Document Yo6760w42G6ZK4OD8LRO19BO

AR226-3395 Repeated Dose Oral Toxicity of 8-2 Telomer B Alcohol Range-Finding Study in Rats G.L. Kennedy,1G.S. Ladies,1J.C. O'Connor,1S.A. Gannon,1R. Jung,2 H. Iwai,3 S. Shin-ya4 TRP* Toxicology Program, 'DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware, USA 2Clariant GmbH, Sulzbach, Germany 3Daikin Industries, Inc., Osaka, Japan 4Asahi Glass, Co., Ltd., Tokyo, Japan Abstract Preliminary to a repeated dose toxicity assessment, a range-finder study involving repeated oral doses o f 8-2 Telomer B Alcohol was conducted in rats to determine the time needed to reach steady-state as determined by total organofluorine blood fluoride levels. Groups o f 10 male and 5 female Crl:CD(SD)IGS BR rats each were dosed daily with either 0 (control), 5, 25, or 125 mg 8-2 Telomer B Alcohol/kg/day. A number o f toxicology end-points such as body weights, liver and kidney weights were recorded during and at the end o f the study. Blood samples were analyzed for total fluoride levels weekly. Steady-state concentrations were reached between test days 60 and 84. At steady-state, pooled plasma samples obtained from males and females over the duration o f the study were analyzed for Telomer 8-2 Alcohol (parent compound), Telomer 8-2 acid, perfluorooctanoate acid (PFOA), and perfluorononanoic acid (PFNA) and total fluorine levels. The level of parent compound detected did not exceed 0.074 ppm in either males or females. In males, PFOA represented approximately 85% o f the total plasma fluorine. In females, PFOA represented approximately 5%. The 8-2 acid o f Telomer B Alcohol and PFNA were also found in plasma of both males and females. Significantly lower mean body weights and increased liver weights compared to control were observed in male rats administered 125 mg/kg/day. Based on these data, the following doses were chosen for the 90-day oral toxicity study: 0, 1,5, 25, and 125 mg/kg/day. * Telomer Research Program Purpose To determine appropriate dose levels for use in a 90-day oral subchronic study with 8-2 Telomer B Alcohol. Structures Telomer C8-2 Alcohol C8-2 Acid (M477) OH PFNA FFF FFF PFOA OH O  Test substance, 8-2 Telomer B Alcohol (99.2% pure) Test species: Crl:CD rat (male and female) Standard husbandry, 5-day quarantine Groups: 10 males, 5 females/group [5 males/group allowed 75-day post-dosing recovery period]. Doses: 0, 5, 25, 125 mg/kg Daily gavage beginning with 7-week-old rats Doses in methylcellulose suspensions, 5 mL/kg dosing volume. Parameters measured (dosing and during recovery) Body weights (2 x/week) Cage-side exams (daily) Total fluoride/parent metabolite evaluation Blood samples collected 1 x pre-dosing weekly during dosing Organ weights - liver, kidney Parent/Metabolite Evaluation At steady-state, pooled plasma, fat, liver, and kidney samples from each group were analyzed for Telomer 8-2 Alcohol Perfluorooctanoic Acid (PFOA) Perfluoronanonoic acid (PFNA) Dose Finding (mg/kg) 0 None 5 None 25 None 125 Striated teeth Clipped teeth Sex Incidence M 10/10 F 5/5 M 10/10 F 5/5 M 10/10 F 5/5 M 7/10* F 4/5* M 4/10* F 0/5 * (p <0.05) different from control Dose (mg/kg) 0 5 25 125 After Dosing (Test Day 81) Male Female 594 44 264 45 564 59 302 22 553 