Document pp7jr9z5e757oqOnj4OyMyREw

;mffi> HASKELL LABORATORY AR226-3375 Common Name: Ammonium Perfluorooctanoate (C-8) Chemical Name: Octanoic acid, pentadecafluoro-, ammonium salt CAS Registry No.: 3825-26-1 Chemical Structure: 0 Physical Properties: CFs - CFz - CF2 - CF2- CF2 - CFz - CFz - C - 0-4^4 Form: Molecular Weight: Boiling Point: Melting Point: Density: White powder 431 Sublimes (a). 11 0C Community Exposure Guideline 0.0003 mg/m3 (24-hour TWA) General Toxicity Ammonium perfluorooctanoate (C-8) has moderate acute oral toxicity with an LD50 in rats of 470 mg/kg1----fl|l9l8b). An aqueous paste of C-8 produced mild to moderate irritation on me skin ofrabbitSHfl|l979c). Clinical signs of toxicity including weight loss and labored breathing occurred at doses as low as 1500 mg/kg^B----lll979d)I.nstillation of the solid into the rabbit eye produced moderate comeal opacity, iritis, and conjunctivitis. The ocular effects ^----A gradually receded. Prompt washing of the treated eye reduced me degree of injury and the washed eye recovered more quickly 979b). By the acute inhalation route, C-8 has a four-hour ALC in the rat of 800 mg/mtf----rfh969). Clinical Human Studies :,L;^,:. Perfluorooctanoic acid (PFOA) has a long half-life in humans. A study ofoccupationally exposed workers at a plant which produces C-8 showed organic fluorine levels in the blood ranging from 1 to 71 ppm. One worker with a level of 70 ppm was removed from the fluoro- chemical production area and his blood analyzed for organic fluorine over several months. After 18 months, his organic fluorine level had decreased only to 39 ppm [45%. reduction] (Ubel et al., 1980). Serum PFOA levels were again measured in 1993,1995, and in 1997. Serum PFOA levels by year were: 1993 [mean 5.0 ppm, range 0-80.0 ppm]; 1995 [mean 6.8 ppm, range 0-114.1 ppm], and 1997 [mean 6.4 ppm, range 0.1-81.3 ppm]. not contain TSCA CSS In the 1997 examination, there was no evidence of abnormal liver function tests, hypolipidemia, or cholestasis associated with these PFOA levels (Olsen et al, 2000). Similar results were seen in an earlier study of 115 workers; serum PFOA levels varied between 0 and 26 ppm with a mean of 3.3 ppm (Gilliland and Mandel, 1996). A study was made of Washington Works employees potentially exposed to C-8. Results of blood chemistry testing (SGOT, LDH, AP, and bilirubin) indicated no conclusive evidence of an occupationally-related health problem among workers exposed to C-8fi----|B981d). Perfluorooctanoic acid (PFOA), a peroxisome proUferator, has produced a dose-related increase in hepatic, pancreatic acinar, and Leydig cell adenomas in rats. m addition, PFOA increased serum estradiol levels through the induction of hepatic aromatase activity. In 1993 and 1995, two cross-sectional studies of 111 and 80 production workers, respectively, were conducted to measure their serum PFOA in relation to several reproductive hormones to determine whether such an effect occurs in humans. PFOA was not significantly associated with:;:" estradiol or testosterone in either year's study. A 10% increase in mean estradiol levels was observed among employees who had the highest levels of serum PFOA, although this association was confounded by bodymass index (Olsen etaL, 1998). Extended Studies in Animals ^'; ".,;.' ;- ^ :..;' m a two-week study, groups of rats were exposed to 11 or 83 mg/m3of C-8; Liver degeneration, enlarged livers, and increases in liver enzymes were observed in both groups ft------|l979a).A second two-week study was conducted with exposure levels of 1,7.6, and 83.9 mg/m3. Mortality occurred at the highest exposure level. Liver changes were noted in me rats exposed to 7.6 and 83.9 mg/m3. These liver changes appeared to be reversibleH----6 ( ? 