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Co ARI2G-O WS \ Industrial 1B 810 I -FRTOENO TSATGELaRbOoArDu.tsuies, Ine. NORTHBROOK, ILLINOIS 60062 REPORT TO 3M COMPANY . 28-DAY ORAL TOXICITY STUDY WITH IN ALFBCI-N1O43RATS .0. NO. 7089088 ) SEPTEMBER 29, 1977 IBT NO. 8532-10654 01687 Industrial 1B 810 I -FRTOENO TSATGELaRbOoArDatoies, Ine. NORTHBROOK. ILLINOIS 60062 September 29, 1977 Dr. J. E. Long 3MaMnaCgoemrp,anTyoxi- co3lMogCyenSteerrvices St. Paul, Minnesota 55101 Dear Dr. Long: Re: IBT No. 8532-10654 - 28-Day Oral Toxicity Study with FPC.-O1.43No.(T-7108794028C8oC, Lot No. 269) in Albino Rats - We are submitting herewith our laboratory report prepared in connection with the above study. ) Very truly yours, ATF A. J. Frisque President 01688 Industrial BVO TEST Lakoratorish, Inc. y REPORT TO 3M COMPANY 26-DAY ORAL TOXICITY STUDY WITH IN ALFBCI-N1O43RATS P.0. NO. 7083088 SEPTEMBER 29, 1977 IBT NO. 8532-10654 ) I. Introduction A material identified as FC-143 (T-1742CoC, Lot No. 269) was obtained from 3M Company for the purpose of conducting a 28-day pilot feeding study in rats to establish feeding levels for long-term studies in that species. This report presents the results of the experiment. 01689 InduBsVtOr-iTEaSlT LaboratoriInsc,. 2 3 IO. Summary A 28-Day oral toxicity study was conducted in which groups of 5 male and 5 female Charles River strain albino rats were fed FC-143 at dietary levels of 0, 30, 100, 300, 1,000, 3,000, 10,000 or 30,000 ppm. All animals fed 10,000 ppm or more died during the first week of testing. No other mortalities occurred during the study. No unusual behavioral reactions were evident. Body weight gains among animals fed 1,000 ppm or more were significantly reduced in a dose-related manner. Slight reductions were noted among males (not females) fed 300 ppm while a marginal reduction in body weight gain was noted in rats fed 100 ppm. Body weight gains among animals fed 30 ppm compared favorably to those of the controls. ) Food consumption among animals fed up to 300 ppm was similar to that of the controls. Reduced food intake was apparent among rats fed either 1,000 or 3,000 ppm. The liver weights among males fed 30 ppm or more, and among females fed 300 ppm or more were elevated as a result of treatment. The absolute liver weights among males fed 3,000 ppm only appear to be similar to controls as a result of severe body weight reductions. Female liver weights among lower test groups were similar to those of the controls. Gross pathologic examination revealed white foci in the cortex and medulla in the kidneys of a 10,000 ppm female. Pelvic dilatation was evident in the Kidneys of a control male and a 30,000 ppm female. No other findings were ' noted. 01690 Industrial BVO -TEST Laborslorias, Inc. Ts Treatment-related morphologic changes were observed in the livers among all male and female test animals. The primary lesion consisted of focal to multifocal cytoplasmic enlargement (hypertrophy) of hepatocytes among animals fed 300 ppm or less, and multifocal to diffuse enlargement of hepatocytes among animals fed 1,000 ppm or more. The severity and degree of tissue involvement was slightly more pronounced among male test animals. The other changes described in the liver and kidneys were lesions of naturally occurring diseases or related to the method of sacrifice. Respectfully submitted, INDUSTRIAL BIO-TEST LABORATORIES, INC. Study conducted by: Report prepared by: Report sproved vy: Michele Metrick Michele Metrick, B.S. TReocghennitciTaonxicity . Amal 00 Rare] JHansg AGrnodurpewLeJa.der flarias, B.S. Rodent Toxicity Dennis W. Arnold, B.S. Acting Section Head, Toxicology J Led, e FTelgohrpglieealKM.anaKgienors,hfta, Ph.D. 1 BViFieice PreMs.idPehnitlliapnsd, Ph.D. Director of Research Data Verified by Quality Assurance Unit ohror/ Quaflty Assurance Supervisor fase 01691 Indsbiol BVO-TEST Laboraloiat, Inc. Co. ) II. Procedure A total of 80 young (28 day old) CharlesRiver CD Albino Rats*, 40 of each sex, was randomly divided into 8 groups of 5 male and 5 female animals each. Animals were allowed a 7 day pre-test period