Document zz9Lr0oZpOvLJMokZxY9VaKwm

AR226-3390 Comparison of Dose and Toxicity after Administration of a Fluoroalkylethyl Phosphate Surfactant by Dermal and Inhalation Routes in Rats C. Finlay, D.P. Kelly, N.E. Everds, J.F. Hansen, andJ.C. Stadler The DuPont Company, Haskell Laboratory fo r Health and Environmental Sciences, Newark, Delaware, USA I Abstract Fluorosurfactants are used as specialty wetting and leveling additives in cleaning and coatings formulations. Previously, this fluoroalkylethyl phosphate surfactant was evaluated for subchronic, developmental, and reproductive toxicity in gavage studies; the liver was the most sensitive target organ. Since the intended uses of this surfactant would predict that dermal qt respiratory tract exposures are likely, studies were conducted to assess internal exposure and toxicity by these routes. In the 28-day study, the test substance was applied to the skin o f male rats each day for 6 hours at doses o f 0 ,1 0 .1 0 0 , and 1000 mg/kg/day (35% ai). There were no adverse effects on mortality, clinical signs, body weights, food parameters, anatomic pathology, or hematology. Aspartate- and alanine-aminotransferases and sorbitol dehydrogenase activities were increased at 100 and 1000 mg/kg/day. The NOEL for dermal exposure was 10 mg/kg/day. In the inhalation study, male rats were exposed nose-only to 0 ,0 .2 , 2, o r 20 mg/m3 o f aerosol for 6 hrs/day. 5 days/wk for 2 wks. There were n o effects on body weights, clinical signs, o r clinical pathology parameters. The only histological effects were mild inflammation in die larynx and lung at 2 and 20 mg/m3. The N OEL for inhalation was 0.2 mg/m3. Internal exposures by die dermal, inhalation, and oral routes were compared by fluorine blood analysis (Wickbold Torch Combustion Method). Minimal levels o f fluorine were detected at the tw o lowest doses administered dermally. Fluorine levels were apparent in all rats exposed by inhalation, however, the levels were equal to or less than levels in rats exposed orally. Based 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. Dermal Study Results M orta li ty : None Clinical Observations: N o systemic toxicity Body Weights: N o effects Food Consumption: Clinical Pathology: No effects No adverse effects on hematology Increased aspartate and alanine aminotransferase activities at 100 and 1000 mg/kg/day were considered potentially adverse (Table l). Anatomic Pathology: No adverse effects on organ weights or gross or microscopic examinations Fluorine Measurements: Total Fluorine in Blood (Table 2, Figure 1): Minimal levels o f 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 2 1blood from rats in 1000 mg/kg/day group. . Urine Fluoride (Table 3): . Statistically significant at 1000 mg/kg/day. Slightly elevated at 10 or 100 mg/kg/day. NOEL: 10 mg/kg/day based on increased liver enzymes at 100 and 1000 mg/kg/day I Figure 1 - Oral, Inhalation, and Dermal Studies O 10mgftiAUyoral 60mgftgttsyoral -e-ttZnififtn* nliatMjos 19mgftgMaydenral `-ie- lOOrng&gtioydeflrat Days on Test Values represent mean standard error of the mean. Secdonoflarynx (at die base of the epiglottis) from a control rat (A) and a rat exposed to 20 mg/m3of die test substance (B). Note squamous metaplasia of die ventral laryngeal mucosa and inflammatory cell infiltrate in the submucosa (arrow). IIntroduction This fluoroalkylethyl phosphate surfactant is used as a specialty wetting and leveling additive in cleaning and coatings formulations. The liver was the most sensitive target organ in previously conducted oral gavage studies. The intended uses o f this surfactant would predict that dermal or respiratory tract exposures are likely. Studies were conducted to assess toxicity 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. I Table 1 - Aspartate and Alanine Aminotransferase Activities <V/L) 0 10 100 1000 14(10) 50 8(10) l l z E... I4S@ 8(10) 41(10) 60 100@ 15(10) 37(10) 1570 79(10) ill 66(10) Inhalation Study - Dav 10 0 0.2 2 20 ino/m3 94 94 94 103 10(10) 12(10) 15(10) 12(10) 38 8(10) 7(10) 6(10) 5(10) Swiulnillyi I Methods Total Fluorine in Blood: Whole blood was combusted using a Wickbold torch, followed by analysis with a fluoride ion selective electrode. U rine Fluoride: Determined using a p h il2 PH meter and a fluorideselective electrode. Test Substance: 35-40% Active ingredients 20% Isopropyl alcohol 40-45% Water Animals: Male, Sprague-Dawley rats I Table 2 - Total Fluorine Levels in Blood <0.5 (PPm?