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AR2 2 t>- SRPTT-6295.8, T-6316.4, T-6868.2, T-707U, T-7132.1 DT15-B 3M MEDICAL DEPARTMENT, CORPORATE TOXICOLOGY Title: Comparative Molecular Biology of PerfluorooctanesoIfonate (PEGS, 1-6295), N-ethyl peril tiorooctanesuIfonamido ethanol (N-EtFOSE, T-6316), N-Ethy! perfluoroocianesulfonamide (N-ltFOSA, T-6868), Perfiuorooctanesulfonamido acetate (FOSAA, T-7071), and/or Perfluorooctanesulfonamide (FOSA, T-7132) of in Rats and Guinea Pigs following Oral dosing. AMENDED Final Report Date: July, 16 2004 Study Numbers. T-6295.8, T-6316.4, T-6868.2, T-7071.1, T-7132.1 Strategic Toxicology Study Number: DT-15-B Sponsor: 3M Specialty Chemicals Division 3M Center, Building 236 Saint Paul MN 55133-3220 Study Location(s): 1. 3M Strategic Alternative Toxicology Laboratory 3M Center, Building 270-SB-181, Saint Paul, MN 55133-3220 2. University o f Minnesota, Duluth Dept, o f Biochemistry and Molecular Biology School o f Medicine 10 University Drive Duluth, MN 55812-2496 Study Director: Andrew M. Seacat Ph.D., DABT Toxicology Specialist 3M Medical Dept. Corporate Toxicology and Regulatory Services Study Toxicologist: Deanna Luebker M.S Senior Toxicologist 3M Medical Dept. In-Life Start Date In-Life End Date In-Life Start Date In-Life End Date In-Life Start Date In-Life End Date Protocol: Protocol: Amendment #1: Amendment #1: Amendment #2: Amendment #2: 11/16/1998 11/20/1998 03/01/1999 03/05/1999 m usam i 02/23/2001 c JJ7 SRPT 1-62.95.8 T-6316.4, T-(*SoS.2f T-707U, T-7132.1 DT15-B The purpose tor this amendment was to change the conclusion drawn ui the summary that Lin Xu and Drag Anders wrote in Appendix 6E (page 59) which read; The original statement. "These data showed that FOSA was consistently identified as a metabolite of PFOS, whether PFOS was administered directly or formed as a metabolite, but the source of the amino group is not readily apparent."' Was changed to read; "These data showed that FOSA was consistently identified as a metabolite of PFOS, but that the source of the amino group is not readily apparent," The rational lor these changes were that the original conclusion was not directly supported by the data presented in this study. That conclusion was not entirely correct because all o f the administered compounds, besides PFOS, have a sulfonamide group within the parent compound. Therefore, the likely source of the amino group for sulfonamide moiety containing compounds would be the parent compound itself. There is quantitative evidence in these studies suggesting that the perfluorooctanesulfonamides were metabolized first to PFOS followed by metabolism of that PFOS back to a sulfonamide. The only evidence for a possib le metabolism of PFOS to FOSA came from foe PFOS dose groups, not the periluorooctanesuifonamido derivative parent compound dose groups. Furthermore, in two out o f three independent studies analyzed at Rochester, the control group liver samples had a high background of FOSA, suggesting possible contamination of the liver samples. Therefore, as stated, the conversion of PFOS to PFOSA would have to be verified by further studies. Dr Anders is in agreement with the amended conclusion stated above. 238 SRPT T-6295.8, T-6316.4,1-6868.2, T-70? 1.1. T-7132.1 DT15- Signatures; Final Repon AnicndiiieM ffi prepared by, M iS / -l , i / / / Andrew M. Seacat. PhD, DABT Study Director ' i L ( O'f Date SEPT T-6295.iL T-6316.4. 