Document RJdo4yDwwvb7z5vD3Z3yr5zva

1 3M Speckally Materials 3M Center '( St. Paul, MN 5514-1000 I 651 733 1110 .I BACK TO MAIN VIA HAND DELIVERY January 18,2001 Document Processing Center (7407) Office of Pollution Prevention and Toxics U.S.Environmental ProtectionAgency 401 M Street SW .Washington, D.C. 20460 Attention: For Your Information Docket - I Docket No. AR-226 Re: Information on PerFluorooctane Sulfonates and Related Compounds Dear Sir or Madam: This continues 3M's voluntary sub-missionsof data on petfluorooctane sulfonates and related compounds, as part of our ongoing dialog with EPA regarding fluorochemistry. Please find enclosed a supplemental submission containing a toxicokinetic study of perfluorooctanesulfonamide (FOSA). We just realized that this report had not yet been executed in final, and thus it was omitted from our recent December production. We will provide an electronic copy of this material with a future submission. We will continue to provide information on a regular basis as it becomes available. Very truly yours, Michael A. Santoro Director of Environmental, Health Safety and Regulatory Affairs Specialty Materials Markets January 18,2001 Page 2 Enclosures - index and study cc: Dr. Charles Auer Dr. Oscar Hernandez BACK TO MAIN 3M Building 236-1B-10 St. Paul, MN 55144-1000 651-733-6374 (phone) 651-733-1958 (fax) E-mail: masantoro@mmm.com ATTACHMENT TO LETTER OF JANUARY 18,2001 SUPPLEMENTAL SUBMISSION BACK TO MAIN TOXICOLOGY AND MEDICAL SURVEILLANCE I FOSA 1 Perfluorooctanesulfonarnide I Pharmacokinetic 1. Final Report, Toxicokinetic Study of PerfluorooctaneSulfonamide(PFOSA;T-7132.2) in Rats, 3M Strategic Toxicology Laboratory, 3M Reference Nos. T-7132.2; ST39, signed January 16,2001 (cover date August 11,2000). BACK TO MAIN FINAL REPORT Study Title; Toxicokinetic Study of PerCuorooctane Sulfonamide (PFOSA; T-7132.2) in Rats Authors: Andrew M.Seacat Ph.D. Toxicologp Specialist 5M Medical Departmen:, Corporate Toxicology Deanna J. Luebker M.S. Advanced Toxicologist 3M Medical Department, Corporate Toxicolog Date: Augusi 11,2000 Testing Facility 311.1 Strategic Toxicology Laboratory 3M Center 270-3s-05 Saint Paul, .MY 55 I44 - . 3Fi Soategic Toxicology Sf39 1.7132.2 PFOSA PK smdy in rats BACK TO MAIN Summary: Purpose: The purpose of this study was to assess the relative absorption, metabolism, and elimina:ion kinetics of Perfluorooctane Sulfonamide (PFOSA)in the :at fol1owir.g a single oral dose. Methods: Two groups of fifieen male rats each received a single dose of either 2%Tween 80, as the vehicle control, or 5 mglkg PFOSA suspended in 2% Tween 80 by oral gavage. Perfluorooctanoate (POAA)was found at a level of 2.5 ng/ml in the dosing solution. The PFOS.4 %as found to be 96 Npure Five rats from each dose group were sacrificed on days 1,4, and 29 post dose. Liver and sera were analyzed for PFOSA md its predicted rnetabolires using high- pressure liquid chromatography/electrospray tandum mass spectrometry (HPLC/ESMSMS). Results: The vehicle control group had no detectable levels of PFOSA or perfluorooctancsulfonate (PFOS) in liver or sera. The PFOSA dose group had decreasing