Document zZ6wzn8ggZ8ZoQxBkzq4q7g3

ft R W 6 - O M H 5 SrtduAfoud BIO-TEST laJymJjwM,, She. 1810 F R O N T A G E R O A D N O R TH B R O O K . ILLINOIS 60062 REPORT TO 3M COMPANY 28-DAY ORIANLATLFOBCXIN-I1CO4I3TRYATSSTUDY WITH P.O. NO. 7089088 SEPTEMBER 2 9 , 1977 IBT NO. 8532-10654 001687 9w3u 6&iUlL BIO - T EST JPcrfyyujJ&ueA. 9n c. 1810 F R O N T A G E R O A D N O R TH BR O O K. ILLINOIS 60062 September 29, 1977 DMra.naJg. erE,. TLooxnigcology Services S3Mt. CPoamulp,anMyin-ne3sMotaCen5t5e1r01 Dear Dr. Long: Re: PIFBC.OT-1. N43No.o(.T8-5713078249-1200C868o5C4, -Lo2t8-NDoa.y 2O69ra)l iTn oAxilcbiitnyo SRtuatdsy -with We are submitting herewith our laboratory report prepared in connection with the above study. Very truly yours, AJF/fd A. J. Frisque President 001688 StiduilUlal B I O - T E S T JalotatauMi REPORT TO 3M COMPANY 28-DAY ORAL TOXICITY STUDY WITH FC-143 IN ALBINO RATS P.O. NO. 7089088 SEPTEMBER 2 9 , 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. 001689 Qdffniifasd B I O - T E S T J aloH tfoiiU, 9hc. 2 n . 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 anim als 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 w eight 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. 001690 jndiU hlal B I O -T E ST la& otaiotlei, hc. 3 Treatment-related morphologie 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 le ss, 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: MTMeiiccchhhenellieeciMaMneettrriicckk, B .S . Report prepared by: RGoroduepnt LTeoaxdiecrity Report approved by: DAcetninnigs SWe.ctAiornnoHldea, dB, .TSo. xicology DVBaiircreercitPeorrMeso.ifdPeRhnetilsleaiapnrsdc,hPh.D . DQautaadiVtyerAifsiseudrabnyce Unit fd/cl 001691 U nduihlal B I O - T E ST Ja 6o*afo i*&, Htte. 4 III. Procedure * A total of 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-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, a 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 examina tion 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. ) * Charles River Breeding Laboratories, Wilmington, Mass. ** Purina Rat Chow, Ralston-Purina Company, St. Louis, Missouri. 001692 Undudhial B I O -T E ST JaiM afoUU, Sue. 5 IV. Results A. Mortality and Reactions All animals fed either 10,000 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) 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. ) G01693 UnJudblel BI O- T EST Jtaio/naionisi, 9mc. 6 TABLE I TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Body Weight Data Summary of Mean Values GrDoiueptaraynd (Lpepvmel) Control (0) (T3-0I) (T1-0I0I) T-IH (300) T-IV ( 1 , 000) (3T,0-V00) Sex FM MF M F M F MF MF 0 1 BodWy2eWeke:ight 3 4 8786 114220 200 163 214846 229159 8796 111480 200 159 247 183 295 210 8786 111471 196 154 213754 228013 88 76 113124 . 