- Dermal Study - Day 22 10 100 1000 TTlv/kt* 0.7 0.6 1.3 0.32(2) 0.09(5) 0.09(3) inhalation Study - Day 10 0 0.2 me/m3 me/m3 mc/m3 mt?/m3 1.3 1.4 1.4 2.0 0.04(5) 0.22(5) 0.1K5) IDermal Study Design Dosages: 0 (control). 10,100, and 1000 mg/kg/day Conditions: 6 hrs/day for 28 consecutive days; seini-occludcd Animals: 10 rats per dosage Recovery Period: None Study Parameters: Mortality, clinical observations, body weights, food consum ption, total fluorine in blood (day 22), clinical pathology, anatomic pathology I Table 3 - Fluorine Levels in Urine Dermal Study - Day 29 0 10 100 1000 UFLU 14.8 Iasi___ 174 19.2 33.9@ 4.3(10) 5.3(10) 2.1(10) Inhalation Study - Dav 10 0 0.2 2 20 7.9 8.1 10.5 2.2(10) 24(10) 1.2(10) 4.8(10) \ Inhalation Study Design Concentrations: 0 (control). 0 .2 ,2 , and 20 mg/m3/day Exposure Mode; Nose only Conditions; 6 hrs/day, 9 exposures over a 2-weck period Animals: 15 rats per concentration . 10 rats/group designated for toxicity testing; half these rats had a 15-day recovery period 5 rats/group designated for blood fluorine analysis and had a 15-day recovery period Study Parameters: Mortality, clinical observations, body weights, total fluorine in blood (day 10), clinical pathology, anatomic pathology IInhalation Study Results Mortality: Clinical Observations: Body Weights: Clinical Pathology: Anatomic Pathology: None No systemic toxicity No effects No effects Organ weights No effects Gross observations 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/m3. Minimal to mild squamous metaplasia o f mucosa lining the ventral floor o f the larynx at 2 and . 20 mg/ro3. Fluorine Measurements: Total Fluorine in Blood (Table 2, Figure 1): Small amounts of fluorine (slightly above background of 0.5 ppm) in day 9 blood from rats in 0.2 and 2 mg/m3 groups. Some fluorine (2 ppm) in day 9 blood from rats in 20 mg/m3group- No above-background fluorine present after recovery period. NOEL: Urine Fluoride (Table 3): Slight elevation in 20 mg/m3 group. No statistically significant differences from control. 0.2 mg/m3based on respiratory tract effects at 2 mg/m3 JM I Discussion This fluoroalkylethyl phosphate surfactant is used as a specialty wetting and leveling Administration o f this fluoroalkylethyl phosphate surfactant dermally for 28 days resulted in elevations o f liver enzymes but not in adverse liver pathology. Previously, liver necrosis occurred in rats dosed orally. The effects on liver enzymes were only seen at the high dose. A clear no observed adverse effect level (NOEL) was established. Administration of this fluoroalkylethyl phosphate surfactant by inhalation in 9 exposures over a 2-week period resulted in mild effects on the respiratory tract. There were no liver effects. A clear NOEL was established. The levels of total fluorine in the blood from rats in the 60 mg/kg/day oral dose group and 20 mg/m3 inhalation group are comparable. However, none of the liver necrosis observed in the oral study was apparent in the inhalation study. T he levels o f total fluorine from rats dosed with 10 or 100 mg/kg/day dermally compares to blood levels in rats dosed with 10 mg/kg/day orally. As with inhalation, no adverse liver effects were observed from dermal exposure- The inhalation NOEL (0.2 mg/m?) converts to a daily dose o f 33 pg/kg/day in a 60 kg man. Therefore, inhalation exposure produces the highest blood levels relative to dose delivered. IConclusions Study results indicate that liver effects would not be expected as a result o f normal uses. Blood levels indicate inhalation is the more sensitive exposure route on which to base potential health effects for individuals using the surfactant. G ea r NOELs have been established for both dermal and inhalation routes of exposure. | Acknowledgements T he authors would like to thank the following: Study Technicians: Sherman Glide and William Ellis Fluorine Analysis: Robert Good and Ward Gibson Poster Preparation: Maryanne Wilford