Icvels of PFOSA, with evidence of conversion of PFOSA to PFOS in liver and sera throughout the study. Liver concentrations of PFOSA averaged 7.0 ppm, 3.7 ppm, and 0.1 ppm on days 1.3, and 29 post-dose, respectively, wirh an apparent liver half-life of elimination of 5.1 days. Serum concentrations of PFOSA averaged 0.3 ppm and 0.1 ppm on days 1 and 4 post dose respectively, and were undetectable by day 29 post-dose. with an appa.r:nt serum half-life of elimination estimated to be less thar, 4 cays. Liver PFOS concentrations were 38.2 p p n , 37.3 ppm and 23.8 ppm, rcprescnting ?lo%, 32.2%, and 25.2% of the PFOSA dosed, on days I , 4 and 29 post-dose respectively. Sera PFOS averaced 8.2 ppm, 8.6 p?m, and 4.6 pprn on days 1,4 and day 29 post dose respectively. The a\.erage total conccntratioiis of PFOS equivalenrs (PFOS'' PFOSA)in iiver were 35.2,41.1, and 23.9 ppm on days 1,4. and 29 post-dose. respectively. The average concentrations of PFOS equivalents in the sera increased from S.5 ?pm on day I post dose to 5.7 ppm on day 4 post do52 and decreased to 4.6 ppn: on day 29 post dose. The !iver to sera PFOS concentration ratio increased throughout the study with values of 4.2.4.8,and 5.4 or,days 1,4, a;?d 29 posr dose, respectively. Total PFOS equivalem in the liver and sera peaked on day 4 post dose at 35.4% and 6.0% of the PFOS cquivalenx dosed. respectively. A n average 0 i O . l pprn POAA was found in the sera on day 1 and day 4 post dose, and equaled 3 1.2% Lid 24.1%of the POA.4 residual present in t!e dose, respectively. Conclusions: Perfluorooc:anesuIfonamide was readily absorbed from the gut and found in the liver and sera following an or21 exposure. PFOSA was progressively metabolized to PFOS, which accumulated in the iiver as evidenced by the high concenwation of PFOS detected in the liver, representing 22.0% 32.3% and 25.2% of the PFOSA dosed, on days 1.4 md 29 post dose respectively. The apparent half-live of eliminarion of PFOSA in the liver was approximately 5.2 days. The PO.a.\ present in the sera on days 1 and 4 post-dose could be accounted for by the residual POA.4 in the dosins solution, therefore, no direct evidence for metajolism of PFOSA to POAA was found in this study. Page 2 of 18 ?MStrategic Toxicolog ST39 T-7132.2PFOSA PK study in ran BACK TO MAIN Introduction The objective of this study was to assess the potential for oral zbsorption, urinary and fecal clearance, and biological persistence of Perfluorooctanesulfonamide (PFOSA)in male Sprague Dawley rats after a single oral dose. Analysis orthe serum and liver for PFOSA and potential metabolites of PFOSA was perfomed by LCMS.L'rine and feces were also collected and may be analyzed by LCMS and perhaps other methods as deemed necessary. Previous studies on N-ethylperfluoroctanesulfonamide(1 ), the N-ethyl derivative of PFOSA, mistakenly concluded that PFOSA was the 3ltin;ate metabolite in rats (1,2); however, the gas chromatography analytical technique used in those studies was unable to detect PFOS. D i e w administration of N-ethylperfluoroctanesulfonamidoethanol @I-EtFOSE) in rats, and in-vitro metabolism by hepatocytes results