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AR226-3375 HASKELL LABORATORY Common Nam e: Ammonium Perfluorooctanoate (C-8) Chem ical N am e: O ctanoic acid, pentadecafluoro-, ammonium salt CAS Registry N o.: 3825-26-1 Chem ical Structure: O v Physical Properties: CF3-CF2-CF2-CF2-CF2-CF2-CF2-C -0^ N H 4^ ;^ Form : M olecular W eight: B oiling Point: M elting Point: D en sity : W hite powder 431 /Sublimes @ 110C --- --- ' .; ' i; /^ Community Exposure Guideline 0.0003 m g/m 3 (24-hour TW A) General Toxicity Ammonium perfluorooctanoate (C-8) has moderate acute oral toxicity w ith an LD50 in rats o f 470 m g/kgJ I M ^ | l 98 lb ). A n aqueous paste o f C-8 produced m ild to moderate irritation on the skin o f rabbits ^ 1 9 7 9 c ) . Clinical signs o f toxicity including w eight loss and labored breathing occurred at doses as low as 1500 m g/kgJB B H lfe 9 7 9 d ). Instillation o f the solid into the rabbit eye produced m oderate com eal opacity, iritis, and conjunctivitis. The ocular effects gradually receded. Prom pt washing o f the treated eye reduced the degree o f injury and the washed eye recovered m ore quickly | m M ^ 1979b). By the acute inhalation route, C-8 has a four-hour ALC in the rat o f 800 mg/m3 1 9 6 9 ). .... Clinical Human Studies ''' T Perfluorooctanoic acid (PFOA) has a long half-life in humans. A study o f occupationally exposed workers at a plant which produces C-8 showed organic fluorine levels in the blood ranging from 1 to 71 ppm. One w orker with a level o f 70 ppm was removed from the fluorochemical production area and his blood analyzed for organic fluorine over several months. A fter 18 m onths, 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]. ISsSpifty Sanitized, Does not contain TSCCBS In the 1997 exam ination, there was no evidence o f abnorm al liver function tests, hypolipidem ia, or cholestasis associated w ith these PFOA levels (O lsen et al., 2000). Sim ilar results w ere seen in an earlier study o f 115 workers; serum PFOA levels varied betw een 0 and 26 ppm w ith a m ean o f 3.3 ppm (G illiland and M andel, 1996). A study w as m ade o f W ashington W orks employees potentially exposed to C-8. Results o f blood chem istry testing (SGOT, LDH, AP, and bilirubin) indicated no conclusive evidence o f an occupationally-related health problem among workers exposed to C -8 ljB M W 1 9 8 1d). Perfluorooetanoic acid (PFOA), a peroxisome proliferator, has produced a dose-related increase in hepatic, pancreatic acinar, and Leydig cell adenomas in rats. In addition, PFOA increased serum estradiol levels through the induction o f hepatic arom atase activity. In 1993 and 1995, tw o cross-sectional studies o f 111 and 80 production w orkers, respectively, w ere conducted to m easure their serum PFOA in relation to several reproductive hormones to determ ine w hether such an effect occurs in humans. PFOA was not significantly associated w ith : estradiol o r testosterone in either year's study. A 10% increase in mean estradiol levels was observed among employees who had the highest levels o f serum PFOA, although this association w as confounded by body m ass index (Olsen et al., 1998). Extended Studies in Animals In a tw o-w eek study, groups o f rats were exposed to 11 or 83 mg/m3 o f C-8. Liver degeneration, enlarged livers, and increases in liver enzymes w ere observed in both groups J ^ m l 9 7 9 a ) . A second two-week study was conducted w ith exposure levels o f 1,7.6, and 83.9 mg/m3. M ortality occurred at the highest exposure level. Liver changes w ere gpted in d ie rats exposed to 7.6 and 83.9 mg/m3. These liver changes appeared to be reversible 1981a). Subchronic studies by the oral and dermal routes confirm the effect o f C-8 on the liver 1980; G riffith and Long, 1980). Groups o fm aie Rhesus m onkeysw ere administered capsules containing 3 ,1 0 , or 30 m g/kg/day for up to 6 months. The high dose was reduced to 20 mg/kg/day on day 22 o f the study and this dose was adm inistered Until the end o f the study for 3 monkeys; 2 cithers had : . dosing discontinued from days 43 to 81 and onem onkey died on day 29. O nem onkey in the . . low -dose group also died but the cause o f death was unclear. No clinical signs o f toxicity w ere seen in the 3 or 10 ing/kg/day groups. Monkeys adm inistered 30 mg/kg/day lost w eight and had ' low food consum ption. A fter reducing the dose to 20 mg/kg/day, these monkeys still ate less than controls but the m arked weight loss was not seen; however, the weight gain o f these' r monkeys w as less"than that o f the controls. No clinical signs o f toxicity 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 seal. Additionally, no hormonal, changes were seen in any o f . . the dosed m onkeys. C-8.1evels in the liver were proportional to the administered dose. Blood \ levels o f C-8 quickly reached a plateau level during dosing and were also quickly reduced after dosing