Document jyXqZBz2kj0XYZnv9BJ08mvvQ

Industrial TEST Laboratories Inc. @ TABLE OF CONTENTS I. Introduction... ... ... II Summary III Procedure A. Method of Exposure Experimental Animals B. Exposure Apparatus and oe . Mortality and Reactions Individual Body Weight Data E. Hematologic Studies oo Pathology IV Results A. Mortality . . B. Body Weight Data . C. Hematology . D. Gross Pathologic Observations E. Histopathologic Findings . 14 . 14 14 14 ~~. . 16 . 18 26 45 45 Protected Document to Protective order JNJ 000060425 Industrial TEST Laboratories Inc. ' @ DIAGRAM TABLE I TABLE II TABLE III TABLE IV TABLE V TABLE VI TABLE VII TABLE VIII _ TABLE IX TABLE X TABLE XI TABLE XII TABLE XIII LIST OF TABLES AND DIAGRAMS PAGE NUMBERS DUST SHAKER MECHANISM 6a OUTLINE OF TEST CONDITIONS 7 MORTALITY 17 BODY WEIGHT AND WEIGHT CHANGE DATA SUMMARY OF MEAN VALUES 19 INDIVIDUAL BODY WEIGHT AND WEIGHT CHANGE DATA ~- MALES 20 INDIVIDUAL BODY WEIGHT AND WEIGHT CHANGE DATA - FEMALES 23 HEMATOLOGIC DATA MALES 27 HEMATOLOGIC DATA - FEMALES HEMATOLOGIC DATA - MALES HEMATOLOGIC DATA - FEMALES HEMATOLOGIC DATA - MALES HEMATOLOGIC DATA - FEMALES SUMMARY OF HISTOPATHOLOGICAL FINDINGS INDIVIDUAL HISTOPATHOLOGICAL FINDINGS ww' ww 36 39 42 47 50 Protected Document to Protective order JNJ 000060426 Industrial TEST Laboratories Inc. REPORT TO JOHNSON & JOHNSON RESEARCH FOUNDATION DAY SUBACUTE DUST INHALATION TOXICITY STUDY WITH CORNSTARCH POWDER BASE - BPC 4030-106 IN GOLDEN SYRIAN HAMSTERS APRIL 19 1977 IBT NO 8562-09039 I. Introduction A white powder identified as Cornstarch Powder Base was received from the Johnson & Johnson Research Foundation for the purpose of con- ducting a day subacute dust inhalation toxicity study using golden Syrian hamsters as experimental animals Protected Document to Protective order JNJ 000060427 Industrial TEST LaboratoriIencs. | 2 ' II Summary A subacute dust inhalation toxicity study was conducted wherein 2 groups of 60 golden Syrian hamsters 30 males and 30 females each were exposed to the dust of Cornstarch Powder Base 7 days per week for a total of 88 consecutive exposures The low test T and the high test T groups received exposures of 43 minutes and 133 minutes per day respectively An additional group of 60 hamsters 30 males and 30 females served as untreated control animals for comparison purposes and received exposures to clean dry air -40 dewpoint only Below is an outline of the target and actual dust concentrations @ Group T II Exposure Length 43 minutes 133 minutes Target Analytical Respirable Dust Concentrations M 1.50 1.50 Actual Analytical Respirable Dust Concentrations mg 1.53 1.56 Observations were made with respect to incidence of mortality reactions displayed and body weight effects Hematologic studies were conducted on 10 males and 10 females from each group prior to inhalation exposure and again at 44 and 86 days At the conclusion of testing all surviving animals were sacrificed and complete necropsy examinations were performed A complete set of representative tissues and organs was obtained from each animal and preserved in 10 neutral buffered formalin Protected Document to Protective order JNJ 000060428 Industrial TEST Inc. Laboratories : @ @ Histopathologic studies were conducted on lung liver lymph nodes and both kidneys from each untreated control animal and II test animal that died or was sacrificed Below is a summary of the mortality data Group Untreated Control Sex F Mortality 30 0/30 T II " F M F 3/30 30 2/30 1/30 There were no untoward behavior reactions noted during the day period Mean body weight gains for T and II hamsters compared favorably with those of the controls * Includes an animal sacrificed in extremis Protected Document to Protective order JNJ 000060429 Industrial TEST LaboratoriIencs. 