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AR226-3388 Evaluation of the Subchronic Toxicity and One-Generation Reproductive Effects of a Fluoroalkylethyl Urethane Polymer G.T. Makovec, D.A. Delker. E. Mvlchreest, andJ.C. Stadler The DuPont Company, Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware, USA %Abstract A fluoroalkylethyl urethane polymer, used as a carpet protectant, was evaluated for its oral subchronic toxicity and reproductive effects when administered to male and female rats by gavage at dosages of 0,50, 250, or 000 mg/kg/day. No compound-related mortality occurred in the study. No adverse clinical signs of toxicity or neurobehavior changes were observed in male or female rats in any dose group. Hepatocellular hypertrophy was observed after 90 days of dosing in male rats at all dose levels. Nasal olfactory epithelium degeneration/necrosis was observed in male and female rats at all dose levels and inflammation o f the olfactory epithelium in male rats dosed with 250 and 1000 mg/kg/day. Thyroid hypertrophy was seen in male and female rats in the 250 and 1000 mg/kg/day dose groups. After a 90-day recovery, hepatocellular hypertrophy was still present in male rats in the 250 and 1000 mg/kg/day dose groups. Nasal epithelial lesions were absent and evidence of reversibility of thyroid effects was observed after the recovery period. No test substance-related effects on reproductive parameters were observed. However, mean thyroid organ weight was significantly lower in the 250 and 1000 mg/kg/day dose groups in the F, generation. There were no histopathologicai changes in the thyroid o f the F, generation rats. Due to die presence of nasal lesions, a no-observedadverse-effect-level (NOEL) could not be determined for the subchronic toxicity evaluation. For reproductive assessments a NOEL o f 50 mg/kg/day was determined based on decreased thyroid weights observed in both male and female F, adults. It could not be determined whether the nasal lesions observed are due to systemic toxicity or local toxicity as a result o f gavage dosing. Based on the other systemic effects observed at 250 mg/kg/day and above, the potential risk o f human health effects from exposure to this product is very low. BillResults Body Weights and Food Efficiency Males After the 90-day exposure period, weight gain and food efficiency in male rats administered 1000ing/kg/day was approximately 23 % and 20 *5 lower than control rats, respectively. Following a one-month recovery period weight gain and food efficiency values were -to controls. IIntroduction The objective o f this study was to evaluate the potential subchronic and reproductive toxicity o f a fluorotelomer-based urethane polymer in male and female rats. The test substance is used as a textile protectant and was administered as formulated product that contained approximately 23% active ingredient and 1.7% hydrocarbon surfactant in water. The test material was administered by gavage, the route selected as the most efficient way to deliver an accurate dosage. In a two-week range-finding study, there was no observable systemic toxicity in rats given a limit dosage o f 1000 mg active ingredient/kg body weight/day. Dosages o f 50,250, and 1000 mg/kg/day were selected for this study, based on this ability of rats to tolerate the limit dosage. Liver Weights Males After tile 90-day exposure period, absolute and relative liver weights were increased, compared to controls, in all male rat dose groups. After 1-month and 3-month recovery periods, absolute and relative liver weights remained elevated in male rats administered 1000 mg/kg/day compared to controls. IStudy Design ,1 =r L L i .......... . . i t _ -- .^ ............ S ___ __ r-- 1 1 ! _ . ______ T " * '- " . . . . . . - ______ in 1 i C _ :_______________________ _______________________i --------- * Body weights, detailed clinical signs, and food consumption were determined weekly througltout the 90-day exposure and l-month recovery periods. Gross otul microscopic patliology evaluations were performed at the end o f the 90-day exposure. 