoXi(nadruocmeatfa-soex)i,dawthiiocnhacnodneveyrttoschtresotmoestPe-r4on5e0tmooensotroaxdiyogl.enPaesreosxbiysobmiendpironlgifteortahteors are peroxisome receptors). proliferation is believed activation that APFO receptoar (PPAR ; induces cytochrome a subfamily ofsteroid P40 XIX (aromatase) hormone by binding to and activating the PPAR. AAlPthEouginhtshiegn1i4fidcaayn-tstiundcriecass,esit ianppLeHarswetrheatniontcrseeaesneiinnSLpIrHalgeuveel-sDacwanlneoytrabtesrauflterd toruetattomebnet of Sitnuvdoilevs.edsi(ginniafdidciatntioinnctroeianscereinasheedpaetsitrcaadiroolmaltevaesle)(iwnhtihcehicnoduncvteirotns otfesLtoCsTterboyneAtPo FOes.traIdnitohle)se aocbtsievirtvieeds aisnstohceiattreedatweidtrhatsd.ecTreesatsoesdtesreonreu,mwtheistcohstiersoynnethleevseilzsedanadndinscerceraesteeddebsytrtahdeioLlelyedvieglscewlelrs,e oisrdreergutloatmeadinbtyaiLnila;deteqsutaotsetetreosnteosatnedroLneHpfloarsmmaa lcelvoesles,d-rleodoupcfeedctdebsatcokstseyrsonteemleivneltshe(cHaPusTedaxibsy. In increased aromatase activity) are expected to lead to increased LH levels through the negative st 000058 sfteueddibeasockfmcehcehmainciaslms.foIrt whahsicbheetnhepopirnotpeodseodutmtohdateionfcarcetasieosn icnalLlsHfmoracylenvoattaeldwLaHy,s abnedsetheantin all acroempseonmseaotfiotnhemaexyplhaanvaetioocncsurfroredfatiolirnegsttooredehtoemcteocshtaansgiessainndLiHnaplperveolpsri(aCtleetgigmeitnaglo.fs1a99m7p)l. ing 3.7.2.3 Mammary Gland Tumors aEsntdratdhieolovhearsexaplrseosbseieonnosfhToGwnFtoashtaismubleaetne stuheggseesctreedtiaosnoonfeTpGoFssiablbey fmaactmomrainrypreopdiutcheilnigal cells S`nuesotpalianseida c(eLlilupertolali.,fer1a9t8i7o)n.ofHemnacmem,airtiys tpousmsoirblceeltlhsatantdhethAePFsOub-sienqduuecnetddeelveevlatoipomneonf oefstradiol lDeavwellseymaraytsalisnoabdedirteisopnontosiLblCeTf(orditshceusdseevdelaboopvmee)n.tIonffmacat,mmthaisryis fcoinbsriosatdeentnowmiatsh itnheSpmreacghuaenism bfaytsw.hIit chhasspboenetnadnecmoounssmtraamtmedarthyatnethoeplcaasrlmysawpepreeardaenvceeloapneddhiinghagsipnogntfaenmeaoleusSpinrcaigdueencDeaowfley emxapmomsuarreytogleannddotguemnooruss iensturnotrgeeanteadn,dapgrionlgacfteinmaalseaSrpersaugltueo-fDaanwalcecyelreartastiisngdueeffteoctinocnrenaosremdal, age-related perturbationsofthe estrous cyele in this strainofrat (Cutts and Noble, 1964; Chapin etal. 1996) 372.4 Pancreatic Tumors TothheermepecrhoaxniissommebyprwohliifcehraAtoPrsFaOlsiondpurcoedducpeanpcarnecarteiactiacciancairnacerlcleltlumtourmsoriss uinn krnatos.wnA.vaAilnabulmebdeartaof (SuCgCgKes)tltehvaetltsheecpoanndcarreyattiochaecpiantairc ccehlolltesutmaosriss (aCroeorkelaetteadlt.o1a9n94i;ncOrbeaosue mincstearl.,um1c99h7o)l.ecCysCtKokiinsian p`arnocwriehatfiacctaocrintahartchealslbieneantssh(oLwonngtnoecsktiemru,la1t9e87n)o.rmHalo,weavdeaprt,ivdea,taanodn ntehoeprloalsetiocf gCrCowKthinof pancreatic tumor formation are conflicting. 4.0 Hazards to the Environment 4.1 Introduction Tmhaedeaqmuoatriecdtiofxfiiccuiltty abyndsehvaezraarldproofbAlPemFsOditsocauqsusaetdicboerlogwa.nisTmhsesweaspraossbelsesmesd.comTphliisctaatsekdwtahse task oFfurdtehteerrmmoirnei,ngthiefsteheprcocboltoexmisciltiymitteesdtstwheerceonvfaildidenacnedthcaotulcdoubledubseedpliancetdheoanssthaesstmoexinc.ity test vthaeluiensh,earnendttthouxsiciintytuarnndlohawzearreddotfheAcPoFnfOidteonacqeuaotficcoonrcglaunsiisomnss.that couldbedrawn in assessing ss 0C0059 G1e)nAervaalrliye,tythoefdaimfmfeorneintumAPsFalOtsorwtihtehtveatrryaibnugtdyelsaimgnmaotniiounms saanltd wloatsntuemstbeed.rsTwheereexatecsttecdo.mposition and identification of impurities, which may affect toxicity, in each lot number used is not known 2r)oAm vaaprpireotyxiomfatteesltyin1g9l7a4b-o1r9a9t6o.rieTshcisonsdituucatteidonthseerAvePdFtOo tionxcirceiatsyesotvuedriaelslotveestrvaarpiearbiiolidotfytaindmethus made inter-laboratory comparisons more difficult. 3m)ajPourrictoyonfcterh.e tPeusrtietdymwaatesrinaolt,sourffpiecriceennttlytceshtarmaactteerriailzeadnidn ptehrecseenttesotst.heIrnmsatoermialt(esst)s, iwt aasppaeared tuhsaetd.10P0ur%ittyesot fchteesmtimcaatlerwiaals duoseeds;afinfeoctthteorxsicaictyheamnidcaslhooufldlebsesetrapkuernitiynt(oapapcrcooxuinmtawtehleyn8p5o%ss)ibwlaes. by expressing toxicity on the same purity basis. 4) Water, an many of the tiosxoipcirtoypatnesotls,soflovrennto,oobrviaocuosmbinidniactaitoendorfebasootn.h wSeorleveunstesdawrietmhitxheedtewsittmhattheeritaelstin `umsaetderiinaltetsotsmawkheeriet mtihsecciobnlceewntirtahttihoenstoefsttdhielutteisotnmwaattereirableafroereextthreetmeesltyislboewguann.d aSovlevreyntssmaalrle aofmtohuensteosfttuedsitcsmawtheryiaalsomluvsetntbewaasdduesdedtoorthweatsesetvcehnamfboeurnsd. to1tbweansecneostsacrlye.ar Ifnrofmactt,he3SMummaries tShuamtmoafrtihzeedtesetascuhbtsetsatnacen.d" stTahtuesd,"Dinattahomseaytesntost accurately relate where 100% test toxicity material owfasthneottesutsesda,mptlhee with tvoaxliuceistyonvaalu1es00h%adtetsot bceheamdijcuasltebdastiost,askoe tihnatottahcetceosutnstctohuelpderbceenctomspoalvreendi.(s), and to express the c5h)eImniaclalltcheosnecetnotxriactiityontsesatrseoinnlsytenaodmailnwaalytsesrt ecchoemmimceanldecodncseontthraattioonnes cwaenreacucsuerda.telMyeadestuerremdinteest tdheetearcmtuianledtestthacthtehmeicnaolmicnoanlcecnotnrcaetnitornattioownhsiacrhe tohnelyt.esftororegxaanmipslmes 5ar0e%exopfotsheed.meaIFsiutriesd c`omnecaesnutrreamteinotnss,ofthcehteomxiiccaitlycvoanlcueenstrwaitlilohnasvheotuoldachcaovredibnegelny tbaekaednjourstmeaddbeya5v0ai%l.ablAen.alTyhteinc,al rVoelcaotvileirtyy)rattheast cmoiuglhdthlaovweerbetehne adcettuearlmcionnecde,natrnadtipohnyssitcoowchhiemcihctahleptresotceosrsgeasni(cs.mg.s wheyrdreoleyxspioss,ed could taken ahnadvethbeeerneltataikoennshiinptoo facbcootuhnt.is kNnoomwinn.als may be used when measured concentrations are tIhneosredetersttolipmriotcaetieodnswiatnhdatnoyassosrutmoef etnhvtitrhoenmneonmtianlalhaczoanrcdenrtervaiteiwonist wwaesreneacne"sasadreyqutaotei"gnore etxoxpirceistsyiaornoe fbatsheedmoenaswuelrle-destteastblcihsehmeidcvaallcuoensc(elnotwratisio>n1s.00Cmrgit/eLr;iamfeodriaussmesosrimnogddeergarteeeoisfa>c1ut1e00 mg/L: high is <I mL) s6 000060 42 Acute Toxicity to Freshwater Species Smeivnenroawl:s(pPeicmieesphwaelrees tpersotmeedltaos)as,sbelsusegtihlelascuuntfeislhox(iLcietpyoomfisAPmaFcOh;rotchheisreusin)c.lwuadteedrthfelefaa(tDhaeapdhnia "maadgjnusat)e.d atond1a00gr%eetenstalcghaem(iSceallenaansdtrtuesmtcraepsruiltcsoramruetpurme).senTtehdeitnoxTiacbiltyeste2st(oerngdapnoiiznetdsbhyavteestbeen ubstance) and 3 (organized by test species). Each value is related to testingfacility and reference. rTauneglevdeftreostms 7w0erteo c$o4n3dmugc/tLe.d w1itihs ufnactlheeaard mwihnynothwiss;ra9n6g-e1 iLsC0S0wivdael.uesAs(sbuasmeidnognthmeosretasltiutdyi)es are wValoida,caunted vdauleuetsotfhoer blliumeigtialtliosnusnfdiisshcuaslsseodianbdiocvaet,etlhoewsetotxoixciictiyty(v9a6l-uhesLCiSnd0iscoatfe4o2w0,toaxincdit5y.69The mg/l), rNainngeeadcuftreomte3st9s1w0e>r1e0c0o0ndmugc/tLe.d wTihtehldoawpehrnivdasluaensdar4e8-ih nECdS0ivcoalfaumetosdi(ebrvaasteeed otonxiicmitmyo,bibluitzathteion) wide range makes interpretation difficult. dSeenvseinttyesctesllwceoruentcso,nadnudctderdywwietihghgtrse)enraanlggeadef9r6o-mh 1.E2 CS100 >v6al6u6esmg(/baLse(tdhoenErgSr0owctehllrdaeten,sictelylvalue oLfoi1c0i0y,0 bmags/eLd iosnexthceluadceudtefcrroitmertihai.sTdhiseculsosiwoenr).valTuheewloouwledravlasloubeeiindnidciactaetsivheiogfh mtoodmeordaetreate mTogx/iLci.tyb,asbeadseodnocneltlhecocuhnrtosn,icformogdreereantaelgcraietewraisona(ls0o.c1a1lc0ulmagt/eLd).in oAne14s-tdudyE.CST0hivsaliuseoinfdi4c3ative hofelmoowscthrsoennsiictitvoexiecistty,spbeacsieeds oinntthhee4ch%ronAicPFcrOitetersitonsa(m1p0lem,g/dLa)p.hnGirdsenwearlegatcheapnepxetarmeodstto be sensitive, and fathead minnows were the last sensitive. 5 000061 FT ecoa rgab mi2ol mSumme ary of AcuteEcological To Buran Vane xicity Datafor APF(OgroRuepleerdbeynetest substance) osSample APFOAammo--n----i-- a _-- -- I [Fathead minnow (Pimephaes promelas) PenL [70CS[0 3M Company. 1974a [9bb6he1eLn.CiS0n_ f17oi6n6. c13aMCCoormrpayny.iom1vs980e8 1 gil sunfih (Lepomis machrochini) or os pia gy eehnLtCSs0 |io4s30 TEC 126 [3CM CoEommmpiapnnyea.n11n99t778yibom-- n.| BS ECR ont Emel abo,| _ oo Taee jf oEwCoEmpaR reosins tecasri a EGNCECss)0TM 3h1o0or N[aVnadaanl.d1099e55r ---------- B Be E 570 a i Company. 0978 | west ee Oome RECCr s]:0r 10060 COompCOaonym.pany11993807641] FFuest Sammiple: AiFRnr Oh o PERC Cop78a "TostSample: APFOammonium salt in 5E0C%wsateTrai IM-- Company i988 -- ad inno Va is a(pPaimmepghaotees promelas) BBPioennktnEeCossto0c. 5J[i2o30 0--0TTofiriimviiosSyyaaasccee111mm95999s0s00 [eB- aoctSeriia (mPheotoPbaFctOeraiummmphao sphareum) si $0% (30min ECS0P= tesconned mouEnvironmental Laboratory, | is~~ Activated sludge T50.min CSO |-500 I ---- 13M Environmental Laboratory, ss 000062 `Test Sample: APcFpOaaemamtmen soaltnin8ib0%euwcatmer[_3[vara --oo] ( Wate Nem s (Dap ra amragt nopis n) " Tr FPvREBCCs)) [[ptaeo [aWaentdesrall o1996n Benecso os maa ame | ira (Pharactorn phosphorcam) 0PminEECS0E(630R [f9eEenvironmental Laboratory. al a Inve side p iin BT CS 668 e[IM Cervirommena Laboratory, `TesJ tSample: APFOin 50%isopropanol CT ews F-enda (Pimps prot) ONL [0 [190Wy Lorre [Wate es apm mages ove [Jog12960Wiley ie rr emp OR10E 5Wi oO o Fat"heetadSmamoplwe: (APPiFOme(p44hr%)aoiimcn es27).9% " wDatReErCaSn0d 27.[921% isopr[oTpRaWniolblur fws Labora" torieosc,| iris Fipor [Bowel avsWb Te] W[Waatteer ccaa Daapphnniiammagan na fis cso Ward stat. 1995 GGrreeenn ssie c(ellennaasstrruanncopcraipcroircmourunm)) pOeCHBECCSsD0 h1 epwaaeetta a19n05oto0|s GVraelvnestwgear(e acdjlusat sf reprcaepsreinctor1n)00% aci6ve inEgCrSed0ient [12 [Wtaalr19d95 "These values maybe inconsistent due to different diets tested. 000063 [Table SummaorfFoylogeal ToxicityDatsfor APFO (grobuysppeecieds) | Fatheadmia (Pimplespromelan) [FSREC70S0_[3Compa197n60 y, 6h LCSO 766 [3M Company, 1980u 1b9e6r1i1c5s0o J[4a0 "T[M3MCCoompamny,pt1o9w7as4bny| 1 6h LCSO 40" EN[TR Wilbury Laboratories.Inc... - | oo I 96H ECS0__ W227 TR. Wilbury LaboratoInrci.,e19s9,5 _ bewcso se Compan 1978 - | EE lnecso [p1" i BMComp1a98n7 y. i 1-day NOEC 22 13M Company, 1984 I rt] 3 [96hECO [900 TR. WilburyLaboratories. ine. 1995 [iPsEdhaEyCSEC)S0 fi|i f[Wnardal, 1081 1995 1 | lSonEc Be[Womainows 96hECSO [12 . Wactar l., 1d 995 --| 000064 Rvs aha phospream [So3mC0E5CS0m0 [i7350n0 C[5M Eonvimronam1en9.t Laborers, 1963 50mmiin EECCsS00 5620087 35EMM EmnviinmennslLabboorrerns..11990985 lo CL BominBcso 190M Evionmenal Laborary,19% [Raed its Fn NOEC [600 [Compr | 1S30o-mmin ECCSS00_~>1000007 [35MM CEonvmipraonnym,en1t9al87L0 abor19a90,] aheissneceaeyode eeasptsdToO1OactirvererrhttEac. a oa] TTeeneeldd bbromanemeasss wwwaasss AAAPPPFFFOOssnaonamassml S04 war: TTocueldSahemmatinmeceAeBwwReassiAADPnFFnOOanm1m590o%% wprasotpetananonld.M31r.2w4aes.oprano a 000065 5.0 References 3M Company. 1976a. Primary Eye Irritation Study-Rabbits. 3M Company. 1976b. Acute Oral Toxicity in Rats-T-1585. 3M Company. 1977. Ready BiodegradoafFtCi-1o4n3 (BOD/COD/TOC). Environmental Laboratory. St. Paul, MN. 3M Company International Research and Development Corporation. 1978b. Fluorad Fluorochemical FC-143 Acute Oral Toxicity (LD) Study in Rats. Study No. 137-091, 3M Company. 1979. Technical Report Summary - Final Comprehensive Report: FC-143. (USEPA AR-226 528) 3M Company. 1980c. ReadyBiodegorfFaC-d14a3(BtODi/CoODn). LabRequest No. 56255. Environmental Laboratory. St. Paul, MX. 3M Company. 1981. Water, Acetone and Toluene Solubility Estimates. Environmental Laboratory. St. Paul, MN. 3M Company. 1984. Chronictoxicityto freshwater invertebrates. 3M Company. Environmental 19854. 96-hour acute static toxicity to fathead minnow Laboratory, St. Paul, MN. Lab Request Number C1006. -- FX-1001. February 2. 3NoM.CC1o0m0p6.anyE.nvi1r9o85nbm.entRaeladLyaboBriaotdoergyr.adaStt.ioPnaoulf, FMXN-.100Fe1br(uBaOrDy/1C4.OD). Lab Request 3M Company. 1987. Activated Sludge Respiration Inhibition Test. Environmental Laboratory: LabRequest Number E1282. St. Paul, MN. S3uMlfoCnoatmep:anCyu.rre1n9t99s,um"mTahreyoSfciehnucmeoanfsOerrga,ahneiacltFhl,uoarnodchteomxiicsotlroyg"yadnadta"".PerFfelburouraoroyct5a.ne1999. (SEHQ-0299-373). 3M Company. 1999. SEHQ-0699-373. Supplement. May 26. 1999. 3PeMrfCluoomrpoaonctya.ne2s0u0l0fao.niVcolAucnitdaaryndUVsaerainodusESxaplotsFuorremsI.nf3orMmaCtoiomnpParnoyfilseubfmorission to USEPA, dated April 27. 2000. 000066 3`AMcidCoamnpdaSnaylt.s. 2300M0bC.oVmoplaunnytasruybUmsiessainodn tEoxpUoSsEuPreA,IndfaotremdatJiuonne P8r,o2fi0l0e0.for Perfluorooctanoic i3MtCopmp.any3,M.2c0o00mc/.aboAubto3utm/3wMorlWdowrilddewirdeel:eas3eMhtPmhlasing Out Someof Its Specialty Materials. 3LaMboCroatmoprayn,yJ.un2e00251.a. InEnUv.iS.ronEmPeAntAadlmiMnoinstirtaotriivne-gReMcuolrtd-CAiRt2y2S6t-ud1y0,3304M Environmental 3M Environmental Laboratory. 1990a. Microbes Microtox Toxicity Test. St. Paul. Minnesota. Lab request number G2882. 3MiMnnEensovtiar.onLmaenbtRaelqLuaebsotrantuomrbye.r1G99208b8.2.Activated Sludge Respiration Inhibition. St. Paul, P3aMul,EnMvNi.ron3mMenLtaablorLaatboorriaetso.ry.3M199L3u.bIRmepqiunegsetrNSutumdbieesroLf3V0o6l,atility of FC-95 and FC-143. St. 3LMabEnRveqiureosntmennutmableLrabPo1r6a2t6o.ry.St. 1996. Paul, Microbes Minnesota. Microtox( Toxicity Test of FC-143. 3M Environmental Laboratory. 1996b. Microbes Microtox Toxicity Test of FC-118. Lab Request number P1626. St. Paul, Minnesota. 3ReMquEensvtirnounmmbeenrtaPl16L2a6b.oraStto.ryP.aul,19M9i6ncn.esoMtiac.robies Microtox Toxicity Test of FC-1015-X. Lab L3aMb ERnevqiureosntmeNnutmableLrabEo0r0a-t1o3r5y1.. 20M0a1rac.hH3y0d.rolysis Reactions ofPerfluorooctanoic Acid (PFOA). S3tManEdnavrir-donTmeesnttCaolntLraoblorRaetfoeryr.en2c0e01#bT.CRC-h9a9ra0c3t0e-r0i3z0at.ioPnhSatsued:ySoolfubPiFliOtyA D(eltoter#m3i3n2a)t.ioPnr.im3aMry Laboratories. St. Paul, MN. cAabrdceilnloagtein,eAsiGs.byPrpeeart,flVu.,orToaopcetran,oiIcLSa. ancdapRioebreordxfirsoio,dm,eMp.rol1i9f9e1r.atoTrh.eTomxoidcuolla.tiAopnpol.frPaharlimvaecrol. LL: 530-537. AFlineaxlanRdeepror,t.BH.Div2i0s0i1oan. ofMoErntvailriotnymsetnutdaylofanwdorOkcecurpsaetimopnlaolyeHdeaalttht,heSc3hMooClototfaPgueblGircovHeealftachi,lity. University ofMinnesota, April 26, 2001. o 000067 ARelpeorxta.ndDeirv,isiBH.on2o0f01Ebn.viMroorntmaelnittaylsandtOocfucwuopdartkieyornsalemHpelalotyhe,dSacthothoel 3ofMPDuebcliactuHreaflactihl,ity. Final Uniovf eMinnresosta,iAprtil2y6, 2001 Behar, B.;Stein, G. Science 1966, Vol. 154. p.1012. SByesatcehm,. S.31M99C5o.mpIannhyib,itEonrvyiErfofnemcetnotfalL-L1a3bo4r9a2totroyM,iSctroPbaiucls,MMNi,cLraobtoTMRexqTuoexsitcintuymbAenarlNy2z1e6r9. July 26. BEnevaicrohSn,m.en1t99a5lb.LabIonrhaitboirtyo,ryStE.ffPeacutlo.fMNL-,13L4a9b2RoenquAecsttivNa2t1e6d9S,luJdugley. 3M 26. Company Beixctgrealh,epLatLiBc,tHuumrtotr,iMn.dEu.c.tiFornabmye,p$e.rRo.x,iOs"oCmoenpnroorli,feJ.rCa.,toarsndinJm.Ca.leCoCoDk.rat2s.001T.oxMiceoclhoaginciaslms of Sciences. 60: 44-55. Biodynamic Inc. 1979. An Acute Inhalation StoufTd-23y05 CoC in the Rat. 3M Company, St. Paul. MN. Project No. 78-7184. Biosearch, Inc. 1976. Primary Eye IrritationStudy - Rabbits. PhiladelphiPaA,. 3MCompany. St. Paul, MN. Boeri, R, Magazu,1, Magna. T-R. Wilbury Ward, T. 1995a. Laboratories, Inc., Acutetoxicityof L-13492 3M Company Lab Request to the Daphnid. number N2332, Dap/mia July 13. BPoiemreip,haR.l,esMapgraomzeul,a1s., WTaR.rd,WilT.bu1r9y95Lba.borAactuotrieesT,oxInicc..it3yoMf CL-o1m3p4a9n2tyoLtahbeRFeaqtuheesatd nMuimnbneorw, N2332. July 13. Boaenrdit,heR.F,reMsahgwaaztue,rJA.l,gaW,aSredl,enTa.st1r9u9m5cc.apGrircoowrtmhutaunm.d reT.pRr.odWuictlibounryToLxaibcoirtaytoTreisctsw,iItnch., 13.1M3492 Company Lab Request number N2332. August 3. BPimoephRea.l.eKrsopwraiolmsek,lia,s.P.T,R.WaWridl,buT.ry1L9a5bdo.ratoArciuetse, TInocx..ic3itMy oCfoNm2p8a0n3y-,2L1a0tbhReeqFuaetshteandumMbienrnow N2803-2. November 16. PBioemreip.haR.l.esKopwraolmseklia,s.P.,T.WRa. rdW,ilbT.ury19La9b5o.ratAocruitees, TInco., x3MiofCcoNm2i8p0ta3n-yy4 LtoatbhReeqFuaetshteanduMmibnenrow, N2803-4. November 21. " 000068 BoNe2r8i0.3-R.2 anKdowtahlesFkrie,shPw.,ateWrarAdl,gaeT., S1e9l9e5nfa.siGrurmowctahpiacnodrnRueptruomd,ucTt.iR.onWTiolxbiucirtyyLTaebsotrawtiotrhics, Inc. 3M Company Lab Request number N2803-2. Novernber 28, aBonerdi,tRh.e,FKroewsahlwsaktie,r APl.,gaW,arSdel,enT.ast1r9u9m6c.apGircoorwmtuhtuann.dRTepRr.odWuicltbiuornyTLoaxbiocriattoyriTeess,t Iwnic.th3NM2803Company Lab Request number N2803-4. March 7. BMoaegrnia,.R.,T.KRo.waWlislkbiu,rPy.L,abWoarradt,oriTe.s.1n9c9.6.b.3MAcCuotempTaoxniyciLtayobfReNq2u8e0s3t-n4utmotbehreND2a8p0i3n-i4d., DMaaprhcnhia 2s. mBaoegrnia,.R.T.RK.owaWlislkbiu,ryP.L,abWoarradto,riTe. s,1I9n9c6,c.3MAcCuotempTanoyxLaibofcReNqi2u8et0s3ty-N2utmobtehre DNa2p8h0n3i-d2,.DaMpahrnciha 25 BSooiyl.d.MSi.ch1i9g93aan.StRateeviUeniwveorfsTiteyc.hniMcaayl R19e,port Summary: AdsorptoifoFCn 95 and FC 143 in Boyd, S.A. 1993b, Review of Technical Notebook. Soil Thin Layer Chromatography. Number 48277, p30. Michigan State University. sBeuvrerriasl, IfMu;orOolcsheenm,icGa:lsS.impInstoenr,imC:ReMpaonrdtel#.1,J.Co(r2p0o0r0a)tDeeOtcecrumpiantaitoinoanlofMesdeircuimnehaDlfe-plairvtemseonft, 3M Company. Cacaimdesroonn,heRp.aGt.ocmaaricdiano,geK.nesTissudiani,tiHa.teadnbdyldti,ctN.hyl1i9t8r2o.saPmrionmeo.tiCvaencefefrecRtesso.f4s2t:e2r4o2i6d-s2a4n2d5.bile Carlfors. J. etal. Colloid Interface Sci. 103, 332 -336.(1985) CdawhleyaraMtns..,RAdriclher.y,TaoMx.iGo,.c1o.l.an66d:J4o9hn6s-o5n0,2D.E. 1992. Sponancous neoplasms in aged spragucCShyamppions,iRuEm, oSvteervvieenws:,en1.Td.,ocHruignheemso,dCu.lLa.t,ioKnelocfer,epWr.oRd.u,ctHieosns., FRu.nAd..anApdplD.asTtooxni,coGl..P.20:119-9167.. CMhaejmogruBarreda,k2h0r0o0u.ghChinemAgFuFaFrdFiIrnec.F.igPhrteissngRFeloeaamseTeRec:hnCohleogmyg.uaJrundeI3n0c,or2p0o0r0a.ted Announces CMliicset,oFpihnearl,RBe.poarntd, MIandruisatsr,iaAl.BJ.io-1T9e7s7t. L2a8b-oDraaytoOrria,l TInocx.icSittuydyStNuod.yw5i3t2h-F1C0-65154,3 3inMAlRbeifneorence No. T-1742CoC, Lot 269. a 0C0063 hCylpeegrgp,lEasDi.a,aCnadoakd,eJn.Co.ma, Cfhoarpmiatni.onR:.E.m,eFcohsatenri,smPsMa.nDd.raenldevDanacsettoonh,umGa.P.ns1.997R.epLreoyddui.gceTlolxicol 11 107-121 CInLfOoGrPm(at4i.o7n1S)ysteCmsa, Ilnc.cwwuowf.ldhayaydlriotgphhitobcioocimnty as Log P(o/w). 2001. Daylight Chemical Ciondoukc.tiJo.nC.byHupretr,oxMiEs.omeFrparomlei,ferSa.tRo.r.sainndCeBli:egel,BLRB(.CD1)99r4a.ts.MToexiccolohgiasot,fn1ex4it:r3a0sh1e,mpaabtssitcratctum#or 1169. bCeuhtatvsi,orJH.ofatnudmoNrosb.leC,anRc.Le.r R1e9s6.4.24E:s1t1r1o6n-e1-1i2n3d.uced mammary tumors in the rat. 1. Induction and PDearkfionr,ma20n0c1e. CoNaotbiunhgsi"koinTsPauidnat,&DaCiokaitniInngduIsntdruisetsryLiMda.g,a"zFilnueo,roJpuonley2m0e0r1E,mpu. l5s6i-o6n6.for HighSDeCrPvi.ce1s9.95D,allDaisr,ecTtXo.ryofWorld Chemical Producers: 1998 Edition. Chemical Information UDuSPEoPnAt., 2d0a0t0e.d JVuonleun2t3,ar2y00U0s.e and Exposure Information Profile. DuPont submission to 3DyMnAaF,F2F00A0g.enLte,tedratferdomAuEgduusatrd2K,l2e0i00n.er (Dynax) to Charlie Auer (USEPA), Re: Phase-Out of Edwards, PIB etal, LANGMUIR 13(10), 2665_2669 (1997) 7E8G.0&3GonBihoatncohmaibcilsiAtqyuoaftiegcgTsoaxnidcoglroogwythLaabnordastuorrvyi.val1o9f78f.ryThoef feaftfehcetasdomficnonnotwin(uPoiumsepeixhpaolseusre 0 promelas). Report ABW-78-6-175. Research reportsubmto 3iMCtomtpaney,dSt. Paul, MN aEl8lispDot.enAt.i.a.l SAo.urMceabofurhayJl,o.gWen.atMeadrtoirngaannidc Da.ciCd.s Gin.tMhueiernv2i0r0o1n.meTnht.ermNaotluyrses: o4f12f,lupopr.o3p2o1l-3y2m4e.rs AEllgnaalbaArawsy,TMesTs.tMaet19h8yo1.d. 3RMepToercthnNiucmalbeRre0p0o6r.t SPurmomjeacrtyN,uMmubleir-P9h9a7s0e03E0x0p0o0s.urOec/tRoebcoevre1r6y. PEnivmierpohSaytsetsepmrso,mIenlc.as.19H90aam.ptSotant,icNAHc.utSetuTdyonuxmbioefrcFwXia-s1t9000y134-t3o.the Fathead Minnow, 000070 EHnavmiprtooSny,stNeIHm.s,EInnvc.ir1oS9y9s0t.emStsastitcudAycuntuembTero9x013io-f3cFXi-1t00y3 to the Daphnid, Daphnia magna. EST. 2000. Cheryl Moody and Jennifer Field, "Perfluorinated Surfactants and the Environmental Implications ofTheir Use in Fire-Fighting Foams" in Environmental Science & Technology, Vol. 34, Issue 18, p. 3864-3870. FMG. 2001. Verbal comments by the Fluoropolymer Manufacturers Group of the Societyofthe Plastics Industry. FMG/EPA meeting. March 7, 2001. Gabriel, Karl. Summary of: Primary Skin Irritation Study ~ Rabbits. Performed by: Biosearch. Submitted to 3M Company, 3M Center. St. Paul, MN. GSaubbrmiietlt,eKdatrol.3MSuCmommapraynyof.: 3PMriCmeanrtyerE,ySet.IrPraiutla,tioMnN.Study -- Rabbits. Performed by: Biosearch. Garry, V.F., 10 % Clonal and Cell RL. Nelson. Line for the Te1s9t81C.heAmnicAaslsaTy-o2f04C2elCloCT.ran3sMfoCromamtpiaonnya,nSdt. Cytotoxicity Paul, MN. in C3H GAamimsoyn.iLuP.mDPr.erfl19u9o5r.ooc3taMnoraeteq:uesStteatdiecxFpiesrht Toevset"r.vieGweoifsy"BEciootaocxciucmoulloagtyi.veIncP.ropMearrtciehs2o0f. GiesJy. P.andK. Kannan, 2001a. Accumulationofperfluorooctanesulfonate and related fuorochemicals in fish tissues. Preparedfor 3M, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A Giesy1. P.and K. Kannan, 2001. Perfluorooctanesulfonate and related fluorochemicals in fishcating water birds. Prepared for 3M, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A GiesyJ. P. and K. Kannan, 2001. Accumulation of perfluorooctanesulfonate and related fluorochemicals in mink andriverotters. Preparedfor 3M. St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A GicsJy. P. and K. Kannan,20014. Perfluorooctanesulfonate andrelated fluorochemicals in oyster, Crassostrea virginica, from the Gulf of Mexico and Chesapeake Bay. Prepared for 3M, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A GiesyJ. P. anJ.dL. Newsted, 2001. Selected fluorochemicals in the Decatur, Alabama area. Preparedfor 3M, St. Paul MN, Project 178401. June. In U.S. EPA Administrative Record AR226-1030A @ 000071 Gibson. S.J. and Johnson, 1D. 1979. Absorptionof FC-143-14C In Rats Afiear Single Oral Dose. Riker Laboratories, Inc. Subsidiary of 3M, St. Paul, Minnesota Gibson. S.J. and Johnson, 1D. 1980. Extent and Route of Excretion and Tissue Distribution of "Total Carbon-14 in Male and Female Rats Aftear Single IV Dose of FC-143-14C. Riker Laboratories, Inc.. Subsidiaryof3M, St. Paul, Minnesota Gibson. 5.1. and Johnson, 1.D. 1983. Extent and Route of Excretionof Total Carbon-14 in Pregnant Rats Aflear Single Oral Doseof Ammonium 14 C-Perfluorooctanoate. Riker Laboratories. Inc.. Subsidiaryof 3M, St. Paul, Minnesota Gillet, James. 1993. 3M-requested expert reviewof"Bioaccumulation Studies". Comell University. March 8 Gilliland. F. 1992. Fluorochemicals and Human Health: Studies in an Occupational Cohort. Doctoral thesis, Division of Environmental and Occupational Health, UniversityofMinnesota. Gilliland. F.D. and Mandel, LS. 1993. Mortality among employeoefsa perfluorooctanoic acid production plant. JOM. 339): 950-954, Gilliland, FD and Mandel5,. 1996. Serum Perfluorooctanoic acid and hepatic enzymes, lipoproteins, and cholesterol: astudy ofoccupationally exposed men. AmJ Ind Med 29:560568. Gaza, S. 1995. Acutedermal toxicity sudyof T-6342 in rabbits. Coming Hazelton, Inc. MadisonW,I. Project ID: HWI 50800374. 3M Company. St. Paul, MN. Gaza, S.M. 1997. Acute Oral ToxicityStudyofT-6669 inRats. Coming Hazleton Inc. CHW 61001760. January 10. Sponsored by 3M. St. Paul, Minnesota. Goldenthal, E.I. 1978a. Ninety Day Subacute Rat Toxicity Study. Final Report Preparedfor 3M, St Paul, Minnesota, by Intemational Minnesota. November 6, 1975. Research and Development Corporation, St. Paul, Goldenthal, EI. 1978b. Ninety Day Subacute Rhesus Monkey Toxicity Study. Final Report Prepared for 3M, St Paul, Minnesota, by Intemational Research and Development Corporation, St. Paul, Minnesota, November 10, 1978. Gortner, E.G. 1981. Oral Teratology Study of T-2998CoC in Rats. Safety Evaluation Laboratory and Riker Laboratories, Inc. Experiment Number: 0681 TRO 10, December 1981 Gortner, E.G. 1982. Oral Teratology StudyofT-3141CoC in Rabbits. Safety Evaluation Laboratory and Riker Laboratories, Inc. Experiment Number:0681 TBO398, February 1982. a 000072 Griffith,F.D., Am. Ind. Hyg. aAnsdsoLc.onJ. g41L(E.8)1:958706.-5A8n3i.mal toxicity studies with ammonium perfluorooctanoate. pHearnfhlijuaorrvoio,ctHa.,nOoaptheaeuxgcr,etRi.oHn.,inanthdeSriantg.erP,roLc.. 1982. Soc. The Exp. sex-related Biol. Med. difference 171:50-55, in pHearfnlhuoirjooactHra.vn,oiMi,c.alciidnednu.rAi.ng sKoujboc,hraonndicV.adKmoinsimsat.rat1i9o8n7.inEtlhiemiWniasttiaornraat.ndPthoaxrimcaictyolo.fToxicol. 61: 66-68 HanhijarviH,. etal. 1988. A proposedspeciesdifference in the renal excretioofn pNeerwflDuoervoeolcotpamneoinctsaciindBiinostchieenbceeasg:le TdhoegiranIdmprlaitcaItni:onBsefyonreLna,bAo.rCa.taonrydAHn.iAm.aSlolSlceiveencled.(Eds). Martinus Nijhoff Publishers. Dordrecht, Netherlands. CHoaenfsfcichi,eCntsa.ndSuLbesot,itAue(nEtdsC.o).nst1a9n7t9.s fCohraCpotrerrelIaVt,ioTnheAnFarlaysgimsenatndMeCthhemoidostfrCyaalcnudlBaitoeldogPya.rtiJtoihonn Wiley and Sons, Inc. HatfieldT,. 2001. Screening Studieson the Aqueous Photolytic Degradatioofn Perfluorooctanoic Acid (PFOA). 3M Environmental Laboratory. Lab request number E002192. St. Paul, MN. Henwood.S. 1997. Inc., MadisonWI,. 5Daily Dose OralToxicSitutdywith Laboratory Project Identification: CHW T-6669 in 6329-197. Rats. 3M Coming Hazleton, Company, St. Paul, MN. Hpeerufvleulo,roJoPc.tVa.noeitcaal.cid19i9n1.maTliessauneddifsetmrailbeutriaotns., mJ.etBaibooclhiesmm., Taonxdiceolliomgiyn.ati6o(n2)o:f83-92. Heuvel, JP.V. etal. 1992. Renal excorfpeerfltuorioocotannoic acid in male rats: inhibitory effect of testosterone. J. Biochem. Toxicology. 7(1): 31-36. Heuvel, Plasma, JP.V. Liver, etal. and Te1s9t9e2.soCfoRvaatls.entChBeimn-dBiinogolf IPnetrefralcutoironisn.at8e2d:3F1a7t-t3y2A8c.ids to Proteins in the HBioowaeclclumRu.lD.a,tivJeohPnrospoenr,Jt.iDe.s,oDfraAkmem,oJn.Bi.u. mYoPuenrfglbuloormoo,ctRa.nDo.ate1:995St.atiAc.sse3sMsmTeencthnoif tcahle Report May 31 000073 iTnherdaat. liTv..erAbiybap,eKr.f,luForuiknuadtae,dKf.attayndacTidasn,akmaet,abM.oli1c9a8l5.lyTihneertinddeurcitvaitoinovefspoefrfaotxtiysoacmieds.prJo.liferation Biochem, 98:475-482 Industrial Bio-Test Study with FC-143 LinabAolrbaitonroieMsi,ceI.nc. 1B1T97N7o.. 8R5e3p2o-r1t06t5o53. M Company: 28-Day Oral Toxicity SIntduudsytrwiailthBiFoC--T1e4st3 LianbAolrbationroieRsa,ts.Inc.1BT19N7o7..85R3e2p-o1r0t65t4o.3M Company: 28-Day Oral Toxicity JSothundsyoonf, T.-D6.061799in5.RabFbiintasl. ReSptourdty, NAnuamlbyetric:alAMSDtTu-dy1.20S6i9n4gl.e1-.Dos3eMInEtnrvaivreononumsenPthaalrmTaeccohknionleotgiyc &Services, St. Paul, MN. TJo6h0n6s7o.n,TJ-.6D.0681,99a5nb.d FTi-n6a0l69ReipnorRtab,bAintasl.ytSitcuadlySNtuudmyb,eSri:ngAlMeD-TD-o0s1e1A0b9s5o.r1p.tio3n MToxEincviitryonSmteundtyalof Technology & Services. St. Paul, MN. Johnson, carbon-14 J.D, Gibson, in rats after aSd.Jm,inainstdraOtbieorn,ofR.aE.mm1o98n4i. uCmho[l1e4sCtpyerrafmliunoer-oconchtaanncoeadtefeocralpoctlaismsiniautmion of [14CIperfluorooctanesulfonate. Fund. Appl. Toxicol. 4:972-976. KachanovaZ,. P.; KosloJv. ,N. Zh. Fiz. Khim. 1973, Vol. 47. p.2107. pKearwlalsuhoriom-ao,ctYa.n,oiUcya-cYiud,ofNp.earnodxiKsoozmakeaf,-o1x.id1a9t8i9o.n,Semxi-crreolsatoemdaldifIf-earceynlcgelyicnetrhoelpihnoduscpthioocnhsolbiyne 0ac0y.ltransferase and cytosolic long-chain acyl-CoA hydrolaisne at iver. Biochem. J. 261: 395- PKheanrnmeadcyo,l.GL$.1(21)9:8354.8-3D5e5r,maltoxicityof ammonium perfluorooctanoate. Toxicol. Appl. pKeerfnlnueordoyoc.taG.nL. oa1t98e7.anIdncrreelaasteed ifnlumooruoscehleimvicearlws.eiTogxhicoflo.lloLweittng3f9:2e95-e3o0f0d.amimonniugm tKoxice ity on fGa.mLm.n,oHnalielu,mGd .pTe.r,fy lBuroirtot,oeclltia,nMoa.tRe.., Bames, J.R., Food Chem. and Chen, H.C. 1986. Inhalation Toxicol. 24(12):1325-1329. Kidde. 2000. KiddeFire Fighting, `Manufacture, May 30. 2000. Press Release Re: 3M Withdraws fromFireFighting Foam C0074 OKrigrakn-iOtch(mHeirg,he1r99A4c.id"sF)l"uoirniKniatrekd-OHtihgmheerr ECnaerybeolxoypliecdiAaocifdsC"heumnidcearl"FTleucohrnionleoCgyo,mp4o"uendd..s,Vol. 11.pp. 551-558, LaCwolloiMra,mTmEa.lia1n99-6m.icMruotsaogmeeniRceitvyeTrseestMwuittahtiTo-n6A5s6s4ayinwtihetSahalCmoonnfeilrlmaat-orEyscAhsesraiyc.hiaComing Hazleton Inc. Final Report. CHVStudyNo: 17750-0-409R. Septemb1e3r. cLoawlliofrm,amTm.al1i9a95n.-miMcurtaogseonmiecirteyvteerssetwmiutthatTi-on63a4ss2ayi.n theSalmonella-Escherichia Laboratory Number: 17073-0-409. Coming Hazleton Inc, Vienna, VA. 31 Company. St. Paul, MN. Lprioul,ifRe.raCtMo.r,,aHmumtot,niMu.Em.,peCrofolku,orJo.oCc.taannodatBeic(gCeSl),,LoBn.he1p9a9t6i.c Eafrfoemcatotafsethaectpievritoyxiisnoamdeult male CrliCD BR(CD) rats. Fund. Appl. Toxicol. 30: 220-228, LEixup,re5s.Cs.i.onSaonffitlriapnpsof,orB.m,inPgergrrootweatuh,fIa,ctDoerrayn(cTkG.FRa.) Sinaldoifmfoenr,enDtiSa.tedanrdat Kmiadwmemlal,ryW.tRu.mor1s9:87. estrogen induction of TGFa production. Mol. Endocrinol. 1: 683-692. Longnecker, DS. 1987. Interface between adaptive and neoplatic growth in the pancreas. Gut, 28253258, LSD. 2000. www. Ipsd.zzzip. nevprojeets him LunS.;aSedkiak,,P. Photoinitiated ReacotfHiydorongesn Peroxide inthe Liquid Phase. J. Photochem. Photobiol. A.: Chem. 1992, Vol.68. pp. 1-33. M3eMndTeelc.hnAi.ca1l97N8o.teSbooilokT.hiOnctLoabyeerr C13h.ro1m97a8t.ogNruamphbyer 4--8F2C-7975.,pF3C0.-14Pr3o,jeFcMt-3N4u2m2b.erEx9c9e7r0p6t1f2r6o0m. MFientarlicRke,poMr.t,anIdnduMsatrriiaasl,BAi.oJ-.Te1s9t77L.abo2r6a-tDoraiyesO,raIlnc.ToxSitcuidtyyNSot.ud8y5w3i2th-1F0C-6153443M.inReAflebriennoceRatNso,. T1742CoC, Lot 269. September 29, 1977. MimopoadctyeCd.bAy. fairned-fJi.ghA.tinFgiealcdt,iv1i9t9y.9.EnDvireon.tScie. Treochfmnpoelri.fl1un9or9o,aca3r3tb,o2xi8y0l0ao-t2e8sni06n. groundwater Muri, H. 1995. Mutagenicity test on T-6342 in an in vivo mouse micronucleus assay. Coming Hazleton Inc.. Vienna, VA. 3M Company. St. Paul. MN. nMuumlbeirH,.17715909-60a-.45M5.u3tMaCogmpetaennsyti.oSnct.Ti-P6atu5l6y,4MNin.anin vivo mouse micronucleusassay. Study " 0C0075 CMhuirnie,seH.Ha1m9s9t6ebr.OMvuatrayge(nCiHcOit)yCTeellsst: owniTt-h65a6C4onMfeiarsmuartionrgy CAhsrsoamyowsiotmhaMlulAtbieprlreatHiarovnesstisn. Final Report. Coming Hazleton Inc. CHV Study No.: 17750-0-437CO. September 16 MBluoloid, LH.ym1p9h9o6c.ytMeustaWgietnhiaciCtoynTfeisrtmaotnoTr-y6A3s42s,ayMeWaistuhrMiunlgtiCphlreoHmaorsvoemsta.l CAobmenrirnga-tHiaozinensltWonh,olInec. (CHV). Vienna, VA. CHV Study No.: 17073-0449C0, MHaumrsit,eHr. O1v9a6rdy.(CMHutOa)geCnelilcsi:tywiTtehstaoCnonTf-i6r3m4a2t,orMyeaAssusraiyngwiCthhrMoumlotsipolmealHarAvbeesrtrsa.tiCoonmsiinngC.hinese Hazelion, Inc. (CHV). Vienna, VA. CHV Study No.: 17073-04370. Nihlespastoonc,aRr.c,inBoegiejen,cBi.t,yoPrfeapte,rVo.x,isEormiexopnr,olKi.fearantdorRs.amCheelmC,..-B1i9o9l1.. IOntnertachte. m7e8:c23h5-a25n0o.ifstmhe NOTOX. Cultured 2000. Evaluation Peripheral Human ofthe AbiolfTi-7t52y4 Lymphocytes. NOTOX to Induce Chromosome Project Number 292062. Aberrations in Hertogenbosch, "The Netherlands. N(MOaTxiOmXi.sati20o0n1-.TesAt). sNOsTOoXef PCrsoonjteacstctnHumympbeeresren2s9ni2t0i2vt7i.tyHteortTo-g7e5n2b4osicnht,heTAhlebiNnetoheGruliannedsa. Pig Nubbe, M. E.; AdamsV,. D.; Moore, W. M. TheDirect and Sensitized Photo- oxidation of Hexachlorocyclopentadiene, Wat. Res. 1995. Vol. 29, No. 5,ppl287- 1203, OMbecohuarnni,smJ.s0.,foFrratmhee.paSn.cRr.,eaBtiecloln,coRHg.eJnri,c LeoffnegcntseocfketrheDpSe.roxElilsiootmte, Gp.rSo.lifaenrdatCorooWyke,thL.C1.41,969473.. "Toxicol. Appl. Pharmacol. 145: 425-436. OECD Guideline for TestingofChemicals, Phototransformationof Chemicals in WaterDirect and Indirect Photolysis, (Draft Document); OECD, 2000,ppl-59. Ogata, Y.; Tomizawa, K.; of Peroxides 1983, p.720 Furuta, K. Chemistryof Peroxides. in S. Patai (ed), The Chemistry Olsen. G.W. etal. with Occupational 1998. An Exposure tEopPiedrefmliuoolroogoicctaInnoviecstAicgiadt.ioJnoOEfM.Rep4r0o(d7)u:c6t1i4v-e62H2o.rmones in Men Oclhsoelne.cyGst.okWi.ni,n,talh. ep1a9t9i8cb.fun3cMtioFninaanldRsepeorrutm: pAenrfleupoirdoeomcitoalnoogiiccaicnivdeslteivgealtsioinnopfropdluacstimoan workers. 3M Company. St. Paul. Sept . n 000076 eOlpsiedne,miGoWlo.giBcuranlaelwy,siMsoMf,epHioscokdiensgo,fBBca,reSkoraft3t,MDJCe,caButrurirs,chJeMm,icMalandaenld,fJiHlm. p2la0n0t1ae.mpAlnoyees, 1993-1998. Final Report. May 18, 2001 Olsen, GW, Burris, JM, LundbergJK,, Hansen, KJ. of fluorochemicals in sera of children in the United Mandel, JH, Zobel, LR. States. Interim Report. 2001b, Identification June 25, 2001 Olsen, GW, Burris, JM, Lundberg, JK. Hansen, KJ, Mandel, JH, Identificationoffluorachemicals in seraof American Red Cross Zobel, LR. adult blood 2001c. donors. Interim report. June 25, 2001. Olsen. 2001d. GW. Logan, Descriptive PW, Simpson, CA, summaryofserum Burris, JM, Burlew, MM, Lundberg, JK, Mandel, JH. fluorochemical levels among employee participants of the year 2000 Decatur fluorochemical medical surveillance program. 2001. Final Report. March 19, Olsen, GW, Mandel, JH. Schmickler, M, Tierens, JM, Logan, PW. Burris, JM, Burlew, 2001e. Descriptive summary ofserum fluorochemicallevels MM, Lundberg, JK, among employee participantsof the year 2000 Report. March 19,2001. Amwerp fluorochemical medical surveillance program. Final Olsen, GW,Madsen, DC, Burris, IM, Mandel, JH. 2001. Descriptive summaryof serum fluorochemicallevelsamong 236buildingemployees. Final Report. March 19,2001 Olsen, GW, Hansen, Clemen. LA, Burris, JM, Mandel, JH. 2001. Identification of Fluorochemicals in Human Tissue. Final Report. Department, 3M Company, St. Paul, MN 55144. Epidemiology, 220-3W-05, Medical "Malley, Study with K.D., and Ebbens, K.L. 1981. T-2618CoC in Albino Rabbits. Repeat Riker Application 28 Day Percutaneous Laboratories. St. Paul, MX. Absorption `Ophaug, R.H. and L. Singer. 1980. Soc Exp Biol Med. 163:19-23. Metabolic HandlingofPerfluorooctanoicAcid in Rats. Proc Pace Analytical. 1997. Ready Biodegradationof FC-126(BOD/COD). 3M Company Lab Request No. E1282. Minneapolis, MN. May 29. Pace Analytical. 2001. The 18-Day Aerobic Biodegradation StudyofPerfluorooctanesulfonylBased Chemistrics. 3M Company Request, Contract Analytical Project ID: CA097, Minneapolis. MN. February 23. 7 000077 PPaelrafzlzuoolroo,ocMt.aJn.oa1t9e93(.CATShiNrot.ee3n8-2W5e-e2k6-D1i)etianrMyaTloexiRcaisty. SFtiundayl wRietphorTt-.51L5a0b,orAamtomroynPiruojmect Identification HWI 6329-100. Hazleton Wisconsin, Inc. sPtausdtioeosr,ofTa.Pm.mLoenei,uKm.Pp,erPfelrruio,roMo.cAt.anaonadteG-iilnldeusc,edPJh.ep1a9t87o.meBgiaolcyhaenmdicpaelraonxdismoomrephproolloigfeircaatlion. Exp. Mol. Pathol. 47:95-109. dPeetteirtmsi.na1t9i99o.n oKfp. oPleatrruin,deertiavl.ati"zleodn-apmaiinro raecviedrsseuds-ipnhgaspeerlfilquuoirdicnharteodmactaorbgorxayplhiyc faocrids as on pairing agent" in J. Chromatography A, Vol. 833, 1999, pp. 147-155. R3eiMneCro,mEpAa.ny,19E78n.virFoantmeoenftaFllLuuoborroatcohrye.miJicunlaytlh1se0. Environment. Project Number 9970612613. Reiner. E.A. 1981. 3M Company Environmental Laboratory. St. Paul, Minnesota, Dec. 7. aRnednneTre,chn20o0l1o.gy,"GVrolo.wi3n5,g ICsosnucee7rnppO.ve1r34PAe-r1f6lu0oAr.inAaptreidlCh1e.m2i0c01als" in Environmental Scicnce RPeirkceurtLaanbeooruastoArbiseso,rIpntci.o,nSaSfteutdyy EwviatlhuTa-ti2o6n1L8aCboorCationrAy.lbi1n9o79.RabRbeiptes.atStA.ppPlaiucl,atMiionnne2s8o-tDaa.y Experiment Number: 09790AB04SS. Riker 1-371 LaboratoriesIn., Safety in Albino Rabbits. St. PEavuall,uMatNi.on ELxapbeorraitmoerny.t #1098838.3EBP0rOiTmSa.ry Skin Irritation Test with ScRriamsnuol,fLu.r3onB,ufPoes,tSic..AS;iP. er19c99,,PV.o;lM.e5a5l.lpiepr9.5P.5;-9M6a1nsour, M.Photolysisand Hydrolysoifs SimisterE,. etalJ..Chem. Soc, Faraday Trans. $8(20), 3033-41 (1993) Sheophalteinciupse,rAo.xKi..s.omAendperrosliofne,raKt.ioannadnDdePreileartreed,pJa.r1a9m9e2t.erTshseheofwfecntososfexp-errefllautoedrodoicftfaenroeincceasciind moinc. Biochem. J. 265:779-783 "STtearplaetso,geRn.iEc.,PoBtuerngteiasls,ofB.AA.m, maonndiuKemrnPse,rfWl.uDo.roo1c9t8a4n.oatTehe(AEPmFbOry)o-inFetthealRaTto.xiFcuintdy.anAdppl. Tox 4, 420-440 T10aktahgei,peAr,oxSiasio,mKe.,prUolmimfeermatuorrsa,,pTe.r,flHuaosreogocatwaan,oiRc. aacnidd Kanudropekraflwuao,r.ode1c9a91n.aicShaocritd-,tcearumseesxposure significant increases of $-hydroxydeoxyguanosine in liver DNAofrats. Cancer Lett. $7:55-60. " Coos Tcaarklaygib.ioA.maSrakie,r Kf.o,r Uhempmaetomcuarraci,noTg,enHeassiesgianwdau,ceRd. bayndpeKruorxoiksaowmae,pYr.oli1f9e9a2t.orHs.epJa. tEonmveirgoanl,y is an Toxicol. Pathol. 11: 145-149. tTerearndssf.orKm.iJn,g Rgormowmtehrtfsa,ctFo.rG-i.a ainndLeDyodrirgincgetllond.urJi.ng t1h9e90d.evIemlmoupnmoehnitsotfocthheemiractaltesdtest.ecMtoiloenc.ofCell Endocrinol. 69:R 1-R6. aTnRd. thWeilFbruersyhwLaatbeorraAtlograi,esS,elInecn.as1t99r5u.m GcraporwitchorannuduRne.prMoadrubclteihoenadT.oxMicAi.tySTteusdtywniutmhbNe2r8B0O33--3TH. PTi.mR.epWhiallbeusrpyrLomaebloars.atMoarribeIlnsec,h.ea1d9.96MaA..AcSuttuedytonxuicmibteyrof8N9218TH03-t3o the Fathead Minnow, mTaRg.naW.ilMbaurrbyleLhaebaorda,toMrAi.es,StInucd.y1n9u9m6bb.erAc8u9t2eTHTo.xicityof N2803-3 to the Daphnid, Daphnia CToomdpda.nyJ.W.Tec1h97n9i.calFCR-e1p4or3tPNhoo.to0l0y2s.is FSetburduyarUysi2n.g Simulated Sunlight. Project 9776750202, 3M USEPA 1998 Fate, Transport and Transformation Test Guidelines, OPPTS 835.5270 Indircet Photolysis Screening Test: EPAT12-C-98-099; United States Environmental Protection Agency, US. Govemment Printing Office:Washington, DC, 1998. ppl-22. USEPA 1998. Fate, Transport and Transformation Test Guidelines: 835.2110: Hydrolysis as a Function ofpi; EPA712-C-98-057; United States Environmental Protection Agency. U.S. Govemment Printing Office: Washington, DC. pVearnfdleuonroHoecutvaneoliJ,c.aPc.,idDainvimsal,eJ.aWt..s:SoImnhmiebristo,ryRe.ffaencdt oPeftteersstoons,teRrEon.e.1J9.92B.iocRheneaml. eTxocxirceotli,on of 131-36. pVearnfdlueonriHneatuevdefl,ayJ.Pa.cKidussltoipkirs,oB.1, aitnndtehPeeiptlenarssmsoan,,liRv.E.er1a9n9d1.tesCtoesvaolferantts.biCnhdienmg o-Bfil. Interact, 2:317.328. dViasntrdiebnutiHoenu, vmeelta,bo1.lP.isKmus,liaknids,elBiLm,inVaatinonoRaffpeelrglhueomr,oMo.cLt.anaonidPaectiedrsinonm,alRe.Ea.nd19f9e1bm,alTeirsassu.e J Biochem. Toxicol. 6(2):83-92. 9Vr9a7s0p6i1r,26G0.0A:..FaMteendoeflF,luAorrtohcuhre.mic1a9l7s9., 3AMnaTleycs7ihsnicfaorl FRleupoorrotcRheepmoirctalNsuimnbBelrue1g3i.llMaFiysh1. Project 000079 WaT.r,Nedviu,s,J.and R. Pimephales promelas. TR. BWoierlib.ury19L9a6bao.raAtcoruitees.tInoc. xLoaifbFRcCe-qi1ue0st1t5tynoumtbheerfaPt1h6e2a4d. minnow, 3M Company, St. Paul, MN. aWnd athTe.rf,Nerdvieu,s,sJalhgaanw,dSeRa.leBtnoaesreti.rrum19c96abp.ricGorromwutuhm.andTRr.eprWoidlubcutriyonLtaobxoircaittoyriteesst, with Inc. FC-1015 Lab Request number P1624. 3M CompanySt.. Paul, MN. mWaargdn.a.T.,TRN.eWvilibuu.r,syan,LdabRo.raBtooerriie.s, 1I9nc9.6.LaAbcruetqeuetsotxincuitmyboefr PF1C6-241.01t35oMDCaophmnpiadn,yD,aSpt.hnPiaaul, MN. WEenlvsihr,onSm.eKn.tal197L8a.borTaetcohryn.ica3lMReCpoormtpaSnuymPmraorjyec-tA9d9s7o0r6p1t2io6n3o3f:FFaCt-e9o5fanFdluForCo-c1h4e3miocnalsso,il.Report Numbe1r. St. Paul, MN. February27. Yheapgaetroc.ar1.cD.inJro.geannedsiYsagienrf,eRm.al1e98S0p.raOrgaule-cDoanwtrlaecyeprtatisv.esCtaenrcoeirdsReass. p4r0o:m3o6t8e0r-so36f85. Viinen. M.. Hanhijarvi, H. JagkonaIh,oan.dPeura, P. 1989. Stimulation by estradofitohle urinary excretionofperfluorooctanoic acid in the male rat. Pharmacol. Toxicol. 65:274-277. Ythleinreant.afMt.e.rsKionjgol.eAa.n.dHsaunbhcihjrdonrivciH,a.dmainnidsPteruatriao,nP.. B1u9l9.0.EnDviisrpoons.itCioonnotafmp,erTfolxuiocorlo.oc4t4a:n4o6i-c5a3c.id in 3 000080 AR226_ 1077 ANNEX 1 ROBUST SUMMARIES " 000081 HUMAN BIOMONITORING DATA Title: Identification of Fluorochemicals in SeraofAmerican Red Cross Adult Blood Donors TEST SUBSTANCE. Identity: PFOA and6other fluorochericals Remarks: The results reported are preliminary. The final reporti expected November 2001 METHOD Study design: Cross-sectional Manufacturing/Processing/Use: N/A Hypothesis ested: To determine levels of PFOA in the scrumof American Red Cross blood banks in 6regions of the US. Study period: 2000 Setting: N/A Total population: Serum pooled fr6oARmC blood bainnvakriosus geographicregionsin the US: Los MAnDg.eles, CA: Minneapolis. Paul, MN: Charlotte, NC: Boston, MA: Portland, OR. and Hagerstown, Subject selection criteria: Unknown Total# of subjects in study: 652 donors. age 20-69 years Comparison population: N/A Participation rate: N/A Subject description: No information was provided on the individuals from whom the sora samples were taken, Health effects studied: 7 fluorochemicals in human blood serum. including PFOA Data collection methods: Blood sera samples were analyzed using high-pressure liquid chromatography/electrospray tandem mass spectrometry (HPLC/ESMSMS). Details on data collection: No information was provided as to how the blood was drawn. stored, ct. Exposure period: Unknown--PFOA serum levels used as surrogate for exposure. 7 000082 Description/delineation ofexposure groups/eategories: N/A Measured or estimated exposure: NA Exposure levels: N/A `iSnttaetrivsatliscawlemreetchaoldcusl:ateAdr.ithCmeenttriaclmteeanndse,nrcaynagensd,dgiesotrmiebturtiiconmoefatnhseadnadts9b5y%agceo,nfgiednednecer., lreolciaatbiiolnityanadsstehesistmernestpeisctailvseo ibnetienrgacatniaolnyzteedr.ms will be done in the final report. A Other methodological information: N/A RESULTS qDueasnctritiabteiornes(ulLtLs:OQTh=e1m.e92anors2e.r1u1m) 0PF5O2A.3lpepvbe.l wAansal5y.s6epspbs.traTtihfeiedrabnygeagwea.sgewnadser<,laonwdergeliomgirtaopfhic location will be forthcoming in the final report. Study strengths and weaknesses: These data are cross-sectional data used to determine PFOS. plreveellismiinnatrhyergeepnoretr.alTphopeulsaatmipoln.e sNioz oithreelradteivseclryipstmiavlelinformation about the subjects is available in this Blood donors cannot be considered representative ofthe general populationofthe US. Research sponsors: 3M Medical Department, Corporate Occupational Medicine Consistency of results: NAINCLUSIONS REFERENCE Olsen. GW,Burris, IM, LundbJKe.Hrangse.n, KJ, MandeJlH,, Zobel, LR. Identification of Muorochemicals inseraof American Red Crossadult blood donors. Interim report. June 25, 2001. 13 000083 HUMAN BIOMONITORING DATA Tile: IdentificationofFluorochemicals in SeraofChildren in the United States TEST SUBSTANCE Identity: PFOA and 6 other fluorochemicals Remarks: The results reported arc preliminary. The final report is expected November 2001 METHOD Study design: Cross-sectional. Manufacturing/Processing/Use: N/A Hypothesis tested: To determine the serum concentrations of selected fluorochemicals in sample of children to provide a more specific understanding ofthe distribution of these compoundsin children. Swetruedyanpaelryizoedd: iCnhSiplrdinsgera19s9a9.mples were collected from January 1994 to March 1995. The sera samples Setting: NIA Total population: Not reported Subject selection criteria: The sera samples were provided (0 3M by the Universityof Minnesota DinefpeacrttiomnesntinofchPielddiraetnr.icsT.heTchheilydwreenrewearbeiarienseiddefnrtosmoaf 2l3arsgteactelsiniincatlhetrUalS.onTGhresoeupchAildsrternepptroecsoeccnatled with signs and symptomsofacute-onset pharyngitis. All ofthe children hadpositive throat cultures at the inital visi "Total#of subjects in study: n ~ 599 children, age 2-12 years Comparison population: N/A Participation rate: N/A Ssuabmjpelcetsdweesrcreitpatkieon.n: No information wasprovidedonthe children from whom the sera Health effects studied: PFOA levels in blood, as well as other fluorochermicals. Dchartoamactoolglrecatpihoyn/cmleetchtordossp:raByltoaonddseemramsaasmsplspeescwtreormeetcorlyle(cHtPedLCu/siEnSgMhSiMgSh-)p.resTshureeslaimqpuildes were collected from equal numbers ofmale and female children residing in 23 states. Details on data collection: No information was provideasd 10 how the blood was drawn, stored. etc. 80 000084 Exposureperiod: NIA cDhesiclrdirpet2nio+n1/d2eyleianerastioolndof exposure groups/categories: Blood sera samples were collected from Measured or estimated exposure: NIA Exposurelevels: N/A Statistical methods: Arithmetic means, ranges, geometric means and 95% confidence intervals wreasrpeecctailvcuelaitnetde.ractCieonntrtaelrmtsenwdiellnbcyedaondndcisitnrtihbeutiinoanlofreptohret.datAa breyliaagbei.ligtyenadsesre,slsomceanttioinsaalnsdotbheeiirng analyzed. Other methodological information: N/A ESULTS DLeLsOcrQibweasres1u.l9t2s:orTh2e.85.meAannalPyFseOsAstsreartiufmieldebveyl awgae,s g5e.n6dpeprb,. anTdhgeeroagnrgaephwiacsl<ocLatLiOonQwtioll5b6.e1 fpoprbt.hcTomhieng inthe final report. lSetvuedlsy isntrU.eSn.gtchhsiladrnedn.weNaoknoetshseers:descriptTihveesienfdoartamaatrieoncraobsos-ustectthieonsaulbjdeactta uissaevdaitloadbelteeirnmithnies PFOA preliminary report. The sample size i relatively smal, Research sponsors: 3M MedicalDepartment, Corporate Occupational Medicine Consistency of results: To date, no other data have been collected on PFOA serum levels in children. CONCLUSIONS NA FERENCE Oflusoerno,chGeWm.icaBulrsriisn,sJM,oefLucnrhdibledarrge,n JinK,thHeanUsneint,edKSJt,atMesa.ndeIln,teJriHm, RZeopboerlt,. LRJ.uneId2e5n.ti2f0i0ca1tion of si 000085 PHARMACOKINETIC STUDY Titles The sex-related difference in perfluoroocianaate excretion in the at TEST SUBSTANCE Identity: Perluorooctanoic acid (PFOA): also referred to as [1-CPerfluorooctanoic acid (ammonium salt, APFO) Remarks: Purity was not specified METHOD Method/guideline followed: Guideline not noted Test type: Mammalian Excretion Speciessteain/cell type or line: Holtzman rats Sex: Male and female: Ae and body weight range of animals used: Not noted Numberofanimals/sex/dose: TesCtongtrrooulp:gr4oumpa:le7s,f6emFaelmeasles Routeof administration: Oral gavage Vehicle:Distilled water Doses: 2 mg ofnonionic fluorine as APFO ina volume of 2 mL. Excretion routes, body fluids, and tissues monitored and/or sampled during study: Blood and urine Statistical methods used: See methods 2M4ethhouords rafetmearrgkasv:agAentirmeaaltsmewnetrweitphlaAcPedFOin.inTdhievibdulaolodmewtaasboallilcocwaegdetsoacnlodtsaancrdiftihceesdebryumcacrodlilaccetpeudncatfuerer: ncecnttarbiofulgiacticoang.esTwhaesvroelcuormdeedo.f tThheeufrioneccfolllueocrtiidoensc.ontinecnltuodfintghethseervuomluamnedoufriwnaetewrasusdeedtetormriinnseed tahtepH e51x0t.raTcthieontotteaclhnfilquuoer.ine content ofthe scrum and urinc was determined by the oxyeen-bomb reverse fFoorrccolnetairnaunocuesstiundfiuessioofnAofP$F%Omaanndniitnoulliin tihseotroatnsicwesarleinaeneasntdhetthiezefdemaonrdalthaertfeerymowraals vceainnnuwlaastecdanfnorulated dIrntarwaivnegnobulsooddosseasmpolfesA.PFTOheaunrdinianruylibnlawdedreergwiavsenaloscoaccahnnaunliamtaedltaondo.bifaion slerlialoacwo4l5il-enmctiginonesqouifluirbirnaet.ion apedrmiiondi.stbelroeoddaannddaudrdiinteiosnaamlpclleesarwaenrceectoelsltesctweedr.e pWehrefnorcmoeldletcotifeosntstwheereeffceocmtpsloeftepdr,obpernocbiedneocnidthweaosrganic. acid transport system 82 000086 hInethaertecruimalulcaatninvuelaetxicornetwiaosn sntoutdyn,eetdheed.ratTshweerreatsprweepraereddosaseddeisvcwriitbhedafmoirxtthuerecolfearraadnicoelatebsetlseedxcAePptFtOhaatnd unlabeled APFO. ESULTS Detailed results: 2T4uohroiunresa(fatserAaPdFmOin)isintruartinonaonfd thheadadosmee,afnemsaclreuamtnsoenxicorneitcefdl7uo6ri+ne2.l7evpeelrcoefn0t.o3f5tphpemd.oseofnonionic I1n.7mpalpems,9no.n2io1ni3c.5flpueorrciennetowfatshien dtohesesoefrunmo.nionicfluorine (as APFO) was excreted. A levelof44.0 + APFO was bound to a similar extent in the plasma ofmale and female rats (97.5% bound). Ilnimfienmaatlieos,n AocPcFurOswbaysanmaarckteidvelysercerdeutcoeryd mbeycphraonbiesnme,ciwdhi(cfhromis 5i.n8hi1b0i0t.e1d1bymlp/rmobienne1c0i0d.g) indicating that "afTtheerApPrFoOb/eniencuildi.n cTlheearAaPncFeO/rantuiloiwnascl1e4a.r5anfcoer fraetmiaolwearsat0s..22Thfeorrmatailoesw,aasnddecdreecarseeadse(d00t.o406.1i2n affetmearles probenceid CONCLUSIONS Tisheexacurtehtoerdsincopnarctlubdyedanthaacttitvhee sheicgrhetAiPoFnOm/eicnhualniinsmc.leaTrahnecedercarteoasien ifnemtaheleAsPpFrOoivniudeldinevcildeeanrcaenctehartaAtoPiFnO AFePmaFlesthfarnominu14l.5intcol0ea.r4a6ncaefsteirntbhoethadsmeixneisstarfatteiroandmofinpirsotrbaetnicocnidofsupprpoobretnsccthiids icnodnicclautseiodnp.artTiahletluobwuelarr arecacbosuonrtpstifoorn otfheAgPreFatOerintobxoitchitsyexoefs.APTFhOisisnemcraeltorrya.mechanism is lacking or inactive in males and REFERENCE eHxacnhriejtairovni,in Ht.heR.ra.OpPhraoucege,dainndgsL.ofStihnegeSr.ocie19t8y2.forTEhxepesrexi-mreenltaatledBdiioflfoegryenacnedinMepdeircfilunoer:oo1c7t1a:n5o0a-5t5e. 83 000087 PHARMACOKINETIC STUDY Title: Elimination and ToxicityofPerfluorooctanoie Acid During Subehronic Administration in the Wistar Rat TEST SUBSTANCE. Identity: Perfluorooctanoicacid (PFOA) Remarks: Purity was not specified METHOD `Method/guideline followed: No specifi guideline was lied Test type: 28-Day subchronic toxicity and elimination study `Speciesistrain/eell type or lines Wistar rat Sex: Female and male Age and body weight range of animals used: Newly-weaned Numberofanimals/sex/dose: 6 animals/sex/dose Routeof administration: Oral gavage Vehicle: 0.9% NaCl solution Doses: 0.3, 10, 30 mekeday Epexrciroedt.itohne aronuitmeasl,sbwoedryefwleuiidgsh,eadnodncteisasuweesemkonaintdo2r4edhoaunrd/uorrinseawmapslecodlldeucrtiedngonstsutduyd:yDduaryisn7g atnheds2t8u,dy b"Tlhoeodbeahnadvitoirssaunedsafmeepdleasndwewraetecrolcloenctseudmpftrioomncownetrreolobasnedrv3e0dmregkularrlayt.s. At the end of the study period. `wSetrateistthiecaplrimnectihpaoldsstautsisetdi:calSptruodecnetd'usretsesuts,edPefaorrstohne pevraolduuacttimonomofenthtecfoirnrdeilnagtsi.on and Fisher's exact test Msaeltinheosdolruetmioanrsksw:asPaFlwOaAystr0e.a5tmmeln/t10o0cgcuarnriemdalovweerig2h8t.coPnsFeOcuAticvoencdeanytsr.atTihoensadinmibnliosotderaenddvuorliunmeesoafmptlhees. were analyzed by gas chromatography. ESULTS DPeFtOaiAle(dmgr/es2u4lthsrsfkrgo)mwDaasyl7o:werOnthatnhethseevdeanltyh ddaoyseofithael stthuedey gperroiuopds.ofthmeamleesa.n uArisntaartyisetixccarleltyion of tsiegsnti)f.icaInnttdhiefffeermeanlceeafnriommaltsh,endaoinlyodftohseewtahrseefogurnodupisn aclxlertehtreeed gsrigonuipfsicoafntmlaylleresastsPF(PO<A0.i0n5thaendurPi<n0.o0n01, day 7 than they were administered. The mean urinary PFOA concentration of the female ras in the lowest 84 000088 hdiogsheesgtrdoaulpywdaossseigonfifPiFcaOnAtl,yhtiheghuerrin(aPr<y0.P0F1OtAhacnonctheanttroafttihoen mwaalsesainginvivfailcs.antlIny thhieghgerrou(Pp<c0e.0i5v)iinngthtehe nthaelmaalneimraalss.; however, this can be explained by the significantly lower (P<0,05) mean urinary volume of wDietthaitlheederxecseuplttisonfroofmthDeay102m8g:'kBgygersotupdawyhi2c8,htshehomwaeldeas ssicgenimfeidcafnotlhyasleowaelrso(Pr<e0a.c0h5e)detxhcerestticoandyofstate, APtFOcaAchthdaonsethleevaedlm,itnhiestmeeraend dPaFilOyAdocsoen.centrations i the plasma ofthe malerats were significantly hliogwheesrt tdhoasnetghroosuep)o.f the female animals (P<0.001 fo th two highest dose groups and P<0.01 fothe Xladteitvaeilteodostdatyistwiecialghatnsaloyfsimsaolfe orragtsanshwoewigehdtssidgindifoitcarnetvepalosanvyedidfofseerenrceessp.onTshee(Pw<e0i.g0h0t1s.ofPetahresoinv).erA {poPs=s0i.b0l5e.cPxepalrasnoant)onhowwaevsetrh.e tshiegndiiffifceanrtendcoeseb-ertewleateendtdheecceoansteolinmathleesboadnydwethieglhotwseostudnodsiengtrhoeumpalweass Tmnorteheohbivgiho-udsostehagnrboeuptwfeeemnalaen,yoofneheordmoosreed mgirlodupisnf(lPEa0m.m0a1t,or6y5f0o)c. were observed in fou vers, which weasts.not significantly diffrent from control females with only one small chronicfocus (Fisher's cxact Metabolites measured: None T1h0etimmeeasnhiugrhienrarhyaenxcirnettihoenmsaulgegeasntimsatlhsa.t tThheesaevxer.raegleatreednadicflfeearreanncceeionfpPlaFsOmAa PinFtOhAe fceomnacelnetrraattsioinsabaoruet binesttheexfpelmaailneedanbiymaalctsiovnelyt.ubuBlyarthseec2r8etiodany,inbtohtehfmeamlaelse akinddneFye.maTlhees setxecardeytesdartoeuwgahlsyatchheicsvaemdebaymo7udnatys.of PFOA in 26 hours as their daily dose cHaindhidjaurrviin,g sHu.bcMh.roYniicinademnAi,n.isKtorjaot.ioannidnVt.heKWaissmtaa.r a1t9.87.PhaErlmiamicnoaltoigoynaannddtoTxoixciictoyloogfyp:e6r1f:l6u6o-r6o5o.ciancic 85 000089 PHARMACOKINETIC STUDY Title: A Proposed Species Difference in the Renal Excretion of Perfluorooctanoic Acid in the Beagle Dogand Rat TEST SUBSTANCE Mdentity: Perfluorooctanoic Acid (PFOA) Remarks: No information on supplier, ot number, or purity of substance tested was given. METHOD Methodguideline followed: NA Test types In vivo `Speciesistrain/eell type or line: Baagle dogs Sex: male/female Age and body weight range of animals used: Not stated Numberofanimals/sex/dose: GSorlouutiponI: at6 1(.37 mmla/lmeisn.andPr3obfeemnaelceisd)wgaisvetnhe3n0amdgmi/nkigstPeFreOdAatwi3t0h continuous infusion mg/kg intravenously. of 5% mannitol Group 2: 4 (2 males and 2 females) given 30 mek PFOA only and kept in metabolic cages. Routeof administration: Intravenous Vehicle: Not stated Doses: 30 meg- seeabove (under Number of animalssex/dose) Excretion routes, body fluids, and tissues monitored and/or sampled during study: Group I: urine and blood samples Group 2: blood samples. SrteadtuicsttiiocnalomfePtFhOoAdscluesaerda:ncPeiainrecdacShtuddoegntbsefeorsetanudseadftteor daedtmienrimsitnreatstiaotnisotficaplrosbiegnneicfiidc.anceofthe 86 000030 Method remarks: GroupI: Dogswere anaesthetized with methoxyflurane. Catheters were fixed in both ureters after mlaeptahroodtsotdoemsycrainbdedcybsotvoet.om)y. Urine was collected at 10 min intervals for 60 min. (Dosing and other Cirou2p: Dogswere kept in metcaagesbafteorthleinjiecticon. alFwerl edetiermivnede forcs ach aPnFiOmaAlcsoenpcareantterlayt.ions were analyzed with a GLC-method. RESULTS dDoetga(ilPe<d 0r.e0su5ltfso:r aPcrhobdeonge)c.id effectively and statistically significantly reduced PFOA clearance in cach PPFFOOAA ppllaassmmaa hhaallff--lliivveess ((mfaelmeasl)e:s)4:7320a2ndan5d4130h5ouhrosurs Metabolites measured: None. It appears that only PFOA was measured. INCLUSIONS fBeemcaaluesseohfatvheeansaacitsitvieaslecsriegtniiofnicmaenccehaonfitshme rfeodruPcFtiOoAn.ofPPlFasOmAa chlaelairavnecse bwyerperolboenngeecridi,n mmaalleess tahnadn females. "PTFheOaAutihsosrismiallasro icnobmoptahrsepetchieesc.leaHroawneceverrat,esthweitahcttihvoesteubiunlaatrss,encortetiinogntrhaattetohfe PglFoOmAulainrtfhieltrraattiaonndradtoeg.of are quite different REFERENCE reHnaanlhiejarvxi, Hc.,oMfr.peYrlefliunoternoTo,.citHaanaooriacnaencni,dainndtThe.bNeevalaaidgnoengl.aned198r8a.t IAnp:rBoepyonseend. sAp.eCc.iaesnddHif.fAe.renScoellinevtehled Ni(Ejdhs)o.ffNPeubwliDsehveersl.opDmoerndtrsecihntB,ioNsectiheenrcleasn:ds.Their Inplications forLaboratory Animal Science. Martinus 87 000091 PHARMACOKINETIC STUDY RTaittlse: Tissue Distribution, Metabolism, and Elimination of Perfluorooctanoic Acid in Male and Female. TEST SUBSTANCE Identity: [1"CJPerfluorooctanoie acid (PFOA, 99% pure, specific activity 5.44 mCiimmol) Remarks: Synthesized and purified according 0 methods described previously METHOD Method/guideline followed: NA Test type:Invivo `Speciesistrain/eell type or line: Sprague-Dawley rats Sex: males and females Age and body weight range of animals used: AWegieghtsi(xmawleeesk)s= 170-195 grams Weight (females)- 130-155 grams N32ummableersoafnadni1m6aflesm/asleexs/dfoorset:iss4ueofelciamcihnasteixonfoerxtpiesrsuiemdeinsttsribution experiments; Routeofadministration: intraperitoneal Vehicle: Propylene glycoliwater (1: vA) Doses: 4 mek lEixvcerr,etbiiloen, freocuetses(,6.2b.odtyisfsluueisdas,blaentdo tmiestsaubeoslmizoenietnodroegdenaonuds/ofratstyamacpildesdorduwreirnegtsartguedty:tisusruiense,foprlPasFmO.A toxicity) Statistical methods used: Not sated Method remarks: none 88 000092 RESULTS Males: Tliivsers.uepldaisstmrai,buktiidonne-ys.Pehrecaretn,t tdeosstes,onfaat (peeprigdirdaymmablasfisa (from pad), highest to lowest) in monitored organs was: gastrocnemius muscle. `The liver and plasma awdamirnitshteraptriiomn.ar|y Tthisesuheisghofdciosntcreinbturtaitoino.n i[nSieveeTrawbalse |ofthe study for examined further percentages in mals by by an time insi after nonracirculating liver perfusion techniqu~e *1% of the PFOA infissed was extracted by the liver in a single pass". Elimination- Urine and feces were both major routesofelimination. Cumulative excretion of PFOA in luirimnienaatnidonfeocfesPaFftOerA2w8adsay15sdwaayss3(63.640%hoaunrds).35.1% respectively. The apparent half-lifefor whole-body Halfilives -- Organ LPilvaesrma KiHdeanrety Gastrocnemius Fat Testis Blood Hrs Days 2217612 n90s 2245966 19044 208 92 192 80 216 90 22 88 Females: Tissue distribution-- Percent dose ona per grambasis (from hight to lowest)in monitored organs was: p[lSaesemTaa.bklied2neoyfst,hleivsetr,udoyvarfioersp.erTcehnetalgiveesr,bypltaismmae,afatnedr kidneys were the administration. primary tissues ofdistribution. Edlaiywmiansat9i1o%n-, wUhreirneeawsatshethaemmoaujnotrirnoufteecoesfwealisminnegaltiigoinb.le.CuTmuhleaatpipvaereenxtcrheatliEo-niofef PFOA in urine for whole-body after 1 climinationof PFOA was < | day Half-lives Organ Hrs PLilvaesrma 38 29 KBildonoedy 3328 Metabolites measured: Defluorinationof PFOAwasmeasuredtodetermine whether it was metabolized. Specific metabolites were not discussed. 89 000093 A sex difference in urinary eliminationof PFOA was observed, resulling in different whole-body cfleimmailneastieolnimhianlfa-tleidvesl.essHtohwaenv1er%,ofthtehree wPaFsOAnodaopspearbeyntthidsirfofuetree.nceSeincobnidli,artyheexgcrreeattieornp--erbsoitshtemncaeleosf and PFOA in male rats was not due to greater formationof PFOA-lipid conjugates. Third, the parent `ccoommppoouunndd aexpcpreeatresd10inbueritnhee aonnldybtilies:sutehestroerfaogreea.fodrimffoefrePntFiaOlAraitneobfotmhetsaebxoelsiatse wfeolrlmaatsitohneboynsleyx was not responsible for sex differences. (The authors also discuss the unpublished resultsof Vanden Heuvel etal. 1992. noting the possible link between testosterone and inhibition of PFOA excretion.) REFERENCE Vanden Heu1v...eKusllik,is, B.1., VanRafelghem. M.L..and PetersoRnE,. 1991. Tissuedistribution. metabolism. and eliminationofperfluorooctanoic acid in male and female rats. J. Biochem. Toxicol. 6218392. 9 000094 PHARMACOKINETIC STUDY Tite: Renal Excretion of Perfluorooctanoie Acid in Male Rats: Inhibitory EfofTfestoestertone TEST SUBSTANCE entity: [1Cl-Peruorooctanoic acid (PFOA, 99% pure, specific activity 544 mCimmol) Remarks: Synhesized according to methods described previously METHOD Methodguideline followed: NA "Test type: Invivo Species'strainicel type or ine: Sprague-Dawley rats Sex: males and females AAgee-ansdixbwoedeyksweight rangeofanimals used: WWeeiigghhtt ((fmeamlaelse)s-) =17103-01-91555grgarmasms Nuom fanib mals'esexdrose: 4sex/dose Routeofadministration: inraperioncally .p) Vehicle: Propylene ycolwater (1: v/v) Doses: 4 my/ks (administered as [17/CIPFOA ane week aftr vehicle, 17bet-estradil, o esosterone implantation) EUrxicnree.tiploansmrao,utfee,cebs,odiyveuritdiss,e,anKdidtniesysuiesssmuoenitored and/or sampled during study: Sotfatviasrtiiacnaclem(eAtNhOoVdAs)u.sedD:uDnifcfearennce'ess bwaestwpeenrftorremaetdme0ntcgormopuaprseweinrdeivdiedtuearlmmieneadnbvyalounees-wwhaeynanalysis ANOVA showed differences. (Level of significance ested was p<0.05.) 