4 @ The hematologic studies conducted prior to exposure and after 44 and 86 days of testing revealed no consistent differences between test and control animals No treatment gross or histopathologic changes were observed Respectfully submitted INDUSTRIAL TEST LABORATORIES INC Report prepared by CelotCelot Push Push/ Alan Bishop B.S. t / Assistant Toxicologist Inhalation Toxicity @ David J. Sullivan D.V.M. Diplomate American College of Veterinary Pathologists John Report approved by John W. Goode Ph.D. Manager Decatur Research Laboratories Laboratories wo Ne CQ My, KLE. = COLE(ea EAD) Lo Florence K. Kinoshita ,Ph.D. Technical Manager Toxicology LG, Wa ToxicologA y Ph.D M. L. Keplinger Manager Toxicology js Protected Document to Protective order JNJ 000060430 Industrial TEST Laboratories Inc. @ III Procedure A. Experimental Animals Young adult golden Syrian hamsters were used as test animals One hundred eighty were selected after having been under observation for at least 5 days to insure their general health and suitability for the study The animals were individually housed in stainless steel cages and permitted a standard laboratory diet plus water ad libitum except during inhalation exposure The animals were separated into 3 groups each consisting of 60 animals 30 males and 30 females These groups were designated as untreated control T low dose and II high dose B. Exposure Apparatus and Method of Exposure The study was designed so that T animals were exposed for 43 minutes and II animals for 133 minutes per day 7 days per week for 13 weeks To facilitate the scheduling of the necropsies the animals received 88 rather than 90 exposures Test group animals were exposed in a specially constructed stainless steel and glass inhalation chamber having a capacity of 5m Each animal was caged separately during exposure to minimize filtration of inspired air by animal fur which often occurs when cage mates huddle together during exposures Untreated control animals were exposed to clean dry air -40 dewpoint only @ * Engle Laboratory Animals Inc. Farmersburg Indiana ** Wayne Blox Allied Mills Inc. Chicago Illinois Protected Document to Protective order JNJ 000060431 Industrial TEST Laboratories Inc. ' ' The test material was generated with a specially designed dust generating shaker mechanism see diagram A stream of clean dry air -40 dewpoint was passed through the generator and the resulting dust mixture then introduced into the exposure chamber An additional stream of clean dry air 40 dewpoint was added to the test material prior to introduction into the exposure chamber at a rate of 320 min The test atmosphere was then exhausted at the bottom of the chamber Air flow rates through the system were measured with rotameters connected | upstream of duct contamination The concentration of respirable test material dust 2.0 to 10.0 microns present in the exposure chamber during each exposure period was determined by sampling the test atmosphere in the breathing zone of the animals Test atmosphere dust concentrations were continuously monitored by means of a Systems Model 10316 Cyclone respirable mass separator During each exposure period 60 second samples were taken every 10 minutes at a rate of 1.7 min At the end of each exposure average analytical concentrations were determined Table I. The average daily respirable dust concentrations are presented in @ * Systems Inc. St. Paul Minnesota Protected Document to Protective order JNJ 000060432 6a DUST SHAKER MECHANISM 16 qr ner or a mr a a [NEREREERARERRARRCEESERE CRE GDGGRE MOGGERS A.A. Electric Vibrating Motor B.B. Foam Rubber Cushion C. Support Springs only one shown D. Test Material Level Incoming Air glass tubing Resulting Dust Mixture to Exposure Chamber rubber tubing Protected Document to Protective order JNJ 000060433 Induddial BIO-TEST Sue. eiqatdsy H-L cc? zh TABLE TABLE TABLE I Ov'T T9'T OE'T 82'T * 82' T Se'T cai Le'T OPT ( SubacuteSubacteTEST sagjuepy odeavy 1SNG I-L Outline Outline of Test Test Conditons Conditons Conditons 860 SVT * t A T9TLv'Tt PO'T <E'T uetwzAg Atmosphere asegq . uapfoy - a9pMog - I Apnyg SUOT}IPD TIGVIL Yoreysuz0g Ayorx]y, SIZ, JO a ydsouny aANS IAg (3H seyour) 10 0 96 6246 62 29.97 30.10 29.97 30.10 90 0 L662 800 <20 O0 G6 <62 1.24 1.24 1.24 bOOE 189, -IVYALN uonepyu VUTINO ; LSAL ysnq aynoeqg azsydoun anjzer9dua(Do) Le 92 Le 29.95 29.95 92 Le 92 Le 9 Sd Le Le 1.42 1.28 Aeq-o6 4S9L y, 1.82= urayW ueay ansodxq Aaquiny T Z v S 9 L APpem g 6 OT Tl cl tI vI AD[P9M 000060434 Document--Subject to Protective Order :erqtea jou ejeqd x JNJ 000060434 Industrial BIO-TEST J , Jue. _ a[qeidsoy TABLE I contiued -L ert TABLE continued continued continued SLT GST b2'T It tZIT