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Haskell Laboratory for Toxicology and Industrial Medicine AR226-3373 October 30,1998 To: From: AG Haskell Laboratory Haskell Laboratory CARCINOGENIC AND DEVELOPMENTAL TOXICITY HAZARD DETERMINATIONS AMMONIUM PERFLUOROOCTANOATE (Octanoic Acid, Pentadecafluoro-, Ammonium Salt) CAS REGISTRY NO. 3825-26-1 Ammonium perfluorooctanoate (C-8) has been reviewed according to DuPont Corporate Standard S18T (Hazard Determination Process) for assessment and control of carcinogenic and developmental toxicity hazards. This hazard determination supersedes the previous letter dated February 29,1988. Ammonium perfluorooctanoate has now been categorized as not likely to be a human carcinogen and as not likely to be a developmental toxin. A DuPont AEL (8-hr and 12-hour TWA) of 0.01 mg/m3 SKIN has been established to protect against all potential toxic effects of C-8. Some additional detail on studies involved in the preceding hazard determination follows: Company Sanitized. Does not contain TSCACBI 1- Carcinogenic Hazard Groups of 120 male and 120 female rats were fed diets containing either 30 (1.5 mg/kg/day) or 300 (15 mg/kg/day) ppm C-8 for up to 24 months, while a control group received only untreated food. C-8 associated changes included increased liver weights, increased size of liver cells with vacuolation of the cytoplasm, and some evidence ofhepatocellular degeneration and necrosis. A low incidence of liver tumors also was seen at the 0,30 and 300 ppm levels - 0 of 50,0 of 50, and 1 of 50 carcinomas in females and 3 of 50,1 of 50 and 5 of 50 carcinomas in males. The incidence of nodular hyperplasia in the liver (females 0 of 50,0 of 50, and 3 of 50; males 1 of 50,0 of 50, and 2 of 50) was also slightly increased, although none of these incidences were statistically significant. Aside from liver changes, the only other remarkable effect was a slight increased incidence ofLeydig Cell adenomas (0 of 50, 3 of 50 and 7 of 50 - the latter was statistically significant) (DuPont 1987). In a related mechanistic study (DuPont 1993; 3M 1993), 300 ppm of C-8 was fed to rats for 24 months. Benign tumor incidences (adenomas) were elevated for liver (10 of 76 vs. 2 of 80 in controls), pancreas (7 of 76 vs. 0 of 80 in controls) and testis (8 of 76 vs 0 of 70 in controls). On the basis of the preceding chronic studies, and several mechanistic studies, it was determined that C-8 belongs in a class of chemicals referred to as peroxisome proliferators. A review of several well-known peroxisome proliferators (drugs like clofibrate and ciprofibrate; chemicals like HCFC-123) showed that such chemicals have produced the same three benign tumor types seen in the C-8 chronic studies (Cook 1992). All three tumor types have been shown, directly or indirectly, to be associated with peroxisome proliferation. Species specific differences for peroxisome proliferation do exist with rats being high responders and other species (guinea pigs, primates and humans) being low-to-non-responders. Thus, these tumor types appear to have little or no biological significance to man. In two limited retrospective mortality studies (Ubel et al. 1980; Gilliland 1993 and Olsen 1996), no causal relationship between C-8 exposure and cancer was seen. The ACGIH (1997) has also evaluated the toxicity/carcinogenicity profile of C-8 and has categorized it as an A3 carcinogen, an animal carcinogen with little or no relevance to man. Based on the proceeding information, the DuPont AEL Committee has categorized C-8 as not likely to be a human carcinogen. CompanySanitized. Does not contain TSCA CBI .2- Developmental Toxicitv Hazard Groups of pregnant rats were gavaged at doses ofC-8 of 1.5,50 or 150 mg/kg on days 6 through 15 of gestation. Maternal toxicity was seen at 150 mg/kg only. No evidence of teratogenicity or embryotoxicity was seen at any dose (Riker Labs 1981). In another study (DuPont 1982), rats gavaged at one dose level (100 mg/kg) ofC-8 on days 6-15 of gestation showed severe maternal toxicity, (including several deaths), along with a slight increased of fetuses with ossification sites on the first lumbar vetebrae. The latter effect (only statistically significant if analyzed by a one-tailed test) was probably a response to generalized stress evoked by the toxic state of the dams. Postpartum development, growth rate, and viability of pups were not affected. When groups of pregnant rabbits were given by gavage 1.5,5 or 50 mg/kg C-8 in distilled water on days 6 through 18 of gestation, maternal toxicity (decreased body weight, for example) was seen at 50 mg/kg but no teratogenic effects were noted at any dose (Riker Labs 1982). In an inhalation study at C-8 doses of 0.14,1.2,9.9 or 21 mg/m3, rats were exposed 6 hours a day on days 6-15 of gestation. Maternal toxicity was seen at 9.9 and 21 mg/m3 (where several dam deaths occurred) and embryotoxicity (decreased pup weight, for example) occurred at 21 mg/m3. No teratogenic effects were seen at any exposure level (DuPont 1981; Staples 1984). On the basis of the preceding four teratology studies in experimental animals showing no unique hazard to the fetus, the DuPont AEL Committee has categorized C-8 as not likely to be a developmental hazard. Contacts For more detail on the studies utilized in these hazard determinations, or the basis for the current AEL for C-8, or a copy of the earlier classification letter (2-29-88) where C-8 was called a "small c" ('"weak animal carcinogen") and a "(D)" - not a developmental toxin, rat Haskell Laboratory. Company Sanitized. Does not contain TSCA CBl References American Conference of Governmental Industrial Hygienists. TLV^s and BEI^s. 1330 Kemper Meadow Drive, Cincinnati, OH 45240-1634,1997. Cook, J.C., et al. Toxicol. Appl. Pharmacol. 113(2'):209-217.1992. DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, HLR88181,1981. DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, HLR 1-82. 1982. J f f l ]BBMM|t DuPont Company, Haskell Laboratory forToxicology and Industrial Medicine, Unpublished Data. L< 1111 "nn *' 10-29-87. DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine Gilliland, F.D., et al. J. Occup. Med. 35(9):950-954.1993. 3M Company. EPA Submission. 8e Notification Letter. 10-11-93,1993 (AEL File 145). Riker Laboratory. Report No. 0681TR0110.1981 (J-5918). Riker Laboratory, Report No. 068ITB03 89.1982 (C-4124). Staples, R.E., et al. Fundam. Appl. Toxicol. 4 (3. Part U: 429-440,1984. Ubel, F.A., et al. Am. md. Hvg. Assoc. J. 41f8):584-589.1980. HJT:jmg 4 not contain.