primarily in the foxmation of PFOS with a minor amount of PFOSA (3,4, and 5). Furthermore, PFOSA has been identified as a potent direct uncouple: of mitochondrial respiration i n - v i m (6). Prior to the current study, direct metabolism of PFOSA to PFOS had not been demonstrated and the relative tolcicokinerics of PFOSA were unknown. Methods were recently validated for the quantitation.of PFOSA and irs potential merabolite, PFOS.in semm and liver down to the low part per billion b e 1 (7). In-vivo studies were. thus, wananted to investigate rhe toxicokicetics of PFOSA. Mater i a Is The test material was identified as Perfluorooctanesulfonamide(PFOSA);Lot number L-10009. Initial analysis by GCMS determined that tne-staring material was over 99% pure (8). Qualitative and quantitative compositional results derived from 'Hand '9F-NMRanalysis revealed that the isomer distribution was approximately 65.8% CF3 (CF2) x-SO2-XH2 (Xormal chain), 18.7% internal monomethyl branch and 11.2% Isopropyl branch (9). HPLCMS characterization revealed low-level impurities of 9,600 ppm PFOS (0.96 YO),and lower conccntrations of several other amides (10).Perfluorooctanoate (P0A.A) was fousd ir, the dosing soluiion at a level of 2.5 pglrnl (0.25% of the nominal dose) (12). Based on the sum of the impurities, the purity of the PFOSA sample was determined IO be approxirnztely 96 YO(8,9 &. 10). Methods Thc protocol (1 1) and malyrical methods (12) used in this study are briefly described below. Dose tmd Dosing Procedures: A single Srngkg dose of PFOSA was administered via oral gavage to 15 male Sprague Dawley rats (obtained from Harlan Laboratories) on day zero of the srudy. The PF0S.S was prepared as a 1% (1 mg/mI) uniform suspension in 2%Tween 80. A volume of 5 ml suspension / kg body weight was administered to each rat. The vehicle control group, consisting of 15 male Sprague Daw!ey rats (also obtained from Harlan Laboratories), received 2% Tween 80 in deionized water a! a volume of 5 mlkg on day zero of the study. .. Page 3 of 18 3M Srrategic Toxicology ST39 T-7132.2 PFOSA PK s ~ d iyn I Z S BACK TO MAIN Specimen Collection: Urine and feces collections were made on dzys 1 - 4 post dose from the animals desigcated for sacrifice on day 29 post dose group. Five animals from ezch dose group were euhmized by CO2 on days 1,4, and 29 post dose and gross necropsy was performed. Sera and liver were collected from cach animal and flash-frozen in liquid nitrogen. Specimen Handling: Specimens (urine, feces, liver, and serum)were rnaintzined at -7O'C and sent to Kris Hmsen, Ph.D., 3M Environmental Technology and Safery Services, for analysis. Liver and sera samples were analyzed by 3M Environmental for t?eparent compound and metabolites. The limits of detection (LODs)for PFOSA were 3.5 ng/ml in the liver and 1.51ng/ml in the sera. The LODs for PFOS were 8.45 ng/ml in liver and 1.74 n@ml in the sera (12). Urine and feces were retained for possible future analysis as appropriate. Results I Control Groups: Bodv and Liver Weiyht The average initial body weight f SD of the fifteen vehicle control ma!e rats was 273.7 ,+ 7.3 g. These rats lost an