EET L9 TLL'T Ov'T sagjuiey Subacute Subacte TEST uetaig adezay jsng I-L Outline Outline ooff TTeesstt TTeesstt Conditons Conditons Conditons Gb to'T BET 09T S9'T Tb't bS'T ev osegq uspjon - wpMod Apnyg penuyos Yoaejsuogy SUOT}IPD azydsou | AyiIxoy SI], Jo FIV VUTINO IANsaig saqout)(3H S00 < <L'O <G00 <30.05 30.06 30.06 90 0 S00 < Iso] 60 0 90 <0 60 0 <20 0 <2.30 ** 96 62 IVALW uoyeluyysng LSHL eazsydounysanyeodura 1.24 aynoeqs (D0) 92 Lz 92 30.09 30.09 Lz 92 GZ Lz 92 LZ 1.38 L2 GZ Aeg-06 159, |, 1.3 1.40 OTGeAS AB][T] ainsodxy DIAOUTLH ueNn ue w JOU PEC SI 91 LT gt 61 02 14 z2 Ez v2 2 92 LZ 8z zequin x APIP2M ApPem xx 000060435 Document--Subject to Protective Order JNJ 000060435 Induthical BIO-TEST 2 Ine. atqesziday II-L bS'T TABLE TABLE 1 continued continued continued Le'T 29'T 92 96'T br'l Z9'T Ist 29'T 8S 90 Subacute Subacte TEST3snq I-L Outline Outline of Test Test Conditons Conditons Conditons PST 6T8b'Z 2tbT bL'T 92T Ob'T 09T edrz9Ay uetzAg Atmosphere asegq uspjoy tepmog ~ Apmig penuryo>s Yyourjstop SUOT}IPD sarydsouy A9IxO]L [| ISI], jo AIEVL suIpNO eansag s2eysut)(3H 86 62 01 OE LOO <30.07 30.07 29.88 20 0 <96 62 qs9IL 9662 9662 4662 6620662 0662 9662 . VINALVW uoTelyUuysng LSaL szoydsunysanjerodwa 1.26 eynoqs Aeq-06 (D0) SOT yj, 92 62 G2 29.95 29.95 S2 S2 . 92 G2 L2 2.48 L2 Le 1.42 1.51= :apqe[ra ura ues jou 6z 0 <TE Ze < rE< GE 9 <LE 8E 6 <OF IP 2P ansodxy TaquIN eyed Aplaem APLPEM x 000060436 Document--Subject to Protective Order JNJ 000060436 10 Industrial BIO-TEST , Ine. ajqesiday li-L TABLE TABLE TABLE continued continued continued continued 09T 8T2sT T3T OFT 06T osT cet s9T 90 Subacute TES Dust3SNG LL Outline Outlineof Test Conditons Conditons Conditons Conditons 29'T 62T vte os T89'T OL'T 80T LS'T odezay uetzAg aseg ueplon - Jepmog Apnyg SUOI}PD penutos | Yysaeui0D Ayotxo] SAL Jo ATaVL ="IVMALW uoneryu GUTPNO jsnqg LSAL eynoqg Aeq-06 aydsouy (3H dANSIg L0O900 <30.0 30.030.00 00100t seyour) J3s, 2 azydsounysanjesodua(Do) 153], J, 92 92 30.06 30.06 30.06 Le 9 062 900 < 00 1.28 1.28 OT 60 Of 1.32 1.32 Of 0 92 Le Le 2.14 2.14 9 SZ ansodx azquiny wean ep by SP oP LY 8Y 60 | AP2M 000060437 Document--Subject to Protective Order ueapy 0S TS 2S S bS GS 9% ApjaeM JNJ 000060437 Industriel BIO=TEST Leloratsrios, Inc ll atqe dsay II-L PS'T TABLE TABLE I continued continued continued continued S2'T 62T vL'T bST 8e'T T3T StT Lb'l Subacute Subacte TEST sagjwepy sdea y isng I-L Outline Outline of Test Test Conditons Conditons Conditons L60 Sb'T 09T t2T 680 63T T9T SPT uetadg asegq uspjoy JepMmodg - p| enuygos YoresutoD AAypontxiogy S3UOsTHI9PLD JO ATav.L TWIALVN uoyeruy sUTINO saydouyansaig s9your)(3H 40 0 ST OE OT Oe 29.96 29.96 80 0 <c2 O < 3s], 2.55 <20 L<U O0<096<62 1.05 1.05 900 < LSaL ysnq aynoeqs saoyduy anjerodus(De) S9S30.00 30.00 92 92 SZ 92 9 S 1.60 1.60 Le Aeqg-06 39, jy, ue w ueaW ansodxy woquny LS 8S 6S 09 19 c9 9 APpem v9 S9 99 L9 89 69 02 ApPem 000060438 Document--Subject to Protective Order JNJ 000060438 ve Industrial BIO-~TEST JL , Ine. 12 etqadsey bP iIl-L SS T TABLE TABLE I continued continued continued abt 98 T 8S'T b9 T 99 T T OL T EST 29 T TEST Subacute Subacte Dust sajwuepyuetiks odeazsy jsNng I-L Conditions Outline Outline of Test Test Conditons Conditons T 5'2 82 2 T3 T Se'T S2 t te'T Te'T 69'T aseg uapjon aepMmog - p| anuos Yourjszt0ogQ AAyponrxioyg, SIUOST}AIPT,D Jo A1TdVL -TVIMALW uonelyu] VUITNO ysng LSAL ainoeqg Aeg-06 aydsoujyaInso1g seyout)(3H 80 60 30.09 00 <0 <0 <30.13 30.13 4662 8662 189, saydsouy anjeaodu (D0) 92 92 Le 30.28 30.28 92 L2 1S3 J, G2" cz 1.38 600 O< <820 O 1.53 $00 <vOOE L2 92 Le Le 1.81 92 Le ueaw ues amsodxy requiny TL el <LbL SL 9L LL APEaM BL 6L 08 18 28 <8v8 APDI29M 000060439 Document--Subject to Protective Order JNJ 000060439 Industrial BIO+TEST Z , Ine, atqeidsay H-L TABLE TABLE TABLE I continued continued SubacuteSubacteDust 90 isang I-L Outline Outline of Test Test Conditons adesay uewzAs aseg uspjoy SUOT}IP penumos azegpMOg Apnig (OH YoAL}sU10D saydoujy aANSaAg { Ayorxo], JISIoE, seysut) 06620862S682 29.85 zoded TWIMGLVA uoyelu] AIGVL 352], j4eyo GulyINO jo . yno avilable Equipment uea malfunctio uo}pnjyrem Sampling out of chart paper paper suryoeu ran Aeg-06 4s2J, yuowdinby Buydweg sajdues satqera 13}[1J :apqe[ra