Document XeGR15yz2xpGRYNzj11Z0M8G

AR226-3391 Repeated Dose Oral Toxidty of 8-2 Telomer B Alcohol Range-Finding Study in Rats G.L. Kennedy,1 G.S. Ladies,' J.C. 0'Connor,1 S.A. Gannon,1 R. Jung2 H. Iwai,3 M. Shinohara4 Telomer Research Toxicology Program 1. The DuPont Company, Haskell Laboratory/or Health and Environmental Sciences, Newark, Delaware, USA 2. Clariant GmbH, Sulzbach, Germany 3. Daikin Industries, Inc., Osaka, Japan ^Results 4. Asahi Glass, Co., Ltd., Tokyo, Japan mi Abstract Preliminary 10 a repeated dose loxicity assessment, a raiiec-findcr study involving repeated reach steady-stale as delermined by loin] organofluorinc blood fluoride levels. Groups of 10 male and 3 female CrLCD^SOIGS BR rats each were dosed doily with either 0 (ccntrol). 3,25. or 125mg3-2Te!oinerB Alcohol/kg/day. A number of toxicology end-points such Blood samples were analyzed for total fluoride levels weekly. Steady-stale concentrations were reached between test flays 60 and 84. At steady-slate, pooled plasma samples obtained ftom males and females over (lie duration of Ihe study were analyzed for Telomer 8-2 Alconol (pareni compound),Tetorner B-2 acid, peinuorooctanoale aciti (PFOA), unil perfluorononanoic acid (PFNA) and lolal fluorine levels. The level of parent compound delecfed did not exceed 0.074 ppm in either males or females, Irs inales. PFOA represented approximately 85% of the total plasma fluorine. In females, PFOA represented approxiinaiely 5%. The B-2 acid ofTcloiner B Alcoiiol and PFNA were also (bund in plasma of both males and fcrnales. Significantly lower rncan body weights and increased Based on these data, the folbwing doses were chosen for ilie 90-day oral wxicity study: 0, 1.5,25. and 123 mg/kg/day. ^Purpose 25 None M F 125 Striated teeth M F Clipped icctli M After DOSing ^mc^g). "" ' 594 44 564*59 553*34 509'S5 264 45 302 23 296*41 29121 After Reco^ _iPost-Dosm&Day.75) 554*100322 41 595 57 348*39 573*83 332 50 54937 3463: Anui^sis or 8-2 Telomer B Alcohiil. 1'FOA. mid FFNA in Seruni and Scit-cicii Tissue Dose Jrnfi^g/aay) Male PFOA (ppm^ Male PFOA Mate Total Convened Plasma F 10 ppm F (ppm) _ Female PFOA (ppml Female PFOA" Female Total Convened Plasma F to ppm F____(ppm) l)HcnTM"iurin( wicaima Toitli; 5.83 ^16 0.05 0.37 1-27 H; Analysis rrom Range-Finder HTndy (TestDnvBl) C8-2A (ppm) Fai Liver Kidney 8-:i Teloiner B Alehol 25 niR/kE/dav 125 srv/ksfdw 0.07(0,01) 0.34(0.13) 1.37(a55) 0.02(0,00) 0.13(0.03) 0.77(0.53) NM 0.01(0.00) 0.07(0.07) PFOA (ppm) Plasma Fat Liver Kidney 2.19 0,09(0.04) 6.96(1.94) 1-&KO.E3) 8.47 0.35(0.12) 18.68(10-38) 8.43(4.14) 65.60 1.90(1.66) 30.69(20.68) 29.11(17.38) PFNA (ppm) Fat Liver Kidney 0.00(0.00) 0.51(0-09) 0.00(0.00) 0.00(0.00) 0.91(0.23} 0.11(0.09) 0.01(0.01) 1.19(1.25) 0-86(0-62i I Structures '^UUU^sr F I F I pi Hi Alcohol "-HHHHt.OH C8.2Ad F F F F 0 Kidney (mg/kg) Se^TeslDaySI Post-DosinBDay75 TesiDayBl 3.0(0,13) 3.2(0.14) 3.1(0,14) 3.2(0.33) 2.9(0.13) 3-4(0.37) 3.1(0,32) Posi-DosinB Day 75 0.65(0.06) 0,70(0.03} 0.67(0,03) 0.7i/(0-07) 0.74*(0.07) Tola] Blood Fluorine Analysis in Mule Rais Dosed ivllli 8-2 Telomer B Alcoiiol ySi^ethods Tesi substance, 8-2 Telonner B Alcohol (99.2% pme) Tesi species: Crl:CD rat (male and female) Slandani husbandry, 5-day quarantine Groups: 10 males, 5 females/group [5 males/group allowed 75-day post-dosing re period]. Doses: 0.5.25.125 mg/hg Daily cavagebeEinninc with 7-week-old rats Doses in meihylcellutose suspensions, 5 llllAg dosing volume. Parameters measured (dosing and during recovery) Body weights (2 x/week) Cage-side exams (daily) Total fluonde/parent tnetabolile evaluation Blood samples coliecled 1 n pre-dasing weekly {luring dosing Organ weights - liver, kidney Pareni/Mctabolite Evaluation At steody-siaie.poa led ptasma. Fat, iiver, and kidney samples trom each eroup we analyzed for Teloiner 8.2 Alcohol Perfluoroocianoic Acid (PFOA) Pcrfluoroiianonoic acid (PFNA) Total Blood Fluorine Analysis m Female R! ^Conclusio Doses of Tcloiner 8-2 Alco 125 mg/hg. Sleady-statc blood flHorine teached higher ievels tlian ' Metttioliics of Telomer 8-2 The 90-day Kudcity siltdy w