Document 9LJx884mRprg9p6KvG2bLqayp

AR226-2780 FOR DD FONT USE ONLY Copies Co: Haskell E. I. du Pone de Beaours and Co., lac. Laboratory for Toxicology and Industrial Elkton Road, P. 0. Box 50, Newark, Delaware 19711 Medicine HASKELL LABORATORY REPORT NO. 61-82 MR N0.^ TestedHaskell No7Other Material Octanoic acid, pentadecafluoro-, aianonium sale (carbonyl C-labelled) 14,129 Hone Code's" Study laic tatted/Completed ^.Material Sut Polymer Products Department D-11070 PLACEMTAL TRANSFER OF ^C-LABELLED C-8 IN THE RAT Sunaary: Radioactive C-labelled perfluorooctanoate (C-8) was transferred from,macernal blood to the fetuses of pregnant rats. A single 10 ag/kg dose of C-labelled C-8 was administered orally by gavage to the pregnant daos on the 19th day <.- gestation. Maternal blood and placenCal levels of C-labelled C-8 increased between 2 and 4 hours after doelne rhen decreased between 4 and 8 hours after dosing. The ug equivalents of C-labelled C-8 per mL of maternal blood were approximately 12 pg/oL at 2 hours, 20 fg/mL at 4 hours and 12 pg/mL at 8 hours after dosing. The fetal levels were 0*7 pg/g tissue at 2 hours, 3 p/g tissue at 4 hours and approximately 3 pg/g tissue at 8 hours after dosing. All other tissues from the pregnant dans were esaaloed for C activity and exhibited trends sisilar to Bateroal blood increasing betaaen 2 and 4 hours and decreasing between 4 and 8 hours after dosing. The data reflected only ulnimal impedence for transfer of C-labelled C-8 from maternal blood to the fetuses. Introduction; The study v&s designed to evaluate placeneal transfer of C-labelled C-8 in the rat. Data regarding placental transfer of C-8 nay be useful for evaluating data from ceratological studies. Procedures: The 14 C-labelled C-8 was obtained from 3M Company as the ssssoniua salt. The cospound "as labelled on the carbonyl position and had a specific activity of 0.5 uCi/mg. The compound was 70 percent straight chained C-8 and 30 percent branched isomers. The radiolabslled compound was readily water soluble, therefore wate was used as the dosing vehicle. The dose was formulated immediately prior to dosing. The pregnant female rats Company Sanitized. Does not contain TSCA CB! - received a single 10 mg/kg dose of C-labelled C-8 orally by gavage on the 19th day of gestation. The rats were Individually placed In glasa etabolisa units loaediaCely after dosing. Two rats were sacrificed at each time interval of 2, 4, and 8 hours after dosing. Rats were sacrificed by exposure to chlorofona. Blood was drawn by cardiac puncture at sacrifice and refrigerated in beparinized Cubes. The placentas, umbilical cords and fetuses were then removed and.; dissected froa each other and weighed. The umbilical cords and placentas were individually placed into paper combustion cones and fetuses stored frozen., The following organs and tissues were also excised, weighed, and frozen: heart, lun^s, liver, spleen, kidneys, G. I. tract, amnionic sac, brain, and fat, skin, and muscle saffiples^ The^carcasses were also weighed and frpnen. Urine and fecal samples excreted between dosing and sacrifice were collected and frozen. The uetabolism units were washed successively with dilute detergent, water, and acetone. The washes were collected and stored in Nalgene* .bottles. The placentas, umbilical cords and fetuses were oxidized in their entirety using a Packard Model 306 Sample Oxidizer. Samples of,the Maternal tissues, carcass and feces were also oxidized and analyzed for C activity by liquid scintillation counting with an Intertechnique SL4000 Scintillation Counter. The urine and cage washes were analyzed directly by liquid scintilJation counting. Results: The data in Table 1 were expressed as pg equivalents of C-labelled C-8 per gram vet weight of tissue for the placentas and fetuses. The ug equivalent levels in the placentas increased between the 2-and 4-hour sacrifice points sad then decreased between the 4-and 8-hour sacrifice points. The placencal values were higher than the corresponding fecal values at each time point, however, the magnitude of the difference was ouch greater at the 2-hour point than at the 4-and 8-hour points. The fetal levels were approximately 0.7 p7 equivalents/gram wet weight at the 2-hour point, then increased substantially (4 fold increase) by the 4-hour point to an approximate average value of 3 ug equivalents per gram wet weight. The fetal values remained constant between the 4-and 8-hour points. The number of viable fetuses per animal had no effect on i.he ug equivalents observed. The average values for ".he placencal and fetal ug equivalents were compared to the corresponding maternal blood values The data in Table 2 show thri maternal pg equivalent