91 000095 MCentthoodd,reemaRrkGs:GTHo eztE1diSfhfarmenPceEiTn cAimSimoaiognoof PeEoOs rboenteweewnasmadlesraned f.oals, ats were iFnacrisoigoennp(osss1rToboerat-esrsdcioa)pcaepsaes wee nseried subcutancously into castrated males (rough an (Tiemstoousgtheraomnerceapmsuolesewderepionssretd0osubeasnceopusay in carted les or ovariectomized mes imGprloaunptseodfwsihhunonpegrstoodlymaalnedssaenrdvefdomalse,ocnassfeordthwealiemsp,lanndtatvisornepctrooniczeed eles were TtnROcNas.tra7tehdomursaafaetrs,PprFoObendemciindswtarstiionn.irttrwedro(a6n5estmhetkizeid.w)it3h0Nmeimpoi!o 1(050admmigniksetra1t)ion of RESULTS Mates: Tissue PFOA Concentrations [f (% Dose ICo -kPFeOA/** oe em [cosmicatesios1t10e5a3roC0no0oe5n T030-003 Sr ignife icanrtoa duipfsf(rsem hnacmeiAien: hficilr,,ciadtersi,daenldnpellaesmaicsoencdnrTioonseofsPF,OAcwaesrrtoebdiseenorsearmoonnsg, Tn TCvaetrataenddeKsitdonesytsa,rPonFOgAroucpo.nciepptlaisomna.wPasFOHAigwhassnhighheesst (handasnimaiagnroucpo,neaenntdr3atnidoni)ghiemstth nthe CaanmniedciTouintdecsoatdaicldhgersoouspcwreornesvgerroyuposw.. Fla PEOA concentrations casted hile and Source: Tae epg. 33 Leinary Himipatpiomn Caredvehis Cred Tease T7otidm goenTe tdhan sn1miimcetugcreeat an smite FsecalcexeacfstnPioOnt:Tdiovse cwasmss teainn iceasreaxmece4tdiaonm_Roesasrdiicssosf nasmhoemtnic.supc.asthne dcucmhuliactive anc etc ups. Fac wa igh te coat cxomtane seo SFhiafmepeohfiacdem,inbiustterreidnugcepdrPoFbOeneceil:imiTnhaitiohnadinncooeuffaecrtdognourvin.aryThPeFrOeAweerleimnionadtiifofneriennces in Tere omeeriefoes of POR rere reamentSone enpronereeil " 000096 HHyiastloipnaetdhroolpolgeitcfaonramlaytsiisondi(danteostrfeovreaPlFfOoArmabtiinodnionfgh1y0amlailne-esdpreocpilfeitcspirnotteheinmaallpehak2iud-ngely.obulin): Females: Tissue concentrations: No significant differences in liver, kidney, and plasma concentrations oavfaPriFcOctAomwiezreedo/bessteorsvteedronaem)a.ngUrtirneaartymeenltimgirnoautpiosn:(shNamovesihgincilfei,canotvadriifcfeetroemniczees:diavlehaiiclsee,liminated about 70% of the PFOA dose in urinein 4 days. Fecal excretion: no significant differenceasl: excreted less than 0.5%ofthe dose. Metabolites measured: None ONCLUSIONS, p"TrhoebseencreesiudltrsesduugcgeedstPFthOatAteesltiomsitneartoinoenpirnetcarsetartamteendtmianlhiebirtastselthiamtinhaatdioinncorfeaPsFedOAPFinOAtheurmianlaer.y eAxlcsroe,tion. Testosterone is akey determinantofthe sex difference in PFOA elimination in ras. Remarks: none REFERENCE p`eVrafnldueonroHoecutvaneoli,c aLPc,iDdaivnism,alJe.Wr.at,s:SoInmhmibeitrosrRy,.,efafnecdtPofetteesrtsoosnt,eRrLoFn.e. 1J9.92B.ioRcehneam.leTxocxriectoil.ono7(f1):31-36. 93 000097 PHARMACOKINETIC STUDY Title: Covalent Binding of Perfluorinated Fay Acids to Proteins in the Plasma, Liver, and Testes of Rats TEST SUBSTANCE Identity: [1-C]Perfluorooctanoic acid ([1-"CIPFOA) Remarks: 99% pure, specific activity = 51.7 mCi/mmol METHOD Method/guideline followed: Not specified Test type: In vivo Speciesistrain/cell type or line: RavHarlan Sprague-Dawley, obtained from Harlan Spraguc-Dawley (Indianapolis, IN) Sex: Male Age and body weight range of animals used: Six-weeks, 170-195 grams. Number of animals/sex/dose: Not specified Route of administration: Inteaperitoncal (ip) Vehicle: Propylene glycol/water (1:1, viv: 1 mike) Doses: 9.4 umolike. Eesxtcersetion routes, body fluids, and tissues monitored and/or sampled during study: Liver, plasma, Statistical methods used: Differences from control were determined by one-way analysis of variance. iTnhdeiclaetaesdt sdiifgfneirfeinccaenst.diTfhfeerleenvceelsotfesstiwgnaisfiucsaendcetofocroamlplaarnealiynsdeisviwdausalPme= a0n.0s5.where analysis ofvariance MethTeosdt raneimmaarlkssa:nd test substances ([119-8"7*)C.PeHrefmlougorlooabcitnan(o2icx acrcyisdtawlalsizsedy,ntdhieasliyzzeeddaannddpluyroipfhiieldizaed)d,esfcarttiybeadcibdyfLrLe.e bRoeviicnheestearlum albumin, and all tissue culture media and supplements were obtained fiom Sigma Chemical `CCoommppaannyy ((SMt.ilLwoauuikse.eM,OW)I.).ReWaagteenrtpgurraifdiecastoilovnenwtasswpeerrefoobrtmaeidnebdy fpraosmsiAnlgddriiscthilClehdemwaitcearl through aMAf)o.ur-RbaotwslweMirlelii-ndQiwviadtuearllpyurhifoiucsaetdioinnssyusstpeemndaendd sata0i.n2l5ess-msiteleelrca(gMeislliinpaorteemCpoerrpa,tuMriel-ford, controlled room (approximately 21. C). A 12-hourlight and 12-hour dark photoperiod was. 9% 000098 pmarionvtiadiendead.dFiobiondum(PutrhirnoaugRhaotutChtohewstNuod.y.50A1n2,acRcallismtaotnioPnurpienraioCdo,ofSta. Leoausits,I-MwOe)ckawnadswaatlelrowweedre befor initiationof the experiment. `Cova[l1e-nCtPbeirnfdliunogroofocPtFaOnAoitcoapcriodt(e[i1n-s "inCIviPvFoOA) was adminisiered to ras in propylene glycol/water a(1n:e1s,thveitvi;ze1dmwiikteh)Naetmabudtoasle o(5f0 m9.4g/kmgo, lip.)iips.sAutesdewseirgenaqtueidcktliymersepmoosvte-dt,refartemeeznet,claatmspewde,reand cSetnotrreidfuagtat7i0on.C.MaBclrooomdolweacsurlaermobvienddiinngawlagshidleytehrempianreidnioznedtinseseudelehoamnodgepnlaatsemsa.wwahsicshepwaerarteed by bacriodu.ghstamupple1s0 r10e% TwaCsAheadndwiptuht 3onmLiceoffmoret1h0amnionluteetsh.erTo(3r1e)m6ovteimaensyaunndbtohuennd3pmearfrlcuotriimmeasted udesriinvge3d m"LCocfoueltdhbyleaecexttartaec.teWdasfrhoimngthwapsroctoeinnt.inOunede,imfinlleicleitsesraorfy.1 uNnNianOoHadwdaitsioandadlePdFtOoAt-he pprreoctiepiintapter.ecTihpeitsaamapnldepwlaacsedthienn nsehuatkrailnigzewdatwietrhba|tMh oavceertniicgahctiadta3n7d C| mtoLsowlausbiulsiezedtohrelpirqoutiedin SwcaisntiplelraftioornmceoduanctcionrgdwihniglteoaOn.oHt.heLroawlirqyuottawlas(1u9s51e)d.fPorFOpAro-tdeeirniavnealdysriasd.ioTachteivpirtoyteiinnaalnaslaymspilses wwiatsh qauaPnatciktaatreddDuPsMina1g-2P-a3cksoafrtdwaLriequpirdogSrcaimn.ilRlatdiioonacAtniavliytzyeirn whiytdhroqluyesnactehscowrarsecdteitoenrpmeirnfeodrimned Hionic-Fluor scintillation cocktail. Binding was expressed as pmol PFOA equim protein. CovaCl-elntabbeilneddingPFofOAPFwOaAs 1a0ddheedmo0gltoubbiesn caonndtaailnbiunmgianlibnunviitnroor hemoglobin in 1.0 mLof phosphate abudfdfeedr ion g1 imvLae2of,p4h.o8s,phoart1e0b0uffMersoolubtiroinn. tIhfemeretahcitoinoinnmeioxrtueryesiucpinteow2ermLe.prAelslenpte,rtihemyewnetrse. Pwreorteeidnowneasuspirnecgiapiftiantaeldvwoiltuhme10o%f bTuCfAf.erToo2fremLm.ovTehaenytifmreeeofunibncouubnadtipoenrfwlausori|nhaoieudr aacti3d.7 C. SSpaumnplaets2w5e0r0erweavoslhuetdiownist/hmiSnumtLeoffoarcemtionnuete5staifmetsr.cSaacmhpalceestowneerewavsohrtsecxpe.d Tfhore|acmciinounteewaansd wtraasnscfoenrtreidnuoefdf.ifPnreocteesinsasraympulnetislwnoeardedittheinonwaalshPeFdOwAit(has$dmetLeromfientedheb2ry aldiqduiitdonscailnttiilmleast.ionWashing counting) could be extracted from the protein. The protein powder was hydrolyzed with 1 mL. of c1'NquiNvianOgHofatpr3o7t.eiCn.ina shaking water bath overnight. Binding was expressed as pmol PFOA Sele"cTthieonliovfert,aprgleatsmias,suaensdftoerstthsewaenraelysseilsecotfePdFaOAt-abrgientdtiinsgsuteospfroorttehiensanalysis of PFOA-binding to porrottheeiynsarbeectaaurgseettohregyanarsefeoirtpheerrTmuaojroirnaitsesdueascoifddtiosxtirciitbyut(iIovnerfoarndPFeOstAe)i.n rats (liver and plasma) RESULTS Deta`iCloevdalreenstublitsn:dingof PFOA to arget tissues in ais wTehreecopvoaolleendtbbeicnaduisnegndoattaimfoer-dPeFpeOnAdefnotr achcahngteisssiune t(h2ehaobusro,lu1tdeaayn,danrdela4tidvaeycsoanfceenrtrractaitomnesnot)f ctoisvsauleen1t15ly~bdoauynsd)prsotheoiwnewdetrheatobtshcerrveewd.asTlheletidsisufefeerleinmcienaintitoinsshuaelcFoinfceenftorraPtiFoOnsAo(faPveOraAgein the 95 000093 rPaFnOgeAowf2ashsoiugrnsif0ic4antdlayysh.igIhnerPFiOnAt-hterpelaatsemdaratthsa,nthien athbesoilvuetre. cOofntcehnettriastsiuoensofexacomvianleedn,tltyheboteusntdes hAapdprtohxeihmiagtheelsyt 0re.l4at%ivoefctohnecteensttreastPioFnOoAfPcFonOcAe-ndterratiivoendwraasdicooavcatilveinttylycobvoaulnedn.tlTyobodeutnedrmtoinperotein. which proteins were modified following in vivo administration of PFOA, tissues were ahmoomuontgoefnciovzauelneddntsluybjbeocutnedd t"oCSDfSou-nPdAwGiEthaiuntotrheasdeiotgisrsaupehs,ynwoitrhadfilouaocrtoigvreapphroyt.eiDnubcantodsthweersem.all detected when SO. protein was separated on SDS-PAGE and the X-ray film was exposed to the gel for up to 2 months at 70. C. Covalent binding of PFOA to hemoglobin and albumin in vitro eTfhfeecctoovfamleetnthiboinnidniengionfpaPraFlOleAl tinochuebamtoigolnso.bin was diminished by the additionofcysteine with no Metabolites measured: [1-"`ClPerfluorooctanoic acid CONCLUSIONS Despite the metabolic inertnessofthe perfluorinated fay acids, the results indicated that PFOA braidnidosacttoipvriottyecionusldinbethefpoluansdmac,ovalilveenr,tlayansdstoecsitaesteidnwaitcohvaplreontteimnafnnoelrl.owiAnlgthtoheugohrgPaFnOicA-edxetrraicvtieodns, the amount of radioactivity associated with any given protein was not enough (be seen fToolllloowwiinngg tShDeaSd-dPitAiGoEnoafutcoyrsatdeiiongeratpohtyh.e Tinhceubinavtiitonr,obcuotvnaoltentthebiandddiintgioonfofPFmOetAhiwoansinreedtuoctehde tihnactubpartoitoen.in sTuhlufsh,ytdhreylabgirloituyposfmyasyicbieneintvoolivnehdib:itsuPlfFhOydAryclovgarloeunptsbmiandyinbgeotfhpersoitteeisnosfscuogvgaelsetnetd attachment of PFOA. REFERENCE aVcainddsetno pHreoutveeiln,inJ.tP,heKupsllaiskimsa,, Bi.vLe,raannddPteetsetressoonf,raR.sE.. C1h9e9m2.. -BCioovl.aleInntterbaicntdi8n2g:3o1f7-p3e2r8f.luorinated fatty 9% 000100 PHARMACOKINETIC STUDY ATmitm:onCihuomle[sCtPyrearmfilnueo-rEonohcatnacneodatFeecoarl PEoltiamsinsaituimon'"oCflPCerafltuoor1on4ocitnaRnacstuslaffotnearteAdministation of TEST SUBSTANCE entity: Ammonium {"ClperTuorooctanaat (("CI-APFO) Remarks: ["CI-APFO:specificactivity= 0.51 uCl/mg.radiochpeurmitiy>c9a5l% METHOD Method/guideline followeds NA Test types in vivo Speciesstrainiell type or line: rat, Charles River CD Sex: male Age and body weight range of animals used: 12 weeks, 300 - 342 grams Number of animals/sex/dose: 5 Routeof administration: intravenous Vehicle: 0.9% NaCl Dcoasne.s:anSiimnagllse dnootsetsrawteerdewiadtmhicnhioslteesrtedyraasmifonlelo-ws:13.5anmigma/lksgtmreeaatned(cwointthroclhoglreosutpy)ramine 13.3 mg/kg pElxacsrmeat,iornedrobultoeosd,cbelolds,yafnlduidlsiv,eranwderteismsouneistmoorneidtaonrde/dorasnadm/polresdadmuprliendg tdhuerisntgd.study: Urine, feces, SutsaetdisttoiceavlalmueattehosdigsniufsiecadnceDoaftadiwfefreereenxcperebsestewdeaesn mtewaongsro&usptsaantdaarsdigdenviifaitciaonncse. lTevheel sofupde<nt'0.s05c.st was Macectehssodtorweamtaerrkfso:rR2a4thsowuerrseprhioousoedadimniniinsdtivriadtuiaolnosfatihleesessst isulbsmteantcaeb.olCiasrmbocnaygle-saabnedlefdas[t'edCwIiAtPhFfOree wparseopabraeidnbeyddifsrsoomlvSiMn.g tChheolteessttsyuabmsitannecweaisn o0b.t9a%inNeadClfr(otmhMe ea`CdJJAoPhFnOsonso.lTuthieodnocsoinntgaisnoeldut2i.o1nmsgw/emrLe). Cahdoiloe-satbyerlaemdineest(dsruibedsaanncdegwraousnaddmriesniinst7e-r6e2d0)aswaassimnigxeedi,nt4r%avbenyouwseidgohts,(waitehraPuariilnaveLia)b. CThwowo.mTLheof h(aed dloisbiintgums)olhuetioonthwearsatasdmwienriestiervede0noarcmahloPfur1i0naatLs.abFiCvheorwt.s Iwneorredgeirvteona4l%owchaocloemsptayrriamsionneofinthfoecd rWeaidgihotmse.triTchreeasvuelrsaogendaoseasbsaoluatdemibnaissit,erheed oradciaoclhabgerloeudpdwoesrees 1w3e.r3emnoet kadj(ucshtoeldesftoyrrianmdiinvei.dturaaltbeoddy ainnidmiavlisd)uaalnrdats131.35 dmayeskaf(cronatdrioilniasntirmaaltsi)o.n oUfrtihnee easntd sfuebcsetsasnacmep.leAshwaireimceo,lltehcterdatastwientreervaanlesstfohretized 97 000101 Cwoieotlhzedwieeurtnehyiplrneetaphalerrseda.npd oexmsanpgubiynacteendifbuygadtriaowni.ngTbhloohidvefsrwoamsthceldleesciednd2in.g awohrotlae. Polragsanmaanadndsorerdedblood REsuLTS Detailed resus: Afr 14daysofcholestyramine atmo, the mean percentageofdose limited via "frTeihcneegsdi((l463f7.r%2en+fcoe5r.wc5o)snwtarfosolus9n.ad8n-1dfob4led1%tshiegfnomirfeicachanlntep.seyrArckeaenmtrianagcde-jourfsadttomeseden)t.eflhoirmeitnhaaemtoaeumdnovtuisnaotffeoccfehscbaoyrbnco1o3.nn,4t:rwoelhxirceathr(ce4i.m4sni=tnh1e.e0d). {14ocbonetxeenrttreedprweesreente1d64%.fnordch8io%ssotfytrhaemidnoe.etrfeoartehdarltesynrdami2n8e%-rfocatceodntarnodl caotns.troTlheramt,earensplecvteiveclayr.bon TSihgenimfeiacanntcyaerbsotn1h4-ancotnhceemntaranticoonnscoefnptelaatinoan ianncdornterdolbsl.o Thecemllesawnitdhatcahorloemstyarnaamliynseestsofamieern,tpwleasrmea. and rd blo allsfocabon-13 content 14 days aftr (1CIAPFO adinisration rs shown in Table Table 1. EffetofCholstyamine TresoniComncnetrnatotnofCarbon4: in Rat Liver, Plas, and Red Blood Cells Afiear Single Intravenous Dose of ["CJAPFO Treatment Grown Cholesyramin esd LCiavrebron: 13 CanconiPailoansma (i ei siRsedoBrlmooidCedlls STi "isso Signin diferent from conr2al2v3a1lu6s2s (5 0.0) Metabolites measured: Nore cThoendcaLtaussuipopnorsth possible tityofcholestyramineas 3 promotor ofthe excreion of peflorooctamoate in humans. Reviewer's Remarks: Th author' conclusions appes obe supported bythedata JRoEhFnsEoRnE.NC.0.E. Gibson, 5.1. and Ober, R.E. 1984. Chlestyraming-cnhanced fecal clinination ofcabon[1144C)aptesrofrcaorcatdamniensiastlrfaotnitoen.ofFaunmdm.oAnipu.m T1o4xCipceolrl4u9o7r2o9o7c6t.anote or potassium 08 000102 PHARMACOKINETIC STUDY "Tithe: Metabolic Handling of Perfluorooctanoie Acid in Rats TEST SUBSTANCE. Identity: Perflvorooctanoic Acid (PFOA) Remarks: Perfluorooctanoieacid (a mixoftliunearraend branched isomers)was supplicd by Minnesota Mining and Manufacturing Company, St. Paul, MN S101. Its purity was not indicated. METHOD Methodguideline followed: Not specified Test type: Fluoride determinations and ultrafiltration studies were utilized --Rat in vivo and in vino; Human serumein virro `Species/strain/eell type or line: Holtzman at; Human serum Sex: Rat-female; Human-not specified Aogtespaencdifbieodd:yHwuemiagnhtsrearnumg-eaogfeaannidmawlesiguhsteodf:soRuartcsewweaigshneodtasppperciofxiiemdately 250 grams. ageofrats was SNeurmumbne-rtwoofaalniiqumoatlss;/sHeuxm/adonses:esuFml-utohrriedee daleitqeuromtisnation --not specified: Ulraflration studies Rats Route of administration: Rats weredosed via stomach intubation Vehicle: Rats were dosed with an aqueous solutionofperfluorooctanoic acid Doses: Rats were dosed with 2 mg nonionicfluorineas perfluorooctanoic acid; additionally, four rats were faelodw fluoride(<0.5 ppm) diet; Human serum-0, 75, or 1500. g nonionic fluorine (as perfluorooctanoic acid) uErxicner.etainodn froocuetsesw,erbeoadnafllyuziedsd,faorndfltuiosrsiudeesdmetoenrimtionraetidonasnda/nodrusltarmapfilletrdatdiuonrisntugdisetsu;dyH:umRaant--sseerruumm.was. analyzedforultafilration studies Statistical methods used: Means were statistically compared by calculating Student' tvalue. A P-value. of 0.025 was chosen as indicating significance. Method remarks: Fluoride determinations --Rats were administered 2 mLofan aqueous solution containing 2 mg of innodniivoindiucalfumoertianbeo,liacs pceargfelsuaornodocfteadnroaitccahciodw. b(yPursitnoam)aacnhditnatpubwaatitoenr. (T1hpepmanfilmuaolrsidwe)eraedlpilbaicteudminfor 4.5, 2di4c,toarn5d2d.i5sthiolulresd. wIantaedrdiftoiroapn.erfiouordorafts9wehroeurpsl.acTehdisinremseutlatbeodliincacasugbesstaanntdiafleddeacrleoawsefliunoriiodneic(<fl0u.o5ripdpem) contentofthe feces and faciltaid the analysis for nonionic fluorine. A few crystalsofthymol were added 9 000103 to the urine containers to inhibit bacterial growth during the collection period. At the endofthe cexapredriiamepnutncatlurpee.rioTdh,ethbelouordinweaasndafleocweesdwte0recloctolalnedcttehdeasnedrtuhme waanessctohlelteiczteeddaanfiemralcsenwterriefusgaatcironifaincdbeyd stored frozen until analyzed. Urine, scrum, and feces were also obtained from undosed animals to provide bcaagseesl.ineanddatthaeTwheeigvhotloufmtehseoffecuersinweecroellreecctoirodnesd,.whAicsmhalilncklundoewdnwaqtuaenrtinteyedofedditsotirlilnesdewtahteemrewtaabsolaidcded to the feces samples, which were then homogenized to a thick slurry. The serum and urinewere analyzed for ofenciecs wflausordiedteeartmpinHed5.a0twpiHth5.0twheiftlhuortihdeefilounor-isdpeeceilfeicterloedcetraodfee.r iTshoelaitoinoincoffltuhoerifdleuoinritdheebdyifdfiufsfautseioonf fthreom p"Tehrechtlootralicflaucoirdinate 6co0ntCen(tothfesfelruourmi,deuriinnep,erafnlduofreocoecstawnaasicdeactiedriminneodt awciitdh ltahbeiolexuyngdeenr-bthoemsbe croenvdeirtsieons). extraction technique. Fificen mLofreditilled water was added to the oxygen bomb (prior to combustion opefltlheet asfafmilptleers)patpoearctpualspaaunodrfiidreed twriapt.hoUutpd0ry0i.n3gminLthofesoexryugmenorboumrbin.e Lwaarsgepripveotlteudmeonst(ouap0to3-3gmrLa)mof Sliegrhutmlylomwodiinfifleudorfiodretwheeraenapliypseitstoefd otnhetofetcheespienlltehtatan1d5 lmyLophoifliozteadl pfroinoirctsotrceonmgbtuhstaicotinv.ityThbeufmfeerth(oTdISwAaBs, Orion Research, Inc.) was added t the oxygen bomb prior to firing instead of 15 mL of water. Blank and recovery samples were carried through the entire procedure. Ultrafiltration studies --The pHoftwo 90-mL aliquots ofhuman serum was adjusted to 7.4 by. cquilibration with a mixtureof95% air and 5% carbon dioxide. Seventy-five. ofnonionic fluorine (as pmeLrfolfuotrhoeocstpainkoeidcsaecriud)mwwaassardedmedovtoeofnoer daeltiqeuromtinaantdio1no50f0the winaitsiaaldcdoendce(n0ttrhaetisoencoonfdp.erAffltueorro2ohcotuarn,oi1c0 acid and the remaining serum containing perfluoroocianaie acid was transferred to an Amicon TCFIO sulatmrpaflieltcrahtaimonbeurnitwafsittfelduwshietdahwitDhia9f5lo%XaMiS,05%mecmabrrbaonned.iowxhiidceh, rpreeasisnusrimzoeldecwuiltehsni5t0r.og0e0n.0adnaldto1n5s.mTLheof ultrafiltrate was collected. An ultrafiltrate was also prepared from pooled serum obiaind from four ats p(edrofsleudorfooroctthaenofilcuoarciidde dbeytesrtmoimnaacthioinntsutbuatdiyon)a4.5nhdofurrsomaf7e5rmrLecoefivbiunfgfetrhe2ed (mpgHo7f.4n)oniisootnoincicflsuaolriinneetaos which 900g of nonionic Muorine had been added. RESULTS Detailed results: Employing the oxygen bomb reverse extraction technique for determination of otal fluorine,a recovery oF80 1.0 SEM? was obtained for perfluorooctanoic acid. The recovery of fluoride from perfluorooctanoi acid was increased 0 94 1.5% when 15 mi of TISAB bufler, insteadof water, was used as the fluoride trap inside the oxygen bomb, The quantity of nonionic fluorine was calculated by sduibvtirdaicntginbgytehiethieorni8c0folruo9r4i%d.e fTrhoembtlhaentkotfaolrftlhueorpirnoecdeedtuerremeimnpedloayfienrgaash0i.n3g-girnatmhefioltxeyrgpeanpebropmublpapnedllet and 15 mL of redistlled water as a fluoride trap was 0.13 0.020. The modified procedure used to determine the total Muaride content of the feces had ablank of 0.40 0.043 "The results obtained in the ultrafilcation studyofthe bindingofperfluorooctanoic acid in serum arc given iSnolTuatbilone b1.ufTfhereecdoanttrpoHl e7x.p4eprriomveindtedinewvhiidcenhcpeerthfaltutohreauolcttraanfoiilctraatciiodnwmaesmabdrdaendetbooaunnidsovteornyiclistalleine psaelrifnleuosrooloucttiaonnowiaesacuildt.raVfiilrtteuraalblley. alTlhoeftahdedintioonnioofnipcerfflluuoorirnoeoc(tasanpoeircflaucoirdootocthaunomiacnacsiedr)uma,ddien damtoo utnhets 100 0C0104 TS [HumanSewn --_ [ Aliuol Nee 77 [oom [oom [T- 1] "Aliquot 3 Perfluorooctanoic acid 0.018 0.025 1 [Conolserun [0032 [oi TT ~ [ 2 [Experimentalserum'| 0.013]__132_|_0016_|_012_] 000105 TNaoblme2i.Ur(iAn barcmrgooannitToArceeanRd Nsoi Forde FollowingAdministoa 24mg Dos of oe [Baseline | imsioa | 0 0| = TTiheeoosu Sar ; or 36 Exe inTgo voarewndomtoroonns T vrWeise Se acodlon5g xr Toms pacing fie "TTMcooanooSrErMid xr tefor he shop tiv sis hese mls were fd ow an for ie accounmwtirerchydiiiornpmoooodnrrToofa iee,Th sheps rcSal5ml5oo3fmhdososeomd andimnalsdnscr0o352..5 J Nr 35 Soiu. w5 A f 4-5pstch ai dmineA dohobfA omogtA heToign wye roefmmnroedmoim hcern Jeirmo od cad 43% ad ee on of erin Tr pe ncn he win eTrasbtlSe3. aPrmciemmoafgthee Adminis D> oofNsonei Horne Recoerid he rie and Feces [T T oeTeisme (hna )ws iUo rine. [iT esi1n0woT031a17 Metabolites messed: onic and onion orn CONCLUSIONS TehedcsitrecoeHatrincgToemseploby 3t5h5schsor.mwAaslhionncrgccsposdrrr2d0s0oo-co0tnaeetneeoasdcmTiporaritiolwnefshtheoevdedorses,dndbtuhne d To eaoinenseahmase3w8otsconenbhentoesSeneoetdbayhlteeehaeesebtte vobeofwpaatmsorrEethoeBctocn1feosl PApoMoRlOeNE end mao in posip + conned fm pr---- 102 00106 Ophaug. RH.andL. Singer. 1980. Metabolic HandlingofPerfluoroactanoic Acid in Rats. Proc Soc Exp Biol Med. 163:19-23. 103 000107 PHARMACOKINETIC STUDY "Title: Stimulation by oestradiolof the urinary excretionofperfluorooctanoic acid in the male rat TEST SUBSTANCE. Identity: Prfluorooctanoicacid (PFO98A%p)ur;e. cRoenmcaenrtkrsa:tioTnheoft2es8t msgu/bmslt.ance was dissolved in a mixtureofpropylene glycol-wate(r1:1) ata METHOD Method guideline followed: NA Test type: in vivo Speciesistrain/cell type or line: rat Wistar Sex: male and female Aragnegean1d50b-o1d8y0gweight range of animals used: age not specified, male bw range 170-300g, female by Number of animals/sex/dose: Dosed with vehicle: 6 males and 6 females: Dosedwith single ioensttrraapdeiroilt,onaenald i1n0jeicnttiaocnt omfalPeFsOAtr:eat6edfewmiatlheso,c6smtaraldeiosl, 10 castrated males, 10 castrated males treated with Route of administration: intraperitoneal injection Vehicle: propylene glycol-water (1:1) Doses: 50 mgrkg. single injection Excretion routes, body fluids, and tissues monitored and/orsampledduring study: urine. serum Sftoartuinstpiaciarledmedtathaod(dsifufseerde:nceosnebe-twwaeyeannamleyasnissooff(vawroiangcroeu(pdsi)fferences between groups), Student's est aMnedthtaopdwarteemrarakdsl:ibiRtautm.s weTrweenhtoyusmeadleisn mweetraebocalsitcractaegdesatitnhgeraogueposfof285.daTyhseaynwdearfetefred wsteaenkdsartdheraytwcehroew used i the test. Haolfthfe operated and 10 inact males were dosed with S00 pkg oestradiol valerate thsueb9e6utahnocuorussalftyerevaesriynsgelceodnodsedoayf fPoFrOtAh.e 14Bdlaoyosd sbaemfpolreestwheerfeestc.olUlercitneedwbayscacorldlieacctpeudnicntutrhee.cagSeesrduumring samples were ulrafliered to determine the protein binodfiPFnOgA in serum. The PFOA contents of urine. serum, and ultrafilrates were measured with gas chromatography. "The free anionic and possible conjugated forms of PFOA inurine were separated and assayed for PFOA concentration. 104 0c0108 RESULTS Detailed results: Castration and administration of oestradiol 0 the male rats had asignificant stimulatory effect on the urinary excretion of PFOA. During the first 24 hours, female rats excreted 72 b5o7t%h(1in-t6a)ctoafntdhecadsotsrea,tewdhemraelass iwnetracetamballee0s eexxccrreetteedPoFnlOyA9in+ u4i%ne(ni=n6)s.imiAlfatrearmtoheunotesstaradfioelmatlreesat(m6e1nt+, 19% and 68 + 14% at 24 h. respectively). The castrated males without oestradiol treatment excreted mPaFlOesAdiunriunrigntehfeaswtheorltehatnestin(tPact<m0.a0l1e)s. (A50t t+he13en%daotf24thhe)t,esbtut(9n6otha, tfhaestcoanscfeenmtaralteisoonroofesPtFraOdAiolintrthaeted Serum ofntact males was considerably higher (17-40 times) than in the serumofother groups. (FPem<al0,e0s5a)anfdteirnttarcetatmmaelnets.trPatFeOdAwmitahyPeFnOhaAnceexctrheeteudrisnleigvhotllyummeoreexcruertiende.than control animals up to 72 h `Ultrafiltration and analysis ofthe urine samples indicated that PFOAis not metabolized and s secreted in ts anionic for. Over 98%of PFOA was bound to proteins in the serum of females and intact males determined in the samples taken during 12 h aftr dosing. Metabolites measured: none CONCLUSIONS No conclusions were given REFERENCE elxicnreent,ioMn.perHfalnuhoirjoaorcvt,anHo..ieJaaackidonianhtoh,e mJa.laendrat.P. PPehuarar.mac1o9l89o.gyS&timTuolxaitcioolnobgyy o65e:str2a7d4i-o2l77o.fthe urinary. 105 00109. PHARMACOKINETIC STUDY Title: Disposition ofperfluorooctanoic acid in the at aftrsingle and subchronic administration TEST SUBSTANCE. Identity: Perflorooctanoic acid (PFOA) from Aldrich-Chemie: purity was not indicated Remarks: T0he.t9es%t sNuabsCtlanscoleuwtiaosndfiosrsionltvreadgianv:age administration and b) propyleneglycol-water mixture (1:1) for intraperitoneal administration. METHOD Method/guideline followed: NA Test type: in vivo Species/strain/cell type or ine: rat Wistar Sex: male and female `Age and body weight range of animals used: 3) newly weanedbw not specified 1b) 10 weeks/bw not specified Number of animals/sex/dose: 3) 0I$20 Route of administration: a)bi)niinrtargaapveargietoneal Vehicle: 3)) 0p.r9o%pyNlaeCnle gsollyuctoioln-water (1:1) Doses: 4b))3.3010m,gakngd,3s0inmggle/idnjaeyct,iodn,aivlyolduomsees=f0o.r2258mcLo/ns1e0c0ugtive days Elixvcerr,etkiidonneyr,oultuensg,,bsopdleyenf,luoivdasr,y,antdesttiiss,suaensdmaodniipotsoeretdissauned/or sampled during study: serum, brain, Statistical methods used: The biological hal fe of PFOA in the serum and other tissues was estimated from the equation (near regression)of the lincar relationship between time and concentration of PFOA ina semilogarithmic plot. Method remarks: The animals were housed at 21! C, with a dark period from 9 pm. 10 7 a.m. They. w`Aefrteergdievceanpittaaptiwoantetrheabnrdairnegwualsarsraamt pclheodwaandd lthienont.herTthisesusecsrwuemrweassamcpollleedctaetdnbeycrcopasryd.iacTphuencture ccohnrcoemnattroagtriaopnhsyo.fPFOA in the serum, issues, and lipid extracts were determined using capillary gas 106 006110 RESULTS oDtehtearilsedureesualntas:lyz2edAwuelrlethriegehedroisn mlaelveelsstihnanthfeegmaavleasge(pst<ud0y..05t)he vTheetsdiosfibPuFtOioAnionfthPeFsOcAruwmasand "1m0a8i)nplyos0ithiveesceorrurmel,atbiuotnlwivaesr,okbisdenrevy,edabnedtwleunegnttihesudsosalsaondhahdehicgohncceonntcreanttiroatnioonfsP. FOAAsifgonuifnidcainntth(ep< lSivaeirc(aFnt- 0c.o0r9r6e)l,atkiiodnnewyas(Ffo-u0n.d93i3n)maslpsl.eenH(owev0er., h9ea9spnld5elenu),ntg.e(sti-s, a0nd.bra9oifnf5ceomn9acleen)st.ratNioonssiomfilParFOA Cormelned positively with the concentration inthe serum (1 0.969. 0.971, and 0.976, respectively), bHyigAhfererininmtarlaepsertihtaonneainl fienjmeaclteiosn,dutrhingcotnhceenwthroalteiotnessto.fPPFFOOAAwiansthmeasinelryumdiansdbuottehde 1t0istshueessearsusma,yebdutwere lPivFerO,.kibdoneuyt, s1p0le%eonf,tahneddborsaeinwiasssufeosunadlsionhtahd hsicgrhumcoonfcfenetmraalteiso,nsc.omTpwaerlevde(h0oaubrosuta4ft0r%adimninmailsezsa.tioAnftoefr ewnukm,sfi,ver,baontd k3i.d5n%eyodfetchredasoesde wina.sdsitslcoenftiniuotuhse fsaesrhiuomn,ofimnadliecsa.tinIgndifsetmianlcetsp,htahsees.PFTOhAelheavleFl-sliivnesthe fRtahlefconocfePntFrOatAioinnotfhePiFvOrAoifnfhemealsecrsadmurwienrget2h4eh farsntdwe1e0k5 wians efsetmiamlaetseadntdobmaele6s0,hr.ewshpeiclteivienlym.aleTsh.ei bWsarsvfeodu.ndtoPbFeOA21w0ash.noItnfmoaulneds,ina tmhaoresinocsfateahltliyiopnisdfhriapctbieotnweofenthtilmveea.ndSPimFiOlAarcloenvceelnstorfatPiFonOwAas w1e4r5ehfaonudr13in0thh wesrpleefenoaundinforthfeelmiavlees(Faenmdalmeasle~s,73rehspaenctdivmeallye.s ~ 170 b). In thekidney.halves of Metabolites measured: none CONCLUSIONS No conclusions wee given REFERENCE hYieirnena,nMg.le.aKnodjosuAb.chHraonrilciajdmdirniysH.t.r,ataionn.Pd.BPuelulreat.in o19f90E.nviDronimenstalpoCofonptearsmfiunciartoiotocnt&ainoTiooeaxcniicdoilnto4gh4y:rea 653 107 0C0111 EPIDEMIOLOGIC DATA Title: Mortality Among Employees ofa Perfluorooctanoic Acid Production Plant TESTSUBSTANCE Identity: Perfluoroctanoic acid (PFOA) Remarks: The cohort was exposed to PFOA during productionof the chemical. Many other chemicals (cz. benzene, asbestos) were also used or produced atthe plant. The workers were exposed 10 these chemicals as well METHOD Study design: Retrospective cohort mortality study. aMnadnupfraoccteusrsiPnFg/OPAr.ocPesFsOiAng/isUsues:edaTshearesurwfaasctnanot,inafnodrmiat tiiounseind tihneasltaurdgyeonnummebtehroodfsiunsduesdtrtioalmanufacture applications and consumer products including plasticizers, lubricants, wetting agents, and emulsifiers Hypothesis tested: To determine whether mortality from any cause atthe 3M Cottage Grove: (Minnesota) manufacturing facility was associated with occupational exposure to PFOA. `Study period: The study population worked at the plant from Jan 1, 1947 to Dec 31, 1983. Setting: Minnesota 3M plant that produced PFOA and other chemicals. "Total population: 3537 employees participated in the study (2788 males and 749 females). 1339ofthis total worked in the Chemical Division. 398 (348 males and 50 females)of these employees were deceased,of which 148 males and 11 females worked in theChemical Division. `Subject selection eriteria: All workers employed for at least 6 months at the plant between Jan 1, 1947 0 Dec 31, 1983, Comparison population: In SMR analyses: U.S. general population death rates;Minnesota population death ates. Women were compared onlywith the U.S. population because cause- and calendar period specific Minnesota ratesforwomen were not available. Inproportional hazards analyses: non-Chemical division workers at the plant. Participation rate: Six workers employedduring this time were excludedbecause they had incomplete rdeecaodr)dsw.asresoublttaiinngedinfaor991.80%op0afrtt%hiceipiantdiiovnidautalcs,(3a5n3d7/d3e5a4t3h).cerOtFifitchaitspesopwuelrateioobnt.aivnietadl fsotrat9u9s.(a5l%ivoefotrhose who died. Subject description:Individuals employed during the study period were identified through company eagresoantndeelatrhecwoardss.56.M4efaonr magaelaets aenmdpl$3o.4ymefnortwfeamsale2s7..3years for malesand 27.6yearsfor females. Mean Health effects studied: Mortality 108 000112 D19a5t2a. caonldlecftrioomntmheetNhaotdiso:nalViDteaaltshtaItnudsewxasforob1t9a7i9n-e1d98f9r.omWtoherkSochiisatlorSieecsuraintdyoAtdhmeirneimstprlaotyieoendfaotra1w9e4r7eodbetpaairntemdenftrsomfocrotmhopsaeneymppelrosyoenenselprreecsourmdse.dtDoebaetdhecceeratsiefidc.ates were abiained from the state health Exposure period: The potential exposure period was from Jan. 1, 1947 0 Dee. 31, 1983, Description/delineation of exposure groups/categorics: PFOA production was restricted to the CwheermeiccoanlsiDdievriesdioenxpoofstehde ptloanPtF.OAE.mplEomypeleosywehesowwhoorkneedverinwtohrekCehdemiinctahle CDhievimsiicoanlfDoirvaitslieoansto| wmoornktehd there for less than | month were considered not exposed 0 PFOA. MmeeaassuurreeodfmoornetshtsimoafteCdheemxipcoaslurDei:viCsiuomnuleamtpilvoeymeexnpto.sure to PFOA was estimated using the surrogate. Exposure levels: Not measured. Employees were considered eitherexposed or not exposed. Statistical methods: Stratified Stndardized Morality Ratios (SMR), adjusted for age, sex. and race, were calculated and compared fo U.S. and Minnesota white death rates for men. For women. only siaic a3tpeesriwoedsrofadvauirlaabtlieo.nofTheempSlMoRysmefnortm(a5l. e1s0,wearned s2t0ratyieafrise)d. foCa3ruslea-tsepneccypiefriciomdosra(l1i0t,1y5f,ataensdwe2r0eyceaormsp)aarnedd between exposed on unexposed workers using stratified SMRs. Relative risk and 95% confidence intervals were estimated for deaths from al causes, cancer, cardiovascular discascs, and other selected causes using proportional hazard models (SAS). Age at fist employment,year of fist employment, and durationof cmployment were included as covariatesin the mwoidtehlg.rapThhiecaalpparnoaplryisaitsoenfeslsogoftvehresupsrofpoolrltoiwo-nuaplthiamzearredlaatsisounmsphliiposnasndwamsodeesltsedthuastintegstsetrdattihfeiesdigmnoifdieclasnce. ofa product erm between exposure and log follow-up time. AOthnoesrolmoegtihstodcooldoegdictaheldienaftohrmcearttiiofnic:ates for underlying causeofdeath for the workers according 10 ICD 8 Data collected includedyear of first employment, age at first employment, durationof employment, and duration ofemployment in the Chemical Division. Length of employment at the plant, length of ewmrpeloaynmaelynztedinttodheetCehremmiincealwhDeitvihseiront,hceyalheanddaarnyeefafreeotfofnrsntucmmbpelrosyomfedneta,thasndfraogme aatlfcirasutscemspalnodymfernomt specific causes. RESULTS DTehsecornilbyeerleesvulattse:d (Faolrthaollugfhemnaoltesiegmnpilfoiyceanets),StMheRSwMasRfofrorlayllmcpahuospeosieatncdcfaonrcaerl.l caanndcewrasswebarseeldesosntohnalny13 sdeiagtnhisf.icaWnthleynloewxeprostuhraen esxtpaetucstewda.sbcaosnesdidoenretdh,eSU.MSR. Sraftosr,alflorcabuostehstohfedeCahetmhiacnadl fDoirvialsliocnanwcoerrksewresraend the other employees ofthe plant 109 000113 In male workers, the SMR were close to 1 for mostofthe causesof death when compared 1 both the wUeSr.eannodetlhoevaMtiendnSeMsoRtsa.deWahtehnraetems.ploWyheeendelaatthesnciynatnhde Cdhureamtiicoanol fDievmipslioonymweenrte cwoemrepacroendsitdoerMeidn.ntehseortea death ates. the SMR for prostate cancer for workers in the Chemical Division was 2.03 (95% C1.55 459), "wTahse SbaMseRdfoonr p4rdosetaatthesc(a1n.c9e7rexfporecwtoedr)k.ersThienrtehewaChsaelrnsiocaalsDtiatviisstiiocanllwyassig2n.i0f3ic(an9t5a%ssCo1cia5tio-n4.w5i9t)h. lTehnigtsh porfoepmorptliooynmalenhtazianrtdhemoCdheelmsi,ctahle rDeilvaitsiivoenraisnkdfporroast1a-tyeecaarnicnecrremoarstealiintye.mplBoaysmeednotnitnhtehreesCuhletsmiocfal Division was 1-3 (95% C1 1.01 10 1.27). Ttrose (03.3 (95% C1 1.02-10.6) for workers employed in the Chemical Division fo 10 years when compared to the ther employees in the plant. The SMR for workers not employed in the Chemical Division was less than expected for prostate cancer (58). Study strengths: Vital status was determined for 100% of the cohart. C`ShteumdiycwaelaDkinveisssieosn:emTphleoryeeweassmaaypotheanvteiableefonr emxispcolsaesdsitfoicPaFtOioAn.of Ienxapdodsiutrieonb,eecxapuosseurmeasnwyeorfe tnhoet nonmeasured; therefore categories of exposure were very broad (ever vs. never exposed). This exposure cmhisecmliacsaslisfiicnattihoenwwoorukplldacbei.as tThheeefafuetchtoersstailmsaotensotteowthaartdtthheerenualrl.e diWfofrekreenrcsesweirneahlesdoisetxrpiobusteidontoofotahgeerat risk among the Chemical Division and non-Chemical Division workers and tha thiscould confound the ersespuelctisaolfltyhfeorsftuedmya.lesThinealre wcearteegoarliseos.smaTlhlenucomhboerrtsnoefeddesattobhseinfomlalnoywoedftfohremcaanteygoyreiaerssforcmoamleesiannodrder to develop an accurate pictare of the mortality experience ofthe employeesofthis plant. Research sponsors: National Institue for Occupational Safety and Health Grant and the 3M Corporation Consistency of results: Currently there are no other morality studies on PFOA workers. CONCLUSIONS `Although an association between employment in the Chernical Division and prostate cancer was. owbistehrdvierde,cttheexproessuulrtes mmuesatsubreemienntetrsprmeitgehdtcahreefluplltyo.coCnofnitrimntuheedasfsoolclioawtiuonp.of this study or other studies: REFERENCE Gpirloldiulcatnid.onF.pDl.anta.ndJMOaMn.del35,(91)S:. 951909.39.54.Morality among employees ofa perfluorooctanaic acid. OTHER "tThhriosusgthud1y99i7s.thIet sheacsonnodtuypedtabteeoefntshuebmmiotrteadlittoyEsPtuAdy. Another update is expected to cover the years no 0C0114 EPIDEMIOLOGIC DATA "Title: Morality StudyofWorkers Employed at the 3M Cottage Grove Facility "TEST SUBSTANCE Identity: Perfluoroctanoic acid (PFOA) and other fluorochemicals Remarks: This study is an updateof the study published by Gilliland and Mandel, J Occup Med 1993, 950.954. METHOD Study design: Retrospective cohort mortality study. Manufacturing/Processing/Use: The 3M Cottage Grove, MN plant has produced perfluorinated cpootmepnotusnyndtshestiinccesu1r9f4a7c.tanAt upsreidmairnyipndruosdturcitalfarpopmlicthaitsiopnlsa.ntAisPaFmOmroanpiidulmy dpiesrsfolcuioartoeosctinanboiaotleog(iAcPmFeOd)i,a1to perfluorooctanoate (PFOA). Hypothesis tested: To determine whether occupational exposure to PFOA and other fluorochemicals is related to the mortality experience of employoeftehse 3M facility in Cottage Grove, Minnesota. Study period: The study population worked at the plant for atleast 1 year since Jan. 1, 1947. The cohort was followed through Dec. 31, 1997. Currently employed workers were assigned De 31, 1997 as their last date of employment. Setting: 3M plant in Cottage Grove, Minnesota that produced PFOA and other chemicals oTnoetayleapro.puEliagthitoyn:per6c6e7n8towfotrhkeercsohwoerrtewiadsentmiafileed. Of these workers, 3992 worked atthe plant for at least cSouhbojretctwasselefcotliloonwecdrittherrioau:ghAlDlecw.or31k,er1s99e7m.plCouyrerdenattlytheemCpoltotyaeged Gworrokveerpslwanetrefoarsastiglenaesdt D| eycea3r1., T1h9e97 as their ast date of employment. Comparison population: In SMR analyses, Minnesota population death rates for whites were used. rMeogritoanlailtymorretfaelrietnycererpaotrestifnrgodmif7ferreegniceosn.al counties were also used o rule out large variations based on Participation rate: Death certificates were obtained for 97% (n~ 590) of the cohort who were deceased. Sfuobljloewc-tupdewsacrsip5t6i.o6ny:ea0rs%, an(nd =th3e1m8e3a)nofntuhmebeemrpolfoyyeeaerssiwnotrhkeecdohaotrttheweprleanmtawlea.s T12h.1e. mTehaen naugembaetr of person-yearsa follow-up was 108195. There were 607 deaths identified in the cohort Health effects studied: Morality m 000115 Data collection methods: A reviewof employee work history recordsofany employee with at least | ybieratrh,eamnpdlodyatmeesnotfwweorrekabhissttroarcyt.edTthoisreccoohrodrtthweawsorlkienrkesd" 0narmeec,orSdSsNf,r3omMtihdeeonrtiigfiicnaatliconohnourmtbteor.upddaatteeotfhe `employment information and verify other data. The National Death Index was searched for all ofthe wtoherkSeorcsi.alDSiesccurreiptaynDcieeasthwiItnhdetx.he origliincaelnsceodhonrostowleogriestrecsoodleveddtahenddedaetahthcserbteiffiocraete1s9o79IwCaDre8.verified in Exposure period: The potential exposure period was from Jan. 1, 1947 to Dec. 31, 1997. Description/delineation of exposure groups/categories: Workers were placed into 3 exposure groups based on job history information. Those groups were: definite PFOA exposure (jobs where call wpernoebarbalteonP.FdOryAinegx.psohsiuprpein(ogtahenrdcphaecmkiacgailngdiovfisPioFnOjAoboscwchurerreedetxhproosuugrheou1t0 tPhFeOhAistwoarysopfostshieblpelabntu)t:with lower or transient exposures); and not exposed to fluorochemicals (primarily non-chemical divisionjobs) Measuredorestimated exposure: estimated based on job history information. Exposure levels: Not measured. Employees were considered exposed (492 workers). probably exposed (1685), ornot exposed (1815). Statistical methods: Standardized Mortality Ratios (SRS) and 95% confidence intervals were derived using the PCLife Table Analysis System software developed by NIOSH. This program computes age. eesntdiemra,teadnbdyramcuel-tsippelcyiifnigc StheMaRge,usgienngdesrt,anadcaer,dalnide ctaablleendmaerthpoedrsi.od tTahbeuelaxtpeedctpeedrsnoun-mybeearrosofdfefaotlhlsowareu.p to tuhseedcoarsrreesfpeornednicnegdcataau.se-specific mortality reference rates. Mortality ates for white Minnesotans were Other methodological information: RESULTS eDxepsocsruirbeegrreosuulpt,s:26670i7n dtehaetphrsowbaebrleeiedexnptoisfuirede ignrotuhpe,coahnordt.29446inotfhtehensoet edexaptohssedwegrreoupin. thTehPeFaOutAhors also Stratified by a minimum ofone-year exposure to PFOA in boththedefintely-exposed and probably e(2x1p9osdeedatghrso)uphsa.d p1r8o2bwaobrlekeerxsp(os1u7redefaotrhsa)t wlaesrteodneefiyneiatrl.y exposed for at east | year and 1673 workers. When all employees were compare1d0 the state mortaliry rates, SMR were les than 1 or onlyslightly higherfor alofthe causes of death analyzed. None of the SMRS were statistically significant ap = .05. wTehreehiogbhseesrtvSedM(R3.r8e3poexrpteecdtewda)s. or bladder cancer (SMR~ 1.31, 95% C1 = 0.42~ 3.05). Five deaths TAhefelwarSgMeRiSntewsetrineee(leSvMaRte=dfo1.r67e),mp1lofyreoemspiannctrheeadteifcinciatnecPerFO(ASMeRxp=osu1.r3e4)g,roaunpd: 1 2frdoematphrsosftraotme ccaanncceerr of d(iSeMfRro=m1c.e3r0)e.broIvnaasdcduiltairon,diseemapsleoy(e5edseaitnhtsheobdseefrinvietde,P1F.O94Aexepxepcotseudr;e9g5ro%uCp1w=er0e.28.53 --ti6m.e0s3)more likely to (InSMthRe=pro2.b7a5b,le95ex%poCsIur=e0g.r0o7u-p,153.3S):MpRanwcereraetnioctacbalnec:erc(anScMeRr ~of1t.h2e4,te9st5is%aCn1d =oth0e.r45m-al2e.7g0e;nitaanldorgans n 000116 smalcigrna,ntrmesepecltiavenlsoo.fmtThaheesSiMnR(orSpr=oMs1t.a4Rt2e,c9a5n%cC er in=t1 0hi.s1r7om5p.11w)a.s O0n.l8y6 (1.n=6, 5an2casdes were "otThheerreurwienraerynoorgnaanasb.lFeoeuxcrecsasseessinweSrMe oRbsiertvheednaonnd-oenxlpyos1e.d89gwreourpe, eexxpceepcttefdor(9c5a%ncCe1of-t0heb.l-a55d.d4e08r),nd cTohhoeret.xceOsnsliyn1dpreoasttahtewcaasncreerpodretaetdhsinthtahte wdeafsinoibtseeerxvpeodsuinrethgerfoiusptwsuhdiy 5wawserneotobssetrrvoendginnthtehipsruopbdaabtleed etxepoassutrsetugdryo.up.HoIwtsedviefri,caullltof1theinteemrpprleotytehesseinreestuhletrsgsrionucepwtheereexpaosssuurmeecdatoeghoraiveesswoemreeemxopdoisfuireed tsoince PaFndOAp.lacTehdetnheew idnetloi2neagtrioounpos.fwehxiploesuthreesfiflumrtphlearntdeefmipnledoytheeschseimlicraelmapilnaentd eimn ptlhoeyneoens-eoxfphoesefdirgsrtosutpu.dy "rTehpearntuemdboerropfryoesaarteschaantcert.hese employees worked at the plant andor were exposed to PFOA was not fTuhretheexrcaensaslmyozretdalbiutsyedinocnenreubmrobvearscouflayredaiesoeafseemnpoloeydmiennmtpaltothyepeleasnti.n thTehdeeefinoiftteheex3podseuartehsgroogeuuprwraeds in (woSrMkRers w1h5o.0w3e,r9e5%eCm1ploy3e.d02in j4o3b.s91w)i.thTdheefointihteerP2FoOcAcuerxrpeodsuinreemfpolromyoereeswtihatnheysearhsanbut| <yea10oyefars ddeeffiinniittee PexFpOosAureexp.oTsuhree.SMWRhweansth6e9se(d9e5%athCs1we-r1e.3f9u.rthe2r0.a2n4a)lyfzoerdebmyplcouymeuelsawtiitvehgerxepaotseurrteha(nimSey-ears of jwoebisghotretdhoascecowridtihng ytoeaerxspoofsudrefeicnaitteegPorFy)O.Awoerxkpeosruswreiwtehre273y.e3atrismoefspmoarseurliekeliyn p0rodbiacblofe cPeFreObAroevxapscousleadr d"ipsocsauserethan th general population. A dose-response relationship was not observed with years of rTehpeorstleigdhtineexmcepslsoyieneblsaedrduemracatnhceeDiencatthurc,ohAolratbaasmaa wplhaonlt,easnhdoublldadbdeernoctaendc.erPmFoOrtAaleixtpyowsuares4s twiemrees H1i3.g0h6e)r. inThwroerekedresatwhisthwehirgehreepxoprotseudr,eajnodbsaltlhaofnthtehemgoecnceurrarlepdopnultahteiohnig(hSMeIxRp-osu4r.8e1,gro9u5p.%CPIF-OA0.h9as--9been uoswedboteitnhgismpalnaunftaacstaunrleadsatomDeecartuirn.luMoarnoupfoalcytmuerre pharsodbuecetniooncocurirtisngpsriondcuece19d959. by-product. ts also SSttuuddyistartetnhgetChowlmteagaekGnresosveesp:lan1stdsiifnciecuthlete0xpcosoumrpearaetctghorrieessulwtesorfetmhoediffiiresdt.andAlstchooungdhmtohretaaluitthyors cIlnaisicmlatshiaftihcaetinoenwoecrcuerxrepdo.surWeitchatoeugtormieeassaurreemdoerxepoascueruersa,ii. itshdiefiscusltil0ajruedagte cthheanecfeahbalttyexpoofstuhree ewxeproesusurbe-cdaitveigdoedriisnttohaPtFwOeAr-ecxdepfoisneedd. gr1osuhposualnddbeth noftieldm tphlaaninetmhpilsosyteuedsy hreemacihneemdicianlhpelan"tnoenm-ployees einxpthoesweodrkgprloaucpe.. NSeevveernttheeelnesd,eaatlhocfertthiefidceaatetshswewreerenoctonlsoicdaetreedda1n0dptrhoebraebfolryehwaevreehnaodteixnpcolsuudreed tion tPhFeOA sStmuadlyl. nuTmhibserisoifmcpaosretsa.ntTbheecraeuasreeiottchoeurldchgermeiaclaylschpraensgeentthnetahnealpylsaents.fo Inhoerdcearu0sescoofndfeaiththteharteshulatsda WTeegraerduisngdcfoeretbhreovraesfceurleanrcedipsocpausleat(iowna.s aTnhearrtesiuclosfdiddeantohtcecrhtainfgiceatecoding). regional mortality res Research sponsors: UniversityofMinnesota `Cosntsriosntgenicnythoifs ruepsdualttse:d cTohheoretx.ceOsnslyin|prdoesattahtewacsanrceepodretaetdhsintthhaet dweafsinoibteseerxvpeodsuirnethgerofiurpstwshtiuldey$wawesrneot 13 000117 ocabtseegrovreidesinwetrhee pmroodbiafbileedesxipnocseutrheeglraostups.tudIy.tsHdiofwfeicvuelrt,0alilnotferptrheetetmhpelsoeryeeseusltisnsciintcheerthgeroeuxppowseruer.e `assumed to have some exposure to PFOA. The new delineationof exposures further defined the chemical rpleamnatienmepdlionyteheesonfont-heexpfiorsstedstgurdoyupa.ndTphleacneudmtbheeromfiynteoa2rsgrtohautpst,hewsheileemptlhoeyfeielsm wploarnkteedmpatlotyheeepslasnttillandor were exposed to PFOA was not reported for prosate cancer. CONCLUSIONS aFdodliltoiwonualpodfeawtohsrkienrclmuodretdaliinttyhiatsCaonatltyasgies,Gritoivsestinleledssmtaollconntuimnbuee.r aAnldthtoheugchohtohretreswsetrilel mreolraetivtehlayny2o0u0ng, GOiFvpeanrttihceulraersuilnttseroefststaurdeibelsaodndefrlucranocrecrh.empircoasltsatien cbaontchera,nicmeraelbsrnovdashcuulmaarnsdi.fseuatshe,ercaanncaleyrsainsidsdiwsaorrrdaenrtsedo.f the liver, and pancreatic cancer REFERENCE AFilneaxlanRdeeporr,t.BH.DivAipsriioln o26f,E2n0v0i1r.onMmoernttaallitaynsdtOucdcyuopfawtoironkaelrsHeeamltphl,oySechdoaotltohef P3uMblCicotHaeaglethG,rUonvievefracsiiltityy. of Minnesota. OTHER "This study differs from the 1993 mortality study in that his one requires | year ofexposure for inclusion `iAndtdhieticoonhaolrcto(huosrtopmpeomsbeedrtos6wemroeniihnsc)l.udeIdna(dndi=ti1o6n9,)tthheatesxhpoousludrehacavteegboereinesinwcelruedemdoirnetshpeecliafsitc.study. Its not clear why these employees were not included in the 1993 study. ns 000118 EPIDEMIOLOGIC STUDY TtiotlPee:rflAunorEopaictdaenmoiiocloAgciicdInvestigationofReproductive Hormones in Men with Occupational Exposure TEST SUBSTANCE Identity: Perfluorooctanoic Acid (PFOA) Remarks: This paper further examinesthe observation initially reportedby Gilliland in his doctoral thesis that totalserum organic fluorine may be associated with reproductive hormone changes in PFOA production workers METHOD Shtourdmyondeessiignns:crTuwmoofcrmoassl-eseecmtpiloonayleesstuadtieas,PuFtiOlAizipnrgogdeuncetriaoln mfaecdiilcitayl. surveillance and analysisofeleven Manufacturing/Processing/Use: PFOA was produced at the plant by an electrochemical process, which involved a four-stage process: isolating and converting the chemical to. salt slurry, convertingthe slurry ttoh:e dsarlytincgakaer,ead.ryPiFnOgA,theacpaoktee,ntansdynptahcektaigcisnugr.faTcthaentg,reiastuesstedliikneilnidhuosotdrifaolraepxpploiscuatrieontso PFOA occurred in Hypothesis tested: Since PFOA has been shown to result in dose-related increases in hepatic, pancreatic acinar, andLeydigcell adenomas in laboratory animals and increased serum estradiol levels, PFOA may sdehcroeawasesidmtielsatroesftfereocneinsehruummanlsevewlist.h regard to reproductive hormones, particularly increased estradiol or Setting: PFOA productionplant (presumedtobe 3M plant in Cottage Grove, MN) Total# of subjects in study: 1993-111 production workers, 1995-80 production workers. Sixty-eight production workers were common to both color years Comparison group/population: Employees were divided into four scrum PFOA level categories, 0-<1 ppm, 1-<10 ppm, 10-<30 ppm, and| 30 ppm. in order 0 determine if an effect existed at the highest Serum levels. Participation rate: Not specified Subject description: Characteorfisusbtjeictss were not described. Health effects studied: Potential changes in: serumcortisol,dehydrocpiandrosterone sulfate (DHEAS), estradiol. follcle-stimulating hormone (FSH), 17. -hydroxyprogesterone (17-HP). free testosterone, total tbeisntdoisntgergolnoeb,ulluitnei(nSiHziBnGg)hormone (LH), prolactin, thyroid-stimulating hormone (TSH), and sex hormone- ns 000113 hDeaitghat,cowleliegchttio,namnedtphoudlsm:onaMreydifcuanlctsiuorn;vesitlalnadnacredcobnisoicshteemdicoafla amneddiucrailnaqlyuseisstitoensntsa:irPe,FOmAessdeutreermmeinnattoifon; and several hormone assays. aDestainlos uopnpedraltiamciotollfecdteitoenc:tiTonheinup1p99e5r. liAmitthofedremtoescptriaoynmoafsPsFsOpeActirnop1h9o9l3owmeatsry80aspspamy,wwahseruseeads ttohere duestinegrmainfelusoerresucmenPcFeOpoAlalreivzealtsioinn 1im9m9u3naonadss1a9y9.5. RaEdlievoeinmmhuonromaosnseasyswe(rReIAa)sswayeerde. usCeordtifsoorlDwHaEsAaSs,sayed eFsStHra,diaonl,d p1r7o-lHacPtianndwetrotealastessatyoesdteursonien.g &Frmeiecrtoepsatrotsitcelroeneenwzaysmedeitmemrumnioneadssuasyi.ngTeSqHuilwiabsriduemtediramliynsiesd.uLsHi,ng achcrhoemmaitlougmrianpehsiccesnacmepilemmpuunriofmiecattrioinc. aBssoauy.ndStHeBstGoswtearsonaessweasssecdalvciulaaatreaddaisotiomtmaluntoesatsossatyeraofnteerless free: estosterone. The same assays ware used for both 1993 and 1995 analyses. Exposure period: Not specified. Description/delineationof exposure groups/eategories: divided into four serum PFOA level categories: 0-<1 ppm, For the siaified analyses, employees were 1-<10 ppm, 10-30 ppm, and 30 ppm in owridtehrsteorduemtePrFmOinAe lifevaenlsefatfec1t0epxpismteodragtrethaetehripgahretsitcispeartuedm ilnevbeolt.h ySeeavrse.nty-five percentofthe employees Measuredorestimated exposure: NA o`Sctfaltiisiteincatls,meatnhdodorsd:inSairympmlueltainvdarsitarbalteifrieedgraensasliyosnesw,earnealuysseidso1f0veavrailuaantceea(sAsoNcOiVatAi)o,ns PbeeatrwseoenncPorFrOelAataionnd cach hormone, with adjustment for potential confounding variables. For stratified analyses, employees owredreerditvoiddeetderimnitnoefoifuarnseefrfuemctPeFxiOsAtedleavtelthceatheiggohreisest:se0r-<u1m plepvmel,s.1F-o<1r0muplptmi,var1i0a-te3e0vaplpuma,tiaonn,d PF3O0Ap,pamgei.n vbaordiayblmeas.ssRiengdreexs(sBiMoInm)o,daellcoshowleruese,fiattnedd cwiigtahrePttFeOuAseenwteerreedexasamaicnoendtiansubooutshvcaartieagbolreicuaslinagndlicneoanrt,inuous. asqnudarbeo,uannddtseqstuoasrteerroonoet twraasnsefvoarlmuaattieodn.s.NoTnhleinpeoasrsidbolsec-nroenslipnoenasrearsesloactiiaotnisohniopfsewsetrraedeixola,mifnreeedtbeystomsotdeerlonfei, p`arnodcbeyducroemspwaerriengaplasoraumseedt.ereSsttuidmyatreessu,ltusswiengreinadniaclaytzoredanudsicnogntSiAnSu.ous variables. Stepwise selection Other methodological information: No additional comments. RESULTS DPeFsOcAribmeearseusurletmse:ntTshewerraengheigohflsyecrourmrePlaFtOedAawmona0g tsh8e068ppemmpilnoy1e9e9s3wahndo0part1i1ci5ppatpemd iinn t1h9e95s.tudSyerum during both years. cPoFnOsuAmpwtaisonn,otBhMiIg,hloyrccoirgraerlcaitcesd. wiMtohstanoyfotfhetheemhpolorymeoenseshaodr wPiFtOhAthsefroulmlolweivneglscoevsasritahtaen: 1a0gep,pma.lcoIhnol a1p99p3r.ooxnimlayte1l3ye1m0plpopymeetso hovaedrs1e1r4umpplme.velsTh>er1e0wpeprme.oannldy 415eminpl1o99y5e.esHionwtehvee3r0,ptphemsePlFeOveAlsgrraonugpedinfrom. ci1t9h9e3roafntdheonlhyigheinst1c9a9t5e.gorTiheesr.efoTrhee, miteiasnliakgeeloyftthahtetheemrpelwoayseensotinctnhoenhgihghpeoswteerxptoosduerteecctadtiefgfoerryenwcaessitnhe 16 000120 dliofwfeesrtenitnfbrootmh t1h9e9o3thaenrdc1a9te9g5or(i3e3s.,3ByeMaIrswaansdl3i8g.h2tlyyeahrisg,herresipnectthievehliy)g.hesAtlPthFoOuAghcantoetgosriyg.nificantly E1s9t95r,adialoll waesmphliogyhleyescowrirtehlaPteFdOwAitlhevBelMsI>(530=p41p, pha<d 0B0M1Isin>19298,3,aalnhdour=gh t3h0i,spef<fe0ct1wians1n9o95t).obsIenrved einro1u9p9s3:. hoEwstervaedri,olhleevdeilfsfienretnhcee3w0asppnmotgsrtoatuipstiincablolythsiygenairfiscwanetr.e T1h0e%auhtihgohresr ptohsatnultaheteotthhaetrtPhFeOsAt.udy may snoctruhmavPeFbOeAenlseevneslistwivaereenloiukeglhybteoldoewtetchteanobassesrovcaibatlieoenffbeecttwleeevnelPs FsuOgAgeasntdedesitnraandiiomlalbesctauudsieesm(e5a5suprpme.d SPuFggOeAstinthtahtetCheDhirag)h.erOenstlryad3ioelmlpelvoeylseeisn tihnethhiisghsetsutdyexhpaodsuPrFeOcAatseegorruymcloeuvledlsstuhgigsehsitgha. thrTehsehyoladl.so. relationship between PFOA and estradiol nFergeaetitveesatossstoecrioanteiwonasbehtigwheleyncPorFrOelAatseedrwuimthleavgeelsiannbdotthest1o9s9t3eraonned. 19T9h5e.reTwheeraeunthoosrisatdiisdtincoaltlyrespiognritfsicant ttersetnodsstenrootnee,d wfoarsPhFiOghAesatnidn ctihtehe3r0pbopumndPoFrOfAregrteosutpositnerboonet.h 1H9o9w3eavnedr,191975-.HP{,0 a precursor of 1995, PFOA was. tsihgenaiufitchaonrtslystaastseotchiaattethdiswiatshsoc1i7a-tHiPoniwnarsebgraessesdioonnmotdheelrsesaudljtsuosfteodnfeorempopslsoiybleeec(odnaftoauwndeerres.notHporwoevviedre,d in the report). There were no significant associations between PFOA and cortisol, DHEAS, FSH, LH, and SHBG. hSteudreyssutlrseonfgtthhiss astnuddy.weaFkinrsets, saelst:hoTuhgehrtehearree wseevreera2lsdteusdiygnyeiasrssue(s19t9ha3t asnhdou1l9d9b5e).ntohteedpowphuleantieovnasluwaetrieng enomtplionydeepeesndwehnto. paSritxitcyi-peaitgedhtinemthpelostyuedsy ipnart1i9c9i5p,attehdusinrebdoutchinyegartsh.e pSoewceorndo,fthheerestwudeyr.e 31 fewer There were also SVceertyiofnoawl deemspilgonyoefesthien sctiuthdeyrdyoecasrnwoitthalsleorwufmorPaFOnA laevoellfstygermespaotreiarlitsthyanof10anppams.socTiahtiirodn,. thSeirncoesst-he ha: aJicfcoomfmPoFdaOtAioisnsteovetrhaelefyfeeacrtss, otfhePaFuOtAho.rsFsouugrgtehs,totnhlaytoitneisspaomsspilbelewathsattatkheenrefmoracyacbhe shoormmeobnieolfoogriccaalch of tthaekesntund'ay ysehaorsr.t tiInmeorpdeerriotdo sgehtoumlodrheaavcecbureaetneumseeadsuforremcaecnhtspafrotricsipoamnte.ofFtihnealhlyo,rmtohenrees,mapyoohlaevdebbleoeond Some measurement error of some of the confounding variables Research sponsors: 3M Company `wCoornkseirsstaenncdyionfcrreesausletds:estArandieoalrlainerdsdteucdryearseepodrtteesdtoasntearsosnoecilaetvielosn.beHtowweeevnert,oailt issdeirfufmicourlgtatnoiccofmlupoarrineetihne results ofthis study to the previous study because serum PFOA in workers was measured in tis study. CONCLUSIONS eInmptlwooyecreosssw-esreectnioontaalpsptaurdeinetsiinne1l9a9t3ioannd{0t1h9e95r,mseigansiufriecadntsehrourmmoPnFalOcAhalnegveelss aasmohandgbteheenmparleeviporuosdluyction mobuscehrvleodweinrltahbaonratthoorsye alneivmeallssr.epoHrotweedvfeor,caiutsseheofufledctbseinnoltaebdortahtaotrPyFaOniAmaslsc.rum levels in workers were REFERENCE n 000121 Olen. G.W. etal. 1995. An Epidemiologic Investigation of Reproductive Hormones in Men with `Occupational Exposure to Perfluorooctanoie Acid. JOEM. 40(7):614-622 ns 0ce1z2 EPIDEMIOLOGIC STUDY pTeitrlfel:uoAronocetpaindoeimcioalciodgipcroidnuvcetstiiognatwioornkoefrpslasma cholecystokinin and hepatic function in TEST SUBSTANCE Hdentity: Perfluorooacitda(nPFoOiAe) Remarks: METHOD Study design: 3 cross-sectional analyses based on workers" medial surveillance data collected in 1993, 1995. and 1997 eMlaencutfraoccthuemriicnagl/Pprroocceessssiinngvo/lUvsien:g cTohnevesrutbisntgantchee cisheamsiycnatlhettiac ssualrtfascltuarnrty tahnadt tishepnro1d0u.2cesdalvicaakae.4-stage. (HyCpCoKt)helseiveslsteasntdeds:crTuomdPetFeOrAminleevwelhseitnhfelaruoprooscihteimviecaaslsopcrioadtuicotnioenxiwstosrkbeertsw,eaenndptloadsemtaecrhmoilneecywshteotkhienrin PFOA may modulate hepatic responses 0 obesity and alcohol. Study period: Medical exams were performed in 1993, 1995, and 1997 Setting: PFOA production plant, Cottage Grove, MN Total population: Not specified Subject selection criteria: None specified. although participation in medical surveillance at the plant was voluntary. T7o4,tarles#poecftisvueblyj.ectTsheinrestwuedrye:68 pTahretincuimpbaenritsnsocfopmarmtoicnipfaonrts19in9319a9n3d, 11999955, a2n0din19c9o7mwmeorne f1o1r1.19890,3 aanndd 1997, and 17 in common for all thre years. Comparison population: N/A Participation rate: approx. 70% Subject description: Workers who engaged in the productionof PFOA. No otheinformation wasprovided. Health effects studied: The effectsofserum PFOA levels on hepatic responses to obesity and alcohol, and CCK levels. sDuartvaeiclollalneccetieoxnammsetwhhoidcsh:coPnlsainsttwedorokefrsquveosltuinotnanraiilryep,aprtuilcmiopantaerdyinfubnicetninoina,lhmeiegdhitc,aland weight rmeeparsoudruecmteinvtesh,obrimoocnheeaiscsaalys.and urinalysis testing. PFOA determination, and some male i 000123 pDretoaviildsedonindaantoathceorllreocbtuisotn:suHmomramroyne(Odlasteanweetrae.o,nl19y98c)o.llected in 1993 and 1995. These results are lSuertuammybliooxcahleomaicceatlictetstrsanisnaclmuidneads:e (alSkGaOlTi)ne,psheorsupmhagtlauste,amgy|ampmyrauvgilcuttarmaynlsatmriannasfseer(asSeGP(TG)G,T)t,otaslerbiulmirubin, idigrleycctebriildireusb,in,blocohodleusrteearonli,trloogwe-nde(nBsUiNt)y,licproepartoitneiinnes, (aLnDdLg)l.uchosieg.h-dHeensmiattyolipoogpyrottesetisnsin(clHuDdLed):. hematocrit, hemoglobin, red blood calls. platelets, and white blood cells. tPhlearsmmoasCprCaKy-(31399w3asanmdea1s9u9r5e)danbdy edliereccttrorsapdriaoyi(m1m9u9n7o)ashsiagyh.peSreforrummanPcFeOlAiquwiadscdhertoemramtiongerdapbhyy mass. spctrometry methods. Exposure period: Not specified. Description/delineation of exposure groups/eategories: For the siaiified analyses, cmployees were odivirdetdoddientteoefromuirrnseeirfuamn ePfFfeOcAtleexviestledcaattegtohreiehsi:gh0e-s<t1speprmu.m 1le-ve1ls0.ppm. 10-<30 ppm, and 30 ppm in Measured or estimated exposure: N/A Exposure levels: N/A oStradtiinsatriycamlulmteitvharoidast:e rSeigmrpelsseioanndwisttrhataidfjiuesdtamneanltysfeosr,pPoetaenrtsioanlccoornrfeloautnidoinncgocvfalriicaibelnets.s, ANOVA,and Other methodological information: RESULTS 6D:e4scprpimbe(rreasunlgtes:0.1 T-h8e1.m3epapnm)P.FOTAhesemreuamnlCevCeKlvianleumeplwoaysee2s8.p5arptgi/cmiplat(irnagngien 8t.h8e -19869.77spteu/dmyi)p.eriTohdewas hhiigghheesrtinCtChKeseva2luceastewgeorreiersetphoarnteidn itnhtehceat2eegoxrpioessugrreecaatetregtohraines1l0pesptmha(np 10 = ppm. 06). The means were 50% When adjusted for CpoCtKenatinadl cPoFnfOoAu;ndheorwse,vmeurl,titvhaersieabdlaetarweegrreessniootnimnocdleuldesdiinditchaeterdepoartw.eaTkhneergeawteirveeansosocsitaattiisotnicablelytween csiogmnpifairceandttdoipfafretriecnicpeasntisn wsietrhumlocwheCmCisKtoryrvPalFuOeAs floerveplas.rticipants with high CCK or PFOA levels oSrewriutmhPaFnyOAhelmeavteollsowgiecrael noort cchoenmsiisstternytlpyaarasmseotceirast,edawnidthnoanneyofvtarhieabvlaesl.uessucfhorassuaclhcophaorlamoertceirgsarweetrtee. usc ShteaptaitsitcicarlelsypsoingsneisfitcoanatbeastiatnyyanofdtohreaPlcFohOoAl. levels. There was no evidence that PFOA levels modify. iSntduidcyatesttrheangtthhesraonssd-swoeeatkinoensaslesst:udyTt fsohromualtd dboeensontoetdpthaet CrCamdKiirweatcst oannallyysmiesasofuraendoibnse1r99v7e.d aTshsoecaiauttihoonrs hwiatnh trheespuecmtbteortiomef.parAtdidciitpiaonntaslliyn,1t99h3e.nuomfpabrtieciparnts in 1995 and 1997 was significantly lower 120 000124 Research sponsors: 3M Company mCoodnusliastteesnchyepoaftircesrueltssp:onsTehse results ofthis to alcohol and study are inconsistent with carlier obesity and that thereisa positive findings that PFOA correlation between PFOA and CCK levels. PTFheOAfolalnodwiCnCg Kexpvallauneast:ions may indicate why this study failed to finda positive association between tlhueisspaomsesibbileocthheamtitchaellhyepiantohcuamracnisn.ogenie effectsofperoxisome proliferatoirns rodentsdo not act + The serum PFOA levels observed in workers may have been 00 low to detect an effect. Effects + inanimalswere observed at higherdoses than most ofthe serum levels found in workers. CCK receptors maybe different between rats and humans, Therefore. the monkey may be a more + appropriate animal model to study the pancreatic effects of PFOA. in humans. The involvementof CCK in the initiation or promotion of pancreatic cancer is controversial. + The rat may not be.an appropriate model in the study ofpancreatic cancer in humans, since acinar cell malignancies inducedbycarcinogens in rats, ar are in humans. C"TOheNrCesLuUltSsIdOoNnoSt suggest that there is an association between PFOA levels and increases in plasma CCK levels, nor do they suggest the presenceofhepatic toxiciy at the PFOA levelsobserved. 11 is unlikely that PFOA levels observed in this study modulate hepatic responses to obesity and alcohol us. REFERENCE hOelpsateinc,FuGnVc.ticotnaalnd19s9e8.rum3MperFfilnuaolrRoeopcotratn:oiAcnaceipdidleevmeilosliongipcroidnuvcetsitoingawtoiornkeorfs.plSats. maPacuhlo,l3ecMysCtoomkipnainny.. Sept. 121 000125 EPIDEMIOLOGIC STUDY TOictcluepsatSieornaulmlyPeErxfpluoosreodocMteannoic Acid and Hepatic Enzymes, Lipoproteins, and Cholesterol: a Study of `TEST SUBSTANCE mIdeeanstuirtye:d dTuoctatlostehreucmosftlouforainnealwyazsinugstehdeassaampsluersrogate for PFOA exposure. Serum PFOA was not hRoewmeavrekrs,:whOernigtihneailrlsy,crcummplloevyeclesswweerreeacnoanlsyizdede,retdhe"suen"euxnpeoxspeodsebda"sewdoroknertshihradjoPbFdeOsAcrilpetvieolnssh;igher than the general population. Therefore, total serum fluorine was used (0 classify workers ino exposure roups. METHOD Study design: Cross-sectional study. Manufacturing/Processing/Use: Thisplant produces PFOA, as well as several other specialty chemicals aHnydpoltihpiedsimsettaebsotleids:m.ToThdeetseeremfifneectisfwhoarvkeerbesenexopbosseerdvetod PinFrOoAdenetxspeerxipeonsceedd c0haPnFgOeAs.in hepatic enzymes Setting: PFOA production plant. 