Document 5bYNRZzdoLgjr3d0Vp4VYgMB4

B 10 - T E S T 1810 FRONTAGE ROAD NORTHBROOK. ILLINOIS 60062 REPORT TO 3M COMPANY 28-DAY ORAL TOXICITY STUDY FC-143 IN ALBINO RATS WITH P.O. NO. 7089088 SEPTEMBER 29, 1977 MT NO. 8532-10654 B 10 TEST -&6&tat&U&,.9,+W. 1810FRONTAGE ROAD NORTHBROOK, ILLINOIS 60062 September 29, 1977 Dr. J. E. Long Manager, Toxicology Services 3M Company - 3M Center St. Paul, Minnesota 55101 Dear Dr. Long: Re: IBT No. 8532-10654 - 28-Day Oral Toxicity Study with FC-143 (T-1742CoC, Lot No. 269) in Albino Rats P.O. No. 7089088 We are submitting herewith our laboratory report prepared in connection with the above study. Very truly yours, 19.7 AJ'F/fd A. J. Frisque President .fm&dsasBl10 T E S T ta&wAo" REPORT TO 3M COMPANY 28-DAY ORAL TOXICITY STUDY FC-143 IN ALBINO RATS WITH P.O. NO. 7089088 SEPTEMBER 29, 1977 IBT NO. 8532-10654 I. Introduction A material idendfied 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 establishfeeding levels for long-term studies in that species. This report presents the results of the experiment. YM&dA"riB 10 -T E 5 T 2 Ii. Summary A 28-Day oral toxicitystudy 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 firstweek of testing. No other mortalitiesoccurred 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 app arent 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 dilatationwas evident in the kidneys of a control male and a 30,000 ppm female. No other findings were noted. #aAahlaBt 10 -T E ST la4o"4144yxa 3 Treatment-related znorphologic changes were observed in the livers among all male and female test animals. The primary lesion consisted of focalto multifocalcytoplasmicenlargement (hypertrophy) of hepatocytes among -,nimals fed 300 ppm or less, and multifocalto diffuseenlargement of hepatocytes among animals fed 1,000 ppm or more. The severity and degree of tissue involvement was slightlymore pronounced among male test animals. The other changes described in the liver and kidneys were lesionsof naturallyoccurring diseases or related to the method of sacrifice. Respectfully submitted, INDUSTRIAL BIO-TEST LABORATORIES, INC. Study conducted by: Michele Metrick Michele Metrick, B.S. Technician Roftnt To.,dcity Report prepared by: Andrew J. LVarias, B.S. Group Leader Rodent Toidcity Report approved by: _,00-4,M" 41.Rgzc,0-4 Dennis W. Arnold, B.S. Acting Section Head, To3dcology Flor e K. KinosVta, Ph.D. Te cal Manager, olo -lX/Oy A"ar@rie M. Phillii;s,"Ph.D. Vice President and Director of Research Data Verified by Quality Assurance Unit Qlty Assurance Supervisor fd/cl Ym&dwd B 10 -T E 5 T lakodoi" YA= 4 M. Procedure A totalof 80 young (28 day old) Charles River 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-testperiod 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 millionparts of diet**. All animals were individuallyhoused with food and water available ad libitum. Daily observationsfor behavioralreactionsor mortalitieswere made. Animals were weighed and food consumption calculationswere made weekly for a 28-day period. At the finalsacrifice,a complete gross pathologicexamination was conducted on allsurviv-ingrats. Animals that died during the investigationwere also examined grossly. At the time of gross examination, a complete set of organs and other tissues was removed and preserved in a formalin solutionfor future histopathologicexamination. The weight of the liver of each sacrificedrat was determined and liverto body weight ratioswere calculated. Microscopic examination of the liversfrom allsacrificedrats was conducted. Also at sacrifice.5 ml of sodium heparinized blood and 10 g of whole liver (pooled) from the Control (OF ppm), T-IV (1,000 ppm) and T-V (3,000 pp m) groups was couected and quick frozen. The samples were submitted to 3M Company for analysis. Charles River Breeding Laboratories,Wilmington, Mass. Purina Rat Chow, Ralston-Purina Company, St. Louis, Missouri. lm&dtialB 10 -T E ST IA.4 5 IV. Results A. Mortalityand Reactions All gnimals fed either10,000 or 30,000 ppm died within the first week of testing. No other deaths occurred during the study. No unusual behavioral reactions were observed during the experiment. B. Body Weights Body weight data (Table I) indicatethatlevelsof 30 ppm