ansodxy D1AyeUTID ueW ueap jou jou xequin API9M Aprys S8 98 48 88 ejeq eyed 4% x4Hx 000060440 Document--Subject to Protective Order 13 JNJ 000060440 14 Industrial TEST Laboratories Inc. C. Mortality and Reactions Inspections of all animals for mortality and abnormal behavioral reactions were made daily during the investigational period D. Individual Body Weight Data Individual body weights were determined before the first inhalation exposure and weekly thereafter The data were recorded as an index to growth E. Hematologic Studies Hematologic studies included determination of total leukocyte and erythrocyte counts differential leukocyte counts and hematocrit These studies were conducted prior to inhalation exposure and again at 44 and 86 days on 10 males and 10 females from each group F. Pathology Arrangements were made to subject any animal which might die during the test to a thorough necropsy and sections of representative tissues and organs were placed in fixative for histopathologic study unless precluded by advanced postmortem autolysis At the conclusion of a day investigational period the animals were sacrificed for pathologic study by exsanguination after they were rendered unconscious with CO2 in a closed chamber A complete necropsy was conducted on all animals and representative sections of the following tissues and organs were obtained from each animal and preserved in 10 Protected Document to Protective order JNJ 000060441 Inc. 15 Industrial TEST Laboratories @ neutral buffered formalin adrenals aorta bladder bone brain caecum colon duodenum esophagus eye gall bladder gonads heart ileum jejunum kidneys liver lungs lymph node mesentery nodes muscle optic nerve pancreas parathyroid peripheral nerve pituitary prostate salivary glands seminal vessel skin spinal cord spleen sternum stomach trachea thymus thyroid tongue and uterus Histopathologic studies were conducted on selected tissues and organs / obtained from each group II and untreated control hamster which included the following lung liver both kidneys and lymph nodes cervical tracheobronchial mesenteric Protected Document to Protective order JNJ 000060442 16 Industrial TEST Laboratories Inc. @ IV Results A. Mortality and Reactions There were no untoward behavioral reactions noted during the exposure period Nine animals died and 2 were sacrificed in extremis during the study On day 57 animal number 66 died and was noted to have broken teeth and to be emaciated This condition was also noted in 5 of the 6 animals which died or were sacrificed in extremis after day 57 All animals which died or were sacrificed in extremis prior to day 57 were emaciated Mortality data including time of death and moribund sacrifices are presented in Table II Protected Document to Protective order JNJ 000060443 Industrial TEST LaboratoriIencs. 17 TABLE II @ | @ TEST MATERIAL Cornstarch Powder Base Day Subacute Dust Inhalation Toxicity Study - Golden Syrian Hamsters Mortality Group Animal Number and Sex Time of Death Test Day UC 27 61 M 62 T . 71 48 66 57 67 89 92 23 94 44 110 85 II . 126 63 | 140 90 157 40 * Sacrificed in extremis Protected Document to Protective order JNJ 000060444 Industrial TEST LaboratoriIencs. 18 @ B. Body Weight Data Body weight means for the T and II animals compared favorably with those of the untreated control animals A summary of mean values is presented in Table III Individual body weights and weight gain data are presented in Tables IV and V. Protected Document to Protective order JNJ 000060445 s mo o - Whewn- . yyy THOTaM 679) waae | YAIN-E AdOETEST DAY SUB. CUTE eS Ly Gb INHALATION INHALATION TOXICITY AG ne rc STUDY - GOLDEN | rel okt SUMARY SUMARY VALUES VALUES 4tl SYLKYH DAY | a BODY WEIGHT ee ot se off ttt NVIMAS 4 A IX N3G1U9 67 6 I X 93 AGA=LS 72 81 85 92 IX ALIOXL IML 72 RVI 35M 84 ayavi 9 79 68 32 74 - 81 90 v unu NOLVIHNE Agog cil Zi ^ 102 104 | 99 102 97 100 103 ... 98 66 ... 