Document YDgEwbMnEzy4V02ZB1ba2a4dN

ST-279 ToxDocs 10-014 TOXICOLOGY ASSESSMENT AND COMPLIANCE ASSURANCE GROUP 3M COMPANY 10-014: ADME Study of MTDI+D 207 (Potassium Perfluorohexanesulfonate, K"PFHXxS) in Mice FINAL REPORT ToxDoces Study Number 10-014 Lot Number(s) 118993-109 Strategic Tox Lab Study Number | ST-279 Other Identification Number(s) L-9051 | | || 19F/IH-NMR Analytical `GID Number Study Director Report|No GID numberassigned; see Appendix 1 for Certificate of Analysis Jill Hart, AAS, LATg Laboratory Administrator Principle Investigator: (Study Monitor) John Butenhoff, Ph.D, DABT, CIH Corporate Scientist | Testing Facility lL [| In-Life Start Date L os In-Life Termination Date ~ [3M Strategic Toxicology Laboratory 3M Center,Bldg 270, room SB314 Saint Paul, MN 55144 February 1,2010 | July 20,2010 lof 12 ST-279 ToxDoes 10-014 TOXICOLOGY ASSESSMENT3MANCDOCMOPMAPNLYIANCE ASSURANCE GROUP 10-014: ADME Study of MTDID 207 (Potassium Perfluorohexanesulfonate, K'PFHxS) in Mice Compliance Statement and Signature Page This study was conducted for research and development purposes and does not conform 10 regulatory guidelines. `This final report has been reviewed and approved by: 5 Li Hout Jill Hart, AAS, LATg Laboratory Administrator Study Director Gin 2. BO John Butenhoff, Ph.D., DABT, CIH. CPorirnpcoirpalteeISncvieesnttiigsattor 26 yan Sou Date 21 An zo Date 20f12 sT279 ToxDocs 10-014 1 Summary "cTohneceonbtjreacttiiovneos finthsiesrusmt,udlyivwea,sktiodnaesys,esusripneer,falnuodrofehceexsanienfCulDo-n1atmei(cPeF(IINx=S4)/sex time pOonintthedofsirestgrdoauyop)ftfohreusptutdoy2(3dwayee1k),smaiftceerarescienigvleedoeriatlhedroscoenotrfoMlT(D0.I5D% 2T0w7ee(nK'2P0FHiXnS). water), | mg/kg K'PFHXS, or 20 mg/kg K'PFHS by oral gavage. Twenty-four hour urine and feces samples were collected from each mouse prior to the scheduled necropsy days. All mice appeared normal during the study and there was no mortality prior to scheduled study termination. At necropsy, serum and liver were harvested, and, together with urine aMnSd/MfSec.es, the specimens collected were analyzed for PFHXS concentration by LC- In male mice receiving | mg/kg K'PFHXS, mean (+ SD) serum PFHXS concentration was 8352 0.53 ugimL at 8 hours post-dose (approximated Coa, declining 0 0.19 + 0.05 uKgP/FmHlXoSn,dmaeya1n62se(rtuhemlPasFtHdXaySocfontcheensttruadtyi)o.n Iwnasma1l3e0m.0i0c+r8e.c8e3ivuign/gm2l0 amtg8/khgours postdose (approximated Coe), declining 10 2.06 % 1.19 g/mL on day 162. In female mice receiving | mg/kg K'PFHXS, mean serum PFHXS concentration was 9.85 = 1.43 ugmL on day 2ofthe study (approximated Cou), declining (0 0.12 4 0.09 ug/ml. on day 162 (the last day of the study). In female mice receiving 20 mg/kg K'PFEIXS, (`maepapnrosxeirmuamtePdFCHaxyS),codneccelnitnriantgitoon 1w.a6s7 at 11.8039.7u5g/+m2L0.o6n1duagy/1m6L2.at 4 hours post-dose. Regardlessofsex, PFHXS concentrations in liver were about 30 -- 40%of that in serum welhiimlienaPtFeHdXiSn bcootnhceunrtirnaetiaonnds fienceksi,dnweiythwtehreeuarbionuarty1r0ou%teofbetihantgimnotrhee sdeormuimn.antP.FHXS was 2 Study Objective "The objective ofthis study was to assess PFHXS concentrations in serum, liver, kidney, uMrTinDe,IaDnd20f7ec(eKs'iPnFCHDx-S1) maticeeit(heNr=41/msegx//ktgimoer p2o0inmte//dkoes.e group)afer a single oral dose of 3 Test Material Information 31 TestSubstance [TMesat terID ial [MTDID 207 T18993-109 F/'H-NMIR Analytical | No GID number assigned; see Appendix | 3of12 sT279 ToxDocs 10-014 [PPahyrsiical State of Test Material 32 Dose Preparation for Certificate of AnalysisofAnalysis To`Wohite powder Dose Preparation Physical State of | administered material [Route of Administration "The test material was suspended in 0.5% Tween 20 as either 0.1 0r 2.0 mg/mL solution. Liquid [Oral] 4 TestSystem 41 Test System Information [Species 7 Mowe] [Strain CDI [Source Charles Rivers Laboratories `Weight at Initiation of Treatment Number and sex `Approximately 30-33 Application Number 42 Animal Husbandry Housing DievWater Housing Environment "All animals were group-housed in solid-bottom cages throughout the study except during urine and feces collection in which mice were single housed in wired bottom metabolism cagingforurine and feces collection for 24 hours prior to designated study termination time. | HarlanTeklad RatMouse 2018 Diet (HarlanTeklad, Madison, WI) and tap water were available ad libitum throughout the study. Temperature Range 72 = 3F | Humidity Range 30--70% Minimum of 10 exchangesofroom air per hour 12 hour light/dark cycle 4of12 ST-279 "ToxDocs 10-014 5 Study Design All mice were dosed on day 1 with either vehicle (0.5% Tween 20) or K'PFHXS