stopped. U rinary levels o f C-8 which were also proportional to the dose, were quickly reduced after dosing was stopped 999). Company Sanitized. Does not contain TSA CBl 2- Carcinogenic Potential Groups o f m ale and fem ale rats were fed diets containing either 30 or 300 ppm o f C-8 for two years, w hile a control group received only untreated feed. ; The m ajor in-life findings associated with C-8 adm inistration consisted of: a dose dependent decrease in m ean body w eight gain and a treatm ent-related increase in food consum ption in m ales; a slight treatm ent-related increase in the incidence o f ataxia was observed in the females. There was no increase in m ortality observed in either treatm ent group when com pared to the control population. -. C-8 related hem atologic changes seen in the treated rats consisted o f decreased red blood cell counts, hem oglobin, and hem atocrit values seen at various tim es throughout the tw o-year test period. W hile the decreases in erythrocyte counts w ere observed very early in the study, this condition did /hot progress into a generalized anem iaby the end o f the tWoryear study: X - H istopathlogically, C-8 associated toxic changes were found in the liver. These changes w ere characterized by increased liver weights, incresd size o f the liver cells w ith vacuolatibn o f the cytoplasm , and some evidence o f hepatocellular degeneration w ith occasional sighs o f necrosis. A s w ith the red blood cell findings, these liver changes w ere noted early in the study and showed vry little evidence o f progression over the rem ainder o f the tw o-year study. The incidence o f tum ors found in this study was relatively low and the types o f neoplasm s *found w ere not different from the tum or profiles commonly found in geriatric rats. H epatocellular tum ors w ere very slightly increased in thehigh-dose m ale rats; however, not to the extent that w ould be expected considering the morphological evnjgnce o f chronic 1 hepatocellular stim ulation first seen at the one-year n e c ro p s y l^ H tifl 1987). A ll o f the liver tum ors w ere carcinomas and the incidence in the control, 30 ppm , and 300 ppm groups (m ales: 3/50,1/50, 5/50; females: 0/50, 0/50,1/50) did not appear to b e dose related. The incidence o f nodular hyperplasia in the liver (males: 1/50,0/50,2/50; females: 0/50,0/50, 3/50) was also slightly increased, though not statistically significantly (DuPont, 1987). > A ll o f th e other rem arkable tum or incidence values produced in this study w ere associated w ith endocrine or endocrinersensitive organs (DuPont, 1987): . :: " ? The incidence o f mammary gland fibroadenomas (10/50 (20% ), 19/50 (38% ), 21/50 (42% )) suggested a oe m pound-related effect. However, w hen compared to H askell's ' historical control incidence for this strain o f rat (37%), there does not appear to be an y - com pound-related effect ' H :. v r : - The incidence o f testicular Leydig cell adenomas (0/50 (0% ), 3/50 (6% ), 7/50 (14%)) was also suggestive o f a compound-related effect. W hen com pared to H askell's c o n tro l. : incidence for this strain o f rat (6.1%, range 1-12%), the incidence in the 300 ppm group shows a statistically significant increase. Company Sanitized. Does nof contain TSCA CB -3 - C-8 was included in a m echanistic bioassay investigating extrahepatic tum or induction by com pounds w hich induce peroxisom e proliferation. In this study, 300 ppm o f C-8 was fed to rats for two years. Increased incidences o f combined (single, m ultiple) hepatic adenomas (10/76 versus 2/80 in ad libitum 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 tum or incidences were outside the historical control incidence range for Haskell Laboratory, and in addition, age-adjustm ent statistics also supported the conclusion that the tum or incidences w ere elevated for the liver, pancreas, and testiaftM M W l993). In a retrospective cohort m ortality study, the relationship betw een m ortality and em ploym ent at a perfluorooctanoic acid (PFGA) production plant were investigated. The cohort consisted o f 2788 m ale and 749 fem ale w orkers employed betw een 1947 and 1983. The all-causes - % ' r standardized m ortality rate (SMR) was 0.75 for m en and 0.77 for women. Among m en, the cardiovascular SMR was 0.68 and the all-gastrointestinal diseases SMR was 0.57. There Was no significantly increased cause-specific SMR fof 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 Diviisioh group (not exposed to chemicals), h i dierChesmical D ivision group therew ere 4 observed and 2 expected deaths from prostate cancer. There w as no significant association betw een any cause o f death and latency in either group. In the Chem ical D ivision group, the SM R for prostate cancer was 1.61 in the greater than 15-year latency group. For all men em ployed at this plant, 6 deaths w ere recorded for prostate cancer versus 6 expected (G illiland and M andel, 1993). Further exam ination o f this cohort by a association exists betw een PFOA exposure and prostate can M utagenic Potential C-8 was negative in the Ames Salmonella assay either in the presence or absenceof a m etabolic activation system. It also was negative in the yeast Sdccharomyces cerevisiae ; (G riffith and Long, 1980). i Developm ental Toxicity Because an initial study in rats suggested a possible teratogenic e f f e c t ^ p l ^ 198la ), three studies in rats and one in rabbits were conducted. No teratogenic effects w ere noted in the foU oyhigstudies:; .