116833 212856 221614 88 76 111152** 115467** 174** 173 201** 196 8786 9903**** 110256**** 111593**** 113781**** ( 1T0-,V00I0) MF --- - 8786 - - -- T-VII (30,000) M F 88 - - - - 76 ' *** SSttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee aatt tthhee 9995%% ccoonnffiiddeennccee lleevveell.. - All animals died during Week 1 of testing. TotC4(ag-hlW/arWneaegtek)eight 211 139 123046 112973 113756 111203 5905 - - G01694 Sndd4ii>Uetl B I O - T E ST fa & 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 evident among rats fed either 1,000 or 3,000 ppm. G01695 ttdLuhlal BI O- TEST 2aia>iai&>a&, Sue. 8 ) TABLE 0 TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Food Consumption Data Group and D(Lpieeptvmaerl)y Sex la Fo(ogd/rCa2Wtbo/en7esku:dma3pytsi)on 4 4-Week ACCvogen/rrsaaugtm/ewpFetieookon)d Control ( 0) FM 112302 112313 114626 114738 152 132 (T3-0I) FM 111354 111490 113761 117365 115266 (T1-0I0I) MF 112098 113183 116333 116390 115210 (T3-0m0) MF 111078 112293 117453 118357 112581 (1T,-0IV00) FM 10853 110154c 112228 114224 111156 T-V (3,000) FM 67 75 74 91 11972 111052 10804 ( 1T0-,V00I0) FM - -- - -- - - T -v n (30,000) FM -- -_ -- -- -- -- CT* P c -===Affvoolalooldduaneccimoornneapssluusrmmedsppeiettniidoot.snn 4rreeappnrrieemsseeannlsttss. aan68-d-daayyinintetrervvaal,l. G01696 Suduihial BI O- T EST fa MatoAs, Sftc. 9 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: D iGe tra(oprupypmLa) envdel Co(n0t)rol ( 1T0-,V00I0) (3T0-,V00H0) Animanadl NSuemx ber 4M 68F* 78F* Tissue Kidneys Kidneys Kidneys Observation Pelvic dilatation - unilateral Ncourmteexroaunsdwmheitdeulfloaci- inbilateral 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 statistical analyses conducted on the liver weights and liver to body weight ratios are 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 similar to controls as a result of severe body weight reduction. G01697 jLsai-oia w w GROUP CONTROL T-I T-I I T - I 11 T-I V T-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 ORGAN - LIVER DIETARY LEVEL ( PPM) ORGAN WEIGHT (G) MALES FEMALES ORGAN/UODY WEIGHT RATIO (G/100 G) MALES FEMALES 0 .0 30.0 100.0 300.0 I ,000.0 3,000.0 12.978 17.858* 16.442 20.824** 15.790 12.240 9.288 8.892 8.398 l 0. 448 11.636* 12.488** 4.3475 6.0434 6.3981 7.9514 7.8729 8.8772** 4.3046 4.2407 4.1333 4.9793 5.9507 7.3080 * STATISTICALLY SIG N IFIC A N T INTERGROUP DIFFERENCES AT THE 95% (P< .0 5 ) CONFIDENCE LE V E L. * * STATISTICALLY SIG N IFIC A N T I NTF.RGROUP DIFFERENCES AT THE 99% ( P<. 01 ) CONFIDENCE LEV EL. o 001698 yndudhlal BI O- T E S T J a&MaitvUsA, Une. 11 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. 001699 tultubal B I O - T EST J att&iai&&t, Une. 12 IBT No. 8532-10654 3M Company July 7, 1977 I have completed a histopathological examination of H & stained sections of liver from control and test (Groups T-I, T-II, T-HI, T-IV, T-V, T-VI, T-VH) 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-VII) 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-III and multifocal to diffuse enlargement of hepatocytes among animals in test groups T-IV through T-VII. 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. 001700 S*idu&Ulal BI O- T EST Jafcvtaf&iJai, Hue. 13 'i 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 se x , in Table IV and Reviewed and Approved by: fd DDVoiepnteloorvmiananatreEy, . APGamtoherrodilcooangn,y CDo.Vlle.Mge.,ofPh.D . 