average of 2.2 g body weight from day zero to day 1 post dose . From day zera . to dal; 4 post dose, the average body weight gain was 24.2 _e and from day zero to day 29 post dose. body weight increased an average of 114.1 g Liver weights and relative liver to body weight percentages are shown in Table 1A. Liver and Sera Concentrations Control animals had no detectable levels of PFOSA or PFOS in liver or ar:s this srudy (data R o t shown). at any timc during PFOSA Dose Groups: Bodv and Liver WeiPht The average initial body wcigllt ISD of the fifteen PFOSA dosed male rats was 270.0 f 3.6 g. These rats lost an average of 4.5 g body weight from day zero :o day 1 post dose . From day zero to day 4 post dose, the average body weight gain was 20.0 ,e and from day zero to day 29 post dose, body weight increased an average of 100.9 g . Liver weights and rtlative liver to body weight perccnqes were equivalenr to control values (Table 1B). Liver and Sera Concentrarions PFOSA and PFOS were detected in the liver and sera of all animals dosed with PFOSA.Liver and sera levels of PFOSA were highest on day 1 post dose and dropped significantly between Page 4 of 18 3M Straregic Toxicology ST39 T-7132.2PFOSA PK study in rats BACK TO MAIN days 1 and 4 post dose and again between days 4 and 29 post dose (Tables 2 and 3). The avcrage liver concentrations of PFOSA decreased from approximately 7.0 ppm 163.7pprn to 0.1 ppm from days 1 to 4, to 29 post dose, respectively (Table 2). The half-life of elimination of PFOSA in the liver was calculated from a log linear regression of the liver PFOSA concentrations to be 5.2 days. The sera concentrations of PFOSA were 0.3 2 0.1 ppm, 0.1 5 0.0and CLOD (1.74 ndml) on days 1,4, and 29 post dose, respectively (Table 3). The half-life of elimination of PFOSA in the serum cannot be calculated from this data, but is estimated to be less &an 4 days. Ave:age PFOS liver and sera levels peaked on day 4 post dose and dec1in:d by day 29 post dose to lower levels than found on day one. Average k SD liver PFOS levels increased significantly from 28.2 f 6.1 ppm on day 1 post dose to 37.4r 5.6 ppm on day 4 post dose. Levels then decreased significantly to 23.8 k 4.1 ppm by day 29 post dose (Table 2). Average sera PFOS values were approximately 8 ppm on day 1 and day 4 post dose, thec decreased significantly to approximately 4.6 ppm on day 19 post dose (Table 3). L,iver and Sera Concentrations as a Percentage of Dose The percentage of PFOSA doszd derected as PFOSA in the liver and sera peaked on day oce post dose at 5.4% and 0.2% respec:ivcly. By day 4 pos: dose. rhese levels had dropped :o 3.3%and 0.0 YOand by day 29 post dose the liver levels dropped TO 0.1 % and the sera levels remained at 0.0% (Table 6). The percent PFOS equivalents dosed detected as PFOS in the liver and sera was 22.0% and 5.2 O/O on d2y 1 post dose and increased IO 32.3% and 6.0% by day 4 post dose. On day 29 post dose, these levels had dropped to 25.3%znd 4.1%, respectively (Table 6). Residual PFOS in the dose could accoun: for j.S%, 2.5%. and 5.6% of the PFOS found in sera, 2nd 5.6%, 2.7%. and 3.9 YO of the PFOS found in liver