Document ZBkqzdooL4096aB9Dj7MZEEbp

Haskell Laboratory for Toxicology and Industrial Medicine AR226-3373 O ctober 30,1998 To: From : AG H askell Laboratory AG 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 D uPont Corporate Standard S18T (H azard Determ ination Process) for assessm ent and control o f carcinogenic and developm ental toxicity hazards. This hazard determ ination supersedes the previous letter dated February 29,1988. Ammonium perfluorooctanoate has now been categorized as not likely to be a hum an carcinogen and as not likely to be a developm ental toxin. A DuPont AEL (8-hr and 12-hour TW A) o f 0.01 m g/m 3 SKIN has been established to protect against all potential toxic effects o f C-8. , Some additional detail on studies involved in the preceding hazard determ ination follows: Company Sanitized. D oes not contain TSCA CBS -1- Carcinogenic Hazard Groups o f 120 m ale and 120 fem ale rats w ere fed diets containing either 30 (1.5 m g/kg/day) or 300 (15 mg/kg/day) ppm C-8 for up to 24 months, w hile a control group received only untreated food. C-8 associated changes included increased liver w eights, increased size o f liver cells w ith vacuolation o f the cytoplasm , and some evidence o f hepatocellular degeneration and necrosis. A low incidence o f liver tum ors also was seen at the 0 ,3 0 and 300 ppm levels - 0 o f 5 0 ,0 o f 50, and 1 o f 50 carcinomas in fem ales and 3 o f 50,1 o f 50 and 5 o f 50 carcinom as in m ales. The incidence o f nodular hyperplasia in the liver (fem ales 0 o f 5 0 ,0 o f 50, and 3 o f 50; m ales 1 o f 5 0 ,0 o f 50, and 2 o f 50) was also slightly increased, although none o f these incidences w ere statistically significant. A side from liver changes, the only other rem arkable effect was a slight increased incidence o f Leydig Cell adenomas (0 o f 50, 3 o f 50 and 7 o f 50 - the latter was statistically significant) (DuPont 1987). In a related m echanistic study (DuPont 1993; 3M 1993), 300 ppm o f C-8 was fed to rats for 24 m onths. Benign tum or incidences (adenomas) w ere elevated for liver (10 o f 76 vs. 2 o f 80 in controls), pancreas (7 o f 76 vs. 0 o f 80 in controls) and testis (8 o f 76 vs 0 o f 70 in controls). On the basis o f the preceding chronic studies, and several m echanistic studies, it was determ ined that C-8 belongs in a class o f chemicals referred to as peroxisom e proliferators. A review o f several well-known peroxisom e proliferators (drugs like clofibrate and ciprofibrate; chem icals like HCFC-123) showed that such chem icals have produced the sam e three benign tum or types seen in the C-8 chronic studies (Cook 1992). A ll three tum or types have been shown, directly or indirectly, to be associated w ith peroxisom e proliferation. Species specific differences for peroxisom e proliferation do exist w ith rats being high responders and other species (guinea pigs, prim ates and humans) being low -to-non-responders. Thus, these tum or types appear to have little or no biological significance to man. In two lim ited retrospective m ortality studies (Obel et al. 1980; G illiland 1993 and Olsen 1996), no causal relationship betw een C-8 exposure and cancer was seen. The ACGIH (1997) has also evaluated the toxicity/carcinogenicity profile o f C-8 and has categorized it as an A3 carcinogen, an animal carcinogen w ith little or no relevance to man. Based on the proceeding inform ation, the DuPont AEL Committee has categorized C-8 as not likely to be a hum an carcinogen. a Company Sanitized. D oes not contain TSCA CBI -2-  Developmental Toxicity Hazard Groups o f pregnant rats were gavaged at doses o f C-8 o f 1.5,50 or 150 m g/kg on days 6 through 15 o f gestation. M aternal toxicity was seen at 150 m g/kg only. N o evidence o f teratogenicity o r em bryotoxicity was seen at any dose (R iker Labs 1981). In another study (DuPont 1982), rats gavaged at one dose level (100 m g/kg) o f C-8 on days 6-15 o f gestation showed severe m aternal toxicity, (including several deaths), along w ith a slight increased o f fetuses w ith ossification sites on the first lum bar 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 o f the dams. Postpartum developm ent, growth rate, and viability o f pups were not affected. W hen groups o f pregnant rabbits were given by gavage 1.5,5 or 50 m g/kg C-8 in distilled w ater on days 6 through 18 o f gestation, m aternal toxicity (decreased body weight, for exam ple) w as seen at 50 mg/kg but no teratogenic effects w ere noted at any dose (Riker Labs 1982). In an inhalation study at C-8 doses o f 0 .1 4 ,1 .2 ,9 .9 o r2 1 mg/m3, rats were exposed 6 hours a day on days 6-15 o f gestation. M aternal toxicity was seen at 9.9 and 21 mg/m3 (w here several dam deaths occurred) and em bryotoxicity (decreased pup weight, for exam ple) occurred at 21 mg/m3. No teratogenic effects w ere seen at any exposure level (D uPont 1981; Staples 1984). O n the basis o f the preceding four teratology studies in experim ental anim als showing no unique hazard to the fetus, the DuPont AEL Committee has categorized C-8 as not likely to be a developm ental hazard. Contacts For m ore detail on the studies utilized in these hazard determ inations, or the basis for the current AEL for C-8, o r a copy o f the earlier classification letter (2-29-88) whore C-8 was called a "sm all c" ("w eak anim al carcinogen") and a "(D)" - not a developm ental toxin, H askell Laboratory. Company Sanitized. D oes not contain TSCA CBl -3-  References Am erican Conference o f Governmental Industrial H ygienists. TLVs and BEIs, 1330 Kem per M eadow D rive, Cincinnati, OH 45240-1634,1997. Cook, J.C., et al. Toxicol. Annl. Pharmacol. 113(21:209-217,1992. D uPont Company, Haskell Laboratory for Toxicology and Industrial M edicine, HL R 8818 1 ,1 9 8 1 . D uPont Company, H askell Laboratory for Toxicology and Industrial M edicine, H L R 1-82, 1982. DuPont Company, Haskell Laboratory fo^Tox^cology and Industrial M edicine, U npublished D ata. Letter fro m ^ M M M |J to y M M W M ^ | 10-29-87. DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine,'! 1993. G illiland, F.D ., et al. J. Occup. Med. 35(91:950-954,1993. 3M Company. HPA Submission. 8e N otification Letter. 10-11-93,1993 (AEL File 145). fPersonal Communie il 1111111 M M M B W 1996. R iker Laboratory, Report No. 0681TR011 0 .1981 (J-5918). R iker Laboratory, Report No. 068IT B 0389.1982 (C-4124). Staples, R.E., et al. Fundam. Appl. Toxicol. 4 (3. Part 11: 429-440,1984. Ubel, F.A ., et al. Am. Ind. H ve. Assoc. J. 41(81:584-589.1980. H JT :jm g .CbttipanySanitized. Does not contain T@CA.CBI -4-