3M Chemolit plant in Cottage Grove, MN Total #of subjienscttudsy: 115 `wShuobjewcetreseelmecptliooynecdridtuerriian:g tPhaertpiecriipoadntosfw1e9r8e5-r1e9c8r9u.ited from all employees at the PFOA production plant Cinommpeaarnivsaolnuesgroofupth/epobpiuolchaetmiiocna:l Aelnldpsouibnjtecstwseproetecnotmiaplalryedw.ere exposed to PFOA. Therefore, differences Participation rate: Presumed to be > 80% `Subject per day daensdcr1i7p%tidornasnkMe1-a3noza.gaelc=oh39o.l2:damye;a7n4bpoedrycemntasssmoiknedde.x = 26.9; 76% drank less th1a0n7. alcohol lHiepaolptrohteeifnfse,ctasnsdtuchdoileeds:terPools,siibnlceluedfifnegct:sosfetriuamlgsleurtuammylflouxoarlionaecoentilcevterlasnosfamhienpaasteic enzymes, c(hSolGeOsTte)r,ols,elrouwm-dgelnustiatmyy]lippyorpurvotiecintsra(nLsDaLm)i,naasned(ShiGgPhT-)d.engsiatmymlaipgolpurottaemiyn!s t(rHaDnsLf)erase (GGT). eDaitgahtcoalnldewcetiigohnt,meatnhdoddso:naPtaerdtibcliopoadntssacmopmlepslebtyeavdenmiepdunicctaulreh.istory questionnaire, were measured for Exposure period: Unknown, 000126 bDaessecrdiopntijoonb/ddeelsicrniepattiioonns:ofheoxwpevoesru,rethgorsoeuwposrckaetresgoprrieessu:meWdortko ehravsewlerlee polracneod PiFntOo Aexepxpoosseurceatheagdortioteasl swocrrkuemrsflwuoerrienellaesvielfse2d0-n5o0 mgerosuphsigbhyertrtahlansetrhuomseolervelis relepvoerlts.ed nEmpthleoygeeneesrawlerpeoppullaatcieodni.ntTohoenrecfoorfe, roups of otal serum fluorine levels: <1 ppm. 1-3 ppm, = - 10 ppm, 10-15 ppm, and> 15 pp. SMuerarosguarteedmeoarseusrteimfaortePdFeOxApoesxuproes:urEexposures were estimated. Total serumfluorine was used as mStualttiisvtairciaaltemerteghroedsss:ionStwrearfeiuesdeadna0lyesvisa.luAatNeOaVssAo,ciaPteiaornssobnetcwoerrecnatPioFnOcAocaflnidcibeinotcs.heamnidcallinecnadrpoins. mFoarssstiantdiefxed(BanMaIl,ysaelsc,oAhoNlOusVe.Aapnrdocbeadcurceos wuesereweurseedin0clausdeedssidnitfheerrnegereesssiinonmemaondevlasluaess.potAegnet,iablody cmoondfeolunfdterwsa.s iNmupmrboevreodfccoimgpaarreetdcswistmhoktheedmpoedredlayuswiangscuasteedgonric(ahlevmariialble5s continuous variable if RESULTS ADepspcrroixbiemarteeslulythsa:lfTohfethreawnogrekoeftrhsefslelrnutmoftlhueor>ine1 v-a3lupepswmacsa0c1g0or.y2.6wphpmi(2m3ehaand3s.3erpupmm)l.evels< 1 pp and 11 had levels > 10 ppm. cThhoelreestwerroel nLoDsLi.gniafnidcaHnDtLd.iffPeFreOnAceswabse,thwoeweenvecart,egaosrsioecsiawthedenwiatnhalHyDzLedluesvienlsg iunnimvoadreiartaeteadnrailnykseerss.forIn cthhoelmeusltteirvoalroiratLe DanLalayfseisr.a(dhjeursstiwnagsfonotal2csoihgonlifciocnasntumapsisoocni,ataigoen,bBeMtIwe,eannodtacilgasreertutem sfmloukoriinnge.anTdhere SweGrPeT.noansdtatGiGstTi.callIynscirgensisfeiscainntSdGifOfeTreanncdesSmGPoTnogcctuhrerceatdewgoirtihesioncfrteogtsailngsetortualmsfelurourminfelufoorriSneGOleTv.els in bcoenssiestweonrtkweirtsh(hBeMpaIti=c 3d5isokrnde)rs,. NNoocwloinrikcearlscraespeosrotfedlihveepradtyiscfduinscetaisoendaisasgoncoisaetsedorwistihgnPs,FoOrAseyxmppolsoumrse were found in these workers Sitnfuodrymasttiroenngptrhosviadnedd owneahkeneesmspels:oyePeFsOcAs.walesngntohtomfeacsmuprleodymdeinrtecetxlpyoasnudret)h.ere Tishenoauetxhpoorssusrteate tht no aisdvneortscelecalrintihcaatl ohuetrceohmaessbeeleantefdoltloowP-FuOpoAfefxopromseurreehmaplvoeybeeese.n oIbnsaedrdvietidonin, tthheeirsteamnpdlaorydedeesv:iahtoiwoenvser, i rienptohreterdesfuosr.theMalvneyr peanrztiycmiepsantwserientvheerysthuidgyhweforremeamnpyloofyetdheienxpproosduurceticoanteogforcioesm,poinudnidcsationtgheirnshtaabnility PFOA Research sponsors: A NIOSH grant and the 3M Medical Department Consistency of results: There are no othr known studsofthis kind on PFOA. CONCLUSIONS PHoFwOeAvewra,sPnFotOAassmoacyiamteodduwliatthemtahrekfeldeheeopaftailcccohhaonlguesseinanhdumobaenssitaysohnadhebpeaetniolbispeidrvaenddixnernoodbeinottsic metabolism. 123 000127 REFERENCE aGnidchlollesitFe.lrDol.a:annAddsJt.,5u.dyMoanfdoelc. c1u99p6.aSterieuxomppnosaeedlmleryn.fAml. JaucoidouaonrfdrIhnendopusaattroiilcaclcnzMyetmdiecsia.nlei.pno2p9ro:otSe6ii0ns-, 368. 124 000128 EPIDEMIOLOGIC DATA "Title: An Epidemiologic Analysis of Episodes of Care of 3M Decatur Chemical and Film Plant Employes, 1993-1998 TEST SUBSTANCE Identity: POSF-based chemicals used at the Decatur plant Remarks: Episodesofcare analyses are not often used inoccupational epidemiologic studies. METHOD Study design: Episode of care comparison Manufacturing/Processing/Use: The 3M Decatur, Alabama plant began production in 1961. Itis made up of the film plant and the chemical plant. The3 major product groups i the chemical plant are (prPoOtSeFct)ivie cthheemmiacjaolrss,uplefornfaotremafnlcueorcohcehmeimciaclasl, maanndufflaucotruorceldasattomDeercsa.turPearfnlduoisrouoscetdanaesstuhlefopnrye!cufrlsuoorritdoethe productioofna variety ofperfiuorinated amides alcohols, acrylates, and other luorochenical polymers. Hwiytphotlhoengs-itsetrems,tehdi:ghTeoxpuosseureepitsoodPeOsSoFf-cbaarseedmeptrhoodduoctlioognyaastahesc3rMeenfacfiolritmyoribniDdeictaytuoru,tcAolambeasmaas.sociated Swteruedyanpaelryizoedd:foErpiwsoordkeesrosfactartheeepxlpanetriwehncoeowfer6e52emcphleomyiecdalfoermaptlloeyaestes1 aynedar6b5e9twfielemnpJlaanntuaermypl1o, y1e9e9s3 `and December 31, 1998, Settings 3M plant in Decatur, Alabama. "Total population: 1311 workers were cligible for the cohort (at least | year ofemployment at the plano). "The total worker population was not reported. Subject selection criteria: All workers employed at the Decatur plant for at feast | year between Jan. 1. e1m9p9l3oaynedesDehi.re3d,1.te1r9m9i8.nateEdp,iosroddeiscdofdcuarriengwetrhee sltiumdiytepdertiootdh.eirHoDweecavteurr, triemceorodfseomfpelmopylmoeynetesfoorn Medicare, long-term disability or who chose HMO coverage were not in the database and would not be: included in the episodesof care for that employee. Ccoommppaarreidsotoncpaocphuoltahteir.on:EmCphleomyiecealcoamnpdarfiilsmonplgarntouepmspwlaoryeedeesfwienreed aancacloyrzdeidngsetpoatrhaetierlypoatnendtitahlen workplace exposure to POS fluorochemical production. GroupA: all chemicalplant employees and all finiltmheplcahnetmeimcpallopyleaenst aelnidgiabllefifolrm tphleanctoheomrpt.loyGeresowuhBpoawlolrkcehedmiexccallupsliavnetlyeimnpthleofyilewmheplosanwt.orGkerdosoulCpel:y. halel cfhielmmipclaanlt.plaGnrtoeumpplDo:yaelelspwliatnht hwiogrhkefrlsuowriotchhehmiigchalfleuxoproascuhreemisccaolmepxaproesdurteo ftohreiarjeob cao1u0nstyeeratprasrtpsriinor tothe study onset compared to thirjob counterpart in the film plant. Participation rate: 97% of Decatur employees were eligible for participationi the study. 125 000129 `Subject description: 82% of the employees in the cohort were male (530 i the chemical plant and 558 oifn tthhee cfihlemmiplcaanlt).plaTntheemmpelaonyeaegse hwaadsw4o5r.1keidn otnhleychienmtihceaclhpelmainctalapnlda4n8t.6anidn athseimfiillamrplpaenrt.cenStiaxgteyopferfcielnmt lant workers had worked exclusively in the film plant. Seventy-six percentofthe chemical plant workers had high exposure jobs. HPeFaOlSt,hceefrfteacitnsesptiusdoideeds:ofMcoarbriediwteyr.e cBoansseiddeornedanaipmraiolrid.ataTahnedy eipncilduedmeido:lolgiivcerstaunddiebslaodndePrFcOaAncearn,d endocrine disorders involvitnhge thyroid gland and lipid metabolism, gastrointestinal disorders of the liver and biliary tract, and reproductive disorders. Data collection methods: The Clinical Care Groups episodeof care software developed by Ingeni, Inc. awnacsilulasreyd steorvpircoevsi,deanadcpormepsrcreihpetnisoinvderuggrsouupsiendgionfthaelvdiisaitgsno(siinsp,attireenattmaenndtoauntpdatmiaennat)g,emperonctedoufrmeso,re than 4r0ec0orddisbcyasseesaorrchcionngdibtiaocnksw.arTdheasnodfftowrawraercdodineticmoensfotrrtuhceathnseaclptihscoldaeiomfscraerceoradrsouthnadt tahree irnedleaxte-dlitgoibtlhee: disease or condition on the index record. The index record consistsofcither procedure codes indicative ofa face-to-face encounter ora pharmacy recordfor a delineating drug. Exposure period: The episodes of care that were included in the study were those experienced between Jan. 1, 1993toDee. 31, 1998. pDoetsecnrtiipaltiwoonr/kdepllianceeateixpoonsoufrees:xpowsourrkeergsrowuhpso/ewaetreegoermipesl:oyeWdorskoleerlsy winertehepclhaceemdicianltoogrrioluipspalacnctosr,dtihnogse.to who had high exposure jobs, and those whoworked at least 10 years in jobs with high potential for fluorochemical exposure. Measured or estimated exposure: estimated based on job history information. Exposure levels: Not measured. Employees were placed into exposure categories based on job description. o`Sbtsaetirsvteidcaltomeextpheocdtse:d eApirsiosdkesroaifocaerpeisofodreocfhecmairceal(RplRaEnPtCe)mpplrooyveiedsedcothmepeasrteidmtaottehoef roibsskebrevtewdeteon the expected episodes ofcare among film plant employes. The expected numberofepisodesofcare for both tphoepuflialtmiaonndinchtehemiUc.aS.l plBaenctaeumspeltohyeecehsemwiacsalcaalcnudlaftieldm from plant health claims dataof the 3M manufacturing cohorts had slghly different age and gender structures, an adjusted ratio was calculated and comparedto the unadjusted risk ratio. In most cases, the. risk ratios were comparable. Therefore. 95% confidence intervals were onlycalculated for the unadjusted isk ratios. Oeptihseordemoeftchaordeolcooguilcdarlepirnefsoernmtaatnioyna:nd1tasllhoiunlcdibdeentncoatseeds,thpartevfarloemntancaesepsi,deamnido/loorgmiicscplearssspiefciteidvec,asaens (both false positive and false negative). In addition, types and counts ofepisodes of care may differ by. tChoentsaoifntwsearrveicuesse,d,suacnhd aist iapbospsriobcleedutrheast a2nddifpfreersecnrtipdtiiaognnsosmeasymnaoyt be be assigned reported 10 the forthe seapimseodcep.isoAdles.o, the endpoint of an cpisode may vary among software programs. The clinical flexibility of the algorithm may differ depending on the software program. 126 0C0120 RESULTS nDeeospclraibsemsroefsutlhtes:maTlheeroenplryodiuncctrievaesesdysritsekmofaenpdisfoordtehse foovrertahlelccoantdeigtoiroynosfocfaapncreirosranindtebreesntigwnergerofwotrhs (ovwehriaclhl cinacnlcuedrecdactaegnocreyr offotrhaell macloempraeprriosdounctgirvoeupssys.teTmh).e iTshkerreatiwoaswaasngirnecarteesatseidn rtihsek gofreopuipsoofdes for the employes with the highest and longest exposures to luorocheicals (RREPC- 1.6, 95% C1~ 1.2- 2.1) cIannccreerasse(dRrRisEkPoCf-epi9.s7o,de9s5i%n Clo1ng=-t1i.1m-e4,5h8i)g.h-cItxpsohsouurledebmepnlootyeedesthaaltstohewacsonrfeipdoerntceed ifnotrermvaallesrevperroyduwcitdivee. ofobrsemravleedrefporrordeupcrtoidvuectciavneccearnscaenrds tihnecshuebm-iccaatlegpolraynotfepmrposltoayteeceasnce(1.r8 .expFeicvteede)p,isoofdweshoifccah4rewewreerperostate cancers. One epiosfporodstaete cancer was observed in film plant employees (3.4 expected). This pnldaintnmgoristailmiptoyrsttaundty.becHaouwseevearn,extcheesuspdinatperoosftattheecsatnudcyerdmiodrtnaoltictyonwfaisrmobthsiesrvfienddiinng.the Cottage Grove Tghreoruep (waRsREanPCin-cr1e.a3s,e9d 5ri%skoC1fe=pi1s.2o-d3e.s0)foarnndetohpelalosnmgs-otfetrhmeemgapsltoryoimnetnetst,inhaglhtreacxtpoinsutrhee ghrigohupex(pRoRsuErpeC 29.95% C1= 1.73.2). Most of the episodes were atributable 0 benign colonic polyps. Similar numbersofepisodes were reported in film and chemical plant employees. cIanntcheere(n1t.i5reexcpoehcotretd,)n.lyBot1 hepoicscoudreroefd cinarfeilwmasplarnetpoermtpeldoyfeoresl.iverOnclaync2erca(s0.e6soefxcpiercrtheods)isanodfth| eforlibvleradwdeerre oibnfseecrtvieodns(0.i9necxhpeemcitceadl)p,labnottehmipnltohyeechse,mbiuctatlheplyanwt.ereTmheorsetlwyadsuaegtroearteecrurrirsiknog fepoiswoedresurofincaarryebtryactthe sofamepeiseompdleosyreeepso.rteIdt.s difficult 0 draw any conclusions about these observations, given the small number Ctohesmciekcaclarpelafnotredmispolrodyeerseosfinthtehebihliigahryetxrpaocstutrhea,nltohnigr-tceorumnteemrpplaorytmienntthegrfoiulmp pwlearnet (2R%REtiPmCes=m2o6r,e9li5k%ely Cp1lant 1wo2r5k.e5rs)., TEhieghstuebe-ncaetpeigsoordieessofthcaarienfwleuerneceodbtsheirsvoebdseirnvcahteimoincawlerpelaenptiesmopdlesooyfeecshoalneldit1h4iaisnisfiwmith caacsuetse ochcocluereryesdiiintschaenmdicchaolleplliatnhtiaesmipslwoiytehesc.hronicorunspecified cholecystitis. Most of the observed dRiiasbketreast,iohsoyfpeerpliispoiddeemsiao,f acnardeoftohrerenedoncridneodoicsrorrnduetirist,niownheailcdhisionrcdleurdse,dwseurbe-cnaottegeolreiveasteodfitnhytrhoeid disease, cnotmhpear9i5so%ncgornofuipdse.ncCeonindtietrivoalnsfowrhithcehhwiegrheexnpootsiudreen,tilfoiendg-ateprrimoreimbpultoywmhiecnht egxrcoluupdiendcltuhdeedn:ulldhiyspoortdehressiosf the pancreas, cysits, and lower urinary tract infections. Septiusdoydesstorfecnagrthessaofntdwawree.aknTehseserse:sulStseocf"tohtihserstmuedtyhosdhooluolgdiocnallyibnefoursmeadtifoonr"hsyepcottihoensifosrlgiemnietraattiioonn.s of d`eAlmtohgoruagphhtihcesebpuitsoddiefofefreantreexdpeossiugrnesa,lltohewseedafre amodainryrecltimciotmatpiaornisstoonothfiswoderskiegrns. with similar Episodesof care arc draetpoaratreed.dinfofticduilstetoaisneteirncpirdeetncbee;cathuesreef@orlea,rgtehiRsRpEarPaCmemtearycnaontnontecbeessianrtielryprientdeidcaitneahniyghotrhiesrkomfainnnceird.encTeh.e oTfhediascnaasley.sisInwaadsdiltiimoint,edmato6nyyoefartsh.e rAilssko,rattihoesfuotirliezpaitsioondeosfhoefaclatrhechaarde vseerrvyicweisdemacyonrfeifdleecntceloicnatlermveadlsi.cal pcraatcetgiocreizpeatdteurnnds.er Ilnadrigevridouralssmamlaleyrbdeisccoausnetceldasmsiofriccattihoanns.onEcpeisiondtehseodfatcaabraesmeabyecianucsleudtehetyhecsanambee b 000131 diinsdaibviliidtuya.l several times.Notall employees were included in the database, such as those on long-term Research sponsors: 3M Company Consistency of results: No other morbidity studies have been conducted on fluorochemicals. "CTOhiNsCsLtuUdSyIsOhNouSl.d only be used for hypothesis generation regarding workers employeadt the Decatur plant who are employed in jobs with high exposure to POSF-bascd fuorochemicals, ROElsFeEn.REGNWC,EBurlew, MM, Hocking, BB, Skat, IC, Burrs, JM. Mandel, JH. An epidemiologic analysis of episodes of careof3M Decaturchemical and film plant employees, 1993-1998. Final Report. May 18,2001. 128 000132 GENETIC TOXICITY STUDIES C"Thiethmei:caAlnTA-s2s9a4y2ofCoCCell Transformation and Cytotoxicity in C3H 10T % Clonal Cell Line for the Test TEST SUBSTANCE Identity: T-2942 CoC. Remarks: White powder dissolved in DMSO; composition and purity not indicated METHOD Method Guideline followed: No guideline number specified Test type: Cytotoxicity and cell transformation "Test system: Mouse embryo fibroblast GLP: No Year study performed: 1950 `Species/Strain/eell-typefeell lines Cells of the C31 107-172 clone Metabolicactivation: None Concentrations tested: 0.1, 1.0, 10.50, 100.200 gin. Statistical methods used: None gRreomwairnkgs:inTEhaeglteesBtamsaatlerMiealdiwuams d(iBsMsEo)l.vedBeinnzDo(MaS)pOyraennde<an2d04doi-fctphoexysboultuatniocnwwearse ausdeddedatsotpohseiticvueltures cdoanttarwolesreanodbtDaiMnSedOinastahesfoolrvemnotfccoynttortoolx.icPirtiyormoeasthuerepmeernftosrmaasnecxeopfretshseedtbraynpslfaotrimnagti(ocnlaosnsiangy),deoffsiecieanncgye.. t"TrhaensafpoprrmoaxtiimoantpeotienntviiatrlooLftDhSeOtceysttocthoexmiicciatly. doTsheewtarsancshfoosremnataisonthaessmaeydwiaans dpoesrefofromretdheinsttuwdoypohftashees: apostseenstsimaeln(tpohfacseel2l).trPahnasfsoerm1awtiaosnpienrtfhoercmoeldoinnysmixodreepl(icpahtaess.e T1)haentdesdtectehremmiincaatliownasofrefomcoivterdan2s4f-ohromuartsion a`afntdersatpapilniecdaattio1n4adnadysthteocsuclotruerefsorwetrraensef-ofremadteiovne.ryP3hdaasyes2fworas14al1s01o 7pedrafyosr.mePdlaitne6s wreeprleicwaatesshepde,r dfoisxee.d, (p1r.o0c.e1s0s.edanatd31800dapygs/amfLl)wirtehmobvuatlaodfitehneeefpsotxisudbesstsaancep.ositive control. In phase 2, the cultures were RESULTS Overall transformation results: Negative 129 000133 Cytotoxic concentration: approximate LD - 50 pg/ml. Statistical results: None CONCLUSIONS fTohceiraeswsaaysmneotheovdisd.ence of transformation observed at any of the dose levels tested in either the colony or REFERENCE Garry, Clonal V.F..and Cell Line R.L. Nelson. for the Test Ch1e9m81i.calAnT-A2s0s4a2yoCofCC.el3lMTrCaonmspfoarnmya,tiSot.n aPanudl,CyMtNo.tonicity in C3H 10% 130 000134 Title: Mutagenicity Test on T-6564 in an In Vivo Mouse Micronucleus Assay TEST SUBSTANCE entity: T6564 Remarks: clear, colorless liquid; composition and purity no indicated METHOD Method/Guideline followed: Protocol No. 455, Edition 17, modified for 3M Corporation Test type: Jn vivo mouse micronucleus assay GLP: Yes ear study performed: 1996 Species/Strain: Mouse! Crl:CD-1E(ICRBR Sex: Male and female No. animalsisex/dose: Five (micronucleus assay), Three (range-finding studies) Vehicle(if used):Deionizedwater Route of administration: Oral gavage DDoossees:Selection Study I: 1000, 1510, 2010,2540,3010 mgrkg. Dose Selection Study II: 1010, 1520, 2020, 2530 meke Micronucleus Assay: 495. 995, 1990 mk Frequencyoftreatment: Once Statistical methods used: Analysis of variance; Dunnet's est Remarks:The initial body weightoftheanimalswas 22.4 28.3 g for femalesand 31.0 37.7 for omafltehse; dtohseeirsealgeectwion 8satwudeyes.kst.heDmoasxinigmuwmastoalcerhaitoevddedosue wsaasveisotlinummaetgeodfa1s02m0L0i0kgm.arBkaes.edA ovenhitchleerecsonutlrtosl, using deionized water. and a positive control, using cyclophosphamide at 80 my/kg, were implemented. SAlniidmesalasndwesrtaeinseadcrwifiitchedMaaty-24G,ru48n,waanldd 7s2olhutoiuornsaanfderGdioesmisnagparnidorb0onanamlaysrirso.wTwhaessleixdtersacwteerde. scpordeeadd foonr aenrayltyhsrios.cytaend(NsCcoEr)edceflolrramtiioc.roOnnuceletihoaunsdantdhePpColEycpherromaantiimcalerwyetrherosccyotreed(.PCE) to nommochromatic 131 000135 RESULTS Effect on mitotic index or PCE/NCE ratio by dose level and sex: Negative Genotoxic effects (unconfirmed, dose-response, equivocal): Negative Statistical results: Negative Remarks: All animals i the micronucleus est group appeared normal immediately after dosing: however, one malefrom a secondary dose group was found dead 22 hours after dosing. All other animals appeared normal. The positive conirol induced significant increases in micronucleated PCE as compared tIon tthhee dveohsieclseelceocnttirooln.studies,there were mortalities at the 1510, 1520, and 300 mg/kg dose levels. Clinical signs of toxicity in the dose selectionstudies were hunched posture, hyposctvity, and rough hair coat CONCLUSIONS "The test article did not inducae significant increase in micronuclei in bone marrow polychromatic erythrocytes andi considered negative in the mouse micronucleus assay. FERENCE Muli H. 1996. Mutagenicity test on T-6564 in an in vivo mouse micronucleus assay. Study number 17750-0455. 3M Corporation, St. Paul, MN. 132 000136 (TiCtHleO:)MCueltlasg:enwiciittayhTConefoinrmTsa-t6o5rt6y4AsMseaaysuwriitnhgMCuhltriopmloesHoamravlesAtbserrations in Chinese Hamster Ovary TEST SUBSTANCE Identity: T-6564, also referred to as L-13167 and EC-1015-X. `Remarks: The specific gravity of the test substance was 1.22 g/ml. Substance was aclear colorless liquid METHOD `Method/Guideline followed: Protocol No. 437C, Edit4iwoans modifiedfor 3M Corporation Test type: In vito cytogenetics Test system: Chinese hamster ovary calls in culture. GLP: Y earstudy performed: 1996 `WSoplefcfi,esU/nSitvreairns/ieteyollf-tCyapelfiefeolmliali,neS:anChFriannecsieschoa.msCteelrl olvianeryhacdelalns/apveerrmaagneenctycclaleltliimnee sofup1p2liteod 1b4yhDoru.rs.5. Modal chromosomenumber was 21. NTyApDePofarme1t.5abmogl/imclacatnidvaitsoicointruisceadc:idAarto2c.l7ormg1/2m5l4. induced rat liver $9 homogenate, 15.0 Lm, plus CRoanncgeefnitnrdaitnigons tested: 0.169, 0.508, 1.69, 5.08, 16.9. 50.8, 169, 508, 1690, 5080 pg/ml (both with and without activation) Initi`alWistthuoduyt --activation: 62.5, 125, 250, 500, 1000, 1500, 2000 pg/ml With activation: 250. 500, 1000, 2000, 3000, and 4000 pg/ml ConfWiirtmhaotuotryacsttiuvdaytion'20.1 hours: 100, 200, 400, 600, 800, 1000, 1200 ug/ml WWiitthhoaucttiacvtaitviaotni2o0n./1d4.+424h.o2urhsr:s: 50, 100, 200, 400, 500, 1000, 1500; 620000.0,80202,501,00205.00a.nd2715200,0anudg/3m0l00 g/m Test conditions: hNouumrbsebreofofrceeltlsr:eatImnentthebmyasicnedsitnugdiaebso(ubtot1h.2wixt1h0ancedllwsitfhooruttheac1ti7v.a8tihoonu)r. cell assay were and 0c.u8ltxur1e0d cfoerlalbfoourt t2h4e. 44.2 hour assay. The culture medium used was McCoy's $a culture medium supplemented with nutrients and antibiotics. 133 000137 Negative Controls: In the nonacivation assays, negative controls were cultures with cells and culture m10e.d0ipulmimlo.nlyI.n tShoelvaecnttivcaotnitornosltsudcioenst,aniengeadtoinvleyatnhdessoollvveennttcfoonrtrthoelstwesetraerttihclees, astmeerialesdtehioosneiiznedthweater at nomactivation studies but also included the $9 activation mix. Positive Controls: MitomyciCn was used for nonactivation studies. Cyclophosphamide was used in the activation studies. Only cells with 21 1 1 centromeres were analyzed. One hundred cals from each replicate culture of rpoesaittmiveentcognrtoruolpscualntdurneesgawteirveeaannaldyszoedl.vent control groups were analyzed. At least 25 cells from the In the main study (afrrange-finding study was completed), both inital and confirmatory studics were done. Softactiasltsicwailthmeatbehrordastiuonssedi:n eFaicshhetrr'esaEtxmeanctt gTresotup(SwoiktahltahendcoRnothrlofl g1r9o8u1p). waLsinueasredre0ndcotmesptasorfeitnhcerepearscienngt numbers of cell with aberrations with increasing dose were also done. Tests were considered 10 be. significant at a p value of< 0.01 RESULTS Overall results: (Without activation Initia eal- negative (no significant increases in cells with chromosomal aberrations observed at concentrations tested.) 2ab0e.r1r-ahtoiuornscoonbfsieermvaetdorayl csotnucdeyntrnaetgiaotnisvtees(tendo.)significant increases in calls with chromosomal 44.2-hour confirmatory study~ negative (no significant increases in cells with. chromosomal aberrations or polyploidy wars observed at concentrations tested.) (2) With activation. Initial ral-negative (no significant increases in cells with chromosomal aberrations observed at concentrations tested.) 20. 1-hour confirmatory study- posiastigniifvicaent increase in cells with chromosomal aberrations was observed at 2500 g/m.) 44.2-hour confirmatory study ~positiv(ae significant increase in cell with chromosomal aberrations was observed at 2750 g/m. Also, a significant increase in polyploidy was observed im cultures dosed with 2250, 2500, and 2750 g/ml) 134 000138 GJeinmot)oxiinctheeffpercetss:encPeosoiftiavcetirveastuilotns. foProcsihtriovemofsorompaollyapbleorirdaytiaonnds eatndtowroedcuopnlciecnattriaotnioinst(he25p0r0esaenndce27o5f0 Cytotoxic concentrations: In the range-finding study, complete cytotoxicity was observed in cultures dosed with S080 ug/ml (both with and without activation). The lowest doses at which cytotoxic effects were seen in themainstudy were: WithoutIniatcitailvat5io0n0 ug/ml 20.1-hr confirmatory -- 600 ug/ml 44.2-h confirmatory- 400 g/m With acItniivtiaatlio-n2000 pg/ml 20.1-hr confirmatory 2000 g/m 442-4 confirmatory - 2250 g/ml Statistical results: Two concentrations in themainstudy (2500 and 2750 ug/l) showed significantly greater numbersofchromosomal aberrations. SRteatmiastrikcasl:siSgtnaitfiisctiacnacles(i3g.n..ifpic<an0c.e0w1awsajsudugseedd ruastihnegrarthualnep t<ha0t.0w5.a)s sNtroictienrftohramnatuisounalwlaysuasveadiltaobjluedgteo. determine whether chromosomal aberrations were significant at p < 0.05. nthe inital trial withoutactivation, mitote index reductions were 25%, 30%, 87%, and 96% at doses of 125,250, 100, and 1500 ug/ml, respectively shen compared with solvent controls. Cinhitrioalmotrsaolmwailthabaecrtriavtaitoinons,waermeitaontaiclyizneddexfrroemduccutlitounroefs 2do%sewdawsitshee1n2a5t.225500,g5/00m, awnhden10c0o0mupga/rmeld. wIinththe Solvent controls. Chromosomal aberrations were analyzed from cultures dosed with 250, 500, 1000, and 2000 pgm) In the 20.1-hour confirmatory trial without activation, mitotic index reductions were 73%, 84%, 1nd 95% aatbedrorsaetsioonfs8w0e0r.e1a0n0a0l,yaznedd f1r2o0m0cgu/ltmulr,esrdesopseecdtiwvietlhy 2w0h0e,n40c0o,mp6a00r,edanwdit8h00soulvge/nmtlcontrols. Chromosomal Inthe 44.2-hour confirmatory rial without activation, mitotic index reductions were 12%, 61%, 639%, and 9ab2e%rraattidoonssewsoerfe5a0n,a4l0y0z.ed60f0r,oamncdul8t0ur0egs/domsledwhweitnhco10m0p,a2r0e0d, w4i0t0h, saonldve6n0t0cuongt/rmolls. Chromosomal Ianndth3e02%0.a1t-dhoousrescoonffi10r0m0a,to1r5y0t0r,ia2l0w0i0t,h2a2c5t0i,vaatinodn,2m5i0t0otpigc/miln,derxesrpeedcutcitvieolnyswwheerne c1o3m%p,a3r8e%d,wi1t5h%,sol1v1e%n,t controls. Chromosomal aberrations were analyzed from cultures dosed with 1500, 2000, 2250, and 2500 ps I5n3t%heat44d.o2s-ehsooufr c1o0n0f0i,r2m2a5t0o,ry25t0ra0l, waintdh2a7c5ti0vagtiomn, mwihtoetniccoinmdpeaxreredduwcittihosnoslwveenrtec1on4t%ro,ls1.7%C,h5r6o%m,osaonmdal aberrations were analyzed from cultures dosed with 2000, 2250, 2500, and 2750 pg/ml. "aTnhaelyazuetdhosrespdaerastcerliybebethceaufsoellsoowmiengddoesveialteivoenlss sfhroomwetdheinprcorteoacsoeld e--nednodroerdeudpulpilciactaitoinonnadndsopmoleysplhooiwdeydwere increased polyploidy. 135 000139 136 000140 CONCLUSIONS "The authors state that T-6564 was considered negative for inducing chromosomal aberrations in Chinese: hamster ovary cells expect ata singledose level (with activatitohnat) induced significant toxicity. Remarks: Significant toxicity was observed in the 20.1 and 44.2h confirmatory tials with activation at the highest concentrations tested. These two concentrations were also positive for chromosomal haboewrervaetrio.ns. The significance oaf positive response in the presenceof excessive toxicity is questionable. REFERENCE Murli, H. 1996. Mutagenicity Test on T-6564 Measuring Chromosomal Aberrations in Chinese Hamster OvHaazrlyeto(nCHIOne). CCelHlsV: SwtiutdhyaNCo.onf1i7r7m5a0t-o0r-y4A3s7sCa0y.wiStehptMeumlbtieprle16.Harvests. Final Report. Coming 137 000141 "RTeivtleer:seMuMtuatgaetniiocnitAyssTaesytwwiitthhaTC-o6n5f6i4miantothreySAaslmsoanyella- Escherichia ColiMammalian-microsome TEST SUBSTANCE entity: T-6564,aso referred to as L-13167 and FCI015-X sRuebmsatarnkcse:. The substance was a lear, colores liquid. No other information was provided on the test METHOD bMetahoodnsGAumiedeeslitdnael.fo(1l9l7o5w)edandCHGrVeePnroatnodcoMlar4i0e9lR.(1E9d7i6t)ion 4. Experimental methods and matrils were "Ceosntfitrympaet:orSyalAmsosnaeylla ~ Escherichia ColiMammalian-mictosome Reverse Mutation Assay witha Test system: Salmonella typhimurium and Escherichia coli sins GL: v Year study performed: 1996 SpeciesSteain/cll-typelell ine: SofalBmiooncehlelmaispthryi,muUnriivuermsisttyoaifnsCaTlAiSfoSr.niTaA,IBOeDr,keTleAy1.S33. and TAIS37 from Dr. Bruce Ames, Department EStsacthieorni,cShcioatcloalnidsain W217 from National Collection ofIndustrial Bacteris, Torey Research NMeat:aPbOol,iNcaascHtiPvOaLti.onl:ucAorsoec-l6o-rph1o2s5p4h-aitned,ucKeCdUrMaelCilve.r 9 homogenate, plus NADP, H0, CRaonngceefnitnrdaitnigons tested: Main stu1d0ydoses from 6.67 0 5000 pg/plate 100, 333, 1000, 3330, 5000 ug plate (with and without activation) Test conditions: Number of eels: Density oftester strain eulureswere 0.5 x 10" bacteriapemi. 5Ne9gmaitxi.veP(ovseihtiicvlee)cocnotnrtorlosl:s: ThTehseesewewreereuspeldatbeodtfhorinalthteepsrteessetnrcaeinasnbdoathbsiennctheeopfrtehseen$c9emainxd; adbisffeenrceentof chemicalswere used depending on the strain bing tested 138 000142 During therange finding study. the growth inhibitory effect (cytotoxicity) of the test article o the test sdeycsrteeamsewaisn tdheetenrummibneerdoufsrienvgerS.taanytpchoilmounriieusmpsetrrapilnatTeAo1r0t0h,innCiyntgotoofxitchietbyawcaksgrdoeutnedrmbiancteedritaolblaeawn. No cytotoxicity was observed in the range-finding study. During the main study, both initial and confirmatory studies were conducted. The authors" criteriafor apositive test result was to produce at least a 2-or 3-fold increase (the amount dheapdetnodbseoanctchoempstarnaiinedtebsteayd)dionsmeeraensproenvseertfaonrtsinpcerreapsliantge ccoonmcpeanrteradtiwointshotfhtehveehtiecslearctoinctlreol. The increase Statistical methods used: None indicated Remarks: RESULTS Overall results: In the initial assay and confirmatory assay, all data were acceptable and there were no pcoosniftiirvmeationcrryeaassessayi,nhnouwmebveerrs, oafnornev-edrotsanetsrepsepronpslaitveeb5o-tfholwdiitnhcarenadsweiitnhonuutmbacetrivoaftirone.vertInantthsewas observed nacSceprtyabplheimaunrdianmo SptorsaiitnivTeAi1n5cr3e7asienstihnenaubmsbeencresooffSe9vemritxa.ntsThpiesrsptlraatienwwaesrereotbessteerdveand all data were Goetnoctoonfxiircmeefdfeucptso:n rAetSe-sftionlgd.increase in revertanis occurred in one strain (see Overall Results), but was Cytotoxic concentration: No cytotoxicity observed in the range-finding tes, and none was noted in the main study. Statistical results: NA Remarks: Since the positive response seen with S. typhimurium TA1S37 occurred at nly one dose atthe beginning of the dose responsecurveand was not repeatable, the test agent, T-636:4 is considered negative in this assay, CONCLUSIONS The authors conclude that under the conditionsof the study, T-6564did notcause a postive increase in the numberofrevertans per plateof any tester strains,eitherin the absence o presence of the S9 mix. REFERENCE Lawlor, T.E. 1996. Mutagenicity Test with T-6564 in the Salmonella- Escherichia Coli Mammalian mCiHcVroSstoumdeyRNeov:er1s7e75M0u-t0a-t4i0o9nR.AssSaeypwtietmhbearCo13n.firmatory Assay. Corning Hazleton Inc. Final Report, 139 000143 "LTyitmlpe:hoMcuyttaegsenWiictihtyaTCeosntfoinrmTa6t3or4y2,AsMseaaysuWriitnhgMCulhtriopmloesHoamravlesAtbserrations in Human Whole Blood TEST SUBSTANCE Identity: T-6342; clear, colorless liquid. Nootherinformation was given on solubility or purity Remarks: METHOD Method/Guidelinefollowed: Protocol No 4490, Edition No: 2, Modified for 3M Corporation Test type: in vitro mutagenicity assay. Test system: Human whole blood lymphocytes GLP: Yes ear study performed: 1996 Species/Strain/cell-typefeell line: Human/whole blood lymphocytes Metabolic activation With and without metabolic activation from the $9 supernatant fraction of mheotmaobgoelniaztiengs efnrzoymmelsiv.ersofratspretreatedwith Aroclor 1254 for the nonspecific induction of Concentrations tested: Range finding assay--0.167,0.500, 1.67. 5.00, 16.7, 50.0, 167. 500, 1670, 5000 g/mL Initial trial (withoutactivation)--127,253, 505,1010, 1510, 2010,2510. wimL; Inirtiail(waitlh activation)-- 253, 505, 1010, 1510,2010, 2510, 3010, 4010 _gimL: Confirmatory trial (replicate cultures, without activation, 22.1 hour assay) 125. 250, 500, 900, 1200, 16002000 gin: Confirmatory tial (replicate culures, without activation, 46.0 hour assay)--62.5, 125, 250, 500, 900, 1200, 1600, 2000 gn: Confirmatory tial (replicate cultures, with activation, 22.1 hour asay and 46.0 hourassay)--250, 500, 1000, 1500, 2000, 2500, 3000 g/m. Statistical methods used: Statistical analysis employed a Cochran-Armitage test for lincar trend and Fisher's Exact Test (Thakur etal, 1985) to compare the percentageofcells with aberrations (and, if atrpepaltiecdabcleel,lsthweitpherrceesunlttasgeforfomcevlelhsicwliethcomntrroels.thTanesotnaertaibcelrersaitginoni)f,icpaonlcyepwloaisdye.staanbdliesnhdeodrwehdueprleicpa<t0i.o0n1 in ANI factors as stated previously were taken into account and the final evaluationofthe est article was based upon scienific judgement. 140 000144 RemaErxkpesr:imental Design hHeupmarainnivzeendoVuascubtlaoiondrsf.roCmulatsuirnegslew.enroermianilt.iahteeadlwtihtyhma0.l3emdoLnoofrbwlaosoddr'amwin.icntuolstei(ld,ose angefinding assey) or 0.6 mL of blood 10.0 mL cule (chromosomal aberrations assays) in 15 ml caennattrmiofusgpehbereeso.fTahboeuetl%l wCerOe iinncauibr.atTedha cualptpurroexmimeadtieulmy 3us7edC woansaRslPoMpIe,1w6i4t0hOloRoHse caps, in raBnigoesc-ifeinncdeisn)gsauspapyl:emLeontteNdo:wiTthO610524%,fcahlrobmoovsinoemsaclrsubmr(raFtBiSo:nsBaissoacy)h.e1m%, pLhoytttohEeSr3m3a1g,edluotsienin (QuPaHliAtMy :BiGoilbocgoi)c.alpe)n.iacinldli2nm(M100L-ugnliuttammLi:neQ(uQaulailtiytyBiBoiloolgoigciacallss)).anDdesioincizpedtwoatmerc((i1P0nr0epuarmed:1 CdeHiVon,izLeodtwa2t0er) awtas tchoncseonltvreanttioofncohfoiSc0e0omrg/thmiLs asTshaey.eTsthearteisetlarstoilculetiwonss adnidsstohlevevdehiincle control deionized wer, weredosed with dosing volume of 1% (10 mL) for this assay. NegaItnivteheannodnaScotlivveanttioCnonatsrsoalyss, negaive controls were culure tha contained only cells and culture medium, Solvent controls were cultures that contained deionized wate at the highest cSoonlcveennttrcaotnitornolussewdeirn tehsetscaumlueraesd(e1sc%riobred100i.ntheLinno)n.acIinvtthieoanctaisvsaatyiso,nbaustsawyist.htthheen$e9gaatcitvievaatnidon mix included PositTiivee Cpoosnittriovle Acgonetnrtosl agents, which were used inthe assays,were mitomycin C (MMC; CASH 5006705.57-1S9i.2m,,SiLgomta#, 4L0oHt2?540384)02fo6r9t)heinotnhaectmeitvatbioolnicsearciteisvaatnidoncsyccrilcosp. hIonspthheamcihdreom(oCsP:omCaAlS! sbereations assays, thee concentrations of MMC (0.08 and 010. nL, intial and confirmatory crhiarlos;mo0s.o1,m0a.l2.abaenrdra0t3ionsg. LOn,c tohfitrdheidao)sealnedveClPs(w2a0s,3an0a,laynzded$0i.n agc/hm)ofhweereaubsererdati0oninadsuscaey:s. Both MVC and CP were dissolved in water Range-ftihnesdeinagssAasyss,aycsultures ere initiated with 0.3 mLof blood' mL culture and sere incubated for 2 days prior to treatment. Assay Without Metabolic Activation "wahsehleydmpfhroocmytthescwlersewiintchubpahtoesdphwaitteh-tbhueffersetdrsiallienefoarn1d9f.r5eshhocuormspaltete37meCd.iuThmeceosnttaaiincinlge was Ctaotelre,emid (fina concentration = 0.1 im.) was added. Th cultures were harvested 2.0 hours Assay With Metbelic Activation his asay. the lymphocytes were incubated with the est rile for 3 howrs at 37 C in the pr2e.s7enmcae mo)fa.aThieve9r Sf9rarcetaicotni(onMomliexctuulraer(T5o9x-i1c5ologViyn.l,ncN.ADLPot- 016.657m)gw/amsL,dearnidveidocfirtoimctahceid otrideerrotfomvaoliedSpprosasgiubel-eDiamwalteiyvartaitos,n wofhsihcohrthavd bdeeannpdrehivgiholuyslryeatcrteiavteediwnietrhmAerdoicaleosrpr12o5d4u.cefndby etxhepo$s9urceypmereiosd. tAhfroeurghthbeienxdipnogsu1r0espeerruimodp.rtohteeicnse,llthweemreedwiausmheddidtwniocehwaivtehFbBufSfedruerdinsgaltinhee. 141 000145 Complete RPMI culture medium was added tothe cultures, which were incubated for 18.5 hours. Colcemid (final concentration = 0.1 gimLy-whieh was added for the lat 2.0 hours to collect metaphase cell. Assay Evaluation mMiettoatpihcasiensdperxesweatsinan1a0l0y0zceodnsefcruotimvethceellssu.rviving dose levels by analyzing the number of Chromosomal Aberration Assay--With and Without Metabolic Activation In the chromosomal aberration assays, replicate culures were used at each dose level and for nweigtatahiv2e2.co0n-throoulrs,haprovseisti_vteicmoentirnoltsh,e ainnidtiasloltvrieanltacnodntwrioltsh.22T.1-heaanbedrr4a6t,i0on-haosusrayhsarwveesrtetciomnedsucitnetdhe confirmatory trials. Chromosomal aberrations were analyzed from the cultures treated at 4 dose levels and from one of thepositivecontrol doses. Aberration Assay Without Metabolic Activation `1C5ulmtuLrceesnwterriefuigneittiuabteesd. 2Tdwayosdparyisoraofertrceualttmuernetiwniittihat0i.on6,mceLlolsfwwehroelterebaltoeoddw/i1t0h.0thmeLtesctulatrutrieclienat predetermined concentrations for approximately 19.3 and 43.3 hours. The cultures were washed with buffered saline. Complete RPMI 1640 medium, containing 0.1 g/ml. Colcemid , was pmaldaec.edTbhaecksloindteso wteherecelslt.ainTewdoinh5o%Guriselmatsr,athseolcuteisonweforrethhaeravneasltyesdisaonfdcahirr-odmrioesdosmlaildes were awbietrhroautitonmse.taTbaoblliec a|ctcivoatinon.tasauimmnarsyof the treatment scheduleof the aberrations assay Aberration Assay With Metabolic Activation `Cultures were initiated 2 days prior o treatment with 0.6 mLofwhole blood/10.0 mL culture in 15 mL centrifuge tubes. Two days afer culture initiation, the cultures were incubated at 37 C `feorxp3oshuoruerpseriniotdh.etpherceelslseownefrcteheweatsehsteadrttiwcilceeanwidtthhebu$f9ferreeadctsiaolninmeiaxtnudret.heAcfetlelrs twheere3-rheofuerd with `complete RPMI 1640 medium. One-tenth wm. Coleemid. was added to the cultures during the ast. 2.0 hours of incubation. The metaphase cell were harvested and prepared for cytogenetic analysis. Harvest Procedure "The cell suspension was centrifuged, the supernatant was discarded, and the cals were treated with hypotonic KCI (0.075 M) for 10 minutes. After centrifugation and removal of the KC, the cells were washed3 timeswith freshly prepared fixative (absolute methano:glacial acetic acid, 3:1, 29). Air-drid slides were prepared from the harvested cells, Slide Preparation and Staining Swliitdhes5w%eGrieepmrseapasroeldutbiyondroorpptihnegantahleyhsairsovefstmeidtaciulctuirnedsexonancdlecahnrsolmiodesso.mTahleabselirdreastiwoenrs.e sAtlalined. slides were air-dried and cover slipped. Abe`rCrealtlsiownerAenasleylseicsteadndforAsgsoaoyd Emvoarlpuhaotiloongy and only cells with the numberofcentromeres equal to the modal number 46 were analyzed. One hundred cell, ifpossible, from cach replicate culture at 4 dose levels ofthe test article, the negative control. the solvent control, andpositive control 142 0c0146 c2u5ltcaulrless wweerreeaannaallyyzzeedd ffoorrtchherdoimfofesroemnatltyabpeersoraftciohnrsofmroosmomthaolsaebceurlrattuiroenssw(iEtvha>n2s5,%19c6el2l)s.wAitthleast chromosomal aberrations. Cells with aberrations were recorded. Mitotic index was assessed by amnitaoltyizcincgellt.heCnhurmobmeartiodfamnitdotiiscoccehlrlosm/a1i00d0gcaeplsl.s:ifothbeserratvieodw,asweerxeprneostseeddianstaheperracwendattaageaonfd were tabulated. They were not, however, considered in the evaluation ofthe abilityofthe test article to ithnedurceesulcthsrwoemroesotmabaullaatbeedr.rations. Percent polyploidy and endoreduplication were analyzed and RESULTS Overall results: positive, negative, ambiguous: Negative Genotoxic effects (unconfirmed, dose-response, equivocal -with/without activation): Negative Cytotoxic concentration: Range-finding Assay Without Metabolic Activation H3e5m%o,l6y%s,is3w8a%s,o1b5s%e,rv1ed8%p,ri5o7r%t,o waansdh1i0n0t%hewceurletuorbessedrovseeddiwnitthhe 5mi0t0o0ticgi/nmdLi.ceRsoedfutchteiocnusltuorfes. dosed with 0.500, 1.67, 5.00. 16.7, 500, 1670, and 5000 g/mL. Range-inding Assay With Metabolic Activation Hemolysis was observed prior to wash inthe cultures dosed with 5000| g/mL. Reductionsof 8%, 5%, 4%, 1%, and 100% were observed in mitotic indices of the cultures dosed with 1.67. 50.0, 500, 1670, and 5000 g/mL. as compared with th solvent control culture. Chromosomal Aberration Asssy Without Metabolic Activation Initia Trial-- Hemolysis was observed prior to wash in the cultures dosed with 2510 g/mL. Reductionsof 38%, 18%, 18%, 50%, 55%, and 95% in the mitotic indices, as comparedwith the Solent control cultures, were observed in the cultures trated with 127, 253, 505. 1010, 1510, and 2010 gm, respeciively. Confirmatory Trial--ln the 22.1-hour confirmatory tial, hemolysis was observed prior to wash of the cultures dosed with 1600 and 2000 g/mL, and a slight evidenceof hemolysis was ovident at harvestof the cultures dosed with 1600 g/mL. Reductionsof2%, 14%, 64%, 74%, 93%, and 939% in the mitotic indices, as compared with the solvent control cultures, were observed in the cultures dosed with 125, 500, 900. 1200, 1600, and 2000|g/mL, respectively. In the 46.0-hour confirmatory trial, hemolysis was observed prior to wash of the cultures dosed with 1600and 2000 gm. Reductions of 59%, 93%, 98%, and 98% in the mitotic indices,as compared with the solvent control cultures, were observed i the cultures dosed with 900. 1200, 1600, and 2000 wml, respecively. ChroImniotisaolmTarliaAlb--eHreramtoiloynsiAssswaaysWoibtsherMveetdabporliiorc0Actwiavsahtiionnthe cultures dosed with 2010, 2510, 3010, and 4010 mL. No cells were visible prior to the additionofColcemid. to the cultures dosed with 4010 g/m. Hemolysis was observed prior o the addition ofColeemid. to the cultures dosed with 3010 g/mL. Reductions of 15%, 20%, 15%, 43%, 77%, and 95% in the mitotic 143 000147 indices, as compared with the solvent control cultures, were observed in the culturestreatedwith 253,505, 1010, 1510, 2010,and 2510 g/mL, respectively. Confirmatory Trial--n the 22.1-hour confirmatorytrial, hemolysis was observedprior to wash `and prio0r harveosft the culturesdosedwith 2000, 2500, and 3000 @/mL. Reductions of 15%. 5cu%l,tu6re9s%,,w8er2e%,ob9s7e%r,veadndin 1th0e0c%ulitnutrhees mtirteoattiecd wiintdihce5s0,0.asc10o0m0p,a1r5e0d0,wi2t0h00t,he25s0o0l.veanntdco3n0t0r0ol `mL, respectively. In the 46.0-hour confirmatory tial, hemolysis was observed priortowash 8an0d%,pr1io0r0(%0,haanrdves1t00o%fitnhetchueltmuirteostidcosineddicweist,ha2s0c0o0m,p2a5r0e0d, waintdh3t0h0e0.solivmen.t.coRnetdruolctciuolntsuroefs,15we%r.e observed inthe cultures treated with 1500, 2000,2500, and 3000 g/m, respectively. `Statistical results: The test substancedidnot significantly increase chromosomal aberrations with or without metabolic activation. Remarks: ChroImniotsiaomTarilalAbe--rNroatsiiognnifAiscsaanyt Winictrheoauset iMnetcealbloslwiictAhccthivraotmioosnomal aberrations, polyploidoyr. endoreduplication was observed at the concentrations analyzed (253, S05, 1010, 1510 gm), `cChornofmiomsaotmoarlyTaebiearlr-a--tiIonnst,hepo2l2y.p1l-ohioduyr, coornefnidromractdourpylitrcaalt,ionno wsaigsniofbiscearntveidncartetahsee cionncceelnltrwaittihons analyzed (125, 250, 500, and 900 g/mL). Inthe 46.0-hour confirmatory tial, no significant increase in cells with chromosomal aberrations. polyploidy, or endoreduplication was observed at the concentrations analyzed (125, 250, 500, and 900. g/L). The sensitivityof the cel culture ifnorthiendcuecltlisoenxopfoscehdrotmooMsMomCa,ltahbeerproastiitoinvse wcoanstroslhoagwennt.by the increased frequency of aberrations ChroImniotsioamTarilalAberNroatsiiognnsifAiscasnatyinWcirtehasMeeitnacbeollliscwiActthivcahtrioomnosomal aberrations, polyploidy, or `endoreduplication was observed at the concentrations analyzed (505, 1010, 1510, and 2010 wil), Confirmatory Trial--In the 22.1-hour confirmatory trial, no significant increase incels with chromosomal aberrations, polyploidy. o endoreduplication was observed at the concentrations analyzed (250, 500, 1000, and 1500 g/mL). In the 46 0-hour confirmatory wal, duetotoxicity, only $2 metaphases were available for analysis in oneof the cultures dosed with 2000 mL. No significant increaseincells with chromosomal aberrations, polyploidy, or cndoreduplication was observed atthe concentrations analyzed (500, 1000. 1500, 2000 mL), execpt foar weak increase inendoreduplication at 2000 g/mL. The suceessfol activation of the metabolic system was illustrated by the increased incidenceofcells with chromosomal aberrations in the cultures treatedwith cyclophosphamide, the positive control agent. CONCLUSIONS 144 000148 bTlhoeodteshtuamrtainclel,yTm-p6h3o4c2y,tweascselclosnwsiitdheraenddnwegiatthiovuet mfoertaibnodluiccinagctcivhartoiomno.sTohmeaslearbeesurlrtastiownesreinvceurlitfuireeddinwhole independently conducted confirmatory trials. REFERENCE BMulloio,d LHyemmaplhaotchyat.es19W96i. tMahutCaognefniircmiattyoTreystAsosnaTy-W6i34t2h,MMuelatsiuprleinHgarvCahsrtso.moCsoornmianlg-AHbaezrerlattoino,nsInicn. Whole (CHV), Vienna, VA. CHV Study No: 17073-04490. 145 000149 (TiCtHleO:)MCuetlalgseWniictiathyCToensftiornmaTt-o6r3y42A,ssMaeyasWuirtihngMuClhtripolmeosHaormvaelstAsberrations in Chinese Hamster Ovary a. Identity: T6342 C: clear, colorless liquid. cRoenmcaenrtkrsa:tioTn-6o3f44298w0asugs/omllu.blien icnulsttuerrielem,eddeiiounmizreedmwaaitneerd 4co.m9p8l0etge/lLy. (stohleubtlesetastuabsptHanocefa7t.a5), METHOD Method/Guideline followed: Protocol No: 437C0, Edition No. 4, Modified for 31 Corporation "Test type: In vitro mutagenicity assay Test system: Chinese hamster ovary (CHO) cells GLP: Ves ear study performed: 1996 Sorpiegciineasl/lSytroabitna/icneeldl-ftryopemfctehellllainbe:orChaitonoefsDrery.haSm.stWoelrloTv,aUrnyicveelrlssi(tyCoHfOC-aWliBfLor)nifa,roSmana pFerarnmcainsecon.tTcheelcleilncl.s tuismeed oinf t1h2i-s1s4tuhdoyurhsadwibteheanmroedcalolnecdhrtoommoasinotmaeinnkuamrbyeortyopfic21.stabTihleityC.HTOhicselcleslwienree hgardowann ainveMrcaCgoeyc'ycsleSa culure medium, which was supplemented with 10% fetal bovineserum(FBS) 17% L-glutamine, and 1% penicillin and sireptomycin, at approximately 37. C. in an atmosphere of about $% CO in air Metabolic activation: With and without at liver S:9 Concentrations tested: Range-finding assay--0.166, 0.498, 1.66,4.95,16.6,49.8, 166,498, 1660, 4980 g/mL: Initial tral (without activation) 125, 250, 500, 750. 1000, 1500,2000 g/L; Initialtral(withactivation) 250,500,1250,2500, 3750,5000 mi. Confirmatory ial(withoutactivation) 125, 249, 498, 746,995,1490, 1990 g/mL: ReCponefaitrtmiaatlor(ywittihaolu(twaictthivaacttiiovant)i--on2)5-0--,24590,0,49182,501,25204,902,49307,403,73409,840970w./mgLimL: SatnadtiRsOtBiIcEa,l m1e98t1h)odwsasuseemdp:loTyheedtFoicshoemr'psaErxeacttheTpeesrtcweintthagaenoafcdjaulsstmweintth for multiple abertations comparisons (Sokal incach treatment `abreorurpatwiiotnhs twhiethreisnuclrseafsrionmg dtoheseso(lAvremnittcaognet.rol1s9.71A) wlianseaarlstorepnedrfteosrtmoedf.inTcersetasairntgicnleusmibgenrifoifccaenlcleswwaisth established where p<0.01. Remarks: ExpeIrnimtehentcahlroDemsoisgonmal aberrationsassays,replicate cultures were used at each dose level and for negative and solvent controls. Single cultures were used for cach oftwodosesofthe positive: 146 ece1s0 c`oanntdrwoli.thT2h0e.0a-bearnrdat4i4o.n1s-ahsosuaryshawreversetctoimnedsuictnedthweictohnafi2r0m.a0t-ohroyurtiahlasr.veCshtrtoimmoesionmtahle ianbietriarlattiioanls dwoesrees.analyzed from the cultures treatedat 4dose levels and from only one of thepostive control Negative and Solvent Controls mnetdhieumn.onSaocltviveantticoonnatsrsoalyssw,enreegactuilvteurceosntcroonltsaiwneirneg ctuhletsuorlevsetnhtatfocronttheaitnesetdaornilyclcealtlsthaehnidgchuelstutre `tchoensceanmteraatsiodneuscsreidbeind tienstthceulnuorneasc.tiIvnatthieonacatsisvaaytsi,onbuatsswaiytsh,tthheen$e9gaatcitivveaatniodn smoilxveinntclcuodnetdr.ols were Positive Control Agents 0"7Th-e7.poSsiigtmiave,cLoontt#ro2l5aHg0en6t1s9,)whfoirchthweenroenaucsteidvaitniotnhesacsiseasysa,ndwecryeclmoipthoomsypchianmCid(eM(MCPC;;CCAASS?# S06055-19-2, Sigma, Lot#67FO155) in the metabolic activation serics. In the chromosomal aberradions assays, two concentrations of MMC (0.08and0.10 gm, inital and confirmatory cwiharlos;mo0s.o50maalndab1e.r0.ratgi/omnsL,ntthhierdCriHalO) acenldl.CPOn(e5o.f0atnhde d10o.0s. legv/emlLs)wawseraenaulsyezdedtoiinncduacceh.of the aberration assays. Both MMC and CPwere dissolved in water. Range-finding Assays In these assays, the cells were cultured for approximately () 24 hours prior (0 treatment by seeding 0.3 x 10cells25 cnr flask into S mLof complete McCoy's Sa culture medium, Table 1 contains a summaryofthe treatment schedule of therange-finding assay. All dosing was achieved witha1% (10 LimL) dosing of cach stock solution and the solvent control culture was. dosed with 101 Limof serie deionized water Assay Without Metabolic Activation wTahsechueldtufrreosmwtehreceelincuwbiatthedphwoistphhathteet-ebsutffaertriecdlesafloirne17a.n8dhofurersshatco|m3p7l,etC.e Tmheedituemtarctoinctlaeiwnainsg. Colcemid harvested 2.(0fihnoalurcsolnatcere. ntrat=io0n.1 mL)wasadded. Thecultureswerethentrypsinizaendd Assay With Metabolic Activation In this assay. the CHOcells wereexposedtothe est article for 3 hours at 37. in the presence omgf/amrLa)t.liThvee$9r$9refaraccttiioonnmi(xMtoulerceu(la$r9<T1o5xicnollo,gyN,AInDc.P-Lot1.#50m5g8/3m)Lw,asanddeirsiovceidtfrcraocmitdhe=i2v.e7r of amvaoliedSpporsasigbulee-Dinaawclteivyatriaosn, owfhsihcohrthalidvebdeeanndprheivgiholuyslryeatcrteiavteedinwtietrhmeAdrioactleosrpr12o5d4u.ceIdnobrydetrhetoS9 epenrzioydm.esAethrrotuhgehebxipnodsiunrgetpoesrciordu.tmhperocteelilnssw,etrheemweadsihuemdtdwiidcenowtithahvbeuFffBeSreddusrailninge.thCeoemxpploestuere McCoy's 5a medium was added 0thecultures, which were incubated for 16.8 hours. wih Colcemid (final concentration ~ 0.1 mL)swhich was addedfor the last2.0 hours o collect msteatianpehdaassedceesllcsr.ibTehdefcourltthuerensonwaecrteivtartyiposninriaznegde, fhairnvdeisntgeda.ssfaiyx.ed. and slides were prepared and Assay Evaluation 147 000151 oMfitmoetticapihnadseexswparsesaenntaliynze1d00f0rocmontsheecuhtigihveesctelflis.ve surviving dose levels by analyzing the number Aber`rCautlitounreAsswsearyeWiintithioautetd Metabolic Activation by sceding approximately 1.2 x 10 cells (20.0 hour assay) and0. x 10 cells (44.0 hour assay) per 75 em' flask into 10 mLof complete McCoy's Sa medium, One day awiftthe cthuelttuerset ainriitilaetioant.pfroerdethteernmiinaeldadnodsecsonofrirambaotuotry17r.i7al(s2,0t.h0ehcoeullrsawsesraye)ianncdub4a1t.e8d(a4t4.137hoCur assay) hours. All dosing was achieved with a 1% (10. LimL) dosingofcach stock solution and the solvent control culture was dosed with 10 Lim of sterile deionized water. The cultures were washed with buffered saline. Complete McCoy's Sa medium, containing 0.1 g/mL. Caonldcaeimri-dd:r.i.edwsalsidpelsawceedrebamcadkeo.ntTohteheslciedlels.weArppersotxaiimneadteilny52%hGouiresmshaatesro,ltuhteiolnlfsorwtehreeanhaalryvseissteodf cinhcruobmaotsedomaatl a13b7erCratfioorn3. hFoourrtshein tthhierdprterisael,ncoenoeftdahyeatfeesrt acrutilctluereininMictiCaotiyo'n,stSheacmueltduiruesmwweirtehout FBS, After the 3-hour exposure periad. the calls were washed twice with buffered saline and the cdeulrlisnwgetrhee rleasfted w2.i0thhocuormspolfetiencMucbaCtoiyon'.sTShaemmeedtiaump.hasOenec-etllesntwhereg/hmaLr.veCsotlecdeamnidd|prewpaasreadddfoerd cytogenetic analysis AberCrualttiuorneAsswsearyesiWniittihatMedetbaybosleiecdiAncgtiavpaptriooxnimately 1.2 x 10 cells 20.0 hour assay) and 08 x 10 caefltlesr (c4u4l.t1urheoiunritaiastsiaoyn.) tpheerc7u5lucrme'sftlhaastkwientroe1t0rematLeod funcdoemrpltheetecoMndciCtoiyon'ssoSfammeetdaiboulmi.c Oacnteivdaatiyon were incubated at 37. C for 3 hours in the presenof the tet article and the S9 reaction mixture in McCoy's Sa medium without FBS. All dosing was achicved with a 1% (10. LimL) dosing of cwaatcehr.stAofckersotlhueti3o-nhaounrdetxhpeossoulrveenptercioondt.roflhecucletlulrsewwearesdwoassehdedwittwhic1e0wiLtimh buofffesrteedrislaelidneeiaonndiztehde cells were refed with complete McCoy'Ssa medium. Onc-tenth g/m.Coleermid. was added to athnedcpurletpuareremdefdoirucmytdougreinnegtitcheanlaalsytsis.2.0 hours of incubation. The metaphase cells were harvested HarvPersitorPrtooctehdeuhraervestofthe cultures, visual observationsof toxicity were made. These observations iTnhcelcuudletduraensawsesreessamlesnotoevfatlhueatpeedrcfoerntthceonpfrleuseenncceeooff tmhitocteilcl omrondoelaadylelrwsitfhlionatitnhgeicnutlhueremefdlaisukms., "iTnhteercpuhlatsuerecselflrsoamndthweedroesetrraatnegde-wfiitnhdi0n.g07a5ssaMy KwCerIehtyrpyoptsoinniiczesdolfuitriston0. cTlhleeectulmtiutroetsiwcearnedfixed `awiirt-hdrainedabssloidleustewemreethparneop:agrleadc.ial acetic acd (3:1, vv) fixative and washed several times before: SlideSlPirdeepsawraetrieonpraenpdarSeudaibnyindgropping the harvested culures on clean slides. The slides were stained With 5% Giemsa solution forthe analysis ofmitotic index and chromosomal aberrations. All slides were air-dried and cover slipped using Depex | mounting medium, Analysis of Aberrations and Assay Exaluation 148 000152 Cells were slected for good morphology and only cells with the numberof centromeres equal 0 etahechmoredpallicnatuemcbuelrtu2re1a1t 4(droansgele=ve2l0s-o2f2t)hweeersetaanratliyczleeda.ndOnferohmunthderendegcaetllisv,eifapnodsssiobllvee,ntrcoonmtrol c2u5ltcuerlelss wweerree aannaallyyzzeedd ffoorrcthherodimfofseoremnatlyapbeesrorafticohnsrofmroosmoomnaeloafbehreratpiosointsi(vEevcaonnst,ro1l96c2u)l.turAetsl,east Cmiltostiwcicthelalb1er0r0a0ticoenlslsw:etrhee rreactioordweda.s eMxiptroetsicseidndaesx wpaesrcaesnsteasgseedobfymiatnoatliyczcilnlg,thCehruommbateirdoafnd iHsoowcehvreorm,atciodnsgiadper,edif ionbsteherveevda,luwaetrieonnooftetdheinabtihleitryaowftdhaettaentdawrteircelet0abuilnatdeudc.e cThhreoymwoesroemanlo, aberrations. Percent polyploidy was alyzed from the 44.0-hour assay. RESULTS Overall resales: positive, negative, ambiguous: Posiive sGuebnstoatnocxeiwcaefsfepcotssit(iuvnecofonrfcilramseodg,endioscea-crteisviptoynsoer, heiqguhliyvooexail rweiatuhm/ewnittshooufsthaocrttivdautriaotni)o:nT(h3ehtoeusrtse)dboth finortphoelpyrpelsoeindcyeoarndthsebshcignhcleoy foxani$t9remaettmaebnotlsic activation system. The tested substancewas also postive "CTyhtisotsoecxtiiconcoonncleyntdreastciriobne:s the eytoxicty observed at concentrations at which sitsticaly significant increases in chromosomal aberrations occurred. ChromosalomTarilalAbeTrrhaetirocnasmAesnstaywiWtihth37M5e0taubgo/limclAwcatsivoantliyonslighty oxic, bu he 5000 ug/ml. nirdcatambeonuttw7a5s%hredyucttiooxnicf,ocatuhseirnegplbiocautte c9u5l%uer.edFulcotaitoinngindmeoadnocleallyeancdondfelbureinscwyerfoersobnuendcaunltt,ure nd only 94 metaphases were nalyzabl from theculturewith greater oxicty (5000 ug/L). CFoonrftihmea2t0orhyouTrrhiaarlvest, the confluencyofthe cultures treated with 4970 ugimL was reduced by a(2b0ouhto0ur%hravnedsyt.hetmhietroetwicasinadpepxrowxaismarteedluycead3b0y%43r%ed.ucFtoironthien ccuolntfulruesentcryeaatneddwiatnh1837%3r0eduugc/tmioln in mitotic index. Aber2r0athioounr AhsasravyesstWitho3ut0%MerteadbuocltiiconAcinticvoantfilonu:en3c-yHoocucrurTrreedatimnetnhte cultures read with 2490 cuoumld.beThexeamnienxetdh.igher dose, 3740 ugmL. was so toxic that only a small number of metaphases i374h0ouurg/hamrlveastnd--tAhe52459%0ruegd/umclti.otnrienatmmoennotleasyuerlecdonifnlauc3n0ey%orcecduurctrieodn.inTthhee cmiutolteicsitnrdeeaxtewdawsith Significantlyreduced (57%) or th high dose (3740 uml) StatiCshtircoamlorseosumlatls:Aberration Assays With Metabolic Activation iia Trial Significant increases incells with chromosomal aberrations were observed in the culturesdosedwith 3750 and S000 g/mL. 149 000153 Confirmatorytrial For the 20 hour harvesta, significant increase in cells with chromosomal aberrations (simple and complex)wasobserved for the cultures dosed with 4970. g/mL. Although the 4970 gm treatmentwas 100 toxic to yield sufficient metaphases for analysis, it was, nevertheless, noted tht the percent polyploid cells increased significantly. ChroAmosisgonmifailcaAnbteirnrcarteiaosne AisnstahyesnWuimtbheoruotfMceeltlasbowliitch Acchtrivoamtoisoon;ma3l-HaobeurrraTtrieoantsmweants observed in the cultures dosed with 3740 g/mL. (7.5%). A significant increasein percent polyploidy was also observed inthe cultures dosed with 3740. g/mL. The mitotic index wassignificantly reduced (57%)forthe 3740 gin. dos. RemaRarnkgse:-finding Assay Without Metabolic Activation Inthe culturetreatedwith 4980 g/m, no visible mitotic cellswereobserved: thecell monolayer was <5% confluent and the culture consisted onlyof debris and dead cells, floating or attached. A severe reduction in the numberofvisible mitotic cells was observed in the culturedosed with 1660 g/mL. The cell monolayer looked unhealthy and the degree of confluency was reduced `about 15%; floating dead cells anddebriswere noted. Floating debris was also observed in the culture dosed with 498 g/mL, but otherwise the culture was similartothe negative control Mitotic indices were analyzed from the cultures dosed with 16.6, 49.8, 166, 495, and 1660. gil. `and compared to the solvent control. At 1660 g/mL, the mitotic index was essentially zero. However, litleorno reduction in mitotic index was observed at the nextlowerdoseof 498 inl. Range-finding Assay With Metabolic Activation An unhealthy cell monolayer wasobserved intheculturedosedwith 4980. g/mL. The cell monolayer confluence was reduced by approximately 85% anda severe reduction in the number of visible mitotic cells occurred (about 63%). At the next lower dose of 1660. im, the monolayer confluence was the same as the solvent control and the mitotic index was only somewhat reduced (about 27%). Chromosomal Aberration Assays Without Metabolic Activation Initial Trial--No significant increases in cells with chromosomal aberrations were observed for the cultures analyzed (750, 1000, 1500, and 2000. g/mL). Unhealthy cll monolayers, floating dead cells and debris, severe ossofvisible mitotic cells, and about 25% reduction in cell monolayerconfluencewere observed in the cultures dosed with 1500 and 2000. g/mL. Slightly muinthoetailcthcyesca,llanmodnaobloauyter1s5,%loraetdiuncgtidoenaidn ccaellllsmaonndoldeabyreirs,caonefdluucetnicoenwienrethoebnsuemrvbeedrionftvhiesible: culturesdosed with 1000 g/mL. At the lowestanaldoysezofe75d0.g/mL, the cell monolayers appeared to be almost normal, with onlya slight reduction in the number ofvisible mitotic cells `and abouta 15% reduction in the degreeofconfluence. Severe reductions in mitotic index. relative 0 the solvent control cultures, occurred ataldose levels (95%, 86%, 67%, and 57% at 2000, 1500, 1000, and 750 mL, respeciively). `ConfirTmraiatlo--Froyr the 20-hour harvest, no significant increases in cells with chromosomal aberrations were observed for any ofthe culturesanalyzed (746, 995, 1490, and 1990 mL). A 95% reduction in mitotic index was observed at 1990 g/mL: whereas, a 25% reduction in 150 000154 mitotic index was observed at 746. g/mL. The cell monolayer confluence was reduced by about T2o5%caotmpe1n9s9a0te,g/1m1L7 amnedtaopnhlayse8s3 wmeertaepshcaosreesdcforuolmdtbheesrceoplriecdatfeicoumltounree.iof hoerdreerpltiocsactoerceualtutroetsa.l of r20o0mmtehteapchulatsuersesdfoorstehidswdiotshe.24F9o,r 4th9e8,447.416-,haonudr h9a9r5v|estg,imciLh.roNmoossoigmnailfiacbaentrriantciroenassweserien caenllaslywzietdh Scchorroemdosatotmhails haabrevrersattitoinmsewaenrdenoobsseirgnviefdicfaonrtainnycorfeastehse wcuelrteurneosteadn.alTyhzee.twPoerhciegnhtesptoalpyppllioeiddydowseass. aobfo1u9t940.0a%ndre1d4u9c0t.iong/smiLn.mwoenroelaleyteharl.coTnrfelautemnecnetawnidth7999%5r|ednucLtionwaisn msietvoetrieclyintdoexxi.c,Artes7u4l6t.ing in re`dmucit,iohnoiwnevmeitro,titcheintodxeixc,ictoymwpaasremductho tlheesssol(vabeonutt c1o5nt%rorledcuulcttuiroesn).in confluency and 18% ChrominoitsiaolmTarilalAberCrhartoimoonsAosmsaalysabWeirtrhatMieontsabwoelriecaAncatliyvzateidofnrom theculturesdosed with 1250, 2500, i3n7c5r0e,asaensdiSn0c0e0.ls wgiith.cihnrtohmeosproemsaelncaebeorfrattheiornas wievreer o$b9smeertvaebdoilnicthaectciuvlautrioenssdyossteedm.wiStihgn3i7fi5c0ant tarnedat5m0e0n0t wgasLh.ighTlhyettorxieca,tmceanutswiintghab3o7u5t09|5w%irmedwucatsiosnliignhtmlyontoolxiacy,ebructotnhfelu50e0n0c.y fgor/moLne culture `nidnd aobnoluyt9475m%etraepdhuacsteisonweforretahnearleypzlaibcalteefcruoltmurteh.e cFullotautriengwditehadgcreelaltseratnodxidcietbyr.isHwoewreevearb,untdheant mitotic index was reduced by only 13%, compared to the solvent control cultures Confimmatory Trial---For the 20 hour harvest, significant incrienaceslles with chromosomal `aobxeirrcattiroenastm(esnitmprleeduacneddctohmepcloenxf)luweanscyobbysearbvoeudfto7r0t%heancudltcuaruessedodase4d3%witrhed4u9ct7i0ongi/nmtLh.e mTihtiostic index. The treatment with 3730 g/m. caused about 30% reduction in the confluency and 18% 4re4d.u1c-thioounr ihnartvheestm,itnootisciginndiefxi.canTtheirncerawsassesinonccellalstsowgietnhiccahcrtoivmiotsy oombasleravbeedrraatti3o7n3s0wegrelo.bseFrovretdhe tfroreaatnmyeontftwhaesctuolotutroexsicantoalyyizeeldd s(u4f9f8i,ci1e2nt50m,e2t4a9p0h,as3e7s30forwamnall)y.sisA,litthwoausg,hntehveer4t9he7l0essg, /noLted that fthoexipceiryceenvtidpenotl.ypTlohiedscueclclessisnfcurleaacsteidvsaitginoinfibcyanttlhye.meAttab3o7l3i0c sgy/smtLo,m wthaesreilwlausstrlateed boyr ntohke.l1a0rge eixncproesaesde tion cpeyrccleonpthcoeslplhsamwiidteh.chromosomal aberrations (at 20 hours harvest) in the cultures ChroFmoorstohema2l0-AhboeurrrahtairovenstA,ssnaoyssiWgniitfhiocuanttMientcarbeaosleisciAncctievlaltiwoint:h3c-hHrooumrosTormeaaltmaebnetrrations were observed in the cultures analyzed (250, 500, 1250, 24901 nL). At 2490. gimL, a 30% {rheadtucotliyonainsmcaolnlflnuuemnbceyrwoafsmoebtsaeprvheads.esHcoweovebre,uetxhalemniendxet.higFhoerstthdeos4e4,-h3o7u4t0hargv/emsLt,, was 50 toxic ch`rmoLm.osAomsailgnaifbiecrarnattiionncsrewaesreeinantahleynzedufmroobmfcteheelrlcsulwtiurtehscdhorsoemdoswiotmhal50a0b,er1r2a5t0i,on2s49w0a,saonbdse3r7v4e0d inthe culturesdosedwith 3740. wml (7.5%). also observed in the culturesdosedwith 3740. A significant increase in percent polyploidy was g/mL. Relative 10 the solvent controls, the 3740 remaltm.enttreraetsmuelnttedreisnualbtoedutin3a0b%ourted5uc5t%ionr.eduTchteiomniainlimconionldaeyxewracsonaflslouesnicgyniafincdantthley 2r4e9d0u.cedgil. (57%) for the high dose. is1 000155 CONCLUSIONS tTrheeattmeestntasrotifclseh,oTr-t6d3u4r2a,tiwoans(ecvza,l3uahtoeudrsas) bbeoitnhgicltahsetopgreensiecncteo caunldtuarbesdeCncHeOocfealns$f9ormehtiagbhollyictoaxcitcivation system, Polyploidywasalso inducedforthe highly toxic treatments. REFERENCE MHuarmlsit,eHreOmvalaartyha(.CH1O99)6.CelMlust:agweintihcaitCyonTfeisrtmoantoTr6yA3s42s,ayMweiatshurMiunlgtiCphlreoHmaorsveosmtas.l CAboerrnriantgi:oHnaszeilntCohni,nIensc.e (CHV). Vienna, VA. CHV Study No.: 17073-0-437C0. 