were well toleratedby the rat. A marginal reductionin 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 significantlyreduced in a dose-relatedmanner. jm&daa B 10 T E S T tdwa&" lw- 6 Group and Dietary Level (ppm) Control (0) T-I (30) T-II (100) T-Ill (300) T-IV (1,000) T-V (3,000) T-VI (10,000) T-VII (30,000) TABLE I TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Body Weight Data Summary of Mean Values Body Weight Week: Sex 0 1 2 3 4 m 88 142 200 244 299 F 76 120 163 186 215 m 89 140 200 247 295 F 76 118 159 183 210 m 88 141 196 234 281 F 76 117 154 175 203 m 88 134 183 225 264 F 76 112 163 186 211 m 88 112** 147** 174** 201** F 76 115' 156 173 196 m 88 .90** 105** 119** 138** F 76 93** 126** 153** 171** m 88 - - - - F 76 - - - - m 88 - - - - F 76 - - - - 4-Week Total Weight Change (g/rat) 211 139 206 134 193 127 176 135 113 120 50 95 - Statisticallsyignificantdifferenceat the 95% confidence level. Statisticallsyignificantdifferenceat the 99% confidence level. All animals died during Week I of testing. ,#aAaAldB 10 -T E S T Yma 7 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 ev-identamong rats fed either 1,000 or 3,000 ppm. Ym&d,s&lBIO-TEST .1 8 Group and Dietary Level (ppm) Control (0) T-I (30) T-II (100) T-M (300) T-IV (1,000) T-V (3,000) T-VI (10,000) T-VII (30,000) TABLE II TEST MATERLKL: FC-143 28-Day Oral To3dcity Study - Albino Rats Food Consumption Data Food Consumption (g/rat/7days) Week: Sex la 2b 3 4 m 132 133 166 178 F 120 121 142 143 m 135 140 171 176 F 114 119 136 135 m 129 138 163 169 F 108 113 133 130 m 117 129 173 185 F 108 123 145 137 m 85 105C 128 142 F 103 114 122 124 m 67 74 92 102 F 75 91 117 115 m - - - - F - - - - m - - - - F - - - - 4-Week Average Food Consumption (g/rat/week) 152 132 156 126 150 121 151 128 115 116 84 100 - - All animals died. a = food consumption represents an 8-day interval. b = fc>odconsumption represents a 6-day interval. c = value represents 4 animals JoAaAwd B 10 -T E S T &&wAo" Yme. 9 D - Pathologic Studies 1. Gross PathologicFindings Gross pathologicfindings observed at time of the necropsy examination for sacrificedanimals and those that died consisted of the following: Group and Dietary Level - (ppm) Control (0) T-VI (10,000) T-VII (30,000) Animal Number and Sex 4M 68F* 78F* Tissue Kidneys Observation Pelvic dilatation- unilateral Kidneys Kidneys Numerous white foci in cortex and medulla - bilateral Pelvic dilatation- bilateral Died during the study. No other findings were noted during gross examination. 2. Organ Weights and Organ to Body Weight Ratios The results of the statisticaalnalyses conducted on the liverweights and liver to body weight ratiosare summarized in Table III. 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 similarto controlsas a result of severe body weight reduction. (31?()UP CONTROL I'-1 'I'1-1 1'-Ill T-IV i'-V TABLE III TEST MATERIAL: FC-143 28-DAY ORAL TOXICITY STUDY - ALBINO RATS FINAL SACRIFICE ORGAN WEIGHT AND RATIO DATA SUMMARY OF MEAN VALUES DI El'ARY LEVL-L (PPM) ORGAN - LIVER ORGAN WEIGIIT (G) MAI-ES FEMALES ()RGA14/13ODY tIElGI-ifRAT (G/100 G) MALES FF--MAI.E 0.0 30.0 100.0 300.0 1,000.0 3,000.0 12.978 17.858 16.442 20.824** 15.790 12.240 9.288 8.892 8.398 10.448 1 1.636* 12.488 4.3475 6.0434 6.3981 7.9514 7.8729 9. 8772** 4.304 4.240 4.133 4.979 5.950 7.308 STATISTICALLY SIGNIFICANT SIAI'IS'I'ICALI-Y SlGt4lFlCANT INIFRGROUP DIFFE[?ENCES AT TfiF 95% (P<.05) Co IN'FF.RGROUP Di FFERFTICFS Af TtiE 99'/Ol(P<.Ol ) Cot Yx4dv.1 B 10 -T E S T 3. Histopathological Examination The individual histopathologicliver changes are presented in Table IV. The histopathologicrenal changes are presented in Table V. The pathologists'statement is presented on the following page. Ym&d4ld B 10 T E S T Yo= 12 IIBT No. 8532-10654 3M Company July 7. 