Document 5LM07JjZvgBBKD5dgbvdEvw4z

AR226-1532 33 PP Screei evel cumul -- \ r \ sment perfluorinated alkyl cids on human health Rich Purdy RECEIVED OPPT NCIC 2003 OCT-9 PM9:30  Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity. Office of Pesticide Programs, US EPA. Ep a 2002. Guidance for Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of action. EPA 1999. Cumulative chemicals should have same "mechanism of toxic action" and "site of toxic effect". Or in other words: Cumulative chemicals have a common mechanism of toxicity. Common mechanism of toxicity pertains to two or more chemicals that cause a common toxic effect(s) by the same or essentially the same, sequence of major biochemical events (i.e., mode of action) Proposed Cumulative Class: Perfluorinated Acids Currently including: PFOS PFOA aaFFnn((ddCCFFiitt22ss))yxhhCSooOOmm32oollooggss:: Justification 1 Common mechanism of action Uncoupling of oxidative phosphorylation is apparently the primary molecular mechanism of toxicity. References: Langley AE, Pilcher GD. 1985. Thyroid, bradycardie and hypothermic effects of perfluoro-n-decanoic acid in rats. Journal of Toxicology and Environmental Health 15:485-491. Schnellmann G. 1990. The Cellular Effects of unique pesticide Sulfluramid (N-ethylperfluorooctanesulphonamide) on rabbit renal proximal tubules. Toxic. In vitro 4:71-76. Wallace KB, Starkov A. 1998. The effect of perfluorinated arylalkylsulfonamides on bioenergetics of rat liver mitochondria. US EPA OPPT AR226-0167 Starkov AA, Wallace KB. 2002. Structural determinants of fluorochemical-induced mitochondrial dysfunction. Tox Sci 66:244 252. PFAs shown to be uncouplers PFOS FOSA (perfluorooctane sulfamide) PFHS (perfluorohexane sulfonate PFOA PFDA (perfluorodecanoic acid) Justification 1b: Data supporting uncoupling as a mechanism Poor body mass gain efficiency is symptom of the uncoupling of oxidative phosphorylation. Most PFA toxicity studies report loss of weight, poor growth, or poor food conversion efficiency can be calculated from data. References Covance. 2000.104-week dietary chronic study and carcinogenicity study with perfluorooctane sulfonic acid potassium salt (PFOS: T-6295) in rats. US EPA OPPT AR226-0956. Case MT. 1999. Oral (stomach tube) Developmental toxicity of PFOS in rabbits. US EPA OPPT AR226-0949*York et al 1999; 3M 1987. Two year oral (diet) toxicity / carcinogenicity study of fluorochemical FC-143 in rats. US EPA OPPT AR225-0437 Campbell SM, Lynn SP, Beavers JB.1993a. Lithium Perfluorooctane Sulfonate [6861D11] A dietary LC50 study with the Northern Bobwhite, Wildlife International Ltd. Project No.: 319-101. Sponsor: SC. Johnson & Son, Inc. ---. 1993b. Lithium Perfluorooctane Sulfonate [6861D11] A dietary LC50 study with the Mallard, Wildlife International Ltd. Project No.: 319-102. Sponsor: SC. Johnson & Son, Inc. Cook JC, Murray SM, Frame SR, Hurtt ME. 1992. Induction of Leydig Cell Adenomas by Ammonium Perfluorooctanoate: A Possible Endocrine-Related Mechanism. Toxicology and Applied Pharm 113:209-317. Borges T, Robertson LW, Peterson RE, Glauert H P. 1992. Dose-related effects of perfluorodecanoic acid on growth, feed intake and hepatic peroxisomal beta-oxidation. Archives of Toxicology 66:18-22. George ME, Andersen ME. 1986. Toxic Effects of nonadecafluoro-n-decanoic acid in rats. Toxicology and Applied Pharmacology 85:169-180. References continued Haughom B, Spydevold 0 . 1992. The Mechanism Underlying the Hypolipemic Effect of Perfluorooctanoic acid (PFOA), Perfluorooctane sulphonic acid (PfoSA) and Clofibric Acid. Biochemica et Biophysica Acta 112:65-72. Goldenthal EI, Jessup DC, Geil RG, Mehring JS. 1978a. Ninety-day subacute Rhesus monkey toxicity study, with Fluorad fluorochemical surfactant FC95. US EPA OPPT AR226-0137 Goldenthal EI, Jessup DC, Geil RG, Jefferson ND, Arceo RJ. 1978b. Ninety-day subacute rat toxicity study, with Fluorad fluorochemical surfactant FC-95. US EPA OPPT AR226-0141 Hansen K. 1999a. Laboratory report: analysis of fluorochemicals in wild bird livers. US EPA OPPT AR226-0079 Langley AE.1990. Effects of perfluoro-n-decanoic acid on the respiratory activity of isolated rat liver mitochondria. J. Toxicol Environ Health 29:329-336. Thomford PJ. 1998. 