Document 76p4ega7zyd5n49QdyOxXkjg

sam Ar226-/510 Date: 2-24-04 IM tetra Loss Report Nos FACT Tot 1 3M Medical Department Study Number: T-7211.1 3M Strategic Toxicology Laboratory Protocol Study No. ST-37 Sponsor: 3M Specialty Chemicals Division (PCDP) Saint Paul, MN 55133-3220 Sponsors Representative: Bill Reagen en 3M Environmental Lab 2-3E-09 Saint Paul MN Study Location: Son Po MN SSAA 3M Strategic Toxicology Laboratory 3M Center, Building 270-SB-314 Study Andrew M. Seacat Ph.D. 3M Medical Dept. /Corporate Toxicology AAR 3M Center Building 220-2E-02 Saint Paul, MN 55133-3220 Study Deanna Nabbefeld, MS Toxicologist: Advanced Research Toxicologist 3M Medical Dept. / Corporate Toxicology PSGoSn Fo MN S55F5A3.00051.7537 3M Center Building 220-2E-02 , 60004 Summary The objective was to provide liver and sera from rats dosed with the Adipate formethod development and qualitative metabolite identification. A single five mg/kg dose was administered via oral gavage to two male and two female `Sprague Dawley rats. One male and one female rat were euthanized on day 1 paren cumulative amountof hese monomers resent n hs ve ces and day 4 post dose. The fluorochemicals quantified in liver were `perfluorooctanesulfonate (PFOS), perfluorooctanesulfonamide (FOSA), `perfluorooctanesulfonamido acetate (M336), N-methyl `perfluorooctanesulfonamido acetate (M570), and MeFOSE-Epi-1-alcohol. The the cumulative amountof these residual monomers present in the dose in both the liver and in the serum. For example, the percentofresiduals that were present in the dose that were present in the liver ranged from 128% on day one post-dose to 825% on day 4 post dose in males. Thus these data suggest that on hen da the Adipatepolymerwas apparently metabolized to some extent by the rat following a single oral dose. However, this studywas designed to provide qualitative data only, therefore, a definitive conclusion cannot be made based Test Material: Name: The "Adipate". (Lot Number: LB-1000-1546-8; L- 15468, 118103-594 ("AdipateTM); R-11483-9, Lot 3, Stripped. Originator: M. Burleigh, 2/16/98. 3M Environmental Lab: TN-A-2432. 3M Medical Department: T-7211). Structure: The adipate is synthesized by the addition of 2 moles epichlorohydrin (epi) to N-MeFOSE and subsequent esterification `with adipic acid. The ideal structure ofthe product should be: [C8F17SO2N-(CH3)-CH2-CH2-0~(CH2-CH~(CH2C1)-0)2-COCH2CH2-]2 However other major N-MeFOSE-epi-adipate products exist consistingofat nls othe Adit report completed oy Richard A. Nowra IM least three primary ester types. These structuresareelucidated in an NMR Corporate Analytical Tech Center (Request C147746, 4/5/99). Purity: The overall purity of the Adipate as identified by NMR (Newmark R. M. Request C147746), and was reported to be: Table 1: NMR analysisofthe Adipate, L-15468, Lot 3, Stripped. | `Analytical characterizationofthis same lot of the FC-Adipate for residual FC alcohols was conducted by HPLC Analysis by Joel W. Miller of the 3M SMMD 2 6000s TstLa R Analytical (Request: 58175, 4/22/1999). These levelsarebased on the weight `percent analyte in the sample as received (Table 2). Table II. Residual FC alcohol levels in the Adipateas determined by HPLC --7 [oom MoEaFeOmSpEI | [C oom --[T oamw | oAfsaldlestchreiNbe-dMcinFtOhSeEm-eEtPhoIdo,ltihgeoNme-rMseiFnOtShEe-sEamPpIle.level is the total concentration Further analysis was performed by LC/MS revealed that therewas 0.0029% perfluorooctanesulfonate (PFOS) in this sampleofAdipate (SMMD Analytical Report 58175, In FACT Tox 141). Procedures: Dose and Dosing Procedures: A single doseofadipate, five mg/kg body weight, was administered via oral gavage to two male and two female Sprague Dawley rats from Harlan Laboratories, Inc., 6-8 weeks old, weighing approximately 310 - 480 g. The dose was be prepared by forminag 5 mg/ml solution of the Adipate in acetone. "Theadipate/acetone solution was then be suspended in corn oil toa final concentration of 1 mg Adipate per ml of 20% acetone/80% corn oil. A volume of5 ml/kgofthe suspension was be administeredtoall rats. One male and one female rat were euthanized on day 1 and day 4 post dose according to the schedule in Table 3. Table 3 Schedule [Group TDose [IN TSacrificcDay | [ Be T TSmmpgkS kggAAddiippaattee [[22((IIMM..1TFF)) Sample Collection: During necropsy, systemic blood (approximately 6 ml) was collected via heart `puncture and transferred to blood collection tubes without anticoagulant. All blood samples were allowed to clot foar period of 15 to 30 minutes at