99 103 LSaL < b6 6 Z6 SLA9'@NS S68 i8 S& AVO-06 Lg el cL GRAMS ) Nt Et tt Ait vit vit oll ro 109 115 cil 105 109 ot a 108 66 eol 107 I 66 110 113 G6 6 06 16 ve 18 ee 6L ve OL &B9 99 &9 d ee bor 000060446 Document--Subject to Protective Order 19 JNJ 000060446 3 Industrial BIO-TEST Laboratories, Inc. SUBACUTE - SIUNDBIAVCUDUTAEL INDVIUAL INHALTION ERX INHALATION INHALATION INHALATION INHALATION TOXICITYTOXICITY TOXICITY TOXICITY STUDY STUDY STUDY - GOLDEN GOLDENGOLDEN SYRIAN SYRIAN SYRIAN HAMSTERS HAMSTERS HAMSTERS HAMSTERS HAMSTERS ev LS 09 IG bS S ved <1 ll stl BODY Gil (Zl zi9E1 ctl bel Ld Bet gol tlt ect ect ^'lGil OtLol 6ol Slcilica) 911 60! pel FE vit 6ll 61 oc o s 0 IVA 70 - -245 VIVG 57 CNO - JONVHD AI 69 LHOTSM 1 67 FVaVL GNV LHO134 15 AdO@ 7219 6-2876 TWNdLAIG! cl Sel Git 5 oul 9tl WEEK WEEK WEEK Stl Oct ect sot 60l ia | Lei rie (4 6it sol rot ran Lo!eral Ctl ell 9E1 BODY BODYBODY WEIGHT BODY WEIGHT e s Ul Scl 9 109 cil 6ll Sil bei ttl Sel L^'tLet v0l Olt sit cet 9 911 sit gol Lol bei elt ec1 Bil 201 ec | CE 911 6lt Bel 6tl "8 93 88522 ell 105 105 Gtl 106 106 11015110Sel 113 113 **** 114 114 **** 112112 116 116 Git 115 115 vil 118 118 E E ctl **** 48 Zit s 89 88522 | vil 104 90 cll 97 97 t 104 104 Lzt 110 110 col 112112 stl 115 61 119 119 6tl 116 116 91 121 121 HERE ttt63 63 Zit 9 S& 9 91 100 105 eli 109 109 ol 109 109 115 115 ict 118 118 101 118 118 114 114 Ot114 114 gt110 11110 0 vel 113 113 OL Fol eu 44 oll 93 95 Fe 87 79 87 83 91 91 103 oll 112 104 vol 105 pel 113 113 Bil 121 119 ool 127 127 125 125 oil 127 127 Ott122122 601 128 128 68 cot 61 61 80! 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DAY WEIGHT WEIGHT HEIGHT SUBACUTE e*St L9 SY Ly <Osb < 9 GG 82 SS49) oL 19 ec <cGS eg am 29 cc Lp vd Ov 0S vG 0S 89 Lb INDVIUALAOE Ct 9C1 401 Git BODY BODY WEIGHTS WEIGHTS WEIGHTS WEIGHTS GRAMS GRAMS GRAMS cgi evt I! 001 Gtl ict Bll <8L01 1St 201 idl ool 90! git L2t vl vel Stl E L! NUMBER 69 NVIYAS 62 ASV 66 NJOT09 YAGMOd - 72 GQ3NILOD AI HOUV.LSNYD AGNIS ALIOXL 69 61 318V1 80 et i ol 6 8 (SWVU9) L 28602678327 SIHOTIM 9 FRE we BODY ccl 4 Ot} 5 5 PG WEEK WEEK 06es601 iri eft 9 G6 oll 10 10 tL11 11 col 12 v6 L6 13 CHANGE CHANGE BODY WEIGHT ZOl 107 107 StleraSut 115 FR ve cllera| 96eeeOtl 130 Let 133 133 Stl 134 134 26 136136 otl 133 901 136 Olt 821 ec 1 <1 ell BOL rel 97 aul 100 100 HERE 104 104^'6ll111 9 102 116 vel 118118 Zit 117 117 (4 115 115 301 110 oll 115 115 921 Icl 6e1 Ott Girl 109 66 Str 115 67 RE 69 69 021 57 57 **** **** vel 115 **** **** **** **** **** **** **** **** 109 109ett l **** **** eel oc **** Zui GTEE 101 101 911 106 109 HEHE 109 109 ttt 112 109 114 114 (ei 114 114 901 111 111 98 112 120 col 104 vil 109 109 Oc! eu Gel Gil GTEL . S21 93 a 95 96 LG 68 68 **** 102****2 102 **** **** 821 **** **** **** **** **** **** **** 110 **** ****109 **** **** Lil vil **** 601 9 9t 132 G Gt 137 +o 110 110 vol 115 115 69 122 122 cot 128 128 131 131 ect 134 134 ol134 134 Lt 137 | 96 132 Ot 142 142 oll Lot | vol | - *TVIMAL NUILWVHNIT 66 LSaL 3SLNOVES 70 AgOG S Lvet Git 87 oo! 115 115 L9 107 107 901 91 97 106 106 Stl 100 100 SII 112 112 EL | 115 115 110 110 101 115 115 S| O bol Git cOl v 201 93 46 73 73 99 104 77 tol 107 79 112 86 Olt 115 115 i 115 115 iL 92 0d] 113 71 c01 118 118 cot col 901 6G ve ) < 120 120 66 127 127 Au 134 134 138 138 06 144 144 oot 149 149 col 148 148150 150 eu 143 143 G6151 151 96 86 col 6 Zh AVG~-06 67 102102 18 107 107 SL110 110 114 114 68 114 114 16 112 112 66 110 110 cL 106 col <894 06 100 100 9% 68 06 L8 1G 103 103 1& 105 105 an 110110 117 117 6& 120 120 cr 124 124 VA 126 126 116128 c6 118 118 1& 127 127 iL 1F ve le Bl t 1 9 0 106 106 &9 115 115 cL 116 116 123 123 16 125 125 an 126126rae) 129 129 131 131 <1826 126 OL 134 134 <tLL OL ek 2.1 1 .2 12.4 12.4 913.7 13.7 99 15.5 15.5 16.6 16.6 16.6 13.5 13.5 13.5 13.5 13.5 LL 14.9 14.9 16.8 16.8 16.8 19.2 19.2 19.2 17.3 17.3 88 68 15.2 15.2 as 000060448 Document--Subject to Protective Order JNJ 000060448 22 Industial BIO-TEST TABLE TABLE SUBACUTE i DAGAOY INDVIUAL WEIGHT MALE INDIVIDUAL INDIVIDUAL BODY BODY BODY WEIGHT WEIGHT AND AND WEIGHT WEIGHT WEIGHT CHANGE CHANGE CHANGE DATA DATA 79 MALE MALE 6 i<by ce 9g vy Ge GE S9 Gp | <1 401 Oct oct BODY BODY BODY WEIGHTS WEIGHTS WEIGHTS WEIGHTS GRAMS GRAMS GRAMS ecl GOt (6 vet 9Et 96 Ret #% Sct cel 201 60 col a] Zul col Zot Get Lit Brel NUMBER 64 NVIYUAS 66 124 76 NIGO 128 - 83 132G3NILOD AGALS 80 AI ALIOTXL 78 aVaVI 71 138 NOTLVIHNT 65 140 SLNDVES 73 cl ti oO! 6 8 (SNVUD) L 89 SLIOESN 9 S AGOd v 901 4^'6ctLol 5 RK 6 WEEK WEEK 7 Ort Olt 8 901 c6 tlBt 10 10 GG 11 11 601 