Document YjMDone92Rk7Q7k25ExnM1wKN

AR226-3390 Comparison of Dose and Toxicity after Administration of a Fluoroalkylethyl Phosphate S Dermal and Inhalation Routes in Rats C. Finlay, D.P. Kelly, N.E. Everds, J.F. Hansen, and J.C. Stadler The DuPont Company, Haskell Laboratory/or Health and Environmental Sciences, Newark, Delaware, USA lAbstract Fluorosurfaciants are used as specialty welling and leveling additives in cleaning and coatings formulations. Previously, this Ruoroalkylelhyl phosphate surfaciant was evaluated for subchronic, developmental, and reproductive toxicily in gavage studies; ihe liver was the most sensitive targel organ. Since die intended uses of dlis surfaciant would predict thai dermal or respiratory tract exposures are likely. studies were conducted to assess internal exposure and loxicity by these routes. In the 28-day study, the test substance was applied to the skin of male rats each day for 6 hours at doses of 0,10.100, and 1000 nig/kg/day (35% ai). There were no adverse effecis on mortality, clinical signs, body weights, food parameters, anatomic pathology, or hematology. Aspartate- and aianine-aminoiransferases and sorbitol dehydrogenase activities were increased at 100 and 1000 ing/kg/day. The NOEL for dermal exposure was 10 ing/kg/day, tn the inhalation study, male rats were exposed nose-only 10 0,0,2, 2, or 20 mg/m3 of aerosol for 6 hrs/day. 5 days/wit for 2 wks. There were no effects on body weights, clinical signs, or clinical pathology parameters. The only hisiological effects were mild inflammation in the larynx and lung at 2 and 20 mg/m3. The NOEL for inhalation was 0.2 nig/in3. Internal exposures by the dermal, inhalation, and oral routes were compared fayfluorine blood analysis (Wickbold Torch Combustion Method). Minimal levels of fluorine were detected at the two lowest doses administered dennally. Fluorine levels were apparent in all rats exposed by inhalation, however, the levels were equal to or less man levels in rats exposed orally. Baaed on the fluorine dosage results in the above studies and the Findings in the respiratory tract after inhalation exposure, inhalation appears to be a more sensitive route of exposure than the dermal or oral routes for this fluorosurfactant, I Dermal Study Results Mortality; Clinical Observations: Body Weights: Food Consumption: Clinical Pathology: Anatomic Pathology: No systemic loxicity No effecis No effects No adverse effects on hematology - Increased aspartate and alaninc aminotransferasc activities ai 100 and 1000 nig/kg/day were considered potentially adverse (Table I). No adverse effects on organ weights or gross or Fluorine Measurement. Total Fluorine in Blood (Table 2. Figure I i: Minimal levels of fluorine (slightly above background of 0.5 ppm) in day 21 blood from rats in 10 or 100 mg/kg/day groups. Some fluorine (1.3 ppm) in day 21 blood from rats in 1000 ing/kg/day group. Statistically significant at lOOOmg/kg/day. Slighlly elevated at 10 or 100 nig/kg/day. 10 ing/kg/day based on increased liver enzymes at 100 andlOOOmg/kg/day Days on Test siandard error of die mean. Section of larynx (at tile 20 mg/iii'of the icsl sub mu<Msa and fonanmiato flla Introduction This fluoroalkylelhyi phosphate surfactam is used as a specialty wetting and leveling additive in cleaning and coalings formulations. The liver was the most sensitive targcl organ in previously conducted oral gavage studies- The intended uses of this surfactant would predict thai dermal or respiratory tract exposures are likely. Studies were conducted to assess loxicity by these routes and compare internal exposures to a previously conducted 90-day oral study. Only male rats were used because they were the more sensitive sex in the oral studies. yS Methods Total Fluorine in Blood: Whole blood was combusted using a Wickbold torch. followed by analysis with a fluoride ion selective elecirodc- Urine Fiuoridc: Determined using a phil2 PH meter and a fluorideselcctive electrode. Test Substance: 35-il0% Active ingredients 20% Isopropyi alcohol 40-45% Water Animals: Male, Sprague-Dawley rats fDermal Study Design Dosages: Conditions: 0 (control), 10, 100, and 1000 mg/kg/day 6 hrs/day for 2B coonnssiecutive days; semi-occluded Animals; 10 rais per dosage Recovery Period: Study Parameters: None Mortality, clinical ob crvations, body weights, food consumption, tola! fh orine in blood (day 22), clinical pathology, anatomic pathology | Table 1 - Aspartate andAlanine Aminotransferase Activities AST (U/L) ALT 8(10) 15(10) 145@ 41(10) 100@ 37(10) 66(101 12(10) 15(10) 12(10) e siaiiiiaiiy lipiificua dii ||jg Table 2 - Total Fluorine Levels in Blood 0 F (coin) <0.5 10 0.7 0.32(21 100 0.6 0.09(5) 1000 1.3 0.09(3) 0 1.3 0-04(5) 0.2 1.4 0,22(5) 2 1.4 0.13(5 20 2.0 O.SK5) | Table 3 - Fluorine Levels in Urine UFLU (Mj) ld.8 HA 19.2 4.0(9) 4.3(10) 5.3(10) 33.9 2.1(10) 2.2(10) 2.4(10) _1.2(i0j 4.EUO) SiHKhnlikiiiilian [Nmnlumf nliu-iiadiBtel in SwuDolly ilfniflouj anfniiif fiamcailrol it 1-^l.OS br nu mi Inhalation Study Design Concentrations: 0 (control), 0.2,2, and 20 mg/m'/day Exposure Mode; Nose only Conditions: 6 hrs/day, 9 exposures over a 2-week period Study Parameters: - 10 rats/group designated for toxicity testing; half these rats til a 15-day recovery period 5 rats/group designated for blood fluorine analysis and had a 15-day recovei'y period Mortality, clinical observations, body weights, total fluorine in blood (day 10). clinical pathology, anatomic pathology VSSInhalation Study Results Mortality: Clinical Observations: Body Weights: Clinical Pathology: Anatomic Pathology: None No systemic toxicity No effects No effects Organ weights No effects Microscopic Observations (Figure 2) Inflammation in lungs characterized by mixed inflammatory cells within scattered alveolar lumina in rats at 2 and 20 mg/m'. Minimal 10 mild squamous metaplasia of mucosa lining the ventra! floor of the larynx at 2 and 20 mg/ro'. : Total Fluorine in Blood (Table 2. Figure I): Small amounts of fluorine (slightly above background of 0,5 ppm) in day 9 blood from rats in 0.2 and 2 mg/m1 groups- Some fluorine (2 ppm) in day 9 blood from rais in 20 mg/m3 group. No above-background fluorine present after recovery period. Urine Fluonde (Table 3); Slight elevation in 20 mg/m1 group. No statistically significant differences from control, 0.2 nig/m1 based on respiratory iraci effects at 2 mg/m1 Hll Discuss This fluoroalkylethyl leveling Administratio 28 days resulted in ele Previously, liver necro enzymes were only se (NOEL) was establish Administration of this 9 exposures over a 2-w There were no liver e The levels of total flu group and 20 mg/m3 i necrosis observed in t oftoial fluorine from blood levels in rais do liver effects were obs (0.2 mg/m') converts inhalation exposure p US Conclu Study results indicate uses. Blood levels in which to base potenti NOELs have been est ffl Acknow The authors would lik Study Technicians: S Fluorine Analysis: R Poster Preparation: M