152 000156 LTyitmlpe:hoMcuyttaegsenWiictihtyaTCeosntfoinrmTa-t6o3r4y2A,sMseaaysuWriitnhgMCuhltriopmloesHoamravlesAtbserrations in Human Whole Blood TEST SUBSTANCE Identity: T-6342; clear, colorless liquid, `Remarks: No other information was given about purity or solubility METHOD Method Guideline followed: Protocol No.:449CO. Edition No.: 2. Modified for 3M Corporation Test type: n vitro mutagenicity assay Test systems Human whole blood lymphocytes GLP: Yes Year study performed: 1996 `Species/Strain/eell-typeleell line: Humanwhole blood lymphocytes Metabolic activation: With and without metabolic activation from 9 supernatant faction of vers of rats pretreated with Aroclor 1254 for the non-specific induction of metabolizing enzymes. Concentrations tested: Range-finding assay--0.167, 0.500, 1.67, 5.00, 16.7, 50.0, 167. 500, 1670, 5000 mL: Initialtrial (without activation) --127,253, 50S. 1010, 1510, 2010, 2510 wimL: Initialtrial(withactivation)-- 253, 505, 1010,1510,2010,2510, 3010, 4010_g/mL: Confirmatory trial(replicate cultures,without activation, 22.1 hourassay)-- 125. 250, 500, 900, 1200, 160.2000 gm: Confirmatory tial (replicate cultures, without activation, 46.0 hour assay)---62.5, 125, 250, 500, 900, 1200, 1600, 2000 g/L: Confirmatory tial (replicate cultures, with activation, 22.1 hour assay and 46.0 hourassay) 250, 500, 1000, 1500,2000,2500, 3000 g/ml Statistical methods used: Statistical analysis employead Cochran-Armitage test for lincar trend and Fisher's Exact Test (Thakuert al., 1985) to compare the percentage of cals with aberrations (and. if atrpepaltiecdacbellelsthweitpherrceesunlttasgeforfomcevlelhsicwliethcomntorroels.thaTensotnaertaibcelrersaitginoinf).icpaonlcyepwloaisdye,staanbdliesnhdeodrwchdueprleicpa<t0i.o0n1 in All factors a stated previously were taken into account and the final evaluation ofthe test article was based upon scienific judgement. Remarks: ExpeHriummeanntavleDneosuisgbnlood from a single, normal, healthy male donor was drawn into sterile. HfienpdairnigniazsesdayV)aocrut0a.i6nermsi..oCuflbtulroeoswde/r1e0m.iLn0itciuatletduwriet(hch0r.o3mmoLs.omofalblaobeordr'atmiLoncsualstsuaryes)(dionse1r5amngLe153 000157 caennatruimfossgpehtebreso.fTahbeoucte%ls wCerOe iinncauibr.ateTdhatcualptpurroexmimeadtieulmy u3s7edCwoansaRsPlMopIe,1w6i4t0hOloRoHse caps, in rBainogsec-ifeinncdeisn)gsauspapyl:emLeontteNdo:wiTth0610524%,fcahlrobmoovsinoemsaelrsuemrr(aFtBiSo;nsBasisoacy)h.em1,% LphoyttioEhSem3a3g1e,lduotsienin Q(uPaHliAtMy ;BiGoilbocgoic)aplen)iacinldli2n (m100L-ugnhtiamti;neQ(uQaulailtiytyBiBoiloolgogiiccaall)s)a.nDdesieocnpirzoemdywcaitner(1(0P0reupga/rmeid-at. CdeHiVon,izLeodukwa2t0e)rwatasa tchoencseantnrattioofnochfoi5c0e0 fmoer/tmhLis.asTshaey.teTsthartteisctleastocluetiwoanssadnidsstohlvevdehiincle control. deionizedwate, were dosedwitha dosing volume of 1% (10 uL/mL) forthisassay. NegaTtnivteheannodnSaocltvveanttioCnonatsrsoalyss, negative controls were culures that contained only cells and culture `medium, Solvent comols were cultures that contained deionized water at the highest concentration used in test cultures (1%or 100. LiL). I the activation ssays, the negative and Smoilxveinntclcuodnetdr.ols were the same as described in the nonactivation assays, but with th S9 activation Posi"tTihvee pCoosnittriovle cAognetnotls agents, which were used inthe gssays, were mitomycin C (MMC: CAS# 500670-375,-1S9i-g2m,a,SiLgomtai,4L0oHt2t54038H)02f6o9t)heinnothneacmteitvaabtoiloincsearciteisvaatnidonccyrcliosp.hoInspthheamcihdreom(CoPs;omCaAlS# aberrations assays, thee concentrations of MMC (0.08 and0.10 g/mL. intial and confirmatory rials; 0.1.02 and 03 g/mL, third igh and CP (20, 30, and 50. wml) were used to inde cohtrhomMosMoCmaalnadbeCrrPatwieonrse.dOisnseolovfedheindwoasteerlevels was analyzed in caocfthhe aberration sssays. RangIen-fhiensdeinagssAasyss,aycsultures wer initiated with 0.3 mL ofblood mL culture and were incubated for 2 days prior to treatment. Assay Without Metabolic Activation: `"Twhaeshleydmpfhroocmyttheescweelrsewiintchubpahotsepdhwaitteh-btuhfefteersetad stalcineoarnd19f.r5eshh ocoumrpasltete37meCd. iTuhmectoensttaaitniicngwas hCooulrcsemlitdr. (nal concentaton~0.1 g/mL) was added. Theculurs wereand harvesi2e.0d. Assay With Metabolic Activation In this assay. the Iymphosytes were incubated with the test ariel for hours at 37. C inthe pr2e.s7enmcge/omfa).atThieve$r9$f9acrteiaoctnio(nMomliexctuulraer(T9o-x1i5c.ologViym.l,ncN. ALDot=Pt 016S67m)gw/amsLd,ernidveidsfoirtoimcthaecid otrideerro0fmaavloeidSpporsasgiubel-eDianwalcteiyvartaitso,nowfhsihcohrthaldivbeedeannpdrehviigohulsylryetarcetaitveediwnitterhmAerdioactleosrp1r2o54d.ucIend by e{hxepo$s9ureenzpeyrmieods. tAhrloueghthbeienxdipnogsuorespeerruimodp,rtohteeicenl,lsthweemreedwiausmheddidwniaehwaivteh FbBufSfedruerdinsgaltihnee `Complete RPMI culture medium was added the cultures, which ware incubatedfo 18.5 hours. meCotlaepehmiads.eee(flisn.al concentration 0.1 /mLy-wwhasiadedehd forthe as 2.0 hours ocollet 154 000158 AMsitsoatyicEvianldueaxtwioans analyzed from the surviving dose levels by analyzingthe number ofmetaphases present in 1000 consecutive cell. Chromosome Aberration Assay--Wiatnhd Without Metabolic Activation Tn the chromosomal aberration assays, replicate cultures were used at each dose level and for negative: choanrtvreoslts,tipmoesiitnivtehecoinntirtoalls,traianldansodlvweintthc2o2n.t1r-olas.ndT4h6e.a0b-ehrorautihoanrvaessstatyismweesrien ctohendcuocntfeidrmwaittohray t2r2ia.l0s.-hour Chromosomalaberrations were analyzed from the cultures treated at 4 dose levels and from onc of the positive control doses. CCuhlruormesoswoemree iAnbietrirataetdi2ondAasyssapyriWoirtohoturteaMtemteanbtolwiicthAc0.t6ivmatLioonf whole blood/10.0 mL culture in 15 mL centrifuge tubes. Two days aftr culture initiation, cell were treated withthe test artile a predetermined. concentrations for approximately 19.3 and 43.3 hours. The cultures were washed with buffered saline. `Complete RPMI 1640 medium, containing 0.1 iL Colcemid. was placed buck onto the cells. Two. hours later, the cells were harvested and air-dried slides were made. The slides were stained in 5% Gtrieeamtsmeanstoslcuthieodnufloerotfhetheanaableyrsriastoifocnsharsosmaoyswoimtahlouatbemrertaatiboonlsi.c aTcatbilvaeti1onc. ontasauimmnarsy of the Chromosome Aberration Assay With Metabolic Activation Cullures were initiated 2 days prior o treatment with 0.6 mL. ofwhole blood/10.0 mL culture in 15 mL pcernetsreinfcsegeoftutbhees.esTtwaortidcalyesaanfdetrhceu9lturreeaicntiitoinatimoinx,tutrhee.cuAlfttuerresthwee3r-ehoiunrcuebxaptoesduarte p3e7rioCd.ftohr3e chelolusrsweirnethe washed twice with buffered saline and the ells were refed with complete RPMI 1640 medium. Onec-tenth `mL Colcemid: wasadded to the cultures duringthe last 2.0 hours of incubation. The metaphase ells were harvested and preparedforcytogenetic analysis. Table | contains a summary ofthe treatment schedule of the aberrations assay with metabolic activation. "The cell suspension was centrifuged, the supernatant wasHdairsvceasrdtePd,roacneddutrhee cells were treated with hypotonic KCI (0.075 M) for 10 minutes. After centrifugation and removal of the KCI, the cells were washed 3 timeswith freshly prepared fixative (absolute methanol:glacal acetic acid, 3:1, vv). Air-dried slides were prepared from the harvested cells Slide Preparation and Staining. SGliiedmessawesroleuptiroenpfaorretdhbeyadnraolypspiisnogfthmeithaairvcesitneddexcualntdurcehsroonmoclseoamnaslliadbeesr.raTthioenss.lidAelsl wsleirdeesstwaeirneedaiwri-tdhri5ed% and cover slipped. Aberrations Analysis and Assay Evaluation Cells were selected for good morphology and onlycells with the umber of centromeres equal (0 the mleovdealls onfutmhbeetres4t6arwteicrlee,atnhaelynzeegda.tiOvneecohnutnrodlr,edthceelslosl,viefpntoscsoinbtlroel.,farnodmpocsaicthivreepcloinctartoelcuclutluurreeast4wedroese: aannaallyyzzeedd ffoorr cthherodimfofseroemnatltyapbeesrorafticohnrsofmroosmomtaholseabceurlrtautrieosnswi(tEhva2ns5,%19c62e)l. Awithlecahsr2o5moceslolmsawlere. ambietrortaitciocnesl.lsC/e1l0l0s0wciatlhs;abtehrerartatiioonswawsereexprreecosrsdeedd.us4Mitpoetriccenitnadgeexowfasmiatsosteissceeldlsb.yCahnraolmyaztinigd tahnednumber of isochromatid gaps, ifobserved. were noted in the ra data and were tabulated. They were not, however. 155 000159 cpoonlsyipdleorieddy ainndtheenedvoarleudautpiloincaotftiohnewaebrileitaynaolfytzheedeasntdartthieclreestuoltisndwuecreectharbuolmaotsedo.mal aberrations. Percent RESULTS Overall results: positive, negative, ambiguous: Negative Genotoxieeffects (unconfirmed, dose-response, equivocal--with/without activation): Negative. Cytotoxic concentration: Range-finding Assay Without Metabolic Activation 3He5m%o,l6y%si,s3w8a%s,ob1s5e%r,ve1d8p%r,io5r7%t,o waansdh1i0n0%thweecruletuorbessedrovseeddinwitthhe 5mi0t0o0ticg/inmdLi.ceRseodfucttheiocnusltoufres dosedwith0.500,1.67,5.00, 16.7. 500,1670, and 5000 g/m. Range-finding Assay With Metbolic Activation Hemolysis wasobservedprior to wash i the cultures dosed with 5000 g/mL. Reductions of 82%, 7%, 4%, 1%, and 100% were observed in mitotic indices of the cultures dosed with 1.67. 50.0, 500, 1670, and 5000 g/mL,as compared with he solvent control culure. Chromosomal Aberration Assays Without Metabolic Activation Initia Trial-- Hemolysis was observed prior to wash in the cultures dosed with 2510 g/mL. Reductionsof 38%, 18%, 18%, 50%, 35%, and 95% in the mitotic indices, as compared with the Solvent control cultures, were observed in the cultures treated with 127, 253, 505, 1010, 1510, and 2010 gL, respecively `ConfirmatoryTrial--In the 22.1-hourconfirmatory tial, hemolysis was observedprior 0 wash of the cultures dosed with 1600 and 2000. g/mL, and a slight evidenceof hemolysis was evident at harvestof theculturesdosed with 1600 g/mL. Reductiofo2n%s, 14%,64%, 74%, 93%, and 93% in the mitotic indices,as compared with the solvent control cultures, were observed in the ccuolntfuirremsadtoosryedtrwailt,hhe1m2o5,ly5s0i0s,w9a00s.ob1s20e0r,ve1d6p0r0i,oarntdo w2a0s0h0ofg/tmheL.curletsupreecstidvoesley.d wInitthhe14660.00-ahnodur 2000 mL. Reductionsof59%, 93%, 98%. and 98% in the mitotic indices, as compared with the solvent control cultures, were observe in the cultures dosed with 900. 1200, 1600, and 2000 win. respectively. Chromosomal Aberration Assays With Metabolic Activation initial Trial --Hemwoaslobysersvediprisor to washin thecultures dosed with 2010, 2510, 3010, and 4010 g/mL. Nocell were visible priotro the additionofColcemid to the cultures dosed With 4010 g/mL. Hemolysiswasobserved prior 0 the additionof Colcemid1 (0 the cultures. dosed with 3010 g/mL. Reductoifo15n%s. 20%. 15%, 43%. 77%, and95% inthe mitotic indices, as comparedwith the solvent control cultures, were observed in the culturestreated with 253,505. 1010, 1510, 2010,and 2510 g/mL, respectively. 156 000160 CanodnfpriimoarttoryhaTrveestioflthtehecu2l2t.u1r-ehsoduorsceodnfwiirthma2t0o0r0y,i2a5l0,0,heamnodly3s0i0s0.wags/cmb.serRveeddupctriioons0ofwa1s5%h. l5u%,re69s9,%,we5r2e%,ob9s7e%r,veadnidn 1h0e0c%ulitnutrhees mrietaorteidcwiintdihce5s0,0.as1c0o00m.pa1r5e0d0,w2i0t0h0h,e25s0o0l,veanntdco3n0t0r0ol anwdimpr,iorretsopehcatrivveelsyt.ofInthtehecu4l6t.u0re-soduorsceodnfwiirtmha2t0o0r0y,r2i5a0,0h,eamnodly3s0i0s0.wags/ombLs.erRveedducptriioornstoofwa1s5h%, 0ob%se.rv1e0d0i%n,tahnedcu1lt0u0r%esintetshteemdiwittoh 1i5n0d0i,ce2.00a0s,c2o5m0p0a,raenddw3i0t00heisomlv.enrtescpoencttirvoelcyu.ltures, were Swtiatthiosutticmaetreasluilct:acTthievatteisotnsubstance did ot significantly incase chromosomal sberrations with or Remarks: CromnioaslomTarlishAbNeroratsiiognniAfsicsaanytsinWcirtehaosuetnMecetlalbslwiicthAccthirvoamtoisonomal aberrations. polyploid. or endoredupliction was observed at the concentrations analyzed (253, 505. 1010. 1510. gm), CCohnrfoimmomsaotmoarly sTrbiealraiIonnt,hepo2l2y.p1l-ohioduyr.coorncfnidmoarteodayptlicaal,tonnowsaigsniafbicsaenvtcidncarehasee cionncciesntrwaittihons ainncarleyazseedin(1c2e5,ls25w0i,th50c0h,raonmdos0om0almsbLe)rr.tinothne s, p4o6ly-phlooiudry.coonfeinrdmoarteodruyplticialtinoon swiagsniofbiscaenrtved at fdohre icnodnuccetnitornatoifoncshraonmaolsyozmedal(1a2b5e.rr2a5t0i.o5n0s0w.easnds9h0o0w.ngbiymLt)h,e nTchreasseensditfirvietqyueonfctyheofcealbecrualttiuorens inthe cells exposed 0 MAIC,th positive control agent. Chromosomal Aberration Assays With Metabolic Activation IannitdioarlodTurpilailca--tNioonsiwgansifbicsaenrtviendcraetasteheincocnelclesntwriatthiocnhsroanmaolsyozmeadl(a5b0e5r.ra1t0i1o0n,s,1p5o1l0ypnlodid2y,01o0r wm). cChornofmiomsaotmoarl sTbreirlat--iIonnst.h 2p2ol.y1p-lhoioduyr,coorncfinrdmoatroerdyuipallc,antowisaoignsniofbisceanrtveidnacreahsee cionnccelnltrwaittihons aonnlayly5z2edme(t25a0p,ha0se,s w1e0r00e,aavidla1b5l0e0.forgiamnLal)y.siIsnitnheon46e,0of-thhourccuoltnufriersmdaotsoerdy rwiitah, d2u000.to gto/xmiLc.ityN.o Soibgsneirfviecadntatitnhcerecaosneceinntrcatliownisthanharloymzaesdo(m50a0l,ab1e0r0a,ti1o5n00s,.2p0o0l0yplgomi)d.oy.rccxncdportedfuoprlaicwaetaikon was iwnacsreilalsuistnraetneddorbeydtuhpelinceartciaosneadt i2n0c0i0dencge/omLf. cTlhle wsiutchcecshsfruolmoacstoimvaaltioanbeorfatthieonmsetianbholeiccuslytsutreesm treated with cyclophosphamide, the positive control agent 157 000161 CONCLUSIONS "bTlhoeodteshtuamratinclel,yTm-p6h3o4c2y,tewsasceclosnwsiitdehraenddnewgiatthiovuet fmoertaibnodluiccinagctcihvartoiomno.soTmhaelseabreersurlattsiownesrienvceurlitfuireeddinwhole independently conducted confirmatory tials. EEERENCE MBulloio,d LHyemmaplhaotchyat.es19W9i6t.hMuatCaognefniircmiattyoTreystAsosnayT-W6i34t2h,MMueltaispulreinHagrvCehsrtso.moCsoommnainlg-AHbaezrerlaitoino,nsInicn.W(hCoHlVe), Vienna, VA. CHV Study No: 17073-0-449C0. 158 000162 GENETIC TOXICITY (IN VIVO) Titles Mutagenicity test on T-6342 in an in vivo mouse micronucleus assay TEST SUBSTANCE Identity: T-6382 Remarks: Iatclesar, colorless liquid. Thepurity andchemical idenoftthietesyt substance were not indicated. METHOD bMyetHheoddd/lGeuietdael.li(n1e98f3)o.lloPwreodt:ocTohliNso.st4u3d5y,wEadsitcoonnd1u7c(tendoruesfienrgemnocdeigfiivceant)i,onmsoodfiftiheedpfroorce3dMureCsorspuogragteisotne.d Test type: Mouse micronucleus assay GLP: Yes ear study performed: 1995 Species/Strain: Mouse/Crl:CD-18(ICRIBR Sex: Male and female No. animals/sex/dose: 15 for treatment groups, for control groups Veh(iifcuslede): Deionized water Routeof administration: Oral gavage Doses: 1250, 2500, and 5000 me/ke; Doses selected on the basis ofa previous study. Frequency of treatment; Single dose Sctiatthiesrtuinctalramnestfohromdesd u(swehde:n Tvhaeriaannacleyssiwseorfethhoemdoagteanweaosusp)erofrorramnekdtursainnsgfoArNmeOdV(Awhe(Wnivnaerri,an1c9e7s1)woerne. (IPet<e0r.o0g5e)nc.2oDuusn)npertotp'osrttieosntso(fDcunenesttw,it1h95m5i:cr1o9n6u4c)lewiaspeursaendimtaodl.eteIrfmtiheneAwNhOiVchAdowsaesgsriogunpisfi,ciafantny, were Stiigmneifaincdanstleyx dciofmfbeirneanttiofnr.om thenegative control. Analyses were performed separately fo each harvest Rapepmraorxkisma:teTlhye24a.ni4m8a,olsr w7e2rehoduorsseadftweirtdhotshienagpfporroperxitartaectaiomnooufnttohfe tbhoenetemstarsruobws,tanTceen aanndimeaultsha(nSimzaeldes afnedmalefse)mwaleerse)awsesriegnreadntdootmhleycaosnstrioglnegdrotuopsc.achThdeosnce/ghaatrivveestcotnitmreolgraonuip.malsTewnearneimdaolssed(5wimtahletsheavnedhi5cle, dcoenitornoilzegdrowuaptesr.werTehecuptohsaintiizveedcoanfttreorl24anhiomuarls.s wAafrteerdotsheedbowniethm8a0rrmogwkwgascyccolllocpehteods,phitamwiadses(pCrPe)a.d oBnottoh 159 000163 tmiidcerso,nudcrlieedi,aannddtshteapinoeldycwhitrhomMaatyc-Gerryatnhwroaclydteso(lPuCtEio)ntaonndoGrimeomcsha.romTahteiselriydtehsrowceyrtee s(cNoCreEd)focerll ratio OpenrecetnhtomusiacnrdonPuCcElSeaptedreanlismablasweedreosncotrhedt.ralThPeCEfrsepqurenecsy oifntmhiecrsocnourceldeaottediceflelds.waTshcexnporremsaeld as Trequencyof micronuclei in this sin is about 0.0-0.4% RESULTS Effect on mitotic index or PCENCE ratio by dose level and sex: femme | | swom[aseor[as oo [00 on Trt |Vor| 8 masa ets RatioPCENCE | Vehiclecontrol__|2[hM|al01e4 0s02| | F0e02mal0e0s2 | 0M6a4le0s07| | F06e3mal0e0s5 | 1c2r5)0 mghe | [37h2h 1|000006 000020[|000022 000022 || 006368 000088 || 007549 000066| 3500 make: 28h | 012 004 | 004 002 | 069 007 | 06d 005 [48h T 002 002 [ 002 002| 019 007 [060654000071 | S000 ekg: [28h 006 004 | 010 004 | 080 00s | 079 005 [1C ois h 009 | 006 002 L"Significantly diferent from the coresponding vehicle c0on.t0r30(p<003.05) Genotoxic effects (unconfirmed, dose-response, equivoeal: Negative Statistical results: Nosignificant increases in micronuclated plychromatc rytheoeyies were observed. `Rreomuapraktst:heD7u2choourtoxhiacrivteys.ttghreoPuCpEw/eNreCEsirgantiifoiscaonftltyhleowmealetshaanndtfheemvaelheisclfeicoomnttrhoelSa0n0i0mamlsg./kg dose 160 000164 CONCLUSIONS "pTohleyctehsrtommaatteiricaelr,yTt-hr6o3c4y2t,esdiudndneotr itnheduccoendaitsiigonnisofifctahntisinacsrseaayseanindmiisccroonnsuicdleeriedinnbeoganteivmearinrotwhe mouse micronucleus assay. REFERENCE IMnucl.i,ViHe.nna1,995V,irgMiuntiaa.gen3iMciCtoyrptoersattoionn.T-6S3t.4P2auinl,an MiNn.vivomouse micronucleusassay. ComingHazleton 161 000165 GENETIC TOXICITY (IN VITRO) "Title: Evaluationof the Abilityof T7524 to Induce Chromosome Aberrations in Cultured Peripheral Human Lymphocytes TEST SUBSTANCE Identity: T7524 Remarks: The specific gravityofthe test substance was 1.23. Substance was a brown pasteof95% purity: the remaining 2% was 1-methyl-20pyrrolidinone. METHOD Method/Guideline followed: OECD Guideline 473; EEC Directive 67/548/EEC; OPPTS Guideline 70.5375 Japanese Minisry of Health and Welfare and Japanese Ministryof International Trade and Industry. Test type: Invitro cytogenetics Test systems Cultured human lymphocytes GLe: v ear study performed: 2000 `Species/Strain/cell-typefeell line: cells obtained from healthy adult mal volunteers `TWyisptearoframtse,toabbtoaliincedacftriovamtCihonarulseesdR:ivreart,fSiuvlerzfmeildc,roGseormmaalnye.nzyAmneismarlosutwienerleyhporuespeadreadt fNrOomTOadXultinmaale special room under standard laboratory conditions, as described in the Standard Operating Procedures a(SnOdPmsi).nceRdaaisndwesruepeimnajteactnetd wiantsraupsecrditfoonrcaalcltyivwatiitohn.Aroclor 1254 induced in corn oil. Livers were washed Concentrations tested: Without $9.- First Experiment: 1000, 3330 and 5000. g/ml Second Experiment: 333, 560,1000, 1300, 1500, 2400, and 3330 g/l, 333,420, $60, 750, 1000, 1300, and 1800 g/ml With 59 (1.8% v/v)= Experiment 1: 1000, 3333 and 5000 g/ Experiment 2:1000, 3333, and 5000 g/ml 162 000166 Test conditions: Range-Finding Test: Lymphocyte cultures (0.4 mi blood ofa healthy male donor plus 5 mi or 4.8 ml culture medium, with and without S9 respectively and 0.1 ml (9 mg/m) phytohaemagelutinin) were cultured for48 hours and thereafter exposed to selected doses of T-7524 for 3 h. 24 h. and 48 h in the aribnsseendceonocfewSi9-tmhiSx moriofforH3BSiSn tahnedpirnecsuebnacteoedfi$n95 mmiix.culAtfutreerm3ebdris,umthfeocrealnlsotehxepros2e0d-2t2ohT-(72542h4fwiexrateion tfiimxee)d. imTmheedciealtlelytraefatteerd 2fo4rh2a4nhdr4a8ndh.4B8ahsr eidnaonbstehnecreeosufltSs9o-fmdioxsewerraengneo-tfirnidnsiendgafttesett,raenatapmpernoptribauttewer. rangeofdose levelswas chosen for the cyorgenctic assay. Experiment 1: Lymphocytes were cultured for 48 hours and then exposed in duplicate 10 selected doses iofncTu-b7a5te2d4 ifnoS3rmlhocuurlstwuirethmeadndiuwmitfhooruatnSo9t-hmeirx2.0-A22fther3r(2h4rsh, ftihxeacteilolnstwiemer)e. riBnasseeddwoitnht5hemmiitHoBtiScSinadnedx of stheecodnodsecyrtaonggeeneftiincdiansgsateyst- atnhed htihgehefisrtstdcoysteogleevneeltitceaessdayi,nhaipbpirtoepdrtihaetemidtoosteicleivnedlesxwbeyreapsperloecxtiemdatfeolryth5e0% or more: the mitotic index ofthe lowest dose tested was approximately the same us the solvent control. E75x2p4erfiomre2n4th2a:ndCe4ll8sh weinrethceualbtusreendcefoorf4S89h-mainxd otrhefroeraf3lehrienxtphoesperdesinendcuepolifcaSt9e-mtioxs.eleAcftteedr3dohsetsroefatTm-ent, cfeolrls44in-t4h6he p(r4e8sehnfciexoaftiSon9-tmimiex).weTrheercienlslesdtorenactedwiftohr 24mhl aHnBdS4S8 ahnwditihnocuutbaSt9e-dmiinxwmelrecunlotturreinmseeddiafutmer treatment but were harvested immediately after 24h and 48 h fixation ime. Chromosome preparation: During the last 3 hof culture, cel division was arrested by additionof the satpi1n3d0le0 irnphimbiatnodr tchoelcshuipceirnneat(a0.n5t uwga/smlremmeodvieudm.).CeTlhlesrneafttheerrtehmeaicenlilncguclteulrepselwleetrewecreentsrwioflulgeedn fboyr55 mmiinn rceelalstmweenrtewfiitxhedhywiptoht3oncihcan0g.e5s6o%f(wm/evt)hapnootla:ssaicuemticchlaocriiddfeixsaotliuvteio(n3:a1t 3V7AC).. Afer hypotonic treatment, the Slide preparation: Fixed cells were dropped on cleaned slides that were immersed for 24 bein a 1:1 mix. 0ide9n6t%ific(avt/ivo)nentuhmabneorltahnedrgarnodupclneuamnbeedr.witThwaotisslsiude.es Twehreesplirdeepsarweedrceulmuarrek.edSwliitdhestwheerNeOsTetOtXo dsrtyuday.nd twhaetnerstaanidnesdetfoor d1r0y-.30Tmhiendwriytshli5d9e%s (wve/rve) Gcliecamrsead bsoyldutiipopninig tinapxwyalteenre. beSfloirdeestwheeyrewetrheenermibnesedddeindtianpMicroMount and mounted with coverslip. Mitotic index scoring: The mitotic indexofeachculture was determined by counting the number of maneatlaypzheadsewserpeer1th0o0se0cceullltsu.resAtwhleeraset t3heanmailtyostaibcliencdoenxcewnatsraitnihoinbsitweedraeppurseodx:imtahteehliygh5e0s%t coorncmeonrtcractoimonpsared mtoittohteicsoilnvdeenxt ocfotnthreol.solTvehnet.mitCouilcuriensdetxroefattehdewiltohweasntidnotseermleedviealtaendaolsyezewdewraesalasbooeutxatmhiesnaedmfaors the. chromosome aberrations. oCfoucnhtrionmgoscohmreomaboesroramteioanbsearnradtsicoonrse:d. ToAnpardehveenstivbeiasl,sbsellidweisthwetrhee rNaOnTdoOmXlysctouddyedIDprniourmobeerxaanmdincaotdieon was stuck over the marked slide. A least 100 metaphase chromosome spreads per culture were examined borymloigrhet imnic$r0osmcetoappyhfaosresc,hrnoommoosroememeatbaeprrhaatsieosns.weIrfeheexamniunmebde.roOfnalbyermreatnatphcealsless(wgiatphs e4x6clcuhdreodm)owseomres.25 were analyzed. Numbers ofcals with aberrations and numbersof aberrations were calculated 163 000167 RESULTS `ceGlelnsotwiotxhiccehfrfoecmtos:soTm-e7a5b2e4rrdatiidonnso.t induce a statisticallyorbiologically significant increase in numbers of Cytotoxic concentrations: Without 8.9: 3 hr treatment; 24 hr fixation: notoxic dose; highest dose tested 5000 g/m. 24 h treatment; 24 h fixation: 2400 and 3330 gn! 48 h treatment; 48 h fixation: 1300 and 1800 g/l With 5-9 3 hr treatment; 24 hr fixation: no toxic dose; highest dose ested S000. g/m, 3 hr treatment; 48hrfixation: no toxic dose: highest dose tested S000. g/ml. CONCLUSIONS `When tested without 5-9 and with 24h continuous treatment, T-7524, induced a statistically significant increase in the numberof chromosome aberrations at 1000 im when gaps were included in the total number of aberrations. However, when gaps are excluded the number of aberrations are within the historicalcontrolrangeofthe laboratory. This increase was not seen a 1000. g/ml with 48 hour `continuous treatment. Because this increase occurred at the middie dose only. included gaps. and the clahbroormatoosroymaendabneorriantciroenassseeoecn.cuerxrceldudwiintgh g4a8pshacronetwiintuhoiunstthreeahtimsetnotr,icatlhecoinntcorelarseanigsenootfctohenspiedrefroerdmitnog. constitute a positive response. Based on the above resus, T-7524 is not clastogenic in human lymphocytes under the experimental conditionsofthe study. Remarks: none. REFERENCE PNeOrTipOhXe.ral 2H0u00m.anEvLaylmupahtoicoyntoefs.theNAObiTliOtXyofPrToj-e7c5t2N4utmobIenrdu2c0e20C6h2r.omHoesrtoomgeenAbboesrcrha,tiTohnse iNnetChuelrtluarnedsd. 164 000168 ACUTE TOXICITY "Titles An Acute Inhalation Toxicity StudyofT-2305 CoC in the Rat TEST SUBSTANCE Identity: T-2305CoC Remarks: Fir white powder, received from 3M Company;composition and purity not indicated. METHOD Methodiguideline followed: Guideline number not stated. GLP: No Vear study performed: 1979 Species/Strain: RavSprague-Dawley (211 10 264 grams) Sex (Males/females/both): Both No.ofanimals/sex/dose: 5/sex/group Routeof Administration: Inhalation dReelmiaverrkesd:inTahetotnaolmvionlaulmteesotfc9on6c0enfttreartoiofndrwaysair1. 8.6Thmeg/tLes.t wmiattheraiaoltwaalsosfie1v7.e9d0 agnrdampsaocfketedstinmfoattehreial dcyulsitn-dleardeonfaairWwraisghptadsusesdtfienetdo tmheec3h2.a3nislmit.er gTlhaessfelxopworsautreoefcdhraymbaeirr whaoussi1n6lgittheerstmesitnuatnei.malTsheforreasnulting `deuxrpionsgurtehereixopodsourfe,onupohonurr.emTovhaelanfirmoamlsthewecrheamobbesre,rvheodurfloyr afbonr4orhmoaulrssiagfntseratre1m5o-vmailnurteomintteesrtvaclhsamber, and daily thereafter for 14 days prior to sacrifice. RESULTS Numberofdeaths at each dose level (by sex): There were no deaths. dReecmraeraskesd:acDtuivriitny.g ltahbeoerxepdobsrueraethpienrgi,odg,astphiensgt,ucdlyoasnedimeayless,exmhuicboiiteddneaxscaelsdsiisvcehalrngcer,imaantdioinrrsengdulsaarlivation, barneoagtehniintga.l fAufr(t9er/1r0e)m,ovdarly rfarloems (t6h/e10e)x,porsedurmeatcehraimalbearr,ourenddntahseaelydeissc(h5/a1r0g)e. (e1x0c/e1s0)s.ivyesealllvoawtsitoanini(n4/go10f)t,he elxaccerismsaitvieonlaacnrdimbatoidoynt(r1e/m10o)r,sahnaddbaobdaytterdebmyorthse(o1n/e10-)howuerrepoasbts-ecrxvpeosdurinetohbeserartvsatEixocnaasnsidtvhesearlevawtaison1,0 red 165 000169 ymeatlelroiwalstoabisneinrgvoefdtahreouanndogtehneiteaylesfuartt(h6/e1t0)woanhdoudrryporsatleesx(p5o/s1u0r)ewoebrseersvtaitlliosne.enRaetdthneasaanledhisocuhrapgoest(-10/10) (`3e/x1p0o)s.urmeuocbosiedrvnataisoanld.isDcuhrairnggeth(e101/140-)d,aydroybsrearlvesat(i8o1n0)p,erdirody,reexdcmeastseirvieallaacrroiumantdiotnhe(6n/o1s0e)(a2n/d10)s.alavnadtion mHouinsgtdirsacleoslo(r1a/t1i0o)nwienr8e1o0bsreatrsve(ad hiingthheerrtahtsa.n nWoerimgahl ignaciindseancpep)eared normal. Necropsy findings showed CONCLUSIONS t15w.a6 smgc/Loncflourdeodnfrhooumr.thIemsmteuddiyatreeseuffsectthsaotftthreetaetstmesnutbswtearnceeexiscensostifvaetalla0crirmaattsiaont,a snaolmiivntaiolne,xdpeocsrueraeseodf yacetlivliotwy.stLaaibnionrgcodfbtrheeatahnion-gg,engiatsaplinfgu.r,claonsdindgroyfrtalhees.eyTehse, pmeurcsoisitdenncaesaolf dliasccrhiamragtei,oni,rsreagluvlaatriborne,amthuicnogi,d `cneasnaladtinseccharrogpes,ydirnydircaaltees,tdhraty threedmamtaetreirailalmaaryouhnadvtehae pnroosleonagneddmoorirsetsiadlueaslalefofnecgtwiatth14ludanygs.discoloration REFERENCE MBiNo./dyPnroajmeicctsNoIn.e.781-977198.4.An Acute Inhalation Study ofT-2305 CoC in the Rat. 3M Company, St. Paul, 166 000170 ACUTE TOXICITY Title: Acute OralToxicity (LD) Study in Rats TEST SUBSTANCE Identity: Fluorad Fluorochemical FC-143, Remarks: White powder, 3M Lot No. 340; composition and purity not indicated METHOD Methodguideline followed: Guideline number not stated GLP (VIN): No ear study performed: 1978 Species/Strain: RatCharles River CD Sex (Males/femalesboth): both Numberofanimals/sex/dose: Ssexdosc Vehicle: 40% acetone/60% com oil Route of Administration: Oral gavage 2R1e5m0armkgs':kgTihneatvesotlmuamteeorifal10waUskad.miniTshteeraetdsatwetiheghfeodll1ow8i0n-g21d8osgeatlesvetlusd:y 1i0ni0t,ia2t1io5n,.4A64n,im1a0l0s0,wearned: odabisleyrvtehedrefaofrimeorrftoarliattyoatanldopfh1a4rmdcaoyst.ovBiocdsyigwnesigdhutrsinwgetrhee rfeicsotrfdoeudr ihmomuerdsiaaftteelrydopsriinogr,toatdo2s4ihnoguarnsdaantd7 aofntdhe14d1a4ydsa.yAonbsiemravastitohantpdeiricodd.on study were subjected (0 gross necropsy as were all survivors at the end. RESULTS `"Tchoemefaollloopawciintgy,clhinyipcoalthseirgmniscwe(0retooubchs,eravnedd:depattohs.is,Sipglnoscroebcsteironv,edhyaptonaecctrivoiptsyy,odfecirmeaaseld wlihmibchtownee,reataxia, sftooumnadchdse;ado orstsaocmraicfhicsedfimlloerdiwbiutnhdfliunicdluidnecd:lu1d)incgondgaersktireodn,orrpiettdinfgluaind,dsrteodmfaocchisincotnhtealiunnignsg;d2a)rkdirsetdended particulate material; intestines filled with stomachs red fluid; waintdh4h)yppaelreemdiisccoorlotrhatiicoknenoefdtmheucloivsear;oS)r ererdossitoaninoifngthaergoluannddutlhaernmousceosaan;d 3) `mmuocuoths.a,Anhiydmraolmsettrhaatosfutrhveivuetdertuosdaanyd1m4othtaldedthcioclkoernaetidosntoofmtahcehkmiudcnoeyssa., Shiygpnesrewmeirce golbasnedruvleadrasttaolmlach 167 000171 treatment levels. Treatment terminal sacrifice. did not appear tohave an effect upon weight ofthe animals that survived to Numberofdeaths at each dose level (by sex): 100 mykg: 1/5 males, 05 females 215 make: 05 males, 0S females 464 mek: 2/5 males, 3/5 females 1000 mg/kg: 315 males, 5/5 females 2150 meg: 5/5 males, SIS females Remarks: LD (mal rats) = LD (female rats) 680 mg/kg, with 399-- = 430 mg/kg, with 295 1157 me/ke 95% confidence 626 make 95% confidence limit limit Da (combined sexes) = 540 mg/kg, with 389- 749 mg/kg 95% confidence limit REFERENCE IFnltueorrnaadtiFolnualorRoecsheeamricchalanFdC-D1e4v3elAocpumteenOtrCaolrpToorxaitciiotny. (LDio) Study in Sponsored by Rats. 1978. Study 3M Company. No. 137-091, 168 000172 ACUTE TOXICITY Tithe: Acute Oral Toxicity StudyofT-6669 in Rats (OECD Guidelines) TEST SUBSTANCE Identity: T6669, a fine white powder. Remarks: None METHOD Methodguideline followed: OECD Guidelines GLP (VIN): Year study performed: 1997 `Species/Strain: albino fatsofCrl:CD (SD)BR strain Sex (Males/females/both): both Number of animals/sex/dose: 5isex/dose: Vehicle: distilled water Routeof Administration: gavage mReimkaerkbosd:y Dweigohto.sf2T5hee0arsnatds w5e0i0gmheedk20w8e-r2e69tegstaend.d Awlerledo8s-e12lweveeelkssweolrde.adCmliinniciasltoebrsaeersdvavtoilounmsewseorfe 10 hcoencdkusctweedraetc1o,n2d5u,ctaenddt4whiocuearsdaafye(rmtoerstnimnatgerainadlaafdtmeimnoisotnr)atfioron1a3nddaycascahnddaoynftorhe1m4odmayis.ngMoofrtDaalyity14, wBeordeyswuebijgehcttsofwearneabdberteevrimaitneeddgornoDssanyescr0o,ps7y,.and 14 or at death ifsurvival exceeded 1 day. All animals 169 000173 RESULTS LDS0: Males: > 500 merke Females: between 250 and 500 me/kg Numberofdeaths at each dose level (by sex): 250 mg/kg --none: 500 mykg 2/5 males and $/S females Rmemkarkasp:peaArleldanniomramlas edxuhriibnigtetdhebostduydyweeixgchetptgifonr tthwrooufgehmoaluetsthtehsattuedxyh.ibAilteldarneidm-asltsaitnreedatfeadceast a25n0doar wtheetaunriomgaelnsittarleaartecdawwiitthhiSn0204mhgo/ukrgsowfertee:st rmeadt-esriiaailneaddmfiancies,tyraetliloonw..sCtlaiinniecdalorsiwgents uorfotgoexniictiatlyaorbesae,rved in rheylpaotecdtilveisiyo,nshuobnscehrevdedpoasttunreec,rosptsayg.gearletdhogauigth, aatnd25e0xcmegs/sikvgeosnaelvfateimoanl.e hTahderlearwgeerpeelnvoistcessti-nmbaotetrhial Kairdcnaesysi.n thAetgSl0an0dumlga/rkgm,ucoonseamaofltehheasdtaomcaacnhn,ibaanldiasedsercigohntdfflaenmka,leonheadfeamcalleearhafdlumiudlitniptlhee dlaurmkenbroofwtnhe bilateral homsofthe uerus. onCLUSIONS None were specified beyond the results REFERENCE G6l1a0z0a1,76S0M.. Ja1n9u9a7.ry A10c.utSepOornaslorTeodxbyic3SMit.utSdty.yoPfauTl,-Mi6nnei6sno6Rtaat.9s. Corning Hazleton Inc. CHW OTHER 170 000174 ACUTE - SKIN IRRITATION "Title: Primary Skin Irtation Study- Rabbits TEST SUBSTANCE Identity: T-1395 Remarks: no other identifying information was given, . METHOD Note pHoftest material: Not specified Method/Guideline Administration and foElnlfoowrecde:meSnitmiRleagrultaottieosnts,in FSeedcetrioanl 1R5e0g0i.st4e1r,~ VHoal.zar3d8o,usNoS.ubs1t8a7n,ceps. a2n7d01A9rt4i,cle2s7, September 1973. Test Type:invivo `Speciesistrainfeell type: albino rabbits Sex (males/females/both): Not specified Number of animals/sex/dose: 6 total "dTroytaalnddoasfet:er aDpopsleiscaotifon 0o.5fg wwaetreerpalatcheedeonndoafntihnetaectxpsetreimaenndt.an abraded sit. Sites were examined while Vehicle: Not specified Length of time but there was no tiensdticmaattioenriaablouits iwnhectohnetractthewsiitteh waansimwaalischeeldl.: RWeraadpipngisngwserweeraelsoremmaodveedata7fi2erho2u4rshours Grading scale: Scores for erythema and eschar formation as well as edema formation were presented. Remarks: Six albino rabbits had their hair lipped from their backs and flanks, and five tenthsofone graaumze(0p.a5tc2h)eosfatnesdt amnateirmipaelrwviaosusplmaacteedrioanlawbraasdewdr-adprpyeodr aitraocutn-ddrtyheprseiptarteodkteesetpstthse, btahenndacgoeveirnedplwaict.h Arfetceorrd2e4d ahcocuorrsdianngd1072a hours the coverings were removed and standardizedscale (the Draize method) the degree of erythema and edema was. ml 000175 RESULTS dIenteacltlecd.aseNsoitcliisnirceaplorstiegdnsthweerperirmepaorrytesdk.in iritation scores were 0, indicating no reddening or swelling Primary irritation score: zero Remarks: There was no indication ofreliability and no QA/QC. CONCLUSIONS Based on the result, the substance was not classified as primary rita, REFERENCE GSaubbrmiictlt,eKdartlo. 3MSuCmommapraynyof,: 3PMriCmeanrtyerS,kiStn. IPratualt,iMonN.Stud~y Rabbits. Performed by: Bioscarch. OTHER `deGteanielreadlrreepomratrkwsa:s aTvhaiilsabslue.mmTahreyrewfaosreb,atsheedcoonntaenstusomfmatrhiys rseupmormtarayn.d oinnlryefleirmeintceed tdoattaheabplreost.ocoNlos and results of thestudy.are limited. mn" 000176 ACUTE - EYE IRRITATION "Title: Primary Eye Iitation Study- Rabbits EST SUBSTANCE Identity: T-1395 Remarks: no other identifying information was given, METHOD Note pH of test material: Not specified AMdemtihnoids/trGautiidoenlainnde fEonlfloorwceedm:enStimRielgaurla0titoensst,iFneSdeecrtailonRe1g5i0st0e.r4,2V-olH.az3a8,rdNoou.s1S8ub7sp.t.an2c7e0s19a+n,d 2Ar1ticles, September 1973. Test Type:invivo Species/strainfeell type or ine: adult albino rabbits Sex (males/females/both): Not specified Nuofmanimb als/e sexidr ose: singledose: "Total dose: 0.1 gram per eye. Length of time test material is in contact with animabicell: S seconds in 3 animals; 30 seconds in 3 animals Observation period: 1 hr, 24 hr, 48 hr, 72 hr, and 5 and 7 days Remarks: The test material was washed from the eyes in3 animals afer$ seconds with 200 cc of water and afr 30 seconds in 3 animals with 200ceofwater. Noother information on themethodswas given. RESULTS Corrosive: Not specified 73 000177 Irritation score: Acfotnejrunctseicv:acAlwlersceo4r,esanfdoriCno|mreababiatn,dthreisscwoerreewzaesro2s, (tfhorroualglhroaubtbittsh)e.oIbsnertvwaotiroanbbpietrsi,osd.cores for After 30sec: AllscfoorCromeeaasndIriswere zeros (forall rabbit). Inonerabbit,scoresfor `wCaosnj4untchtriovuagchwouetreth4e aotbs1e-r4v8athriso,napnedriiondcraenadseidn 0 6 at 72 hrs and | rabbi the score at was and 7 days. In | 6 throughout the rabbit, th score: observation period. rTiotoaltiuosnedBytoHaaszsaerdsosusscoSrueb:stSacnocreisn.g was done accorditnogthe Ilustated Guide for Grading Eve Description oflesions: None Remarks: None CONCLUSIONS "The only conclusion provided instudy was tha th tes substance was not an ocular iiant Remarks: This conclusion is suspect due [0 the positive scores observed during the study. However, wbiotuhtouttheadrdeistulitosn,al information on the scoring method, there is no way to provide an informedjudgment REFERENCE Gabriel, Karl. Summary of: PrimaryEye Irritation Stu~Radbbiyts. Performed by: Bioscarch. Submitted to3M Company, 3M Center, St. Paul, MN. OTHER General remarks: This summary wasbasedon a summary report and only limited data ables. No rdeestualitlsedofretphoertstwuadys,aavraeillaibmliet.ed.Therefore, the contentsofthis summary. in reference o the protocols and 4 000178 ACUTE - EVE IRRITATION Title: Primary Eye Irritation-Rabbit TEST SUBSTANCE Identity: 3M identified the test substance as T-1395. Remarks: The test substance was not further characterized. METHOD Note pH of test material: Not specified Method/Guideline followed: The methods employed in the testing, evaluation, and gradingofthe test `material are those described in Section 1500.42 Hazardous Substances and Articles, Administration and Enforcement Regulations, Federal Register, Vol. 38, No. 187. p. 27019, 27 Sept 1973. Test Type: in vivo. Species/strain/cell type or lines Albino rabbitNot specified Sex (males/females/both): Not specified Numberofanimals/sex/dose: 6/single dose Total dose: 0.1 gram Test conditions: The test subswtasainnsticlleed into the right eyes ofthe test animals; the left eyes were not treated and served as controls. The test substance was not washed from the treated eyes. Length of time test material is in contact with animalcell: The exposed eye was not washed following administration of the test substance. Observation period: 1.24, 48, and 72 hours post-exposure; S and 7 days post-cxposurc: Scoring method used: Interprtation of the results was made in accordance with the grading system outlined in "Hllustrated Guide for Grading Eye Irritation By Hazardous Substances" Remarks: Healthy youn adult animals were used in this study. RESULTS Corrosive: Not specified Irritation score: No overall iritation scorewasgiven. Individually. 1 hour after application of the test substance, 6/6 animals exhibited iri irritation scores of$ and 4/6animals exhibited conjunctiva iritation 175 000179 scores of continued 10: to the remaining two display iritationof animals the ris eaxnhdibciotnejduncocntjiuvnaci(iivmiateatiirointastcioorness:cor$easnod6f2-6a,ndre8s.pe6c/t6ivaenliym)alusp to 4de8crheoausrcsdabtyedraaydmi7noifsttrhaetisotnudoyf. tahtewthesitchsutbismtaenc2e/6. aIrnriimtaatlisonexshciobrietseadnidiinicmiitdaetnicoenosfcoirietsatoiof$n hanadd 1/6 `aanniimmaall etxhhriobuigtheoduta cthoenjstuundcy.tiva irritation score of2. No comeal irritation was observed in anyof the oTuotollinuesdeidnt"oIlalsussetsrastesdcoGrue:ideInftoerrpGrreatadtiinognoEfyteheIrrietsautlitosn wBays HmaazdaerdionaucscSourbdsatanncceesw"i.th the grading system Descriptionoflesions: Not specified Remarks: None CONCLUSIONS cRoenmsairdekrse:d tBhaesteedstosnubtshtearnecseulttos boefthaipsrismtaurdyy aocnudlatrhersioaurnc;e usaegdrefeorwiitnhtetrhpirsetcionngcltuhseiorne.sults, the authors REFERENCE 3M Company. 1976. Primary Eye Irritation Study-Rabbits. OTHER Remarks: This summary was basedon a summary report; therefore, the contents of this summary, in reference to the protocols and resultsof the study, are limited. 176 000180 ACUTE - SKIN IRRITATION "Tite: Primary Skin Iriation Test with T-3371 in Albino Rabbits TEST SUBSTANCE Identity: Riker Laboratories, Inc. identified the test substance as T-3371 Remarks: The test substance was not further characterized. METHOD Note pH of est material: Not specified Method/Guideline followed: ICAO. Test Types in vivo `Species/strain/eell type: RabbitNew Zealand White Albino Sex (males/females/both): Female Numberofanimals/sex/dose: 3/exposure period Total dose: 0.5 gram Vehicle: None Lengthoftime test material is in contact with animalicell: 3 minutes, 1 hour, or4 hours aTnedstfcloannkdsiotifonesa:chOrnabebidt.ayFoprrioeractho arpabpbliitc,attiwoon otefstthseitetesstwesruebstsealneccet,ed.theThhaeirtewstassisthsavweedrefrlaotmeratlhetobatchke. midlineofthe back and approximately 10 centimeters apart The test substance was applied to cachofthe ttehsetn,sittehse atnrudnkococflucdaecdhwaintihma2l-inwcahsswqruaarpepegdauwziethpaitcmhpeesr.viTohues pplaatscthiecsswheeerteinsgecfuorredthweitdhuragtaiuozneowfratphe;. feoxrpiorsruerveerpseirbiloedd.aAmfaegretahnedesxcpoorseudrefopreeriroydt.healmlawarnadppeidnegmsa.were removed and the est sites were examined gGrraaddiinnggSesaclaeleo:f Th-e4.auTtehsotrssiptreessweenrteedaslespoaorbatseerivreridtaftoironthsecoprreessefnorceeroyrtahbesmeancaenodfedcehemmai,ccaalcbhubma,seedscohnara, necrosis, and epithelial sloughing. rRoeommasrkwsit:hAfnoiomdaalnsdwwearteerhoofufseeredd iandsltiabnitduamr.d wire-mesh cages in temperature and humidity controlled " 000181 RESULTS Rheosuurltcso:ntaTcthepertiesotd.suMbosdtearncaetepreordyutcheedmairaenvderesdieblmea,tiasssuweeldlamaasgcehefmoilclaolwibnugm,a 3es-cmhianru,tea,nd1-nehcoruors,isanwder4e-. produced following all three contact periods. An endpoint was not achieved du to the extreme iritation Tollowing cach contact period. Primary irritation score: Not reported Remarks: CONCLUSIONS eTrhyetchheemmaicaanld eprdoedmuac,ecdhermeivcearlsibbulrent,isesscuheard,amanadgenetcorotshiess.kiInnaodfeqfueamtaeleinaflobrimnaotiraobnbiwtass: ipnrcelsuedniengd miondtehreate. report to evaluate qualityof the study and validityofthe conclusion. REFERENCE Primary Skin Irritation Test with T-3371 in Albino Rabbits. 1983. Safety Evaluation Laboratory, Riker Laboratories, Inc. St. Paul, Minnesota. Experiment 40883EB007. 178 000182 ACUTE TOXICITY. Title: Acute Oral Toxicity Study-Rats Identity: 3M identified the test substance as T1585. Remarks: The test substance was not further characterized. METHOD Methodiguideline followed: Not specified GLP (Y/N): No earstudy performed: 1976 Species/Strain: RaySherman-Wistar. 200-300 grams Sex (Males/females/both): Male and female. Number of animals/sex/dose: S/sex/single dose Vehicle: 50% water Routeof Administration: Oral Test conditions: Each animal was weighed and dosed by direct administration of the test substance into. hsuebssttaonmcaecwhabsydmoesaednsaosfaas$y0r%iwnigve asunsdpdeonssiinogn nineewadt.er.ThFeoldlooswaigen-glaedvmeilniwsatsra1t.i0o0n0omf at/hkegteastndsutbhsetatenscte. the animals were allowed food andwater ad libitumforthe 14-day observation period, during which time the rats were observed for siofgtonxicsity and mortalities. Remarks: The test animals ware deprivoefd food (not water) for 24 hours prior to dosing. RESULTS LD: 1.000 mgrke Numberofdeaths at cach dose level (by sex): 1.000 mgrkg-3/5 males, 45 females SRuebmsatarnkcse:; t6he0r%efoofre,matlheesL(D3/S50) waands 8de0t%eromfinfeedmatloebse(4</51).d0i0c0dmfg/oklgl.owiSniggnasdomfitnoisxtircaittiyonoinfcltuhdeedteasnt eroded 179 000183 tahsrtereicsumruvicvoisnagaanndimwarlistheixnhgi:bittheednnuomcbhearnogfeaniimianiltsi,alwahnidchfineaxlhibboidtyedwetihgehste.signs, was not specified. The "ONCLUSIONS Remarks: The authors concluded the Lio o be < 1,000 mk; agree with this conclusion. REFERENCE Acute Oral Toxicity in Rats-T-1585. 1976. 3M Company. OTHER hRiesmsaurmkmsa:ryT,hiisnsruomfemraerncyewtaosthbeaspreodtoocnoalssaunmdmarreysrueoplofrttthsseubstmuidtyt,edarbeyl3imMi;tetd.herefore, the contents of 180 000184 ACUTE - EYE IRRITATION "Title: Primary Eye Irritation Study - Rabbits TEST SUBSTANCE Identity: T-1585 Remarks: No other specifications regarding the test substance were noted METHOD Note pHoftest material: Not specified EMneftohrocde/mGeunitdeRleigunleatfioolnlso,weFde:derSaelctRieognis1t5er0,0.V4o2l-. 3H8a,zNaor.do1u8s7,Supb2s7t0a1n9c,esSaenpdteAmrbtiecrle2s7,,A1d9m7i3n.istration and Test Types: in vivo Species/strainfeell type or ine: RabbivAlbino Sex (males/females/both): Not specified Nuofmanimbals/e sexdr ose: singledose Total dose: 0.1. Lengthoftime test material is in contact with animalieell: 7 days Observation period: 1h, 24 h, 48h. 721, 5d. and 7d `Scoring method used: Used grading system outlined in "Illustrated Guide for Grading Eye Iritation by HazardousSubstances" Remarks: The test substance (0.1 ) was administered 0 the right eyeofeach rabbit, while the untreated yeyeessweervreedsacso.recdonftorrolc.omTehael toepsatcmiattyerainadlawreaas,niorts.waansdhecodnjfurnocmtitvhaeleyreesd.nesAst, ccahcehmoosbss,eravndatdiisotcnhhea,rgtere.ated. RESULTS Corrosive: Not specified Irritation score: Comeal opacity and area=4 Iis =2; Conjunctival redness = 2; Conjuncival chemosis 4 Conjunctival discharge~ 3 "Toolusedtoassess score: "Ilustrated Guidefor Grading Fe Irritation By Hazardous Substances." Description of lesions: None 181 000185 Remarks: The scores for al the abbits were the same for each category and observation. The scores remained the same through day 7. Only a summary tableofscores was given, with no descriptionofthe effects. CONCLUSIONS pTrheesetnesttedsuibnstthaencreepisorattporiemvaarlyuaotceultahre qiurailtaintty aofndthreeqsutiurdeysacnaduttihoenavraylidliatbyelionfg.theIcnoandcelquusaitoensi.nformation is REFERENCE Bioscarch, Inc. 1976. Primary Eye IrriSttuday--tRiabobints. PhiladelphiPaA,. 3M Company. St. Paul, MN 182 000186 ACUTE TOXICITY Title: Acute Dermal Toxicity Study of T-6342 in Rabbits TEST SUBSTANCE Identity: T-6342;a lear, colorless liquid. Remarks: None METHOD 4M0e4thfoodr/DGeurimdaelliTonxeicfiotyl.lowOeEd:CDOGEuCiDdeGluiidnedelosinenotTPb2e0g7i1n._witMholsetttelriskealnyddthoisnosthoguoladshbeigOhEaCsD4 nGuumibdeelrisn.e GLP: Yes ear study performed: 1995 Species/strain: RabbitsHra(NZW)SPF Sex (males/females/both): Both Numberofanimals/sex/dose: S males, females'single dose. Total dose: 2000 mk Vehicle: None Routeof administration: Dermal Remarks: Substance The rabbits had was applied to the the hair clipped inact skin. The from area their backs before of application was the appropriate covered witha amountof gauze patch the test and an ococlcllaurssivaenddredsrseisnsgi.ngsCowlelraersrwemeorveedu.sedT1h0eretsesttrasiintetshewearniemawlas.sheAdfiweirththteap24wahtoeurraenxdpodsiusrpeospaebrlieodp,aptehre towels. Clinical observations and mortality checkswere made at approximately1.2.5, a4nhodurs after tteesstt mmaatteerriiaall awdamisniasptprlaiteido.naatnDdatywi7ceadnadiloynthDearyeaf1e4r. fTohre14indiatyasl. deBromdayl wierriigthattisonwerreeaddientgerwmaisnemdabdeefo3r0e minutes after removal of the test material and on Days 3, 7. 10, and 14. AU the endof the study, the animals were euthanized and subjected (0 necropsy. 183 000187 RESULTS Numberofdeaths at cach dose level (by sex): none xTRnceomedapurriakotsen: corfAyloltnhaeenmim.maalleesdeatmhpaapt,ealarosnetdd wnaeotirogmnhaitl,dauanrndidnegxstltiihgbehittiedrdse.sbqowuedaemkaw.teiiogDnhe,trgcmaoairlnsscietiohaursoinuoegnshso,cuotnastnhidestsfetidusduoyrf.inswgli.itghhttNhtoeo ibe lesions were observed at necropsy. The dermal LDSO in rabbis was greater than 2000 mgs. CONCLUSIONS "pTrhoedduecremdaslliLgIhtDStOoomfoTd-e6ra3t4e2dwearsmaglreraatetriothna.n 2N0o00clmingi/ckalesiingmnsaldeurainndg ftheemasluedryabobrisv.isibTlheelfeessitosnusbasttance necropsy were noid. GPraojzecat,S.1D;19H95W.IAScOuRtOeDdSe7r4.mal3MtoxCiocmiptyasntyu.dyo+.fTPa-u6l3,4M2Ni.n rabbits. Coming Hazelton, nc. MadisonWI,. 184 000188 SKIN SENSITIZATION DATA Tithe: AssessmentofContact Hypersensitivity to T7524 i the Albino Guinea Pig (Maximisation-Test) TEST SUBSTANCE Identity: T7524 Remarks: Purity was 987%; the remaining 2% was |-methyl-2-pyrrolidinone. Substance was abrown paste, withaspecific gravity of 1.23 METHOD CMoemtmhiosdsgiuoindeDliirneectfiovell9o6w/eSd4:/EECC; OmEetChDoGduisdefolrintheeNduetmebremirn4a0t6i;onMoafgtnouxsicsiotny,aansdlaKsltiagmmeannde19d70b.y Study duration: about 90 days GLP (VIN): Y Year study performed: 2001 Species/strain: Guinea pig; Dunkin Hartley strain Sex: Females Numberof animals per dose group: 10/reatment group; 5/control group Route of administration: Intradermal and epidermal administration Range-finding study: C1o%n,ce2n%,tra$t%i,on1s0:%,St2a0r%ti,ng50a%n,d asunbdse1q0u0e%n,tacnodncdeonstersatlioownesrwtehraen1ta%kenifnfereodmedth.e fTohlelroewiwnagssenroies indication about which doses were used for induction or challenge. Vehicle not indicated. Vehicle: not indicated Induction method: Intradermal injections of four concentrations were used. Dermal reactions were assessed at 24 and 48 hours CDhearlmlaelngreeacmteitohnsodw:ereepaisdseersmsaelda2p4plaincdat4i8onhwouarssdaofneeruexspions4ugret.est substance concentrations 185 0001839 Main study: Induction (concentration and method): Day 1: (1) 1:1 wTihrveemiixntjuercetioofnFsrweeurned'msadCeomaptlaetcleiAppdejduvsacnatpuwliatrhrewgaitoenr:, ((23)) ates1:t suwbsitanmciext1ure5%ofco1n0c%entteasttisounb,staanndce with Freund's Adjuvant. "The vehicle was not indicated. bDeatywe7:enTiennjepcteirocnenstitesso:dtihuims-pdrodoevcoylk-esaudlfmaitled(iSnDfSl)amwmaatsoarpyplrieaccdticopni.dermally 10a clipped area. Daraeya 8a:ndFhieftlydpienrpcleanctetwesitthsuMbisctraonpcoerceontcapeen.traTthieondrweasssianpgplwiaesd reepmiodveerdmaaflletro4t8hehsS.DS-treated Induction vehicle: Not indicated. Challenge (concentration and method): cDlaiypp2e2d:flAankf.iftVyepheirccleentwacosncneonttirnadtiicoatnoedf. the est substance was applied epidermally to the Challenge vehicle: Not indicated. Post-observation period: Sites were assessed 24 and 48 hours aftr induction and challenge phases. Gwerraedigrnagdesdc.aleR:esTuhletsswoeurrceeeovfatlhueatesdalaeccwoarsdinnogttiondEiCcatcerdi,terbiuatfboortchlaisrsriiftiatciaotnioannadncdhallalbeenlignegrreeaqcutiiornesments for dangerous substances and preparations. Statistical methods used: Non. hReexmyalrekisn:namAicraellidaebhiylidtey cashoacpkoosfittihvee tceosnttr(oslt.udSykdianterenaocttiionndsicwaetreed)iwndaiscadtoivneeoufsaisnegnsailtpihsaa-tion rateof100 percant for this compound. RESULTS TBooxdiycwreeisgphotnssealnedffbeocdtsy bwyeidgohsteglaeivnelw:erNeosimmoirltaarlibteytowceceunrrceodntarnoldsnaondsytsrteeamtiecd gtorxoiucpist.y was observed. rIenadtumcetnito.n aDnudricnhgalchlaelnlgeengsec,orneos:skiDnurreiancgtiionndsucwteiorne,esvkiidneneftfeacftesrwcehraelleennhgaenicnetdrebaytetdhegr1o0up%sSaDnSd cChoanltlreonlgse.).LigThhteysetlalionwinsgtdaiindinnogtwhaasmspeearnsactotrhiengteosft stuhbesstkainncer-etarcetaitoends skinsites (24 and 45 hours post Sensitization: A sensitization rateof0percent was determined. 186 000190 Remarks: none. CONCLUSIONS There was no evidence that T-7524 caused skin hypersensitivity in guinea pigs. Remarks: none. REFERENCE (NMOaTxiOmXi.sati2o0n01-.TestA)s.sesNsOmeTnOtoXfPrCoojnetcatctnuHmypbeerrse2n0s2i0t2i7v.ityHtoeT-r75t2o4 ign tehTenhAeblbNoientohseGrculaihnnde,sa.Pig 187 000191 REPEAT DOSE DATA "Title: 5 Daily Dose Oral Toxicity Study with T-6669 in Rats TEST SUBSTANCE Identity: The test material was perfluorooctanoic acid, ammonium sal, T-6669 (FC-143), Lot No. 235 CASRN 3825-26-1 Remarks: Its describedas a white powder that is 93-97% ammanium perfluorooctanodte. METHOD dMaettehdoDdegcueimdbeelirne20,fo1l9l9o6weidn:clTudheedistudthyewraespocrotnducted in accordance witah company protocol TPG78S Study duration: 20 days GLP (VN): ear study performed: 1997 Species/strain: RauCrlCDR(SD)BR VAF/Plusts Sex: Male Number ofanimals per dose groups 10 Routeof administration: Oral gavage Doses tested and frequency: 0,5.0, 14.0, or 42.0 mg/kg/day. Doseswereadminisotnceerdaeildy for consceutivedays. Post-treatment observation period: 1 days Statistical methods used: Methods are outlined in the report and include ANOVA (Winer. 1971). Levene's Test (Levene, 1960), and Dunnett multiple comparison test (Dunnett, 1964) Remarks: Ina deviation from the protocol, the animals weighed between 303 and 395 gat study initiation: the protocol stated weights between 210and 250 g. The animals were provided food and water a`aniimbailnsumw.ereRoebvseersreveodsmtowiscieswaatdeayrwfaorsumosretadlaisttyhaenvdemohriibcuanlndeidtyt.he dEoasceh vaonilmuamlewwas 5raemmioskvged. frTohmeits dcoasgee aadnmdineixsatmriatnieodnfaonrdcldianiilcyalthseirgcnasflbre.forBeoddoyswienigghatnsd wateraeppmreoaxsiumraetedldyail1y..2.5B.laonodd4sahmopulrsesafwterrecach c6o.l9l.e1c5t.edaonnd D20a.ysOn-2D(apyred6o,sef,ivethaonuigmhaltshepeprrgortoocuopl wsetraetssatchratiftihceedp,raendodstchesalmivpelrewiasscorlelmeoctveeddofnrDoamyea+c1)h. animal and weighed. The right lateral lobe of the liver was collected from cach animal,weighed, and 188 000132 OannalDyazyed20f,ortphaelrmeimtaoyilniCnogAanoixmiadlassewearcteivsiatcyr.ifTicheed arenmdatihneiinglilvievresr tissue was also were collected collected and and weighed. weighed. RESULTS NOAEL (dose and effect): Greattehretlhoawenst42domsge/tkesg.tetdhbeahsiegdheosnt hdiogsheertehsteepda.ticApNalOmiEtLoyo!fC<o5A.0oxmigd/akseg:, activity was determined by the study author. L5.O0 AmgE/Lkg(,dboaseseadnodnehffiegchte)r: heGpraetaitcerpatlhmainto4y2]mCgo/kAeo,xtihdeasheigahcetsitvidtoysreeptoerstteedd. inAstLuOdyE. L of Toxic responsefeffects by dose level: All animals survived to scheduled sacrifice. No treatmentrelated clinical signs were observed in any groups 5.0 mk: higher hepatic palmitoy] CoA oxidase activity (24 1U/G compared to 5 U/G for controls) p1a4l.m0imtyo/ykle:CosAignoixfiidcaasnetlayctrievdiutyce(d39me1aUn/Gbocodmypwaeriegdhttoga$in1sU/duGrfionrgcdoonstrionlgs)period, higher hepatic 42.0 mykg: significantly reduced mean body weight gains during dosing period, higher hepatic palmitoyl CoA oxidase activity (39 U/G compared to $ IU/G for controls) `SSttaattiissttiiccaalllyrseisgunlitfsi:caTnhtecolmopwaerremdetaoncobnotdryolwse(ig=pht0g.a05i)n.s for the mid- and high-dose groups were dRoesmianrgkpse:rioTdh,otuhgehy sthheowmeidd-raencodvheriyghu-sduoaslelylewvietlhgirnotuhpesfeixshtib3idtaeydslaofwteerr dboosdiyngwewiagshtcogmapilnesteddu.rinTghtehe overall mean body weight gains were not significantly different between any groups. CONCLUSIONS "iTnhdeicaauttihoonrofstpaetredoxtihastobmaeseprdoloinfesriagtniiofni,caatntalilndcroesaeselsevienlsthteeslteevde,ltsohefnpaolemfiftecoty]leCveolAofoxTi-d6a6s6e9acitsilveistsy,tahann 5.0 mykg when administered to male Cr:CDR(SD)BR VAF/Plusirats for Sconsecutivedays. Remarks: The author palmitoyl CoA oxidase designated the no effect evel based on activity. However, enzyme induction significant increases may be transient and in in the the levels of absenceofother changes is not clearly indicativeof a toxic effect, therefore no LOAEL was determined by this study. REFERENCE Henwood. S. Madison, WI. 1997. 5 Daily Dose Laboratory Project Oral Toxicity Identification: Study CHW with T-6669 in 6329-197. 3M, Rats. Corning St. Paul. MN. Hazleton, Inc., 189 000193 REPEAT DOSE DATA Titles 28-DayOralToxicity Study with FC-143 in AlbinoMice: [BTNO. 532-10655 TEST SUBSTANCE Ipdeernftliutoyr:oocFtlaunoorataed,iPFFlOu,orFoCc-h1e1m6ic,aFlC-F1C2-61,43F,Ca-l1s6o9r,efFeCrr-e1d 403oar,saPsFaOmAajaomrmcoonmipuonmesnatlt,ofamFXm-o1n0i0u3m (octanoicacid,peniadecafluoro-, ammonium salt, CASRN 3825-26-1) T-1742CoC, Lot No. 269. Remarks: The purityof the test substance was not indicated. METHOD Method/guideline followed: Not stated Study durations 28 days GLP (VIN): N ear study performed: 1977 Species/strain: Charles River CD albino mice: Sex: maleand female Numberofanimals per dose group: 10 (5 males and $ females) Routeof administration: Dict - Purina rat chow Doses tested and frequency: 0, 30, 100, 300. 1000, 3000, 10000, 30000 ppm Post-observation period: None `Statistical methods used: A test was used to compare mean body weights, liver weights, and liver 0 body weight ratios among groups, but the type oftest was not noted. Rmeeamsaurrkesm:enDtasilwyeorbestearkvean.tioGnrsosfosrpbaethhaovlioogriaclerxeaacmtiinoanstioorn wmoarstaclointideusctweedrea mfaidnea.l saWceiefkicleyboondaylwseuirgvhitving mniecuet.ralIbuwfafsersetdatfeodrmthaaltin"aorrepfruetsuernetahtiisvteopsaetthoofloorgigcanexsamainndaottihoenr."tisHsuoewsevwears,roermgoavnesdexanadmipnreedsewrevrede innot Scpoencdifuicetde.dLoinvelrivweerisgfhrtosmaanlldslaicvreiftiocbedodmiycew.eiSgahmtplreatsioosfwveerrescaalncdulbatleodo.d wMeircerossecnotp0ic3eMxamfoirnaatnailoynsiwsa,s but the results. ifthe analyses were completeadr.e not included. 190 000194 RESULTS NOAEL (dose and effect): none; effects atalldoses. eLcOtoAsEisL: (cdyotsoeplaansdmiecffveacctu:ole3s0; pbiplme d(uhcetpaptroocleilfelrualtaironh;ypienrctrreoapsheyd:lhiveepratwoecieglhltu:lairncdreegaesneedraftiion1v0abnedo/doryr weight ratios; body weight los). Toxic responseleffects by dose level: 31000pppmp:m:[sienecrLeOasAeEdLl]iver weight; cyanosis; hepatocellular degeneration andor necrosis: bile duct p3r0o0lipfperma:tiomnu;schuelpaartocweelalkunlaershsy;perroturgohpehdy:fcurytcoypalnaossimsi;chleippaitdovcaecluloulleasr;dbegoednyerwaetiigohntalnosdsor necrosis; bile duct proliferation; body weight loss h1e0p0a0topcpelml:ulmarushcyuplearrtrwoepahkyn:ecsyst;oprloasumgichvfaucrsuoclyeasno(sbiesf;orheepdaetaotchelblyuldaaryde9g)eneration andor necrosis; 310000000pppmp:m:mumsucsuclualrarwweeaaknkensess:s;roruoguhgehdedfufrur(b(ebfeofroerededaetahthdduurriinnggwweaeckk1)1) 30000 ppm: muscular weakness: roughed fur before death duringweek 1) Statistical results: The following parameters were significantly different from controls at a level ofa leastp < 0.05): (A3)0Bpopdmy:wefiegmhatlelsosas:t week 4 100 ppm: males at weeks 1-4: femalesatweeks 2-4. 300 ppm: males at weeks 1-4; females at weeks 1-3 1000pp: males and females at week 1 (animalsdied after week 1) (B3)0Apbpsoml:utmeallievseranwdeifgehmtaliencsrease: 100 ppm: males and females `Not reported at other doses because mice died before day 28. (3)0Replpamt:ivfeelmiavleersweight increase: N1o0t0rpeppmo:rtemdaalteosther doses because mice died before day 28 Remarks: Body weight was suppressed in adose-related manner; increased amounts of food were c1o0n0s0upmpemd aalntdhohiugghherf:ooadllwmaaslteeswaansdalfseomaslceens.diedwithin the fist 9 daysoftesting. 