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AR226-3392 Subchronic Toxicity 90-Day Oral Gavage Study of of 8-2 Telomer B Alcohol in Rats G.S. Ladies,1 G.L. Kennedy,1 J.C. O'Connor,1 N.E. Everds,1 L.A. Malley,1 S.R. Frame,' S.A. Gannon,1 R. Jung2 H. Iwai,3 M. Shinohara4 Telomer Research Toxicology Program 0 The DuPont Company, Haskell Laboratory/or Health and Environmental Sciences, Newark, Delaware, USA Clariant GmbH, Suhbach, Germany Daikin Industries, Inc., Osaka, Japan Asahi Glass, Co., Ltd., Tokyo, Japan USAbstract 8-2 Teloroer B Alcohol <8-2 TBA) is a fluorinaied chemical intermediate used lo manufacture specially polymers and surfacianis. The potential subchronic toxicity and the reversibility of the effects of this chemical were evaluated following approximately 90 days of oral gavage dosing to Crl:CDfSD)IGS BR rats. A complete toxicology profile including neurobehaviorai assessments and liepatic poxidation were conducted at selected intervals and a group of rals was included for a 90-oay post-dosing recovery period. Dose levels tested were 0 <control). 1.5,25, and i25 mg/kg/day. No test-substance-related monality occurred. Raisatl25 rag/kg/day developed striated teeth such that these animals were switched to ground chow at 77 days. No ireatmeni-rclalcd alterations in body weight, food consumption, neurobchavioral parameters, or hematology/clinicai chemistry were found. Hepatic p-oxidation was increased in males at 125 mg/kg/day and in females at 25 mg/hg/day. In both males and females, plasma fluorine levels were significantly increased at 125 mg/kg/day and urinary fluorine was elevated at 5 nig/lcg/day. Degeneration/disorganization of enamel organ ameloblast cells was seen in males, but not females at 125 ing/kg/day. Liver weigh! increases accompanied by focal hepatic necrosis were seen at both 2S and 125 mg/kg/day in males and chronic progressive nephrotoxicity occurred in females administered 125 mg/kg/day. With the exception of hepaiocellular necrosis observed in males administered 125 mg/kg/day and the incidence and severity of chronic progressive nephropathy in the 125 mg/kg/day female group, which increased after 3 months, all other changes showed evidence of reversibility. The no-ohserved-adversc-cffecl level for me 90-day study was 5 mg/kg/day. VIS Introduction The test substance, 8-2 Telomer B Alcohol, is an organoiiuorine compound. The 1, 5,25, and 125 mg/kg/day dose levels for this study were selected based on the ioxicityobservedinan84-dayrangefindingstudywith5.25.and 125 mg/kg/day 8-2 Telomer B Alcohol <2004 SOT Abstract tt778) and subchronic studies with similar fluoroielomcr-based alcohols and perfluoroocianoic acid (PFOA}."-13-41 HfS Objective The objective of mis study is to evaluate the potential subchronic toxicily and reversibility of 8-2 Telomer B Alcohol when administered by gavage to male and female rats. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. IHI Experimental Design Five groups of young adult male and female Crl:CD{SD)IGS BR rats were administered 8-2 Telomer B Atcohol daily by gavage at dosages of 0. I, 5, 25, and 125 mg/kg/day for approximately 90 days. Body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology samples werccollected on weeks 7,13, and near the end of the 3-month recovery period for hematology, clinical chemistry, urinaiysis, coagulation (end of study only), and plasma and urine fluoride (end of study and 3-month recovery period). Neurobehavioral assessments were also performed prior to dosing and during week 13. Biochemical evaluations (hepatic p-oxidation) were performed on animals after 10 and approximately 90 days of dosing and following the 3-month recovery period. After approximately 90 days of dosing, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathology examination. Approximately 3 months after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery of toxic effects. SSSRBesults In-Life Toxicology Parameters No test substance-related mortality occurred in the study- A test substance-related. toxicologically significant increase in the incidence of striated teeth was observed in the 125 ing/kg/day male and femaledose groups. On test day 77, alt male and female high dose animals were placed on ground chow due to test substanceinduced alterations to the teeth. There were no test substancc-roiaied, lexicologically significant alterations in body weight, body weight gain. food consumption, or food efficiency observed in any of !he male or female dose groups. Ncuroloxicology Parameters No adverse changes in neurobehavioral parameters w female rats in any dose group. Biochemical Toxicology The rate of hepatic p-oxidation, a measure of peroxisome proliferation, was significantly increased in females administered 25 ing/kg/day B-2 Telomcr B Alcohol and in males and females administered 125 mg/kg/day 8-2 Telomer B Alcohol. Following a 3-mondi recovery period, the rate of hepatic p-oxidation w lower but sliil significantly increased in males administered 125 mg/kg/day 8-2 Telomer B Alcohol, and had relumed to control levels in