1981 a)^ubchronic studies by the oral and dermal routes confirm the effect of C-8 on the liver 1980; Griffith and Long, 1980). Groups of male Rhesus monkeyswere administered capsules containing 3,10, or 30 mg/kg/day for up to 6 months. The high dose was reduced to 20 mg/kg/day on day 22 of the study and mis dose was administered until the end of the study for 3 monkeys; 2 others had ^ . dosing discontinued from days 43 to 81 and one monkey died on day 29. One monkey in the .:;..: low-dose group also died but the cause of death was unclear. No clinical signs oftoxicity were seen.inthe3 or 10 mg/kg/day groups. Monkeys administered 30 mg/kg/day lost weight and had ; low food consumption; After reducing the dose to 20 mg/kg/day, these monkeys still ate less than controls but the marked weight loss was not seen; however, the weight gain of these' r monkeys was less than mat of the controls. No clinical signs oftoxicity were seen in 2/5 :..; . monkeys after the dose was reduced. Liver weights were increased in all dosed monkeys but no pathological liver changes were seen. Additionally, no hormonal, changes were seen in any of.. me dosed monkeys. C-8.levels in the liver were proportional to the administered dose. Blood levels of C-8 quickly reached a plateau level during dosing and were also quickly reduced after dosing stopped. Urinary levels of C-8 which were also wpportional to the dose/were quickly reduced after dosing was stoppedftBMHHRMHf 999). 'Company Sanitized. Does not contain TSCA CBl -2- Carcinogenic Potential Groups of male and female rats were fed diets containing either 30 or 300 ppm ofC-8 for two years, while a control group received only untreated feed. The major in-life findings associated with C-8 administration consisted of: a dose dependent ^ decrease in mean body weight gain and a treatment-related increase in food consumption in males; a slight treatment-related increase in the incidence ofataxia was observed in me females. There was no increase in mortality observed in either treatment group when compared to the control population. ...... C-8 related hematologic changes seen in the treated rats consisted of decreased red blood cell counts, hemoglobin, and hematocdt values seen at various times throughout the two-year test period. While the decreases in erythrocyte counts were observed very early in the study, this condition didnot progress into a generalized anemia by me end of me two-year study.'-1 - Histopafhblogically, C-8 associated toxic changes were found in the liver. These changes were characterized by increased liver weights, increased size of the liver cells with vacuolatibn of me cytoplasm, and some evidence ofhepatocellular degeneration with occasional signs of necrosis. As with the red blood cell findings, these liver changes were noted early in me study and showed very little evidence of progression over the remainder of the two-year study; The incidence of tumors found in this study was relatively low and the types of neoplasms '' found were not different from the tumor profiles commonly found in geriatric rats. Hepatocellular tumors were very slightly increased in the high-dose male rats; however, not to me extent that would be expected considering the morphological evijgnceof chronic hepatocellular stimulation first seen at the one-year necropsy ft----11987). All of the liver tumors were carcinomas and the incidence in the control, 30 ppm, and 300 ppm groups (males: 3/50,1/50, 5/50; females: 0/50,0/50,1/50) did not appear to be dose related. The incideneeof nodular hyperplasia in the liver (males: 1/50,0/50,2/50; females: 0/50,0/50, 3/50) was also slightly mcreased, though not statistically significantly (DuPont, 1987). . . All of theother remarkable tumor incidence values produced in this study were associated with endocrine or endocrine-sensitive organs (DuPont, 1987): , '^'i": The incidence of mammary gland fibroadenomas (10/50 (20%), 19/50 (38%);21;/50 (42%))suggested a compound-related effect. However, when comparedto Haslcell's ^ -historical control incidence for this strain of rat (37%), there does not appear to be .any - - compound-related effect. : .,. .