12 col 921 13 CHANGE CHANGE CHANGE | 10 WEIGHT Felt 901 76 Lei 0180 RXR 87 87 ell 92 92 901 SE 96 10l 103 103 cel 104 104 GL 106 oc! 106 106 101 107 107 ol901 le] vi G Gl 102 102 ccl 110 110 MRK 112 112 eit 111 111 113 113 10% 121 121 lel 122 122 16 127 103 129 129 66 130 130 oo! col lei ti Ged col 114 Ic 113 113 AKER 112 112 etl 109 109 LOI 94 (ot **** **** **** ******** 1 **** **** ******** **** G4 **** **** oo | col **** etl Veet 96 95 cu 102 102 6 101 101 601 108 108 109 109 1Ot 112 112 <21112 112 101 112 112 114114 c^'112 112 eol 86 vel 601 Ve t! 132 108108 Ve 112 112 601 116 116 sol 122 122 107 128 L6 132 107 it1l34 134 ool 139 Sel 140 140 Ls 140 140 Lo G6 Fil cot Ptih 28 88 elt <965 cil 96 96 io! 97 97 101 101 96 101 101 bie 101 101 L6 101 101 106 106 88 105 105 v6 96 ett cot Fett 114 103 103 Ou 110 110 Cul 114 114 col 117 117 123 123 S6 125 125 on 127 127 96 133 133 138 138 6L 136 136 6% c6 Sol 66 oth 106 90 col 113 96 vel 97 97 G6 100 100 101 101 68 130 99 0191 91 06 75 132 16 55 6L **** ****bts 18 **** GG 2 6 6L 109 S6 115 115 Ol 119 119 C6 125 97 128 101 bB 123 123 10) 127 102 Ce 130 130 131 131 el 107 132 Bs 98 col C6 67k AVO-06 75 c SL 79 68 79 79 16 88 88 og 87 87 68 92 cB 95 95 16 99 99 98 101 c6 103 103 IL 103 103 Sa ca 86 68 pred ' OL 84 Gb 89 89 694 94 v& 97 97 102 102 1f 100 100 98 100100 A 103 103 103 103 eh 105 105 or QL 18 OG 6 9 (0) 102 102 og OL 106 8113 113 es 114 114 124 124 69 126 126 el 127 127 el 131 SL 134 134 19 135 135 OL cL OL el c 9o 7.4 YAaWAN Iz 9.7 9.7 11.9 11.9 11.9 II.1 II.1 62} 11.1 11.1 12.1 12.1 12.1 12.2 12.2 Lel 13.1 13.1 Ort 15.1 15.1 17.4 17.4 17.4 13.8 13.8 avi ov 12.0 12.0 as 000060449 Document--Subject to Protective Order JNJ 000060449 23 Industial BIO-TEST LZ , Inc. LHOTSM TEST fb St bp dL 1S ec 19 te th 6S ve ed LY be6Yv de 8LG Gb Ov 0S &b 9f Iv bl SLv 8S a9 eL 0S Industrial SUBACUTE SUBACUTE C1 etl 00 90I isl fl | 00 cel Lot Ltltoreall Git del vit 901 Stl 901 Stl ccl ltt iitill GI Lolr| ae 6vl tel cll 6cleral] cul Sul BIO | <4 SHAIVH 4 J1VWAS HVIYAS - 101 101 ASV@ 75 NIGV9 118 WAGCMOd - 93 93 105 85AGNLIS 38 97 HOUVLISNYO ALIDXOL SLHOISM 40 77 NSN 101 79 95 AGOG 62 83 NOLIVHNE67 96 3LNOVES 80 87 AVG-06 90 93 91 BODY BODY WEIGHTS WEIGHTS WEIGHTS ( GRAMS GRAMS ) it bit thi ert g01 B11 601 vit Ecl 201 10l dil 801 Lol R01orl Lil 801 91 iloct Ltt TEST 5 col Loi 6 WEEK col 7 td 8 8 ttt vel Stl Zo! 10 vol itcl sot 00! 12 601 13 13 CHANGE CHANGE CHANGE CHANGEG. ) tl Laboratories i 106 106 Ol106 106 110 110 bol 113 113 Gol 114 114 Lot 112 bol 116 116 gol 115 115 got 112 112 cel cll Stl 7375853 ^'lcel ctl Laboratories 110 127 127 vol 132 132102140 sot 144144 sot 148 104 901 151 103 155 155 vol 155 106 sol 106 157 6c Git pit 7375853 dit ee) vie Laboratories 114 98 col 92 92 127 96 dot 102 102 Oi 97 97 100 100 100 102 102 oot 66 97 901 100 100 eet 801 vil 7375853 ol ect el Inc. 92 92 col 94 94 108 108 vol 113 113 01113 113 86 107 cot 114 114 v6 114 114 10% 117 117 8cl itl sit 44 col stl BOI GS*Ot E OI 107 107 96 116 116 115 115 00) 123 123 <0132 132 131 131 96 134 134 06 141 141 oo 137 137 <scol 6th 72 001 tes col | 114 96 99 96 92 92 86 97 00! 99 104 66 ||| 106 107 107 G6 107 107 L8 108 108 96 106 106 Bll 96 49 44 L6 gO 00 0 6 l | 94 94 vo 97 97 101 101 vO 109 109 6107 107 108 108 v6 117 117 vB 114 114 L6 115 115 Oli 16 48 48 06 16 L6 GL 116 ved 92 92 06 93 93 ig 97 86 99 99 68 100 100 ba98 16 100 100 eB 101 101 v6 16 L6 vO} v6 86 40 92 16 C6 108 50 95 95 18 98 100 101 101 L& 109 109 cs 100 100 103 103 Ss 107 107 LL 107 107 98 107 107 6 9B 36 36 id131) by Ok 96 96 dl 105 123 THE THE Ib 108 108 LL 115 115 112 112 C& 122 122 LL 117 117 BL 149149 04 v8 53 53 OL ch 6L YG 90 107 107 eg 110 110 116 116 <1L20 120 IL 127 127 126 126 69 132 132 99 126 126 L9 129 129 GL 89 58 58 09 a9 89 Gir WHINY 97 NVAM 100 100 103 103 se 108 108 BE 112 112 IP 114 fb Pr 113 OF 117 117 6r 117 117 cS 113 113 SS 9G 50 50 6S 09 as 000060450 Document--Subject to Protective Order JNJ 000060450 24 Industrial BIO-TEST LaboratorieIsnc,. JUOTAM SUBACUTE SYRIAN ( 9) INHALTION ok Ib 8E 9cs eg cy TOXICITY ov LS 09 SS Lg LS Gy GOLDEN GOLDEN GOLDEN SYRIAN GL HAMSTERS HAMSTERS HAMSTERS eg 09 ve Ov Ie cols) DAY90 <1 LOI MER col MR 9Ot gt Sck (ot bit Ol olbel Gel 9E| cl ell 66 