to adjust to the caging system. Groups were fed 0 (control), 30, 100, 300, 1,000, 3,000, 10,000 or 30,000 parts of FC-143 per million parts of diet. All animals were individually housed with food and water available ad libitum. Daily observations for behavioral reactions or mortalities were made. Animals were weighed and food consumption calculations were made weekly for a 28-day period. At the final sacrifice, 3 complete gross pathologic examination was conducted on all surviving rats. Animals that died during the investigation were also examined grossly. At the time of gross examination, a complete set of organs and other tissues was removed and preserved in a formalin solution for future histopathologic examination. The weight of the Liver of each sacrificed rat was determined and liver to body weight ratios were calculated. Microscopic examination of the livers from all sacrificed rats was conducted. Also at sacrifice, 5 ml of sodium heparinized blood and 10 g of whole liver (pooled) from the Control (0 ppm), T-IV (1,000 ppm) and T-V (3,000 ppm) groups was collected and quick frozen. The samples were submitted to 3M Company for analysis. ) *** CPhuarrilneasRaRtivCehroBwr,eeRdailnsgtoLna-bPourraitnoariCeos,mpWainlym,ingStt.onL,ouMiass,s.Missouri. 601692 Industiol BAO TEST Luboratorst, Jn: s ) IV. Results A. Mortality and Reactions All animals fed either 10,000 oF 30,000 ppm died within the rst week of testing. No other deaths occurred during the study. No unusual Sehavioral reactions were observed dusing the experiment. B. Body Weights Body weight data (Table I) indicate that levels of 30 ppm were well tolerated by the rat. A marginal reduction in body weight gain was seen among rats fed 100 ppm. Males (not females) fed 300 ppm showed slightly reduced body weight gains. Body weight gains among animals fed 1,000 ppm or more were significantly reduced in a dose-related manner. J 01693 Industrial BNO -TEST Loboralorist, Inc. 6 "Grew amd DLieevtaerly (ppm) Control 0) T-1 30) TI (100) T-m (300) Tv (1,000) T-V (3,000) T-VI (10,000) Tv (30,000) `TABLE I TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Body Weight Data Summary of Mean Values BodWyeeWke:ight Sex 01 2 3 4 M 88 142 200 264 299 F 7% 120 163 186 215 M 89 140 200 247 295 F 76 118 159 183 210 M 8 11 19 234 28 F 7% u7 154 175 203 M 88 13a 183 225 264 F 76 u2 163 186 211 M 8 112% lamer 17am 200% F 76 us 156 m3 196 M 88 90%* 105%* 119%* 138% F 76 93% 126%% 153%x 171% M 88 - - - - F 76 - - - - M 88 - - - - F 7% - - - - iWex TotCahlaWnegieght (g/ran) am 139 206 134 193 127 176 135 13 120 50 95 - - - * Statistically significant difference at the 95% confidence level. ** Statistically significant difference at the 99% confidence level. - All animals died during Week 1 of testing. ) 01694 Industrial BVO -TESTLaboratories, Inc. C7 C. Food Consumption Normal food consumption data was obtained from animals fed up to 300 ppm FC-143 during the 28-day feeding period (Table II). Reduced food intake was evident among rats fed either 1,000 or 3,000 ppm. 01695 Industrial BIO -TEST Loksraloriet, Ine. :8 ) TABLE I TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Food Consumption Data Group and Dietary Level (ppm) Sex Control M F Food Consumption (g/rat/T days) Week: 1a 2b 3 4 132 133 66 18 20 121 142 14 Week Average Food Consumption Cg/rat/week) 152 132 T-1 G0) M F 135 M0 1m 17 me we 136 13 156 126 T-1 100) M F 129 18 163 169 08 13 133 130 150 121 T-m M ur 129 113 18s 200) F 108 123 145 137 151 128 T-Iv (1,000) M F 85 105 128 142 103 4 122 124 us 16 T-V M 67 "2 102 8 (3,000) F 75 a ur 1s 100 Tv M (10,000) F --- - Pzp T-v M -- - - (30,000) F -- - - - All animals died. . a b = = food food consumption consumption represents represents an 8-day interval. a 6-day interval. = value represents 4 animals. 01696 Industiol BVO TEST Laboratorist,Inc. Ty \ D. Pathologic Studies 1. Gross Pathologic Findings Gross pathologic findings observed at time of the necropsy examination for sacrificed animals and those that died consisted of the following: DGiretoawrypwLedvel (ppm) Gontrol v1 (10,000) (3T0o,v000) Animal Number and Sex Po carn Ta * Died during the study. Tissue Kidneys Kidneys Kidneys Observation Pelvic dilatation - unilateral Numerous white foci in cortex and medulla - bilateral Pelvic dilatation - bilateral No other findings were noted during gross examination. 