on days 1,4, and 29 post dose. respectively (Tables 4 and 5 ) . The percent PFOS equivdents dosed detccted as PFOS equivalents in the liver and sera was 27.2 % and 5.3 % n day 1 post dose and increased to 35.4% and 6.0 % by day 4 post dose. On day 29 post dose these levels decreased to 25.4 % and 4.1 % in the liver and sera respectively (Table 6). Sera P O M Concentrations Perfluorooctanoate (POAA) was found at a level of 2.5 ng'ml in the dosing solution (12). Sera samples in the PFOSA dose group contained P0.4A at average values of 0.1 and 0.8 ppm POAA on days 1 and 4 post-dose respectively. These values equzl 30.8% and 23.5%, respectively, of the POLU dosed (Table 7). Conclusions: KOcompound related effects were observed on body weigh:. liver weight, or livedbody weight ratios under treatment conditions. Both PFOSA and PFOS were found at high conmuations in the liver and sera of rats one day foIlowing an oral dose. Approximately 38% of the PFOSA dosed was convened to PFOS four -. Page 5 of 18 3M Strategic Toxicology ST39 T-7132.2 PFOSA PI<Sady in BACK TO MAIN days post-dose, PFOSA levels diminished in both sera 2nd liver over time! wkh a liver half-life of approximately 5.2 days, and a much shontr residence period in the sera'. Significantly more PFOS w a s found in the liver and sera at all time points than were present in the dose, therefore metabolic conversion of PFOSA to PFOS occurred. KOdirect evidence for metabolism of PFOSA to POAA was found in this study. The route of elimination of PFOSA in this study was not determined. No glucuronide or other conjugates were analyzed for, and further investigation of possible conjugates in the urine and feces is warranted. It is possible that some of the PFOSA was eliminated through the lung via expiration, but this has not bcen determined. The present results suggest that the PFOSA from the dose is progressively convened to PFOS and that the resdting PFOS is accumulated in the liver. Page 6 of 18 3M Suarcgic Toxicology ST39 T-7 132.2 PFOSA PK study in rau Repon Prepared by: Signa tu res ad. Deanna Luebker, M g Advanced Research Toxicologist #- 1fl Andrew M.Seacat: Ph.D. Toxicology Specialist Report Reviewed by: John L.Butenhoff, Ph.D., DABT,CIH . Senior Laboratory Manager BACK TO MAIN .OIh@3/ 00 Dare Date Date ..-. Page 7 of 18 3M Straregic Toxicology ST39 f-7132.2 PFOSA PK arudy in rats BACK TO MAIN References: 1. Grossman M.R. and Bowen J.M. (1990) Tissue analysis of fluorinated sulfonamide pesticide: an evaluation of disrribution, elimination, and potential for bioaccumulation in orally exposed rats. M.S. Thesis, Univ. of Georgia, Athens, GA. (also possibly published as: Grossman Mark R. and Bowen J.M. (1 990) Tissue distribution and elimination of a fluorinated sulfonamide pesticide in rats. Fundam. Appl Toxicol., bur notfoundj. 2. Grossman M.R., Mispagel, M.E.and Bowen J.M. ( I 992) Distribution and tissue in rats during - and afier prolonged dietay exposure to a highly fluorinated sulfonamide pesticide. J. Agric. Food Chem. 40:2505 2509. 3. Mulvana D.E.and Henion 1. 