Document 7dM2Eq1nDQzQJxDX5wbwboK8

6 all 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, Subsidiary of 3m St. Paul, Minnesota Inc. 55144 May to June 1981 S. J. Gibson and J. D. Johnson Report by: D. Jo on, MS Research ND'/peocrcial ist Drug Metabolism Date Reviewed by: G. J. Conard, PhD Manager, Drug Metabolism Date -2- Summary 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 mgag) - 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 non@regnant rats. Thus, there is not likely to be any accumulation of 4C-perfluorooctanoate 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 14C-perfluorooctanoate within 24 hours after intravenous administration. 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 r-arboxylic 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 testosterone (female rats). The effects of castration, ovariectcmy, 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 14C-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. Methc>ds Ammonium 14C-Perfluorooctanoate The carbon-14 label is at the carbonyl carbon. The specific activity of this lot of ammonium 14C-perfluorooctanoate is 0.51 liCi/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. -3- Animals Six female Charles River a 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 b dosing. The rats were allowed free access to Purina- ground chow and water before and after dosing. Dosing Solution The dosing solution was prepared by dissolving ammonium 14 C-perfluorooctanoate in 0.9% aqueous sodium chloride. The dosing solution was analyzed radi(xnetrically 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 rat with a steel intubation tube fixed to a 3 ml plastic syringe (Monoject @c-). Each rat received 2.0 ml of solution; the mean dose was 15 mg/kg. sample Collection Urine samples were collect ed 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 centrifugation and the tissue and plasma samples were stored frozen. Sample Analysis 0 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 recounting. only urine samples were measured. Results and Discussion 14 Of the six rats dosed with ammonium C-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 ratf, Thuse 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 mg/kg 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. bl?urina Lab Chow, Ralston Purina Company, St. Louis, Missouri. ESherwood Medical Industries, Inc., Deland, Florida -4- References (1) Johnson JD: Extent and Route of Excretion of Totil Carbon-14 in Male and Female Rats FC-143--@C (Report) January 30, 1980. and Tissue Distribution after a Single IV Dose of (2) Hanhijarvi H, Ophaug RE, and Singer L: The Sex-Related Difference in Perfluoroc>ctanoate Excretion in the Rat. Proc. Soc. Exp. Biol. Me 171:50-55, 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 14 and Johnson JD: Synthesis and Characterization of FC-143- C (Report) December 28, 1979. -5- Table 1 Carbon-14 Content of Urine of Pregnan@.and Nonpregnant Female after a Single Oral Dose of Ammonium C-Perfluoroc>ctanoate (t4eanDose, 15 mg/kg) Rats Time Interval (hours) 0-12 12-24 24-36 36-48 Rat Identification Number Pregnant Rats 2 4 5 7 iE 92.92 88.6 92.0 93.5 91.8 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 Nonpregnant Rats 1 6 87.0 69.2 78.1 12.2 29.6 20.9 0.4 1.0 0.7 0.4 0.3 0.4 2Data 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). -6- Distribution List M. T. Case S. P. Chang G. J. Conard H. E. Freier F. D. Griffith D. P. 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 DH Central Files Technical Communications 218-3S-03 270-3S-05 270-3S-05 201-lS-07 220-2E-02 201-IW-29 270-3S-05 270-3S-05 270-3S-06 236-lB-21 220-2B-O2 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 oLr _31 OLO,