> . : Groups o f pregnant rats were administered by gavage 0.05, 1.5, 50, o r 150 mg/kg o f C-8 on days 6-15 o f gestation. M aternal toxicity occumed at 150 mg/kg. No teratogenic or embryotoxic effects were n o te d H flB M 1981b). Pregnant rats were administered by gavage 100 mg/kg o f C-8 on days 6-15 o f gestation. M aternal toxicity was noted. A slight developmental effect related to the stress evoked by the toxic state o f the dams was noted. Postpartum development, growth rate, and viability were not a ffe c te d flp H M f1982). Company Sanitized. Does not contain TSCA CBl -4-  Groups o f pregnant rabbits were administered by gavage 1.5,5, or 50 m g/kg o f C-8 in distilled w ater on days 6-18 o f gestation. Dams administeredSOmW kg lost w eight as com pared to the controls. No teratogenic effects w ere n o te d jp B H ^ 1982). * Groups o f pregnant rats were exposed by inhalation to 0 .1 4 ,1 .2 ,9 .9 , or 21 m g/m o f C-8 on days 6-15 o f gestation. M aternal toxicity was noted in the dams exposed to > 9.9 and 21 m g/m unbryotoxicity was noted in the 21 mg/m3 group. N o teratogenic ; effects occurred p B W C fl9 8 1 c). Reproductive Toxicity N o inform ation was available. Basis for G uideline ' --` : v :l B ased on the 1 m g/m 3NOEL determined in the second tw o-w eek inhalation study, an AEL o f 0.01 mg/m3 (8-hour TW A), initiaM bpirm ended in 1979, w as reconfirm ed in 1982. :-.v ' .;- iif 'f f ; i : ; . v-v ~ : The 30 ppm dose levl in the two-year feeding study was a mM-ginal:effect level for liver - toxicity and a N O EL for tum origenicit. 'TM M ose 1 ^ is e q u iv alen tto l.5 m g/kg/dy for both sexes combined. A ssum ing 100% absorption o f an inhaled dose, a 70 kg body weight, and ~ inhalation o f 10 m 3 o f air in an 8-hour workday, an airborne C-8 concentration o f 10.5 mg/m3 w ould yield this dose level in a worker. Exposure a tth e 0.01 mg/m3 AEL would result -in about a 1000-fold safety factor. Therefore, based oh the 30 ppm m arginal effect level for liver toxicity and the slow clearance o f C-8 from human blood, no change was made in the AEL. The 0.01 mg/m3 AEL 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 o f C-8 in the blood. Accordingly, a CEG o f 0.3 ug/m3 was recom m ended. C-8 was updated in 1993 and the data found (mechanistic study and epidem iology results) added to the AEL docum entation. Based on these additional data, the.current AEL and CEG values appear appropriate and no change was recommended at this time. C-8 w as updated again in 1999 when results o f a monkey study became available,E ased on increased liver w eights, which m ight be related to enzyme induction, no NOEL was determ ined in this study. These data need to be further evaluated to determ ine the significance of;this liver effect. Even if it is considered compound related, thecurrent AEL o f 0.01 mg/m3provides a 20Q0x safety factor from the 3 mg/kg/day dose level.: Therefore, no change was made at this tim e in the current A EL or CEG recommendations. ; ;/ C-8 was updated again in August 2000 w ith the inform ation found added to this, documentation. These data do not warrant any change in the current AEL or CEG. tSompany SanzeS, Bees Hotcontain ISSA BI -5 - R eferences (1999). Personal Communication to] H askell Laboratory Data: 1969. |H L rl60-69 1979a. -253-79 1979b. IH L -635-79 1979c. IH L -6 3 6 -7 9 1979d.| [H L -659-79 1980. [h L-589-80 1981a. H L -205-81 1981b. Ih L-295-81 1981c. [L-8 8.1-81 1981d. R eportby 1982. IL-1?82 1987. Personal com m unicatio 1993. . . . f`L'A dated January 15,1981 Slated 10-29-87 (AEL File 145) G illiland, F D. and J. S. M andel (1993). ):950-954. ' G illiland, F . D. and J. S. M andel (1996). Am. J. Ind. M ed.. 29(5):560-568. G riffith, F. D. and J. E. Long (1980), Aim Ind. Hve. Assoc. J.. 41(81:576-583. 2000). Personal Communication to Olsen, G. W. et al. (1998). J. Occun. Environ. M ed.. 40(7):614-622. O lsen, G. W. et al. (2000). D rue and Chemical Toxicology, 23(4):603-620, 1981a. Report M -601 (C-4124). 1981b. Riker Laboratory Report 0681TR0110 (J-5918). 1982. Riker Laboratory Report 0681TBQ398 (C-4124).,, : 1987. R iker Laboratory Report 0281CR0012 (J-7446); T, - r Ubel, F, A. et al. (1980). Am. fik-H vg. Assoc. J.v 4 1('8):584-589. M arch 8,1988 Updated by: Sanitized. Does not contain TSCA CB1 -6 -