1996. Qualitative investigation of the in-vitro metabolism of T- 6292, T-6293,T-6294 and T-6295 by rat and human hepatocytes using ion spray L C N S and LC!MS/MS. h a l j ~ i c aRl epon: 96iZDEMO1.?MA,dvanced Bioanalytical Services, Inc. JSpp. 4. Poon G.K., Lowes S. 1998. Additional Characterization of metabolites of T-6292, T-6293 and T-6294 from rat and human heparocyes by TurDoIonSpray L C M S and LC/MS/.VS. Semi-quantitative analysis of T-6295ir. rat and h n a n hcpatocrcs incubated with T-6292, T-6293 and T-6294 by LC&lS/MS. Analytical Report: 96AGKPO1.3>1, Advanced Bioanalyrical Services, Inc. 69pp. 5. Scacat A.M., Thornford P.J..Hmsen K.J. and Butenhoff J.L.Sub-chronic Dietary N-Ethyl PerfluorooctanesulfonamidoEthanol To.uici:y in Rars. (in preparation, 8 4 I /2000). 6. 1,'allace K.B. and Starkov A. 1998. The effect of perfluorinated arylalkylsulfonamides on bioenergeks of rat livcr rritochondria. Drpt. of Biochemistry and Molecular Biology, L'nivmsity of MTZ School of Medicine. 3ulutn. hih' 55812, USA. Supported by a grant from 3 1 Company 7. K.J. Hanscn, L.A. Clemen, M E .Ellefson, H.O. Johnson. (1999). Compound Specific Characterization of Organic Fluorochemicals in General Population Human Sera Samples. 3M Environmental Lab, S:. Paul. MN 55 133. 8. Pager R.M. GUMS analysis of PFOSA (L-10009). SA&C Analytical Request Yo. 59426. Report 9/24/99. 3M..SA&CLab Building 236-2B-1 I . 9. Tom Kesmer. Chemical Characterization of PFOSA,L-10009. by IH and I9F-NMR Spectroscopy Reauests rt 59426.34 Specially Adhesives & Chemicals Analytical Laboratory SMMD-236-2B-11, September 25, 1999. - + 10. DeRoos F.L. Characterizarion of PFOSA Samples, 7'-7132-1 (L-10009) and TN-A-3583. Request A-15 1254. Report 10/7/99. Corporate Analytic21 Technology Center, Building 201-1-29, CATC Chromatography Group. "Page8 of 18 3M Strategic Toxicology ST39 T-7132.2PFOSA PK srudy in fais BACK TO MAIN 11. Seacat & Luebker. Protocol for Study KO.1-7232.2; ST-39, PK.4R!!ACOKhrETIC STUDY OF PFOSA IN k4TS.3M Medical Department, Corporare Toxicology. October 1999. 12. Laborarory Report: ~ n a l y i c aRl eport of Data for PFOSA (T-7132.2)Pharmacokinetic Study in Rats (Sera and Liver). Laboratory Report No. FACT-TOX-145(W2814). Testing Laboratory 3M Environmental Techcology & Safev Semices, 3M Environmental ' Laboratory, Fluorine h a l y i c a l Chemistry Tearn. Laboratory Contact: Kris Hansen, Ph.D. 13.Alman and D i m e r , Blood and Other Body Fluids. FASEB, 1971, p5 .... Page 9 of 18 3M Strategic Toxicology ST29 T-7132.2PFOSA PK srudy in rats List of Tables: Table 1: BioIogical Parameters 1A: Control Group 1B: PFOSA Dose Group. Table 2: Liver PFOSA and metabolites in the PFOSA Group. Table 3: Serum PFOSA and metabolites in the PFOSA Group Table 4: Percent Dose:Liver PFOS equivalents in PFOSA Group. Table 5: Percent Dose: Serum PFOS equivalents in PFOSA Group. Table 6: Summary:Percent of dose in sera and liver. Table 7: Serum POA4 in the PFOSA Group. .