Document 8OQ9LNBLkY3BYkZO0djX1pLVa

/)RX-OM58 fii* /TU'1 ,* < V Extent and Route of Excretion of Total Carbon-14 in Pregnant Rats 14 After a Single Oral Dose of Ammonium C-Perfluorooctanoate June 30, 1983 Conducted At: During: Conducted by: Riker Laboratories, Inc. Subsidiary of 3M St. Paul, Minnesota 55144 May to June 1981 S. J. Gibson and J. D. Johnson Report by: D. JohA^bn, MS Research Specialist Drug Metabolism Date Reviewed by: G. J. Conard, PhD Date Manager, Drug Metabolism 002907 - 2- Sununary Hormonal changes during pregnancy do not appear to cause a change in the rate of elimination of carbon-14 after oral administration of a single dose of ammonium 14C-perfluorooctanoate (mean dose, 15 mg/kg). At 8 or 9 days after conception, four pregnant rats and 2 nonpregnant female rats were dosed and individual urine samples were collected at 12, 24, 36, and 48 hours postdose and analyzed for carbon-14 content. Essentially all of the carbon-14 was eliminated via urine within 24 hours for both groups of rats. These data are consistent with previously reported data for nonpregnant rats. Thus, there is not likely to be any accumulation of 14C-perfluoro octanoate in tissues of pregnant rats during repeated dosing in teratology studies. Introduction In a previous study (1) and in published work (2), it has been reported that female rats excrete essentially all of a dose of 1^C-perfluorooctanoate within 24 hours after intravenous adminis tration. During the same time period, male rats excrete only 20% of the dose; male rats excrete 83% of the dose via urine by 36 days postdose. A similar gender difference has been reported for rats dosed with 1-aminocyclohexane carboxylic acid (ACHC); ACHC is excreted in urine about ten times faster for female rats than for male rats (3). The gender difference in elimination of ACHC is strongly influenced by hormone treatment; the rates of excretion between the sexes can be reversed by castration and treatment with estrogens (male rats) and by ovariectomy and treatment with testos terone (female rats). The effects of castration, ovariectomy, pregnancy, or treatment with sex hormones on perfluorooctanoate elimination are not known. If there were a shift from fairly rapid elimination to slow elimination during pregnancy as a result of a change in hormone state, the change in metabolism could have a bearing on teratology studies in rats. To provide data relevant to teratologic assessment with ammonium ^C-perfluorooctanoate pregnant rats were dosed with a single oral dose of ammonium 14C-perfluorooctanoate and the rate of elimination of carbon-14 in urine was measured. Methods Ammonium ^C-Perfluorooctanoate The carbon-14 label is at the carbonyl carbon. The specific activity of this lot of ammonium 1^C-perfluorooctanoate is 0.51 uCi/mg. Details of specific activity, chemical characterization, and radiochemical purity have been reported separately (4); the material was found to be suitable for metabolism studies. 002908 - 3- Animals Six female Charles River-- rats were bred at 8 or 9 days prior to dosing. The body weights ranged from 217-265 g, (mean, 238 g). The rats were conditioned to individual metabolism cages^for 24 hours prior to dosing. The rats were allowed free access to Purina-- ground chow and water before and after dosing. Dosing Solution 14 The dosing solution was prepared by dissolving ammonium C-perfluorooctanoate in 0.9% aqueous sodium chloride. The dosing solution was analyzed radiometrically and found to contain 1.82 uCi/2.0 ml or 3.58 mg/2.0 ml. Dosing The dosing solution was administered intragastrically to each rgt with a steel intubation tube fixed to a 3 ml plastic syringe (Monoject -- ). Each rat received 2.0 ml of solution; the mean dose was 15 mgAg Sample Collection Urine samples were collected for each rat from 0-12, 12-24, 24-36, and 36-48 hours postdose. Rats were killed at 8 days and necropsied to determine pregnancy. Liver, lung, kidney, and blood were collected from each rat. Plasma and red blood cells were prepared by centrifu gation and the tissue and plasma samples were stored frozen. Sample Analysis Duplicate 1.0 ml aliquots of urine were counted in Aquasol in a liquid scintillation spectrometer. Counting efficiency was determined for each sample by adding a known amount of internal standard and recount ing. Only urine samples were measured. Results and Discussion14 Of the six rats dosed with ammonium14C-perfluorooctanoate, two were found not to be pregnant. The results of the urine analysis from the four pregnant rats and the two nonpregnant rats are shown in Table 1. The urine data are expressed as percent of the total carbon-14 in urine. In terms of dose, these totals are 104-113% (mean, 109%). At 24 hours there does not appear to be any difference in the cumulative amount of carbon-14 eliminated via urine by pregnant rats as compared to the amount eliminated by nonpregnant female rat|^ Thus, the gender difference in rate and extent of elimination of C-perfluorooctanoate in rats (1,2) is not affected by pregnancy at 8 or 9 days after conception. In addition, since no radioactivity was detected in tissues of nonpregnant rats at 17 days after a single 17 m g A 9 dose (1), there is not likely to be any accumulation of perfluorooctanoate in plasma and tissues of pregnant rats during repeated dosing in teratology studies. ^Charles River Breeding Laboratories, Wilmington, Massachusetts. ^Purina Lab Chow, Ralston Purina Company, St. Louis, Missouri. SSherwood Medical Industries, Inc., Deland, Florida - 4- References (1) Johnson JD: Extent and Route of Excretion and Tissue Distribution of Total Carbon-14 in Male and Female Rats after a Single IV Dose of FC-143- C (Report) January 30, 1980. (2) Hanhijarvi H, Ophaug RH, and Singer L: The Sex-Related Difference in Perfluorooctanoate Excretion in the Rat. Proc. Soc. Exp. Biol. Me 171i50-55, 1982. (3) Janssen FW, Young EM, and Ruelius HW: Effect of Sex Hormones on the Disposition in Rats of 1-aminocyclohexane Carboxylic Acid, a Metabolit of a Semisynthetic Penicillin. Drug Metab. Disp., 4^:540-546, 1976. (4) Behr FE. and Johnson JD: Synthesis and Characterization of FC-143- C (Report) December 28, 1979. 002910 - 5- Table 1 Carbon-14 Content of Urine of Pregnan^and Nonpregnant Female Rats after a Single Oral Dose of Ammonium C-Perfluorooctanoate (Mean Dose, 15 mg/kg) Time Interval (hours) 0-12 12-24 24-36 36-48 _______________ Rat Identification Number____ _______ Pregnant Rats______ _____Nonpregnant Rats 2 4 5 7X 92.9 -- 88.6 92.0 93.5 91.8 1 87.0 6 69.2 X 78.1 6.8 10.5 6.7 5.2 7.3 0.2 0.7 0.9 0.8 0.7 0.1 0.3 0.5 0.5 0.4 12.2 0.4 0.4 29.6 1.0 0.3 20.9 0.7 0.4 a -Data are expressed as percent of total carbon-14 eliminated within 48 hours. (The mean percent of dose eliminated via urine was 109.7%+ 3.2). C02911 BEST COPY Hi'kl -6- Distribution List M. T. Case S. F. Chang G. J. Conard H. E. Freier F. D. Griffith D. F. Hagen L. I. Harrison J. D. Johnson E. G. Lamprecht J. D. Lazerte W. C. McCormick R. L. McQuinn R. A. Nelson/T.C. Coyne R. E. Ober W. H. Pearlson R. A. Prokop F. Ubel/D. Roach C. E. Weeks DM Central Files Technical Communications 218-3S-03 270-3S-05 270-3S-05 201-1S-07 220-2E-02 201-1W-29 270-3S-05 270-3S-05 270-3S-06 236-1B-2T 220-2E-02 270-3S-05 270-3A-01 270-3S-05 223-6S-04 236-2B-01 220-2E-02 270-3S-05 270-3S-05 201-2CN-12 I\o._ . 6 133tJ 002912