prepared in vehicle at concentrations delivering either 1 or 20 mg/kg. Mice that were scheduled to be sacrificed were placed individually into metabolism cages for overnight urine and feces collection (approximately 24 hours). All mice were euthanized via CO asphyxiation at designated times followed by gross necropsy with blood (for serum), Ce em Group| Dose livers, and kidneys collected. (mg/kg) `mice/sex/dose group were sacrificed : UTM] Toy ordosng day 1804 4 20 [vm]a] `mice/sex/dose group were sacrificed at Ls[1 [TFk 0 # l2,o4,nadnwds82h@oiurhsmp,osst-1dsose2,2a3s 6wel5l%,as Lo[ooTe[ a [otter 6 Parameters Evaluated 6.1 Clinical Observations Each animal was observed immediately followingdosingand throughout the study for `mortality and morbidity. Any notable findings were recorded. 6.2 Body Weights All animals were weighed prior to treatment for the purposeofcalculating dose volumes, weekly thereafter (when applicable), and prior to necropsy. 5o0f12 sT279 ToxDoes 10-014) 63 Urine and Feces Collection Overnight (24-hour) urine and feces samples were collected from all mice prior to the scheduled necropsies. The urine volumes were approximated and recorded. Feces `samples were weighed and the weights were recorded. The samples collected were stored at -70C pending analysis. 64 Serum Collection At euthanasia, blood was collected via the abdominal aorta and transferred to labeled collection tubes without anticoagulant. The blood samples were allowed to clot for 15 to 30 minutes at room temperature and then centrifuged at 2000 x g for 15 minutes. The serum was transferred to 1.7-mL polypropylene microcentrifuge tubes labeled with a tube code and stored frozen at 70C pending analysis 65 Gross Necropsy, Organ Weights and Tissue Collection Following euthanasia, a gross necropsy was performed on all animals. Liver and kidney samples were harvested and the corresponding weights were recorded. All samples were stored ina freezer set to maintain -70 C for future analysis. No other issues were collected. 7 Statistical Analysis `There were no statistical analyses performed on data collected in this study 8 RawData `The raw data for body weights, organ weights and dosing volumes are recorded in 3M Notebook # 154823, pages 55- 77. 9 Results " 9.1 Clinical Observations "There were no mortality occurred in this study, all mice survived until scheduled necropsies. Clinical observations were normal throughout the study. 92 Body Weights and Organ Weights Pre-dose body weight data and terminal body weight data for male and female mice are presented in Tables | and 2, respectively. All mice gained weight during the study. Liver weight and kidney weight data are also presented in Tables 1 and 2 for male and female mice, respectively. 6of12 sT-279 ToxDocs 10-014 9.3 Urine Volumes and Feces Weights Also presented in Tables 1 and 2 are urine volumes and feces weights collected during the study. All mice excreted urine and feces during the scheduled collection periods. 94 Gross Necropsy "There were no gross lesions or other abnormalities noted in any control or K'PFHXStreated mice during necropsy. 95 Organ Weights Liver and kidney weights are presentedin Tables 1 and 2 for male and female mice, respectively. They were stored frozen at -70C pending analysis. 9.6 Analytical Results PFHXS concentrations in serum, liver, urine, feces, and kidney are presented in Tables 3 and 4 for male and female mice, respectively, In male mice receiving | mg/kg K'PFHXS, mean (+ SD) serum PFHXS concentration was 835+ 0.53 ug/ml at hours post-dose (approximated Cae), declining 10 0.19 + 0.05 uK'gP/FmHLXoSn,dmaeya1n62se(rthuemlPasFtHdXaySofcotnhceensttruadty)i.on Iwnasma1l3e0m.0i0ce+r8e.c8e3ivuign/gml2.0 amtg/8khgo.urs postdose (approximated Cua), declining t0 2.0=6 1.19 ug/L. on day 162. In female mice receiving | mg/kg K'PFHXS, mean serum PFHXS concentration was 9.85 1.43 ug/mL on day 2 ofthe study (approximated Cony), declining to 0.12 + 0.09 ug/ml. on day 162 (the last dayofthe study). In female mice receiving 20 mg/kg KPFHXS, mean serum PFHXS concentration was at 183.75 20.61 ug/mL at 4 hours post-dose (approximated Cas), declining to 1.67 + 1.09 ug/ml. on day 162. Regardlessofsex, PFHXS concentrations in liver were about 30 ~ 40% of that in serum while PFHXS concentrations in kidney were about 10%ofthat in the serum. PFHXS was eliminated in both urine and feces, with the urinary route being more dominant, 10 Conclusions In conclusion, MTDID 207 (K'PFHXS) administered by oral gavage to mice was absorbed in serum, liver, and kidney and it was excreted in the urine and feces. 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