2. Organ Weights and Organ to Body Weight Ratios The results of the statistical analyses conducted on the liver weights and liver to body weight ratios are summarized in Table Il. Treatment-related increases were noted in the liver weights among males fed 30 ppm or more, and among females fed 300 ppm or more. The absolute liver weights among males fed 3,000 ppm only appear to be similar to controls as a result of severe body , weight reduction. G01697 as es MTEL FG-143 .:I 20a Oral TOXICITY STUDY - ALBINO RATS Fw sacairce x g ORGAN WEIGHT AND RATIO DATA summary of Mea vaLuzS onan - Liven P sow SLfEia n oweeol aI anna0SE)a me conor 0.0 ere eam eum ese Tw-1n 3100.0.00 low 17.858" wm 8.892 eww 6.0434 ew 4.2407 -=u 3L0o0.w0 o sme 20.824% 1n0e.4s48e nasser 7.9514 4.9793 ad 3,000.0 12.240 12.488 8.8772* 7.3080 g2 +3 SSTIARTTIISSTHIEOLNELYY SSIIOUUHFIEGNUTE IaIsIEiRaONnOUsS DDIIFFEEEEIREFIIGGEESS AATT TTUEE 3939% ((pbeeo.n0y cCoONeEiIoDmEnIcCeE e15vveELr. 25 2 Industrial BIO-TEST Laboratories,Inc. n 3. Histopathological Examination The individual histopathologic liver changes are presented in Table IV. The histopathologic renal changes are presented in Table V. The pathologists' statement is presented on the following page. 01699 Industrial BIO TESTLabonalovias,Ine. C1 I3BMTCNoom.pa8n5y32-10654 July 7, 1977 1 have completed a histopathological examination of H & E stained sections of liver from control and test (Groups T-I, T-1I, T-HI, T-IV, T-V, T-VI, T-VID rats of IBT No. 8532-10654. In addition, sections of both kidneys from two female test animals (No. 68, Group T-VI, and No. 78, Group T-VI) were also examined since grossly visible lesions were reported at time of necropsy. Treatment-related morphologic changes in the liver were observed among all male and female test animals. The primary lesion consisted of focal to multifocal cytoplasmic enlargement (hypertrophy) of hepatocytes among animals in test groups T-I through T-IIl and multifocal to diffuse enlargement of hepatocytes among animals in test groups T-IV through T-VIL. The lobular distribution of the hypertrophy was centrilobular to midzonal among those animals where the lesion was focal to multifocal whereas the same lesion was panlobular where the lesion was diffuse in distribution. The hypertrophy of hepatocytes was accompanied by acidophilic degeneration and/or necrosis of scattered liver cells with no lobular distribution. The severity and degree of tissue involvement of the above lesions are slightly more pronounced among male test animals. J 01700 Industrial BIO TEST Loboratorias, Ine. 13 Y The other changes described in the liver and of the kidneys were lesions of naturally occurring diseases or related to the method of sacrifice. The individual liver findings are summarized by sex, in Table IV and the renal lesions tabulated in Table V Reviewed and Approved by: @ ait aPassnalogRioeset AE rrr DVDieopenlrooivmmaaantre,yE.APGmaoenrrodiloconag,ny CDo.lVl.eMg.e,ofPh.D. 01701 rt et St PA ae ee Sm, ER tiiE e S. R bn i Sae i eeTr wo : .. 5 4 aemvau oify e-- e --e-- tr-- ee -- sm---------------- 2832 x- s3 eewr om 8 8-ODr Taesyty Std AineBae a din Hgatiti Live Change CmG e m--_ -- f5na ppeaetTDpem, mn TBG EEe om am mmm SE o i [EI gi Eps 8n ` -- .DoE. : : wow on : _-- 55z22 5: g [TTST EaT Fei td Wg tr con 3z8 Cra m, -- E fn tE e be BwEep i Gbe e lOeEan gm an, EN anoi gmoo a . -: _-- 325g2 5 = 00 Ort Testy say - Ate tt 5 TS_ rTi , EjoET ea e nhtdn Wotpuelege ver Chen C Dl wip o GiEEee mglme aa owlm-- n i4o ii zo . SpE woe ZI ------ g mE he, BB v4e0ss =MMarokeddSeeivrenrSiaetvyetriety =Ditivee. 3 353 ~ TABLE V = TEST MATERIAL: FC-143 ? ] 2I-ndDiavyiduOarlalHiTsotxoipcaltthyolSotgiucdyRe-naAllbCihnanRgaetse mn ToGroup and ESemxme Finding Grade vi wr Pyeloncphritis, Acute, Multifocal Bilateral 2-3 --- vi we Cyst, Cortical Unilateral OO" 233 = & 5