room temperature, then centrifuged at 1100 x g for 5 minutes. The serum was transferred to labeled 1.5 ml microfuge tubes and centrifuged again at 2000 x to remove anyremainingred blood cells. The serum was transferred to labeled polypropylene microfuge tubes and frozen on dry ice. Livers were removed, 6130006~ TSRTIER placed separately into labeled tubes and frozen on dry ice. Samples (iver and isceeraumn)d wsehirpepsetdortoe:d Kirnias fHraeneszeern,se3t MtoEmnaviinrtoaninme-n6t0altoT-e8c0hnColtohgeny paancdkSeadfeitnydry Services \ Analysis: `Lciovmerpoaunndd,semreatshaymlpFleOsSwEeraendanmaeltaybzoelditbeystahlel 3N-MMeEFnOvSiEr-ocnmpein-taadlifpoarttehepropdaurcetnst. `An aliquotof the dosing solution of 1 mg/ml adipate suspended in acctone/com oil (20:80) is report FACT included for Tox-141). analytical verificationofdosing material (Amende. d Results and Discussion Body weight, liver weight and dose amount are shown in Tabl4e.No effects of treatment were noted during the in-lie phaseofthe study or by gross observationofintemal organs at necropsy. The residual fractions (W/W ) and amount (4g) of PFOS, N-MeFOSE, N-MeFOSE Epi-1 Alcohol and the Total residuals in dose are shown in Table 5. `The analytical results for fluorochemical concentrations in the liver are shown in Table 6, and the fluorochemical concentrations in the serum are shown in `Table 7. The fluorochemicals quantified in liver were ppeerrfflluuoorrooooccttaannccssuullffoonnaatmei(dPoFaOcSe)t,atpee(rfClFu1or7oSo0c;tNan(eHs)uClHfo:nCaHm:idOeH;(FMO5S5A6)),, N`methyl perfluorooctanesulfonamido acetate (CsF17S0;N(CH:)CH:CH;OH; M570), and MeFOSE-Epi-1-alcohol (CaF1780:N(CHs)CH,CH:0(CH:C(HYCH;CIYO)H; Epi-1-OH). The cumulative amountof these monomers present in the liver exceeded the cumulative amountofthese residual monomers present in the dose in both the liver and in the serum. For example, the percentofresiduals that were present in the dose that were present in the liver ranged from 128% to 825%. These analyses support the conclusion stated in the 3M Environmental Lab report FACT TOX 141) that the levelsof (MeFOSE-OH metabolites) detected (in the liver) greatly exceeded theoretical levels predicted based on MeFOSE-OH residuals in the dose material". However, one should use caution not to over interpret the quantitative aspectofthis study as it was not designed as a definitive study to quantify the metabolitesof Adipate. Thus, these data suggest that the Adipate polymer was apparently metabolized to some extent by the rat followinag single oral dose. However, a definitive conclusion can not be made based on these data alone. 4 COBLG. - a TRI FR Signatures: A, indies INL. Seeniad , 2 [24/0 . Andrew M. Seacat Brie TSotxuidcyoDliorgeyctSoprecialist 60008 TR2ALIFR ST-37 References AAlmtemraincPanLSaoncideDtiitestmfeorreDxSp,erBilmoeondtaalnBdiOotlhoegyrB(oFdASyEFBlu)i,d1s9.71B,eptShesd,a Maryland. Federationofthe (HRaenfseernenKc.eAnmuemnbdeerd11An8a1l0yt3i5c9a4l)LainbrRaetpolirvte.r aDnadtasefroar mseatmapbloelsit~eAidpeinltoitfisctautdiyo.n oFfALC-T15T4O6X8-A1d4i1p,atLeRNW2430, 122000 5650009 TRALIFR 5137 `Tables `Tabl4e Biological Parameters [ST-37. T-7211.1 Adipate PiotStudy in Rats - BW & LiverWi Data. [anima #] [Da0y [Adipate [terminal [sRo3- [Body [Dose [Bodywt Juxx Wt limo) lig) [Smeg $25 male dy 1 post 478 53 asdimpuatkeg. s72]fema_l_e|ddyos1epost | se 313) a a paSdiempeat]ge.. Te 71 female ddyaos4reposst i 314) 01 104) 1. There are 32T.3 mTLE PlasE ma per T Kg ofr at (e Amansand Dittmer, B1 iood and Other Body F1luids. | (FASEB, 1971, ps) 7 600010 sTtarR Table 5 Fluorochemicals in the Dose Sys adipi|1 TDohsaet(smg) [Rtersacitdiuoanl rresaduaclofiF[aN-octnor Treosadual fTeAsdmuoaluon lForsoesin NMoeFOSE e[EFpiose [droascetoninf(eMeFOSE wiv) dose. Aono ww) (orn (wit) rouessneiduailn !|dose(ug) 73]I 1675, 000008] 000044] 000280] 00031808 oatestiuf s S18+ 8 Ges oie odes ours 1 rrr [oFo mAdiWgaifloe1r Wr.esScWoMDFCAavloyincl spor Recusst #575 Api 22 1998 HPLG-OV analysis cdno1z ETE EY | B3i5z ge & Bsszz 8s FIENNES g 8 gE 2 FIP CE THEE LB3s] 8Ls B clB REE lE[ : Pasteed fps s 3 Pllaienko Elk Pen [Sgg jS aPBgnye T5o8E3e2gl[8 FFPS5T [8 EE8EEEREAg [CTEM ET BRIBERE TFPCE FEEhSe 22s8e Eg E fox is ls | s 3 3S8E T 5k = | Eh 584 : z Pie HE 00012 i EET 1L15 L,e LrEEE1 E | aise [11F Le ||E2igeseits a| es J8 | 8@ gfoee FBRER gER 5l| f)| waa iH i 5 Bos 5 te Ii l| Ep1s8s oFlErESi oie Sik HEE I Parlale Cr 0 Hl on SETHI gL ula aiil i iI Bo 8 fai sl Ee , Hg 5 EE 35 BE Reales? [110 Bae = El 7 14 8/5 8g "e | 128s . 600013