-. BACK TO MAIN Page 10 of 18 3M Shatcgic Toxicology ST?9 T-7132.2 PFOSA PK Study KIU BACK TO MAIN . Table 1A: Biological Parameters. Control Group Time ]Dose ]animal # I Initial I Terminal I BW Gain I Liver I Liver wt as lAvg I 1 274.7) 272,6] I ISD I 5.61 8.31 D a y 3 Contrail ~ 235 266.9 -294.51 ' D a y 4 1 Day 4 Day 4 Dav 4 Control IControl ]Control 1 )Control 1 236 275.8 237 261.9 238 279.0 239 268.3 301.8 283.4 302.7 291.21 -2.21 3.21 27.61 26.01 21.5) 23.71 22 91 11.71 ~0.5- 1 11.61 11.41 11.91 11.31 10 71 --4.3% 0.1 % 3.9% 3.8% 4.2% 3.7% 3.7% Page 11 of 18 3M Strategic 'T~xicologyST39 T-7122.2 PFOSA PK ~ t ~ idn ry;iU BACK TO MAIN I (SD I 10.91 8-71 1.51 0.3%1 ..-. Page 12 of 18 3 M Saaregic Toxicology ST39 T-7132.1 PFOSA PK study in rats Table 2: Liver PFOSA and metabolites in the PFOSA dose Group I t1 II Time Dose Day I ( 5 mgkg Dav 1 IS meke lsnirnal 1I I 245 I 246 1 I IILiver [;PFOSA] 23.71 1 6.02 32.31 7.02 BACK TO MAIN Livcr PFOSA PFOS Day 4 15 mgkg D a v l 15makkn Day4 (5rngkp Day 1 15 m g k g Avg SD Range n L Day 2915 mgkg Day 2915 mgkg Dav 2915 mehe -~ 1 2501 2511 I 253 1 254 I Min Max 1 51 1 255 I 2561 I 257 I 36.81 1 - 32.61 36.9) I 36.31 37.4 * 3.6 32.6 42.6) 51 20.3 . . .. 20.6 1 22 .o I __ 3.52 1 3.47 8.8 I 5 1 3.52 3.47 2.45 4.1 1 3.70 0.31 3.45 I 4.1 1I 51 0.09 0.02 0.10 ":lj I 3.45 4.1 1 5.45 I - __ I 0.101 -* = significan!ly different from day 4 values by a two tailed T-test ( ~ ~ 0 . 0 5 ) PQL = practical quantitationlimit in h e r (PFOS = 30 ng/g: PFOSA long) MDL = method detection llmit in liver: (PFOS = 15 nglg, PFOSA = 5 ng/$ I J Page 13 of I8 3M Snategic Toxicology ST29 T-7132.2PFOSA PK study in rats Table 3: Serum PFOSA and metabolites in the PFOSA Group . BACK TO MAIN Sera PFOSA PFOS eq PPm' 0.28 0.44 0.2c 0.33 0.28 ~~ ~ 0.31 0.08 0.26 ~ 0.44 5 0.06 0.06 0.08 0.06 0.06 0.06 0.01 .~ 006 U .a 5 5 I1. Assuming a l:l.rarioof PFOSA :PFOS equivalents. Sera PFOSA PFOS equivalenrs =Sera PF OSA concentration * = significantlydifferent from day 1values by a two !ailed T-test (p<0.05) *- = significantty different from day 4 values by a two tailed T-test (pc0.05) MOL = method detection limi! (PFOS = 4.75 ng/rnl; PFOSA = 2.89 ng/mf) LOO = iimi?of detection (PFOS = 1.74 nqlml: PFOSA = 1 51 nolml) Page 14 of 18 BACK TO MAIN P;ti!c I5 nl' t W BACK TO MAIN Table 5: Percent Dose: Serum PFOS equivalents in PFOSA Group Time Dose animal PFOS eq c m c PFOS eq Liverlserurn Total PFOS Serum T o b l PFOS Lived Serum PFOS eq /a' PFOS eq Residual uA of PFOS in Day 1 Day1 Day1 D- a y 1 Day1 # 9R03xnx -Smglkg 245 5mglhg 246 5rnglkg 247 Srnglkg 248 1 5-_ mglk.g 249 Av9 so ' in Serum (PPm) conc in PFOS ratio Eq inwhole liver (ppm) (ppmlppm) liver (ug) 7.2 29.71 4.1 - -- _- 11.2 96 70 7.6 . . ..8- .-5 1.8 . 39.3 3.5 42.5 - . 4.4 ' 279 4.0 36.6 4.8 I 35.2 4 . 2 _ . - _ _ _ I _ - - - 6.2. . 0.5 309.3 40 1.4 462.0 261.7 392.1 369.5 73.4 volume (mIj2 Eq in Serum IU9)' PFOS Eq ratio' - 6-.-3 8.4 8.5 8.5 8.5 8.5 0.1 60.0 ' 5.2 --. 94.1 - 4.3 81.9 5.6 59.6 4.7 65.0 6.0 72.1 5.2 15.3 0.7 in dose dosed found PFOS in serum from (US)' 1316.0 1330.5 1332.5 i3sa.o 1343.5 1331.7 1o--.i in serum' dose tug]' residual PFOS in dose rh)' __ . 4.6 - -. 12..6 -. . . - . . .. 21.1% - 7.1. - . . _ 12.8 - _ 13.6% - - 6.1 - - 1- 2-._8 . . __ .. 15.6- %- . 4 . 5 -.. 12...-8 2 1.5% ~ 4.8 - ... 1. 2..9 - . . . ,19.8% 5.4- ---. 12.8 17.7% . .