1977 I have completed a histopathologicalexamination of H & E stained sectionsof liverfrom controland test(Groups T-I, T-II,T-III,T-IV, T-V, T-VI, T-VII) rats of IBT No. 8532-10654. In addition,sections of both kidneys from two female testanimals (No. 68, Group T-VI, and No. 78, Group T-VII) were also examined since grossly visiblelesions were reported at time of necropsy. Treatment-relatedmorphologic changes in the liver were observed among all male and female test animals. The primary lesion consistedof focalto multifocalcytoplasmic enlargement (hypertrophy) of hepatocytes among animals in testgroups T-I through T-IIIand multifocalto diffuseenlargement of hepatocytes among animals in testgroups T-IV through T-VII. The lobular distributionof the hypertrophy was centrilobularto midzonal among those animals where the lesion was focalto multifocalwhereas the same lesionwas panlobular where the lesionwas diffusein distribution.The hypertrophy of hepatocytes was accompanied by acidophilicdegeneration and/or necrosis of scatteredlivercellswith no lobular distribution.The severityand degree of tissue involvement of the above lesions are slightlymore pronounced among male test animals. JoAmAid B 10 -T E ST 13 The other changes described in the liver and of the kidneys were lesions of naturallyoccurring diseases or relatedto the method of sacrifice. The individualliver flndings are summarized by sex, in Table IV and the renal lesions tabulatedin Table V. Reviewed and Approved by: fd ynaldo J. Arceo, M.D. "V"@@tafftaffPathologist Donovan E. Gordon, D.V.M., Ph.D. Diplomate, American College of Veterinary Pathology Group and Dietary Level (ppm) Control (0) T-1 (30) Animal Number and Sex Im 2m 3M 4M sm 6F 7F aF 9F 10 F 11 m 12 M 13 M 14 M Is m 16 F 17 P 18 F 19 F 20 F TABLE IV TEST MATERIAL: FC-143 28-Day Oral ToxicityStudy - Albino Rats Individual lfistopathologiLciver Changes liepatocellular flepalocellular Degeneration If pertrophy and/or Necrosis IF M D FM D Necrotic flepatille F Cytoplasmic Vacuolation Lipid Ilydropipic F F Lymphoid Infiltrations Periportal Sinusoid;l F F + + + + + + Bile Duct Proliferatio F +-++ + + +-++ + + + + + + +-++ +-++ +-++ ++ +-++ + + + + + + + + +-++ + + + + + + + + + 4 + + Group and Dietary Level (ppm) T-11 (100) T-111 (300) Animal Number and Sex 21 m 22 m 23 M 24 M 2s m 26 F 27 F 28 F 29 F 30 F 31 M 32 m 33 M 34 M 35 M 36 F 37 F 38 F 39 F 40 F TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rate Individual]fistopathologiLciver Changes liepalocellular Hepatocellulor Degeneration llyrertrophy and/or Necrosis IF M D FM D +-++ +-4+ +-++ +-++ +-++ + + + + + ++ +-++ +-++ + + + + + Cytoplasmic Necrotic Vacuolation flepatitis Lipid flydrophic F F F + +-++ +-++ + + + + Lymphold Infiltrations Periportal Sinumoidal F F + + + + + + +-++ ++ + 4+ + + + +-*+ + ++ + +-*+ + + + + + + + + + + Bile Prolife F + + Group and Dietary Level (ppm) T-IV (1,000) T-V (3,000) Anitnal Number and Sex 41 M 42 M 43 M 44 M 45 M 46 F 47 P 48 F 49 F 50 F 51 M 52 M 53 M 54 M 55 m S6 F S7 F 58 F 59 F 60 F TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats IndividuallfintopathologiLciver Changes flepatocellular liepatocellular Degeneration [I pertrophy and/or Necrosis PF M D FM D +-++ +-++ + + + +-++ + *+-+++ ++ ...... ...... ++ ++ 4i +-++ + +-++ + +-++ +-++ +-++ ...... +4-+*+ +++ ...... ++-+++ ++ ++ ++ Cytoplasmic Necrotic Vacuolation lfeeatilin 1.1-oldIlydrophTc- F F F + + Lymphold Infiltrations Periportal Si-n-u-a-oTT&T F F Bile Duct Proliferatio F + + +-++ Group and Dietary Level (ppm) Animal Number and Sex T-VI (10,000) T-Vil (30,000) 61 M* 62 M* 63 M* 64 M* 6S M* 66 F* 67 F* 68 F* 69 F* 70 F* 71 M* 72 M* 73 M* 74 M* 75 M* 76 F* 77 F* 76 F* 79 F* so F* TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral ToxicityStudy - AlbiiioRate IndividuallfistopathologiLciver Changes Hepatocellular liepatocellular Degeneration liypertrophy and/or Necrosis IF M D FM D + +-++ +-++ ++ +-++ + + +-++ +-++ + ++ ...... ...... ++-+f+ ...... ++ ++ +-*+ ++-+++ Necrotic liepatitin F Cytoplasmic Vacuolation Lipid flydrpphic p F ++ +-++ + +-++ + Lymphoid Infiltrations Periportal Sinueoidal F F + +-++ +-++ + + +-++ +-++ + + +-++ ...... ++ ...... ... ++-+++ ++-+++ ...... ...... ...... ...... ++ +-++ + ++ +-++ +-++ + Bile D Prolifer F Animal found dead. Grading System and Abbreviations + - Minimal In Severity 4+ - Mild in Severity *++=Moderate In Severity ....= Marked Severity F m Focal M = Mullifocal D = Diffuse Group T-VI T-VII Animal Number and Sex 68 F 78 F TABLE V TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Individual Histopathologic Renal Changes Findin&r Pyelonephritis, Acute, Multifocal-Bilateral Cyst, Cortical-Unilateral