4-Week capsule toxicity studies with perfluorooctane sulfonic acid potassium salt (PFOS; T-6295) in Cynomolgus monkeys [includes draft final report, cell proliferation report, protocol and memorandum from Marvin Case re histopathology review of liver tissue. US EPA OPPT AR226-0144. Justification 2 Common sites of toxic effects seen Similar effects on tissues are observed across the class Thymus atrophy Thyroid hormone decrease Thyroid mass increase Liver enlargement References Goldenthal EI, Jessup DC, Geil RG, Mehring JS. 1978a. Ninety-day subacute Rhesus monkey toxicity study, with Fluorad fluorochemical surfactant FC95. US EPA OPPT AR226-0137*. Goldenthal EI, Jessup DC, Geil RG, Jefferson ND, Arceo RJ. 1978b. Ninety-day subacute rat toxicity study, with Fluorad fluorochemical surfactant FC-95. US EPA OPPT AR226-0141* Covance. 2000.104-week dietary chronic study and carcinogenicity study with perfluorooctane sulfonic acid potassium salt (PFOS: T-6295) in rats. US EPA OPPT AR226-0956*. Van Rafelghem MC, Baskin MJ, Bruner RH, Andersen ME 1987. A timecourse study of perfluoro-n-decanoic acid pathology in male Fischer-344 rats. Fund & Appl Toxicol 11:503. Van Rafelghem MC, Inhorn SL, Peterson RE. 1987. Effects of perfluorodecanoic acid on thyroid status in rats. Toxicology and Applied Pharmacology 87:430-439. Van Rafelghem MC, Mattie DR, Bruner RH, Andersen ME. 1987. Pathological and hepatic ultrastructral effects of a single dose of perfluoron-decanoic acid in the rat hamster, mouse, and guinea pig. Fund and Appl Tox 9:522-540. References, continued Langley AE, Pilcher GD. 1985. Thyroid, bradycardie and hypothermic effects of perfluoro-n-decanoic acid in rats. Journal of Toxicology and Environmental Health 15:485-491.29-336. Case MT. 1999. Summary PFOS rat two-generation reproduction study. US EPA OPPT AR226-0569 Metrick M, Marias AJ. 1977. 28-day oral toxicity study with FC-143 in albino rats. US EPA OPPT AR225-0445* Thomford PJ. 1998. 4-Week capsule toxicity studies with perfluorooctane sulfonic acid potassium salt (PFOS; T-6295) in Cynomolgus monkeys [includes draft final report, cell proliferation report, protocol and memorandum from Marvin Case re histopathology review of liver tissue. US EPA OPPT AR226-0144 Thomford PJ. 2000. 26-week capsule toxicity study with perfluorooctane sulfonic acid potassium salt (PFOS: T-6295) in Cynomolgus monkeys. US EPA OPPT AR2260957 Seacat AM, Hansen K. 2000. Analytical laboratory report from the 26-week capsule toxicity study with Perfluorooctanesulfonic acid potassium salt (T-6295) in Cynomolgus monkeys. US EPA OPPT AR226-0981. Thomford PJ 2001. 26-week capsule toxicity study with ammonium perfluorooctanoate in Cynomolgus monkeys. US EPA OPPT AR226-1052a Structurally Similar F(CF2)xSO, F(CF2)yCO2 Reasons for Thymus Thymus effects seen in every study in which it was evaluated. No NOEL yet established, so could be most sensitive toxic response. In early development thymus health is extremely important. References for Study Used Thomford PJ. 2000. 