oot col 4H GEI 6el bo Lei tel Lil eel G6 601 ict il w'^'l ro | ANIMAL 2 NUMBER 91 - 81 ASVG V.LVG 92 78 WIGMOd - JONVHD 85 HOUVISNYDC3NIOD 97 73 LHOIgM 71 78 A 10 GNV 43 M IWRALV 84 77 DVI 104 LHOTSe 87 20 106 AGO LSAL v TH TYNGAI 80 1 3 78 68 81 vd XR 26 MER BODY BODY BODY WEIGHTS WEIGHTS WEIGHTS ( GRAMS GRAMS ) ollrAeH| 98 26 oI 4eRE 61 ced 89 9El oc! <dlGE 86 601 vor Otl < O2 3 OR bot RENE cot 5 ict Oot 6 ra eel 7 921 8 91vit tot bol v9 10 10 bet 11 vel 12 12 ee 1 13 13 CHANGE CHANGE G. 83 | FR 87 87 Ol 88 88 oot 93 93 OC 98 ict 98 98 ett 101 101 100 100 9l101 101 bel94 94 GE | 107 107 | o01 41 Gtul 72 RR 70 70 Otl 56 56 66 41 SOl **** **** 6tl 95 95 **** 99 99 **** 102 bel **** 104 {cl **** **** **** 102 **** 901 38 OLt 93 CR 101 101 Lol 103 103 S6 103 col 112 112 vit 115 111 15 0 sot 114 114 124 112 ict 121 115 Sel 112 112 <1e1l8 125 10t 52 G9t 83 OR 91 91 Lol 99 99 6 99 66 103 103 ttt 107 107 201 110 110 108 108 dil 113 113 Lit99 99tral 114114 66 52 FOl 89 93 93 901 94 94 100 100 G6 ||| ||| 901 115 115 001 116 &B 118118 ra 124 124 601 Git 96 iit 124 124 16 60 E BI 120 O 124 124 vol 107 107 107 137 v6 112 112 GO| 141 121 121 R6 128 128 128 128 10}126 126 601116 116 Lot 128 128 16 57 ETSI 72 79 79 Gol 84 87 eg 90 16 vl 99 vO} 96 96 699 99 100 100 cot 101 101 col 92 86G56 99 99 rad) 41 Zt 80 E E 77 77 zol 87 87 BL 84 es 88 88 869696 16 94 OL 126 81 16 64 64 **** **** **** **** **** **** i **** GTEh 87 LS 81 81 968383 OL 70 SL 68 68 16 73 73 as 70 eb 16 71 18 69 698&8 68 68 v8 64 64 6L -5 G*6 88 GL 87 87 6b 96 96 VL 96 69 106 106 Ls 108 108 iL ||| eo 112 112 iL 116 116 vL 123 123 a 117 69 th 62 Lee 77 73 L9 89 73 08 80 80 6S 30 910791 OL 93 93 106 95 LG 105 91 99 108 96 R9 98 98 109 95 69 v9 38 o'9 101 31 31 90 c6 94 94 G6 9898 86 99 001 107 107 col vO} Gol 114 114114 113 113 il 114 114 vil 110 110117 117 611 Ocl 50 gs 000060451 Document--Subject to Protective Order JNJ 000060451 I] w Indutiial BIO-TEST TABLE TABLE DAY SUBACUTE INDIVDUAL INDVIUAL C1 roa | SUIWVH tt 70 NVIYUAS - 154 74 NAGTW9 157 - 59 99 160G3NILG@D AGALS 70 86 91 A ALIONXE 68 X33 82 73 aIaVL 69 78 165 85 71 NOTLVIHNT170 74 SLNOVAS 70 80 AVG-06 30 INDIVIDUAL BODY BODY WEIGHT WEIGHT WEIGHT WEIGHT AND HEIGHT HEIGHT HEIGHT HEIGHT CHANGE CHANGE CHANGE DATA DATA Ov FEMALE FEMALE FEMALE L9 b9ims) ve vG Le ov OL SS eS bord WEIGHT SEI cot BODY BODY WEIGHTS WEIGHTS WEIGHTS WEIGHTS (GRAMS GRAMS ) Stl 401 ofl v0l ra | Lit 6sl G6 2 6f1 ottzetlen! G2i co! 0lerCoral | inal bo} Ovi bol C6 5 el Let 6 WEEK | ra 7 60t GZI S01 | me) Gt! toe SO | 10 ici 11 v6 RE I 12 12 L6 13 CHANGE v6 BODY WEIGHT CHANGE CHANGE WEIGHT L 9t 112 112 96 114 G2] 109 109 90! 119 119 G^'I112233 123 cot 131 L401 131 133 133 951 06 141 9F1114400 140 oot 135 tol 101 Bel 65 75 75 77 ell 103 103 66 86 Ol 9 91 | 101 101 106 106 oll 107 107 66 113 113 ol 117 94 120 120 Sot 123 123 A | 123 123 6ct 119 119 66 125 <ll86 ici 55 etl Levi 93 99 102 102 sol 108 98 66 100 100 vil 119 102 124124 vol 103 121 ive 125 125 vel 125125 131 107 ett 96 O160 otl Gtht 108 79 79 (8 87 oul 115 1 5 dL 95 95 801 100 100 104 104 <1608 108 9d! 105 105 Bit 103 103 68 107 s0l 06 eit 45 col Leet 82 vB iL 90 Lot 94 94 el 103 103 col 108 Zot 113 113 96 116 116 ict 120 120 ela 118 cc 127127 901 68 olt 58 66 6 Gt - aa vv 76 de 121 77 col 126 79 BL 86 86 66 87 <1648 90 96 152 90 etl 90 90 go} 94 159 95 66 OL 001 31 G6 94 114 114 0Ot 118 118 a 124 124 16 129 06 133 133 56 136 oot 83 YL ol 87 c6 89 89 &9 96 96 es 99 ee 99 97 L6 98 98 68 100 100 16 97 6Ol 101 101 SB OLLis34 cB 6 79 eL 69 89 te 90 90y9Y 696 an 98 te 8S 98 Ob 136 136 lf 101 101 101 101 001 103 103 BL OY Ib 46 OL t d ues 9) ol 19 co cy bi 19 115 6S 120 120 tL re By 127 127ego 127 127 Ve v9 131 130 130 ve Ly Id G9 Lg L9 55 89 TWHIHV 12.3 14.3 14.3 15.9 15.9 15.9 13.7 13.7 RSI 14.5 14.5 91 14.7 14.7 15.4 15.4| 15.4 15.1 15.1 691 16.6 16.6 16.7 16.7 16.7 16.4 16.4 16.4 &LI 6L\ 14.4 NVI GS 000060452 Document--Subject to Protective Order JNJ 000060452 Industrial TEST Inc. Laboratories | 26 ' C. Hematology The results of hematologic studies done on male and female hamsters from the control group and from treatment groups T and II are presented in Tables VI through XI Mean values for total leukocyte and erythrocyte count differential