300 ppm: all mice except | male died within 26 days of testing. S3h0oawnedd1e0n0laprpgmemteensttagnroduoprs:disocnoeloarnaitmiaolndoief|d ionrcmarchegirovuepr.loNbouleostihneradleaatnhismaolccsursraecdr.ifiGcerdosafsteprat2h8odlaoygsy. 191 000195 CONCLUSIONS No conclusions were given by the study authors. Rloesmsaesrkins:micAellfmedic3e0,fe1d00A,PoFr O30f0opstpwme.ighAt. doRsee-druecltaitoendspianttbeorndywawseisgehetn gianinthweedreeprfeoslsleodwebdobdyywweeiigghhtts. Relative and absolute liverweights were increased in mic fed 30 ppm or more APFO. Gross. cphatahnogleosgiwcearleexoabmsienravtedioinn otfhkeidlinveeryssaomroontghearllorAgPaFnsObterseiadteesd lainviemrsaliss niontclduidsicnusgseedn.laTrrgeeametnmtenatndr/eolrated discoloration of 1 ormore liver lobes. Histopathologic examination of all APFO treated mice revealed daicfcfoumsepacnyiteopdlbaysmfioccaelnltoarmguelmteinftocoalf cheyptaotpolcaystmeisc tvharcououlgehso.utDtehgeelnievreart(ipoannlaonbdulfaorr nheycpreorstirsoopfhyh)epatocytes. and focal bile duct proliferation was also noted inmicewithin all groups. REFERENCE ChristopherB,. andMarias, AJ. 1977. 28-Day Oral Toxicity Study with FC-143 in Albino Mice, Final Report. Industrial Bio-Test Laboratoriensc,. Study No. $532-106535M,ReferenceNo, T-1742CoC, Lot 209. 192 000196 REPEAT DOSE DATA Title: 28-Day Oral Toxicity Study with FC-143 in Albino Rats TEST SUBSTANCE Identity: Fluorad FluorochemicalFC-143,also referred to as PFOA ammonium salt, ammonium perluorooctanoate, PFO, FC-116, FC-126, FC-169, FC-143, or as a major componentofFX-1003 (To-c1t7a4no2iCc0Cac,idL,optenNot.ade2c69a.fluoro-, ammonium salt, CASRN 3825-26-1). Remarks: Purity of the test substance was not indicated METHOD Methodguideline followed: Not stated Study durations28 days GLP (VIN:N Year study performed: 1977 Species/strain: CharlesRiver CD albino rats Sex: male and female: Numbeorf animals per dose group: 10 (5 males and $ females) Route of administration: Dict - Purina at chow Doses tested and frequency: 0, 30, 100, 300, 1000, 3000, 10000, 30000 ppm Post-observation period: None Statistical methods used: body weight ratios among A test was groups, but used to compare mean body weights, the ype of test was not specified. liver weights, and live to Remarks: Animals were observed daily for clinical signs of toxicity. consumption were determined weekly. Liver weights,bodyweights, Body weight and and iver weight to food body weight ratios were determined a terminal sacrifice. Gross pathological examination was conducted on all scuormvpilveitneg sractt.@ o10f istisstsauteesd atnhdat otrhgeasntsuwdyerienecxlaumdienadedc.ombputletthee examination specific list ofgross pathology and Aa s not supplied. Liverswere wlieviegrsheadndtobldoeotderwmeirnee sreelnattitove3oMrgfaonr waeniaglyhstist,hebnutsttahieneredsuflotrs,hiisfttohpeaathnoalloygsiecs ewxearmeincaotmipolne.teSda,maprleensotof included. 193 000197 RESULTS NOAEL (dose and effect): none; effects observed at lowest test dose: LOAEL (dose and effect): 30ppm(increased liver weight and hepatocyte hypertrophy) Toxic responseleffects by dose level: All animals given 10000or 30000 ppm did within the first week of testing. There were no premature deaths or other clinical signs of toxicity in the other groups. Males 1.300 ppm showed slightly reduced body weight gains. Body weight gains among animals fed 1000 ppm. oartsmofredecwietrheer1si0g0ni0foircan3t0l0y0repdpumc.edTrineaatmdeonste--rdeelpaetneddenmtormpahnonleorg.icRcehdauncgeeds finootdheinftiavekre wwearseeovbisdeenrtveadmong. `among all male and female test animals. The primary lesion consistedoffocal to multifocal cytoplasmic emnulltairfgoecmaelntto(dhiyfpfeurstereonplhayr)goefmheenptatofochyetpeastoacmytoensgwaansimsaelesn ianmtoenstggarnoiumpasl0s. i3n0,teastngdr1o0u0psp3p0m0,an1d000, and 3000 ppm Statistical results: Differences in body weight between the control and treatment groups were mSaatliesstiactal3l0y0sipgpnimfiacnadntiant f1e0m0a0leasnadt 31000000 papnmd. 30A0b0soplpumt.e lRievlerawtievieghlitvsewrewreeigshitgnwiafiscasnitglnyifiicnacnrtelaysed for increased for males at 3000 ppm. Rbeesmiadersksli:verGs.rosTshepamtahoilnogeiffceacltewxaasmfdoicadlnotot mruelvteiaflocraelaicmyetnotp-lraeslmaitcedeneflfaercgtesmienntkoifdnheeypsatoorcoyttheers oarmgoanngs. animals fed 300 ppm. In animals fed 1000 ppm or more the effect was multifocal to diffuse enlargement of iepatocytes. The severitdegreeoftissue involvement of these lesions was more pronounced in male cteosnttraonlimsaolns.ly bAbescoaluusteeoflivbeordwyeiwgehitgshtinrmedaulcstioain 1n00t0heahnidgh3e0r0d0ospep. manairmeanlso.t significantly different than CONCLUSIONS "The authors gave no conclusion. wReeimgahrtkgsa:insAlwlearneimraeldsuciendtihe t1h0e,g0r0o0uapnsdr3e0c,ei0v0i0ngpp1m00g0roorupmsordeiepdpbme.forReedthueceedndfoofodthientfairkset wwaeesk.obsBeordveyd in rats fed1000 ppm or higher in adose-related manner. Relative liver weights were increased in males fed 30 ppm or more and females fed 300 ppm or more. Treatment-relatedchangeswere observed in the livers among all APFO treated animals. The severity of effects was more pronounced in male test animals SFERENCE Merrick, M. and Marias. A.J. 1977. 28-Day Oral Toxicity Study with FC-143 in Albino Rats, Final Report. Industrial Bio-Test Laboratories, Inc. Study No. $532-106534M, Reference No. T-1742CoC. Lot 269, September 29, 1977. 194 000198 REPEAT DOSE DATA "Title: Ninety-Day Subacute Rhesus Monkey Tosicity Study TEST SUBSTANCE Identity: Fluorad Fluorochemical FC-143, alsoreferredtoas PFOA ammonium salt, ammonium p(oecrtfalnuooireooacctiadn.opateen,iaPdFeOc,afFiCuo-r1o1-6,amFCm-o1n2i6,umFCs-al1t6,9C,AFSC-R1N433,82o5ra-2s6a-1m)ajor componentof FX-1003 MRNe.maTrhkes:lotThneumtbesetrsoubfsEtCa-n1ce43usuesdedininthtisisstsutduydywawsasob3t4a0i.neTdhefrtoemsttshuebsstpaonncseorw,a3sM.awChoimtpeapnoyw,deSrt.. Paul, METHOD Methodguideline followed: Not stated Study duration: 90-day GLP (VIN): No ear study performed: 1978 Species/strain: Rhesus monkey Sex: Male and female Numberof animals per dose group: Twopersexper group Routeof administration: Oral gavage Doses tested and frequency: 0 (control group), 3, 10, 30, and100 mg/kg/day. 7 days/week, f9o0 darys Post-abservation period: None Statistical methods used: Al statistical analyses compared the treatment groupswith the control group, by sex. The tests were compared by analysisofvariance (one-way classification), Bartlet' test for h(1o9m6o0g)enuesiitnyg Daunndnetthet'asppmruolptriipalteect-otmepsatr(ifsoorncqtuaablleosr0unjeuqdugaelsviagnriifaicnacnecsaeos)fddiefsfcerriebnecdesb.y Steel and Torrie Remarks: Ten male rhesus monkeys (2.60- 3.90 kg) and 10 female rhesus morikeys (2.95- 3.80 ke) cwaegreesuasnedd mianitnhtiasisnteuddy.inTahteemmpoenrkateuyrse,wehrumeihdiotuys,edanidndliivgihdtucaolnltyrionllheadnegnivnigrwoinrmeenmte.shP,ur"isnqauMeeozneketyypeC"how was fed twice/day and fresh apples were fod 3 times/aveek. Water was available ad libitum. Prior test substance administration, thestaffveterinarian conductead complet physical examination. Only w`maosnkaedymisniinstgeoroedd hbeyalgtahvwaegreeastaelfecrteeqduefnocrytohfe7studday.ysT/hweeetkesftocr9om0pdoauynsd.,Alslusdpoesnedsewdienre0.gi5v%enMiinetahococneslta,nt vdoolsuemsew.arTehebassaemdeuvpoolnutmheeobfo0d.y5w%eiMgehtthsoocbetlainwedaswegeikvleyn.tTohtehemvoenhkicelyescwonetrreolobgsreourpv.edintdwiivciedudaalildyaifolry 195 000199 cgeonnedruacltepdhyisnictahleacpopnetraorlanpceer,iobdehaanvdiomro,natnhdlypdhuarrimnagcotthoexsitcudsyi.gnsB.loGoednearnadl uprhiynseicsaalmpelxeasmwinearteioonbstawienreed for `analysis from all monkeys once during the control period, then again | and 3 months afer study initiation. w`AifttherSecronmypllaent'i0on(oPfhtenhceyctelsitdisnuebsHtCaIn)c,e eadxmsiannigsutirnaattieodn, paenrdionde.cralolpssiuerdv.ivAitngnemcornokpesyy.stwheerheeaarn,estlihveert,ized adrenals, spleen, pituitary. kidneys, tostes/ovarics, and brain were weighed: representative tissues were cwoalslewceteidghiendbuafffteerefdixnateiuotnr.al H1i0st%opfaortmhaollion,gyEwyaesspweerrfeorfmixeeddoinn Rthuesfsoelll'owfiinxgatoivreg.anTshefrtohmyraollidm/opanrkaetyhysroinid cthoerocnoanrtryovlesasnedlst),readtumoednetngurmo,upisl:euamd,rejneajlus,nuamo,rtcae,cbuomn,e,cobrlaoinn,,reccstoupmh,agkuisd.neeyyse,s.ligvaelr,lblluandgd,ers,kihne,art (with mesenteric lymph node, retropharyngeal lymph node, mammary gland. nerve (with muscle), spleen, pancreas, prostate/uterus, rib junction (bone marrow), salivary gland, lumbar spinal cord, pituitary, iSdteonmtaicfhy,intgesttaetst/ooov,araincds,antyhyrtosisdu,esp(asr)atwhiytrhoildes,iotnhsy.muHsi,sttroapcahtehao,ltoognysiwlastopngeuref,orumreidnaoryn btlhaeddfeorl.lovwaignignao,rgans. aflrlobmlaaidldemro,nkheeayrst i(nwitthehccoonrtornoalraynvdestsreelast)m.ednutogdreonupusm:,aidlreeunma,lsj.ejduonrutm,,bconeec,umb,raicno.lone,sorpehcatguums,,keiydense.ys. liver, lung. skin, mesenteric lymph node, retropharyngeal lymph node, mammary gland, nerve (with muscle). spleen, pancreas, prostatc/uters, ibjunction (bone marrow). salivary land, lumbar spinal cord, pViatguiintaa.ry.idsetnotimfaycihn,g tteatsttoeos,/oavnadriasn,ytthiysrsouieds,(sp)arwaitthhyrloeisdio,nst.hymus, trachea, tonsil, tongue,urinary bladder, RESULTS fNrOotAhyEeLme(sdiossewearnedoecfcfaescti)o:nal0l(ycoonbtsreorlv)eadnadt3bomtkhgof/tdheasye--doSosfatgestloeovle,lsm.oderate to marked diarrhea, and aLdOreAnaElsL, (bdoonseemaanrdroewff,ecstp)l:ee3n,0amnyd/lkygm/pdhanyod--eCs,lianndisdciegaantlshosf.toxicity, adverse histologic changes in the Tleovxelisc. rTehsrpcoensmeo/enfkfeeycstsibnythdeo3s0e lmegv/ekl:g/Tdhaeyrdeowsaasgengormoourpt.aalintdyaalltt4hemo0n,3k,eyasndin10thmeg1/0k0g/mdga/ykgd/odsaaygedosage. roup, died during tis study. 3 mg/kg/daySoft stool and/or moderate to marked diahea, frothy emesis were noted at this dosage level 10 mg/kg/day The following symptoms were noted in one monkey: anorexia during week 4, pale and swollen faceduring week 7. and black stools during week 12. 30 mykgday- Three monkeys died during weeks 7. 12, and 13 of the study. From week 4, sthoemseet3immeosnskeevyerse,wedreecraenaosreexdiacc.tiAviltly.4 mInoandkdeityisoni,ntshwiosllgernoufpacse,hoewyeesd,salnidghtvutlovam,odaesrwaetlel, aasndpallor ofthe face and gums were noted inall 4 monkeys. Other sympioms observed insome/all monkeys included the following: emesis, ataxia, black stools, dehydration, ptosisof the eyelids, and lossofbody weight. The surviving male had dpleactreleeatss.odPnruomtbhreormsobfinertyitmheroacnydteasct,ivdaetcerdeapsreodthhreommobgilnobtiinm,e dweecrteeaaslesd ihnecmraetaoscerdi.t,Tahnedseininccrreeaasseeds awlekraelianpepaprheonstpahata| smeolnetvhelbsuattwoenreemmouncthh (m3o6r5evmsa$r9k7edinatthtehrceoentmroonlt)hsw.hicThhepreerwsiassteda ndectrheeaosnee:in surviving male (360 vs 851 IU/L in the control) at 3 months. SGOT levels were reduced at one 19 000200 month (59 vs 29 IU in the control) and in the ane surviving male at 3 months (88 vs 45 1U/1 in the (46 control). SGPT was elevated at v5 31 101 in the control group). | month (44 vsa control value of Cholesteroli the ane surviving m1a5l1eU/w1a)sanedleavtat3edmo(n2t4h0svs a16c5onmtrgo/l10le0vemlio).f $To2t1al2/pr1o0t0eimniaannddatlotbalumailnbuinmithniswaansim2a.l00wversae rceodnutcreodl:letvoetlalopfrot4e.8i2n/w1a0s05m.5l2 vs mDaulreinagntdhefepmaatlheolmoognikcaelyss:tudmieasr,ktehdefolilplidowdienplgetcioomnpooufntdh-ereadlraetneadlss,ysmlipgthotmtso mwoedreeraotbes.erved in ypocellularity of the bone marrow, and moderate atrophy oflymphoid follicles of the spleen and Iymph nodes. 100 mgkg/day-- All monkeys from the 100 mg/kg/day dosage level died during weeks 2- 5 of mthoenskteuydys.doIsn eadddi3t0onm,g/tkhgedmayo.nkHeoywseiverth,isthgerosuipgnss hoofwtoexdictihteysoabmseersviegndsionfthteoxi1c0i0tymgas/ktghe/day adcotsiavigtey.grproousptr(aatnioorne,xbiao.dyfrwotehiyghetmelsoisss,,apnadlebfoadcye,tpraelmeblgiunmgs),aspwpoelalreend feaacreliaerndineythees,stduedcyretahsaendwas observed in the 30 mg/kg/day dosage group. During the pathological studies, the following compound related symptoms were observed in male and female monkeys: marked diffuse lipid daetprloepthiyoonfofltyhmephaodirednaflosl,liscilgehotfttohemosdpelreaenteanhdypolcyemlplhulanroidteysof the bone marrow, and moderate Statistical results: There were statistically significant decreases in body weight for the male monkeys at the 30 mg/kg/day dosage level during week 13ofthe study. The female monkeys of the 30 mg/kg/day dStoastaisgteiclaelvleylsaingndiftihceanmtonvakreiyatsioofnsthines1e0x0-gmrgo/ukpg/mdeaayndwoesiagghetsleoveflawfeerweaolrrgeaandsyocdceuardreadt btheitswteimeen. the control and experimental groups. The statistically significant variations were the following: decreased absolute and relative heart weight for females in the 10 mg/kg/day dosage group (p = 0.05, p< 0.01. raensdpeicntcirveealsye)d, dreelcarteiavseepditaubistoalruytweebirgahitnfwoerimgahltefsorinftehmeal3esmyi/nktgh/eda10y mdgo/skagg/edgay rdo(soapg<eu0g.r0po5)u.p T(phe<s0e.01), variations wereof unknown biological significance and were not accompanied by morphologic alterations. Remarks: Following one month of treatment, glucose was significantly elevated in the 3 mg/kg/day group (117 vs 89 mg/100 ml in the control). The authorsofthe report atribut this t0.a single high value for mal #7366 who had a value of131. The other three monkeys in th3e mu/ke/day group had levels of m1u12/,101005,mia,nrdes1p2e0ctmivee/l1y0.0afmtle.r aGnleucmoosnethleovfeltsreianttmehnet.10Aatndth3e0emme/koe/dnoafyttgrreaohtumpessnwte.rgelu1c0o4seanldeve1l2s2were 81.96. 58. and 66 mg/ 100 ml in the control. 3, 10 and 30 mg/kg/day groups respectively. SGPT was e"Tlheevraetewdrien tnhoe t1r0eaatnmden3t0rmeluakteed/dcahayndgoesseingruoruinpaslyatsis| msotundtihe,s batutanwyerteimceompperairoadblsteudtioedc.ontrol at 3 months. 197 000201 CONCLUSIONS "The test substance caused elinical signsof toxicity, adverse histologic changes in the adrenals, bone marrow, spicen, and lymph nodes, and deaths in male and female thesus monkeys when administered at dosage levelsof30 and 100 mg/day. Remarks: The test substance was not sufficiently characterized. REFERENCE 3M Company, International Rescarch andDevelopment Corporation. 1978. Ninety-Day Subacute Rhesus. Monkey Toxicity Study. Laboratory study number 137-090. 198 000202 REPEAT DOSE DATA "Tithe: Ninety Day Subacute Rat Toxicity Study TEST SUBSTANCE pIdeernltuiotryo:oFctiaunooraatde,FlPuFoOr.ocFhCe-m1i1c6a,lFFCC--114236., AFlCs-o16r9.efeFCr-e1d43t.aosrPasFaOAmaajomrmcoonmipuomnseanltt,oafmFmXo-n1i0u0m3 {octane acid. pentadecaffuoro- ammoniumsalt, CASRN 325-26-1) Rinedmicaartekds.: White powder, 3M stock no. 98-0211-0008-0 Lot 40; purity of the fst substan was not METHOD Methodiguideline followed: No guideline number sad Study duration: 90 days GLP (VIN): No Year study performed: 1977.7 Speciesstrain: Charles River CD rat Sex: Male and female Number of animals per dose group: S animalssex/group Route of administration: Dictary Doses tested and frequency: 0, 10, 30. 100, 300, and 1,000ppm Posttreatment observation period: None Srtaotiustwicaasl pmetehodrs ubsfyeda:noalSytasrtiissotmifcavlaearniaadlnycseis(ocnoem-pwaayr)i,ngBarlelseuts'sofetstefroreaommeongtegnrcoiuypsowfivharithaencceosnatnodl sheiagppnropirifostfiedciifsafetrne(ncfcoeres.qualorunequal variance) sing Dunes multiple comparison table to judge mRaemlasrwkass: 2I2n2it-i2al54aggneodf thteheeisntitaanlimwaeilgshwtaosftnhoet gfievmena;leshowwaesve1r5,1h-1e70meganThienietsalt bcohdemyiwceailgwhtasoftmihxeed WToixtihciSty00agndoffofremeodrtaatliwteye.klIyndinitveirdvualasl.boTdhyewreaitghetdsawerne riewceomrredeoadbwsleeerkvlsey.d twBilcoeoddaainldyufroirncelsinaimcapllesisgnwseroef bcioolchleemitstprryio,rutroisntuadlyynsaasnt,disoenruamnsdamatpl1 easn.dF3oomodnctohnssuomfprteitonmewnatstoreccvoradleuda.teAhte9ma0todalyosg.y,theanimals p`weerrfeosramcerdifoincedthaenfdolnleoswrionpgsoirdgafonrs mfarcormosrcatospifcroamndthmeiccornotsroclo.pi1c00e,xa3m0i0n.atainodn.1.0H0i0stpoppmathdoolsoegygrwoausps: abrdariennawli.thTucnegr,vihcealarcowridt.hlcuomrboanrarsypivnaelssceolr,d,aopretrai,phspelreaeln,nermvees,eneteersi.cpiltyumitpahryo,dhey,rotihdymwuist,h bpoarnaethwyirtohid. 199 000203 Kniadrnreoyws,(usrtienranruym)b,lasdadleirv,areystgelsa,ndo,vasrmiaelsl, ipnrtoessttaitnee,stduuosd,enskuimn,(jmeajumnmuam,rylgulamnd)),coalnony,spsaunec(rse)asw,itfihvegrr,oss JVeiseironss.amLpilveesrsfformomalaltdsosferogmrotuhpes1w0earnedf3r0ozpenpmanddosseentgrtooutphsewseproensaolrsfoo exaanmailnycsidsmicroscopically and RESULTS NMaOleAs:EL30 ppm Females: 300 ppm LMaOleAs:EL100 ppm decrease in food consumption, lve lesions) Females: 1,000 ppm (live lesions, increased liver weight) RTheemsaerkdsea:thOsnweerfeemnaoltecionnstihdeer1e0d0 faobndeontrceaftemmeanlterienlatthede.30A0llpopthmergraonuipmadliscdsduurrviivnegdcoulnlelctsicohnoedfublleodod sacrifice iTnhtehree cwoanstaolsiggrnoiufpi)c.antForeodducctoinosnuminptmieoannwbaosdyrewdeuicgehdtiinnmmaalleessiinntthhee11000,0030p0pamngdr1o0u0p0 (p3p6m2gvro5u4ps6,6but he differences were not statistically significant eMnadleosf itnhethterc3a0t,me1n00t, pe3r0io0d.andTh1e.0v0a0lpuepsmwegrroeu7p.s95h,ad7s.0i5n.i7.1c6a,nt6l.y72r,eadnudc6e.d9n4umibn etrhse ocofnterroylt,hr3o0c.yt1e0s0,at30th0e aonsde1g0r0o0uppsp,mbugtrwouepr,e srteastpiesctticiavlellyy.sigMnaifliecsanhtaadtrtehedu3c0e0d pTepumkogcryotuevpaolnuye:scloeumkpoacryetedvtaoltuheescwoenrteo1l0.i64a,ll Si5mi8l,a9r.3p3h.e9n.o3m5,en7o.6n3,waansdse8e.n06wiitnhthheeomongtleolb,in10v,a3l0u,es10w0hi,c3h00wearned r1e.d0u0c0epdpast aglroduopsse, erevsepelctbiuvtelwy.ereA {Sihgenciofnitcraonlt, a10h,e301,0p10p0,md3o00seanldev1el00o0nlyp.pmHegrmoougplso,brienspvecatliuveeslyw.erTehe1r6.e2w,a1s4n.7o, 1s5i.m0i.la1r5.e4f,fe1t4p9,on13.t1hein hematological parametes of female rts i the study. `Mwaelreessaattstthieca3l0l,y1s0i0g,ni3f0i0c,anatnad a1.l0b0u0tptphem 1d0o0seplpemvedlsohsadlevienl.creRaespeodrgtleudcgolsuecolesveellsve(lmsgw/e1r00e m1i2)1.wh1i2c0h. l1e3v6e,ls13w4e,re14e3leavnadte1d3i5nmmga/l1es00atmtihefo1r0t0h.e300,0.10a.n3d011.0000,03p0p0madndos1.l0e0v0elps,pmegarnouvpasl,uerseaspst9i0vedlayy.s wBeUreN. i2h0e.4c,on2t3r.o9lsa.ndAl3k5a.1linme/p1h0o0spmhlatfaosretwheasthcrleevadtoesd ignromuaplse,srienstpehceti1v0e0l,y,30c0o,mpaandre1d.0t0o01p6.p2mmggr/o1u0p0s;mtlhefor Cloenvetlrsasw.erFee1m4a7l,es20s4haonwded21n2o 1siUm/ilfaorrcthhaentgherseigrboiuopchsermeiscpaelctmievealsyu.recmoemnptasr.ed 10 104 1L/1 for the Nfeeimtahleersmraolemsanllorgrfoeumpaslesshsohwoewedadhaingyhetrrefartemqeunetncryeolaftoecdccuhlatngbelosoidn uirnitnhaelyusriisnepatrhaamnedtiedrsmaalletsh.ough eTnhlearogneldy vgreorsss cwhriocphssyhoowbesdcvvaatriyoinngwadesgrneoetseodifnsumrafalcseadtitschoelo1r,a0t0io0n.ppNeidtohseer efveemla,leTshersoemantihmea1l.s00h0ad pom dose lov nos male or females from he lower dose levels showed such efecs. 200 000204 pBoptmhgarbosuoplsutaenadndinroenlaetifveemlailveerinwetihgeht1s,0w0e0rpepsmiggnriofuipc.antCloympinocurneda-sreedliantmeadlevserinltehseio3n0s,o3c0c0urarnedd 1i,0a0l0l mtoalsleigrhattshiynpetrhetr1o0p0h.yo3f00heapndat1o,c00y0tpeinpsmcegnrtoruiplso.buTlharesteo mliedsizoonnsaclonrseigsitoendsofoffotchealaftfoecmtueldtilfiovcearll,obvuelreys.sliIgnht some instances these lesions were accompanied by increased amount of yellowish-brown pigment reisnceimdbelnicneglainpdosfeuvsecriitnyionftthheeclyetsoipolnsaswmasofhmeopractopcryotneosunacneddoacmcaosnigonmalallyeirnatssinautstohieda1l,0l0i0nipngpcmaldlsi.etTahrye level, CONCLUSIONS The test substance resulted in a significant eduction in mean body weight in males at 1000 ppm, a sTiegsniiofniscianntmeadluecstaiton10i0n, t3h0e0nandu10om0f0eprbpymt.herocyrtes in males at 30, 100. 300 and 1000 ppm, and liver REFERENCE Goldenthal, E., D. Jessup. R. Geil, N. Jefforson, and R. Acco. 1978. Ninety day subacute toxicity study: Fluorad Fluorochemical FC-143. 3M Company. Study no. 137-089. 201 000205 REPEAT DOSE DATA "Tithe: 13-Week Dietary Toxicity Study with T5150, Ammonium Perfluorooctanoate. (CAS No. 3825-26-1) in Male Rats TEST SUBSTANCE Identity: T-5150, Ammoniumperfluorooctanoate (APFO), CASNo. 3825-2L6o-t1No,. 115. Iisa lightly colored powder. Remarks: Purity of the test substance was not indicated. METHOD Method/guideline followed: Guideline 82-1 (source not specified). The study was conducted in compliance with Hazleton Wisconsin, nc. (HW) protocol TP9321 dated November 30, 1990. Study duration: 13weeks GLP (VIN): ear study performed: 1993 Species/strain: RavSprague-Dawley. Cri:CDEBR Sex: Male Numberof animals per dose group: 55 in cach group, except pair-fed controls, which had 45 animals Routeof administration: Dietary Doses tested and frequency: 0 (pair-fed and nonpair-fed controls), 1, 10, 30, or 100 ppm (approximate man compound consumption at week 13 of 0.05, 0.47, 1.44, and 4.97 mg/kg/day) fed ad libitum. Fifteen eaxnciempatlspapierr-fgerdocuopntwreorles)sawcerriefiscaecdraitfi4c,ed7,aafntdr 1133 wweeeekkss.ofTthreeartemmeanitnianngd10waneiemkaslwsitpheorug!rtoruepat(maelntg.roups Posttreatment observation period: wecks `Statistical methods used: Levenc'stest was used totest forvariance homogeneity. Incasesof hpeetrefroorgmeendeiotnyotfhveahroimaongceenaetopusor0.t0r5a,ntsrfaonrsfmoerdmadtaitoan.s1wfetrhee uAsNedOtVoAstawbaislisziegtnhifeivcaarnita,nGcea.meAsNaOndVAHowwealsl Modified Tukey-Kramer test was usedfor pairwise comparisons between groups. One-way ANOVA was hsoerdmotoneanvaallyuzees,boordgyanwewieghitgsh,s.cuomruglaanti-voe-bbooddyywweeiigghhttpgearicnesn,tafgoeosd,caonndsourmgpaino-n10,-bclrianiincawlecihgehrtnisraitriyo.s. B(eoxdcyepwtepigahit-sf,edcucmountlraotlisv)eubsoindgy twheeiSghAtSgapirnosg.raanmd afcocoodrdcionngsutompHtWiIon mveatlhuoedss.werGeroaunaplcyozmepdafroirsaolnlsgrwoeurpes et0v.a1l,u1a0t.e.d30a,t tahned5.0%1t00wop-ptmaAiPleFdOpwreorbaebciloimtpyalreevedl.toItnhethceonatnraollysainsiomfatlhsei datthae, naonnipmaailrs-fiendggrroouupps.ewxhpiolseed the data from the pair-fed control animals were compared to animals exposed to 100 ppm APFO. 202 000206 Remarks: Male rats were usedto characterize theeffectsofthe fest substance on testicular physiology. At study initiation, the animals were approximately 41 daysold and weighed 181 10 229 g. The alipbpirtoupmri1a0tethaemaonuimnatlso.f tChoenttersotlsugbrsotuapnscoefwpaasirt-hfoerdoaungdhlnyonmpiaxieed-wfeidthrartosdweenrtecmhaoiwntbaeifnoerdeopnrovibadsianlgdiitcatd ndiocttcaroyntcaoinncienngtrtahteitoensotfsutbhsetatnecset.subAlsltadniccet;stwheerreeafatsesra,yweedewkeleykalnyalfyosretshewefirrestpfeorufrowremeekdson(0tdheetceornmtirnoel dtiheet and one test diet, selected sequentially. Throughout the study, animals were obscrved twice daily for signsoftoxicity. Individual body weight data were recorded on the firs day, weekly thereafler, and on the dayof necropsy. Food consumption cdaotlalewcteerdefcroolml1ec0teadndiamiallysf/ogrrpoiurp-afteedagcrhosucphseadnuldewdseaeckrliyfifcoerwneornpeaairn-afleydzegdrofuoprs.estSraedrioulm, ostaamlples taensdtossutbecrountea,neloutuesinaidziipnogsheotrimsosnueesw,eraendcotlelsetcmtaetderfiraolmcconatcehnta.niAmtalnaecnrdopfsroyz.esnafmoprlpeossosfibvleerte,sttemsattees,rilaulngs, raensiimdaules/angarloyuspisa.t aAcshecstcihoendouflleidvesracwraifsicoebitahienleidvefrrwoamsalalsasnaiymeadlsfoarttchaeclhevseclhoefduplaeldmistaocryi!fiCceo.A Foxoird5ase as an indicator of peroxisome proliferation. Fifteenanimalsgroup were necropsicd aftr 4, 7, and 13 weeks oefxarmcianmaetinotn,saisnwcelluldeadst1h0e aexntiemranlasl/gsurrofuapceaotfttheheenbdoodfyt,haell8o-riwfieckes,retchoevcerraynipaelricoadv.ityT,thheemeaxctreorsncaolpic: Surfacesofthebrainand spinal cord, the nasal cavity and paranasal sinuses, and the thoracic, abdominal, aprnodstpateel.viccocaagvuiltaitesinagngdlavinsdc,eruar.ethTrhae) wbrearien,weiivgerh,edl.ungOsr,geasnt-etso,-abnoddyacwceeisgshotrypesrecxenotraggaenssa(nsdemoirngaaln-vteos-icle. brain weight ratios were calculated. The following were examined microscopically (when presen): leevsailounast,ebtriasisnu,eslivferro,mhutnhges,brtaeisnt,esl.ivaenr,dlaucncgess,stoersytess,exanordgaancsc.essEolreyctsreoxnomrigcanrso.scopy was also used to RESULTS NOAEL (dose and effect): 1.0 ppm LO(doAseanEdeffL ect: 10 ppm 4Todxuiectroesspeovnesrcelneefcfkectsosrebsy,dboutsealleovtelh:erOanneimaanlismsaulravtivtehde u1n0ti0lpspcmheddousleedlesvacerlifwiaces. saNcroifcilciendicdalursiinggnswoefek toxicity were observed in any groups during treatment of recovery. 10 ppm --higher hepatic palmitoyl CoA oxidase activity, decreased mean body weight gains. increased absolute and relative iver weights, and hepatocellular hypertrophy 30 ppm -- higher hepatic palmitoy] CoA oxidase activity, decreased mean body weight gains, increased absolute and relative iver weights. and hepatocellular hypertrophy h1i0g0heprphme--patilcopwaelrmibtoodyy]wCeoigAhtosxiadnadsecuamcutilvaittiy,veinbcordeyaswedeiagbhstolguatiensa,nldowreelratfiovoedlicvoenrswuemipgthitos.n, hepatocellular hypertrophy, and elevated estradiol levels Sctuamtuilsatticiavlerbeosudlytsw:eiHgihgthgadionssecaonmipmaalrsedextohtibhiotseed coofnstihestneonntplayisri-gfneidfigcraonutpl.y lTohweery balosdoycwoenisguhtmsedand s1i0g0nipfipcmanetxlhyilbeistsefdohoidghtehranhetphaetniconppaalimrit-oeyd]cConotArolosxiadtawseeeakcstiv1itaineds 2t.hatAwneirmealsstaattisdtoicsaelllyevseilgsnioffic3a0ntaantd 203 VL0207 twheaetkwsas5,s8a,taisntdic1a4l.y Asniginmiaflicsanftedat1w0epepkm5.haAdbstroalnustieenatnlydhrieglhateirvehelpiavteircwpeiagmhittsoyw]erCesoiAgnoixfiidcaanstelaycthiivgihteyr in the animalsofthe high dose group than the pair-fed controls at wecks 4, 7, and 13. Rreepmoarirckdsd:urTihngoutgrehasttmaetnistt,icnalolydisfifgenriefnicceanwtasinscereenasaesftirn thheepat-iwcepcaklmrietcooyv]erCyopAeriooxdi.dasTehaectefifveictteswawserdeosedweepreenodbesnetrvaendd rienvaenrismibale.feIdncr1e0,as3e0d.aobrso1l0u0teppamn:d areblsaotliuvteelaivnedr wreeliagthitves lainvderhweepaitgohcselwluelraershiygpneirftircoapnhtyl.y hpriogghreersisniotnheofahneipmaatlosoceflltuhlearhihgyhpedrotsreogprhoyudpidthnaonttahpeppeaairr-ofebdecoanftfreocltsedatbywetehkesle4n,g7thaonfdtr13e.atmTehnte, The acshsaoncgieastoebdsweirtvhepdearoexissuogmegeprsoltioifefvraetitoens.t mTatheerriealwacsecnto oevnidinetnrcaeceolfluilnarcrmeeatseadbolliivesrmwaenidghmtasoyfbeanimals eaxfheirbittheedrceocnosviesrtyenptelryiosdi,gnwihfiiccahntilyndliocwaert bthoadlythweeifgfhecstsanwdarceumruelveartsiivblee.bodAyniwmeailgshtingtahiensitghhandtohsoesegroofup atthewenoenkpsai1r-afnedd2.conOtvreorlalglr,ounpo. sTighneifyicaalnstodciofnfsruemnecedisnigmneifaincanftoloydlceosnssfuomopdttihoannbtehtewneoennpaniorn-pfaeidr-cfonetdraonlsd phaei-hfiegdh gdroosuepasnwimaaslsnoatpedp.earTehdoutoghbetheelreevawtaesd natowteieskt5i. cal significant difference, the estradiol levels in CONCLUSIONS "wThheenstfueddyaadutlhboirrcuomn1c0luadtesdfotrhaatttlheeansoto1b3sweerevkesdwaadsve1r0s0e epfpfmecanldevetlha(tNthOeAnEoLo)bsfoerrvtehed teefsftestublsetvaelnce (NOEL) was 1.0 ppm. nReamyabreksc:onsIindearneidmaaldsvefresde,10i,nc30l,udainndg i1n0c0rpepasme,d atbhseorleuptoertanddesrcerliabteisvetIrcvaetrmweenitg-hrtesl,tehdeplaitvoecreelflfuelcatrs that hfyinpdeirntgrso.phthye. LanOdAsEiLgniwfaicsan1t0lyppinmcraenadsetdheheNpaOtiAcEpLalwmaitsoy1l.0CpopAm.oxidase activities. On the basisofthese REFERENCE NPoa.laz3z8o2l6o-.1)M.in 1m9a9l3e.rat1s3.-WHeaezkledtiocntaWriysctooxnisciinty,sItncu.dyMwaidtihsoTn-,S1W8I0., a3mMmoCnoimpuamnype.rflSuto.rPoaouelt,aMnoNa.te (CAS 204 000208 REPEAT DOSE DATA Title: Two Year Oral (Diet)ToxicityCarcinogenicity Study ofFluorochemical FC-143 in Rats TEST SUBSTANCE Identity: Fluorad Fluorochemical FC-143, also referred to as PFOA ammonium salt, ammonium p(oecrtfalnuooircooacctiadn,capteen,taPdEecOa,ftFuCo-r1o-1,6.amFCm-o1n2i6,umFCsa-l1t6,9C,AFSCR-N14383o2r,5-a26sa-1m)ajor component of FX-1003 aRpepmraorxkimsa:teTlhyeotnesetyseuabrsrtaonmceta,hewshtiatte opfotwhdeers,tuwday,s aanndalaytztehde pterrimoinrattihoenosafrtthoeftdhoesisntgudpye,riaofd.terNo dtheetemcataibnlebocdhyanogfesthweesrteudfyournepdo.rt.The composition and purity of the test substance were not indicated in METHOD Methodguideline followed: Guideline number not stated Study duration: Two years GLP (VIN: Yes Year study performed: 1981 - 1983 Species/strain: Sprague-Dawley rat Cr: COBS" CD(SD)BR] Sext Male/female Numberofanimals per dose group: The control and high-dose groups contained 65 rats'sex and the low-dose group contained 50 ratsses. Routeof administration: Diet Doses tested and frequency: Low-dose: 1.3 mgke/day (males). 1.6 mg/kg/day (females) Highedose: 14.2 mekg/day (males), 16.1 mg/kg/day (females) Post-treatment observation period: None `Statistical methods used:Bartlet' test for homogeneity of variance was usedtoanalyz the test data, If rthiosutesot wtahse cnoonttrsioglngifriocuapntuastinaglpahatw=o0-.ta0i0l1e,d tDhuendnaettacwsetreestfautrtthheeraalnpahlay-zed0.b0y5 csiogmnpiafricianngcecalcevhelt.reated sReeamrairnkcsl:udTeedst1Sanriamtaslssexwefrroem39b.0ot4h1thedcaoynstorfolaagnedwhhiegnh-tdroesaetmgeronutpsb.eganA.ll Aannimianltserwiemrteerombisneartvieodn daatiolnye. `tahnrdopuhgahroumtactohteodxoiscinobgseperrviaotdi.onsW.eaBkoldyyphwyesiigchatlseaxnadmifneaetdicoonnssiunmcpltuidoend wpealrpeatrieocnorfdoredanwyeemkalsyseosr bpir-esent pweearkfloyr.medEyaet tehxeamoinnea-tyieoanrspeursiiondg. inCdliirneicctalopphatthhaollomgoyscdoeptyeramnidn/aotriosnist ilnacmlpudbeidomhiecmraotsocloopgyy.wcelrienical (scrum)chemistry and urinalysis. Tests were conducted on samples obiained at 3.6, 12. 18, and 24 20s 0002039 months from randomly selected animalsof ach dose group. Hematologictestsincluded total red and. wchhietmeisbtlroyopdacrealmlectoeurnstsi,nchleumdoegdltoobtialn,bihleimrautbionc,rittot,alapnrdotaeidni,ffaelrebnutmiailn,whbiltoeodbluoroedacneiltlrcooguennt.(BCUlNi)ni,cagllucose. alkaline phosphatase (AP), creatine phosphokinase (CPK), aspartate aminotransferase, and calcium. MUertianbeotleisctseixnacmliundaetdiopnHs, isnpevcoilfviecdgcroalvlietcyt,iaolnobufmiurni,neglaucnodsef,ablilsiraumbpilne,so.ccPuolsttbmlooordteamndexkeatmoinneast.ions were. performed on all animals and the weightsofthe adrenal glands. brain, tests. heart, Kidneys, liver, spleen, and uterus were recorded from 15 randomly selected rats/sex/group. Samples of many different tissues were collected and observed microscopically from these animals. RESULTS S"Guernveirvaalllyr,atseusr:vival rates for the FC-143-treated rats were good during the ull two yearsofthe study. Fewer deaths were seeninhigh-dose males and females than in the controls. Neoplastic effects: Percent Neoplastic Lesions in Males oe or | Pheochromoeytoma. benign | 4[Tw TR |Pheochromocytoma.malig.| 0 TT 0 [Hepatocellular carcinoma[6Ta TT0 eTT&T=| [CLeydigeeliadenoma 1 0T[ a wr | [Mhyroa 7 [Ceeelladenoma ToTa [CeSeouerlcle:caTracblieno1m9a [5 7] 0 0 "Significantly different (p <0.05) from controls 206 000210 Percent Neoplastic Lesionisn Females AdPruocmosthromos tom. brign CanT t - oow [PheToechromoetoma.mabe [0 |0] Feprossilareinoms10[0 F`m Ahdeneome a dal Carino >7 o0 Fi1 rymopahdaenngcirossrzons =o 5o) Tigh 2| 3 o1 w2e PI Tohyrioidson-- -- [3T -- oTo | SaTree:FTable 19 I------ "Signicanly diffrent (p <0.5) rom controls STtrtaimsiccoantlraolsn: pa<to0.f0yn9c:osplaistsi effets (i. percent hatwas statistically significantly diferent NFemaalmesa(16g.l1anmdibkre:oadens MLaelyedisg(c14e.l2amdge/kngo)m:as in ests Nonncaplasti effects: NOAEL (os and effect): none LOAEL (dose and effect: ii1.v3 ammanhc,gyiotfSdheyot(sdmcaiamsps)loiendbdaaasnneadsspioaanlisnnfaoocrftyohns.lahsnoidwoesnvewarittdhahnspusrrpteecetsetdhoaft vie was not sonfimed) s1.a6imskcgimdye(FeSmiagln,es) - basd up ovarian tubular hyperplasia (1nd 207 000211 Percent Non-neopastic Lesions in Males C Rdremat TGwar [tw ii P--fSoeianrrisoiidya pdeeases sT = a E-- % w 2 | Tierosm avo 5% | % 2 PHCopnatdoceolsnaar basopil. [hy[pMeelroicaystioesnsoqse |0%41 [ [ 2w 0 1s n . || 1 17 or I Neeroe ss F CT---- Tw ot Tw96] THemr orage -- ---- Peta. mon T 2 oa] r o a0 [PcuVmeonltanm,imneorlasaittiaoln 3ve | |e se[|es|| [Vasrcurlap r ---- .--------0---- 1 --------------is --] BT nyraid --S---------- SaAclinaarrysro land ww wm Sialadenitis. chronic 2 27% EN 1 BeoSwiensi,eaTntey d2i0ffT rent (20.05)F from controlsTT] 208 000212 1 Cowl Tow igh ] `Nodular hyperplasia [Swsoidaieowss oT6 18 | ws 1 1 z wm | `Myocarditis, chronic Cw 1 weTaw] = : `Cyvioid degencration Hepatocellularalt. basoph. 0] |__ 16 _| 7 16 -- a |Hyperplastic nodule ---- 0 4 Necrosis. 10 2 a [Th"oAlmvoeomlahramgacerophage[ s | w 28 e 26 | 38 38 ] [Trervas.monomil 26 | ar | 28 Phcumonia, interstitial ew 6 18 Tubularatrop 1 1 [Vascularmin_ |] [PCroudwarbyperpiass [ 1 0 5] Tw aT r] u32] ThCyrcoiedl.l hyperlasia Co 1 2 7 + Fowiegmnss Tw[a 10] [CAcmramophy 12 wT5] [Siaadenits.chrome[2[2 5 Hemosiderosis 30[eT mw] 000213 List of statistically different non-neoplastic effects (increased compared with controls, unless indicated;p < 0.05): MaClherson(i1.c3smiaelead)e:niti (salivary gland) pInetreirvstaistciuallaprnmeounmoo.niinafi(l.lu(nlgn)g) Hemosiderosis (spleen) Ma`lCeyssto(1i4.d2degmeen/keer)a:tion (iver) MPoergtaallomyotnoosniuscl(eliavrerc)ell inflation (liver) Alveolar macrophages (lung) HVaesmcourlrahramgiene(rlaulnigz)ation (estsiepididymis) PeCrhirvoansicculsiaarlmadoennoit.is isnfaill.iv(alruynggl)and) Fe`Vmaascluelasr m(1.6inmeerael)iz:ation (lung) "CThurbounliarc hmyypoecraprldaistiias"(ovary) PeHreimvsaisdceurloasrimson(os.pleinefinl.) (lung)* FemMaelgealsoc(1y6t.o1simsg/(lkigv)e:r) HTeumbausliadrehryopseirspl(asspilaee(no)v"ary) "Decreased incidence relative to controls Genetic toxicity studies (study type and results): None Remarks: Dosc-related decreased in mean body weights in excess of 10% was observed in high-dose males and f"UehMmreaolaeunsz,hfeoeud tchoensstuumdpytwiohnen(acsogmrpaamrsedditeoumkalbeuc)onwtarsolinfcereedacsoednsiunmpaltlioofn.theOvFeCr-a1ll4,3 tthreeavtaerdiamtailoness were rheilgaht-eddoosetmhaelveasriraetliaotnivientboocdoyntwreolisghftoratmhoenfgirgsroyuepasro. fAtchteuasltudmye.an feed consumption was decreased in ""DAowsaer-irsetactaeldlyocsicgunrirfeincacneto(fva<t0a.x0i5a)dinecfreemaasleesinwarsedtbhelooondlyceclllinpiacraalmietgenrsobwsaesrvneodted in the high-dose: m"aXlseastiassticcoamllpyarsiegdniofictahnetc(opnt<r0o.l0s5.) increase in relative liver and kidney weights was found in high-dose. males and an increase inrelativekidneyweightswas found in high-dose females. 210 000214 ""UHriisntaorpyatfihnodlionggiscienfcfleucdtesdwienrcerenaosteeddiinncithdeenlcievearnodfsheivgehr-itdyoosefamlabluemsianndanfdemoaclceusl.t blood in all male and Female control pronounced in amanldeFsCt-h1a4n3-itnrefaemtaeldegsraotupthseatte1r2m,in1a8t,iaonndof24thmeosnttuhdsy.. These findings were more "bReattwseeginvtehnetfhierstesatndarstieccloenedxpmoenrtihesnocfeatdhseussptuedcyt;edhoowutebvreera,kothfespiraelsoednacceroyofaadvniirtuss w(aSsDAn)ovticroanlfiirnmfeedc.tion CONCLUSIONS The sI. tudTyreraetsumletnst-arreelsautmedmacrhiaznegdesaswefrolelofwosu:nd more commonly in males than in femalesof cach of the thiwgohetrreraettmeennttiognrooufpFsC,-w1h4i3chbywemraelessuptphoarntefedmablyesc.arlier pharmacokinetic studics demonsirating a 2. Tthumeotresstinmattheerimaallewsasancdonmsaidmemraedrytogbleancdartcuimnoorgseniincfienmatlheesr.at, inducing testicular/Leycdeilgl 3. hBaesmeadtoonldoegcirecaanasdlesihenpbatoidcysywsetiegmhst, gtahien,LiOnAcrEeLasefoirnmlailveer aanndd fkeimdanleey rwaetsigihst3s0a0pndpmtoxi(cmiatlye:in4t.h2e `smlyankdgs/iaalyad;enfietmiaslei:s 1b6a.s1cdmeu/pkoen/,dayt)h.e (The LOAEL for male LOAEL for female ras rats is 1.6 is 1.3 mg/kg/day ifsalivary me/kg/dayif increases in the incidences of ataxia (a clinicalsign)andofovarian tubular hyperplasia (may be reversible) are 4. Tbahseeddouspeo-nd.ependent increases in neoplastic and non-neoplastic lesions were as follows: testicular Leydigcell adenoma (p <0.05 at high dose) and vascular mineralization of the testes (p<0.05 at high dose) thyroid C-ccll adenomas in low-dose males thyroid C-cell hyperplasia in high-dose females `mammary gland fibroadenomas in females (p <0.05 at high dosc) lung lesions in males (p <0.05 at high dose) salivary gland sialadenitis in males (p <0.05 at low and high doscs) ovarian tubular hyperplasia in females (p <0.05 megalocytosis in the fiovfmealres and females at low and (p< 0.05 a high doses) high dose) with increases in relative liver weight and elevations cystoid degencration and of scrum enzyme activities indicativeof fiver toxicity portal mononuclear cell infiltation in the liverof males (p <0.05 at high dose) rReesmpaornskes:(0 tIhnefleusetncseoubfsptoatnecnetiisalovticrlaelair.nfeScitailoondaicnrmyaoaldeeSniptriasguvier-uDsa(wSleDyAVra)isisatabcoothmmdoosnesviornaltihnefection oifnfFe3c4ti4onraftosu;nedvanlouactoinosniosften2t9 idnifeltuceonncteoroflvaitraglrionufpesctaitonodnibffoedreyntwleaibgohrta,tosruirevsivwailt,horantdumwoitrhporuetvvailreanlce (Rao, cal. 1988). REFERENCE 3FlMuoCroocmhpeamnicyaRlikFeCr-1L4a3boirnatRoartise.s,ExInpce.riTmweontYNeoa.r 0O2r8al1C(RDOicDtI)2T.oxiStc.itPya!ulC,arMcNi.no;geSnEicHiQty-S1t0u87d-y0o39f4, Oct. 16. 1987. 211 000215 wRaeoi,ghGtNa.nd.sEudrmviovnadlosofnF,isJ.chaenrd3H4a4sreatmsaTnoxLKi.coIlnofgliusentc,eo1f66v,ir1a9l85i.nfections on tumor incidences, body 202 000216 REPEAT DOSE STUDIES Tithe: Mechanisms of Extrahepatic Tumor Induction by Peroxisome Proliferators in Male CD Rats TEST SUBSTANCE Identity: Ammonium perfluorooctanoatc Remarks: The substance was 98-100% pure METHOD Method/guidelinefollowed: None Study duration:2 years GLP (VIN): Unknown Year study performed: 2001 (publication date) `Species/strain: Crl: CD BR rats from Charles River Breeding Laboratories (Raleigh, NC). Sex: Males Numberof animals per dose group: 156 Routeofadministration: dict Doses tested and frequency: 0, 300 ppm Post-observation period: None ``Satamtoisntigcraloumpestwhaosdssiugsneifdi:canOtn,ep-awiarwyisaenacloymsipsaorfivsaornisanwceer.e mWahdeenwciotrhreDusnpnoentdti'nsg tFe-stt.estThfoer Bdiafrfteerte'nsceesst fToorr chqoumaolgemnecdiitaynosfavnadriMaanncne-WwhaistanlesoypUertfeosrtmfeodr.paNiornwipsaeracmoemtpraircispornosc.edures included Kruskal-Wallis test R1e3m.a6r.9k,s:12,H1o5r.m1o5n,aalndan2a1lysmiosntwhassacfoenrduicnitteidatiinono10frtahtse. stBuldyo.odSwearsumcolwlaesctperdefpraroemdtahendtafilrovzeeinn aanbdoutthen caonnacleynzterdatfioorntse.stAolsltesraomnep,lecssrwaedrieola,nlailcyizneidzisnigmuhlotramnocnoeu,slfyolilnicdlueplsitciamtuel.ating hormone. and prolactin eRaptisdiwdeyrmiedeeust,haancicezsesdoartyisnetxergilmaindme(ApSeGri)odusni(t1w.i3t,h6,fl9u.id1,2c,o1a5g,ul1a8t,iangndgl2a1ndm/onstchmsi)n.al Tvessitcels.e (with fluid removed). prostate, and lives were weighed 213 000217 Altan2d4/smeomnitnhasl, vseusrivcilveisngwirtahtsfwlueirdernecmroovpesdi,edp.rostBartaei,n,ephiedaritd,ymiivdere,s,spaincdent,esktiedsnweyesr,eAweSiGghutnietd, actonaegcurloaptsiyn.g Liver, testes, pididymides, pancreas, and organs with gross lesions were examined microscopically for lesions. Si rats/group were selected for evaluationsofcal proliferation. For cach issue type, 1000 cells were scored. Six and ratsgroup were selected Leydig cellperoxisomes for evaluationofperoxisome proliferation. was measured at all interim time points. | -oxidation activity from oxidation activity was. liver determined using the method of Lazarow (1981). RESULTS Toxic responses and effects: dBeocdryeawseeidghint,thfeooCd8 cgornosuupmvpetrisouns,fhaenaddlsiurbviitvuaml:conFtrroolm gtreostupd.ayThse1d0e6c3r0e,asbeoddybowdeyigwhetigwhatswsaisgnpirfiimcaanrtillyy dcuoemptaorreedduwcietdh "thfeoocdonetfrfoilcigenrcoyu'p. (Ostnatidsatiyca7l1s4igonfitfhiecatnecste,nsoutrviinvdailcatiendt)h.e C[8Hegmratooulpogwiacsalincchraenasgeeds were discussed ina separate artcle.] Li1v0e.r0s5)wRheelanticvoemlpiaverrewdeiwgihtthsoanncdorhempaotricc.co-notxriodlagtrioounpsa.ctivCi8typwreordeusciegdniafisctaatnitsltyicailnlcyresiagsneidfiactaanltltiinncreesas(ep (p= 0.05) in incidence ofhepatocellularadenomas (10/76, 13% vs. 2/30, 3% in controls). "ITnecsitidse:ncTeesstoifs Lweeiygdhitgscwelelrheyspteartpilsatisciaallaynsdigandifeincoamntalsy wienrceraelasso(esptdat<is0t.ic0a5l)lyatsi2g4nimfoicnatnhtslyiinnCcSr-etarseeadte(dp<rats 0.05); the incidence of Leydig cell tumors was 8/76(11%%) as compared 10 0/80 (0%) in controls. P18a,ncarneda2s1: mPoanntchrse.atiIcncaicdineanrceceolflacpironlairfecrealtliohnypwearslpsatsaitaisatincdalalydesingonmiafiscawnatlsysiingcnirfeiacsaendtl(yp i<nc0r.e0a5s)eadti1n5,C8 Fcaotmsb(ipn<ed0.i0n5c)i.deCnacrecoifnaocmianawrasceolbsaedrevneodmian aonndecCa-rtcrienaotmeadwaats (8n/o76st(a1ti1s%t)icawlhleyrseiagnsiftihcaatnot)f.thTehe.control was 0/80 (0%). Sate1r,u3.m6h,o9r,maonnde1m2emaosnutrhesmecnotmsp:areSdertoumcocnsttrroaldigorloucposn.cenTthrearteiownesrweenroe csoingsniifsitceannttldyifefleerveantceeds (ipn s<e0r.u0m5) testosterone, FSH, prolactin, or LH concentrations in the treated rats when compared to the controls. Statistical results: Statisticallysignificant results ae reported above. wRheemtahrekrst:heAmafumlml ararnygegloafnodrtgamnosrasndobtsiesrsuveesdwiansthneoteaerlxiaemrimnueldi-hdisotsoelsogtiucdalyly(.3MT,he1r9e8f7o)rwe,astisinudnuckendowinn this study. 214 000218 CONCLUSIONS "tTehsetisstaudnyddpeamnocnrseatsr)atien tChIaDt rCat8s.a,Dpaetraoxfirsoommethipsrosltiufedryataolrs,o siungdguecsetsthhetpatthiec iansdwuecltlioansoefxtLreayhdeipagtcieclltumors. tumors by C8 is a result of a sustained increase in serum estradiol concentration RLaesmtarMkosdi:finoende:. 703/01 REFERENCE xBitcrgaebl,epaLtBi.c,tHuumrotr,inMdEuc.tFiornabmyep,eSr.oRx.,is0om"epCroloifme.rCan.to,orasnridnJ,.maCl.eCoCoIk.rat2s.001T.oxiMceolcohgiacnalisScomifsences. 60: 4.55. 3{Mp.erfFliunoarloorceptoarntanoef*aTmwmooniyeuamrcaorrablox(ydliaet)e)tosiinciattys.anVdolc.ar1c-i4,noMge/niRcIitKyEsRtudEyxop.f Nlou.or0o2c8h1eCmriocoall2F;CS-E14H3Q1087-0394, Oct. 16. 1957. 25 000219 DEVELOPMENTAL TOXICITY Title: Oral Teratology Study ofT-2998CoC in Rats TEST SUBSTANCE Identity: Ammonium Perfluorooctanoate (APFO) or T-2998CoC (FC-143) Remarks: Purityofthe test substance was not indicated, METHOD Misestuheoddi/nGJuainduealryi,ne19f6ol6l(o"wGeudi:deTlhienepsrfoocredRuerperocdoumcptliioensSwtituhdhiefogrenSearfaeltyreEcvoalmumaetnidoanotifoDnrsougfsthfeorFHDuAman UEsveaTMl)u.atiTohneLsatbuodryatwoarsy'csonSdtuacntdearddaOcpceorradtiinnggtoPrtohceed1u9r7e8s.Good Laboratory Practice Regulations and Safety GLP (VIN): Yes. Year study performed: 1951 Species/Strain: RauSprague Dawley-derived CD. Number of animals per dose: 22 Routeof administration: Oral gavage Danodsi1n5g0rmegg/ikmge/nd:ayFAivPeFgOroiunpswoatfe2r2bytigmaev.amgaeteodnSgperstaagtuieo-nDdaawylse(yGrDa)s 6w-e1r5e. adAmicnoinssttearnetddo0.se0.v05o,lu1.m5e, of milk was administered. Doses: 0,005, 1.5,5, and 150 mg/kg/day oSftarteisstoircpatliomneittheosd,snuseud:omfDuimnbpnleatnett'attrieosnt sfiotresdaanmdannudmpbueprowfeicgohrtps,ornaufmubteear; oCfhifestquuseasr.enfuormber percent abnormalities. rReesumlatsrkosfa--raDentgaei-lfiannddindgisstcuudsys,aannyuspipgenrifdiocsaentlepvreoltoofco1l5p0amrya/mkeyt/edrasyawnadsdsecvifaotritohnes:defBiinsiteidveonsttuhdey in Wmhgi/ckhg/fdiavye gArPoFupOs ionf2di2stitlilmeed-wmaatteerdbSypgraavgaugee-Doanwlgeesytartatisonwedrayesa(dmGiDn)istered0,0.05. 1.5. 5 and 150 S1a5n.sofDotosxeiscitwye.reIanddjiuvsitdeudalacbcoodrydiwnegigthotbsowdeyrweeirgehcto.rdeDdamosn wGeDre3,m6on,i0to1r2e.d15o.naGndD203.-20Afnoircmlailnsiwcaelre iSamcrbiefirceodfcoonrGpoIra20lubtcya,cenruvimcbaelrdiosflvoicaabtlieonaannddntohne-voivaabrilees,feuttuesreis,.annud mcboenrteonfrtesswoerrpteieonxaimtiene.danfodr nthuember o`fApipmrpolxainmtaatteiloyn sointes-.thiFredtoufsetshewefreteusweesigwheerde afinxdedseixneBdoaunidn-ssubsjoelcutteidontoaenxdteerxnaamlignreodsfsonrevcirsocpesrya.l 216 000220 iannogmaslairesrboyd.res hand stoning. The remaining fetuses wer subjctd 0 skeletal examination RESULTS eNhOAdEaLy.GoTsheanNdOAefEfLectfo)rmdaeteelronpamlenatnadldoescilopmien1t5a0l:mgTkhgehNiOy.AEthLe fhoirgmhastedronasle ttooidiy is 5 WLOEAEEL,(dbosaacndanesfcenctta)i-clmlaytegrinaal nantd dredsneclhoopnmsenitnale:anThmeatLeOrnAaElLbofdoy mwaetiegrhnta,lioixiacinydid15o0h Ne nSofdevlopmentl oxi were observed at any dose evel, FToivrearetspsoncseiieofnetsinbcyadnosmeavrecla- mbaotdeyrnwaeli:ghSsigonns GofIa.t13l. anfdox15i:iyancdonssiastiedaonfdsdiessttc.aalllly he iEh-dose trou of 150 mekdy. "dTeovsdioprmeesnptoanlseoinefictcswbeytdoeseelnevaelsr-ydedvoesleovpmeental: No satisiclly significant signs of Stsicat results: oMadtyerwnaeligdhattaw:eSrteatoisbtsiecralvleydsognnigfaiteainoendduacytsi.on1(2.Dnudnn15t. 'Nosts,aips<t0i.c0a5l) iinnfomremaantiomnawtaosn atiableTo thr igs of mitemal oct (tis and dei) oFestalcdbsae:rveAd astattihsetihciaglhleysstidgnoisfeicda-nrtocurpeoafse15(0Chmi-sgquaraey,.p<0.05) inane semcbra ising Remark-s Additonal information to adequately sscss the data: SigIns>o.f ma1t2e:ranmadl 1t5 icthecionhsdisotesdeofgrsoautpisafe1al5l0ymsiEgnificdaanyt: edMuecatniomnairn mleabnomyatweerniaglhtboondyGwDei2g0hts eChonnstsinrouftedmdau1tmer.enmalNaooittohwerereoftfchecacutnrsciwonengrteoonlr,eypaoAtrichhde.ouHhAigdthm-edioissresgeironounep owifnacAslPundFoeOtd sadautvtsiitincaeansldtyadstieigonhnifcidchdasneto.rtveOadthpienpra Lo aff th ovaries reprodutive act conaet ofthe ds. rosiugnoiffi1c5a0ntmgH/ikgghedrayi:nchiodewnecveeirnteiassskeeslewtailhvaantemiiosnsisngsseerccabrrda iwahocbosneortvsaandthhesiahboerstehc oernmo s(eatoed.sNoinscigennitfiecabnuttiTorneernhae bheetwheiegnh-edoesedgraonugp)caonmdrtlhgerroeufoprsewweassooticdofnordoett0 hdeevmeloompmmeanm)bpoaroafmretseorrsptihoant ismheesl.udpedltaheamhaonn niusm,beeroorpfomraellsiasnad femmalneseortasl wnedighdte.ad Lfiekeowsi,sc. rcFaoaolfothve enmdbirnyognanllclyeudesscwriabeadtneradevatreirtryeodfr{0obemaan SmeocrpthoologfhiecafloechaanngdesSltoocanliiznegd ftoechhenique nd theron not conser 0 be wsmentrelated. 217 000221 Comment on author's conclusions and whether you agree: Conclusions are summarized above and this reviewer agrees. REFERENCE GEoxpretrniemreE,n.t #1098618.1 OTrRaOlIT10,eDercemabSetrutd1y9o5o1fTl-2o098gCoCyin Rats. RikerLaboratories,Inc. St. Paul, MN. 218 000222 DEVELOPMENTAL TOXICITY Title: Oral Teratology Study of T-3141CoC in Rabbits TEST SUBSTANCE Identity: Ammonium Perfluorooctanoate (APFO) or T-3141CoC (FC-143). Remarks: According to the study authors, the analytical report (Appendix IV) demonstrated that T3141CoC has an analysis within specifications. is stable and i representativeofcommercial material. By this analysis, the Ci acid was 97.6% and 98.4% ofthe test substance pre-study and post-study, respectively. METHOD Method/Guideline followed: The procedure complies with the general recommendationsof the FDA issued in January, 1966: AGuidelines for Reproduction Studies for Safety Evaluation of Drugs for Human [Ne "Typeofstudy: Developmental Toxicity GLP (VIN): Yes Year study performed: 1951 `Species/Strain: New Zealand White/Minikinrabbits Numberof animals per dose: 18 Route of administration: Oral gavage Dosing regimen: Four groups of 18 pregnant New Zealand White rabbits were administered 0, 1.5, 5. and 50 mgke/day APFO in distilled water by gavage on gestation days (GD) 6-15. A constant dose volume of I mig was administered. Doses: 0, 1.5, 5, and 50 mg/kg/day Statistical methods used: Dunncti=s {test fordam and pup weights, number of fetuses, number of resorption sites. number of implantation sites and numberofcorpora lutea; Chi-square test with Yates. correction forpercent abnormalities. Remarks - Detail and discuss any significant protocol parameters and deviations: Bascd on the results oaf range-finding study, an upper dose levelof SO mg/kg/day was set forthedefinitive study in which four groups of 18 pregnant New Zealand White rabbits were administered 0, 1.5, 5, and 50 `my/ky/day APEO in distilled water by gavage on gestation days (GD) 6-18. Pregnancy was established in cach sexually mature followedbyartificial fomale by iv. insemination injection of pituitary with 0.5 ml of pooled lutenizing hormone in semen collected from order to induce ovulation, male rabbits; the day of insemination was designated as day 0of gestation. A constant dose volume of 1 mi/kg was administered. 219 000223 Individual body an GD 3029 for weights were measured abnormal clinical signs. on GID 3, On GD 29, 6,9, 12, 15, 18, thedoswere aenudth2a9n.izTedheadnodetsheweorvaeriocbss,erutveerdusdaainldy CSiotnest.entFseteuxsaemsiwneerdefeorxatmhienneudmbfoerrgorfocsosrapbonroarmlaultietai,elsivaendanpdladceeaddifnetus3e7s, Creisnocruptbiaotnosr faonrdai2m4plhanotuartion `SAurbvliovoald cshaemcpkl.e Pwuapsstwaekernefsruobsmesqiuxendtolcys epurtiohran0izdeodsainngd eanxdamtihneendofnorGvDisc1e5raalndan2d9:skaelleitvaelr saabnmoprlmealwiatsies itankfeonrmfartoimonthweassaumnaevaainliamballes aotntGheDti2m9.e ofAltlhissamrepvlieesw.were sent fo the sponsor for analysis. This RESULTS NdoOseAtEesLted(.dofsoer amnatderefnfaelctt) -omaxtweiranscailnidainctdatedyde.velAopNmeOnAtEalL: fAorNdeOvAeEloLpomfen5t0almtkogxi/cidtayyc.outlhde nhoitgbheest established since signs of developmental toxicity were seen at all doses, with statistical significance at the highest dose. aLtOaAnyEdLos(edolseveela,ndTheeffeLctO)A-EmLatfeorrndaelvealnodpmdeenvtealloptomxeinctitayl:isNSo0 msigg/nksg/odfamya,tbeamsaeldtoonxidcoistey-wreelraeteodbserved increases in a skeletal variation, with statistical significance at the high-dose group. sTiogxniifcicraenstpotnrsaens/ieefnftecrtesdubcytidoonsseinlebvoeldyBwmeaitgehrtnagali:n oSnigGnsIoDf m6-a9 twehrennalctoomxpicairteydcofnosciosntterdoolfss;tbatoidsytiwcealilgyht ain retumed to control levels on GDI12:29, "doTsoe-irerleastpedonisneclreefafseetisn bayskdeolseteallevvaerliaBtidoenv,eelxotrpameinbtsalor: S13ignrsob,fwdietvhelstoaptmisetnictaallsitogxniicfiitcyanccoensaitsttheedhogfah dose group of 50 mgrkgday. Statistical results: Ma<t0e.r0n5a)lbdeattwa:ceSntatgiessttiactailloyn sdiagyni6f-i9canwterreedoubcsteiornvsedininmtehaenhibgohdeystwediogshetd-ggarionusp(oDfuSn0nemtgt/kgf/edsat,y. Aer gestation 9. mean body weight gains wer comparable o control animals for all dosed-groups. (FDeutnanletdta=tsa: Dtoesste,-r0e.l0at5e)d aitnctrheeasheisghi-ndaossekeglretoaulpv(ar3i8a%tioatn,5e0xmiga/kigb/sdoary.1330%riba,tw5itmhekstgaitidsatiyc,al2s0ig%niaftic1a.n5ce mibgs/-ksepduaryr,cdaoncdcu1r6re%d aitn 0thmeem/ikde-ddaoys)e. grAousptaotisftSicmayl/lkygs/idganyi.ficant increase (Dunnett test, p0.05) in 13" Remarks- Additional information to adequately assess the data: SGiDgn6s-o9fwmhaetenrcnaolmptaoxriecidtytoccoonnstirsotlesd;obfosdtyatiwsetiigcahltlygsaiignnsifriectaunrtnetdratnosiceonnttrroeldulcetvielosnsoninGbDod1y2:w2e9ightgainon cAodnmtiennitsstroaftithoenodofesA.PFSOixddueraitnhgs goecsctuartrieodn dduirdinnogttahpepsetaurdyt:o hafofweecvtetrh,e foivvaerioefsthore rseixprdoedautchtsivweertreacatributed to gavage errors. No clinical or othe treatment.related signs were reported Nfeomasliegsn,ifdiecaandtodriflfieverefnecteussewse,raendnofteetdalbweetiwghetesn. coLnitkreowlissaen,dthterreeatweedrgernooupssigfnoirfitchaenntudmibfeferroefnmceaslreespoarntded forthe numberof resorption and implantation its, corpora lutea, the conception incidence, abortion ate, 20 000224 ournrtehmear2k4abhloeu.r mTorhtealointlyyisnicgindoefncdeeovfeltohpemfeentutsaels.toGxircoistsy cnoencsriosptseydoafnda sdkoeslee-traell/avitsecderianlcreexaasmeiinnaatsikoenlsetwaelre variation, 30% at 5 extra ribs or 13" mgkgiday, 20% aitb,1.5wimtgh/kstga/tdisatyi,calansdig1ni6f%icaatnc0e mat/kthge/dhaiyg)h.-doAsesugtrisotuipca(l3l8ys%igatni5f0icmagn/tkg/day. siingcnriefaisceainnceo13f ribs-spurred this effect is ocurred uncertain in the since mid-dose group ofS in both the high- and mg/ke/day; however, the biological low-dose groups, thiseffect occurred at the same rate and was not statistically significantly different from controls. cCoonmclmuesinotnsonofatuhtehaourt=hsorcsonthcaltusthieonfsinadnindgowhfeetxhtrear you ibs, agree: or 13 rTihbi,sinretvhiisewpearrtdicouclsarnosttuadgyraerecwniotthathseign of daenvaetolmoipcmaelntvaalritaotxiiocnistyi.s While it is difficult to agreed assess. that the biological significanceofan the incidence of 13" ib in this study altered incidence of showed a dose-related ithnecrreefaosreewiistehvsatlautaistteidcaalssaigpnoisfsiicbalneceinadtitchaetihoingohfesdtevdeolseodp-mgernotuapl, tionxitchietya.bsence of maternal toxicity, and REFERENCE GCoormtpnaern,yE..GR,ikeE.rG.LaLbaormaptrorIenMiccTe..shS.Ctt.asP,eau.l, 19M8N2.. OErxaplerteirmaetnotloNgoy.st0u6d8y1oTfBOT3-93S1.4F1eCborCuianryrab1b9i8t2s.. 3M 2 000225 DEVELOPMENTAL TOXICITY Titles The Embryo-Fetal Toxicity and Teratogenic Potential ofAmmonium Perfluorooctanoate in the Rat EST SUBSTANCE aIdmemntointiy:umApmemroflnuioruomocptearnfosltueo,roaomctmaonnoaituem(ApPerFfOl)u.orpoecanptraydleactacf,luPoFrOo,ocFtCa-n1o1ic6,acFiCd-a12m6m,oFnCi-u1m69s,altF,C-143. or asa major componentof FX-1003 (CASRN 3825-26-1) R55e1m4a4)r.ksI:s pTuhreittyeswtassub>s9t5an%c:e,thAePcFonOta[mCiFn5a(nCtsF;p)r.esCeOnOtNwHe.r)e, [waCsFAo(bCtaFi;n)e,dCfOrOoNmH3]Man(Sdt.PPFaOulA, MN isomers. No inhibitor, caricrs, oradditives the temperature was to exceed w2e5r0eCpr(eusnenptu.bliDsehgerdadDautiPoonnotfdaAtaP)F. O was considered insignificant unless METHOD Method/Guideline followed: Not specified GLP (VIN): Not specified Year study performed: 1954 `Species/Strain: RauSprague-Dawley derived, Cel:CD (SD)BR strain. Number of animals rats/groupiteial. Two per dose: additional, Fpoari-tfheedinghraoluaptsio(n6pdoarmtsio/ngrooftuph)e. swteurdeya.dtdweodttioalsExwpietrhim1e2nmtat1e(diefreatmoalloegy). acxnpdotswuroegproorutpison(6ofdatmhes/sgtruodyu.p)25wearneda1d2demdatteodEfxepmearliemreatns2tat(dcaacmhs eaxlplooswuerdetcoonlicteen)t.raFtoironthweegraevaingcel-uded in Experiment 1 (eratology) and Experiment2 (dams allowed to liter). respectively. Routeof administration: Inhalation and oral Dosing regimen (list all with 12 pregnant Sprague-Dawley units): rats pe For the inhalation portion of the study, group exposed (0 APFO by whole-body the two tials consisted of vapor inhalation 0. 0.1, f1a.d10t,o athned 1205amndg/2m56'mgh/omu'rsgdraoyu,pso,nweGrDea6d-d15e:dttwoocaadcdhittiraoinl.al Ignrothuepsor(a6l dpaomrtsiopnerofgrtohueps)tutdhya,t w2e5raenpdai1r2- SApPrFaOgiuen-Dcaowmloeiylbraytsgfaovratghee ofinrsGt aDn6d-1s5econd trial, respectively, were administe0raend 100 mg/kg/day Doses: 10and For inhalation exposures: 25 mg/m' groups; for oral 0,0.1,110, a,nd 28 exposures: 0 and 100 mg/m', with mg/kg/day. two additional groups pair-fedto the `Statistical valuation methods used: The litter wasusedas (Staples and Haseman, 1974: Haseman the experimental unit for the purpose and Hogan, 1975). The significance of satistical of differences in tphreobianbciilidteyncteeostfp(Srieeggnela,nc1y95,6)c.linAictalwosi-gwnasy, aanndalmysaitseorfnavlardieaantchewwasasdeutseerdmtionededtbecytudsieffoefrethneceFsisinhefre-ecdxact ctoontsesutmtphteiostnataismtiocanl sbirgeneidfiicnagncloetsofanddifbfeertewneceesn bgerotuwpese.nDtuhnenceotntt'rsolteastnd(SAtePelFOandgrToourprsi,in 1m9a6t0e)mwaalsbuosdeyd m 000226 weight, in body weight gain, and in feed consumption when the one-way analysisofvariance was sdiegtneifrimciannte.d TbhyeJopnrceksheenecreeo'fscteosntc(eJnotnrcakthieoe-reel,at1e95d4r)e.sTphonesseisgfnoirfihceancienhoafldaitfifoenrpeonrcteisoninoftinhceidsetnucdeyowfas Structural alterations between the control group and the APFO group was determined by application ofthe FiMsahnenr-'WsheixtancetyprUobatebsitli(tMyatnenstawnadsWahpiptlnieeyd,(H19a4s7e).maWnhaennd mHooerle,th19a7n4)7.57T%hetelsevoecluofrsriegdniinfitchaendcaetas,eltehceted wasp 0.05. Variability about means was expressed as standard errorof the mean (SE). In addition. several reproductive indiceswerecalculated for some results from Experiment 2 (dams allowed to liter). cRoenmsiasrtkedso--faDnetaiinlhaalnatdiodnisacnudssananoyralsipgonriifoinca,nctapcrhotwoictohltpwaortamieateorrsexapnedridmeevnitast.ioTnsh:e fTihres rsitauldywadessithgen dTearmastowloegryepaolrltoiwoneodf1t0hleitsetruadyn,ditnhewhpiucphs twheerdeasmacsriwfeirceedsoancrdifaiyce3d5opnosGtD-pa2r1tumw.hilFeorinthteheisnheacloantdiotnra, the portion of the study. the two trial consisted of 12 pregnant Sprague-Dawley rats per group exposed to o'rAaPlFpOorbtyiownhooflteh-ebosdtyudyv,ap2o5rainndhal1a2tiSopnra1g0u.0c,-0D.a1w,l1e,y10r.atasndfor25thmegfi/rsmt '6anhdousresc/odnady,troianls,GrDes6p-e1c5t.iveIlny,thweere. administered 0 and 100 mg/kg/day APFO in com oil by gavage on GD 6-15. For both routes of bardemdi.nitshteryatwieonr,e freamnakleeds wwietrheinmbarteeeddionngadnayass-bnyeebdoeddybawseiisghatndanwdheansstihgenendu0mbegrrooufpsmabtyerdotfaetmiaolneisn woerrdeer of rank. Finally, two additional groups (six dams per group) that were pair-fed to the 10 and 25 mg/m' groups, were added to cach trail. For the teratology portion of the study (tial on), dams were weighed on GD 1,6,9, 13. 16, and 21 and bserved daily for abnormal clinical signs. On GD 21, the dams were sacrificed by cervical dislocation aannidmeaxlawmaisneedvalfourataendy. gTrohsesoavbanroiremsa,liutiieersu,s lainvdercownetiegnhttsswweerreeerxeacmoridneeddafnodr tthheerenpurmobdeurctoifvceorsptaotruasolfutaeac.h live and dead fetuses, resorptions and implantation sites. Pups (live anddead) were counted, weighed and `serxoeudpafnetduseexsawmeirneedexfaormiexnteedrfnoalr,vviisscceerraall,aalntdersaktelieotnaassl awletlelrataisonmsa.croT-heanhedamdiscorfoaslclopciocntervoallaunatdiohnigohf-dtohese For tial vo, in which the dams wer allowed to liter, the procedure was the same as that for ianalinodnieviudpuatlocGagDe. 21.TheTwdaotedoafypsarbteufroirteitohneweaxspencotteedddaanydodfepsairgtnuartietdioDn,ayca|chpodsatm-pwaratsumho(uPsP)e.d in Dams were weighed and examinedforclinical signs on Days 1,7, 14, and 22 PP. OnDay23 PP. aElalcdhapmuspwwearse ssaucbrsifeiqcueed.ntlPyuwpesiwgehreedcaonudntiends,pewcetiegdhefodr,aadnvderesxeacmliinniecdalfsorigenxsteornnaDlaaylste4ra.t7i.ons1.4, aponrdti2o2nPaPn.dTohneDeayyess o2f7tahnedp3u1psPwPefroer atlhseogeaxvaamgienpeodrtoinonDoafytshe15staundyd. 17PuPpPsfowrertehesianchrailfaitceidonon Day 35 PP and examined for visceral and skeletal alterations. RESULTS NOAEL (dose and effect) - maternal and developmental: devIenlhoaplmateinotna:l Ftooxricriitay iosne10-mtgh/emN'.OAFEoLr rfoarlmtatweornatlhetoxNicOiAtyEiLs |fomrgm/amt'e;rntahle tNoOxiAciEtLy ifsorImg/m'; the NOAEL for developmental toxicity is 10 mg/m'. 