1-6868.2, T-7071.1, T-7132.1 DT15-B E. Technical Report: Liver Fluorocarbon Metabolites - University of Rochester. Title: Summary of Quantitative Analysis o f Fluorocarbon Metabolites in Rat Liver Samples Lin Xu and iVl. W. Anders This is a brief summary of the analysis of liver samples from rats given a range o f fluorocarbons. The parent and metabolites of the fluorocarbons were determined in liver samples by LC-MS/MS. The results are presented below. Three groups o f liver samples were analyzed: The first group (Group I) consisted of livers from control rats, from rats given 40 mg/kg/day FOSA orally, and from rats given 160 mg/kg/day FOSAA (M556) orally. The concentrations of parent compounds and their metabolites in livers were measured (fable )). The data show that PFOS was the major metabolite found in the livers o f rats given FOSA; FOSA iV-glucuronide was identified as a minor metabolite. Two metabolites were identified in the livers of rats given FOSAA (M556): PFOS and FOSA. It is noteworthy that the control animals (1RQ0742, 1R00743, and 1R00743) contained significant concentrations of FOSA. A parallel analysis of livers from Fischer 344 rats maintained in the University of Rochester Vivarium did not show detectable concentrations of FOSA. The second group (Group 2) of rats was treated in November, 1998. Group 2 contained livers trout control rats, from rats given 40 mg/kg/day PFOS orally, from rats given 40 mg/kg/day /Y-EtFOSE alcohol orally, and from rats given 40 mg/kg/day A-EtFOSA orally. The concentrations of parent compounds and identified metabolites are shown in Table 2. The data show that livers from rats given PFOS contained parent compound PFOS; FOSA was also found in these samples. The livers from rats given A-EtFOSE alcohol contained several metabolites. The major metabolites were A-EtFOSAA, PFOS, and FOSAA (M556), The minor metabolites were FOSA, FOSE alcohol, A-StFQSE alcohol glucuronide, and FOSA iV-glucuronide. PFOS was the major metabolite in livers from rats given /V-EtPOSA; FOSA and FOSA .V-glucuronide were identified as minor metabolites. In contrast to Group 1, the livers from control rats did not contain detectable concentrations of parent compounds or metabolites. The third group (Group 3) was treated in March, 1999. Group 3 contained livers from control rats, from rats given 40 mg/kg/day PFOS orally, and front rats given 160 mg/kg/day A-EtFOSE alcohol orally. The concentrations o f die chemicals and metabolites are shown in Table 3. As with Group 2, PFOS and low concentrations of FOSA were identified in livers from rats given PFOS. In the livers of rats given A'EtFOSE alcohol, fV-EtFOSAA. PFOS, and FOSAA (M556) were identified as major metabolites, and the minor metabolites identified were FOSA, FOSE alcohol, A-EtFOSE alcohol glucuronide, and FOSA Nglucuronide. Similar to Group 1, control animals showed detectable hepatic concentrations of FOSA. Discussion: These data allow- conclusions about the overall metabolic fate o f the fluorocarbons studied (see Scheme), but do not allow- inferences about the exact routes of metabolite formation. FOSA was consistently identified as a metabolite of PFOS, but the source of the amino group is not readily apparent. Whatever its route of formation, FOSA was metabolized to FOSA A`-glucuronide. A'-EtFOSE alcohol gives rise to a range o f major and minor metabolites. FOSE alcohol could ansc from the A'-deethylation o f A-EtFOSE alcohol, and A-EtfOSAA could arise by the oxidation o f the alcohol to the carboxylic acid. Glucuronidation o f the parent A-EtFOSE alcohol would give the observed A'-EtFOSE alcohol glucuronides. FOSAA could be formed by the A?-deethylation of A-EtFOSAA or by the oxidation of FOSE alcohol, or both. FOSA could be formed by the A-deethylation of A'-EtFOSA or by the removal o f the carboxymethyl group o f FOSAA as glyoxylate. FOSA A-glucuronide may be formed by the glucuronidation o f FOSA. 3 -< t6 Revised page 59