- 1.1 0.1 3.5% Hange Min . . -M..a_x N S D a y 4 5rnglkg 250 ~ a y 4 rmglkg' 251 Day4 Day4 Day4 ..- -.5m91kg . Srnglkg -.5mglkg -252 253 .254 ml - --SD-- Hange .-Miri ._____ Max N 5 7.0 27.9 11.2 42.5 5 5.00 7.8 - . ... 40.3 7.5 36.1 11.4 -- 46.6 6. 1 40.4 n-.O - . 42.4 8.7 41.2 .--.- .- 1-.6 .-- 7.5 - -- 11.4- .~ 3.8 . 36.1 -. - -46.G 5 5 3.5 4 .e 51 5.1 4.8 4.1 4.7 5.3 . 4.0 0.5 4.1 5.3 5 .2~8-1.-.7 462.9 5 455.81 122.2 __ 5.-6- 3..6 .. - 456.1 496.4 478.8 54.2 422.2 563.6 5 8.3 59.6 .8- ..5 94.1 5 5 9.2 72.5 9.5 9.5 9.4 _.____. 81.6 . 9.3 74.2 .. -- 9.4 81.7 0.1 15.3 B.2 . - . _ _ 71.1 9.5 108.2. - . 5 5 4.3 1316.0 6.0 1343.5 5 5 6.3 1333.0 -. ...- -. 5.6 __ 6.1 5.9 0.6 5.2 6.7 5 1359.0 1364.5 1355.1 .- - 12.6 1333.0 133.5 5 4.5 . 12.6 13.6% 7,) 17.0 - - . - 21.5% 5 5 5 - __ 5.4 ...-. 12.8 - 5.3 13.1 .- I7.6% 18.2% I _ - 8.0_ - 13.0 - 12.1-%. - - 6.0 -- . -1-3.0 - - 5.4 -13.1 16. .0.% 17.6% 6.0..-___13.0 .. , 15.9% -- 1.) -0.1 5-.3 12.8 --- 8.0 13..-1 . 2.5% 12.1% -- 18.2% 5 5 5 Day29 Fay-2-9 Day29 Day29 Day29 5 m g k g 255 5 ing&.' 256 5mg/kg 257 5mglkg - 5mglk!j *vg 258 -.. -. 251) SO- fiange tiiu Max 3 .G 4 .O 4.0 4- .1 7.4 4.6 '* -1.s 3.6 7.4 - 20.4 .-. 20.6 -. 22 1 26.3 - 30.2 23.9 *' - 4.2 20.4- _ . - 3-0.2 -.. .- . 5. .7 5.1 5.5 6.4 4.1 5.4 - . 0.8 4.1 6.4 _ _ ~ ~ _ _ I _ _ , 310.4 2_96_.9. ' 307.3 304.6 383.6 342.6 41.2 296.9 3R4.5 12.4 12.3 . . -12.1 ... 12.0 11.5 12.i~ -0-.4 11.5 12.4 44.7 48.0 48.8 49.5 04.8 55.3 16.6 44.7 842 7.6 1376.0 .. --_- 6.1 1368.0 6.3 1357.0 - 7.8 1372.5 4. ..5 13--43.5 6.5 1363.4 1.3. .-_- 13.2 -- -- 4.5 1343.5 ---_ 7.8 1376.0 -.-. 3.2 3.6.-. 3.6 .- 10.2- . . 13.1 13.0 ---- - -- 29.6% 26.fJYu 26.7% - -3~.6 13.2 6.3 12.0 , - 26.6% 1.5-.2.."./I1 - -- 4.1 - - .-1..-3. .- 13.1 -_--. 0.-1 - 23.7% 5.6% - 3.2 - 6.3 --. 12.9 -_.___ 15_ .2% 13.2 . ...__?-9~.ij0h N 5 5 5 5 5, 5 5 5 5 5 5 1. PFOS equiuabnls in sera (ppm) = seta PFOS (ppm) + seta PFOSA PFOS equiva\enls ippm); 2 1here are 32.3 mL Plasma pcr Kg 01 rat. (9); 3 Tolal PFOS equiwlerils in seta (ug) = I'FOS equivalent concentration in sera (ppm) serum volume (mi); 4. Lived Serum lolal PFOS Eq rafin = lolal PFOS equivalenls in whole liver (up)/ lob1PFOS equivalents iii seiurn (ug); 5. Assuming a l . t ratio O! PF0SA:PFOSA PFOS equivaknls. PfOS equlvaleills in dose (ug) = lnilial BW (g) dos5 (mglkg)= BW.5; 6% PFOS equivalents dosed In serum = (PFOS gulvalenh in seta (ug)/ PFOS cquivalenls in dose (ug)) '100; 5. Residual PFOS in dose! (ug) dosese'0.g6%= (~mglkg'BW)O.OOYB6: . % oI1'FOS tn sera finnt residual I'KStn dotc = (tsidual YFOS in d o x I l o i n l I'FOS cq tn scra)*lOU; Sign. dillarellt Corn dy 4 ,values by a huotailed T-test (pC.O.05); MOL = nwthod deledon limit in sera: (PFOS = 4.75 nglrnl: PFOSA = 2.89 ncjml) 4 3M Straicgic Toxicology S'I39 'r-7112.2 PFOSA I'K sfudy ia ralc; BACK TO MAIN liver sera I liver 8 sera 22.0 2 5.2 5.2 1 1 27.1 2 6.21 32.3 +_ 3.7 6.0 5 1 1 38.3 4.81 25.2 L3.0' 4.1 5 1.2 29.3 2 3.8 T MS r oy essrra BACK TO MAIN Ab1e 7:Serum FORA Ta he FOS Tro - ff e EE errmeE n Tm e a -- l oe), a = e e --jere m e m--e --d21 a b iTr r a a a a od pf s erCfTe--e e en--e es1hne eBlLe--n eeE hs e ens era R a] sy Ivot spre Fe ros S : cn, . Fae thorn