23 000227 portQuiaoln:oftAhNeOsAtuEdyLucsoeudldonnloy obneeddoetseermlienveeld. for cither maternal or developmental toxicity since this LOAEL (dose and effect) ~ maternal and developmental: inhalation (Fcoornstriisatlionngeo-f wtehte aLbOdAomEeLnsf.orcmhraotmeomdaalcrtyooxircrihteyai,s1c0hrmogm/amrh'i,nobrarsheeda,onatnraedatgmeennctr-arleautnekdepctlianpicpaelarsaingcnes). ain5d25simggn/ifmi'c,anbtarseedduoctniroendsuicntifoonosdicnomnesuamnptfeitoalnbaonddybwoediyghwtesigahntd: tahsetaLtiOstAiEcaLllyfosrigdneivfeiclaonptmiennctraelasteodxicity incidence offetuseswith partially ossfied stemebrac cFoonrsriastlingtwoof--wettheaLxlOoAmeEnLs,focrhmraotmeordnaaclrytooxrirchietys,isch1r0ommgor/hni'n,orbtahseead,oanndiraeagtemneenrta-lreulnakteedptclaipnpiceaalrasnicgnes: the wLeOiAgEhL for developmental foxicty is 25 mg/m', based on statistically significant reductions in pup body porOtriaoln:ofAthLeOsAtuEdLy ucsoeudldonnloytboneeddeotseermeivneeld, for cher maternal or developmental tricity since this Toxic responseleffects by dose level ~ maternal: Inhalation consuAmUpIt0iaonndan2d5bmoydny'w,eitgrheta;tmaetnt2:5remlga/tme'd.clsitnaitciasltiscailglnyssoifgnmifaitceamntalintcorxeiacsiteys.iannidverredwuecitgihotnss: ilneftohoardgy and death. Ol `ConsumprAiton1.00remdgukctgi/odnasyi,n tbhoedoynwleyidgohstegtaeisntse,d:ancdlidneiactahlss.igns of toxicity. reductions in food Toxic responseeffects by dose level - developmental: Inhalation A125 mem, reductions in mean fetal and pup body weights and statistically significant increases in the incidence offetuseswith partially ossified stemcbrac onl A100 mgfkgiday. the only dose ested, no signsof developmental toxicity were observed. Statistical results: aAsLsLigOneadn)d, s2i5gnmigfi/camnt rreeadtumcetnitoonrseilnatfeododclcionincsaulmspiiginosnof(2m1a.t8er1n0a.l4t6ivcsit23.y4 (n1o.0s.ta3t8isitniccaolntsrioglnsi)f.icaanndce 4S1i.g2n5ifmicga/nmt "redsutacttiisotniscalilnybsoidgnyifwieciagnhttinwcirtehassetastiisntimcealansiglinviefricwaenicgehtats 2(5wom-elami'le(dDMunannent-tW'shittesnt,ey0<U0.0te5s)t:, Pn<h0al.ti0o5n): lethdaervgeyl(o4pmoeunttoafl 12) and death (3 out of 12 dams). 24 000228 At 25 mg/m, reductions in mean fetal (p = 0.002) and pup body weights (p = 0.02), and istnactiidsteinccaelloyfsifgentiufsiecsanwtitihncpraeratisaelsly(po~ssi0f.i0e4dbsytemtchebrtawco.-tailed Mann-Whitney U test) in the Oral maternal A100 mg/kg/day, theonly dose tested: clinical signsoftoxicity (no statistical significance assigned), reductions in food consumption (nostatistical significance assigned), reductions in body weights gains (p = 0.05), and deaths (3 out of 12 dams). Oral = developmental No statistically significant differences were noted between treated and control groups for any of the parameters measured. Remarks ~Additional information to adequately assess the data: 25 000229 ohalason Exposure "Trial One: "gTriena'tmeanntd ceolnastiesdtceldinoifcwaeltsibgndsoomfemnast,ercnharlomooxdiicctryyofrorrhtcraia,lchornoem(otrrhaitnolrodghye)a,occugrerneedraalt1u0nkaenpdt 25 appearance, and lethargy in fou dams at theendof he exposure period (high-concenration group only). Three out of 12 dams died during treatment at 25 mg/m' (on GD 12, 13, and 17). Food consumption was. s{ricgantiefdicaanntdlyparierd-ufcdedgraotupbso.thS1i0g.nainfdic2a5ntmrge/dmu'c;tihonosweivnebro,dnyowseiiggnhitficwaenrtedialfsfoeroebnsceersvweedraetntohteesde between Sciognnciefnitcraanttioinnsc,rewaistehs sitnatmiestaincallisviegrnwiefiicgahntcsewaetrteheseheingha-tcothnecehnitgrhat-icoonngnleyn.tatLoinkegwriosuep,.sUinsdteiraltlhey cinodnidciattieodnsofthe study, a NOAEL and LOAEL for materal toxicity of | and 10 mg/m', respectively, was bNoodyofwfecitgshwtserweeorbessrigvneidfiocannthley dmeacirnetaesneadncientohfep2r5egmneamn'cy gorrohuep ainncdidinentcheeocfornetsoolrpgtrioounp.paiMre.afend fe2t5al mg/ar'. Adetailed microscopic visceral and eye examinationofthe fetuses did not reveal any treatment r{ienlcarteeadseefdfiecntcsi:dehnocweeovfefretinustehsewciotnhtrpoalrtgiraolluypotshastfweadstpeamire-bfreade25wamsga/bmse'ra,vesdt.atiUstnidcaelrlythseigcnoinfdiciatnitons of tihnedisctautdeyd. a NOAEL and LOAEL for developmental toxicity of 10 and 25 mg, respectively, was Tris Two: dCleisneirciabledsifgonrs roifalmaotnee.rnaMlatteoxrincailtybsoedeynwaetig10htagnadin25dumrgi/nmg'trweeartemesnitmialtar25inmtgy/pme'awnadsinlceissdetnhcaen acsontthroosles, though the difference was not satstcally significant. Inaddition, 2 out of 12 dams died during. otrteaetmefnotr aatny25ofmtgh/em'm.easNuoreomtheenrtstroefratempernotd-urecltaitveed epfefrefcotrsmwanecree. reUponrdteerd,tnheorcwoenrediantyoiafodvnhesersesteuffdeyc,ts NOAEL and LOAEL for maternal toxicity of| and 10 mg/m', respectively, were indicated. Signsofdevelopmental toxicity in thi group consisted ofstatistically significant reductions in pup body cwoenitgihntuoend tDoaryemIaPiPn(o6.w1erattha2n5cmognt/rmo'lsv,s.al6t.h8ougihn tchoentdrioflsf)e.rencOenwaDsaynsot4satnatdis2t2icaPlPl.y pSiugpnibfoidcayntwe(iDgahyts4 PSiPgLn0i.fi7cagnattf2e5emsg/wme'rev5e.1p0o.rteidn cfoonltlroowlisn:gDeaxyter2n2alPPe:xa4m0i.n0agtaiton2o5fmthge/mp'upvss.o50w.i1thinocpohnitrhoallsm)o.scNopoic: Cxaminaion of the eyes. Under the conditions of he study, a NOAEL and LOAEL for developmental toxicity of 10 and 25 mg/m', respectively, were indicated. Ons Exposure Trial One: TwhoreoenouGtDof122)5. dClaimnsicdailesdigdnusrionfgmtraeattmeenttooxfic1i0ty0 imgt/hkegdAamPsFOtdhautrdiincgdgweestraetisoinmil(aorne10dtehaotsheoSneeGnDwi1t1h: Cionnhtarloalt.ionNeoxpoasduvreer.se Fsoigondscoofntsouxmicpittiyownearnednbooteddyfwoeriagnhytsofwetrhee rreepdruocdeudctiinvterepautreadmeatneirmsaslucchomapsared to maintenanceofpregnaney or incidence of esorpions. Likewise,nosignificant differences between 26 000230 treated and control groups were noted for fetal weighs, or in the incidences of malformations and. variations: nor were there any effects noted following microscopic examinationof the eyes. "Trial Two: Similar observations for clinical signs were noted for the dams as in rial one. Likewise. no adverse: effects on reproductive performance or in anyofthe fetal observations were noted. CONCLUSIONS Comment on author's conclusions and whether you agree: The author's conclusions appear 10 be supported by the data REFERENCE Provide full citationofstudy reviewed: Staples, R.E. ct al. 1984. The Embryo-Fetal Toxicity and Teratogenic Potentialof Ammonium Perfluorooctanoate (PFOA) i the Rat. Fundamental and Applied TMoexdiiccoilnoeg,y.Ne4w:a4r2k0,-4D40E.T1h9i7s1s1tudy was performed at Haskell Laboratory for Toxicology and Industrial 21 000231 Ecotoxicity Study TTEOSXTICSIUTBYSTTAONACQEU.ATIC PLANTS (SELENASTRUM CAPRICORNUTUM) Identity: Perfluorooctanoic aid. etrabutylammonium salt; may also be: referred 10 2s PFOA tetrsbutylammonium salt, te`tcroampbounteynatmomfoLn-i13u4m92p.er(fOlcutoarnoaocitcaancoiadt,e,peNn2ta8d0ec3a-il2ou,roraos-,a major tetrabutylammonium salt, CAS # 95658-53-0) Rreefmearrekdso:bTyheth3eMtepstriondgucltaiboornatlootrymuamsbLe-r13w4a92s.23T2h7.e TT.hR.e tWeistlbsuarmyplsetuidsy number is 841TH. The purity of the sample was not sufficiently c4h4a.r9ac%tetrtirzeadb.utalytlhaomumgohnciuurmrepnetrfilnufoorromoacttiaonnoaitned,ic2at7e.s9i%twiataseorl,utanidon27of.2% isopropanol Thefollowing summary applies to the test sample as a mixtureof the ctehsatrSaucbtesrtiaznecdecionnacnenitsraotpiroonpsaonfolimwpautreirtiseosl.utDiaotnawmiathyinnoctomapclcuertaetleyly relate toxicityof the tet sample with thatofthe test substance. MMeEtThoHdO:DU.S. EPA-TSCA Guideline 797.1050 Test: Acute static GeLaPr:cYoemspleted: 1995 Species: Selenasirum capricornutum Source: Originally from The Culture CollectionofAlgac at the University oMfarTbeixcahseaadt,AuMsAt.in, maintained in culture medium at TR. Wilbury, Inc.. Element basis: growth rat. "ETxesptosorugraenpiesrmisodl:ab9o6-rhaotuorrsy culture: Algac cultures were growing in US. EPA-recommended sterile enriched medium for at least 14 days prior to tSetsattiisntiiticaatliomn.ethods: The average specific growth rate was calculated as the natural log of the numberofcellsmL at the exposure period minus the natural log of the numberofcells/mLat hours divided by the exposure. pSeurbitorda.ctTihngetpheercternetatcmheanntgaevefrraogmetshpeecciofnitcroglrowwatshcralactulfartoemd tbhye control aspveecriafgiec sgpreocwitfihcrgarteowitnhthreatceo,ndtirvoli,dianngdthmeuldtiifpfleyrienngcethbayt tvhaeluaevebryag1e00. The ECS0 values were calculated based on nonlinear regression estimation parpoacreadmuerteri(cBrouncee-waanyd Vanearlsytseiesg,of19v9a2r)i.anTcheeanNdOtEheCawvaersadgeetsepremciinfeicd using rToeswtiChonidnictaicohnst:es vessel at the end ofthe test Dilution water source: The alga medium was prepared to U.S, EatPrAierntecsotomcmkse.ndTehdecpoHncoefnttrhaetsioynnsthbeytispiaklgianlgmdeedioinuimzeadt wteastter with initiation was 7.5. Stock and test solutions preparation: A 16 my/L primary stock 28 000232 S`oalmuotuinotnsowfatshipsresptaorcekdisnolustteiroinleweenrreiacdheddedmeddiirae.ctlAypptroodpirliuatitoen water to formulate the test media. A 1,000 mg/L isopropy! alcohol sock solution was also prepared and evaluated. 1E0x0pomsLuroefvteesssteslosl:ut2i5on0.mL glass Erlenmeyer flasks containing Agitation: Continuous at 100 rpm Number of replicates: 3 NInuitmibalearlogfalccoenlclelnotardaitnigosns1:.0FXive10p4lucaesllnse/gmalt.ive control WLiagthetrincgh:em~i4s0t0ryf:ic fom continuous cool-white fluorescent lighting p7H5-r1an0g4e:((co0n-tr9o6l ehxopuorss)ure) 77..4471.06.4((116,m0y00/Lmge/xLpiossuorper)opylalcohol exposure) Test temperature range: (0-9 hours) 2RE4S-U2L3T7SC Nominal concentrations: Blank control, 1.0, 2.0,4.0, 80, 16.0 mg/L. Athtaetsrtepwraesspeentrsfo2r7m%edosfiLm-u1l3t4a9n2c,oautsl4y.w4iatnhd i1s,o0p0r0opmygl/La. lcaochomopolne,nt Element value and 95% confidence interval: 224ch4ourE-ErrCCSh100((gogrroowwutthhrrraattee)) =~ <115.(09.m8g/- L16(C)1mngo/tLcalculable) 524-chhoouurr EErxCC1900 ((ggrroowwtthh rraattee)) == ><11.60(m7.g7/L->(1C61)nmogt/cLalculable) 48-hour EXCS0 (growth rate)= 14 (8.2 - >16) mg/L hour EXC90 (growth ate) = >16 mg/L (CI not calculable) 7722--hhoouurr EEXrCC1S00 ((ggrroowwtthh rraattee)) == 7<.11.0(4m.g1/L~ (11C)1mngo/tLcalculable) 72-hour ErC90 (growth rate)=>16 mg/L (Cl not calculable) 9966--hhoouurr EErRC1C0S(0g(rgorwowtthh raattee))==4<1.90 m(3p.5/L6(.C7)l mnogt/Lcalculable) 9966--hhoouurr ENrOCE9C0:(g1r.0owmtgh/Lrate)=16 mg/L (Cl not calculable) `Algal growth was not affected by isopropyl alcohol concentrations of 4.4 or 1,000 m/l. Element values are based on nominal concentrations. 29 000233 Biological observations after 96-hour: CNonocmenication,| TNuemaber |Foboirvteion va | IPnrheieionvia mt iofCeliper | Density | Growth Rte [[C-- roommiTti amo00s [[ 3to f| o w| jo sno o[[m stoooo w T [os o w Tr se] s|| 6 CBoinotgriaearesopbosnesrev:atSiuonissacfoerry36-hour for isopropyl alohal: NConocomnration| VNuimeber |FInrhieveiion et ane Ce | vDeansity CfT iTs --o E o[r -- 5n CC =--| eObasenrvaoftdieonsst: Ailcgtaoseclopceocuonutnstisnweiachh esetmvoeesyelomweerterdeAtefrrmi6nedhboyus oaFhcaxpsouars,otthherMwaesrkesnio shiensCoofiargorreangyaettieoatnm.enNtorocoeduuit.rieocn ndiotmihoanl.ogtesrwehweenreconmopaortecdcablheecchomaon. cell 7. color or dReeervmeinresditboaflGrgowatheInbhaisbeidtioonn:heFeoeuloftohfethseptossubsdteainnce wasest cWeompaersk: Toswatsciondnuctged onthe mixture as described nthe Tos oSubesianTce Reemarkes heed rThreovarlteds orepored py fo that mix and CTOhNeCtLUsSamIpOlNeS96-hour E50 and 95% confidence neva for Sconcfidnencse nceapaplriofcor3.5n.6w. sldLe.tmiThneed360hboew4n9o mbg/eLeWrihoaf9e5t% Ciognaccegnraoiwotnh (i NOthEe vsfosr thceonnisunbgstpanrcoepiymlsoaalcioohnolvwaass1.0nmot agcd 2I1n541o34r91200ca0nmnLo,,byinsdilca,ticngeothuanttthfeorsehnecennriattiyonooffL-i1so4p0ro8py1l ssllohgol hNee esgtrastoslrigtmong.itTihosn,stIosvusblstaatnocne,woans dherermmienewde1r0 bmeiAedEoRmy oF SPuab.miMciemress3ot,C5om1p5a3ny, Environmental Laboratory, 0. ox 33331, t. 2% 000234 DATA QUALITY Reliability: Klimisch rankin2g.The study lacks analytical measurement ooftessutffsiucbisetnatlnycechcaornaccetnetrrizaetdi.ons in the tet solutions and sample purity is 31 000235 REFERENCES This study was conducted at T.R. Wilbury Laboratories, Inc., Marblehead, MA, at the requestof the 3M Company. Lab Request number N2332, 1995, OTHER `General remarks: The major concem for rying to determine the validity for this test is that ONLY NOMINAL TEST CHEMICAL CONCENTRATIONS were used. OPPT recommends that measured test chemical concentrations be used. so that one can accurately determine the test chemical concentration to which to the test organisms are exposed. IF it is determined that the `nominal concentrations are only. for example 50% of the measured concentrations. the toxicity values can be and mustbe adjusted downward by 50%. IFanalytical measurementsofsome sort had been furnished, we could calculate chemical recovery rates, and take into account hydrolysis. olatility, and other physicochemical processes that might lower the actual test organism exposure concentrations. Purity of the test material also is amajor concern and was not sufficiently characterized in this test. In some tests it appeared that 100% test chemical was used, for otahcehemricsal of lesser purity (approximately 85%)wasused. Water, asolvent (isoproorapcaomnbinoatlio)n of both was uscd in other tests, for no obvious stated reason. In fact, 3M intheirsummaryof ach test state: "Data may not accurately relate toxicity ofthe testsample with thatof the test substance." agree with this concem. In addition, if this was a "typical" TSCA section 4 review, | would reject these studies. pending receipt of additional information on purity and studies on analytical measurements of the test chemical in the test `medium. 232 000236 Ecotoxicity Study TTOEXSTICSIUTBYSTTOANACQEUATIC PLANTS (SELENASTRUM CAPRICORNUTUM) Irdeefnetrirteyd:toPearsfPluOorAooctteatnroiacbuatcyidl.amtmeotnriaubmutsyallatmmonium salt; may also be: tectormapbounteynatmomfoLn-i1u34m92p.er(fOlcutoarnoooictcaancoiadt,e,peNn2t8ad0e3c-a2f,luoorrao-,a major tReetmraarbkust:ylTahmemo3nMiumprsoadl,uctCiAonSl4ot9n5u6m58b-e5r3-w0a)s 2327. The test sample is rneufmebreerditso8b9y0-tThHe.teTsthiengpulraibtoyroaftotrhyeassaNm2p8l0e3-w2a,sTnhote sTu.fRf.icWieinltbluyry study 4ch4a.r9ac%tetreirzaedb.uatlytlhaomumgohnciuurmrepnetrfilnufoorromoacttiaonnoaitned.ic2a7te.s9%itwsataesro,lautnidon27o.f2% Tihseopfroolplaonwoling summary applies o the testsample as a mistureof the tcehatrsaucbtsertiaznecde cionnacennitsroaptiroonpsaonfoliwmaptureirtiseosl.utDiaontawimtahyinncootmapclceutrealtyely rMeElaTteHtOoxDicityofhe testsample with that ofthe test substance. TMeestth:oAdc:utUe.S.staEtiPcA-TSCA Guideline 797.1050 GYeLaPr:cYoemspleted: 1995 SSpoeucricees::OSrcilgeinnaaslliyrufmrocmapTrhiecoCurlntuuurne CollectionofAlgac at the University oMfarTbelxehaesaadt.AuMstAin, maintained in culture medium at T.R. Wilbury, Inc.. EElxepmoesnutrebapseirsi:oAdl:ga96l-cheolulrcsount (cells/mL), and specific growth at. "ETPesAtcorregcaonmimsemnsdleadbsoriattioryencruilcthuerde;meAdlgiauemcfuolrtuartelseawsetre14gdraoywsinpgriinotUro.S. eStsattiisntitiicaatliomn.ethods: The average specific growth rate was calculated us ntahteunraaltulroagolfotghoeftnhuembneurmboefrcolflcsemlLlas/tm0aLt.hotuhresedxipvoisduerdebpyertihoedemxiponsuusrtehe pseurbiiorda.ctTihngetpheercrecnattcmehnatngaevefrraogmetshpeecciofnitcroelrwowatshcraaltceulfartoemd tbhye control aspveecriafgice sgpreocwitfihcrgartowitnhthreatceo,ntdriovli,dianngdtmheuldtiifpfleyrienngcethbayt tvhaeluaevebryag1e00. The dEeCtSe0rmvianleudesusweirneagcpaalrcaulmaetterdicbyonperowbiatyanaanlaysliyss.isTohfevNarOiaEnCcewaansd the vaevsesrealgeatstpheeciefnicdgofrtohwethers.ac and the mumber of cells/mL. in cach test "DTielsuttCioonndwiattieonrss:ource: The algac medium was prepared 0 USS. EnuPtrAierntecsoocmkmse.ndTehdecpoHncoefnhtreatisyonntshbetyiscpailkgianlgmdeedioinuimzeadt wtaestter with `iSnittoicaktiaonndwatses7.s5.olutions preparation: A 160 me/L primary stock 23 000237 saomlouutniotnsowfasthpirsesptaorcekdsionluttieoniweenrreiacdheddedmeddiirac.elAypptroodpirlitaitoen water tEoxpfoosrmuurleaveestsheelste:st25m0edmiia. lass Erlenmeyer flasks containing 50 `nALgitoaftiteosnt:sCoolunttiionn.uously at 100 rpm Nnuimablearlogfalrceepllliclaotaedsi:ng: 10X 10 cell. NLiugmhtbienrg:oCfcoonntciennutoruastiloignhst:inFgiavte3p8lu0san-egautsiivngeccooonlt-owlhitc uWoarteesrcecnhetmlisatmrpys: p75H ra1n0ge8s(0co-nt9ro6l ehxopuorss)ure) T7e:5st t8e4mp(e1r6amtuLre reaxnpgoes:ur(e)0-96 hours) 2R3E4S-U2L3T.S7C NEloemmiennatlvcaolnuceenatnrdat9io5n%s:cBonlfaikdecnocnetrionlte0rv9a9l,:20,4.0. 8.0, 160 mg 2244-.hoouurr EECCHODceeslldedennssitiyt)=y=)>1416(07-.97.-02)16m)/lm.e/L 2244--hhoouurr EE1CCS0((cgerlodwetnhsiatty))~= 1~166mmag//LL.((CCl1nnootlccaallccuullaabbllee)) 4388-hhoouurr EECCIS0O ((cceellll ddeennssiittyy))=~ 71.21((<06.0-998.61.m6g)/mL.g/L h45o-huourr EFCC9S00(c(ezlrlodwetnhsirtayt)e)=->~1166mmg//lL.((CCl1nnootccoallecuullaabbllee)) 7722--hhoouurr BERCC1I0O(c(eglrodwetnhsirtaye))=<20..299(1(<602..999) m1.g9/)Lmg/L 722-h2our-EECCSh0S(c(oeglrloduwetnhsirrtayt)e)-~281(1.(19:4-5815)) mmaer/lL 7722--hhoouurr EEACC9900cgerlowdtenhsirtayt)e)~=81.46(4.5mg1(6C)1 nmog/cLalculable) 9966--hhoouurr EEXCCHIOOc(eglrlodwetnhsirtayt)e)==12..43((<<0.09999- 23..46))mmg/gL/.L 9966--hhoouurr EECCS0Sc(eglrlodwetnhsirtayt)e)=-289..14.0(59 -71.74)mmgg//LL 9966--hhoouurr EFICC9900c(eglrodwetnhsiatiye))==6>.10.63.m5g/-L1(6C)l mnogt/Lcalculable) 9966--hhoouurr NNOOEECC ((cgerlolwdtehnsaittey)):: 02.909mmg/Ll. ECloenmternotl vreaslpuoensswe:ereSabtaissfeadctoonrynominal concentrations. 234 000238 EE [C0.o99mo 0 4.0 3207000 1-1-7777 L[ ess2 ona T [3s a51 02g |s700| [eioo0 Tos Tes 000239 O`GNenLeYralNOreMmIarNkAsL: T`TEhSeTmaCjHorEcMoIncCeArLn fCorOrNyCiEngNTtoRdAeTteIrOmiNnSe twheervealuisdeid.ty fOoPr PthTisrteesctoimsmtehnatds cthhaetmimceaalsucroendcetnetsrtacthieomnitcoalwhciocnhcetontthreatteisotbnoesrguasneids.mssoatrheatexopnoesecda.n aIcFciutriastdeeltyedremtienremdintehatthtehetest vnaolmuiensalcacnonbceeantnrdatmisontsbaereaodnjluys,tefdordeoxwanmwpalredSb0y%5o0f%t.heImfeaansaulyrteidcaclonmceeansturrateimoennst.stohfe stooxmiceitsyort hvoaldatibleitny,faunrndiosthehde.r wpheysciocuolcdhceamliccualaltepcrhoecemsisceaslthraetcomviegrhytroatwese.ratnhde atcatkuealintteostacocroguanntishmydrolysis, exposure concentrations. Purityofthe test material also is a major concern and was not sufficiently characterized in this est. In some tests it appeared that 100% test chemical was used,foothers achemical of lesser purity (otahpeprrotxeistmsa,tfeolryn8o59o%b)viwoaussussteadt.ed Wreaatsoenr.a,Isnolfvaectn,t3(iMsoipnrothpeainrosl)umormaarcyoomfbcinaacthiotnestofbstoatt:h "wDaastausmeadyinnot aacdcduirtaitoenl,yi.ftrheilsatweatsoxaii"rtyypoifctahl"e rTeSstCsAamspeclteiownit4h trheavtieowf,th|ewtoeustldsurbesjtecatncteh.e"se1satgurdieees,wiptehndthiinsgcornecceeirpnt.ofTn amdeddiituimon.al information on puriy and studies on analytical measurementsofthe test chemical in the test 26 000240 Ecotoxicity Study TTEOSXTICSIUTBYSTTOANACQEUATIC PLANTS (SELENASTRUM CAPRICORNUTUM) aIsdePntFiOtyA: aPemrmfolunoiruoomctsaalnto,iAcmacmiod,niaummmopneirfulmuosarloto;cmtaanyoaales,oPbFeO,referred to FC-116. FC-126, FC-169. or FC-143. (Octanoic acid, Rpeenmtaardekcsa:flTuhoreos3-Mamprmoodnuictuimonsallotf,nCuAmSbe/r3w8a2s5-42267.-1)The test sample is WFCi-l1b4u3r.y sretfuedryrendutmobbeyrtishe89te5s-tTlHa.boTrahteorpyuraistyNo28f0t3h-e4.samTphleeTwRa.s not sufficiently characterized, although current information indicates it is a mixtureof96.5 - 100% test substance and 0 3M.E5%TCH6O.DC7,andC9 perfluoro analogue compounds. Method: U.S. EPA-TSCA Guideline 797.1050 Test: Acute static GYeLaPr:cYoemspleted: 1996 SSpoeucricees:: OSreilgeinnaaslilyrufmrcoampTrhiecoCrunluttuurme CollectionofAlgae at the University of Texas at Austin, maintained in culture medium at T-R. Wilbury, inc.. MEalrebmleenhteabda.siMs:AAlgal cell counts (cells), and specific growth rates. SEtxaptiosstuicraelpmeertihoodd:s9:6-Cehloludrensities, growth rates and percent inhibition Valles used to estimate the EC10, ECS0. and EC90 values and 95% cStoenpfhiadne.ncTehleimniotosbwseerrevecdalceuflfeacttedcounscienngtrtahteicoonm(puNtOeErCs)ofwtawsarceaolfcuClEat.ed uAsnianlgytoincea-lwmaoyniatnaolryisnigs:ofpvHarainadncteem(pAerNaOtVurAe). ATlegsatlConnudtriiteinotnsm:edium; U.S. EPA-recommended sterile enriched mTehdeipuHm.opfrtehpeasryendthbeytiscpiakliganlg dmeeiodniizueadmweastterinwiititahtinountrwiaenst7s.5t.ocks SSttoocckksaolnudtitoenstwsaosluptrieopnasrepdreipnasrtaetriiloene:nrAic1h.e0d00memdgi/aL.. Apprpirmoaprryiate `amounts of this stock solution were added directly to dilution water tEoxpfoorsmuurleatveestsheelste:st25m0edmiLa glass Erlenmeyer flasks containing 50 mAgLiotafttieosnt:sSohluatkieonn. continuously at 100 rpm Number of replicates: 3 InNiutimablealrgoaflccoenlcelnotardaitnigo:ns1:.0FiXve10p4luscealnlesgmaLt.ive control WLiagthetrincgh:e~mi4s0t0ryf:l. from continuous cool-white fluorescent lighting. PH range: (0 96 hours) 57.547.94.6 .1(,co0n0tr0olmgex/pLoseuxrpeo)sure) 237 000241 Test temperature range: (0-96 hours) 235 -23.7C RNoEmSiUnLaTlSconcentrations: BK control, 62, 130, 250. 500, 1.000 mg/L. E7lem2entE-CvaIlh0u(ecaoenlddu9en5s%irtyc)on~fi3d1e0nc(1e1i0nt-e4r4v0al) mg/L. 72-hour ErC10 (growth rate) = 470 (380 - 550) mg/L 7222--hhoouurr EFrCCSS00c(eglrlodwetnhsirtayt)e)==5~210,0(02050m-g/1L,0(0C0.L).mngo/tLcalculable) 7722--hhoouurr EEfCC9900((ceglrlodwetnhsirtayt)e)==>11.,000000mmLe/.L((C.C1..L nnoottccaallccuullaabbllee)) 9966--hhoouurr EErCCI010(g(crelolwdtenhsirtayt)e)==92720(7(7 =11-2620)800m)g/mL.g. 96-hour ECS0 (cell density) = 310 (280 - 350) mg/L 96-hour ErCS0 (growth rate) = >1.000 mg/L (CI not calculable) 9966--hhoouurr EErCC9900((cgerlodwetnhsirtayt)e)=- 11,.0000(083m0g/-L>1(,C0.100)nomtgc/aLlculable) 96-hour NOEC (cell density): 62 mg/L 9E6l-ehmoeunrt NvaOlEueCs (bagsreodwtohnrantoem):in5a0l0cmogn/cLe.ntrations Biological observations after 96-hours: `CNoonmciennatlration,|MNeuamnber PInehricbeinttion via.| IPnehricbeinttion via mg/L ofCells per | Density Growih Rate mL [Comwrol--Tid --T-070 1- 010 ] [2 Thassoo [3 --To [250 Tossoo0 TaT e i] [s-- oo "TaTs eo oo as 0| [o-- oo"Tiw [srio Taoo OCbosnetrrvoaltrieosnpso:nsAel:gaSlacteilslfaccotuonrtys in cach tet vessel were determinbeyd mofeeaxnpsosoufrdei,retchtermeicwreorsecnoopseicgonusnotsfwiatghgreagahteimoonc,yftloomcceuelra.tioAn ofr a9td6hheeoruernrcse of the algac 10 the flasks in the control or any test treatment group. In amdodripthioanl.otghyerwehweenreconmopnaorteidcetaotbhleechcoanntgroels. in cel size, coloror Reversibility of Growth Inhibition: Effect of the test substance was determined to be algisatic based on the results of the post-definitievset eCxOpoNsCurLeU. SIONS "STehleeneassttsraummpclaep9r6i-choorumrutEuCmSw0asanddet9e5r%micnoendfuisdienngcetwiontceravlaclulfaotrion mcthods. By call density, it was 310 (280 - 350) mg/L, and by growth rate 28 000242 1,000 mg/L. The 96-hour NOEC was determined to be 62 mg/L using cfelll doenscitcy aounrdlad5ah00etrmein/coLewnuesri,engngortoewdtihn raantey.oNfotshiegntessot fsaolgugtrieongsa.tiTohni,s `feSsutbmsituterb: 3swMatCsodameptnaenrmyci.neeEndvtiorobnemaelngtiastlaiLca.boratory, P.O, Box 33331. St. Paul, Minnesota, 55133 DReAliTabAilQitUyA: LKIliTmYisch ranking = 2. The study lacks analytical tmheeassaumrpelmeenptuorifttyesits nsoutbssutfafniccieecnotnlcyecnhtarraacttieorniszeind.he test solutions and REFERENCES "MTAhi,sastutdhyewraeqsuecsotndoufcttheed3atMTCRo.mpWainlyb,urLyaLbabRoerqauteosrtiens,umInbce.r MNa2r8b0l3-e4h.ead, OTHER OGeNnLerYalNOreMmIarNkAs:L TTEhSeTmaCjHorEcMoIncCeArnLfCorOtNrCiEngNTtoRdAeTtIeOrNmSitnwheervealuisdeid.ty fOoPPthTisreesctoimsmtehnatds that measured test chemical concentrationsbeused. so tha onc can accurately determine the test cnhoemmiincaallccoonncceennttrraattiioonnsatroownhliych, tfortheexaemsptloerg5a0ni%osmfstahreemeexapossuerde.dIcfonitceinstdraettieornmsi,nethdetthoaxtictihtey vHaaldubeseecnanfubreniasnhdemd,uswtebceoualddjucsaliceudldatoewcnhweamridcbalyr5ec0o%v.ery1 arnataelsy,taincdaltamkeeasinutroeamcecnotusnotf shyodmroelyssoirst. volatility, and other physicochemicalprocessesthat might lower the actual test organism exposure concentrations 239 000243 Ecotoxicity Study Title: Multi-Phase Exposure/Recovery Algal Assay Test Method. TEST SUBSTANCE IAdmemntointyi:umPerpefrlfulouroaroocotcatnaoniocataeci,d,PFaOm,moFCn-i1u1m6,saEltC;-1m2a6y, aFlCs-o1b6e9,reofrerFrCe-d1t4o3.25 (POFcOtaAnoaimcmaocindi.um salt, pentadecafluoro- ammonium salt, CAS # 3825-26-1) cRoemmpalrektesl:y Tchhaera3cMterpirzoedd,ucatlitohnoulgothniunmfboremratwiaosn 3i7n.dicTahteeseisttissaammpilxetuwraesofFC9-61.453-.100Thpeerpcuernittytewstassunbosttance and 03.5% Ci, Cs, and Co perfluoro analogue compounds. `The chemical is soluble in water at ambient room temperature. METHOD AMeGt.hoPda/ygnuei.de(alsindeescfroilbleodweidn:UMSoEdPifAie6d00fr9o-m78a0n1d8m)odeled after ASTM-E-35.23 Draft No. 2, OECD; Test type: Static GLP (VIN): No ear study performed: 1951 Species: Selenastrum capricornutum (7 day old stock) `Supplier: USEPA- ERL in Corvallis, Oregon. Measure of growth used: biomass in cell dry-weight (mg/L): cell count (no ml.) Concentrations used: Range-finding: 0.100,250, 500, 750, 1000, 1500 mg/L: Main study: 0. 100, 150. 320, 560, 1000, 1800 mg/L (nominal values). Exposure period: 4,7, 10, and 14 days. Analytical monitoring: There was no information on the measurement of the chemical during the test. There was no information on detection limitsof the chemicalor impurities. Statistical methods: ECS0 values and 95% confidence limits were calculated using the linear regression model 3M Sixcur 20 000244 ~TTeshtecaogndaitciuolntsu:re was sored nthe dark at 4C before us. The inital algal cell count in the stock culture waMsin2e7r7a.l0(0i0ncoreganlic.) standard nuit medium was used for culturing sting algae, This was prepared "awsistahysa.l mTihniesrnaultrniuetnrtiemntesdiesusmentwiaasl otherdailluengtrofwotrha.l TopheeraptHionwsasthaadjuussetdedal1g0a7e.5in0c.h1uprdiitohnregtopruespeariattihoen o"fEsxtpoocskurseoluvteisosenlss. were 250 mL. Erlenmeyer flasks with 50 mLof est solution and stoppered with a"uDtuorcilnagvethd ftoeastm, ptlhuetgsemperature was 23.8 2C. The light was by fluorescent lluination of 400 ft icnaintdilaels alg1a0l%l,oaadnidngcuwlatusre1s0wxer1e0agcietlaltsemdLi.th continuous shaking platform at 100 1pm, Algal recovery response was evaluated following the exposure periods. "TThhreereerweaplsicnaoteisnwfeorrmeattiaoknenoan dcialcuhtidoonsew.ater source, contaminants, or chemise ofthe water. oRtemparreksesn:tedp,H values were acceptable according to OPPTS Harmonized Guidelings. Water hardness was SULTS Dose associated with each endpoint (3s mg/L): ECs0s Number of Days Exposed Cell Dry Weight (mg/L) Cell-Count (ao.celvm) 43 174093(4571-1384)0) 23092018.7450)) 014 27392155-91467)) B27a85a0)n 95% Confidence Limits Ecos Number of Days Exposed Cell-Count (no. celsimL) 47 0 14 95% Confidence Limits 5333047)) 2901-5) 5(2-8) ECons Number of Days Exposed Cell-Count (no. celvimL) 4 624 (CL. not caleulacd) 21 000245 70 238836 ((C1.5L.0-n5o9t0)calculated) 1 307 (CX. not calevlated) 95% Confidence Limits Was control response satisfactory (vesimofunknown): unknown Statistical results, as appropriates No p-values were reported Rreesmuasrpkesn:dedAifntefrreesxhpnousturrieenctemaseeddi.utmheinaltghalacblselnrceeocofvehreedeaxntdsurbesstaunmceed. logarithm growth when CONCLUSIONS, cAomnmfiodneincueminpteerrfvlauloorfoo1c4t.a0naa81temx/hilbis a 14-day ECSO (cel count) valu of43 mg/L with a 95% `quSaulbimtyiteesrtsi"ngreamtatrhkest:imeThitewaausthcoornsduicnteddi.caHtaoKwleivmeirs,chthreasntkuidnyg olacf2k.edTihnefosrtmuadtyiomneeotnsttehset csruibtsertiaancfeor purity nd actual measurements ofthe est substance in solution REFERENCE FTlensstbMaertahuoedy., M.RTe.por1t98N1.umb3eMrT0e0c6.hniPcraoljeRcetpoNrutmbSeurmm9a9r7y0,03M0u0l0i0-.PhOacsteobEexrpo1s6urc/Recovery Algal Assay OTHER dGeetnaeilreadlrrepeomratrwkass:Tahvaiislabslue.mmTahreyrewfaosreb,atsheedcoonntaenstsumofatrhiys rseupmomrtarayn.d oinnlryelfiemriteeed odattaheabplreost.ocoNlos and "eTsheamsaojfotrhceonscteurdyn.faorretrliymiintgedt.o determine the validity for this est is that ONLY NOMINAL TEST `coCnHcEeMnItCraAtLioCbnOesNuCsEedN.T5R0AthTatIoOnNeScwaeraeceuusreda.elyOdPePterrmeicneomtmheenedsst cthhaetmimceaalsucroendcetenttacthoenmitcalwhich 0 {5h0e%teostf otrhegamneiassmusreardeceoxnpcoesnetdr.ati1on1s,sthdeettoexrimciinteydvatlhuatesthceannobmeinaanld cmounsctebnteraatdijounssteadredoonwyn.wafrordebxyamSp0l%e aanndaltyatkiecianlomaecacsouurnetmheyndtrsoolyfssiso,mveolSaotritlihtya,dnbdeenotfhurmipshhyesdi,cowcehecmoiucladlcaplruolcaetssecshethmaitemailghrtecloovweerry trhatees, ctu est organism exposure concentration. As i iswe ar operating in the dark on ths suc. uw 000246 INVERTEBRATE TOXICITY Title: Acute Toxicity to Aquatic Invertebrates (Summary ofthree 48-hour studies in diet) TEST SUBSTANCE Identity: Perfluorooctanoic acid, ammonium salt; also referred to as PFOA ammonium salt, ammonium paemrmflounoirouomctsaanlct,atCeA,SPHFO3.82F5C--261-116). FC-126, FC-169, or FC-143. (Octanaic aid, pentadecafiuoro-, cRoemmpalrektesl:y chTahreac3tMeripzreodd,uaclttlhootunghumibnefrorumsaetdiownaisnd3i7.catTehdeittwesatssaammpilxetuwraesofFC9-61.453.-10101%slpeusrtistuybwsatasnncoet and 0-3.5% C6, C7, and C9 perfluoro-analogue compounds. METHODS Method/guideline followed: Not stated Test type: Static GLP (YIN): No, Vear study performed: 1952 Species: Daphnia magna alegneg=thFi=rs0.t5-I-ns1t.a5rmyomung Supplier: USEPA-ERL Duluth, MN Cnoomnicneanltrcaotnicoenntsrtaetsitoends: 0, 10, 30, 100, 300, 1000ma/L in two ests; 0, 10, 100, 500, 1000 in third study; Exposure period: 48 hours Analytical monitoring: No monitoring of the test substance concentrations was done Statistical methods: Chi-square test was used ""TDeisltlcioonndiwtaitoenrs:used wascarbon.lered well water (al three tests), with a temperature of24C in two Tests (the temp. in the third est was not given). ""TTewsot sroelpultiicaotnesswweerreemtaadkeenfroma common stock solution with a concentration of Sg/L. 243 000247 "NumberofDaphnia were 10-20perreplicate "Exposur"eWavteesrseclhsewmeirsetr2y5d0urmiin.ggtlhaesstebsetawkaerssacsofnotlalionwis:ng 200 mL test solution (6 cm in depth) Temp ranged from 22-24C DPOHwawass8.8.72-f8o.r5tpheptmesftosrintewsthsiicnhwihtiwchsirtewpaosrtreedp(omrteeadsuarneddfaor4w8hihcohurist)could be read (measured at 48 hours) Remarks: pH and hardness measurements were not presented for dilution water: hardness during the fest sas not presented. Informationondiet wasalsonot prescnied. RESULTS Doseofeach endpoint (as mg/L): 45-hour ECS0 ranged from 126me/L (with C.L. $6 t0 183 mg/L) to > [Le Remarks~:Lowest test substance concentration causing 100% mortality was 500 mg/L (from both replicates ofa single est) ~- MAobrntoarlimtayol frecsopnotnrsoelss iwnacslu1de0d%mianrokneedrreepdluiccattieonofinonleoctoemstotion at 1000 mg/L in one test `Was control respanse satisfactory (yes/no/unknawn): [appears that the control response was. satisfactory, given the information provided. Statistical results, as appropriate: Some statistically significant results are presented (p values `associated with Chi-square tests), but it is unclear what they refer to. CONCLUSIONS "The test sampleresults ic. the largerange in ECS0values) were inconsistent. The authors Suggest that this difference may be due to differences in diet. Submitters" remarks: The Klimisch ranking for the study was 3. Several reasons were indicated, ainnacllyutdiicnagl:ctohnefimremtahtioodnowfastensottsduebssctrainbceed,cosnacmenptlreaptuiroinst.y wTahsenyaotlspornoopetrelythcehavraalcuteesrifzreodmamnudltliapclkeedtests contradict cach other. The authors also note that they conducted the studies specifically to evaluate diet. Reviewers! remarks: Although the authors indicate that diet may be the causeof the differences in ECS05. no information on diets is presented. 244 000248 REFERENCE Not enough information except what submitters include in thir reference section, which states: "These studies were conducted by the 3M Company, Environmental Laboratory, St. Paul, MN, completed from May (0 June, 1982" OTHER General remarks: This summary was based on a report and only limited data ables. No dpertoatiolceodlsreapnodrtrwesausltasvoaifltahblee.stuTdhye,raerfeorlei,mittehde.contents ofthis summary. in reference to the "The major concer for trying to determine the validity for this test is that ONLY NOMINAL TEST CHEMICAL CONCENTRATIONS were used. OPPT recommends that measured test ccohnecmeinctarlatcioonncteonwthriacthiotbonesthuesteeds,t soorgtahantisomnse acraeneaxcpcousreadt.eIlyFditetiesrdmeitneermtihenetdestthcahtetmhiecanlominal concentrations arc only, for example S0% of the measured concentrations, he toxicityvalues can be and must be adjusted downward by 50%. IFanalytical measurementsofsome sort had been afnurdniosthheedr.pwheysciocuolcdhecmailccuallatperoccheesisecsalthartecmoivgehrtylroatweesr. tahnedatcatkuealntteostaocrcgoaunnitshmyderxoployssuirse, volatility, concentrations. 25 000249 INVERTEBRATE TOXICITY Title: Chronic Toxicityto Freshwater Invertebrates (Daphnia magna) TEST SUBSTANCE. Ipdeernftliutoyr:ooPcetrafnlouaotreo,ocPtFaOn,oiFcC-ac1i1d,6,aFmCm-o1n26i,umFCsa-l1t6al9os,orrFeCf-e1r4r3e.d 0(OacstPanFoOicAaacdm,mopnenituamdescaalftl,uaomrom-o,nium ammonium sal, CAS# 3825-26-1) Rcoemmpalrektsel:yTchhaera3ctMeprirzoeddu,catltlohtounguhmbinefroursmeadtiownasin2d6i4c.ateTdheittwesatssa miaxtumwraeopsfF9Cl6-.154e3-.1001%'spteusrtistuybwstaasncneo.t and 03.5% C6, C7, and C9 perfluoro analogue compounds. METHODS Methodguideline followed: USEPA-1952, OECD 1981 "Test type: Semi.statc life-cycle toxicity GLP (VIN): No Year study performed: 1984 Species: Daphnia magna Age= < 24-hour neonates `Supplier: 3M Environmental Laboratory St. Paul, MN CChornocneinctrtaestt:ion0,s5t,es8t,ed1:3,A2c2u,t3e6.teastn:d2650,4m0g/,L6.3,no1m0i0n.al16c0,on2c5en0t,r4a0ti0o,ns6.30 mg/L. (Results, however, were based on mean measured concentrations~see below.) Exposure period: 21 days Analytical monitoring: Not stated StCaotrips.tiDcuallutmhe,tMhoNdsr:eAcacluctuleateesdt:stPatriosbtiicts ainnal1y9s9i5s.. CNhOrEonCiscatnesdt:LmOoEvCisnwgaerevgeenearrantgelademuesgitnhgoedT.oxsAtas,cl Rfoerprsuordvuicvtail.on1wCaSs0sno(fromrraelpraondduhcotmioong)enwoeurse tgheenreerfaotreedDuusninnegt'ICsppTresotgrwaams.uSsuedr.vivFiaslheErC'sS0Tseswterwea.s used enerated using "Trimmed Spearman-Karber'. 246 000250 Test conditions: "Dilution water source was aerated carbon-filtered wel water "Dilution wathearrdcnhesesm:ist2r4y0wmags:/L as CaCO3 alkalinity: pH: 723%0 mg/L as CaC03 CoD: 04mg M"Eexdpioasurreenveewsaslelisnfwoerrmeat2i5o0nrmaltigolnaasles:beamkeedrisu(mcownatasicnihnagng2e0d0omnLcoefesveorlyuttiowno tdoayasdepthof about 5 c~mA;mb1ieanntimlaalboprearto4r0ymlli,ghntoinagerwaatsiounsdeudr(icnogolt-hwhtietste)fluorescent, at ambien levels, 16 hours per Four redplaiyc)ate beakers were used ""TWhaetreer wteermepe2r0ataunriemdaulrsipnegrtchoentceesntwraatsio2n 2+(5p2eCrreplicate) -A suspension of fish food and yeast containing S me dry solids per | ml mixture was fed on a daily basis hRaermmaornkisz:edpgHuiadnedlihnaersdsnteastse tmheaatshuarredmneenstsssohfowualtdebr eadurmianxgitmheumesotfw1e8r0emnaot/LpraesseCntaeCd.O3Adlsuor,intghethOePtPesTt:Sif chemistry prior to the test was indicativeof during the test, the hardness valueof240 mg/Lof the dilution water was too high. RESULTS Dose of each endpoint (as mg/L): 14 day NOEC (survival) = 60 mg/L 14 21 day day NNOOEECC ((sruerpvriovdaulc)ti=on2)2 ~mg/mLg/L. 21 day NOEC (reproduction)~ 22 mg/L 14 day ICS0 (reproduction) = 40 (28-38) mg/L. 21 day C50(reproduction) =43 (35-46) mg/L. *eAnldlpocilnetmevnatluceosncaernetfrratoimotnhsewreeraenablaysseidsoofnthmeeadnatmaebaysuArseeld cCoonrcpe.ntrations and the reported Remar ks: mgAl/lLsturrevaitvmienngtsf,irssturgveinvearlatwiaosnsdtaatpihsntiicdasllaypdpiefafrereedntnofrrmoamltahtetnheegeatnidvoeftcohnetrtoelstg.roIunp.the 36 and 60 - Neonates surted 0beproduced on Day 7. Reproduction was statistically significantly different from tmhue/cLontterstolso(lDuutninoentst'ats)21atdtahyse.13, 22. 36, and 60 mg/L. concentrations ater 14 days, and in the 36 and 60 ~ 100% mortality was not observed at any dose: - No morality was seen in the controls 47 000251 m`oWraaslciotnyt.rol response satisfactory (yes/no/unknown): Yes, based on the fact that there was no. `cSotmatpiusttiecralprrienstuoluttss,. usHoawpepvreorp,rialatcek:of inIftoarmpapteiaorns msaodmee rtehseusletsdiafrfeicsutlattitsotiicnatlerlpyresti.gnificant, basedon CONCLUSIONS There were no adverse effects on survival or reproduction at concentration<s 22 mg/L. for21 days. `Submitters' remarks: The Klimisch rankingwas3. The study was apparently well conducted `according to the methodology available at the timeof the start ofthe test. Reviewers! remarks: none REFERENCE 3M Company. Chronic toxicity tofreshwaterinvertebrates. [No other information available] or `General remarks: This summary was based on a summary report and only limited data tables pNrootdoectoalisleadndrerpoertswuaoslfttahvseailsatbuldey., Tahreerleifmoirtee,dthe contentsof this summary. in reference to the tAhlesoa,cuatnetaecsuttewatesstnwoatsvecroyndculcetaredr,opmostshieblsytuadsy.arange finding study. However, the purpose of The major concern for trying to determine the validity for this est is that ONLY NOMINAL `TEST CHEMICAL CONCENTRATIONS were used. OPPT recommends that measured test `echoenmciecnatrlactoionncetnotwrhaiticohnstbetuhseetdes,tsoorgtahantisomnseacraeneaxcpcousreadt.elIyfdetietisrdmeitneertmhienetdestthcahetmhiecnaolminal concentrations are only, for example 50%ofthe measured concentrations. the toxicity values can be and must be adjusted downward by 50% . If analytical measurements ofsome sort had been afnurdniosthheedr,pwheysciocuolcdhecmaliccuallatperoccheesmsiecsalthartecmoivgehrtylraotweesr, tahnedaactkuealntteostaocrcgoaunnitshmyderxoployssiusr,e volatility, concentrations. 248 000252 INVERTEBRATE TOXICITY Title: Acute toxicityto aquatic invertebrates (Daphnia magna) TEST SUBSTANCE pdeernftliutoyr:oacPiearnfolautoer,ooFcCt-a1n1o6i,c aFcCi-d1,2a6m.mFoCn-1i6u9m,soarl;FCa-l1s4o3r.efe(rOrcetdanoaise aPciFdO,Apeanmtamdoenciafulmuosraol-,aammmmoonniiuumm sal, CASH 3825-26-1) Risempaurriktsy:wsThnoet3suMffpicrioednutcltyiochnalroatctneurmibzeedr, waaltsho39u0g.h cTuhrerenfetstinsfaomrpmlaetiwoansinFdCi-c1a2te6s,iat iwshaitmeixptouwrdeeorfy7s8o-lid 93% test substance and 7-22%C3. C6, and C7 perfluoro analogue compounds METHODS Method/guideline followed: No stated Test type: Static GLP (VAN): No Year study performed: 1957 Species: Daphni`aAgmea=gn<a24 hour neonates Supplier: 3M Environmental Labs Concentrations tested: 0, 100, 150. 320. 560, and 1000 mg/L. nominal concentrations. Exposure period: 48 hours Analytical monitoring: None because concenrations were nominal. Statistical methods: Probit analysis Test conditions: "Dilution water source was carbon-filereTdewmepllwwaaste2r1wCith th following chemical characteristics: HDOawsas7994 ppm ""STteasbtilsiotlyuotfitonhseweesrtepcrheepmairceadlbsyoludtiiroenctwwaesignhottsnaodtdeidtion 249 000253 Exposure vessel was 250 mL Pyrex glas baker containing 200 mL et solution 10a 6 cm "Numberdoepftdha)phnids per replicate was 10 "Water chemiDstOry during est: c1o0nt0r0olm:g/L9.0 emxpoLsure: 5.8 mg/l pCiotnol: 80 1000 mg/L: 8.1 Temp 210 Remarks: No other deals ofthe est conditions were prescned, including water hardness. RESULTS Dose of cach endpain (as mL): 48-hour ECS0 was 221 mg/L (95% CT: 186-261) RemarksL:owest tet substance concentration causing 100% mortality eas S60 mg/L at 48hours (both There wraepslincoatmeso)rality inthe controls mWoartsalciotnytrol response satisfactory (yes/no/unknown): Yes. based onthe fact ha here was no Statistical resus, as appropriate: Not presented CONCLUSIONS The 48-hour ECS0 was determined tbe 221 mL (wai95t% Ch.L. of186-261) S(eustbimngi.tteHorwserveemra,rskasm:plTehpeudrattya wquaaslintoytKplriompieslcyhcrhaanrkaicntgerwiazsed2.anTdesitilnagckmeedtsntahleytcireitaelricaonffoirrqmuaatliiotny of est substance concentrations Reviewers' remarks: none REFERENCE A3pMriClo0m.pany. 1987. [Retitpenootirvent.] Lab Request Number E1252-1. Completeodn OTHER NGeondeertaalilredemrarkes:wpaTshaoivsaisrluambtlmea.ryThwearsebfaosre,dtohneacosmuemntmsaroyf rtheipsorstumamndaroyn.lyinlirmeiftreedndcaetaotatbhlees protocols and resus of the study, are limited. 250 000254 "The major concer for trying io determine the validity for this tes s that ONLY NOMINAL TchEeSmiTcCalHcEoMnIceCnAtLraCtOioNbnCesEuNsTedR,sA0TtIhOatNoSnewecraenaucsceud.ratOePlyPdTetreercmoinmemetnhdestetshtatchmeemaiscuarled test concentration to which tothe test organisms are exposed.11i is determined that the nominal cboencaenndtmrautsitonbseaardcjuosntleyd. dfoorwenxwaamrpdleby500%%o.f thIFeamneaalystuircealdmceonacseunrtermateinotnss,ofhesotmoexiscoirttyhvaaldubeesecnan `faunrdniosthheedr.pwheycsoicuolcdhecmailccuallatperoccheesmsiecsalthartecmoivgehrtyorawteesr, athnedaactkuealin(tesotaocrcgoaunnitshmyderxoployssuirs,e volatility, concentrations. 251 000255 TOXICITY TO INVERTEBRATES Title: Static Acute Toxicity ofFX-1003 to the Daphnid, Daphnia magna TEST SUBSTANCE. Iadmemntointyi:umPeprefrlfulourooroocotcatnaoniocataec,idP,FaOm,mFoCn-1i1u6m,sFaCl-;1m26a,y FaCls-o16b9e,rFeCfe-r1r4e3d.tooras5PaFOmaSjoarmmcoomnpiounmenstalto,fFX1003. (Octanoic acid, pentadecafluoro-, ammonium salt, CASRN 3825-361) Remarks: The 3M production lot umber was 2327. The purity of the test sample, FX-1003, was not sufficiently characterized, though available information indicated it was a solution of <45% ammonium apnerafllougoureooccotmapnooautned,s.S0%water, <3% inert perfluorinated compoundnd. 1 - 2% Cand C; perfluoroMETHODS Method/guideline followed: OECD 202 Test type: Static GLP (VIN): Yes Year study performed: 1990 `fSrpoemciaesn:inD-ahpohunsiedcsulutsuerde tinhatthweatsesmtawienrteailneessdtuhnadner24eshtoucrosndoiltdiaotnsthfeorstatatleoafstth1e4dteasyt.s.ThPeryiowretroetepsrtiondgu.ced daphaids were maintained in 100% dilution water collected from wells at EnviroSystems in Hampton. Nweerwe Hfraemeposfhiarpepa)ruenndtesricsktanteiscs,coinndjiutriioenss,.anDduraibnngoramcaclliitmiaetsiaon.tdhaepbhengiidnsniwnegreofntohtettreesta.teDdfaoprhndiidsseawseeraendfed Dyeaapsth,nitdrosutwecrheorn,otanfeddtdhuerfirnegsitvhveateesrt.alga Selenasirum capricormunm once daily before the test. `Supplier: EnviroSystems-daphnids, 3Mtcst substance c`oCnocnecnetnrtartaitoinosnsoftthesetetde:stAsusbcsrteaennciengwetreset0w.a1,s1p.e1r0f0oramnedd 1p0ri0o0rmtgo/tLh:e tdehfeinniutmibveertooxifcrietpylitecsat.teNsowmaisnanolt indicated. For the definitive test, four replicatesof exchof the following fest substance concentrations. were used: 0 (blank control), 150, 250, 400, 600, and 1000 mg/L. Exposure period: 48 hours Analytical monitoring: Test substance concentrations were not measured during the study. tDeisstscohlavemdbeorxycgoennta,ipnHi,ngcoinvdetucetsitviatnyi,maalnsd. temperature were measured and recorded daily in cach 252 000256 (StSatteipsthiacnal, m1e9t8h3o)d.s:TheRepsruolbtisto,fmtohveintogxiacvietryatgees,t worelrieneianrteirnptreertpeodlabtyiosntamnedtahroddstwaatisstuiscealdtteocchanlicquuleaste the 48-hour EC (based on immobilization) using nominal concentrations of the test substance. "cToelsltecctoenddiftrioomnsw:elWlataterEnuvsierdofSoyrsatcecmlsimiantHiaonmopftotnh,e tNeestworHgaamnpisshmisr,e.anWdatfoerralwlatsoxaidcjiutsytteedsttoinag,hwaardsness of 150 mg/L as CaCO, and aerated in S00-gallon polyethylene tanks prior to test initiation. During the astcocclkimsaotliuotniopnerwiaosd p(r2e4p-ahroeudr,sapritohrettoestthseutbessttainncietiawtaiosn)a,dtdheedddiilurtcieolnywtaotdeirlutteimopnerwaattuerer cwoantsai1n9e.d8 iCn.thNeo tceosntcvaenstsrealtsiownisthoofutthethteesutsseuobsftaansoclevewnet.reT0he(bsltaanbkilcitoyntorfotlh,e1t5es0t, s2o5l0u,ti4o0n0s,w6a0s0.noatndin1di0c0a0temd.g/LN.omFionuarl raempolincgatfeosourfereapclhicatteestsocfonacecnhtrtarteiaotnmewnet.reEuxspeod.suTrweevnetsyseldsapwhenrieds25w0ermei.ragnladsosmlbeyaaknedrseqcuoanltlayindiinsgtr2i0b0utmeLd. dofurtihnegtetshtes4o8l-uhtoiuonr (teastp.prDouxriimnagtetlhye7tecstm, tdheeptfho).llToewsitngvewsasteelrscwheermeisrtarnydroamnlgyesar(r0ang4e8d hinouarns)inwceureb:ator determined: Conductivity 800-900 mhosiem (control exposure and 1000 mg/L exposure): pH 8.1 - 8.2 (control 1000 me/L exposure), exposure); D8i.s3s-ol8v.e4d(01;0090.0m~g9/.L5exmpgo/sLur(ec)o;ntTreomlpeexrpaotsuurree),199..51~- 20.1 9.5 C (control exposure mg/L (1000 mg/L. and. eaxcpcoesputraeb)l.e Aleevrealst.ioAn1w6a-shonuortlriegqhutiraenddd8u-rhionugrthdearsktupdhyottoopmeariinotdawiansdiasustoolmvaetdicoaxlylgyemnacionntcaeinnterdatwiiotnhscaobool-ve white fluorescent lights that provided an intensityof45 approximately 0.018 gL. Em". Loading rate during the toxicity test was Remarks: No additional comments. RESULTS Dose of each endpoint (as mg/L): Screening test: LCy= 1000 mg/L, NOEC = 100 mg/L. Definitive test (based on immobilization): 24-hour EC: >1000 mg/L, 48-hour ECy = 584 me/L (95% confidence level~400 1000 mg/L) R1e0m0a%rksusr:vivFaolratthaellsoctrheeernitnegstteedstc,oanfcteenrtr4a8tihoonusr.soFfoerxtphoesduerfei,nitthievreetewta.sal6l0t%estsvuersvsiveallsamtai1n0t0ai0nemdg/a Lclaenadr appearance throughout the study. 100% survival oceurred in the control exposure. Control daphnids had awnasavaeprpargoexiwmeattewleyi0g.h01(8blgo/tLt.edEdxrpyo)soufre o0f.0d00a7pghnaitdtshe0enthdeorfetfheeretnecste. tLoxoiacdaintn,gsroadeiduumridnogdetchye]tsouxlifcaittey,test resulted in a 48-hour LCepof 33 mL and a48-hour EC of 16 mg/L. `Was control response satisfactory (ves/no/unknown): yes Statistical results, asappropriate: No additional comments CThOeNtCesLtUsSamIpOlNeS48-hour ECSO for Daphnia magna was determined to be 583 mg/L, with a 95% confidence intervalof 40-0 1000 mg/L. 253 000257 csSouanbmcmpeilnttertapeturirsio"tnysr,weamsarnkost:prKolpiermliyscchharraancktienrgiz2e. dTaensdtinnog mateteetmsptthweacsrimteardiaeftoorcqouanlfiitrymttesottinsgu.bHsotawnecveer, Reviewers" remarks: The subilers' conclusionsappearto be accurate, based on the data, REFEREHEanNvmCipErtooSny,stNcHm.s,EInnvc.ir1o9S9y0s.teSmtastisctuAdcyutneumTboseirci9t0y13o.f3FX-1003 to the Daphnid, Dapiiia magna, OTHER tOGheNantLemrYeaalNsuOrreMemIdarNtkeAsstL:chTTeEhmSeicTmaalCjcHoornEccMeonIntcCreaArtLniofCnosrOtNbreCyiuEnsNgedTt.osRdoAeTttheIartOmioNnnSee twcheaenrveaacluicsdeuidr.taytefOloyPr PdtheTitsertreemscitonimesmttehhnaetdtsest vocahmleiumneisaclaclacncoonbnceceenantntrdraatmtiuiosontns tbaoerewaohdiliucysh,icofdtordheoexwatnemwsptalorerdg5ab0ny%i5osm0fs%th.areeImefexaapnsaolusyretdei.dcaclIoFnmitceeainsstudrraetteiemorenmnsit,nsoetdhfetsthootxmietchietsyort `vheoalxdaptoibsleuiertnye,cfaounnrcndieosnthtehrdea,rtiwpohenyscsoiuclodchceamliccuallatpercohceemsiscesalthraetcmoivegrhyt rlaotewse.ratnhde tacatkuealintteostacocroguanntishmydrolysis, ptPeuusrtr,iittyyTn(oafstpohpmreeoxteeissmttasmtaeitlteyarpipa5el%aa)rleswdoaitssahautscm1da.0j0or%Wactotesnetcrce,ahrsneomlaivncedanltwwaasissnoouptsrseoudpf,afinfcooirle)onotthrleyrscchaoarmcabhcietnmeairtciiazoeldnoofifnlbtehosistsehr sawtagatsree:ues"eDwdaittihnaomtthaihysercnotonetcseasrc,nc.fuorranItnoeaoldybdvirtieilooaunt,se tisftotxhaiitceisdtywraeoafssotanh.e"ttyeIpsnitcfasalca"tm,pT3lSeMCwAiintshtehtcehtiairrosonufm4tmhraeerveyiseotwf.scu|abwscothuanl(codset." mreejaescturtehemseentsstuodfiets,hepetensdticnhgemriecceailptionfthaeddteisttiomneadliiunmf,ormation on purity and studies on analytical 254 000258 AQUATIC PLANTS TOXICITY cTaitplrei:coGrrmouwttuhm and Reproduction Toxicity Test with N2803-3 and the Freshwater Alga, Selenastrum TEST SUBSTANCE pIdeennttaidteyc:aflPueorrfol-u,orCoAocStaRnNoi3c3a5c-i6d7;-m1)ay also be referred to as PFOA, FC-26, or FX-1001. (Octanoic acid, Rlaebmoarartkosry:asThNe2830M3-3p.rodTuhcetipounriltoytonftumhbeesrwamapsle26w9a.sTnhoet tseusftfiscaimenptlley wchaasraFcCt-e2r6i,zedr,efaelrtrhedoutgohbcyurtrheenttest pienrfofrlmuaotrioo-nhoimnodilcoagtueedcitomwpaosuandmisx.tuTrheeofte9s6t.s5a--mpl1e00w%atseastwshuibtsetpaonwcdeera.ndA0.s- st3a.t5ed%bCye,thCe-,saunbmdiCtoer, the swaatmeprl:eisporperpoapraantoilonsodliurteicotni.onIsngtihveepnrotototchoellaamboernadtmoeryntw,eritewoasdisstsaoteldveththaetehsetsmaamtpelreiawlaisn cao5m0b:i5n0ed with isopropanol ina 50:50 ratio prior to use. METHODS Method/guideline followed: USEPA-TSCA Guideline 797.1050 Test type: Static GLP (VIN): Y ear study performed: 1995 f`eSapsetcie1s4:daTyhseparligoarc0wethreedeafcicnliitmiavteetdesitn.sTtehreiles,uben-rsiacmhpelde moefdailagaaenudsmeadinotaiinnoecdulaateesmtedcionadaittitohnesstfaorrt aotf the definitive test was from a 10-day old culture. `ASuustpipnl,ier: The supplier ofthe algae culture was the Culture CollectionofAlgac at the UofTexas at Measure of growth used: number of cells/mL, growth rate Cusoendc:en0t.r0a5t0,io0n.s50t,e5s.t0e,d:anFdor50thmegr/aLng(et-hfeinnduimnbgetreostf, rtehpelifcoaltleoswiwnagsconontcesnptercaiftiieodn)s. oFfotrestthesudbesftiannitcievweetreset, oinsoepdriolpuatnioolnawnadtetresctonsturbosltaanncdef(iNv2e8n0o3m-i3n)alwacsonccoennstirdaetrieodnstowebree1u0s0e%d itnestthseusbtsutday.nceThdeur5i0n:g50them.ixture of (pe5r0f%orNm2a8n0c3e-o3ftahned t5o0xi%citiysotpesrto.paAnlollr)esaunldtstewsetrseubrsetpaonrtceedasb-ortehceoinvetdhe(bNa2s8i0s3o-f3tewsittshuobusttaisnocperoapsa-ntoels)t.edThe a0s.-3t2e.s6e3d,co13n0c,en2t5r0a.tiaonnds 5w0e0rem:g/0L,.63T,hr1e2e5,r2e5pl0i.ca5t0e0s,ofanedac1h00c0onmtgro/lL:antdheteasst-croencceeinvterdactoinocnenwterraetiuotnisliwzeerde: under static test conditions. Exposure period: 96 hours 255 000259 PAnHaliyntciaccahl tmeosntivteosrsielngw:asComnecaesnutrreadtiaotntshoebfetghientneisntsgubasntdaenncdeowefrtheentoetst.meIanscuurbeatdordutreimnpgerthaetusrtuedwy.asThe mwietahsutrheedteastndverseseclosr,dewdasdaicloyn.tiTnhueoutselmyperreactourrdeedi.na representative vessel of water, which was incubated Setsattiimsattieca7l2-meatnhdo9d6s-:hoCuerllECdeinqsivtaielsu,esgarnodwt9h5r%atec,onafniddepnecrceelnitmiitns,hibwietrieoncavallcuuelsa,tewdhuiscihngwetrhee. used to bcienlolmviiaml.inttheerapvoelraatgieonsmpeetcihfoicdg(rSotwepthhanr,ate1,98a4)n.dAtlhle ncaolmciunlaalticoonnscweentrreatpieornfsoorfmtehdeusteisntgstuhbestnauncmeb.erThoef noo(bAsNerOvVeAd-)c.fftehcet-ncuomnbceenrtroaftcieolnls(iNmOL,ECa)ndwtahsecaavlecrualgaetesdpeucsifiincaggrpoawratmhertartiecionncea-cwhatyesatnavlesysseils oatftvhaerieanncde.of the est. `Tceosmtbiconnidnigtdieo-niso:niTzhede waalgtaelrmaenddinuutmriweanst sptroecpksa.reWdaatcecrorudsiendgftoorUthSeEaPccAlirmeactioomnmoefndtheedtceotncoerngtarnaitsimosnsabnyd ufosreal(lthteopxiHcoitfyttheestsiynngtwhaetsicstaelrgilael,menerdiicuhmedatmetdesita,inaitdijautsitoendwtaosa7t.4a)r.getAlpgaHlofm7e.d5iuwmitwha0s.1usMedHfCoIr cpurlitourrtiong afnordmauslatthe tdeisltuemnet.diaA,chweamsicpearlfocrhmaerda.ctPehriozsapthioornooufsa,rneiptrraetsee,ntaantdivcehlsoarmipdleeweorfetedsettmeecdtiead,aantdhewfaotlelrowuisnegd to cmoendceinutrmatiinocnlsu:ded0.c4a6.dm0.i0u8m. a(0n.d001042mem/gL/,L)reasnpdelcteiavdely(.0.0H8eamvg/yL)m.etOatlhsedretpeoctteentdiainl tchoendtialmuiennatnatsndweterset at or below active ithnegrleedvieelnotfadnedtetcotbieons.taTbhlee test substance under storage a(nasd-rteecsteiinvgedc)onwdaitsioansss.umAed101000hamvge/La purity of 100% primary stock Seonlruitcihoendofmetdhiea.teAstppsruobpsrtiaantcee a(maos-uensttsedo)ftwhaiss psrteopcakrseodlubtyiocnowmebrieniandgdNed28d0ir3e-c3t(layst-otedsitleudt)ioannwdatsteerritloe, o1r0,m0u0l0atceeltlhse/mtLe.stEmxepdoias.urAelvgeasesewlesrceondsiisstrtiebdoutfed25a0momnLg gthlraeses rEerplleicnamteeysoerfcfalacshkstcroenattamiennitnagt5t0hemrLateofoftest Solution. Test vessels were randomly arranged on4 rotary shaker adjusted to 100 rpm in an incubator wduerriengintthheetersta.ngTehoefp2H.9o-f4t.ah0teessttsionliuttiaitoinosn.oArsthseta2t5e0d.b5y0t0h,easnudbm1it0t0e0r,mgth/iLs leoxwpopsHuremacyonhcaevnteraatdivoenrssely ahfofuercst)edwetrhee sausrvfoilvlaolwsa:ndpsHubrsaenqgueen=t7g.r4o~wt1h0.o3f (tchoentarlgoalc.exTpohseurmee)a,s2u.9re-d w3a.0te(r1c0h0e0mimsgt/rLyevxaplouseusre()0,-9m6ean mteamipnetraaitnuerdewriatnhgceo~ol2-3w.h5it-e24f.luCo.reAsce2n4t-hlioguhrtsitghhattapnrdov0-ihdoeuadrldiagrhkt pinhtoetnospietryoifoadpwparsoxaiumtaomtaetliyca3l8l0y `fcoooutnctasndwiictsh.aAlhgeamloccyeltlomceotuenrt.s in each test vessel were determined daily by means ofdirect microscope Remarks: Water hardness was not indicated. The pH for many exposure concentrations was outside the. accepted range for S. capricormunm toxicity testing (1.50.1). As stated by the submitir, there appearstobea discrepancy between the sample preparation dircetions given to the laboratory and the procedure conducted by the laboratory to prepare the test solutions. RESULTS dDeofsineiotfiveeascthudeyn.dtphoei9n6t-h(aosurmgE/LC):(aTnhdeasNsOocEiCatefdor9t5h%ercaonngfei-dfeinncdeinlgimsittus)dywwasas15800 mmg/LL. (F1o2r5 t-he2.50 mg/L). based on test substance as-ested (50% N2803-3 and 50% isopropanol) and 90 mg/L (63 - 130 256 000260 `mmgL/L), .rebsapescetdiovneltye,stbsausbesdtoanncefesats-sruebcsetiavendc.e Tahtees9t6-.hoTuhreN9O6E-hCouarndNOLEOCECanvdalLueOsEwCerveal1u2e5s awnedre25630 and a1b3l0emg| /L, respectively,basedon he test substance as-received. The cell growth data is presented are c"Taapbrleic1:orCmelulnmgrowth dataofacute toxicity test with N2803-3 and the freshwater algae, Selenastrum "Ncoonmceinntraatlion Numberofcellyml x10 (hour) InPheirbcietniton|| InPheirbcietniton Gasmetelsted), | Hours I EE = 7 [>] Devnisaity | GrRvoiwoath [Come Tio TRI Se[aa [wert| - [- 63 [wo ToaTee Ta [ame[4| 2 2s The ar eeTs use |v 0 250 To eeTeoTao cio Te[doo | [ Co sooT To oT Ti=oTi<o01< =t0o [<=ii [i10w0 | 1t0o0o]] Rheemaalrgkase:totAheffl9la6shkesouinrrtsheofecoxnpiorsoluroer,antyhrfeeswtetrreeantomesnitgngsrooufp.agIgnreagdadtiitoionn,,ftlhoecrceulwaetiroen,noornaotdihceearbelenocfe cdehtaenrgmeisniendcteolbseizael.gicstaoic.olrnomtooralpghirocdlao,lg,ybawsheednocnotmhpearreesdulfisotfhethceonptrooslt.-dTehfeiietfvfeetteosft Nex2p8o0s3ur-e3. wAaSs (sWtaatredd.beytatlh.e s1u99b5m)idteem,onbsiiolroagtiecdaltdhaatta1g0e0n0emragt/eLdboyfisaopprreovpiyolusalecxophooslurdeiod fnoatlgianchi0biigsroopwrtohp.ylTahlicsofhionlding oifndNi2c8a0te3d-3t.hatTetshte scuobnsctenatnrcaetcioonncoefntirsaotpiroonpsylabaolvceoho1l25imteh/eLtersetdcuhceemdicpaHl vdailduneostt0ac4.c0 ouanntdfolrowtehr;totxhieciotwy. `cpoHncmeantyrahtaivoen coafutseestdsiunbhsibtiatnicoenoofbsaelrgvaeedgtroocwatuhsae 1h0ig0h%ermocrotanlciteynwtarsa2to5i0fotmengs/stL.substance. The lowest Was control response satisfactory (yes/o/unknown): yes Statistical results, as appropriate: No additonal comments CONCLUSIONS "gThLe,NObaEsCedfoornttheestrasnugbes-tfainncdeinasg-stetsutdeyd,waansd090mmg/eL..Fboarsethdeodnefeisntitsiuvebssttaundcye,ast.heoc9e6i-vheodu.r ETCh:eq9w6a-sho1u5r0 'reNsOpeEcCtivaenldy.LOEC values were 125 and 250 me/L (s-tsted) and 63 nd 130 meL (as-received), cSounbcmeintttreartsi"onrseimnatrhkese:stKsloilmuiticohnsr.anSkaimnpgl3.e Tpuhreitsytuisdynoltacskuscaincanlyttliycaclhamreaacseurrizeemde.ntAdodfitteisotnsaulblys,tatnhceere appears tbea discrepancy between the sample preparation directions given to the laboratory and the 257 000261 phraovceebdeuerne cadovnedruscetleydabfyfetchteedlbayborianittoirayl tloowprpeHparvealtuheestienstthseohluitgiohnesr. tSeustrvsiuvbasltaanncdegcrooncwetnhtroafttihones.algae may fRuervtiheerweirnsc'reraseemdargkrso:wthThienhciobintcilouns,iwoanssacplepaeralry 0satbeedsuapspaoprotsesdibblyetshoeudractae.ofThrreolro.w pH, which may have REFERENCE "FTrRe.shWwialtbeurrAylgLaa,boSrealteorniaesst,ruInmc.ca1p9r9i5c.orGnruotwutmh. MaanrdblReehperaodd,uctMiAo.n TSotxuidcyitnyuTmebsetrwBiOt3h-NT2H,803-3 and the OTHER `General remarks: ONLY NOMINAL The major concern TEST CHEMICAL for trying to determine CONCENTRATIONS the validity were used. for this test is that OPPT recommends tchhaetmimceaalsucroencdetnetsrtacthieomnitcoalwhciocnhcteontthreatteisotbnoesrgwasneids.smsoatrheatexopnoesecda.n aIcFciturisadteetlyerdmeitneerdmitnhatthtehetest vnaolmuiensalcacnonbceenatnrdatmiuosntsbaeraedojnulsyt,efdordeoxwanmwpalred5b0y%oSf0t%.he Imf eaansaluyrteidcaclonmceeansturrateimoennst,sthoef tsooxmiceitsyort vhoaldatibleietny,faunrndiosthehde,r wpheysciocuolcdhceamliccuallatpercohceemsisceaslthraetcomviegrhyt rlaotwese,ratnhde tacatkuealintteostacocroguanntishmydrolysis, exposure concentrations. 258 000262 TOXICITY TO INVERTEBRATES "Tite: Acute Toxicity ofN2803-3to the Daphnid, Daphnia magna TEST SUBSTANCE Identity: Perfluorooctanoie acid: mayalsobe referred tas PFOA, FC-26, or FX-1001. (Octanoic acid. pentadecaluoro-, CASRN 335-67-1) sRaemmpalre.ksF:C-2T6h,e w3aMs prerfoedrurcetdioton bloyttnhuemtbesetrwlaabsora2t6o9r,yTahseN2te8s0t3s-u3b.stTahnecepuwraistyaowfhtihteespaomwpdlere.waTshenottest sufliciently characterized, although available information indicated it was a mixture of 96.5- 100% test substance and 0 ~ 3.5% C. C7, and Co perfluoro- homologue compounds. METHODS `Method/guideline followed: U.S. EPA-TSCA Guideline 797.1300 Test type: Static GLP (Y/N): Yes, with one excepiion: the stability ofthe test substance was assumed, but not verified Year study performed: 1996 `Species: Water used for acclimationofthe test organisms was deionized water collected at TR. Wilbury sLpabeocriamteonrsiewseirneMparrobdluecheedadb,yMadAu.ltDdaapphhnniiddssctmhaptloweyreed mianitnhtasitnueddyuwnedreer tfeestsctohnadni2ti4onhsoufrosr omlod.reTetshtan 7 days. The original culture was obtained from Aquatic Research Organisms, Hampton, NH. During aacbcnloimmmaatliiotn,esdaatphensitdsiniwteiarteionn.otTthreeraetewdfaosrdniosemaosret.alitthyeyduwreirnegftrheeeo4f8ahpopuarrsepnrtesciecdkinnegsst,heinsutraitcso,fatnhed test. dTahielycudlutruirnegwaacsclsiumaptpiloine.d wDiatphhaniydesaswtetrreountotcfheodwdumriixngantdhethteestf.reshwater alga Selenastrun capricornutum `Supplier: TR. Wilbury Laboratories supplied the test organisms. 3M, the sponsor, supplied the test Substance. Concentrations tested:Forthe static screening test, the nominal concentrations of the test substance (acsaecrheccoenicveendt)rwaetrieon:w0er,e05us0e,d.0.5T0.h5e.0fol50l.owainndg Sn0o0mimnga/lL.conFcoerntthreatsitoatniscwdeerfieniuttiilviezetde:st,0tw(bolraenpkliccoanttersoo)f, 130. 