26-week capsule toxicity study with perfluorooctane sulfonic acid potassium salt (PFOS: T-6295) in Cynomolgus monkeys. US EPA OPPT AR226-0957 Seacat AM, Hansen K. 2000. Analytical laboratory report from the 26-week capsule toxicity study with Perfluorooctanesulfonic acid potassium salt (T-6295) in Cynomolgus monkeys. US EPA OPPT AR226-0981 Observations of Atrophied Thymus Control Females 0 of 4 Males 1 of 4 Low 4 of 4 2 of 4 Mid 4 of 4 3 of 4 High 3 of 4 2 of 2 Concentration PFOS in sera of low dose females at end of study: 11.4 - 17 ppm Identification of fluorochemicals in human sera. III. Pediatric participants in a group A Streptococci clinical trial investigation. Olsen GW, Burris JM, Lundberg JK, Hansen KJ, Mandel JH et al. 2002. US EPA OPPT AR226-1085. Chemical Perfluoro sulfonates C6 C7 PFOS C9 CIO Perfluorofatty acids C6 C7 C8, PFOA C9 CIO Cll C12 C13 C14 C15 C16 Sum Perfluorinated acids: Cone, ppm Female rat sera NOELS for PFOS and PFOA PFOA: 0.15 mg/l PFOS: 5.3mg/l Reference: Metrick M, Marias AJ. 1977. 28-day oral toxicity study with FC-143 in albino rats. US EPA OPPT AR225-0445 Belisle J.1978. FC-143 analysis of serum samples from rats from 28 and 90-day studies. US EPA OPPT AR2250442 Case 1999. Summary PFOS rat two-generation reproduction study. US EPA OPPT AR226-0569 Chemical C6 sulfonate C7 sulfonate PFOS C9 sulfonate C10 sulfonate C6 fatty acid C7 fatty acid C8, PFOA C9 fatty acid C10 fatty acid C11 fatty acid C12 fatty acid C13 fatty acid C14 fatty acid C15 fatty acid C16 fatty acid High Cone, ppm Median Cone, ppm 0.50 0.00^ 9 0.22 9 0.03 99 99 99 9 0.03 9 0.00^ 99 99 99 99 99 99 99 99 Perfluorodecanesulfonate (PFDS) estimated to be equal to PFOS Rational: Detected in samples where PFOS levels are close to limits of detection. Reference: Hansen K. 1999. Laboratory report: analysis of fluorochemicals in wild bird livers. US EPA OPPT AR226-0079. Hansen K.1999. Analysis of FCs in samples of children's sera. US EPA OPPT AR226-0961 Perfluorodecanoic acid (PFDA) estimated from PFOA level Based on bioaccumulation factor (>500 times that of PFOA) and the relative level in a dominate product, Zonyl BA. References: Hansen K. 1999. Report of data for exploratory 28-day oral toxicity study in rats: telomer alcohol, telomer acrylate, PFBS, PFHS, PFOS. US EPA OPPT AR226-0951 duPont material safety data sheet on Zonyl BA Concentration (ppm) in rat liver PFOA PFDA C12 Dav 1 0.16 1.69 1.20 0.117 0.029 Dav 14 0.016 1.36 1.20 0.085 0.035 Dav 28 <.003 2.24 0.81 0.101 0.036 *Gavage telomer alcohol mixture for 28 days. Stopped dosing on day1 Half-lives of PFOS and PFOS in Sera Rats Humans PFOA 4.8 days 4.4 years PFOS 7.5 days 8.7 years Reference: Gibson SJ, Johnson JD. 1979. Absorption of FC-143-14C in rats after a single oral dose. US EPA OPPT AR226-0455 Gibson SJ, Johnson JD. 1979. Absorption of FC-95-14C in rats after a single oral dose. US EPA OPPT AR226-0007 Burris JM, Lundberg JK, Olsen G, Simpson C, Mandel J. 2002. Determination of serum half-lives of several fluorochemicals. US EPA OPPT AR226-1086 C12 and C14 perfluoro fatty acids estimated from PFDA Reference: Mabury, S. 2002. Fascinating fluoro facts of perfluorinatedalkyl carboxylates and sulfonates. SETAC 2002 meeting presentation. C9, C11, C13 and C15 estimated to be same as homolog with one less carbon. Reference: Mabury, S. 2002. Fascinating fluoro facts of perfluorinatedalkyl carboxylates and sulfonates. SETAC 2002 meeting presentation. Estimated Concentration of Perfluorinated Acids in Sera of 2-year-old Girls. Highest Measured C h e m ica l Conc. ppm Perfluoro sulfonates C6 0.50 PFOS 0.22 C10 ND Perfluoro fatty acids C8, PFOA 0.03 C9 ND C10 ND C11 ND C12 ND C13 ND C14 ND C15 ND Estimated Median Highest Measured Conc. ppm Conc. ppm 0.62 0.004 0.22 0.03 0.18 ND 0.04 0.004 0.04 ND 12 ND 10 ND 19 ND 15 ND 25 ND 20 ND Estimated M e d ia n Conc. ppm 0.005 0.03 0.02 0.005 0.005 1.4 1.3 2.3 1.8 3.0 2.0 Highest Estimated Measured Highest C hem ical Conc. ppm Conc. ppm Perfluoro sulfonates C6 0.50 0.62 PFOS 0.22 0.22 C10 ND 0.18 Perfluoro fatty acids C8, PFOA 0.03 0.04 C9 ND 0.04 C10 ND 12 C11 ND 10 C12 ND 19 C13 ND 15 C14 ND 25 C15 ND 20 Sums: 102 Level causing thym us atrophy<11.4 Median Estimated Measured Median Conc. ppm Conc. ppm 0.004 0.03 ND 0.005 0.03 0.02 0.004 ND ND ND ND ND ND ND 0.005 0.005 1.4 1.3 2.3 1.8 3.0 2.0 12