34 296 41 509* 55 291 2 1 After Recovery (Post-Dosing Day 75) Male Female 5 5 4 100 322 41 595 57 348 29 573 83 332 5 0 549 37 346 31 * (p <0.05) different from control Results (Continued) irgan Dose Liver (g/lOOgbwt) Kidney (g/lOOgbwt) (mg/kg) Se Test Day 81 Post-Dosing Day 75 Test Day 81 Post-Dosing Day 75 X 0 M 3.9(0.28) F-- 3.0(0.13) 3.2(0.14) 0.76(0.03) -- 0.65(0.06) 0.70(0.03) 5 M 3.7(0.20) F-- 3.1(0.14) 3.2(0.33) 0.76(0.06) -- 0.67(0.03) 0.71/(0.07) 25 M 4.1(0.19 F-- 2.9(0.13) 3.4(0.37) 0.75(0.04) -- 0.69(0.05) 0.73(0.06) 125 M 5.5*(0.39) F-- 3.1(0.32) 3.6*(0.05) 0.87(0.11) -- 0.74*(0.07) 0.78*(0.02) * (p <0.05) different from control Results (Continued) Total Blood. Fluorine Analysis in Male Rats Dosed with 8~2 Telomer B Alcohol Results (Continued) Total Blood Fluorine Analysis in Female Ruts Dosed with 8-2 Telomer B Alcohol Resals (Continued) Analysis of 8-2 Telomer B Alcohol, PFO, and PFNA In. Serum and Selected Tissues Dose Male Male PFOA Male Total Female Female PFOA Female Total (mg/kg/day) PFOA Converted Plasma F PFOA Converted Plasma F (ppm) to ppm F (ppm) (ppm) to ppm F (ppm) 0 0.07 0.05 NM 0.0 0.0 NM 5 2.19 1.51 NM 0.08 0.05 NM 25 8.47* 5.83 8.11 0.54* 0.37 5.88 125 65.60* 45.16 53.24 1.85* 1.27 23.20 Determined using Wickbold Torch; * Mean o f 2 separate runs. Tissue Analysis from Range-Finder Study (Test Day 81) 8-2 Telomer B Alcohol (mg/kg/day) 5 25 125 ` C8-2A (ppm) Fat 0.07(0.01) 0.34(0.13) 1.37(0.55) Liver 0.02(0.00) 0.13(0.03) 0.77(0.53) Kidney 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) 1.64(0.83) 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(0.62) NM = not measured. Results (Continued) Plasma PFQA Concentration in Male Rats Cone (ug/ml) Plasma PFOA Concentration in Female Rats --- 0 mg/kg/day * --5 mg/kg/day -A-- 25 mg/kg/day -K-- 125 mg/kg/day Cone (ug/ml) R em its (Continued) Plasma 8-2 T elo m er B Alcohol Concentration in Male Rats ---- 5 mg/kg/day A .25 mg/kg/day X - 125 mg/kg/day Plasma 8-2 T elo m er B Alcohol Concentration in Female Rats ---- 5 mg/kg/day --A-- 25 mg/kg/day x... 125 mg/kg/day Results (Continued) Plasma PFNA Concentration in Male Rats ---- 0 mg/kg/day ---- 5 mg/kg/day i t-- 25 mg/kg/day X-- 125 mg/kg/day Cone (ug/ml) Plasma PFNA Concentration in Female Rats -#-- o mg/kg/day -a-- 5 mg/kg/day -A-- 25 mg/kg/day X-- 125 mg/kg/day Cone (ug/ml) Results (Continued) P la s m a M e t4 7 7 C o n c e n tra tio n in M ale Rats 20000000 -, 18000000 16000000 - 14000000 12000000 j? 10000000 - < 8000000 - 6000000 - 4000000 2000000 - 00 Xr * 7 T es t day - S eries2 --A-- S eries3 - S eries4 P la s m a M e t4 7 7 C o n c e n tra tio n in F em a le Rats 20000000 -, 18000000 16000000 - 14000000 12000000 ^ 10000000 8000000 6000000 t 4000000 2000000 0 0 ..- 5 m g/kg/day - A - - 25 m g/kg/day --X - -1 2 5 m g/kg/day 7 14 21 28 35 42 49 56 63 70 77 T est day Conclusions Doses o f Telomer 8-2 Alcohol were well tolerated; number o f endpoints were altered at 125 mg/kg. Steady-state blood fluorine levels were attained between weeks 8 and 13 o f dosing; males reached higher levels than females. Telomer 8-2 Alcohol was extensively metabolized by both sexes o f rats. The 90-day toxicity study would employ dose levels o f 0, 1, 5, 25, and 125 mg/kg.