levels increasing. from 14 to approximately 22 ug livalents/iaL between cbe 2-and 4-hour sacrifice points. The blood le\ 3 then decreased to approximately 12 pg equlvalents/mL beween che 4-and 8-hour tine points. The most revealing data were the maternal blood/fecal ratios for each animal at the different time points. The ratio dropped substantially from an average of 22 to 8 between the 2-and 4-hour sacrifice points. These data reflected the greater fold increase in the fetal fig equivalent concentrations compared to the increase observed in the maternal blood. The ratio also diminished somewhat between the 4-and 8-hour time points reflecting the decrease in maternal blood levels while fetal levels remained unchanged. - 2 Coffipanjf'SaniSFzs'd,Dsss nc^ co^arn 7SC-5 CBi The fetal aod placencal /ig equivalent -oncentrations were also compared In Table 3 to other tissue levels. The kidneys aod liver had the highest pg equivalent level regardless of the tiae pcinEo The ug equivalent levels ia all tissues and organs tended to increase between 2 and 4 hours then decreased between 4 and 8 hours. The fetal levels were lower at t-he 2-hour sacrifice than other tissues presented in Table 3. By the 4-hour sacrifice the fetal concentrations were sioilar to the concentrations observed in the spleen, heart, and fat. The fetal levels were sliilar Co the heart and lungs at the eight-hour sacrifice. The magnitude of the jig equivalent: conceacration increase was far greater in the fetal tissue than any other organ or tissue examined. Conclusion: Placenta! transfer of C-labelled C-8 was shown to occur after adainiscration of & single orel dose of C-labelled C-8. The comparison of fetal levels of C-8 at 2 and 4 hours relative to the concentrations observed in the maternal blood, placenta and other organs revealed evidence cf resistance to placencal transfer of C-8. However, by 4 hours the fetal concentrations of C-8 increased substantially more than all ether organs and tissues esfisined. In contrasc to other tissues exaained, C-8 levels in the fetuses did not decrease between ^ and 8 hours. The peak fecal C-8 concentrations were. similar in magnitude to the levels observed is the spleen, heart, lungs and fat. Significant quantities of C-8 can therefore be transferred from the placenta to the fetus with the placental barrier offering minimal resistance to transfer. Synonyms: o o 'o o ABaonium perfluorooctrnoace C-8 CAS Registry No.: 3825-26-1 company Sanitized. Does not contain TSCA CW Report by: ^ ^ JA / / ^L^. Jl^dJ^^ IStephen G. Hundlei[ Research Biocheaiac Approved by: SGH:tae:WF:3.2 .Date Issued: May Her ore No. 61-82 Q 18, 1982 /C^/y^y^v-. ^alph y, narfl^mvo^ V SecCiou Supervisor Biocheaical Toxicology . ^ ^ ^ M W ^ K ' ^ .-r.'.zlnTSCACa TABLE 1 ^C-Labelled C-8 Concentrations in Placenta* and Fetuses froa Pregnant Rats Dosed Once Orally ith [ C] C-8 jatf and Tine Point Bat fl 2 hours Bat fZ 2 hours ug Equivalents Per Gram Wet Weight* Placentas Fetuses (Ave. + S.D.) (Ave. S.D.) 4.8 ^ 0.5 C^)*1 0.6 ^ 0.1 (13) 6.1 ^ 0.3 (4) 0.7^ 0.1 (4) Rat fl Bat f2 4 hours 4 hours Rat fl Rat f2 8 hours 8 hours 10.1 j: 0.6 (6) 7.0^0.5 (8) 5.1 t 0.6 (11) 4.9 + 0.4 (13) 3.6^ 0.4 (6) 2.4^: 0.1 (9) 3.5^ 0.4 (11) 2.5 + 0.2 (13) * ug Equivalents were based on 1.1 x 106 DPM/mg as the specific ^C activity for ("C] C-8. a Numbers in parentheses indicate the number of placentas or fetuses. 5 - Company Sanitized. Does not contain TSCA CD; TABLE 2 Caparison of cbe pg Equivalents of "C-Lefcelled G-8 la the Maternal Blood, Placerta and fetus Sat & Tine point Rat fl Rat f2 2 hours t hours ug Equivalents/g (OL) Maternal Blood Placenta* Fetug 14.7 4.8 0.6 14.2 6.1 0.7 Maternal Blood/ Fetal Ratio 23 21 Ra H 4 hours 25.3 10.1 3.6 7 Bat f2 4 hours 19.4 7.0 2.4 8 Bat fl 8 fcoare 13.4 5.1 3.5 4 Bat f2 8 ^ours 11.7 4.9 2.5 5 * The placenta and fetus values are the averages fror the total ncber of placentas and fetuses in each animal. - 6 . .poe-^-^31"'^^00' ^P^S^11^-1-0^ TABLE 3 Tissue Liver Kidneys Heart Lungs Skin Spleen Fat Placenta* Fetus* ][nternal DisiCributlon <of ^C-I^belled C-8 ie Prefifoanc Female Bats FolLwing a Single Oral Dose ^ Equivalents {^Cl C-8 Per (,raa Wet Weight (a) 2 Hours Sat H Rat f2 4 Hours Rat fl Hat f2 8 Hours Rat fl Hat f2 17.5 14.3 21.9 13.3 9.5 8.5 20.2 22.8 40.1 21.2 17.0 14.6 3.9 4.6 5.5 3.9 3.1 2.8 5.8 5.4 3.3 3.7 9.8 7.0 7.1 4.8 3.9 3.0 2.8 1.9 2.0 1.8 3.2 2.0 1.3 1.3 0.9 1.9 4.8 6.1 5.1 2.0 10.1 7.0 2.8 0.6 5.1 4.9 0.6 0.7 3.6 2.4 3.5 2.5 a The pg equivalents were based upon the specific activity of 1* 4C, -labelled C-8. 1.1 x 10 DPM/Bg. * The values for the placenta and fetus are averages froa the cocal auaber of placentas and fetuses found in each pregnant rat.