1-month recovery, and 3-month recovery periods. Reproductive evaluations were performsd prior to mating and during the mating, gestation, and lactation periods. Developmental landmarks and gross patltology was also assessed on F, adults. Histopathology Males Test substance-related microscopic findings were present in nose, thyroid gland and liver 0 W-Dsv Exposure Nose: Degeneration/necrosis. olfactory epitlielium Inflammation, subacule/chronic 0/10* 0/10 50 250 1000 8/10(0.9)' 10/10(1.7) 10/10(2.1) 0/10 5/10(0.5) 6/10(0.6) Alteration, colloid Hypertrophy, hepatocellular One-Month Recoven Nose: olfactory epitlielium Thyroid gland: Alteration, colloid Liver: Hypertrophy, hepatocellular 8/10(0.8) 8/10(1.1) 10/10(1.4) 0/10 1/10(0.1) 10/10(1.8) 0/10 NA NA 3/10(0.3) 6/10(0.7) NA NA NA Alteration, colloid Liver: Hvoertronhv iienalocellular 515 (12) n/s 4/5 (1.2) Ofl 3/410.8) 4/5(08) Test substance-related microscopic findings were present in nose and thyroid glandof female rats. 90-Dav Exposure Nose; Degeneration/necrosis, olfactoryepitlielium Thyroid gland: Hypertrophy, follicular Alteration, colloid RiKrMviUhRrwvm Thyroid gland: Hypertrophy, follicular Alteration, colloid 0 50 250 1000 raa/ia/dav mr/ke/dav ma/ke/dav 0/10" 2/10(0.2)" 4/10(0.5) 8/10(1.0) 0/10 0/10 2/10(0.2) 7/10(1.0) 3/10(0.3) 5/10(0.5) 6/10(0.6) 10/10(1.1) 0/10 6/10 (0.6) NA NA 5/10(0. NA 7/10(10) Thyroid gland: Hypertrophy, follicular 0/5 0/5 0/5 1/5(0.2) 3/5 (0.6) 5/5(10) 4/5 (0.8) 3/5 (0.8) Olfactory Epithelium Micrograph o f olfactory epithelium from control rat (A) and from rat administered 1000 mg/kg/day lest substance (B). Reproduction No test substance-relatedeffects on reproductive parameters were observed. Ttere were no adverse effects on estrous cycle or sperm parameters. Ttere were no adverse changes ittF, litter size, pup weights, and survival during lactation. Ttere were no te a substance-relatedchanges in body weights, food consumption or developmental landmarks in the F, generation. Thyroid Weights (P2aud F, Generations) Mean thyroid weiglu (absolute and relative to body weight) was significantly lower in the 250 and 1000 mg/kg/daydose groups in die F, generation, but not in the P, generation. However, there were no histopathologica] changes to die thyroid of tlte F, generation rats. P Generation IL- -StH F, Generation IJL- :I t lit --E3 ISummary Increased liver weights and/or hepatocellular hypertrophy were observed In male rats of all dose levels and female rats administered 1000 mg/kg/day. Thyroid hypertrophy was observed in male and female rats administered 250 and 1000 mg/kg/day. Olfactory epithelium degeneration / necrosis was observed in male and female rats of all dose groups. Incidence and severity of nose lesions decreased after one month of recovery and were not observed after three months of recovery. No test substance-related effects on reproductive parameters were observed. Mean thyroid weight was significantly lower in llie 250 and 1000 mg/kg/day dose groups HiConclusions Increased fiver weights and hepatocellular hypertrophy were considered a test substancerelated physiologic response to a xenobiolic and not toxicologically adverse. Thyroid hypertrophy in P, generation animals and decreased thyroid organ weights in F, generation animals were considered adverse findings and may be caused by exposure to organic iodide impurities in tlte test substance. Olfactory epitlieliumdegeneration/necrosis was also considered adverse but it could not be determined wlieiher tlte nasal lesions observed were due to systemic toxicity or focal toxicity os a result of gavage dosing. Based on systemic effects (otlier titan nose) observed at 250 mg/kg/day and above, tlte potential risk of human healtheffects from exposure to this product is very low.