female rats. There were no toxicologically significant changes in clinical pathology parameters observed in rats dosed with up to 125 mg/kg/day B-2 Telomer B Alcohol. Plasma fluoride levels were significantly increased in males and females dosed with 125 mg/kg/day, but returned to control levels following 3 monihs of recovery. Urine fiuoridc excretion was significantly increased in males and females dosed with 5 mg/kg/day and > 25 mg/kg/day, respectively. After 3 months of recovery, urine fluoride levels in females relumed to control levels, while levels in males were significantly reduced compared to those at the end of the exposure period. Increased plasma and urine fluoride indicates exposure to and metabolism of a fluorine-containing compound. The presence of fluoride after 90 days of recovery indicates continued metabolism of the test substance. Anatomic Pathology Test substance-related, lexicologically significant degeneration/disorganization of enamel organ ameloblast cells occurred in male rats administered 125 nig/kg/day 82 Telomer B Alcoliol. In addition, alterations in thyroid colloid were observed in male and female rats at all dose levels. Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats,151and since there were no other microscopic alterations in the thyroid gland, altered colloid was interpreted as not biologically meaningful and non-adverse. A test substance-related, biologically adverse increase in the incidence and severity of focal hepatic necrosis was observed in males administered 25 and 125 mg/kg/day. An increased incidence and severity of chronic progressive nephropathy occurred in me 125 mg/kg/day female group that was considered adverse. Test-subs lance related and statistically significant increases in liver weight parameters were present in males and females administered 25 or 125 mg/hg/day for approximately 90 days. The increased liver weights correlated with microscopic hepaiocellular hypertrophy in die 125 mg/kg/day male dose group. Hepatic enzyme levels, however, were not elevated. Test-substance related and statistically significant increases in kidney weight parameters occurred in males administered 25 mg/kg/day and males and females administered 125 mg/kg/day. The increased kidney weights correlated with microscopic renal tubular hypertrophy in the 25 and 125 mgfltg/day male groups only. However, there was no hislomoiphologic evidence of renal damage, and renal clinical pathology parameters were not indicative of adverse effects. Alter 3 months of recovery, rats dosed with 125 mg/kg/day showed reversibility of some effects. The amcloblastic degeneration/disorganization persisted with decreased incidence and severity in the 125 mg/kg/day male group. Increased liver weight parameters and hcpatocellufar hypertrophy (males only) were no longer observed in the 125 mg/kg/day male and female groups. However, the incidence of hepatocellular necrosis in the 125 nig/kg/day male group increased after 3 months of recovery. Increased kidney weight parameters and renal tubular hypertrophy (males only) were not observed in rats sacrificed after 3 months of recovery. In contrast, the incidence and severity of chronic progressive nephropathy were increased in the 125 mg/fcg/day female group following 3 months of recovery. Summary ofPurfKiaimal "-Oridaium Acliiit.v in Male Kals iicpalicrtrceiison-ffll p-Oimlalion Activity Offle/he/Ay tm^s/a^ imgABAliy1' 23 mslkg/day' 25 msfi.fl&.y _ 34.111.7<1 20.6 2jg_______14.0 i2,Q- Suniiiiary ofPerow I jl-Oxidaliilit Activity in Feniiilfc ttats oms/^y----2^2,2- ImgABAhy" 213s 1.5 SmBS;g/diy' 25 mEAEl&iy1 23.8*4.5 23.2il3 11S^sldw_19.S4M__39.t4jj_, ^T'" ^ <UE/mL| ^ ^v '-^100% ^r'100% "y100% '^rM0% UFLU Male Mean Final Bodv, L'ner, aiid Kntnr)- Weights ror Male Rnf> anor90-n!i;' Test MA.,.L.on,agSL^Asaa?.,,g,^J" .417(10) 0.346(10) kLBODV 100 0.225(10) FINAL BODY IQO__Q.Oi'l(lB) 0140110} 0.14B]10) 0124(101 0410(101 Q.076(IQj_ 0:069(10)----O.P35J10)------O.OW.O)-- Mean Final Bodv, Liver, and Kidiiti Weights ror Female Rats aflcr flu-Day Tea Snhstiinra Exposure Ow<k(M;y MEAN FINAL I i,TwviM-sai LIVER TW 0.849(10) 0.982(10) OB45(!0) SL 1.076110) 0.972<10) KIDNEYS 2,339 FINAL BODY V""|>S" 1147 0 231>110> 0173110) 25 107(10) 294,090 MEANRELATI VEORCiANWElGHTSiaiirlnxly.TOBhO 0.267(10) 26.045(10) O^IO) S,, FINALBODY- 100 KIDNEYS/ 0158(10) 0762 021211t 0732 Incidences ami Average In Miilf aiid Female Itnf -------------------------------------- Littf HypCTUophy. h Kidney HypcuniFhy.l Tliynild Gland Allcraiion, oH N<TM^.fTMl I Summar TesI substance-related, leeih occurred in (he 12 relatcd. lexicologically ameloblasts cells occur consis(<ail with Ouoride ameloblasis persisted, a hepaiocellular and rena adaptive response by ih adverse,'''-'-1'' 25 ttig/fcgftiay female a period, the increased ra Ihe 90-day lime point, A leal substance-relate of focal hepatic necros increased incidence an both the incidence of li incidence and severily fUS Conclus 'nic no-observed-cneci le based on the increased in 25 mg/kfi/day. 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