001701 DGiert(oaprupypmLa)envdel Co(n0t)rol (T3-0l) aNAnundmimSbaeelxr 12461S13890 MMMFMMFFFF 111111123564 MMMMFM 21110789 FFFF TEST TABLE IV MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Individual Histopathologic Liver Changes Hepatocellular 1 HF y p eMrtro pDh y aHnDFdeep/goaertMnoNecreealcDtliuroolnasris HNeeFpcarotittiics LCFViypatiocdupolHalsaymtdiForiocnphic P e rFipIonLfryitmlatlrpahtioSoidninsuFs o id a l 4 44 4 4 44 4-44 44 4 ++4~4 4 4~44 *4 + 4 4 4 4-44 4-44 4-44 44 4-44 4 4 4 4 4 4 4 4-44 "4 4 4 4 4 44 4 4 44 4 PrBoillieFfeDrautciot n m eEdxutlrlaary HemaFtopoiesis 1 4 4-44 4 4-44 4 4 4 4 4 4 4 4 4-44 4-44 4 4 4-44 4 4-44 OHmi-n4 K. ir?t V OO o B I O- T E S T Jc 001703 DGiertoauryp Laenvdel (ppm) (T10-I0I) (T3-010II) aNAnundmimSbaeelxr 2222222213245768 MMMFMMFF 2390 FF 34333333331320456789 MMMMMFFFFF TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Individual Histopathologic Liver Changes HHeyppaetortcreolpluhlyar |F M D aHnDFdeep/goaertMnoeNcreealcDtliuroolnasris HNeeFpcarotittiics Cytoplasmic LFVipaicduoHlaytdiForonphic P e rFi pI noLfryitlamtlrpaht iooSindinsuFs o id a l 4" 44 4-44 4-44 4-44 4+ + 4 +4+44-4-44-4-44-44 4 4 4 4 4 4 4-44 4 4 4-44 4 4 44 44 4 44 4-44 4 4 - 4 4 4 4 4 4 44 44 44 4-44 44 4-44 4 4 +-+4 4 4 4 4 4 P rBoillieFfeDrauticot n HemmeEadtxuotplrloaaireysis FI 44 4 4 4 4 4 4 4 4 4-44 4 4 4 4-44 4 4 O' DGierto(apurpypmLa)envdel T-IV (1,000) (3T,0-V00) aNAnundmimSbaeelxr 4444444413246578 MMMMMFFF 4590 FF 5512 MM 555555345678 MMMFFF 6509 FF TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Individual Histopathologic Liver Changes H e p a to c e llu laHr |Hf y pertroph md y epaanDtFodec/goeelrMlnuNelraearctDiroonaia HNeeFpcarotittiics LCFViypatiocdupollallyasmdtiFroiocnphlc P e rFi pi noLfryitlmatlrpaht iooSindinsuFs o id a l 4~44 4-44 4-44 4-44 4-44 4 4 +4 - 4 4 4 + -+ + 44 44-444 44-444 44 / 4-+4+ 4-44 4-44 4 4 4 4-44 4- 4-44 +-4- +-4-44-4.4. 4-44 4-44- +-4-4- 44-444 44-444 444 44-444 44-444 44 44 44 4-44 4-44 4 PrBoillieFfeDrautciot n Extra HemmeadFtuolploaireysis 1 4 4-44 4 4-44 .4 4 4 4 4 4-44 4 IP o r oh* DGierto(apruyppmLa)envdel (1T0-,0V0I0) (3T0-,V00U0) NaAnundmimSbaeelrx 66666666761234659708 MMMMFMFFFF********** 77777778771243567089 MMMMMFFFFF********** TABLE IV continued TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rata Individual Histopathologic Liver Changes 1HHFeyppaetMortcreolpDluhlyar aHnDFdee/pgoaertMnoNecreealctlDiuroolnasris HNeepFcarotittiics LCFViypatiocdupoIlallyasmdtlFroiocnphic P e rFipinoLfryitlmatlrpaht iooSidninsuFs o id a l 4 4-44 4-44 44 4-44 4 4 4-44 4-44 4 444 44 44-444 4 4--4+4 4+ 44-444 44 44 4-44 44-444 44 4-44 4 4-44 4 4 4-44 4-44 4 4 4-44 4-44 4 4 4-44 4 44-444 44 44-444 444 44-444 44-444 44-444 44-444 44-444 44-444 4 44 4-44 44 4-44 4-44 4 4 * Animal found dead. Grading System and Abbreviations O -A + +++++ ===s= MMMMiiaolnrddikmeeirandalteSSineeinvvSeeSerriivettyyevreirtiyty oA FMD === FDMoiufcflatuilsfoecal PrBoillieFfeDrautciot n HemmeEadtxoutplrloaaireysis F _ |_ oa O <m/> r 4 4 4 H-4-* BIO-TEST Jc TABLE V TEST MATERIAL: FC-143 28-Day Oral Toxicity Study - Albino Rats Individual Histopathologic Renal Changes Group Animanadl NSuemx ber Finding T-VI 68 F Pyelonephritis, Acute, Multifocal" Bilateral T-VII 78 F Cyst, Cortical - Unilateral Grade 2 -3 P O o -I oCi 00