^ r : - The incidence oftesticular Leydig cell adenomas (0/50 (0%), 3/50 (6%), 7/50 (14%)) was also suggestive of a compound-related effect When compared to Haskell's eontrol. . incidence for this strain of rat (6.1%, range 1-12%), the incidence in the 300 ppm group shows a statistically significant increase. :;!.. PompanySanded. Does nog contain TS.CACB! C-8 was included in a mechanistic bioassay investigating extrahepatic tumor induction by compounds which induce peroxisome proliferation, m this study, 300 ppm of C-8 was fed to rats for two years. Increased incidences of combined (single, multiple) hepatic adenomas (10/76 versus 2/80 in ad libitwn controls and 3/79 in pair-fed controls), Leydig cell adenomas 8/76 versus 0/79 and 2/78 in control groups), and combined pancreatic acinar cell adenomas (7/76 versus 0/80 and 1/79 in control groups) were noted. The tumor incidences were outside me historical control incidence range for Haskell Laboratory, and in addition, age-adjustment statistics also supported me conclusion that the tumor incidences were elevated for the liver, pancreas, and testia^H----^1993). Epidemiology In a retrospective cohort mortality study, the relationship between mortality and employment at aperfluorooctanoic acid (PFOA) production plant were investigated. The cohort consisted of 27&8'male and 749 female worlcers employed-between 1947 and 1983. TheaH-causes ^ ^ '-: standardized mortality rate (SMR) was 0.75 for men and 0.77 for women. Among men, the cardiovascular SMR was 0.68 and the all-gastromtestinal diseases SMR was 0.57. There was no significantly increased cause-specific SMRafef either men or women. The SMRs for prostate ' cancer were 2.03 in the Chemical Division group (exposed) and 0,58 in the non-Chemical Division group (not exposed to chemicals). In&eiChemicalDivisiongroupilfaere'were 4 observed and 2 expected deaths from prostate cancer. There was no significant association between any cause of death and latency in either group, m the Chemical Division group, the SMR for prostate cancer was 1.61 inthe greater than 15-year latency group.For all men employed at this plant, 6 deaths were recorded for prostate cancer versus 6 expected (Gilliland and Mandel, 1993). Further examination of this cohort by a 3M epidemiologist shows no association exists between PFOA exposure and prostate cancertfpBJR^OOO). Mutagenic Potential C-8 was negative in the Ames Salmonella assay either in the presence or absence of a metabolic activation system. It also was negative in the yeast Saccharomyces cerevisiae : (Oriffith and Long, 1980). ' . -, Developmental Toxicitv ;. :. -;;, .''; . ;; : . :..^..',^.." j | f | ''-"':'' ' Because ' an ' ' '' initial study ' in ' ' ' ' rats"s' uggested: a ' possible teratogenic effect ^s-^^^^f' 198 ' la), ' three studies in rats and one in rabbits were conducted. No teratogenic effects were noted in the foUo^^g^studies: i , , ... :'. ..'...:' .';'. ...'^ '-.^v^s..