200, 360, 600, and 1000 mg/L (estaes da 50:50 mixtureof est substance and isopropanol). The annodmi5n0a0l cmogn/cLe.ntrationoftest substance (as-received) in solution was 0 (blank control, 6, 110, 150, 300, 259 000263 Exposure period: 45 hours fAensatlsywteircealbamsoenditoonrinnogm:inTaelstcosnucbesnttarnacteiocnosncoefnttersattsiuobnsstawnecer.e nDoitssmoelavseudreoxdygdeunr,ingpHt,hecostnudduyc.tiAvliltyt,oxaincdi.ty tteemmppeerraattuurree wineraebemaekaesruorfedwaatnedrrienccourbdaetdeddaaimlyoningetahcehtteetstvcehssaemlbsewratsharteccoonrtdaeidnceodntliivneuoanuismlaylsd.urTihngethe test `Statistical methods: LC:o and EC values were calculated, when possible. by probit analysis, moving `average method, or binomial probability with non-linear interpolation (Stephan, 1983) Test conditions: aWtatTeRr. uWsieldfbuorryacLcalbiomraattioornioesftinheMatresbtleohregaadn,isMmAs.anWdatfoerrawlaossaidcjiutsytetdesttoinaghwaarsdndeesisonoifze1d60wate1r50comlgle/cLteads tCharCoOu,gaahndpasrotriteed fiinle5r0,0u-lgtarlalvoionleptolsyteertihlyizleern,eatnadnkasc,tiwvhaetredeciatrwbaons.aeAractheedmaincdalccohnatriancutoeursilzyatpiaonssoedfa representative sampleofdilution water detected iron at 0.03 mg/L: al other potential contaminants were. breecleoiwvetdhefrleovmeltohfedseptoencstoiro,nwoirthnoitsopprresoepnatn,olThineate5s0t:s5u0bsrtataon.ceHwowaesveprre.patrhedtbeyt csuobmsbtiannicnegpNr2ep0ar3a-t3i,oansdirections given 10 thelaboratorywere todissolvethe test material in a 0:50 watersopropan solution, aTrheisre5p0o:r5t0edmioxntaurneacwtaisvethienngrceodinesnitdbearseidsto(acbteiv1e 0i0n%grfesdtiesnutbisstathneceesdtursiunbgstthaencteoxaisc-irteycteeisvte,dbumtinalulsretshuelts isopropanol). The test substance was assumed (0 have apurity of 100% active ingredient and to be stable under storage and testing conditions.Forthe test organisms, measurements made during the 7 days prior 0 the startofthe definitive test with N203-3 indicatead culture temperature range of 19.5 20.5 C and. a dissolved oxygen concentrationof at feast 9.1 mg/L. A 1000 mg/L stock solution was prepared by cfionmalbivnoilnugm2eo.0fgo20f0t0hemLt.estTshuebsttesatncvees(s5e0ls:5w0ermiex3tu0r0emoLf Ng2la8s0s3b-e3akaenrdsitshaotpcroontpaainnaeodnld)25d0ilmutLioonftweastter to a solution (approximate depth was 9 cm) during the test. Appropriate amounts of the stock solution were w`aedrdeedintoddiislcurtiimoinnatwealtyeanidn teeqsutavlelsysedlissttroibfuotremdualamtoentgestt moedriepaliwciatthestohfecuasceohftaestscolovnecnetn.trTatwieonn.tyTdeastphnids vessels were randomly arrangedin an incubator and loosely covered during the 48-hour tes. During the definitive test, the following ranges were estimated from measurements: dissolved oxygen = 8.7 - .3 `mayn/dLS,-htoeumrpedraartkurpeh=oto1p9e.r4i~od20w.i7thaC,1c3o-nmdiucntuitveittrya=nsiSt7i0on pe61r0i.od wmhaossiaeutmo,maptHic=all$y3ma-8i.n5t.aiAned16w-ihtohurcoloilg-ht white fluorescent lights that provided a light intensityof$8 footcandlcs. Aeration was not required to maintain dissolved oxygen concentrations above an acceptable level. A static test was conducted with 390 mg/L isopropanol andadilution watercontrol. Two replicates of ctahechtecstonwcietnhtrNa2t8i0o3n-3a.nd1Me0asduarpehnmiednst/srempaldiecaduwreirnegutsheed.7 dTahyiss tpersitorwa(0s conducted in a mannersimilar to i2n0i.t1i-ati2o0.n9oafnthde iasdoipsrsooplavneodlotxoxyigceitnyctoenstc.enTthreasteiomnoeafsuatrelemaesntt8s3inmdgi/cLa.teTdahecutelstturveestseemlpsewreatruererarnadnogmeloyf easrtriamnagteeddifnarowmamteearsbuartehmaenndtsthdeuriignhgt tihnetetnessitt:ydwiassso1l3v-ed 205; f=oo8t.c1a-ndl8.e5s.mTgh/Le,ftoellmopweirnagturraeng=e2s0w.e4r-e 209 C. conductivity = 530-540. mhosiem, pH = 8.3 8.5 260 000264 Remarks: No additional comments RESULTS DoseofBcaascehdeonndpeositnstu(basstamngc/eLa)s:-rLecCei.veadn:d EC.valtes and 95% confidence intervals 2244--hhoouurr ELCCs==4S2000 ((337000 -- >459000))mmagl/lL c48h-hoouur LEC.Ca=~.430q600 ((330500-4- 65000)) mmgg//Ll Based onhtoesut srubNstOaEncCe~as-1t8e0stmedL(50:50 ratio of N2803-3:sopropanal): 2dehoouurr ELCCx.o=~ $140000(7(4600-0-9170)0m0gm/0Lg/)L h48ochuourr LECCa.y == $70200 ((760600--798200)) mmgg//LL 48-hour NOEC= 360 mg/L oRbesmearrvkeds:anDdurtihneg48t-hehotuorxiEciCtiyqeasndwLitChio39va0lumegs/wLeriesop>ro3p9a0nomly,/Ln.o mFoorrtatlhietsycorreesnuibnlgettheaslte(f4f8e-cthsouwresrpeoste1x5po%susruer)vi,vhaleraei Sw0a0smag/lLe.as(tsu9r5vi%visnugrvdiavpahlanitd0s(ebxlpaonskecdon0tro5l0)0. m0.y0/5L0,w0e.r5e, ainmmdob5i.0limzge/d)L.. ADlusroi,ngthtehree was deexfpionsiutriev,e ttohxeicciotnytrtoelstdwaipthhniNd2s80h3a-d3a,nnaoveirnasgoleubwleetmwaeteirgihal(wblaosttnedo)teodfdur0.i53nmget.heTtheest.feAsftisourbs4t8anhcoeu:rs of c(onNt2ro8l0sd3u-rd3iin)dgntohtecdaeufsienit1i0ve0%tesmtorotralsictryeeantianngytecso.ncTeanbtlreat1iodnepeiscttesdc.uNmuolamtoirvaelipteyrcweants moobrstearlvietdy oifntthhee definitive tes. "Table 1. Cumulative Percent Mortality Wsaatsisfcaocnttorroyl | co[nNcrenitnraaltaiosnte(smge/dl) Whours Whours [~Blankeontol[0] 0 [me 0 0 ene Te10 01 [Teo 7Th0 ] is Chew 50 1] 30. (yesimolunknown): Yes Statistical results, as appropriate: No additional comments response CONCLU"TSheIOasN-Sested est substance (N2803-3) 48-hour LCS0 for Dapiinia magna was determined to be 8ho0u0rmECLS0wifotrhDaa9p5hn%icaomnfaigdneancweaisndetteerromfivn7ae0dl0t~o b9e2072m0e/mLg./L.Thweitahs-es9t5e%d tceosntfsiudbesntcaencinet4er5v-al of 261 000265 6w6a0s -367080mgm/gL/.L.ThTehe48a-sh-otuerstLdCtSes0tfsourbDstaapnhcnei4a8-mhaogunra,nob-aosbseedrovendt-heeffceoentc-ecnotnrcaetnitornaotfitoens(tNOEC) 4s6ub0stmaLnc.e iTnhseol4u8ti-ohnouwrasECd.eqtefrormiDnaepdhtnoibaem4a0g0nmag/bL.asewditohnath9e5c%onccoennftirdateinocne oifntteersvtasluobfst3a5n0ce--in s4o8l-uhtoiuorn nwoa-sodbesteerrvmeidn-eefdetcot-bceon3c6e0ntmrga/tLi.onwi(tNhOaE9C5)%focrotnhfeideesntcesuibnsttearnvacleoifn 3so0l0u-tioSn00wamsg/1L5.0The mg/L. Scounbcmeintttreartsi"onrseimnatrhkest:estKlsoilmuitsicohnsraanndksian3mg.plTehpeursittuydyi lnaoctkssuafnfailcyiteinctallymcehaarsaucrteermiezendt.ofAdtdeisttisounbasltlayn,cet.here appears to bea discrepancy between the sample preparation directions given to the laboratory and the. procedure conducted by the laboratory to prepare the est solutions. Reviewers" remarks: The author's conclusions appear 0be supported by the data. REFERENCE TR. Wilbury Laboratories, Inc. 1996. Acute Toxicity of N2803-3 to the Daphnid. Daphnia magna. Marblehead, MA. Study number $92-TH, OTHER General remarks: The major concern for trying to determine the validity for this test is that OthNatLmYeaNsuOrMeId NteAstLchTeEmSicTalCHcoEneMeIntCrAatLioCnsObNeCuEsNedT.RsAo TthIatONonSe wcearneacusceudr.ateOlyPPdeTterremcionmemtehnedtsest chemical concentration to which to the est organisms are expased. Ifit is determined that the nvaolmuiensalcacnonbceenatnrdatmiuosnts baereaodnjluys,tefdordeoxwanmwpalred5b0y%oSf0%t.heImfeaansaluyrteidcaclonmceeansturrateimoennst,sthoeftsooxmiceitsyort had been furnished,we could calculate chemical recovery rates, and take into account hydrolysis, volatility, and other physicochemical processes that might lower the actual test organism exposure concentrations, 262 000266 AQUATIC PLANTS TOXICITY Title: Growth and reproduction toxicity test with FC-101S and the freshwater alga, Selenastrum capricornutum `TEST SUBSTANCE AIdmemntointyi:umPeprfeurlfolruooorcotoacnatiacnoaec,id,PFaOm,mFoCn-i1u1m6,saFlCt;-1m2a6y,alFsCo-b16e9,reFfCer-r1e4d3toorasasPtFhOe Amaajmormoconmipuomnesanltt, of FC-1015. (Octanoic acid, pentadecafiuoros ammonium salt, CAS #3825-26-1) Remarks: The test sample is FC-1015. Lis purity was not sufficiently characterized, though current iTontfnorummabteiornwiansdi"caHtOesGiEt is20a5.3"0%Dasttaraimgahyt cnaortbaocncucrhaatienlyverresliaotne otofxiFcCi-ty1o4f3thine8t0es%t swaatmeprl.e Twihteh3thMatporfotdhuect test substance. Data were used (0 compare toxicity of the branched!straight chain ammonium apemrmflounoirouomctpaenrofaltueohrooomcotlaongotmeixitnuFrCe-i1n0E1C5-143 v. what is supposed tobe the 100% straight carbon chain METHODS. Methodguideline followed: OECD 201, USEPA-TSCA, Guideline 797.1050 Test type: static GLP (VIN): N ear study performed: 1996 Species: Selenastrum capricornutum Supplier: Universityof Texas at Austin Measure of growth used: algal cell counts (cells/mL), cell dryweights Concentrations used: 0,210, 430, 830, 1670, and 3330 mg/L. The concentrations were nominal. Three. replicates at cach concentration were ested. Exposure period: 96 hours Analytical monitoring: none `Statistical methods: Probit analysis "Test Conditions: The algac were grown in sterile enriched nutrient medium per USEPA 1978 guideline anuntdriweenrtseaelslseonwteiadl 1fo4rdaalygsalfgorroacwctlhimaantdioanlstoostehrevecodnadsittihoensd.iluTehnet nfuotrrailelnatlmgaeldoipuermpatrioovnis.dedTahelpmHionefrathlis s3y3n3t0hemtiyc/Lalgsatlocmkesdoiluutmiownawsaasdjpursetpeadre0d 7b.y5dpirliuotring 3u.s3e3ign aosfsatyess.t suFbosrtparnecpearinat1iolntoefotfhewaetsetr.soAlultiiqouno,tsa 263 000267 wuseerde wtehrene a2d5d0emdid.irEerelleynmteoydeirlsutcioonntwaaitneirngin1t0e0stmvie.sesesltsstooluctrieoanteantedstcsaoplputeidonwsi.thTihneveerxtpeodsgulraessvebsesaeklesrs. 1"0Th0ervpems.selFsowuerrheulnodardeedd fwoiotth-caanndilneistaolflciognhctenitnrgawteiorne opfro10vxided10byceclolnst`imnLuouasndcosohla-kwehnitceonftliunoureosucselnytat 7Vi.g4h7ti.n6g/.(3T3h3e0 wmagt/eLr cehxepmoissutrrey) apnadratmeemtpeerrsatmueraesu=re24d.0d-u24r.i2ng(itnhceubeasttori)nc.ludTehdr:eepHrep-li7c.a5t-e1s0o.8f cthoentrol) and e`Axpppeernidmiexntfowrepraerapmereftoerrmseda.nd Mdeetaescutrioenmelnitmisto).fdiTlhuetioonnlywactheermcihceamlisdtertyectweedrewaaslsiorponerafto0r.m0e3dm(gs/cLe. wRietmhainrktshe:aTccheeptpaHblrearnagnegef.orWtahetecronhtarrodlnwesass,oduutrsiindgetahcecespttuadbyl.ewlaismitnso.lbiuntditchaeteod.ther tested sample was RESULTS Dose ofeach endpoint (as mg/L): Val2u4ehs cEaClcSu0la=t2ed51u0si(n1g3c4e0ll-3c3o3u0nt) (mgc/eLllmy 3782hh EECCSS00>=32303400 m1a1l9l0.-3330) mg/L 9966 hh NECOSE0C==1291800(m1g7/1L.0-2360) mg/L 96h LOEC- 430 mg/L V2a4lueEsCcSa0lc~ula1t7e0d0u(s6i7n3g-t3h3e00a)vemrga/gLe.specific growth rate: 3782h EECCSS00>> 31333300 mmgg/L 9966hh NECO5E0C>-3433300 mmgg//LL 96 LOEC = 830 mg/L RToeumras.rkBsa:seAdloinquogtrsowotfhthoebs3e3r3v0edmgi/nL.thteesrtecsoolvuetriyonphwaesree, dthieluetfefdecwtitohn aallggaallmgerdowituhmwaansdfcouulniudrteod bfeor 72 alist. Was control response satisfactory (ves/no/unknown): yes Statistical results, a appropriate: none CONCLUSIONS FatCe-1v0a1l5ueoexfhi>b3i3ts3039m6g/hLo.urTEheC9O6chelolurcoNuontOvbasleurevoefd 1E9ff8e0ct(1C7o1n0c-e2nt3r6a0tmiogn/L()NaOnEdC)a 9is62h1o0urmgE/CLSOfogrrcoewllth cceolulnctoaunndt 4an3d0 $m3g0/Lmeo/rLfgorrowgtrhowratthe. raTteh.eTLhoiwsestetstOsbusbesrtvaendceEfwfaesctdeCtoencremnitnreadttioonbe(LalOgiEsCta)tici.s 430 mg/L for mSuebtmsitrtietrrsi!arfeomraqrukasli:tyFtoerstdinagt.a rHeofawbeivleiry., thilsacsktsudiynfwoarsmaatsisoingnoendatheKlpuirmiitsycohfrtahteinegostf2s.ubsTthaencsetaudnyd thacetu4alK mheoaursurvealmuegnstswoefrtehien aexmcoeusnstofof24teshtosuurbvsatlaunecs.e in solution. Also, no explanation i given a5 10 why 264 000268 Reviewers' remarks: none REFERENCE WaT.r, Nedvius,, J. and R. Boeri. 1996. Growth and reproductiontoxicity testwith FC-1a0n1dt5he freshwater alga, Selenasirum capricormunm. TR. Wilbury Laboratories, Inc. Lab Request number P1624. 3M CompanyS,t.Paul, MN. OTHER General remarks: The major concen for trying to determine the validity for this test is that OthNatLmYeaNsuOrMeId NteAstLchTeEmSicTalCcHoEncMeIntCrAatLioCnsONbeCuEsNcdT,RsAoTthIatOoNnSe wcearneacucseudr.ateOlyPPdeTterremcionmemtehnedtsest chemical concentration to which to the test organisms are exposed. IF i determined that the vnaolmuiensalcacnonbceenatnrdatmiuosntsbaercadojnulsyt,efdordeoxwanmwpalredSb0y%5o0f%t.he ImFaenaasluyrteidcaclonmceeansturrateimoennst,sotfh stooxmiceitsyort hvoaldatibleietny,faunrndiosthehde,rwpehycsoiuclodchceamliccuallatpercohceemsisceaslthraetcmoivegrhyt rlaotewse,ratnhde atcatkuealintteosatcocroguanntishmydrolysis. exposure concentrations. Pteustr.ityTonfstohmeetteessttsmaittearpipaelaarlesd itshaat m1a0j0or% ctoesntccehrnemaincdalwawsasnoutsesdu,fffoircioetnhtleyrschaarcahcetmeirciazleodfinletshsiesr purity (approximately 5%) was used. Water,a solvent isopropanorla) combination of both swtaatse:us"eDdatian omtahyerntoetstasc,cfuorrantoelyorbevliaotues tsotxaitceidtyreoafsotnh. teIsntiscatm,p3leMwiinththtehiartsouftmhmeartyestofsuebascthantecset." Treajgercetethweistehstthuidsiecso,ncpeernnd.inIgn raedcdeiitpitono,fiafddtihitsiownaasl ain"ftoyrpmiactailo"nToSnCpAursietcytaionnd 4sturdeivesieown,Ianwaoluyltdical measurementsofthe test chemical inthe test medium. APPENDIX Parameter: Metals AArlsuemniicnum Boron CCahdrommiiuumm Cobalt Cforopnper Lead NMiecrkceulry. Silver Zine Detection Limit: 00.011mmgetl 0.5 mg 00..00100m2g/mgL/L. 0.03 mel 00..00305mgm/ol.t. 0.005 mL 00..00300m3emle.lt. 0.02 mel. 002mg 265 000269 Nitrate 005 mg NIL Chloride Img Fluoride 0.1 mel "TToottaall porhgoasnpihcocraorubson 0I.m03glmLp. OrTgoaxnoacphhleorniene Pesticides 025 g OrDgiamneotphhooastpeh:orous Pesticides 0.5 pg/L201 TEPP 20pgl penMsonocrtophos, 0250ppg 266 000270 INVERTEBRATE TOXICITY Title: Acute toxicity of FC-1015 to Dapheid, Daphnia magna TEST SUBSTANCE. AIdmemntointyi:umPeprefrlfulourooroocotcatnaoniocataeci,d,PFaOm,moFCn-i1u1m6,saFlC;-1m2a6y,alFsCo-b16e9r,efFeCr-r1e4d3toorasasPtFhOe Amaajmormocnomipuomnesanltt, of FC-1015. (Octanoic acid, pentadecafluoro- ammoniumsall, CAS #3825-26-1) Rinefmoarrmaktsi:onTihneditceasttessaitmpislea i3s0F%C-s1t0r1aSig.ht TciasprubrointcyhwaiansvneortsisounffoicfieFnCt-l1y4c3hairna8ct0e%rizweadt,ert.hoTuhghe c3uMrrepnrtoduct lot number was "HOGE 205. METHODS Methodiguideline followed: USEPA-TSCA, Guideline 797.1300 Test type: satic GLP (VIN): N ear study performed: 1996 Species: Daphnia magna. ess than 24 hours old, wet weight =0.35 mg. Suppliers initial brood stock from Aquatic Biosystems Concentrations used: 0,430, 730, 1200, 2000, and 3300 mg/L. The concentrations were nominal. Two replicates at cach concentration were ested Exposure period: 48 hours Analytical monitoring: none Statistical methods: Probit analysis "mTge/stLC(oansdCiatCiOoyn)s,: wThhiecdheiisonwiitzheidnditlhuetaicocnewpattaebrleusraendgen. thTeheteswtatwearswaadsjupsatsesdetdotahrhoaurgdhneasspaorfti1cu6l0a-t1e8f0ilter, ultraviolet sterilizer, and activated carbon, Water used for the test had hardness of 176 mg/L and an aolrkgaalniincitcyarobfon1,08 Fmugr/tLhearsmCeaaCsOuyr,emaenndtsiot fcodnitlauitnieodn <w0a.t0e1r cmhge/mLisprarytiwceurlaetealmsaotpteerrfaonrdme<d1 (msgce/LAptpoetnaldix. wfoerrpeacrraemaetteedrsbyanddiredcettewcetiigohntlsimaidtdsi)t.ionT.heGolnalsysbcehaekmeicrasl(d3e0t0emctLe)d wcoanstarinoinngat 205.003mmLg/Lte.st sToelsuttsioolnut(i9oncsm. depth) were used as exposure vessels. They werelightlycoversd during the experiment. Two replicates. ach of10 daphnids, were tested at each concentration. Cool-white fluorescent lights at 130 foot-candles. 267 000271 pweerrieoduswcadsfmoarilnitghatiinnge.d tAhrdoauiglhyoupthotthoepteersitoidngofpe1r6iohdours ight and ours dark with 13 minute transition m"Thheowvateemr c(hceomntirsotlr)yapnadr7a1me0t-e7r2s0mheasouresd du(r2in0g00thmegs/tLudeyxpiensculurdee)d,:pcHon~du8c2t-i8vi3y(rcaonntgreol=)a6n1d0-62801.8.2 (di2s0s0o0lvmedLoxeyxgpeons~ure8)..19t.e1mpmeraatlurceo~ntr2o0l.)4-an2d0.87.C19(.c1onmtr/olL) a(n2d00200.m3g-/2L0e.x8pCos(ur2e0)0.0 mThLe 2e0x0p0osmugre/)L, and 8(sehcoounrds.highes) concentration ws sed because he highest concentration resuled in otal mortality by Remarks: Water hardness, during the study, was not indicated. RESULTS Dose of cach endpoint (as mg/L): 234 hhoouurr EECCSS0O-= 11729000 ((713505-02-020007)0)mmge//lL 48 hour NOEC = 730 mg/L Remarks: none Was control response satisfactory (yesino/unknown): yes Statistical results, as appropriate: none ONCLUSIONS "2T0h7e0FmC-L1.015T4h8eh4o8uhroEuCrSN0owOabssedrevteerdmEifnfeedcttoCobnece1n2t0r0atmieo/nL(wNiOthECa)9w5a%sc7o3n0fimdge/nLc.e inteorfv7a30lSmeucbtmsitttheerrs'irceamarfokrsq:ualFiotrydtaetstainrge.liabHiolwiteyv,etrh,e sthteudsytuwdayslaasckisgnienfdoramKaltiimonisocnh pruartiitnyg oofft2h.eTtehset sstuubdsytance and actual measurements ofthe amount of test substance nsolution. Reviewers' remarks: none REFERENCE mWaagnrad.,TT,RN.eviWuisl,lJu.ryanLdabaR.ratBooreircis, 1I9nc9.6.LaAbcurteequtersitcintuymobferFCP-1160241,5 t3oMDaCpohmipda.nyD.apSht.niPaau, MN OTHER `GeOnNeLrYalNrOemMarIkNs:ALThTeESmaTjoCrHcEoMnIceCrALforCyOiNnCgEN0TRdAetTeImOiNnSthewevraeldusicyd.orOtPhiTs tersetcsomthmaetnds cthhaetmimceaalsucroendcetnetsrtacthieomnitcoalwhciocnhcetnotrtahteieonsstboergsaendi,smss atrheatexopnoesecda.n aIccituriastdeeltyerdmeitneemdintehathtehetest lnoumicnalcacnobnecenatnrdatmiuosnts breeaodjluys.tfedordeoxwanmwpalredSb0y%5o0ft%h.eImFeaansaulyrteidcaclonmceeansturrateimoennst,sthoef osxoimcetsyort had been furnished, we could calculate chemical recovery rats. and fake int account hydrolysis, 268 000272 volatility, and other physicochemical processes that might lower the actual test organism exposure concentrations Purity of th test material also is a major concern and was not sufficiently characterized in this fpeusrt.ityIn(saoppmreoxtiemsatsteitlyapp5e%a)rewdatshautse1d.00%Watteset rc,ahseomlicvaelntwaissoupsreodp,afnoorlo)tohreracsomcbhienmaitciaolnofolfesbsotehr was used in other tests, or no obvious stated reason. In fict, 3M in their summaryofcach test sVtaagter:ee"wDiatth mthaisycnoontcearcnc.uraItnealdydirteiloant,e tifoxtihciistwyoafshae"teyspitcasla"mpTlSeCwAitshetchtaitoonft4hreevreisetws,|ubwsotaunlcde." meiecacsturtehemseentstsudoifest,hepteensdticnhgemriecceailptionfathdeditetsitomnaeldiiunmf.ormation on puriy andstudies on analytical APPENDIX Chemical measurements of dilution water Parameter: Detection Limit: Metals AArlsuemniincum CBaodrmonium CCohbraolmtium TCroopnper Lead NiMcekrceulry. silver NitrZaitnee Chloride FTloutoalriodreganic carbon TOontgaalnopchholsoprhionreouPsesticides `OrTgoanxoapphhoesnpehorous Pesticides Dimethoate: TMoEnPoPcrotophos, PCBs 0.1 mgt 0.0 mpl. 00..500m02gmg/L. 00..0013 mmg/gl 00..00305mmg.L 0.005 mL 00..00300m3emlg./L. 0.02 mall. 002m0g.05 mg NL 1 mg/L 0m.1gmrgL 00.503pmeell. 0.5 pg/L2p 20 2200g 05 pl 269 000273 Ecotoxiciy Study ATCESUTTESUTBOSXTIACINTCYETO AQUATIC INVERTEBRATES (DAPHNIA MAGNA) Ldentity: Perfluorooctanoie acid, ammonium salt may also be refered to FasC-P1F1O6.AFCa-m1m2o6n,iFuCm-1s6al9t,, AormmFCo-n14i3u.m(pOecrtfalnuooircooacctiadn,oate, PFO, Rpeenmtaardekcsa:flTuohreo-3,Mamprmoodnucituimosnallto,t nCuASmbe#r3w8a2s5-42267.-1)The test sample is WFiCl-b1u4r3y, sretfuedryrendutmobbeyr tishe89te5stTHl.aboTrhateorpyuraistyN2o8ft03h-e4.saTmphleeTwRa.s. no sufficiently characterized, although current information i0n3di.ca5te%s iC6i, C&7m,ixatnudreCo9fp9e6r.f5lu-or1o0a0n%aleosgtuesucbosmtpaonucendasn.d. MMeEtThoHdO:DU.S. EPA-TSCA Guideline 797.1300 "Test type: Acute satic GYLePa:rYCeosmpleted: 1995 Species: Daphnia magna ISnucp.plMiaerr:bleOhbetaadi,neMdAfrformocmulatnuroersigmianailnctulatiunrbeeydfrToRm.AqWuialtbiucrRyesLaebaorrcahtories Organisms, Hampton, NH. AEnxaploystuircaelpmeorniiotdo:r4i-ngh:ouDrOs, conductivity, pH, and temperature. STteasttisotricgaalnmiestmhoagdes::<In2t4e-rhporuertesd by standard statistical techniques. `Computer methods (Stephan, 1983) were used to calculate LCS0s and ECS0s. TDeisluttcioonndwiattieorn:s Deionized water adjusted 10.3 hardness of 160-150 mDiglutiaosnCwaatCeOrIcLhemistry: HAlakradlnineistsy:: 116046mmg/Lgaass/CCaaCCLOO}3 RTeOsCi:du=al1c0hlmorgi/nLe: <0.1 mg/L Lighting: Cool-white fluorescent bulbs with an intensity of 110 lc. tPrhaontsoiptieorniopderioofd.16-hours light, -hours dark with a 1 minute SSttoocckksaolnudtitoenstwsaosluptrieopnasrepdreipnadrialtuitoionn: wAate1r..00A0ftmerLmixpirnigm.artyhe primary stock was proportionally dilutedwith dilution water0 prepare the test concentrations. No insoluble material was noted dEuxrpionsgutrhee tveesst.sels: 300 mL glass beakers containing 250 mL of test solution. The approximate depth of test solution wa9csm. NNuummbbeerr ooff dreapplhincaitdess:p2er replicate: 10 Number of concentrations:fiveplus a negative control 270 000274 48-hour NOEC = 360 mg/L. TT [Convo To To i -- ---- fo To Ts | [oo ThT eo oo] 000275 RThEiFsEstRuEdyNCwEasSconducted at T.R. Wilbury Laboratories, Inc., Marblehead, OMAT,HEatRthe request of the 3M Company. Lab Request number N2803-4 General remarks: The major concern for trying to determine the validity for this test is that OthNatLmYeaNsuOrMeId NteAstLchTeEmSicTalCHcoEnMcIenCtArLatCiOobnNesCEusNedT.RsAo TthIatONoSn wcearneacusceudr.ateOlyPPdeTterremcionmemtehnedtsest nchoemmiincaallccoonncceennttrraattiioonnstaorewhonilcyh, tfoortheexatemsptloerg5a0n%iosfmsthareemeexapossuerde.d c[oFnicteinstdreattieornmsi,netdhet(hoaxtitchiety vhaalduebseecnanfubreniasnhdedm,uwsetbceoaudljducsatlecduldatoewcnhweamridcablyr5ec0o%v.eryIfraatneas.lytaincdaltamkeeasinutroeamcecnotusnotfhsyodrmoelyssoirst, Veoxlpaotisluirtey,caonndceontthreartipohnyssicochemical processes that might ower the actual test organism m 000276 Ecotoxicity Study ACUTE TOXICITY TO AQUATIC INVERTEBRATES (DAPHNIA TIdEeSntTitSy:UPBeSrfTlAuoNrCooEctanoic acid, etrabutylammonium salt; may also be: referredto as PFOA tetrabutylammonium sal. ceotmrpaobnuetnytlaommfLon-i1u3m492p.erf(lOucotraonoocitcanaocsitde.,poentaasdeacmaafljuoorro-, etrabutylammonium sal, CAS f 95658-53-0) TRheematresktss:amTphleei3Mrepfreordruecdttioobnylotthneutmebsteirngwalasbo2r3a2t7ory as L +13492. The RTe.Rq.ueWsitlbNuurmybsetrudiys Nn2u3m3b2.erTihse$4p0u-rTitHy.ofTthhee3sMamEpnlveiwroansmneonttaslufLfaicbioernattloyry characterized, although current information indicates it i asolution of 44.9% tetrabutylammonium perfluorooctancate, 27.9% water, and 27.2% iTshoepfrooplalnoowling summary applies to the testsample as a mistureof the test substance in water solution with incompletely characterized cofotnhceenttersattsiaomnpsolfe wimiptuhritthiaetso.ftDhaetaemstaysunbsottaanccceu.rately relate toxicity MMeEtThoHdO:DU.S. EPA-TSCA Guideline 797.1300 Test type: Acute static GYLeaPr:CYoemspleted: 1995 Species: Daphnia magna `Supplier: Obtained from cultures maintained by T.R. Wilbury Laboratories Inc. Marblehead, MA from an original culture from Aquatic Research OAnraglayntiiscmasl. mHoanmipttoroinn,g:NHD.O, conductivity, pH, and temperature were monitored daily. "ETxepstosourrgeanpiesrimoda:ge:48<-h2o4u-rhsours `Statistical methods: LCS0 and ECS0 values calculated, when possible, by probit analysis. moving average method or binomial probability with non-lincar interpolation using the computer softwareof CE. Stephan. `DTielsuttcioonndwiattieorn:s Deionized water adjusted toa hardness of 160-150 mDyi/lLuatisonCwaaCtOer3/cLhemistry: Not given. BACK TO MAIN.Lighting: Cool-white fluorescentbulbs with an intensity of 20 Photoperiod of 16-hours light, -hours dark with a 15 minute tSrtaoncskitiaonndpetreisotd.solutions preparation: A100 mg/L primary stock Solution was preparedindilution water. Afier mixing, the primary stock was proportionally diluted with dilution water to prepare the test concentrations. No insoluble materialwas noted during the MAGNA) fi. tEexstpososluurtieonv.esTsehles:ap3p0r0oxmiLmagtleasdsepbtehakoefrsesctonstoaliuntiionng 250 was mL of 9 cn. 2m 000277 "NTuhembveesrseolsf wreeprleiclaotoesse:ly2 covered during the es. NNumubermooffbcaopnecheinrdtrsatpieornsr:epilviecatpel:us1a0negative control WDiastseorlvcehdemoixsytgreyn druarnigneg(t0he4s5tuhdoyu:rs): 85588.77 mmgyr.((1c0on0trmogl/eLxpeoxspuorseu)reconc) 2Co0nd6uc3ti0vimtyoravngee ((0con4tr%olhoeuxrpso)sure) P2H0ra6n4g0e (m0o-4v8ehour(s1)00 mg/L exposure conc) 845-85.6 ((c1o0n0trmogl /eLxpeosxurpe)oscuonrc.e) 2T0es5t te2m0p.e7raCt(ucroentroalneexp(o0sur4e8) hours) 2E0l.e5men2t0.b6asCs:(1m0o0rtmagli/tLy eaxnpdosiumrmeobciolnicz.a)tion RNoEmSiUnLalTSconcenteations: Blank contel, 13, 22,36, 60. 100 mg. Element value: 24-hou ECS0 = $9 (60> 100) my/L 24-hour LCS0 = >100 mg/L (CI not calculable) 438$--hhoouurr hour LENCCOSSE00C===737413((6m30g-0/-L3190)0)mgm/gL/.L ERleemmaernktsv:alTueesstibnagsewdasonconnodmuicntaeldcoonncenmtirxattiuornes.as described in the Test oSutbstthaenNcueoRreocmhaermkiscafledc.omTphoenevanltueaslonree.ported apply to that misuur and Cumalatve percent immobilization (includes mortality): Cone. mg [Comrol To To 71 TT o o] 15 | feo [oo To Two | TT o wo] CCoOnNtrCoLlUrSeIspOoNnsSe: saisfctory "bTehe77tesmtg/sLu.bswtiatnhce 4985-%hocuornfLiCdSeOnceforinDtaerpvhalnioa m6f0a-gn1a00wamse/dLeteTrhmeineesdtto siubLstawnicteh438-9h5o%urcEonCfSi0defnocreDianpehrnviala omf3ag0n-a3w9asmdee/tLerTmhineetdesttosbuebs3t4ance S5u-bhmoiutrtenro:o3bsMerCvoemdpeafnfyec,t cEonnvciernotnrmaetnitoanl(LNaOboErCa)towrya,s P1.3O.mBLo.x 33331, St m 000278 PDaAulT,AMiQnnUeAsLotIaT, Y55133 oRfeleisatbisluitbys:taKnlciemciosnccherntarnaktiionn2gs.iTnhtehestteusdtysollauctkisoannsaalyntdicsaalmmpelaespuurreimtyenits not sufficiently characterized. "RThEiFs EstRuEdNyCwaEsSconductedat T.R. Wilbury Laboratories, Inc.. Marblehead, MA, at the request ofthe 3M Company. Lab Request number N2332. 1995. OTHER`General remarks: The major concern for trying to determine the validity for ths test is that OthNatLmYeaNsuOrMeIdNteAstLchTeEmSicTalCHcoEncMeIntCrAatLioCnsObNeCuEsNedT,RsAoTthIatOoNnSe wcearneacucsuedr.ateOlyPPdeTterremcionmemtehnedtsest cnhoemmiincaallccoonncceennttrraattiioonns taorewhonilcyh.tfoortheexatemsptloerg5a0ni%osmfstahreemeexapossuerde.dIcfonitceinstdraettieornmsi,ntehdetthoaxtictihtey vaadluebseecnanfubreniasnhdedm,uwset bcoeualddjucsaltceudladtoewcnhweamridcablyr5ec0o%v.ery[Fraatneasl,ytaincdaltamkeeasinutroeamcecnotusnotfhsyodmreolyssoirst, evoxlpaoisluitrye,caonncdenottrhaetriopnhsy,sicochemical processes that might ower the actual test organism SPuormietytoesftsthiet atepsptemaarteedritahlatal1s0o0is%atemstajcohremciocnaclewransanudsewda,sfonrotosutffihacicehenetlmryicchasalroacftleersiszeerd ipnurtihtiys test. In o(tahpeprrotexsitms,atfeolry8no5%ob)viwoaussussteadt.edWraeatseonr.a,sIonlfvaectn,t3(iMsoipnrotphainrols)umormaacroymobfienaacthiotnesotfstbaotet:h w"Daastausmeadyinnot `aacdcduirtiaotne,liyftrehliastweatsosaii"ttyypoifctahl"eTteSstCsAamspeclteiownit4h trheavtieofw,t|hetwoeutldsurbesjteacntcteh.e"se1satgurdeieesw,iptehndthiinsgcornecceerinp.t ofIn `maedddiituimo.nal information on purity and studies on analytical measurementsofthe tes chemical in the test 275 000279 Eeotoxicty Study ATCESUTTESUTBOSXTIACINTCYETO AQUATIC INVERTEBRATES (DAPHNIA MAGNA) rIedefnetrirteyd: toPearsfPluFoOroAoctteatnroiacbuatcyidl,amtmeotnriaubmutsyallta,mmonium sal; may also be cteotmrpaobnuetnytloafmLm-o1n3i4u9m2p.er(fOlcutoarnoaoicteaancoiad,te,peNn2t8ad0e3c-a2flouroraos-a, major tRtermaabruktsy:laTmhmeo3niMumprsoadltu,cCtiAoSn l#o9n5u6m38b-e5r3-w0a) s2. TThRe.tWesitlsbaumrpylsetuisdyrenfuermrbeedr{0isb8y8t9h-eTtHe.stTihngelpaubroirtaytoofrythaes sN2a8m0p3l-e2.wasThneot SSuoliuctiieonnotlfyc4h4a.ra9c%tetreitzreadb.uatlytlhaomumgohnicuurmrepnetrfilnufoorromoacttiaonncaitncd,ic2a7t.es9%it wiastaer, aTnhdef2o7l.l2o%wiinsgopsruopmamnaolr.y applies to the testsample as a mixtureofthe tecshatrsaucbtsetraiznecdecionnacennitsroaptrioopnasnoofli/mwpautreirtiseosl.utDiaontawimtahyinncootmapclceutrealtyely rMeElaTteHtOoxDicityofthetessample with thatof the test substance. Method: U.S. EPA-TSCA Guideline 797.1300 GTeLsPt:tyYpees: Acute static SYpeeacrieCso:mDpalpehtneida: m1a9g9n.a ISnucp.plMiaerrb:leOhbetaadi,neMdAfrformocmulatnuroersigminaailntcauiltnuerdebfyroTmR.AqWuiatlibcurRyesLeaabrocrhatories AOnraglayntiiscmasl.mHoanmipttoorni,ngN:H.DO, conductivity, pH, and temperature were mEoxnpiotsourreed dPaeirliyo.d: 48-hour S"Tteasttisotricgaalnimestmhaogdes::<L2C4S-0hoaunrds ECS0 values calculated, when possible, by pirnotbeirtpoalnaatliyosnisu,simnogvtihnegcaovmepruatgeermseotfhtwoadreooffbiCn.oEm.iaSltepprhoabna.bility with non-linear "DTielsuttcioonndwiattieorn:s Deionized water adjusted to hardness of 160-150 Dmigl/uLtiaosnCwaatCerOcLhemistry: AHlakradlniensitsy:: NNoott nnootteedd pLiilg:htNiontg:noCtoeodl-white fluorescent bulbs with an intensity of 110 fic tPrhaontsoiptieorniopderioofd.16-hours light, -hours dark witha 15 minute SSotlouctkioannwdastesptresoplaurteioinnsdpirleutpiaornawtaitoenr:. AAfl2e0r0mmigx/iLn.g,prtihmeaprryismtaorcyk S{etsotckcowncaesntprraotpioorntsi.onNalolyindsiolluutbelde wmiattherdiiallutwiaons wnaotteerd 0duprrienpgartehethe st 276 000280 F a E r a i ri e E A -- a a n a i R i hn. Dissolved oxygen range (0 -- 48 hours): a a =T n iy e e . es e i a R a E aLr n R e --- T C i Ea LELT --m-- F or laad [ComTr o ol ""0 fT e oT 1 RT 55 30 [as] Sm T nmsA a R a aT: 100 [T ss wo] - 000281 C"TOheNtCesLtUsSubIsOtaNnSce 48-hour LCSO for Daphnia magna was determined to bSueb9s3tamncge/L48w-ihotuahr E9C5S%0cofonrfiDdaepnhcneiiantmeravgalnaofw7a4s -de>t1e0r0mimnge/dL.toTbhee6t2est mSugb/sLtawnicteh48a-9h5ou%rcnoonfoibdseenrcveedienftefrevcatl ocofn3c6e-ntr1a0t0iomn L(N.OETChe) tweasts 13 mSuybLm.itter: 3M Company, Environmental Laboratory, P.O. Box 33331. St. DPaAulT,AMiQnnUeAsLotIaT,5Y5133 Reliability: Klimisch rankin2g.The study lacks analytical measurement of est substance concentrations in the test solutions and sample purity is ot sufficiently characterized. "RThEiFs EstRuEdyNCwaEsSconducted at T.R. Wilbury Laboratories, Inc., Marblehead, MA, at the request ofthe 3M Company. Lab Request Number N2803-2. 1996, OTHER`General remarks: The major concern for trying (0 determine the validity for ths testis that ONLY NOMINAL TEST CHEMICAL CONCENTRATIONS were used. OPPT recommends cthhaetmimceaalsucroendcetnetsrtacthieomnitcoalwhciocnhcetnotrtahteitoensst obreguasneids,mssoatrheatexopnoesecda.nIafcicutrsatdeelytedremtienremdintehatthtehetest nominal concentrations are only. for example 50%of the measured concentrations, he toxicity avadlubeseecnanfubreniasnhdedm,uwset cboeualddjucsaliceudladtoewcnhweamridcablyr5ec0o%v.eryIFarnataelsy,taincdaltamkeeasiuntroeamcecnotusnotfshyodmroelyssoirst. volatliy, and other physicochemical processes that might lower the actual test organism exposure concentrations. Purity of the test material asoisa major concern and was not sufficiently characterized in this test. In S(aopmperotxeistmsatitelaypp8e5a%re)dwtahsatu1se0d0.%Wtaesttecrhae,msioclavlenwtas(iussoepdr,opfaonrool) torahaccohemebmirincaastlioonfolfesbsoetrhpuwraistyused in other tests, accurately for no relate obvious stated reason. In toricityofthe test sample fact, 3M with that in of tthheeitresstusmumbasrtayncoefc.a" c1hagtersetewstiatteh: t"hiDsatcaonmcearyn.norIn `addition,ifthis was a "typical" TSCA section 4 review, | would reject these studies. pending receipt of `additional information on purity and studies on analytical measurements of the test chemical in the test medium, 278 000282 TOXICITY TO FISH Title: Acute Toxicityto Fish TEST SUBSTANCE Identity: Perfluorooctanoic acid, ammonium salt; mayalsobe refered to as PFOA ammonium salt, Ammonium perfluorooetancate, PFO, FC-116, FC-126, FC-169, or FC-143. (Octane acid, pentadecafluoro-, ammonium sah, CASRN 3825-26-1) Rwaesmanroktss:uffTihcieen3tlMy pchraordaucctterfioztedn,umtbheorugwhascur8r3e.nTthienftoerstmastaimopnleinwdiacsatFeCs-i1t4i3s,a mTihxetuprueriotfy9o6f.5the-- s1a0m0p%letest substance and 0- 3.5% Ci, C; and Cy perfluoro analog compounds. METHODS Method guideline followed: Not sated Test type: Static GLP (YN): No ear study performed: 1974 `Species: Fathead minnow (Pinephalespromelas) `Average weight = 1.6 Average length = 2 inches Supplier: Not stated Concentrations used: 0, 10,20, 30, 40, 50 mg/L nominal Exposure period: 96 hours Analytical monitoring: The test substance concentrations were not measured. Statistical methods: There were no statistical methods given by the study authors; the LC was determined graphically. ~TOesnteCroenpldiictaitoenwsa:s performed ""DpiHssroalnvgeed(o2x4y-g96enhoraunrgse=)(27.04-9-67h.1o(ucrosn)t=ro4l.)7a-n5d.76.4mL.6.5(c(o5n0trmolg)/aLnedx4po0s-u4r.e)9 mg/L (50 mg/L) ""TWeamtpeerrhaatrudrneesrsanwgaes=n7ot0 i-n7d2icdaetgedrees Fahrenheit "Dilution water was carbon-filtered city water rom St. Paul, MN. Remarks: Further details on the test conditions and procedures were not provided. 279 000283 RESULTS cDoonsceenotfcraatciohnsendpoint as mg/L): 96 hour LCi=70 mg/L. (C.1. not caleulted) bas on nominal Rmoermaalriktsy:wiOtbhstehreveexdcempotritoanliotyf2o0f%themocrotnatlriotlys iwatshe1$00%mat/blotghro7u2p.and96 hours. There was no other Was contrl respanse satisfactory (yesno/anknown): unknown, sce Remarks shove Sobttaatiinsticcaalreeusullttesd, aLsCaappvraolpe.riate; Percent survival versus concentration (mg) was ploted concLUsIons "cTahleulsattueddy)aubtahsoerdsocnonncolmuidneadltchoantctehnetraactuitoensL. C to futhead mimnow was cqual 0 70 mg/L. (C1. not Smuetbhmoidtotleogrys.RTehmearLksC:waReslieabxitlriatpyol-atKeldimrioscmharnaniknisunfgfi3.cieTnhterneumwbaesrionfsdufafitcipeonitndtso.cuTmhenetgaetnieornalofprteh-etest aTnaclylticaanldcaognefiorfmafitsihonweorfetensottsnubostt.ancSeacmopnlceenptuartiitoynsa.s not properly characterized nd tacks HRheoviwaetweerr'hsarRdenmeassrkwss: nTohtegipvHen.leTvelsstidnugrisnhgotuhde ehatvepebreieonddwoenreewwiitthhitnwtohereapclciecpaas.bleThreanngu:mbheorweovfer, organisms pe dose and he loading rte wer not indicted 3M Company. [No ie given} Lab Request number 2340. St. Paul, MN. omer rReepmoarrtkwsa:sTavhaiislabslue.mmaThreyrewfaosreb,atsheedcoonntenstusmofmtahriysrseupmormtaraynd. ninlryefleirmeintceed dattahetapbrleost.ocoNlos adentdairleesdults of ihe study. are limited "CTHheEmMaIjoCrAcLonCcOerNnCfEorNrTiRnAgToIOdNetSerwmeirneeutsheed.valOidPiPtyTfrorechoimmsesndiss tthhaatt OmeNaLsuYreNdOtMesIt NheArLmicTaElST choentceestntorragatniiobsnmessurseede,xspostehda.t anIeicaisndaecccrurmaitnleyddtehtaertmhienneotmihnafelstcocnhceemnitcraalticoonnsceanrteroantliyo.n oorwchxiacmhpltoe F5a0n%aotfitchaelmmeeaassuurreedmceonntcsenotfrastoiomnes,sotthehtaodxibceiteynvfaulmuiesshceadn, bweeacnodulmdusctalbcuelaatdejucshteemdidcaolwnrvecaorvderbyya0cs%. acntdlakfestnooragcacsoumntCXhpyodrSoIlRySsicso,ncveonltartailtiitoyn.s.andAothi eir physaircoocpheermaitcianlgpinrothceedsasrkthoant mtihgihstuleo.ver he 20 000284 TOXICITY TO FSH "Title: Acute Toricity to Fish TEST SUBSTANCE peennttiadteyc:afPlruofrlou-o,rCooAcStaRnNci33a5c-d6:7-m1a)y also be referred to 35 PFOA, FC-26,or FX-1001. (Octanoie acid, sRuefmfiacrieknst:ly 3chMarpacrtoedruiczteido,ntlhootunguhmcbeurr2t69.inTfhorematetsitosnmipndliecawtaestFCs-&26m.ixTthueepoufrt9y6.o5ft-h1e00s%amesptle was not substance and 0-38% C,. Cs, and Csperfluoro homologue compounds. METHODS Method/guideline followed: Not sated Test type: Suc GLP (VIN): No ear study performed: 1974 Species:`AFvaetrhaegaedlemnigntnh-ow2i(nPcihmeepshales promelas) Average weight = 15 Supplier: Not stated Concentrations used: 0. 50,125,250, 375, 500 mg/L nominal Exposure periods 96 hours Analytical monitoring Nominal concentrations were not measured Sdteatteirsmtiicnaeldmgertaphhoidcsa:llyThere wenostratisteical methods given by the study authors: he LC was "TOesnteCroenpldiictaitoenwsa:s performed. "Temperature 69-70 degrees Fahrenheit Dibsestolwveeedn o3.5xayngedn5r.a2ngmeg/(L24f-o9r6thhoeur3s7)5wmags/Lbetetswt eexep4no.s7uraen.d 5.7 mg/L for the control exposure and pWHatrearngheard(n2e4s:s95whaosurnsot) gwiavsen7.0107.2 or the control exposure and 6.0 6.7 or the 375 mL. exposure 281 000285 Remarks: No further details wre provided on th es: conditions or methods. RESULTS concerns Dose of each endpoint (as mg/L): 96-hour LC = 440 mg/L (C.1. not calculated) based on nominal SRemmaarlksw:asor10c0on%ce8nt2r4athioounrsso.fbut0100975at m4g5/.L9, shorrsl was 00%. For he S00m/L. concern, Was control response satsactory(yesontunknawaly You SSthataimstaicnalLrCesus, as appropriate; Conceniraton (mg/L) versus erent survival was graphed to concLusions Sinufbomrimtattieorn'aRnehmearmkest:hodRoelloagyb:ilSyam-pKlleimpiasrcihsrwaanksinngtopfr3o.peTrhliys cshturdcytalarcikesdd.ocTuomoetnctoatnicoennaantdons were ot chmtenesd. Condi of he oy Fr To Sty WR ot wn, SRteuvdisewpeerr'snRweamsarmkos:isTns.inTgodsmhoudaavofembgeeenenpoermfoprrmeddosine tawnod pheiaosa,dmWraatteewhraerdnmoetssmdduirianegdhe REFERENCE SM Company. [Ne ie given), Lab Request Number 2485. St.Paul, MN. orHER Roevmamrkmsa: ThiTsesvuememraonroycwas tbhaseeTdeotoncaesaunmdmoarlysrepoofrhtesusbmdit,edaebyeSMt, therefor, th contents of CThHeEmMaIjoCrAcLonCcOeNnCfEorNTyRiAngTtIoOdNeStewremrisnuhseed.valOidPitPy froecroimmcesntdiss thta OmeNaLsuYreNdOeMtIcNAhLiTcEST hceonevnoarnions be vaereelcaopotsetd. e1e viasGntsreemuirnteldy Gaotrhiennominatlsceonremanaaltioonnsceamrieraantyo.nfaorwehxiacmhple SIF0a9noalfitchaelmmesesrsedsseonseeonfrstoimones.sottehfdobciovfalrcesdca:n bweeacnodusd ctablcauuicheedmicdaolwnrwecaorvderoyyaSt0s% ihmduiaekesitoorgaacnciosumntxhpydroolsysiCs,ovonlacliaty..andaab1er pwheys1icocohpemaicRaIl prtohccosrekholn iightsuleo.wer he 000286 TOXICITY TO FISH Title: Acute Toxicity to Fish TEST SUBSTANCE Identity: Perfluorooctanoic acid, ammonium salt may be referred t0.as PFOA ammonium salt Apemnmtaodneciauflmuopreor-f,luaomromoocntainucamtesa,liP,FCOA,SFRC-N11368,25F-C2-61-216), FC-169, or FC-143. (Octanoic acid, wRaesmanroktss:uffTichieen3tlMy cphraordaucctteiroinzeldo,t tnhuomubgehrcwurarsen8t3.inTfhoermtaetstiosnamipndliecawtaess tFCi-1s43m.ixTtuhreeopufri9t6y.o5f-t1h0e0s%atmepslte substance and 0-3.5% Ci. Cs, and Cs perfluoro analogue compounds. METHODS Methodguideline followed: Not sated Test types: Static GLP (VIN): No. ear study performed: 1978 Species: Bluegill sunfish (Lepomis machrochirus) `Average length = 4 cm Average weight =0.20 `Supplier: Not stated Concentrations used: 0, 135, 150, 240, 320, 420 mg/L nominal Exposure period: 96 hours Analytical monitoring: Concentrations were not measured. Statistical methods: Not sated T"DeisltutCioonn:dictairobnosn:-iliered well water, "tDeimlpuetriaontuwraete=r1c9hedmeigsrterye:s Celsius dissolved oxygen= 9.1 ppm OpnHe=r7ep9licate "Exposure vessels were tanks containing 16 liters of test olution "22L0oafdiishngperratree-pli0c.at2e5: gL 283 000287 "Water chemistry during study (24-96 hours): dissolved oxygen = 53-69 mg/L (control, 5.1.7.3 me/L (420 mg/L exposure) tPeHstrtaenmgpee-rat7u.r9e(~con1t8r-ol1)9,d7e.8g-r8.e0e(s4Ce2l0simusg/L exposure) "Water hardness was not stated Remarks: No further details were provided on the test methods orconditions. RESULTS Doseofeach endpoint (as mg/L): 96-hour LCS0> 420 mg/L based on nominal concantrations Remarks: No mortalities occurred inthe controls or 135-240 mg/L groups. Moralites in the 320 and 420 mg/L. groups both consisted of one in twenty fish dead at 72 hours Was control response satisfactory (yes/no/unknown): Yes Statisticalresults,as appropriate; Not stated CONCLUSIONS Submitter's Remarks: Reliability- Kimisch ranking3. Testing lacks information on the method sfuoslpleocwte,d.SaNmoplienfpourrmiattyiownasonnosttopcrkopoerrlteystchsaorlaucttieornipzreedpaanradtiitonlsacwksasanparloyvtiidceadl.coAnvfeirramgaetiofinoshfweesitght is substance concentrations. Reviewer's Remarks: Only one replicate was performed. Water hardness during the study period was not indicated. REFERENCE 3M Company. [No ite given]. Lab Request number 384. St. Paul, MN. OTHER Remarks: This summary wasbasedon a summary report submited by 3M, therefore, the contents of this summary, in reference to theprotocolsand resultsofth study, are imited. CThHeEmMaIjoCrAcLonCcOerNnCfEorNtTrRyiAngTtIoOdNetSerwmeirneeutsheed.valOidPiPtyTfrorectohimmteensdiss tthhaatt OmeNaLsuYreNdOtMesIt cNhAerLniTcaElST concentrations be used, so that one can accurately determine the test chemical concentration to which to t5h0e%teostftohregamneiassmusraerdcceoxnpcoesnetdr.ati[oFnist,ithdeettoexrimciintyedvatlhautesthceannobmeinaanld cmounsctenbteraatdijounssteadredoonwlyn,wafrordebxyam5p0l%e 1 analytical measurementsofsome sort had ben furnished, we could calculate chemical recovery rates, aacntduaalkteestimoorgaacnciosumntexhpydorsoulryesicso,ncveonltartailtiitoyn.s.ind other physicochemical processes that might lower the 284 000288 TOXICITY TO FisH Title: Acute Toxicity o Fish "TEST SUBSTANCE Identity: Perfluorooctanoic acid, ammonium salt; may also be referredto as PFOA ammonium salt, Ammonium perfluorooctanaate, PFO, FC-116, FC-126, FC-169, or FC-143. (Octanoic acid, pentadecafluoro-, ammonium salt, CASRN 3825-26-1) Rsaemmpalreksw:asTnhote s3uMlicpireondtulcyticohanrlaocttenruimzebde,rtwhaosug8h3.curTrheentteisntfsoarmmaptlieonwaisndFiCc-a1te4s3.itsTh4empiuxrtiutryeooff9t6h.e 5 100% test substance and 0- 3.5% Ci. C5, and Co perfluoro analogue compounds. METHODS Method guideline followed: Not stated Test ype: Static GLP (VN): No, ear study performed: 1978 Species: Blucgill sunfish (Lapomis machrochirus) AAvveerraaggee wleeniggthht=-3.01c.2mg Supplier: Not stated Concentrations used: 0,420, 560, 750, 1000, 1350 mg/L nominal Exposure period: 96 hours Analytical monitoring: Concentrations were not measured. Statistical methods: Not stated T"eDsitllCioonndiwtaitoenrss:ource: carbon-filtered well water O"Dniellireopnliwcaattee,r2c0hemfiisshtrpye:r rteepmlpiecartaeture= 19degrees C. dissolved oxygen =9.9 ppm. pH= 7.6 "Test performed i tanks containing 16 ltrs test solution "WLaotaedricnghreamtiest=ry1.5 dgu/riLngtest (24- 96 hours): Dissolved oxygen range = 5.6 0.6.5 my/L (control) and 4.9 0 5.9 mg/L (750 mg/L exposure) PH range = 7.8 (control) and 7.6.10 7.8 (750 mg/L exposure) 285 000289 WTaetmeprerhaatrudrnees=s n1o9t10g.i2v0endegrees C Remarks: No further details were provided on the testing methods or conditions. RESULTS Doseofcach endpoint (as mL): 96-hour LCS0 = 569 me/L.,based on nominal concentrations Rtheema1r00k0s:andTh1e39505%mgc/oLnfciodnecnecnetrianttieorvnaglrwoaupss.500 -636 mg/L. 100% mortality occurred by 48 hours in c`oWnatsroclongtrrouopl.response satisfactory (yes/no/unknown): One outoftwenty fish died at 48 hours in the. Statistical results, as appropriate: Not stated CONCLUSIONS TSoulblmoiwtedt.erN'soRienmfaomraktsi:onReolniasbtiolcitkyo-r Kelsmisoslhutriaonnkpirnegp3a.raTteisotninwgalsacpkrsoviindefdo.rmaStaimonploenptuhreitmyetwhaosdnot properly characterized and th study lacks analytical confirmation ofes substance concentrations. Reviewer's Remarks: Only one replicate eas performed and water hardness during the test period was not given REFERENCE 3M Company. No ttle given], Lab Request umber 3844. St. Paul, MN. OTHER {Rheismasrukmsm:aryT.hiisnsruefmemraenrcyetwoatshbeaspreodtoocnoalssaunmdmrasruylrsepoofrtthseusbtmuidty,edarbeyfi3iMt.edt.herefore, th contents of "CTHheEmMaIjCorAcLonCcOerNnCoErNtTrRyiAngTItoOdNetSerwmeirneeutsheed.valOidPitPy frorecthoimsmteesntdiss tthhaatt OmeNaLsuYreNdOtMesIt NchAerLniTcaElST iconnceesnttroartigoannsibsemuasrcedexspoostehda.t on7e4caindaectceurrmaitneleyddtehtatertmhienneotmhienatelstcocnhceemnitcraalticoonnscernetroantliyo,n ftoorwchxiacmhpltoe 51a0n7a%loyftitchaelmmeeaassuurreedmceonntcsenotfrastoiomnes,ortthhtadocbeieynvfaulruneisshceadn,wbee acnodulmdsctalcbuelaatdejucshteemdidcaolwrnecwoaverbrydyr0ate%s. aScntdaalkteestinotrogaacnciosumntexhpyodrsoulryesicso,ncveonltartaitliitoyn,s.nd othr physicochemical processes that might ower the 286 000290 TOXICITY TO FisH Title: Chronic Toxicity to Fish TEST SUBSTANCE Identity: Perfluorooctanoic acd, ammonium salt; may also be referred 10 as 78.03, PFOA ammonium spaelnti,aadmecmaoflnuiourom-,pearmflmuoonroiouctmansoalatt,eC,APSFO#,3F8C2-51-1266,-1F)C-126, FC-169, or FC-143. (Octanoic acid, Rreefmerasrtkos:it aTsh"e783.M03.p"roTdhuectpiuorniylootfntuhmebesarmwpalse 8w3a.sTnohtestuefsftisciaemnptlley cwhiasracFtCe-r1i4z3e,d,Tthheoutgeshticnugrrleanbtoratory information indicates it being a mixtureof 96.5%- 100% test substance and 0- 3.5% Ce, C, and Cy pefluoro analogue compounds. METHODS Methodguideline followed: The methodologyforthe cae and fy exposure closely followed that presented in "Proposed recommended bioassay procedure for egg and fry stages of freshwater fish," U.S. EPA, 1972. Test type: Flow through GLP (YIN): No, ear study performed: 1978 Species:PrFea-ttrheeaatdmemnti:nnEogwg(sPiwneerpehpallaecsepdrionmael6a0s)mg/L malachite green solution for 15 seconds to eliminate possible fungus growth. Test fish age: Eggs within 48-hours afer fertilization Supplier: U.S. Environmental Protection Agency's Environmental Research Laboratory in Duluth, MN. Concentrations tested: Blank control, 6.2, 12.5, 25, 50, 100 mg/L Exposure period: 30 days post hatch WAneaelkyltyicsaalmmpolneistwoerriengt:akeTnemfpreormatcuarceh, adqiusasorlivuemd fooxrydgeetnercmoinnacteinontorfataimonmnod,npiHumwepreerfmlounoirotoocrteadN0dAaiLley. c3o1n,c1en9t7r8at1i0ont.heA3llMsaCmopmlpeasntya.ken during the test were stored in polyethylene bottles and shipped on May Statistical methods: Meansof measured biological parameters from duplicate aquaria were subjected to `paenracleysnitsaogfevsaurrivaivnacle a(nSdteepleercaenndtaTgoerrhia,tch19w6e0,recotmrpalnestfoerlmyerdatnodoarmeizseid sbqluoacrkedreosoi!gon,fpPe=r0c.e0n5t).agDeatpraiofror(0 analysis. 287 000291 TonconditiA ons: er A HL N WA Tm essen) Drood nmd 30t-o133m8amn a25c4y0, Shek ad oa A scar. ot oper dlih0 S0ton cr vas B esSaA m66a mfs A poeatameE dn rooA dt soi ck cov ncmtir eonfm mmeteedwatGsotPHosA ht gigrh, ambeeriofnhSe0t63nO0,51L30. cm witha 17.5 om ih A A oer ewanoAeoEAchbg y enL 19 vAn oIdDgly Dit: Fendi Dete5r0 es Fry ven elle bir cu mrot enkeepgei eo9nwn peor dey,diiice a Wes dl 1 rafglonsss BOr eEssee n e US ore Ar JDoaor dyyom: 05% saurion porats: 25 1 ders Celio, minindbywate bh m cmd 4 fred fy rwhe they hom heI Her . ot ago weerovi. oom mbi a toof ensns pon offe mre ant pic cep o he Trl Jr Descofcach endpoint (1 mg 30-y NOAEL = 100 mgt. i Nomn| o T pm n en eatA ] (mg/l) iHn mNm nme | Control A5 598 592 0 562 | 2 A 9% 9% ) = 000292 i [BT sw T 220) 7 8 ss 100 210: 2 n 0 5s 2G 0 xB 35 8 " a 2000) 5a 200) @ Tet Viral Comet | 0P0ermtuLoroAorcumnocantiea i ObNsmerbveatrioofns Ww W | Fisopatholotgigals T1T0LVarimfalavycehanrge 31Ep0itGhielllihuympe1rplasia | $S17100LNiovremrafl y change 2110Gill yperiasia | (Epithelium) t aRreemfairstkeds.: TShuebamniltyrt'ssNaotceha-nOgnelsyotbsheorsveidsswueersewhhyipcehrpwleasrieamoifgssiilnglourncoanrtapiniehdedlemuomnsatnrdabflaettychcahnagnege hoFeahtehyTvfeirs.h.TAhuetsoeliephianOggeislwlerssuuedwgads a1bsbeervmeidniimnaslcvaenrdalcofnisshi.stTehnitswcihtahncgheawngaesspsroobeabrloyutdiuneeloy itnhe poor penirtion ofthe buiferd formalin tothe posterior dorsal portion ofthe il pace. Was contra response satisfactory (sesmo/unknawn): Yes Statistical resus, a appropriate: No siatstcally significant findings were reported concLUsIONS aBidovloorgiacaol edataupgeonnerhaetead itn thcis shtuoday oibngdgiicoartleupthtotntthheemsoumrivnivaallcaonndcegnrtorwattihoonfoift1h0e0admmginnhaodwnfoy through 30 days posthatch, vSuabmsitctoemrds"uereedm,abrkus:hasKlsiemveirsaclhdraainikoinin2eg.s.Thtisacstkusdiynfmoeremattiaolntoh iptietryaofforthqeuaelittystucbssitnagnea,t haendthimee production ot number from which he est sample was taken. Thre no information avaiable on the analysisofthe test solution concentrations or on the preserved fry and frozenfry samples. aRsevpairetweofrsth" reamnaayrskiss:ofWtaesttecohnadirtdinoenss.s was not monitor during the study period or at study completion 29 000293 REFERENCE "fTahteheeafdfemtisnnofocwon(tPiinmueopuhsaleexspopsruormeeltaos)7.5.01397o8n. hcRtecphoarbtiTliBtWy-7of8.c6g-g1s7a5n.d Rgersoewatrhcahnrdepsourrtvisvuablmoifttfeyd 1o0f3M Company. St. Paul, MN by EG&G Bionomics Aquatic Toxicology Laboratory, Wareham. MA OTHER GNeOnMerIaNlArLemTaErkSsT:CTHhEeMmIaCjoArLcoCnOceNrCnEfNorTtRArTItyoOdNeiStewnremrigeneustehde.vaOliPdiTty froectohmimstenedsstithtahtatmeOaNsLurYed test cwhheimcihca0l tchoencteesnttroartgiaonnissbmes uasrede.xp5o0stehda.t o1ne ciasndaectceurrmaitneeldy tdheattetrhmeinneomtihnatlestcocnhceemnitcraalticoonnscaernetroantliyo.nfoor ebxya5m0pl%e 5F0a%noafttihcealmemaesausruerdecmoennctesntorfatsioomnse.stohrtthoaxdicbiteyenvafluurensischaendb.ewaencdoumludstcobleeualdtjeusctheedmdiocawlnward nreicgohvterlyowreartehs,eaancdtutaalkeGitntOragcacnoiusnmtehXypdorosluyFseisc.onvcoelnattirlaittiyo.nsa.ndAosthtespwhyesiacroscohpeemriactailngprionctehsesedsarhkaton this 200 000294 FISH ECOTOXICITY Title: 96-hour acute static toxicity to fathead minnow ~ FX-1001 TEST SUBSTANCE. Identity: Perfluoroctanoic acid, also referredtoas PFOA, FC-26, or FX-1001. (Octanoie acid, pentadecafluoro-, CAS # 335-67-1) Remarks: The 3M production fot numberwas not noted. Thetest sample was FX-1001. Its purity was. snoutbsctoamnpcleetaenldy1c-h5arpaecrtceernitzepde,rfallutohrooucghhemiincfaolrmianteitosn indicated it was a mixtureof95-98 percent test METHODS Method/guideline followed: Not noted Test type: Static GLP (Y/N): No ear study performed: 1985 Species: Pimephales promelas, a`avveerraaggee wleeniggthht==40..15c0 m: age not noted Supplier:Dale FaotfBiradgy, NB. Concentrations used: 0, 690, 750, $10, 870, 930 mg/L (nominal values) Exposure period: 96 hours Alinmailtystoifcatlhemcohneimtiocrailngo:r iNmpourmietaisesurienmtehnetssawmeprlee taken. Also, here was no information on detection Statistical methods: Probit analysis 291 000295 TeFsitshCownedrietpiroentsr:eated with 25.0 mg/L tetracycline HCL, $ months prior to study to fight diseases Dilution water chemistry: Carbon ilered well water DOS ppm PTHemp7819C - Water chemDiisstsroyldvuerdiongxytgheenesrtange (24-96 hours): 76317-.677 mmpLl ((c8o7nt0romlg)/L)* PH range (24-96 hours): 75 - 7.7 (control) #870 mg7/L5-test7g5ro(u$p70(smeec/oLn)d*highest concentration) data given because total mortality occurred in the higTheesstttteemsptecraantguernetr(a2t4i-o9n6bhyou4rs8):hours. Stock solution w1a9s.2p0rCepared by dissolving 45g test substance (neutralized with NaOH to pH 7.5) in 3 liters water Test solutions were prepared by transferring stock solution aliquots to make - LoadinSgTriaeer:s a0t.t5h0egseflieschteLd test concentrations. ~ StabilitEyxopfotshuerteestvecshseemliscwaelrseolgultaisosnbsewaakesrsnowtintohtaed24 cm inside diameter and a 26cm depth, and contained $ liters test solution. "Two replicates were taken at cach dose, with fish per replicate hRaermmaornkisz:edWgautideerlihnaesr.dness was not presented. The pH values are acceptable according 0 the OPPTS RESULTS cDoonsceeontfreataicohnsendpoint (as mg/L): 96-hour LCS0: 843 mg/L (CL: 811-878), based on nominal Remarks~:930 me/L was the lowest test substance concentration causing 100% morality (seen at 45 ~ There whaousrsn)o mortality in controls Surfacing ofthe ish occurred at dosesof 810, 870, and 930 mg/L. Was control response satisfactory (ves/no/unknown): Yes, based on zero mortality. Statistical results, as appropriate: No p-values were reported. 202 000296 CONCLUSIONS "The test sample 96-hour LCS0 for fathead minnow was determined to be $43 mg/L with a 95%C.1. of SI-S78 mel. `Submitter remarks: The data quality ranking was a Klimisch ranking of2 because esting met criteria cfoornfqiuramlaittyiotneostfintge.stHsouwbesvtaenrc,escaomnpcelnetrpautriiotnys.was not properly characterized and it lacked analytical Reviewer remarks: none REFERENCE 3LaMboCroatmoprayn,yS.t. P1a9u85l., M9N6.-hoLuarbacRuetqeuessttatiNcutmobxiecritCy1o006f.athFeaedbrmuianryno2.w ~ FX-1001. Environmental OTHER `General remarks: This summary was based ona summary report and only limited data ables. Nprootdoectoalisleadndrerpeosrutlwtsasofatvhaeilsatblued.y, Tahreerleifmoirteed,.the contents of this summary, in reference (the "TTEheSTmaCjoHrEcMoIncCeArnLfCoOtNryCiEngNtToRdAetTeIrmOiNneStwheervealuisdeidt.y fOorPhPiTsrteesciosmmtehantdOsNthLatYmNeaOsMurIeNdAtLest chemical concentratiobnes used. so that one can accurately determine the est chemical ccoonncceennttrraattiioonnstoarwchoinclyh.tofotrheextaesmtpolreg5an0i%smosf atrhceemxepaosseudr.edIcFointciesntdreatteiromnisn,etdhethtaotxtihceitnyovmailnuaels can fbuemiasnhdemdu,swtebecoaudljdusctaeldcudloatwenwchaermdicbayl5r0ec%o.verIyF arnaatleyst,iacanldmteaakesuirnteomeanctcsoounftshoymderolsyosritsh,avdolbaetielnity, `and other physicochemical processes that might ower the actual test organism exposure concentrations. 293 000297 FISH ECOTOXICITY Title: Acute Toxicity to Fish TEST SUBSTANCE Identity: Perfluorooctanoic acid, ammoniumsal; also referred to as PFOA ammonium sal, ammonium pSaelrtf,lCuoArSoo#ct3a8n2o5at-e2,61FC)-116, FC-126, FC-169, or FC-143. (Octanoicacid. pentadecafluoro-, ammonium Rsoelimd.ark1s':s pTurhiety3wMaspnroodtucctomlpoltentuelmybcehraruascetedrwizaesd,390a.lthTohueghesitnfsoarmmpaltieownais FnC-1d26,iiatwwcahsaiattemipxeotwuddreeroyf 7893% test substance and 7-22% C6, C7, and C9 perfluoro analogue compounds. METHODS Method/guideline followed: Notstated Test type: Static GLP (VIN): No ear study performed: 1957 Species: Pimeph`aAlveesrapgreomleenlgatsh = 3.5 em `Averageweight = 0.30 Supplier: Dale Fatt of Brady, NB Concentrations tested: 0. 100, 150, 320, 560, and 1000 mg/L Exposure period:96 hours Analytical monitoring: None because nominal concentrations were used. `Statistical methods: Probit analysis Test conditions: "Dilution water source carbon-filered well water "Dilution water chemistry: TDeOmopro9f.231pCpm pHOf79 "Test solutions were preparedbydirect weights addition 204 000298 ""SEtxapboilsiutryoefvteshseeltseswt echree4micLaitlersoPlyurteioxnls awassbneoatkenrotsecd.ontainin3g ltrs test solution "TSiwxofriesphlpiceartersepwliecraeteuwseedre used "WLaotaedrincgheramtiestwraysd0u.r6inggLtest DO range (24-96 hours): 6.67.4 mg/L (control) 5.666 my/L (320 my?) PHrange (24-96 hours): 2.779 (control) 77-80 (320 mg/L*) T*Tehmips g(r2o4u-9p6whaosursu)s:ed2b0eCcause total mortality occurred at higher doscs wRietmhianrakcsc:epNtaobolteherrandegteasilasccoonrdteisntgctoondOiPtiPoTnSs wHearremoginviezne,dingucilduedliinngesw.ater hardness. The pH values are RESULTS mDyos/eL o(f9e5a%cChI:end2p44o-i3n7t0)(.as mg/L): The 96-hour LCS0 for fathead minnow was determined to be 301 Remarks: - SLuorwfeasctintgesotfsfuibsshtawnacseocbosnecrevnetrdaattio1n80caaunsdin3g2010m0%Lmo(rbtoatlhitryepwlaiscatSe6s0) me/L No mortality was observed in the controls Was control response satisfactory (yes/no/unknown): Ves, based on the fict that there was no. mortality Statistical results, as appropriate: Not presented CONCLUSIONS wRaosunddeitnegrmtihneerdestuoltbset3o020smiggn/iLficwaintthfaig9u5re%s,ctohnefitedsetnscaemipnlteer9va6l-ohfou2r4L0-C3S700fmogr/fLa.thead minnow `QuSaulbimtiyttteerstsi'ngr.emHaorwkesv:erD,atthaeqsuaalmiptlyewpausritgyivweansa nKoltipmriospcehrlryanckhianrgacotef2r.izeTdesatnidngit mleatcktehde acnrailtyertiiacaflor confirmationofthe test substance concentrations Reviewers! remarks: none REFERENCE 3M Company. 1957. St. Paul, MN. Lab Request Number E128201, completed on May | 295 000299 OTHER GNeonedertaalilreedmraerpkorst:waThsiasvasiulambmlea.ryThwearsefboarsee,dtohne acosntuemnmtsaroyf trheipsorstumamnadroyn.lyinlirmeifteerdendcaetaotatbhlees. pTrhoetomcaojlosracnodnrceseurltsfoorfttyhiensgttuodyd.eatreermliimniettehd.e validity TEST CHEMICAL CONCENTRATIONS were used. for this OPPT rteesctoimsmtehantdOsNthLatYmNeaOsMurIeNdAtLest cCCohonenccmeeinncttarrlaattciiooonnncseatnortewrahotilicyohn.stofboetrhueesxetadem.tpsoloregtSahan0ti%somnosefactrhaeenemaxecpcaoussreuadrt.eedly[cfodtnectieenrtdmreiatnteierotnmshi,eneehdsetthctaohtxeitmchiiectynaolvmailnuaels can bFeurannisdhemdu,swtbeecoaudljdusctaeldcudloawtenwchaermdicbayl5r0ec%o.verIFyarnaatleyst,iacnald mteaaksunrteomeanctcsouonftshoymdreolsyosritsh.avdolbaetielnity. `and other physicochemical processes that might ower the actual test organism exposure concentrations. 296 000300 TOXICITY TO FISH Title: Static Acute Toxicity of FX-1003 to the Fathead Minnow, Pimephales promelas aIdmemntointiy:umPeprefrlfulourooroocotcatnaoniocataec,idP,FaOm,mFoCn-i11u6m, sFaClt-;1m2a6,y FaCls-o16b9e,reFfCe-r1r4e3d,(or03sasPaFmOaAjoarmcmoomnpiounmenstaot,f FX1003. (Octanoic acid, pentadecafluoro-, ammoniumsalt, CASRN 3825-26-1) Remarks: FX-1003 waTsheno3tMsufpfriocdiuencttliyonchlaortanctuemrbizeerd;wahsow2e3v2e7r.,TahveaitleasbtlseaimnpfloermwaatsioFnX-i1n0di0c3a.teTdhiet purity was a of Saonldut1io-n2o%f <C4e5a%ndamCm;opnerifulumorpoe-rfalnuaolroogoucetacnooamtpeo,un5d0s%. water, <3% inert perfluorinated compound METHODS Vethodiguideline followed: OECD 203 Test type: Static GLP (VIN): Yes Year study performed: 1990 `uSnpdeecriesf:lowP-rtiohrrotuogthesctoinndg.itjiuovnesniilneanfatalhleagdlamssinanquoawrsiuwme.reFiaschclwiemraeteadccfloirm6at3eddatyostihne 100% target dilution est water temperature disease and (232 C)for 14 days beforetest initiation. were freeof apparent sickness, injurics, and During acclimation, abnormalities a test fishwere initiation. not Fish treated for were fed a vcaolmumeesrocfiatlheifsihshfowoedr,eo3.n8 cecmor atwnidc0e.d4a5ilgyr,afmos (thweetac)crleismpaetcitoinvelpyer.iod. The average length and weight SRuepspclairecrh:OrTghaenifsiosnhs,usHeadmpintotnhe, tNoxHi)c.ityThteestspwoenrseorp,ur3cMh,asperdovfirdoemd athceoemsmterscubisatlasnucpep.lier (Aquatic Ccoonncceennttrartaitoinosn:s0t.e1s.te1d,:10A. 1s0c0r,eeannidng1t0o0x0icmigt/yLt.estFowrasthpeedreffionrimteidvewtiotxhictihtey ftoeslt.lofwiivnegnfoimviennaolminal concentrations and one blank used in the definitive toxicity dilution test and twhaetenromcoinntarlolcownecreentursaetdi.onTswtoesrteepdlwiceartee:sof0,c1a5c0h, 2co5n0c,e4n0t0r,at6i0o0n,waerned: 1000 me/L. Both tests were performed under static conditions. Exposure periods96 hours Arencaolrydteidcadlaimloyniintocraicnhgt:esDticshsaolmvbeedrotxhyagtecno.ntpaHi.necdonidvuectfiivshi.tyC,oancnednttermapteiroantsoufrethweerteesmtesausbusrteandcaenwdere not measured during the test. 27 000301 Softatthiesttiocxailcimteyttheosdt sc:oulNdonnlotinbcearinitnetreprrpeotleadtiboyn,smtoanvdianrdg satvateirsatgicea,l atnedc/honriqpureosbidtuaenatloys1i0s;0%hoswuervveirv,alraetsutlhtes highest tested concentration. Test conditions: "The test sercening substance utnesdtewrassimpielrarfocromneddiutsiionangsnotmhionsaeolfctohnceendetfriantiitoinvse (fe0s.t1., 1.0, 10, 100, and 1000 mg/L)of the WfraotmerweulslesdatforEnavcicrliomSaytsitoenmosfitnhHeatmespttoorng,anNiHs.msW,aatnedr fwoarsalaldtjouxsitceidty0esatihnagr,dnweasss woelf$l8 wmagte/rLacosllCecateCdO anantdursatlorweedllinwtaatnekrs.uswehderaes tithewadisluatriaotnedw.atAercfhoermtichaltocxhiacriatyctteersitzwataisonpeorffaorrmeepdr:estehnetaftoilveloswaimnpglvealoufesthe. owregraendoeptheorsmpihnoerdo:uspHpes=ti7c.i4d,ecso,nadnudctiPvCiBtsy~we1r5e00b1elmohwotsh/eeml.eveOlrogfandoecthecltoiroinn,eofpensotitcipdreess.ent. The test cVme)s.selSstawbeilrietyo1f9.t6he gtleassssuabqsutaarnicaethwaatsconnottaiinndeidcat1e5d.LoNfoessttocskolsuotliuotnio(napwparsoxpirmeaptaerewdaatsertedsetpmtahtewraisal17was. `naodmdiendadlirceocntcleynttoradtiilountsiownewraeteursecdonitnatihneeddeifnintihteivteesttesvte:ss0e,ls15w0i,th2o5u0t,t4h0e0,us6e0o0f,aasnodlv1en0t0.0 mTLhe.foTlwleownitnyg dfiesthewrmeirneedratnodboemlaypparnodxiemqauatlellyy d0i.s3t0rigb/uL.tedTeasmtovnegssetlwsowreerpleicraatnedsoomflcyaacrhrtarnegaetdmiennt.a Twahteerlobaadtihngdurraitengwatshe.. 