Document ERo39oqL8QjRpo1EjLz0XOag

AR226-3387 A 90-Day Gavage Study with One-Generation Reproduction Evaluations in Rats with a Fluoroalkylethanol Mixture E. Mylchreest, J.C. Stadler, G.T. Makovec, N.E. Everds, andG.S. Ladies The DuPont Company, Haskell Laboratory/or Health and Environmental Sciences, Newark, Delaware, USA yflS&Abstract Tire objective of ttussiady was to evaluate ttesulKluonic and reproductive toxicity of a fluoroalkylethanol mixture which is employed as flti intennediate in tlie production ofoilier fluoroorganic conyounds utilized as pToiectaiits and surfactanis. Test malerial was administered hy gavage at dosages ofO, 25, 100, or 250 mg/kg/day, No test substance-related mortality or neurotoxicily occurred in the sludy. Body weights and/or nutritional parameters were sqmificantly reduced at 100 and 250 mg/kg/day tHil similar to contiol after recovery. Broken and absent teeth were observed at 250 mgflcg/day. Micioscopic looih lesions (aineloblasi degeneration/disorganization) (iccurred at !00 and 250 nie/hg/day and persisted after recovery, Plasma and urine [Imiridc levels were elevated in a dose-dependent manner. Decreased red cell mass parameters occurred at 250 rng/kg/day and persisted after 36 days of recovery. The 100 and 250 mgAg/day groups had increased (p < 0.05) liver weights which persisted in the high dose after recoiery and correlated with microscopic hepatocelhilar hypertrophy iB males and females {250 mg/kg/day subchronic animals only). Hepatic Boxidaiion was increased in a dose-dependent manner and persisted after recovery at 2SO mg/kg/day. Increased kidney weights occurred at 25 (females only). 100 and 250 mgAg/day wliicli persisted in ihe lijgh dose after recovery and correlated wilh microscopic tubuiar hypertrophy (males oniy). Thyroid folliculnr hypertrophy was present at 100 and 250 mg/hg/day but was not present after recovery. The test material contains 2% residual iodides. Lilter size at birth and pup weights during lactation were reduced at ;: 100 mg/kg/day. No other reproductive parameter was affected. There were no adverse 25 ing/kg/day. A wide margin of safety crisis between potential human exposure levels ami the doses which resull in adverse effects, [ Study Design W ^---- f--~--ML ,, ife?B@ss!a-i >"K :rt;- -. ;;&& "---- i "'""""" f Liver Effects Increased liver weiglits at all dose levels and cenirilobuiar hcpatocellular hypertrophy at S 100 mg/kg/day (males), and 250 me/kg/day (females). Increased liver weight {males and females) end hepaiocelhilar hypertrophy (males) persisted after one and three monili recovery period at 250 nig/kg/day. Increased rate of hepatic (i-oxidalion in males aaii females at S 100 mg/kg/day. which persisted after the one- and three-month recovery period at 250 mg/kg/day. | Tooth Effects Absent or broken teeth observed clinically at 250 mg/fcg/day Degeneration/disorganizaiion ofenamel organ aineloblasi celis (males and females) at 100 mg/fcg/ilay. Ameloblastic degeneration/disorganization persisted witli decreased incidence and severity at 250 mg/fcg/day<inales and females) after a one- and tliree-month recovery pcrioti, and at 100 'mg/kg/day (males) after a three-month recovery period. fPup Num Day4 Day Day Day Day Sex Gest Mea 0-4 D Lact Lifte ml Introduction The test substance is an iiiiennediate in the production of other fluorotelonicr-based products that are used as protectanis mid surfactanis. The test material was administered by gavage. the route selected as the most efficien! way to deliver an aceurale dosage. Dosage levels for this study were selected based on the loxicily and phannacokinetic analysis of plasma fluorine concentrations from a range-finding study. Toxicily (LC., body weight effects or clinical observations) was not observed in rats exposed to 200 mg/kg/day for 35 days. however, piasma fluorine levels approached levels previously seen when mortality occurred. The high-dose level of 250 mg/kg/day was expected to produce loxicity williom excessive mortality. TIB low dose of as mg/kg/tiay was expected to tie the no-observed' effect level, while the tOO mg/kg/day dose was expected to induce minimal or no loxichy. f Thyroid Effects Increased thyroid hypertrophy at 100 ing&g/day (males) and 250 ing/kg/day (females), No thyroid hypenrophy after one month recovery. fBlood Effects ^Reproduction Evaluation Periluoroalkylethanol Study Material Composition Plasma Fluoride vcre ^q-ciijTipound.ielaied effects on the following paran ^1--y--.IF--4aI^h--BIS----BHT- --""----------------------- /). ^ "B-B-w c< - ca ca cm cis. Mildly increased at 100 nng/kg/day (males and females: No increase after one-month recovery Urine Fluoride Increased at S 25 mgflig/day (males and females) Body weights, body weight gains, foou consumpiion and food efficiency in P, female rats during gestation and lactation Esirous cycle and sperm parameters in P, rats * Body weight gain. prepinial separation and vaginal opening in F, rats There were correiound-related effects on tlic following pannneiers: 94.67% F(CF;CF^.CH,CH30H 2.01% P(CTiCF^Ct^CH,I 5150 ppm Total Elensetal Iodine [ 1 ] 12ppmfreelodiaetr] | Objective Evaluate the potential subchronic and reproductive toxicity of a fluoroicloniernlcolK (a-k.a. perfluoroalkylethanol) mixture in male and female rats. Recovery evaluations Minimally decreased red cell mass paraineiers, along wilii correiative changes in other hemaioiogy parameters and red ceil morphology at 250 nig/kg/day (males and females). Aftci some changes were still present in other heniatologica! parameters. Male rats still had decreased red cell mass effects, and associated nlterations in oilier hematologicat panureiers. No lexicologically significant clianges in clinical chemistry parameters observed at any dose level. BodyweigliisinP,nalerats(89-91%ofcantrol)at250mgAg/day. mthe absence of any concomitant reduction in body weight gain this was not considered loxico logically significant. * Number of pups born, born alive and alive on day 4 al 3:100 mg/kg/day (see lable). Implantation efficiency (ft pups born/implants) in P, female rats al 100 mg/kg/day (83.4 nnd 84.5% respectively compared to 96.6% in tht control group) and reflects the reduction in me number of pups born. . Pup weights during lactation at 250 mg/kg/day (see table). * Post-weaning boily weights in F] male and female rats. In the absence of any concomilniu reduction in body weight gain, ilia was considered due to llie lower body weight at weaning and was not considered loxicologicaily significant. fPup We Dose (mg/kg/da DayO Day4Precuiling Day 4 Poslculling Day 7 Day 14 Day 21 ylll Discuss The increases in plasma The presence of flnoride containing compounds a teeih are consistent with Liver effects that include indicated by elevaied fi-o Thyroid effects may hav Reproductive toxicity oc inilicaling that protection Ifff Conclus NOEL forSubchroiuc females was 25 mg/kg/d degeneration and/or diso NOEL for Reproductiv 2Snig/kg/day based on