^:.:-^^' ,.. Groups of pregnant rats were administered by gavage 0.05,1.5, 50,orl5pmg^:gof C-8 on days 6-15 of gestation. Maternal toxicity occurred at 150 mg/kg. No teratogenic or embryotoxic effects were notedpHQ 1981b). Pregnant rats were administered by gavage 100 mg/kg of C-8 on days 6-15 of Igestation. Maternal toxicity was noted. A slight developmental effect related to the stress evoked by the toxic state of the dams was noted. Postpartum development, growthrate, and viability were not affectedfl|BB|il 982). .Company Sanitized. Does not contain TSCA CBl ,4-  Groups of pregnant rabbits were administered by gavage 1.5,5, or 50 mg/kg of C-8 in distilled water on days 6-18 of gestation. Dams administered 50 mg/kg lost weight as compared to the controls. No teratogenic effects were noted1Bil----[l982). Groups of pregnant rats were exposed by inhalation to 0.14,1.2,9.9, or 21 ing/to3of C-8 on days 6-15 of gestation. Maternal toxicity was noted in the dams exposed to 9.9 and 21 mg/m^mbryotoxicity was noted in the 21 mg/m3group. No teratogenic effects occurred J----ffl981c). Reproductive Toxicitv No information was available. Basis for Guideline ' A: Based on the 1 mg/m3NOEL determined in the second two-week inhalation study, an AEL of 0.01 mg/m3 (8-hour TWA), NtiaUy^commended in 1979, was reconfirmed in 1982. The 30 ppm dose level in thetwo^-yearfeeding;study was a marginal'effect level for liver ^toxieity and a NOEL fo^tumdrigedcity. :'l1a^^ sexes combined. Assuming 100% absorption of an inhaled dose, a 70 kg body weight, and inhalation of 10 m3 of air in an 8-hour workday, an airborne C-8 concentration of 10.5 mg/m3 would yield this dose level in a worker. Exposure afrthe 0.01 mg/m3 AEL would result m about . a 1000-fold safety factor. Therefore, based on the 30 ppm marginal effect level for liver toxicity and the slow clearance of C-8 from hutoan blood, no change was made in the AEL. The 0.01 mg/m3AEL was reduced to account for the longer exposure period (24 hours versus 8 hours), for the diverse population found in the community (the aged, the infirm, the young, etc.), and for the long half-life of C-8 in the blood. Accordingly, a CEG of 0.3 ug/m3was recommended. - C-8 was Updated in 1993 and the data found (mechanistic study and epidemiology results) added to the AEL documentation. Based on these additional data, the.current AEL and CEG values appear appropriate and no change was recommended at this time.: C-8 wa$ updated again in 1999 when results of a monkey study became available.sBased on ;;' increased liver weights, which might be.related to enzyme induction, no NOEL was determined - : in this study. These data need to be farther evaluated to determine the significance cffthis liver .effect. Even if it is considered compound related, the current AEL of 0.01 mg/m3provides a . 20QOxsafety factor from the3 ing/kg/day dose level. Therefore, no change was ma-de'at this time in the current AEL or CEG recommendations. ; ; : C-8 was updated again in August 2000 with the information found added to this, documentation. These data do not warrant any change in the current AEL or CEG. ,f nt^"^fWlPS< fHffWVf ^ffVMU&tsSltllisng Ti f%tMf References (1999). Personal Communication Haskell Laboratory Data: 1987. 1993. HL-160-69 EL-253-79 HL-635-79 HL-636-79 HL-659-79 HL-589-80 HL-205-81 lHL-295-81 lL-8ai-81, Report by ^1-8^ Personal communicatio: dated January 15,1981 -- Slated10-29-87 (AEL File445) Gilliland, F. D. and J. S. Mandel (1993), J. Occap. Med.. 35(9):950-954. Gilliland, JF. D. and J. S. MandeL(1996). Am.:J:Ind.Med.. 29(5):560-568. Griffith, F. D. and J. E. Long (1980), Am. Ind-Hve. Assoc. J.. 41f8'>:576-583. M[iftfPI----W(2f000). ' Personal Commumcation toC|--___--___--__--_^^------Bg Olsen, G. W. et al. (1998). J. Occun. Environ. Med.. 40(7):614-622. Olsen, G. W. et al. (2000). Drug and Chemical Toxicology. 23(4):603-620. |l)ata: - 198 la. Report M-601 (C-4124). 1981b. Riker Laboratory Report 0681TR0110 (J-5918). :, . 1982. Rtker Laboratory Report 0681TB0398 (C-4124),, : ^1987. Riker Laboratory Report 0281CR0012 (J-7446)::, , ^. ,:^bei,-P.A. et al. (1980). Am. mMyg. Assoc. J.. 41(8)^84-589. Mareh8,1988 ; - Updated by: : . . , December 7,1993, November 12,1999, and August 24,2000 Does not contain TSCA CBl .6