9ph6o-thoopuerrtiesotd. wSatastiacutcoomnadtiitciaolnlsywmearientmaaiinnetdaiwnietdhtchoroolu-gwhhoiutte tflhuosrteusdcye.ntAli1g6h-thsotuhratipgrhotvaindded-ahloiugrhtdark cionncteentnrsaotifit3ony5s abEosvemr"a.ccAeeprtaatbiloenlewvaelss.emFpislhoyweedraeftneort4f8edhdouurrisngtothmeaitnestta.iTndhiessfoolllvoewdionxgywgaetner chemistry ranges 1300 (0 - 96 hours) weredetermined: conductivity = 1200- 1500 1600 mhosiem (1000 mg/L exposure): pH range = 7.4 ~ 8.4 mhos/em (control exposure). (control exposure), = 7. - 8.2 (1000 9m.g2/mLg/eLx.po(scuornet)r;olteexmppoesruarteu)r,e range ~ 6.2 9=.211.(01-00220.mgC/(Lceoxnptroosluraen)d.1T0h0e0pmHe/Landexhpaorsdurnee)s;s dissolved 0: 6.1 were within the accepted ranges (6.0 = pH <8.5: 40<hardness=180 mg/L) forthe durationofthe study. Remarks: No additonal comments RESULTS Dose of each endSpcoreiennti(nagstemsgt:/L): 96-hour LCS>01000mg/L, 96-hour NOEC > 1000 mg/L. Definitive est 96-hour LCS0> 1000 mg/L, 96-hour NOEC > 1000 mL eRxepmoasrukres:anAdlalllteostthveerstseeslts remained exposures cilneatrhetshcrroeuegnhionugt the test test. and 1in00th%edseufrivniitviavletoecsctu.rred in the control Was contral response satisfactory (yes/no/unknown): Yes `Statistical results, statistical methods dauseatpopr1o0p0ri%astuer:vivalaRestuhletshoigfhtehset tteosxtiecditcyontcesetntcroautlidonn.otbe interpretedbystandard 298 000302 C"TOheN9C6L-UhoSuIrOLNCSS0 and 96-hour NOEC were determined 0be>1000 mg/L `SSaumbpmliettpeurrsi'tyrweamsarnkost:prKolpiemrilyscchharraancktienrgiz2e. dTaenstditnhg mteesettslatchkeedciatnrailyatifcoarlqcuoalniftiyrmtaetstiionngo.fHotewsetvseurb,stance concentrations. Reviewers" remarks: The conclusions appear besupported by the daa pErnovmierloaSsy.stHeammsp,tIonn., N19H9.0.SSttuadtyicnAucmubteerTwoaxsic9i0t1yo4-f3.FX-1003 to the Fathead Minnow, Pimephales OTHER `The majoGrenceornacelrrnefmoarrtkrsy:ing to determine the validity for this testis hat ONLY NOMINAL TEST CcoHncEeMntIrCatAioLnsCbOeNusCeEdN,TsRoAthTatIoOnNeScawneraeccuusreadt.elOy PdePtTerrmeicnomtmheentedsst cthhaetmimceaalsucroencdetnetrtacthieomnitcoalwhich to h50e0%teostftohregamneiassmusraerdeceoxnpcoesnterda.tiFonist,sthdeetteoxrimciinteydvatlhautesthceannbomeiannadl cmounsctebnteraatdijounssteadredoonwlnyw,afordebxyam0pl%e aanndaltyatkiecianltomaecacsouurnetmheyndtrsoloyfssios,mveolastoirltithy.adanbdeenotfhuerrnpihshyesdi,cowcehecmoiucladlcaplrcoucleastseeschtehmaticmailghrtecloovwereyr trhaetes, `tual test organism exposure concentrations. 209 303 TOXICITY TO FISH Title: Acute toxicity ofN2803-3(0 the Fathead Minnow, Pimephalespromelas TEST SUBSTANCE pIednetnatidteyc:afluPoerrof-l,uoCroAoSctRaNnoi3c35a-c6id7;-1m)ay also be referred to as PFOA, FC-26, or FX-1001. (Octanoie acid, sRaemmpaler.ksF:C-T26h,e w3aMs prreofedrurcetdio(n0 bloyttnhuemlbaebrorwataosry26a9s. NT2h80e3-te3s.t sTuhbsetpaunrcietywaosftahewhsiatmepploewwdaesr.noTthe test SSuubfsftiacniceentancdha0r-a-c3t.er5iz%edC:i,hoCsw,evaenrd,Ca.vapielrafbllueorion-fohrommaotlioonguiendcicoamtpeodunitdwsa.sTahmeixtetsutrseoubfst9a6n.c5e-("1as0-0% test mreicxetiuvreed"w)aswarsecfoemrbedin(e0daswittheh"iasso-tpersotpeadn"olsuibnstan5c0e:.50 ratio prior 0 use. The substance resulting from this METHODS Methodguideline followed: U.S. EPA-TSCA Guideline 797.1400 Test type: Static GLE (VIN): Yes Year study performed: 1996 `tSanpke.cieDsu:rinJguvaecncilliemaftaitohne,adthmeiinsnhowwserweernoetatcrcelaitmeadtefodruinsdceasref.loTwh-ethfrioshugwhecroendfireteioofnaspipanare2n7t0 sLicfkinbeesrsg,lass Dinujruirincgs,thaend14a-bdnoarympaelriitoidesbeatfotreestteisntitiinaittiiona.tiMono,rttahleiatcycdluirmiantgiotnhetefmipnaelra4t8urheourrasnogfewaaccsli2m1a.0t.ioCn w~a2s2.3<3%C. xancdeptthedduirsisnoglvtehde 4o8xyhgoeunrscoinmcmeendtiraatteiolny wparescaetdilnegastth8e.0tesmt.g/TLh.eDauvreirnaggeactcolailmalteinognt,hfaisnhdwweertewfeeidgdhatiolfyt,he test organisms were 33.4 mim and 0.35 grams, respectively `sSpuopnpsloire.r:3MJ,uvseunpiplleiefdatthheeadtemstisnunbostwasncwee.re procured from Aquatic Biosystems, Fort Collins, CO. The Cwoenrceeunsterd:ati0o,n0s05t,es0t.e5d0:,F5o.r0,t5he0,satantdicSs0c0remegn/iLn.g tFeosrt,tthheesftaotlilcdoewfiinngitniovmeitneasltc,ontcheenftorlaltoiwoinnsg, naosm-irneacelived, ciosnocpernotpraantoilo,nsn,omaisn-taelstceodn.cwenetrreatuiseodn:s o0,f013(0d,il2u2t0i,on3w6a0t,er60co0n,traonld) a10n0d05m0g0/Lm.g/FLo.ritshoeprstoaptaincotleswtewirthused. Exposure period: 96 hours Arneacloyrtdiecdadlaimloyniintocraicnhgt:estDicshsaomlbveerd, oTxhyegetne,mppeHr,attuermepeirnaotunree,tesatndvecsosenlduwcaisvirteycowredreed matealesausrtehdouarnldy during the test. Concentrations of the tet substance were not measured during the study. 300 000304 SDtoatsihstii,calusmientghpordosb:it aLnaClysviasl,umeosvwienrgeacvaerlaugelmaeebtdhyodn.onofinbcinioemnialeprrobpabiolit(yStephan, 1983), when FToesrttchoensdiatiionssc:reen,i0n.g50te,st5,.0n.om0i,naalndco5n0e0enmagt/iLonTshoefscreeentingsu6b51n4e2t5spaesr-freocremievdedu,nwdeerrsei0mi(ldairlution FCoonditaiotnsoas.th0o.s0e5of the definitive tes r acclimation ofthe test organisms, and foral toxcty ee, Btoebd tdoeaiohnairzdendeswsaotefr40 - 48 rataortuseCTdACRfoOg.,haWnpiadlnbsicuolrreyedlLairnb,poorilaryoaervbiyislleiennteMsatreabniklsze.heen,atdah:nedMsAnc.lkWvaettelorSEWaoLbtoCnm".ya/dLjt.unsOaatrchaheteremdimceatanaldlcschoaanrnatdcitnpeuortoieuznsatltiyiaoln Oar roiuie hesopseratomhppealrenbooeflndoalwutSthiUeo:Snv0ewraltaoeofrdpeotreoncrtatioosnu,sdeeotrTeohcitfsedrS1e0s05t0.FF"sEhsuFme5d0Ft`ooSuhtbahsvteeannaccpeou,nrsaiistd-yererocefedi1vte0od0b,%eWas So toatwsiun cbhstcaonnnctedadiunredibne1ga5hbLeloetfoxutincsdietsyroseltutot.riaongTe(htapntpedsrteossxtuiibnsnatglaecnoMcneEdCiBtCEiSoen"psaiTEhwRaSs51o8fcvemcsa)sc.ehlsTtrwweeeanrttmeey2nt0f.aLthgelaadss SN oepkair.ae twhe amdoniudani.tsscrTomhftieneeatsctsluycbosantcnaednntccreoauwtailoelnys,iasdadiesbdusldiertdecta0lmyo0tnhgeS(dLewfeCinPCitIiwrvareta1en8rg0eidnEitnhIaesetea0s.ttev1re3sb0as,te2hl20df,uor3i6n0,g t6h0e0. Aimal.ihTnhoeteuds vrhewstistehalnscdowohelrowehuifrotsedeaHlroykrcpeohsvoceteroneptderFaiingodhdtsawhniatdlhaoprr[oavSiSdmC"ailLighttcoiCnntce0ennstiprteayrotiifood3n,s1waabosve. oe a evoer.6t.o4Mnea8sw.ua1rsmeendlawattceeodrnctahfoetlmries7xt2proyhsoudururers)i,ntgo=mt5haei2ne-usa9tinpOriomsvisedes(23200Tmorglo/llLoewxeipxnopgsousrruarene)g),e;s=C(3o0.n0-du9-c67t:4ihvoui2rts2y)0:= mel e0x.possauhrae)siTmem(pcoe6n0rt,arot6l0u0ar,ne=dan22d12.0180m0g02/2.mL6 ge/xLCpeo(xcspooents)ruorpleHacno=dnc72.1e2n3tr0a7ti6oLn(sceoxHnptoesurCeL).thTeohrxeiacnpigtHey ovsatfluduie3.c0s-os4f(63t.h0eat SHEoRn5.sHarfdTonheetsshees3wloawspwiHthailnutchsewdecrceepotuatbsiedasnthgeaocrcp(laXbileeraundgiecfso(S400-1180t mg/L, as CaCOY. FForr tihensetaindtdoxeilciintiyivteettopveircfitoyrmteesdtsweiwstihtvhessNos2pe8rl0os3p-wa3en.rae0lrianstdiolmolrny rwaroarcaoencgoce)odnVtirnLoal)fwoaalntledorw5be0ad0athmgat/nhdLattifhsoeorpltrihgoheptanol ansiintyt wcoansce2n8trfaotoiteoann)diwcesr.e usd. T `Remarks: No additional comments RESULTS DoseofeaEchOenpdp"to>i-enhtonu(trasLaCmtsga/iL=o)2ni8n0,t(he2es2dte0-fei3nd6i,0ti)vamengdt/eLas.ts:soialcd 95% confidence Lis: 3T98a6---hhhooouuurrr LLLCCCaaang === 222888000 (((22222200-0- 333666000)))mmmggg///LLL.. 301 000305 96-hour NOEC = 220 mg/L "Test subs2t4a-nhcoeurcoLncCeyn=tgrat1i4o0n,(1a1s0-r-ec1e8i0v)edm,ga/Ln.d associated 95% confidence limits: 48-hourLC = 140 (110 - 180) mg/L. 9762--hhoouurrLLCCasa== 114400 ((111100- -113800)) mmgg//LL.. 96-hour NOEC = 10 mg/L cRoenmtraorlk.s9:0%Fosrurtvhievaslcraete0n.i0n5g tmegs/t,L.the10fo0l%loswuirnvigvsaulravtiv0a.l5r0a,te5.s0,wearned o5b0semrgv/edL:, a1n0d0%0%susruvrivviavlalinatthSe00. mg/L. For the definitive test, no insoluble materialwasobserved inanyof the test vessels during the sstuubdlye.tha1l0e0f%fescutsr.viFviaslhoicncuthrere1d30inatnhde c2o2n0trmogl/eLxpeoxspuorseuraendcotnhceesnetrfaattihoenasd ampipnenaorweds ndoirdmanlo.t eTxohtiablitmoarntyality wloawseosbtsceornvceendtwriattihoinn, 2w4hihocuhrcsaiunstehde 136000,%6m0o0r,taalnidty,10w0a0sm3g6/0L megx/pLo.suDruericonngcetnhtertaotxiiocnist;y tthesetrewfiotrhe,0t0he mg/L isopropanol, no mortalityo sublethal effects were observed; the 96-hour Cia value was >500 mel. `Was control response satisfactory (yes/no/unknown): Yes Statistical results, as appropriate: No additional comments CThOeNaCsL-tUesStIedO9N6S-hour LCsp was determined to be 280 mg/L, with a 95% confidence intervalof 220- 360 mg/L. The as-tested 96-hour no-oberved-cffect-concentration (NOEC) was 220 mg/L. The 96-hour LC. based on of 110 the 180 test substance as received, my/L. The 96-hour NOEC was determined (0 be forthe test substance, 140 mL. with a asreccived, was 95% 110 confidence mg/L. interval `Submitters' remarks: Klimisch ranking 3. The study lacked analytical measurement of tet substance. concentrations in the est solutions and sample purity was not sufficiently characterized. Additionally, tthheerperaopcpeedaurreedtcoonbdeucatdeidscbryetphaenclyabboreattwoereyntothperespaamrpelethperetepsatrsaotliuotniodnisr.ecTthieonasbgsievnecnetooftphaertliaablomroarttoarlyiatyndat intermediate doses resulted in a sharp dose-response curve. Asaresult, the LC:o valus determined in this study may not accurately reflect the concentrations tested may have had true toxicity ofthe solution. The an adverse effect on survival. low pH values observed in the high Reviewers" remarks: The conclusions appear to be supported by the data RTRE.FEWiRlEbNurCyELaboratories, In. 1996. Acute toxicity of N2803-3 to the Fathead Minnow, Pimephales promelas. Marblehead. MA. Study number 891-TH. OTHER General remarks: The major concern for rying to determine the validity for thi test is that tOhNatLmYeaNsuOrMeIdNteAstLcThEemSiTcalCHcoEncMeIntCrAatLioCnsObeNuCscdE. NsoTthaRt AonTwcIearnOeauNcsceuSrda.teOlPyPTdetreercmoinmemethnedtsest cnhoemmiincaallccoonncceennttrraattiioonns a10rewhonilcyh, 0fortheexatemsptloerg0an%iosmfstharee exposed. measured IFit is determined that the concentrations, the toxicity values can be and mustbe adjusted downward by 50%. Fanalytical measurementsofsome sort 302 000306 vhoaldatbileietny.faunmdisohtehde,r wpheycsiocuolcdhceamlicculaaltpercohceemsisceaslthraetcomviegrhyt rlaotweso,ratnhde aackteualnttoestacocroguanntishmydrolysis, exposure concentrations. Purity of the test material als is a major concern and was not sufficiently characterized in this test. In some tests it appeared that 100% test chemical was used, for otheras chemical of lesser wpuarsituys(eadpipnrooxtihmeartteelstys,8f5o%r)nowaosbvuiseodu.s sWtaatteedrre,aassooln.ven[tn fiasco,pr3opManionl)thoerr sucmommbairnyatoifocnaocfhbtoetsth Sate: "Data may not accurately relate toxicityofthe test sample with that of th test substance." rFeajgercteethweistehstthuidsiecso,ncpeenn.dinIgnraedcdeiitpitono,faifdtdhiitsiownaasl ain"ftoyrpmiactailo"nToSnCpAursietcytaionnd 4sturdeiveiseown|.anwaoluyltdical `measurementsofthe test chemical in the test medium. 303 000307 FISH ECOTOXICITY Title: Acute toxicityofFC-1015 to the fathead minnow, Pimephales promelas TEST SUBSTANCE IAdmemntointyi:umPerpefrlfulourooroacoteatnaoniocataeci,d,PFaOm,mFoCn-i1u1m6,saFlC;-1m2a6y, aFlCs-o1b6e9.reFfCer-r1e4d3toorasasPtFhOeAmaajmormocnomipuomnseanltt,of FC-1015, (Octanoic acid, pentadecafluoro-, ammonium salt, CAS #3825-26-1) Rinefmoarrmaktsi:onTihnedicteasttessaitmpslae 3is0F%C-s1t0r1ai5g.ht lcsarpbuornitcyhwaaisn vneortsisounffoifciFeCnt-l1y4c3hairnac8t0er%izweadt,ert.hoTuhghe c3uMrrepnrtoduct lot numwabs"eHOGrE 205." Data may not accurately relate toxicityofthe fest sample with that ofthe fpeesrtfsluubosrtoaoncctea.noaDtaetahowmeorleougsemdixttoucroemipnaFrCe-t1o4x3icivtsy.owfhahteisbrsaunpcphoesdesdtrtaobigehtthceha1in00a%mmstornaiiguhtmcarbon chain ammonium perfluorooctanoate in FC-1015. METHODS Method/guideline followed: USEPA-TSCA 1993. 797.1400 Test type: static GLP (VN): N ear study performed: 1996 Species: Pimephalespromelas. The fish were juveniles with an average lengthof 35 mm and average. weight of 0.36g (wet). Supplier: Aquatic Biosystems. rCeopnlciecanttersaatticoancshucsoendc:en0t,ra5t3i0o,n8w3e0r,e1p3e3r0f,or2m1e0d0., and 3300 mg/L. The concentrations were nominal. Two Exposure period: 96 hours Analytical monitoring: none `Statistical methods: LCS0valueswere calculated using the Stephan computer program, 1983 a"TepsatrtCiocnuldaitteiofinlste:r, Tulhteradviiloulettiosntewrailtiezreru,saenddwaacstidveaitoendiczaerdbowna.teTrhaedjduisltuetdiofnorwahtaerrdncehsesmainsdrypawsassedmteharsouurgehd alisgfhotlilnogw.sc:oohla-rwdhnietses f~lu4o4remscge/nLt alsighCtasCatO3.0alfkoaolti-nciatnydi=es29w-e3r0e mugse/dL.asACdaaCiOlyy,pahontdopTerOiCodo<f| mg/L. For 16 hours light atensdt sohluotuirosnsdawrekrewictrheaate1dS bmyinduitreecttriannsdiitviiodnuaplerwieoidghwtasaddmiatiinotnas.ineAdfttherarou1g4hoduatytahcectleismtaitngiopnerpieordi.od,Thtehe ish were exposed, at a loading of 0.24g fish. in 20L glass aquaria containing 15 liters test solution at 304 000308 an approximate depth of 18 cm. Two replicates were tested at cach concentration. Twenty fish were used in cach replicate. "JTuhmehwoastieermc(hceomnitsrotlr)yapnadra3m0e0t-e3r2s0myemashuorse'demdu(ri2n1g00thmegs/tLudeyxpionsculrued)e,d:pcHond= u7c.t3i7v.it9y(rcaonntgreo-l) 1an5d0-71.920-7.7 (2100 mg/L exposure), temperature- 22.0-22.4 C (control) and21 8-22.5 C (2100 mel. exposure), and d(issescoolnvdehdigohxesytg)enc-onc5e.n8t9r.a2timogn/Lwa(scuonsterdolb)eacnauds5e.7t-h9e.h2igmhee/sLt c(o2n1c0e0ntmrga/tiLonexrpeossuulrtee)d. inTthoetal21mo0r0tamlgi/tyLat 72 ahlousros.perTfhoermpeHd r(asenegeApwpaesndwiitxhifnortphaeraacmceetpetrasblaenrdandgeet.ectMieonasluimrietsm)e.ntTsohfedoinlluyticohnemwiactaelrdcehteemctiesdrwyawserieron a1 0.03 mg/L. Remarks: Water hardness, during the study, was not indicated. RESULTS Dose of cach endpoint (as mg/L): 9966 hhrr LNOCESC==2$43700 m(g2/1L0.0-3330) mg/L. Remarks: none `Was control response satisfactory (yes/no/unknown): yes Statistical resultsas, appropriate: none ONCLUSIONS c"Tohnefitedsetnscaemipnlteerv9a6lhoofu2r1L0C0-S3033fo0rmfga/thLe.ad minnow was determined to be 2470 mg/L with a 95% `tShuebcmriitttereiras'forreqmuaalriktsy:tesFtoirngd. aaHorweelivaebril,itsya,mtphleestpuudryitwyawsasasnsoitgnperdopaerKllyimcihasrcahctreatriinzgedoaf2n.d Titelsatciknsg meets analytical confirmation ofest substance concentrations. OReNvLieYweNrOs'MrIeNmAarLksT:ESTTheCmHaEjMorIcCoAncLerCnOfNorCtErNyiTngRAtoTdIetOeNrmSinweerteheusveadl.idiOtyPfPoTr trheiscotemsmteisndthsat that measured test chemical congentratiobnes used.so that one can accurately determine the test chemical concentration 0 which o the test organisms are exposed. IFit is determined that the vnaolmuiensalcacnobneceanntrdatmiuosntsbaeraedojnulsyt.efdordeoxwanmwpalred5b0y%5o0f%t.he ImFeasnsaulyrteidcaclonmceeansturrateimoennst.sothfe stooxmiecitsyort hvoaldatiblietyn, faunrndisohtehde,r pwheycsoiuclodchceamliccuallatpercohceemsiscesalthraetcmoivegrhyt rlaotweesr,tahned atcatkuealintteostacocroguanntishymdrolysis, exposure concentrations. Purityofthe test material alo isa major concern and was not sufficiently characterized in this pfeustr,ityIn(sapopmreoxtiemsatsteilt yap$p5e%a)rewdatshautse1d.00%Watteesrt,chaesmoilcvaelntwa(issoupsreodp.anfoolr)otoherrscaomcbhienmaitciaolnoofflbeostsehr was used in other tess, for no obvious stated reason. In fact, 3M in their summary of each test STtaagter:ee"Dwaittah mthaiys cnoontcearcnc.uraItnelayddirteiloant.e itfoxtihciistwyaofstah"ettyepsitcasla"mpTlSeCwAitshetchtaitoonft4hreevrieestw,suIbwsotaunlcde." 305 000309 reject these studies, pending receipt ofadditional information on purity and studics on analytical `measurementsofthe test chemical in th test medium. REFERENCE Ward, T., Nevius,J.and R. Boeri. 1996. Actie toxicity ofFC-101Sto the fathead minnow, Pimephales promelas. TR. Wilbury Laboratories, Inc. Lab Requestnumber P1624. 3M Company. St. Paul. MN. OTHER General remarks: none APPENDIX "homical messusements of dilution water Parameter: Detection Limit: MeAtlalusminum Arsenic CaBodrmoin um Chromium CCoopbpaletr Iron LMeeracdury NSiiclkveerl Zine NCihtiroarriede: Fluoride "Total organic carbon "OTrogtaalnopchhoisoprhionreouPessticides Toxaphene OrDgiamneotphhooasptheorous Pesticides TEPP PCMBosnocrotophos. 0.1 mg. 001 mglL 00.500m02gmglL. 00..0013 mmgp/lL 0.005 mL 0.03 mel. 0.005 m0L.0003 mg/L 00..0023 mmgg//ll.. 002m0g.05 me NL 0m1g/mLg | my 00053uemle.l 2p 0.5 pg/L20 204 0250 uplgl 306 000310 ALTdCEeSnUtTTitESy:UTBPOeSXrTIflCAuINorTCoYEocTtaOnoFiIeSaHcid(,FaAmTmHoEnAiDumMsIaNltNmOaWy)also be referred to aF3C-P1F1O6,AFaCm-m12o6n,iFuCm-1sa6l9t,,AormmFCo-n14i3u.m(pOecrtfalnuooireooacctiadn.oate. PFO, Rpeenmtaadrekcsa:fluTohreo-3,Mamprmoodnucituimonsallot,f nCuAmSber3w8a2s54-2276.1)The test sample is WFCi-l1b4u5r3,y rsetfuedryrendutmobbeyrtishe89te5s-tTlHa.boTrhateorpyuraistyNo2f80t3h-e4s.aTmphleeTwRa.s innodtiscuaftfeisciitenitslay mcihxartaucrteeroifze9d6,.5al-t1h0ou0g%h fcsurtresnutbsitnafnocremaatnidon0 -- 315%C6, C7, and C9 perfluoro analogue compounds. MMeEthToHd:ODU.S. EPA-TSCA Guideline 797.1400 Type: Acute static eGLaPr: cVoemspleted: 1995 SSpuepcpileise:r:PiAmqueapthiacleBsiopsryosmteelmass, Fort Collins, CO `EAxnpaolystuircealpmeroinoidt:or9i6n-gh:ouDrOs, conductivity, pH and temperature ``aSntaaltyissitsi,camlomveitnhgodasv:erLaCgeS0mevtahlouedsocrablciunloamtiead,l wprhoebnabpiolsistiybwlei.thbynopnr-olbiintear Interpolation using the computer softwareofC.E. Stephan. LTeesntgtfihshanagde:weNiogthtn:otAevde.rage length = 25.6 em LAovaedriangge:w0e.i13ghg=t/L0.198 (wet) TPersettrceoantdmietnito:ns:None mDiglluLtiaosnCWaatCeOrV:LDeionized water adjusted (0.3 hardnessof40-45 DLiilguhttiionng:waCotoelr-cwhheimticsftlruyo:reNsoctenntotbeudl.bs with an intensity of 30 fe. Photoperiod of 16-hours light, -hours dark with a 15 minute Strtaoncsiktiaonndpetreisotd.solutions preparation: Test substance added Cdiornecctelnytrtoattihoendsilduotisoinngwartaetre;inOtnhceetest vessels. `wSatasbinloitteyodfdutrhiengtetshtecthesetm.ical solutions: No insoluble materia! LExopfotseustresovleustsieolns,: w2a0teLr gdleapstshaaqpuparroixaicmoanttealiyni1n8geampproximately 15 NNuumbmerbooffefriresphlpiceatrerse:pl2icate: 10 WNautmebrercohefmciosntcreyntdruartiionngst:hefisvteudpyl:usanegative control 7Di2ss8o.lv5edmoLx.yg(ecnonrtaronlgeex(p0o-su9r6e)hours): 67-85 mg/L (1.000 mg/L exposure) 307 000311 C1o4n0d-uc1t3i0viptmyhroasnigeem((0co-n9tr6olhoeuxrpso)sure) 2p5H0-ra3n8g0e p(0un-h9o6s/heomur(s1).000 mg/L exposure) 77:34 7.7.65((1c,on0t0r0olmegx/pLoseuxrpeo)sure) 2Te2s0t-te2m2p.e6raCt(ucroentrraolngeexp(o0su-r9e6) hours) 2R1.8ES-UL2T2S5C (1000mL `Nominal concentrations: exposure) BK control, 160, 250, 400, 630. 1.000 mg/L. E24lcehmoeunrtLvCaSlu0e =a>nd19,0500%mcyo/nLfi(dCe.nLcenoitntcearlvcaullable) 3782--hhoouurr LCS0 LCS0 = = 790 760 (630 (630 -- - 1,000) 1,000) mg/L. mg/L. 9966--hhoouurr LNCOSE0C= =744000(6m6e/0L-.830) my/L. ESetlraetemiesdtneitctaevlarlmEuivenaseldbuaabstyeidboinonnoofmniMoaomlritniaanltliertcpyoo:nlcaTteihnotenr.4at8Piroaonnbsdit7w2-ahsouusreLdCtSoOcavlacluluaetse tB2hi5eo0l.9o6ag-nihcdoa4ulr0o0LbCsmSeg0r/.vLateixopnossuafrteerco9n6c-ehnoturrast:ionFsisahppineatrheedconnotrrmoall.anDdarthke 160. i`osbcsoelrovraattioinonpearnidoderirnattihces1w,i0m0m0mign/gLofetxpwoosfuirseh wcoansceontbrsateironv.eadtthe 24-hour Cumulative percent mortality: T[Neosmtinal Cone. ml Comval 160 250 643000 Toon | 2h4o-urs Tho-urs | 9h6o-urs 100 JoJo} po to fo 1 fo_fo1 I op fT o o e ] [15 foo Joo [90] LMoorwteasltitcyonocfecnotnrtartoilosn: cNaounseing 100% mortality: None 308 000312 CONCLUSIONS 7T4h0e mteyst/Lsawmiptlhe2996-5h%oucronLfCiSde0ncfoerifnatterhveaaldofm6in6n0ow83wa0smdg/eLt.ermTihneed96t-ohboeur nSuobombitsteerrv:ed3eMffCetosmcpoancneyn,trEantviiornon(mNeOnEtCa)l Lwaabsor4at0o0rym,g/P.LO.. Box 33331, St Paul, Minnesota, 55133 DReAliTabAilQitUyA: LKIliTmYisch ranking = 2. The study lacks analytical measurementoftest substance concentrations in the test solutions and sample purity is not sufficiently characterized "TRhiEsFsEtRudEyNCwaEsSconducted at T.R. Wilbury Laboratories, Inc. Marblehead, MA, at the request ofthe 3M Company. Lab Request number N2803-4 OTHERGeneral remarks: The major concern for trying to determine the validity fo this est is that OhaNtLmYeaNsuOrMeIdNteAstLchTeEmSicTalCHcoEnMceInCtrAaLtioCnsONbeCuEsNedT,RsAoTthIatOoNnSe wcearneacucsuerda.teOlyPPdeTterremcionmemtehnedtsest chemical concentration 10 which o the test organismsare exposed. IFit is determined that the vnaolmuiensalcacnonbceenatnrdatmiuosntsbaereaodnjluys,iefdordeoxwammwpalred0by%50o%f.theIFmeanaasluyrteidcaclonmceeansturrateimoennst,sthoefstooxmiecitsyort Tvoaldatbileietny.faunrndisohtehde,r wpheysciocuolcdhceamliccuallatpercohceemsiscesalthraetcmoivegrhyt rlaotewse,ratnhde atcatkuealinttoesacocroguanntishmydrolysis. exposure concentrations. 309 000313 ACUTE TOXICITY TO FISH (FATHEAD MINNOW) TenEtSiTtyS:UPBeSfTluAoNrCooEstanoc acid, tetrbutylammonium salt; may aso be terreafbeurteyd 1a0mamsoPnFiOuAm tpeerrafbluuotryoloactmamnoonatieu,mNs2a8l0,3-2, oras a mor c{oemtpaobnuetnytlaomfmLo-n1i1u4m92s.ah(,OCcAtaSno#i9a6c5id8,-p5e3n0ta)decafiuon-. rReefmearrekdst:o Tbyheh3eMtepstriondgucltaiboonratlootrynuambLe-r13v4a9s2.2.TThheeTeRs.t sWialmbpulreysstudy uN2m3b32e.rTishe39p-uTriHt.y oTfhtehe3sMamEpnlveirwoansmennottaslufLfoibcioernattloyrcyhaRreaacuteesrtizNedu,mber is al{tchtosubguhtycluarmeinmtoninifuorpmearthiounorinodoiscattaens ots2st7,a.9s%oluwtaiotneo,fa4n4d.297%.2% isopropanl tTeChsheatrsfauocbltsletorawinizecndegcisonunamcenmnaitrrsayotpairpoopnlpsiaoenfsetilomwptauhtreietteisseostl.ustaDimaoptnlawemiatahsyiannmcoiotxmaptclucerutereaoltyfetlhye eMlEutTeHtOoDiciyofthetest ample with that of the test substance. "MTeytpeh:odA:cuUt.Se.stEatPicA-TSCA Guideline 797.1400 GYLePa:r cVoemspleted: 1995 SSpuepcpileise:r:PiAmqeupathiacleBsiopsryosmteelmass, Fort Collins, CO m`Aonnailtyotriceadldmaiolny.itoring: DO, conductivity. pH and tempera were EStxaptoisstuircaelpmeertihodo:ds9:6-LhCouSr0svalues eaeulatd, when possible, by probit ainnatleyrspiosl,atmioonviunsginavtehreacgeommpeutthoedsoorftbwianroemioaflCpEr.obaSbciplhitaynwith non-linear LTeesntgtfihshanagde:weNiogthtnootfedfish in control: Average length-32.8 mm ALovaedriangge:w0e.i19g.ht fs0h.2/5L & PBrAetCrKeatTmOenMt:AINoNne "DTielsuttcioonndWitaitoenrs: Deionized water adjusid toa hardness of40 - 45 nDigl/uLtiaosnCwaatCeOrIcLhemistry: Not noted LFihgohttoipnegr:ioCdoooflw1h6i-theoulruoirgeshc8e,nt-hbouulrbss dwairtkhwaintinhate1n5simtyinout2fe fc. r`Aaenrsaittiioonn:pIenritoadted afc the 72-hour DO measurements. aSdtdoecdk dainrdcettelsyttsootlhuetidoinlsutpironepwaaratteiiornnsthTeestetstsuvbessstealnsceonwaas weight volume basis. No insoluble materia was noted duringthe 310 000314 CFoxnpcaeonatrreatvieosnsseldo0si1n.g lraatess qOnacrei containing approximately 15 lLooofseleystcsoovleurteidond,uwraitnegrhdeepftsht.spproximaely 18 am. Vessels were NNumubermooffbrfepsleicpaetrresr;ep2icac: 10 NWautmebrerchoefmicsotnrceyntdruartiinognst:hTe svtupdylsfronemgaativreepcroensternotlative sHaamrdpnleesosf:d4i4lumtioen w5ateCra):CO} pAH l79ka3l8imgn/LiastCayCO:3 1Diss8ol5vedmoxLyg(ecnonrtaonl eex(p0os-u9r6e)hours): N51o-8t9e: aemraeti.on(w1a.s00s0umppeliledefxopeossturvee)ssels at 72oCurosndurcantgei(0v-9i6 htouyr) 210700-125100 pumohosscim ((1o.n0t0e0lmxgpoxpso)sure) D727i9 range(c(on0t-r9ol6ehxopuorssu)re) 73-75 (1m0plL0 expos0ure) 22T2e1s19t-t2e22m2p22erCCat((u1cr.oe0n0tr0oalnmgeeexlp(o0seuxrp9eo6)suhroeu)rs) BATOCMAKIN RNoEmSiUnLalTSconcentrations: Blank control, 130. 20, 360, 600, 1.000 mg/L. 2E4lhemoeunrtLvCaSl0ue=a1nd00905(%6c0o0n-f1id0e0n0ce) imntlerval: h72ohouurr LLCCSS00- $99400 ((660000-~11000000)) mm//ll 9966--hhoouurr LNCOSE0C=-$69000(m6g0/l0.-1000) m/l ERleemmaernkts:valTueesstibnagswedasonconnodmuicntaeldcoonntcehnetrmaitxitounrse. as described i the Test SnoutbstthaenRceuoRreomcahrekmsiaflikcd.omTphoenevanltuelsonreep.orted pply to that mixture and CNoummiunlaaltive|pe2r4c-ent mortality: Bo re fours hous hours [Cmomle _T0----T0 Too] 50 To To To an 000315 220 [eo [ooo L000 [" 0 To To I To To To To 1] To"To To To] [so Teo To J70 ] LMoorwteasltitcyoonfcecnotnrtartoilosn: cNaousning 100% mortality: None C"TOheNtCesLtUsSubIsOtaNnSce 96-hour LCSO for fathead minnow was determined to bteest$s9u0bsmtga/nLcew9ith 6a 95-i%oochbosnefoirdveenduceeffirnetcetrvcaolnocfen6t0r0ati- o>n1(,0N0E0Cmg)/Lw.asT6h0e0 ml, BACK TO MAIN `PSauublm,itMtienrn:es3otMa,Co5m5p1a33ny, Environmental Laboratory, P.O. Box 33331, St. DATA QUALITY oRfetleisatbisluitbys:taKnlciemicosnccherntarnaktiionn2gs.iTnhtehestteusdtysollacuktsioannsalayntdicsaalmmpelaespuurreitmyenist not sufficiently characterized. "RTEhiFs EstRuEdyNCwaEsSconducted at TR. Wilbury Laboratories, Inc., Marblehead, M1A9.95at the request ofthe 3M Company, Lab Request number N2332, OTHER OGeNnLerYalNrOeMmIarNkAsL: TThEeSTmaCjHorEcMoInCceArLn fCorOtNrCyiEngNTtoRdAeTteIrOmiNnSe twheervealuisdeidt.y fOoPPtiTsreesctoimmtehnatds cthhaetmimceaalsucroendcetnettracthieomnitcoalwhciocnhcetnotrtahteitoensst boerguasneids,mssoatrheatexopnoesecda.n aIcFciutriastdeeltyedremtienremdintheatthtehteest nvaolmuiensalcacnonbceenatnrdatmiuosnts baereaodnjluys,tefdordeoxwanmwpalred0by%o50f%.the ImFeaanasluyrteidcaclonmceeansturrateimoennst,stohfestooxmiecitsyort Tvoaldatbileietny,fuarnndisohtehde,r wpheysciocuolcdhceamliccuallatpercohceemsiscesalthraotgmoivegrhyt rlaotwese.ratnhde tacatkuealinttoesacocroguanntishmydrolysis. exposure concentrations Psuormietytoesftsthiet atpesptemaarteedritahlatal1s00is%atemsatjcohremciocnaclerwnaasnudsewda,sfnoorotthsuefrfsicaiecnhtleymicchaalraocftelreiszseedr pi urtihtiys tes. In (otahpeprroexsitms,atfeolryn8o5o%b)viwoauss ussteadt.ed Wraeatseorn,. a Isnolfvaectn,t3(Miinsthoeipr sruomormap4rcayomonbfinoaactliho)ntesotfsbtoatt:h w"aDsatusmeadyinnot accurately relate toxicity of the test sample with that ofthe test substance." | agree with this concern. In `aditon, ifthiswas a "typical" TSCA scetion 4 review,| would reject these studies, pending receipt of amdedditiiuomnal information on purity and studics on analytical measurementsofthe test chemical i the test 312 000316 TAECSUTTSEUTBOSXTIACNICTEY.TO FISH (FATHEAD MINNOW) Identity: Perfluorooctanoic acid, tetrabutylammonium salt; may also be treefterrarebduttyolaasmmPoFnOiAumtpeetrrfalbuuortoyolcatmamnooantieu.mNs2al8t0,3-2,oras a major `component of L-13492. (Octanoie acid, pentadecafluoro-, tReetmraarbkust:ylTahmemo3niMumprsoadl,uctCiAonSl4ot9n5u6m58b-e5r3-w0a)s 2. The test sample is ruemfebrererdits08b8y8-tThHe.teTsthiengpulrabioyraotftorhyeassaNm2p8l0e3-w2a.sTnhote sTuRf.iciWeinltblyury study c4h4a.r9ac%tetreitzread.baulttyhloaumgmhonciuurmrepnetrfilnufoorromoacttiaonnoaitned,ic2at7e.s9i%t iwsatesro,lautnidon27of.2% isopropanol Thefollowing summary applies 10 the testsample as a mixtureofthe tcehsatrascutbesrtiaznecde cionnaceninstorpatrioopnasnooflfiwmaputreirtiseosl.utDioantawimtahyinncootmapclceutrealtyely rMelEaTteHtOoxDicityof he tes sample with thatof the tet substance. Method: US. EPA-TSCA Guideline 797.1400 GTLyPpe:: YAecsute static Year completed: 1995 `SSpuepcpileiser::PiAmqueapthiacleBsiopsryosmteelmass, Fort Collins, CO m`Aonnailtyotriceadldmaoilnyi.toring: DO, conductivity, pH and temperature were: Exposure period: 96-hours Statistical methods: LCS0 values calculated, when possibie, by probit ainnatleyrspiosl.atmioonviunsigngavtehreagceommpeuttheordsoorftbwianroemiofalC.pEr.obaSbtielpihtayn.with non-lincar LTeesntgtfihshanagde:weNiogthtnootfedf.ish in control: Average length= 34.9 mm Average weight- 0.36 & LProeatdrienagt:me0n.t2:4 gNofnisehiL DTielsuttcioonndiWtaitonesr:: Deionized water adjusted 10.3 hardness of40-48 mg/L as CaCOIL LDiilguhttiionng:waCotoelr-cwhheimtiesftlruyo:reNsoctenntotbeudl.bs with an intensityof25 fe. tPrhaontsoiptieorniopedrioofd.16-hours light, -hours dark witha 15 minute Acration: Initiated aftr the 72-hour DO measurements. ``Satdadcekd adinrdecttelsyttsootlhuetidoinlustpiornepwaartaetriionn:thTeetsetstvsuebssstealnscoenwaas wCoenicgehnttvroaltuimoensbadsoiss.ing rate: Once. LExopfoessutresovleustsieolns,: w2a0teLr dgleapstshaaqpuparroixaicmoantaeilnyin18gacpmp.roVxeismsealtselwyer1e5 loosely coveredduring the test. 313 000317 NNumubermooffrfbephliepcaetrersre:plicate: 10 WNautmebrerchofecomniceyntdruatriionnst:heFisvteupdlyus negative coniol 6Di3ssol8vedmoxe(ncomrraonlgeex(p0o-s9)hous): 6No0re8s4emrueio.n (w1i0s0s0umppLede10xpeotseve)ssels a 72 JConwductivity range (096 hours) p11i7400r-1a1n53g00e (mw0no-h9ov6ioehnou((r1t).o0n0t0ompeto.seuxrpoesure) 73257% 7c7ont.roml1eex.p0oseuxr0peos0e) 22T01os06t te22m11p95eraCCt((u1ro.en00ra0alnmgeLex.p(o0seuxrp9eo6)suhroeu)rs) RNoEmSiUnLaTlSconcentrations: Bink coniol, 160,250, 400,630, 1000 mL. 2E1lehmoeunrtLvCaSlDue a2n1d.09050%mcoenfi(dCe1nncoetneernvael:) S72hhuourr LLCC3S0D 19.7000.063m0a210(C0l0)ntmesla.leable S2e6chhoouurr LNCOSE0C -966300(m8i30.-1000) ml. Element vats wer bved on nominal concentrations RSuebmsatriknsee: RTeemstairnkgswiash.conTdhuctvaelduoens rthpomredisxpaytsd1ueshrraitbeemdixinihneaTndsk nCutmuolatthivTeapoeorccehntommolrtcaloimtpyo:nent sone [TNoemtinal 2f4ours 4[h8ours | 2 hows | 9ho%ws | CmS l -- ---- -- f 20 afe o] ] a@oo Tofoo]loo] Crow Ts fas Is Is] MLoowreisatlicyonocfecnotnrtartoilosn cNaounseing 100% morality: None CONCLUSIONS 314 000218 "bTehe96t0estmseu/bLstwaintchea969-5h%oucronLfCiSd0enfcoerifnattehrevaadlomfi8n3n0ow- >w1a,s00d0etmegr/mLi.neTdhteo mtegs/tL.substance 96-hour no observed effect concentration (NOEC) was 630 `PSauublm,itMtienrn:es3otMa,Co5m5p1a33ny. Environmental Laboratory, P.O. Box 33331, St. DATA QUALITY oRfeltieasbtilsiutbys:taKnlciemicsoncchenrtarnaktiinogns2. iTnhtehesetsutdysollauctkisonasnaalnydtiscaalmpmleeaspuurrietmyeinst not sufficiently characterized. RThEiFs EstRuEdyNCwaEsSconducted at T.R. Wilbury Laboratoris, Inc., Marblehead, M19A9,5 a the requestofthe 3M Company, Lab Request number N2803-2, OTHER O`GNenLeYralNrOeMmIarNkAsL: TTEheSTmaCjHorEcMoIncCeArnLfoCrOtNrCyiEngNTtoRdAeTteIrOmiNnSe twheervealuisdeid.ty fOoPrPthTirteecsoimsmtehnatds htheamtimceaalsucroendcetnetsrtacthieomnitcoalwhciocnhcetnotrtahteitoensst oberguasneids,mssoatrheatexopnoesecda.n aFcicturiastedleytedremtienremdintheatthtehetest vnaolmuiensalcacnonbceenatnrdatmiuosntsbaeraedojnulsyt,efdordeoxwanmwpalred$b0y%5o0f%.the ImFeaansaulyrteidcaclonmceeansturrateimoennst,sthoef stooxmiecistoyrt Vhoaldatibleitny,faunrndiosthehde,r pwheysciocuolcdhceamliccuallatpercohceemsisceaslthraetcomviegrhyt rlaotewse.ratnhde atcatkuealintteostacocroguanntishmydrolysis, exposure concentrations. sPuormietyotefstshiet atpespteamarteedritahlata1s0o0is% temsatjcohrenciocnaclerwnasanudsewda,sfonrototshuefrfsicaiecnhtelymicchaalroacftleersiszeerd piunrtihtiys test. In o(tahpeprroexsitms,atfeolryn8o5o%b)viwoauss ussteadte.d Wraeatseorn,. asIonlfvaectn,t3(iMsoipnrtohpeainrosl)umormaarcyomobficnaacthiotneostfsbtoatteh: "wDaastausmeadyinnot aacdcduirtaitoenl.y.iftrheilsatweatsoxaicittyypoifcatlh"eTteSstCsAamspeclteiownith4 trheavtieowf,th|ewtoeustldsurbestcatncteh.e"se1saugrdese,wiptehndthiinsgcornecceerinp.t ofIn additional medium, information on purity and studies on analytical measurements ofthe test chemical in the test 31s 000319 TOXICITY TO MICROORGANISMS Title: Microtox Toxicity Test TEST SUBSTANCE pIedrefnltuitoyr:oocPtearnfolautocr.ooFcCt-a1n1o6i,c aFcCi-d1,2a6m,mFoCn-1i6u9m,soarltF:Ca-l1s4o3.refe(rOrcetdantoaisc aPciFdO,Apeantmamdoecnaifluumorsoa-l,, aammmmoonniiuumm salt, CAS 3825-2611) iRsempaurriktsy:waTsheno3t Msufpfriocdieuncttliyonchfaortacntuemribzeerd,waalsth39o0u.ghTihnefotremsattsiaomnpilnediwcaasteFdCit-w1a2s6aa,mwihxittuerepoowfd7e8r.y93solid. percent test substance and 7-22 percent CS, C6, and C7 perfluoro analogue compounds. METHOD Methodguideline followed: Beckman's Microtox "BASIC" Procedure Test ype: Static GLP (VIN): No Year study performed: 1957 Species/strain: Photobacterium phosphoreim Supplier: Not noted Concentrations tested: 0,420, 560,750, and 1000 mg/L as nominal concentrations Exposureperiod: 30 minutes Analytical monitoring: No measurements ofthe test substance were taken throughout th fest. Statistical methods: Not noted Test conditions: "Diluent was 2% NaCl Microbic's Reagent "- DAei2o0n0i0zemdgw/aLtesrtopcHk was6.5 solution was prepared by dissolving 200 mg tet solution in 100 mL diluent. -- MTeesdtiasolwuatsionnostwreerneewpreedpared usingaliquots of thestocksolution "StEaxbpiolsiutryeovfetshseeltseswtecrheemciucvaetlesso,lutions was not noted. "Two replicates were taken, Remarks: none RESULTS 316 000320 Doseofeach endpoint (as mg/L): $ minute EC20 $10 mg/L S minute ECS0 = 1000 mg/L. S15mimniunteECE2C0R0= 52>0 1m0g0/L0.my/L 15 min ECS0= >1000 mg/L. 15 min ECS0 = >1000 mg/L. 30 min EC20 = 420 mpl 3300 mmiinn EECC5S0-= >7100(08010m-g9/3L0) mg/L. Was control response satisfactory (yes/no/unknown): unknown `Statistical results, as appropriate: Not noted Remarks: none INCLUSIONS The 30-minute ECS0 was determined tobe 870 mg/Lwith95% confidence intervals of 8100 930 mg/L. `Submitters' remarks: A Klimisch data qualityrankingof 2 was given. Testing meets all criteria for qtuesatlistaymptelsetiinsg,albsuotllaacckkisnga.nalytical confirmationof tes substance concentrations. Characterization ofthe. Reviewers' remarks: none REFERENCE 3M Company. [Notiegiven.] Lab Request Number E1282. St. Paul, MN. OTHER Gdeetnaeilreadlrrepeomratrwkass: aTvhaiilsabslue.mmTahreyrewfaosreb,atsheedcoonnatsenutmsmofathriysrseupmormtarayn,d oinnlryefleirmeintceed doattaheabplreost.ocoNlos and results of the study. are limited. 317 000321 TOXICITY TO MICROORGANISMS DATA "Title:MicrobicsMicrotox: Toxicity Test TEST SUBSTANCE I1d2e6n,tiFtCy-:16P9.FOFCA-1a4m3m,oonraiusmasmaaltjoarlscoormepfoenreendtfoofasFaXm-1m0o0n3iu(omctpaenrofilcuoarcoiod.ctpaennataatdee,caPfFlOu,crFo-C,-1a1m6m,oFnCi-um salt, CASRN 3825-26-1),a stated in the submitier's summary. Remarks: The 3M production lot number was 2327: the test substance was FX-1003. The purity owfastahe steosltutsiuobnstoanf<ce4w5a%sanmotmosunfifiucmienptelryflcuhoarroaocctetrainzoeadt.e,th5o0u%ghwactuerrr,en<t 3in%foirnmearttipoenrfilnudoirciantaetdedit compound, and | 2% Cs and C perfluoro-analogue compounds. METHOD Methodguideline followed: Microbics Microtox "BASIC" Procedure Test type: Static GLP (VN): No ear study performed: 1990 Speciesistrainisupplier: Photobacteriumphosphorcun/M Doses (concentrations) tested: 0 (blank control), 125, 250, 500. and 1000 mg/L Exposure period: 30 minutes Analytical monitoring: Concentrations ofth tet substance were nol measured during the study. uTseisntgcaolnidqiutoitosnosf:thTwsotorcekplsioclautteisoonf, caa2c0h0o0fmtgh/eL.fosuorlutetsitoncopnrceepnatrreadtiionnMsialnldipbolraenMkiclloin-tQr.ol wweatreer.pr2ep%ared HN:aSC0l,:Mifcorroobisem'ostiRceaadgjeunsttmweanstsu.se2d00asmtgheNdaiClulenwt.asThaeddiendititaol 1p0Homifo6f.8sawmpalse.adTjuhsetefdinoal pSoilu6t.i7onwsitwherdeilute oclregaarniasnmds.coilnorrleesfsr,enCeavee(tottchsewmeeranusleidghtasgtehneeexrpoastuberyde vtehessceolnst.roPleorrcgenatnoisfmlsi,ghwta-lsosussebdy0theasdsoesssedthe toxicityof the test substance. SptraotviisdteicdalfomreMtihcordost:oxCio and ECs values were calculated usinag statistical linearregression program Remarks: The test conditions and procedures were not futher described. 318 000322 RESULTS Dose of cach endSpeomiinnt E(cCalcu>l1a0t0e0d bmyLstatistical inear-regression program): 3105-mmiinn EECCan 11000000 mmge'Llt Was control response satisfactory (yesio/unkaowa): Unkaown Statistical results, as appropriate; Not specific oSfubtmeisttteesurb'srteamnacreksc:oncTeensttriantgiomnes.t Aalllsoi,ttehrerae fwoarsquallaictkyotfescthianrg,acbtuetrilzaactkieodnoafnalthyticteasltcsoanmfpilrem.ation Reviewer's emarks: Unable to determine % mortalityofthe controls. C"TOheNaCuLthUoSrsIcOoNnSclude the FX-1003 30-minute ECs for Photobacterim phoshphoreun tbe >1,000 mg/L (nominal concentration) Stuhbmteistttseurb'sstarnecmearinksw:ateKrlismoilsutciho-nrawniktihngin2c.omTphleetsetluydcyhasruamcmtaerriyzeadppciocnscefnotrtahteieosnts osfamipmlpueriastias.miDxatturae of may not accurately relate toxicity ofthe es sample with that ofthe test substance Reviewer's remarks: Non TR3eMEquFeEEsntRviEnruNomnCbmEeerntGa2l88L2ab,oratory. 1990. Miobics Mirotox. | Toxicity Test. St. Paul, Minnesota. Lab. OTHER Rreepmoratrkwsa:s aTvahiilsabslue.mmTahreryefwoarse,bathseedcoontnaentssuomfmathriys sreupmomratrayn,dilnifmietredenrcae dtoatt.heNporodteotcaoillsedand vesuls ofthe study. are limited 319 000323 TOXICITY TO MICROORGANISMS Title: Microbics Microlox Toxicity Test of FC-143 TEST SUBSTANCE IAdmenmtoitnyi:umPeprefrlfulourooroocotcatnaoniocataeci,d,PFaOm,mFoCn-i1u1m6,saFlCt;-1m2a6y,alFsCo-b16e9,reofrerFrCe-d14to3.as PFOA ammonium (Octanoie acid. sali, pentadecafluoro-, ammonium sall, CAS # 3825-26-1) Rinefmoarrmaktsi:onTihneditceasttessaitmpislae misixFtCu-r1e43o.f 9I6t.s5pu--ri1t0y0w%astenstotsusbusfftiacniceentalnydch0a-rac3.5%teCriize,d, Ctih,ouagnhd cCuorrpeenrtfluoro analog compounds. The 3M product lot number was 427. METHOD Method/guideline followed: Microbics Microtox "BASIC" Procedure Type (testtype): static GLP (YIN): N earstudy performed: 1996 Speciesistrain: Photobacterium phosphoreun Supplier: Microbics Concentrations tested: 0, 125, 250. 500, and 1000 mg/L. replicatesof each were tested at each concentration. The concentrations were nominal. Two Exposure period: 30 minutes Analytical monitoring: none. MStiactriosttoixc(ael.methods: ECS0values were calculabtyead statistical linear regression program provided for "pTHestofcotnhdeisttioocnks:soAlutpironimwaarsy t2h0e0n0amdjgu/sLtesdtofcrkomso5l.u8titoon7w.a6suspirnegpa1r.e0dNinNMaiOllHi.porAenMoislmolt-iQcTMadwjautesrt.menTthe was made using 200 mg NaCl dissolved in 10 mL stock solution. Appearance of est solutions was noted as "clear and colorless." The water hardness was not report. All test solutions were made by `proportional dilutions. vessels. Two replicates The testtemperaturewas not noted. at each of four concentrations were tCeasvteedt,teaslo(n3gmwLi)thwtewroecounsterdolass. the exposure iRnedmicaartekds.: The numberof microbes per replicate and thegrowth phase of the microbes were not RESULTS 320 J10324 Doseofeach endpoint (as mg/L): S minute CSO 1000 mg/L. 310S minute minute ECS0 ECS0 = = 800 730 (790~ (630- 520) 850) ma/L. mg/L. `Was control response satisfactory (yesino/unknown): unknown Statistical results, as appropriate: none Remarks: none CONCLUSIONS "The FC-143 30 minute ECS0 for Photobacterium 95% confidence interval of 630 10 $50 mg/L. phosphoreun was determined to be 730 mg/L with a `Submitters' remarks: For meets all criteria for quality dteasttainrge,libaubtililtayc,ktshaensaltyutdiycawlacsonafsisrimganteidona Koflitmeistscshubrsatnaknicneg coofnc2.entTreasttioinnsg. There is alsao lackof characterization ofthe test sample. Reviewers' remarks: none REFERENCE 3M Environmental Laboratory. 1996. Microbics Microtoxto Toxicity Test of FC-143 Lab Request number P1626. St. Paul, Minnesota. OTHER dGeetnaeirleadlrRepeomratrwkass:avTahiilasblseu.mmTaherryewfaorseb,atsheedcoonnteantssuomfmtahrisy sruepmomratrya.nd ionnrleyfelrimeintceedtodatthaetparbloetso.colNsoand results ofthe study, are limited. 321 000325 TOXICITY TO MICROORGANISMS Title: Microbies Microtox Tonicity Test of FC-118 TEST SUBSTANCE AIdmemntointyi:umPeprefrlfulourooraocotcatnaoniocataeci,d,PFaOm,moFCn-i1u1m6,saFltC:-1m2a6y, alsobereferred to as PFOA ammonium salt, FC-169, FC-143, or as the major component of FC-118. (Octanoic acid, pentadecafluoro-~, ammonium sal, CAS # 3825-26-1) Remarks: The test sample is FC-115. information indicates it is 20% FC-143 Its purity was in 80% water. not sufficiently characterized. though current The 3M product lot number was not noted. Data may not aceurately relate toxicity of the testsamplewith thatofthe test substance. METHOD Methodguideline followed: Microbics Microtoxie "BASIC" Procedure Type (test type): static GLP (YN): N earstudy performed: 1996 Speciesistrain: Photobacteriun phosphoreun Supplier: Microbics TDowsoesre(pcloicnacteenstrwaetrieontess)teudseadt:ca0c,h6c2o5n,ce1n2t5r0a,ti2o5n00, and 5000 mg. Theconcentrations were nominal, Exposure period: 30 minutes Analytical monitoring: none SftoartMisitcircoatlomxe.thods: ECS0 values calculated by statistical linear regression program provided "oTfetshteCosntodciktisoonlsut:ioAnwparsi6ma.r0y(1n0o ga/dLjsutsoctkmsoelanunttdi)oannwoassmoptriecpaardejdusintmMeinltliwpaosremMaidleliu-siQnTMgw2a0te0r.mgTNhaeCplif dissolved in 10ml test solutions were stock made solution. Appearanceof by proportional dilutions. test solutions was noted as The test temperature was "clear and not noted. colorless." Cuvettes (3 All mL) were used control. as the exposure vessels. Tworeplicates were tested at ach concentration, as well as the iRnedmicaartkeds.: The numberof microbes per replicate and the growth phaseofthe microbes were not RESULTS 322 000326 Doseof each endpoint (as mg/L): S minute FCS0 = 4460 (40-429500) me/L. 3105mminuite EEn CCSS00u ==33135t 600((2e 3901900-- 33464210)) mmgg//LL.. `Was control response satisfactory (yesinofunknown): unknown Statisticalresults,as appropriate: none Remarks: none CONCLUSIONS "9T5he%FcCo-n1fi1d8en3c0emiinntuertvealEoCfS2O91f0or-3Ph4o2t0obmagc/tLe.riun phasphoreum was determined to be 3150 mg/L with a a`lSlucbrmiittetriearsf'orrqeumaalritkys:tesFtoinrg,dabtuatrlealciakbsilaintayl,yttihceasltcuodnyfwiramsataisosniogfnetdesatKsluibmsitsacnhceractoinncgenotfr2a.tioTness.tinTghemreeetiss also a lackof characterization of the test sample. Reviewers' remarks: none REFERENCE 3M Environmental Laboratory. 1996. number P1626. St. Paul, Minnesota. Microbics Microtox Toxicity Testof FC-118. Lab Request OTHER d`eGteanielreadlrRepeomratrwkass:avTahiilasblseu.mmTaherryefwoarse,btahseedcoonnteantssuomfmathriys sruempomratray.ndionnrleyfelriemnicteedtdoatthaetparbloetso.coNlsoand resultsofthe study. are limited. 323 000327 TOXICITY TO MICROORGANISMS. Title: Microbies Microtoxi Toxicity Testof FC-1015-X TEST SUBSTANCE IAdmenmtoitnyi:umPeprefrlfulourooroocotcatnaoniocaatcei.d,PFaOm,moFCn-i1u1m6,saFlCt;-1m2a6y, aFlCs-o1b6e9,reFfCe-rr1e4d3.ooarsaPs FthOeAmaajmomrocnoimupmonseanltt, of FC-1015 or FC-1015-X. (Octanoic acid, pentadecafluoro-, ammonium sal, CAS # 3825-26-1) Rinefmoarrmaktsi:onTihnedicteasttessaitmpislae 3is0F%C-s1t0ra1i5g-hXt.carItbsonpucrhiatyinwavesrsniootnsuofffFicCi-e1nt4l3y cinha8ra0c%tewraitzeerd., tThhoeug3hMcuprrroednutct sTuotbsntuanmcbee.r wDaatsanwoetrneotuesd.ed D1a0tcaommpaayrenottoaxciciutryoatfetlhyerelbartaenctohxeidc!itsytroafigthhtectheastinsaammpmloenwiituhmthatof the est perfulorooctanoatc homolog mixture in FC-143 vs. FC-1015-X. METHOD Methodguideline followed: Microbics Microtox "BASIC Procedure: Type (test type): static GLP (VN): N Year study performed: 1996 Species/strain: Photobacterium phosphorein Supplier: Microbics DTowsoesre(pcloincacteenstrwaetrieontses)teudseadt:c0a,ch4c1o6n,ce8n3t2r,at1i6on6.5, and 3330 mg/L. The concentrations were nominal. Exposure period: 30 minutes Analytical monitoring: none SftoartMisitcircoatlomxe.thods: ECS0 values calculated by statistical linear regression program provided "PTHestofCothnedisttioocnkss:olAutiporniwmaasry6.69.6a6n0d/aLn ossomcoktiscolaudtjiuosntwmaenstpwreapsamreaddeinuMsiilnlgip2o0r0e mMigllN-aQC"TMdiwsatseorl.vedThine 10 mL stock solution. Appearance of test solutions was noted as "clearand colorless. All test solutions wtheereexmpaosduerebyvepsrsoelpso.rtiTonwaol rdeiplultiicoantse.s wTehreetteesstteedmaptecraacthurceonwcaesntnroattinoont,eda. wCeulvlestttew(as3mcoLnt)rowlesre used as Rinedmicaartekds.: The numberofmicrobes per replicate and the growth phase of the microbes were not RESULTS 324 000328 Doses of each endpoint (as mg/L): minute ECS0 = 2300 (2070 - 2560) mg/L 3105 minute minute ECS0 = ECS=0 1960 1950 (1730 (1760 - 2210) 2160) mg/L mg/L `Was control response satisfactory (ves/no/unknown): unknown Statistical results, as appropriate: none Remarks: none CONCLUSIONS 9Th5e %FCc-o1n0f1i5de-nXce30inmtienrvuatleoEfC1S7060f-o2r1P6h0otmogb/aLc.teriumphosphoreum was determined to be 1950 mg/L with Salulbcmriittetreirasf"orRqeumalairtkyst:estFiongr,dbautta lraelcikasbialniatlyy,ttihceasltucdoynfwiramsataisosnoigfnetdesat sKulbismtiasncche rcaotnicnegntora2ft.ionTse.stiTnhgermeeeitss also a lackofcharacterization ofthe test sample. Reviewers' Remarks: none 3M Environmental Laboratory. 1996. number P1626. St. Paul, Minnesota. MicrobicsMicrotox(oToxicity Testof FC-1015-X. Lab Request OTHER GdeetnaeilreadlrRepeomratrwkass:avTahiilasblseu.mmTaherrycfwoarse,bathseedcoonnteantssumofmathriys sreupmomratrayn.dionnrleyfelrimeintceedtodatthaeapbrloetso.colNsoand results of this study. are fimited. 325 000329 TOXICITY TO BACTERIA Titles Activated Sludge Respiration Inhibition TEST SUBSTANCE IAdmenmtoitnyi:uPmerpfelrufolruooorcotoacntoaincoaatcei,d,PaFmO,moFnCi-1u1m6,salFtC;-m1a2y6,aFlsCo-1b6e9r,efoerrFreCd-1t4o3a.s PFOA ammonium (Octanoic acid, salt, pentadecafluoro-, ammonium salt, CAS # 3825-26-1) sRuebmsatrankcse:wa`Tsheno3tMsupfrfiocdiuecnttiloynchlaotrancutemrbiezredw,atsho3u7.ghTchuerrteesntt sianmfpolrmeawtiaosn FiCn-d14i3c.atThitewapsuriatymoifxttuhree of 96.5 100% test substanceand 0 -- 3.5% C C, and Cs perfluoro analogue compounds, METHODS Methodiguideline followed: Protocol reference EAR, 11/879 Test type: Not noted GLP (Y/N): No Year study performed: 1950 Test organism:Activatedsludge mixed liquor Source: Metro Wastewater Treatment Plant, St. Paul, MN. Concentrations tested: Blank control, 1000 mg/L. Exposure period: Seven minutes Analytical monitoring: None `Statistical methods: Graphed dissolved oxygen versus time in minutes. "mTLestwciotnhdDi.tI.ionwast:er.Not noted other than the stock solution was prepared with 0.6 g FC-143 diluted to 100 Remarks: No further details on testing methods were provided by the submitter. RESULTS 326 000330 mDogs/eL owfietaahchcoenntdapcotitnitme(aos f7mg/mLin)u:teNso. acute inhibitoryeffect on activated sludge respiration rate at 1000 Remarks: Results based on nominal concentrations. Was control response satisfactory (yes/nofunknown): unknown Statistical results, as appropriate: Not noted CONCLUSIONS. oLfimaictteidvacteodntsalucdgiem.e estimates that ammonium perfluorooctanoate is not expected to inhibit the activity `nSoutbamnitatgeersn'cyreampparrokvse:d Kmieithmoids.ch Trhaenrkienigs 3l.acTkoesfticnhgarlaacctkesrirzeactoirodnoofftmheethtoesdtoslaomgpylueseadn.d eTshtesmoleutthioodnswnaost analyzed for test substance concentrations. Reviewers! remarks: No ECS0or other effect level was given, REFERENCE 3M Company. [No ttle given]. Lab request number S625S. St. Paul, MN. OTHER NGeondeertaalilredemraerpokrst:waThsiasvasiulambmlea.ryThwearsefboarsee,dtohencaosntuemnmtsaroyf trheipsorstumamndaroyn,lyinlirmeifteerdendcaetatotatbhlees. protocols and resultsofthe study. are limited. 327 000331 TOXICITY TO BACTERIA "Title: Activated Sludge Respiration Inhibition Test TEST SUBSTANCE. pIedrefnltuitoyr:ooctPaenrofaltueo,roFoCc-t1an1o6i,cFaCc-id1,26a,mmFCo-n1i6u9,m osralF;C-a1l4s3o.ref(eOrcrteadntooicasaPciFd,OpAenatmamdeocnaifulumorsaol-t,aAmmmmoonniiumum salt, CAS 3825-26-1.) "RTehmeaprukrist:y wTahsen3otMcpormopdluectteiloynlchoatrnacutemrbizeeidrs, 3a9l0t.houTghheitnefstorsmaamtpiloen wsuagsgeFstCed-it1wa2awsh6iat,meipxotwurdeeorfys7o8l.i9d3 percent test substance and 7-22 percent CS, C6, and C7 perfluoro analogue compounds. METHODS Methodiguideline followed: OECD 209 Test type: Static GLP (Y/N): No Vear study performed: 1987 "Test Organism: Activated sludge mixed liquor was used the same day it was collected. Source: Metro Wastewater Treatment Plan, S. Paul, MN. cCoonntcreonlstr+a0timoen/sLte-swteerd:e u0s,ed10,0s, 1w8e0l,l3a2s0,a 5re6f0e,raenncde1s0u0bs0t0anmcge/.)L test material solution. (Twoblank Exposure period: 30 minutes:3 hours Analytical monitoring: [twas not stated whether the concentrations were monitored throughoutth test. Statistical methods: Not stated. Test conditions: - Dilution water was aerated, distilled. deionizedwater with a pH of 6.7 -- SSyunsipheentdiecsdseowlaigdeswwearsep2r.e7pagr/eLd according to OECD Guideline #209 ~diTsetisltlesdolwuattieorn,s 1w6ermeLprseypnatrheetdibcyseawdadgiengfeiendd,ivainddua2l0we0imghLtsintoocsuolluumt.ioTnshecopnHtoafintihneg 2S8ol4umtiLo.ns was aSodljuutsitoend o10f 73.,05-udsiioncghlo|rNophNeanOaHl,. The reference solutions were created using S00 mg/L stock 38 000332 c-opnHcoenftrtahteioanctwiavaste7d.4sliundigtealm)iaxnedd 8.l1ifquionraw)as 7.8 initial and 8.0 (Final): pHofthe 1000 mg/L test ~ Temp~eErxapotosfuutrrheevetsessetlwtayspe20w-a2s1 n(otfdoescbroitbhed3.0 min and 3 h), -~ RNeusmpbiraartioofnrienphliibciattieosnnwotasstdateed.etxceeprbymthmaiteatnswuoeribdlnagndkiscsoontlrvoeldsowxeyrgeeunsecdo.nsumption Remarks: Hardness of the dilution water was not presented. RESULTS Dose of each endpoint (as mg/L): AUS his: ECS0(for respiration inhibAitUi3on0) m=in>: 1E0C00SmOg/(fLor respiration inhibition) = > 1000 mg/L Remarks-:A reference substance was used, but no results were presented. -None of the doses resulted in 100 percent inhibition. p`eWracsenctonrtersoplirraetsipononrsateesaitnihisbfiatcitoonroycc(uyrreesd/.no/Alusnok,notwhn)d:iffCeornetnrcoelbreetswpeoennsethaepptewaorecdonatdreoqlsuawtae:s l2e.s2sptehracnen|t at 30 cach omtihenru.tesand0.8 percent at 3 hous; this meats the guideline criterionofbeing within 15 percent of Statistical results, as appropriate: none CONCLUSIONS mTgh/eLauatfheorr3s shaotuertshaotftehxepoessutrem.aterial induced 38 percent inhibition in respiration rate at 1000 `mSeutbmsitttheercsr'itrereimaafrokrsq:uaTlihtey easuttihnogr.s sHtaotweetvheart,thteheKlsitmuidsyclhadcaktead cquhaalriatcyterrainzkatiinognwoafsth2e, atensdt stuhbasttahencsetudy purity and compound, analytical confirmationofconcentrations. Also. no results were presented for the reference Reviewers' remarks: REFERENCE 3ReMquCeosmtpNaunym.berAcEt1i2v8a2t.ed SSt.luPdaguel,ReMsXp.iration Inhibition Test. Environmental Laboratory; Lab. OTHER NGeondeertaalilredemraerpokrst:waTshiasvasiulambmlea.ryThwearsefboarsee,dtohne caosntuemnmtsaroyf trheipsorstumamndaroyn,lyinlirmeifteerdendcaetatotatbhlees protocols and results of the study. are limited. 329 000333 TOXICITY TO BACTERIA Title: Activated Sludge Respiration Inhibition TEST SUBSTANCE AIdmemntointyi:uPmerpfelrufolruooorcotoacntoainccaatcei,d,PaFmOm,oFnCi-1u1m6,salFtC;-m1a26y,alFsCo-1b6e9,refEeCr-r1ed43t,o as or PFOA ammonium salt, as a major component of FX- 1003. (Octanoic acid, pentadecafluoro-, ammonium salt, CASRN 3825-26-1) sRuebmsatrakncse:wTasheno3tMsupfrfiocdiuecnttilyonchlaotrancteurizmedw.batshe2o3u2rg7h.avTahielatbelset isnafmoprlmeatwiaosn iFnXd-i1c0at0e3d. itTwheapasuristoyluotfiotnheoftest C<; 45pe%rfalmuomroo-nianuamlopgeurfelucoormopoocutnandosa.teT,hSe0te%stwastuebrs,ta<n3ce%wianserta pcleerafrluloirqiuinda.teTdhceormepfoeruenndceansudbs1t2an%ceCsusaendd for this study, 3,5-dichlorophenol, was Aldrich red label, lot number D7-060-0. METHODS Method/guideline followed: OECD 209 Test type: Static: GLP (Y/N): No Yearstudy performed: 1990 "TTheesttoesrtgoarngiasnmi:smMsiwxaerdeulsiqeudoor nacttihveadteady solbutdagienewda.sTchoellceocntdeidtifornoomfMtehteroorgWaansitsemwsatwearsTnroetatsmpeecnitfiePdl.ant Supplier: Meiro Wastewater Treatment Plant C(3o0ncmeinnturtaetsiaonnds 3tehsotuerds:). 0T(wbolanrkepcloinctartoeslo)fatnhde1b0l0a0nkmgc/oLn.trFoXl-a1n0d0o3nweerreepluiscaetdefoofrc1a0c0h0 emxgp/oLsuFrXe-p1e0r0i3od cwoenrceenutsreadtifoonr ocafc1h0emxgp/oLs.urOenpeerrieopdl.icAatereoffertehnecreecfoenrternocle,c3o.n5t-rdoilcwhalosruospheednoflo,r wcaacshienxcplousduerdeatpeariod. Nominal concentrationsofthe test substance and reference control were used during this study. Exposure period: 30-minutes and 3-hours Arensapliyrtaiticoanl imnohniibittoiroin,nga:s dDeitsesromlivneeddobxyygoexnygceonncceonntsruamtpitoinosnw.ere monitored in order to determine `Statistical methods: Not specified "wTaesstccroenadtietdiboynsa: mTahses aidndoictuilounm(0coanstoaliunteidon3.2 congt/aLionfinmgi2x8e4d mliLquMoirlsluispopreendMeidlsloili-dQs.waTtheer,tes1t6smuLb.stance 330 000334 enSrylennpceeosseofwlheiatgaoencfvteades,dcansid u2d0d0immLni. gidno0icuolurmm.EwT,ahseSos7ctkanssdulb7sat.a1tncreoefw3ea5ss-tcvapehayorreTnethplhyiemnilslcibpTleihwooitshelwa1td0e0r0 A hrmeeleipcstaosfroclaaucihancaonwnacensraw7.ta3i.sonT2o0hfe f2F1iXl.1rp0l0i3onf(t1th0he0e0rsmyan.T)cTanasdrt3op,o5n1o0r-mfoLph.h0en3So.l-k(d1i0cohmoneo)lph,eonwnerd,eonww.edn 7.5for Ch expan pod (30 mito nd 3 hos Remarks: No additional comments resus Dose af cach endpoint as mg/L): 30-mTihnuotue EECC500-11000000 mmp/ll.. 0Re0marktshatTmeiisntawaasndconntduhceted o1nSutbhsetaincte.r fhe described st sistance, Th ales report Wascontol response satisfactory (ysiorunkaonn: Yes Steal revolts, as appropriates No addiional comments concLuTmsheei.oFXn-s1003 hour ECSO for activated sade respiration nbn was dtemined ob 1000 aaSnmuapbllymetii,ctaelTrchsoenrefnmmagtrikrosn:oocfKecltniswsabssainkatinncFgcl2o. noTcsnritnomgnsc.,tTelric3raackoorfhualraycesrianngonbuofctkhesst vReavilewiersf"o aremtarekss: Tshsesconhcelusions appar ob suppboy trhe dis, over, mtd a ers RR3MEeFsEEnevRiEmrNoanmCmeEernaGl2La8boratory. 1990. Activated Suds Respiration niin, St.Paul, Mines. Lab ome dIGearnlteraeacrrelapemsomratrswkesau:ssvThaifastse.umsmuTadsrh.yorrwslasoh,baehseeddcoonmntssuafehyssspuomrmtarany. iin irdecdsa btlts, No 33 000335 TOXICITY TO BACTERIA Title: Activated Sludge Respiration Inhibition Test TEST SUBSTANCE sHadlet,ntAitmym:oPneiruflmuopreorofcltuaonrooiocctaacindc,ataemPmFoOn,iuFCm-1s1al6:, mFaC-ya12l6s,obFeC-1r6ef9e,rrFedC-t1o4a3s,PoFrOasAatmeatjroarbuctoymlpaomnmeonntiuomf GC-1015 or FC-101S-X. (Octanoic acid, pentadecafluoro-, ammonium sal, CAS # 3825-2611) iRnefmoarmraktsi:onTihneditceasttseaimtpislea 3wa0s%FsCt-ra1i0g1h5t-cXh.ain10vserpsuirointyofwaFsC-n1ot43suifnfi8c0ie%ntwlaytecrh.araTchteeri3zMed,ptrhooduugchlcoutrrent `naummmboenriwuamsp"erHfOluGoEroo2c0t5a.n"oaDtaethaowmeorleoguuseedmtioxtcuormepainreFCt-he14t3oxiwciitthy wohfattheisbsraunpcphoesde!dsttorbaieghtthech1ai0n0% straight carbon chain ammonium perfluorooctanoate in FC-1015-X. METHODS Method/guideline followed: OECD Test #209 Test type: static: GLP (VIN: no Year study performed: 1996 Test Organism: activated sludge `Supplier: in St Paul, TMhNe. activated sludge mixed liquor was collected from the Metro Wastewater Treatment Plant `wCeornecaelnstorattesitoend.s tTeshteedc:on4c2e0n,tr8a4t0i,on1s6w0e,reanndom3in3a2l0.mg/L. Two blank controls and reference substance. Exposure period: 30 minutes and3 hours Analytical monitoring: none Statistical methods: none. rTeefsetrcenocnedistuibosntsa:nceT,he3.d5i-lduitciholnorwoaptheernouls,edwwaassprMeiplalriepdorbeyMdiilslsiol-vQiTMngwaSt0er0,mgA isnto1c0kmsLo.luItiNonNoafOHth,e did o1f0.t3h0emrLe,fertehnecnebsroolvugthitontowtahsempeoainstuorfedintcoibpieen7.t2.preTchiepitteasttiosnubwsittahncIeNwHa,sSaOd;daendddidricleuttleydootIhLe. teTsthe pH Vessels. Synthetic sewage per OECDguidelines (Test #209) was used. EN 000336 ATthtehteeempnedoraftutrhee ranged from test, TSS= 1.3 19.1 1022.1 wL. The C._ Initially, inital pH = 7.8, twothalilsuesptehnedfeidnsalolpiHds were = 7.9. Tmheaesuwraetedrath3a.r2dn2esgsL. was not indicated "The clement basis was respiration inhibition as determined by oxygen consumption. Remarks: Authors reported that values were corrected to 20C for calculations. RESULTS Doscofeach endpoint (as mg/L): 30 min ECS 3320 mg/L. INECS01 3320 mpl rReemmaarrkkssf:ieldT.estTihnegvwaalsuecsonredpuocrtteeddoanpptlhyetmoitxhtautremioxftutrhee taenstdsnuobtstthaencteesatssudbesstcarnicbee.d iAn trheefetreesntces.ubstance. substanceof3,5-dichlorophenol was used, but ECS0 values were not reported. Was control response satisfactory (yes/no/unknown): unknown Statistical results, as appropriate: none CONCLUSIONS rTaheteFrC-t1h0an153-3X203mhgo/uLr. ECS0 for activated sludge respiration inhibition was determinedtobe qSuuablmiityttteerssti"ngr,ebmuatrklasc:ksTahnealsyttiucdaylwcaosnfaismsaigtnieodnaofKlteismtissucbhstraannckeincgonocef2n.traTteisotnisn.g mTeheetrse ailslacrliatcekrioaffor characterization of the test sample Reviewers" remarks: none REFERENCE 3M Company Environmental Laboratory. 1996. Lab Request N2169. St. Paul, MX. OTHER NGeondeertaalilreedmraerpkorst:waTshiasvasiulambmlea.ryThwearsefboarsee,dtohne caonstuemnmtsaroyftrheipsorstumamnadroyn,lyinlirmeifteerdendcaetatoabtlhees. protocolsand results of the study, are limited. 33 000337 MTIECSRTOSBUIBCSS'TAMNICCEROTOX TOXICITY TEST Iredfeenrtrietdy:10PearsfPluFoOroAocttearnaobiuctyacaidm,mtoentiraubmutsyallta,mmonium salt; may also be tectormapbounteynatmomfoLn+i1u34m92p.er(fOlcutoarnoooicctaancoiadt,e,peNn2t8a0d3e-c2a,louorraos-,a major tReetmcaarbkust:ylTahmemo3nMiumprsoadlu,ctCiAonSl#ot95n6u5m8b-e5r3-w0a)s 2. The test sample is rweafsernroetd s0ufbfiycitehnetltyescthianrgacltaebroirzaetdo.ryalatshLo-u1g3h49c2u.rreTnhteipnufroirtmyatoifotnheinsdaicmaptlees it wiaasters,olauntidon2o7f.24%4.is9o%prtoepatnroalb.utylammonium perfluorooctanoate, 27.9% teTshtesfuoblsltoawnicneg sinuamnmairsoyparpopplaineosltwoattheertsesotlustaimopnlweiaths ainmcioxmtpluerteoelfythe crehlaurtaecttoexriiczietdyocfonhceenttreastsioanmspolfe iwmiptuhrtithiaetso.fDtahteatemsat ysunbosttaanccceu.rately MMeEtThHoOdD:!Microbics' Microtox "BASIC" Procedure GLP: No YeSpaercieCso:mPphloteotbaecdte:riu1m99p5hosphoreun ARenpalliycaitaels:m2onitoring: pH. light output Statistical regression pmreotghroadms:prEoCviSd0edvaflouresMiccarlcoutloaxted by statistical linear Test Test oCorngdaintiisomnss:ource: Microbics Corporation, Carlsbad, CA SDtilouctkioanndwatteesrt:soMliultliiopnorpereMpilalria-tQioTnM: Awaptreri.mary 2000 mg/L stock ssotlouctkisoonlwutaisonprweapsartehdeninadMjiulsltiepdorferMomi4l.l7-Q0.TM6.w7atuers.inTgh0e.1pNHoNfatOheH `1a0ndmaLn ostsomcoktiscoluatdijoun.stmAepnpteawraasncmeadoef tuessitnsgol2u0t0ioNnasCw!asdinsostoeldveadsin "diclluetaironasn.d colorless" A I test solutions were made by proportional NExupmobseurreofversespellisc:at4esm:lTgwloass cuetes NEluemmbeenrt oBafsciosn:cePnetrrcaetnitonlisg:htFloous.r plus blank control. RESULTS NEloemmiennatlvcaolnuceenatnrdat9io5n%s:cBolnafnikdecnocnetrionlt,er12v5a,l 250, 500, 1000 mg/L S-minute ECS0=630 (590 - 665) mg/L 3105--mmiinnuuttee EECCSS00-=320600((222700 --333000)) mmgg//LL ERleemmaernktsv:alTueesstibnagswedasonconnodmuicntaeldcoonncaenmtirxattuiroensa.s described in the Test SoutbstthaenfcueoRreocmhaermkiscafileldc.omTphoenevanltueaslorne.ported applyto that mixture and CONCLUSIONS 334 000338 dTehteertemsitnseadmtpolebe320-6m0imngut/eLEwCitShO3fo9r5P%hoCroonbfaicdteenrcieumInptherovsaplohofr2e2u0n-3w0as0. SmugblLm.itter: 3M Company. Environmental Laboratory, P.O. Box 33331, St. Paul, Minnesota, 55133 RDeAliTaAbilQitUyA: LKlIiTmYisch ranking 2. Testing meetsal eiteia for quality itnestthineg,tesbtutsollauctkisonasnaalnydticsaalmpclonefpiurrmiattyioisnnooft tseusftfsiucibesnttalnycechcaroanccteenrtirzaetdi.ons "RThEiFs EstRuEdNyCwEasSconducted by the 3M Company, Environmental Laboratory, OTHER St Paul, MN, Lab Request number N2169, 1995 335 000339