leukocyte count hemoglobin concentration hematocrit and erythrocyte indices MCV MCH and MCHC of treated hamsters were not different than those values obtained from control untreated hamsters prior to and after 44 and 86 days of treatment Protected Document to Protective order JNJ 000060453 Indushial BIO=-TEST Lobarateries, Ine. 27 98 cle S 6F - 9b S*tb 9 05 Pep T 9F S 0s 9 Lb 8 Lb HWAIo}ewayL :Aeqg T' 6 ane, (%) bb 6 9F Z'^'r 66 bts bP 0 9b 6 9b T* 6b 0SF 6' 9FS'Lb 1say, TEST MMAATTEERRIIAALL MATERIAL Cornstarch CCoorrnnssttaarrcchh Powder Base Top L 2b 28b bed 6<b 98 Erythrocyte Erythrocyte - 102 Vor 9 02 Hemoglobin Hemoglobin 8 61 6 6T 6 6T thousand ulqo[ZwapyuoTe2}Ua90590/3)(im iAeg 27 Test Day 2'st S'6L Ist -1 0 8T Day <'6r 86 0 61 qsay 8.7 eseq 7.26 9 91 8.06 6 91 8.33 L 9t 16.6 L ST 18.6 6 ST 19.4 S bI Japmog 6.1 - SITEW 1A 20.6 - 10.1 yoaesucen9.6 WIYALVN 88..09 1.4 ayAd0yAaq /suoyru) LSIL 7.39 e 8 9.14 - 9.18 18 8 16.3 <o 8 19.5 ST 6 20.1 98 8 (4 shed qune9 7.19 90 8 8.16 bL'8 9.16 10'8 16.0 o's 19.9 Te <"B 20.6 9b'8 3saL T- 92'L 8.66 6S L 8.72 99 L 61'2 66 9 19.0 S6 9 0272 be 20.5 8.8 1 .9 98 7.20 8.46 - 8.86 0'6 PIL 14.5 19.0 z 6 19.9 T'0r (wu eq ayAd04NF7] yunoy bb L 8 19 9 02 o's 68 2711 o 8 8 8 6 01 6 I bor 1s9y, /spuenoy?)[e]O], I- S*b s 8 s'8 8 38 9 6 1 8 2 <1 B82 2'8 9''3 yeuy qzaquiny T Z b S 9 L 8 6 or usw perp [euny dnoan on = 000060454 Document--Sub ject to Protective or der JNJ 000060454 Indudstial BIO-TEST Laboratories, Inc. 28 S' 8 6 98 bly L*8t bP Lb b Sb - - L Ly b eb 0 9b OP yasoewsapy :Aeq b' 8 2 an[ea () bP 0 0S TABLE TABLE continued continued 2 05 SP 9 15 0 0S Lb 6b 189 Cornstarch 2 T- TEST MATERIAL MATERIAL eb Cornstarch Powder Base 2b a 28 bp 9 &P 98 2 02 Erythrocyte Erythrocyte 6 6L < 6t - - Hemoglobin Hemoglobin 0 6T S 6t 4 ulqo,swayeajyUuaUeDot/3)uel} am :Aeq by 02 Test Day 86 s'6T eat 9 8L Test Day 86 U'6r 18a] asegq 15.3 I- 7.10 9.48 2 9t 8.40 UstT o 9t 15.5 < ST 9 ST 19.3 19.3 tapmog 10-.6 sajew - 9.4 18.0 eyed yo1esutoD8.5 9.0 10.9 2IVNGLA 9.5 IWBopyewa ayAzs0ayAg LSa.L 98 6.94 8.58 b2 8 8.88 SL 8 - - 92 8 0 8 19.9 19.9 (ui :4eq qunog /suon bP 7.15 8.94 29 83 8s 8 Tb'6 b6 8 16.0 18.3 86 8 9 8 06 8 3891 yw) T- 6.91 9.35 beh 8.26 10 L Sth 15.3 19.4 b6 9 19.8 19.8 12.1 nN 10.0 . 98 7.10 8.90 S 6 8.40 S Ol - - 19.1 6'L 19.5 19.5 ayA0xNa|] yunoy :Aeq bb ST 901 8 6 b 6 0 6 2Or S 6 0OT et 00t 901 189, (,wu/spenoy)]eIOL 1- L 8 8 8 8 6T 0 81 s 8 6 01 S ol Bk Lut S TT 2'st pewruyaoquin 19 29 9 v9 $9 99 Lg 89 69 OL ueoW perp jeury dnoan I-L = - 000060455 Document--Sub ject to Protective or der JNJ 000060455 Sndustial BIO-TEST Laboratories, Inc. O 8 S 2 98 S SP <'lb 6h 6 P 6 0F - e eb bt bP 2b bb jlz90; :Aeq 1 0 9F O'Lb 9 15 e ts (B) bb 6F t' O 6b Lb 8 8 LP Sb 9 8 5 8b an[eaeWa]{ L 389 t- bev TABLE VI continued continued cee 6 tb 9 eb 6 6E S 6 <a4 2 Hematologic Data 0 98 z 6t Hematolgic Hematologic Data Males - 8 st Sst bot <*^'t6T Leukocyte uenajyuo7 aseg Day Sowsp 90/3) uLqo[ (1m :4eq Concentration 0 0 bP milions milions mm ^'l $ St 2 6L Concentration 100 Concetraion 6L 6T 189L [- U9t 2 90 <or 6 FT ost vor S 9t Ug ST < St9 sT Jepmog 8.8 - sapewW - - 7.3 7.9 10.7 6.85 9t 8 8.66 61'8 8.19 Bork - Lv 8 18.4 L2'8 19.2 02'8 yoaejsuto)9.8 (gui 8.5 ayhn0ay 9.1 sAeg -FVIELA 7.6 qunog/suoty 6.39 69 8 8.41 99 38 7.68 3 15.4 1L 8 18.5 89 6 18.5 68 8 hag |i) saL 10.4LSAL L- 86 9 8.71 s3 9 8.17 6 9 16.5 SEL 18.1 6h 9 18.8 s8 9 amoeqng Aeq-06 6.45 9 6 9.07 L ol 7.96 9b - 29 19.0 S OT 19.3 *'8 ayAr04NI] qunoy :Aeg by 8'8 s L ek s 8 bor 389.1 (,wu/spenoy)[210.1 ul z'8 8 83 6 9T L 6 8 6 I- b8 c 6 6'L 8 6 16 gL el 9 6 01 29 9 8 yewluya2quinN Tel rat <21 ber S21 921 Lz 82l 621 Ol ueaw dnoay II-L i Protected Document--Sub ject to Protective or der 29 JNJ 000060456 Industial BIO-TEST Laboratories, Inc. 30 U' 8 < O 98 L eb bb o eb eb U'9b O eb bP L th 0 9b Lb b'bP anteaA930; sAeq e' 6 9 (%) bP Lb 2b 0 90 Lb T'db 9b 9% L 8b 0 9b T'8b 2 90 eurd 389] FH] I- L 0b < 2b T bb TABLE l'eb lb S 0b O <b O-lp bbb 47 Females 93 6 LT Hematolgic Hematolgic Data 6T Females eel 0 61 POL *6t L 8t thousand ulqo[Zura}yuaTerpU2OZ(10/3) aseg 44 :Aeq 6 2 6 Concentration bb Lt milions mm oat ost at LT / ml S'at 0'8t 1s31 lL 6.58 8.21 2 ot 7.49 st L ST 15.4 17.9 L St 17.917.9 19pmog 8.4 sajeuiag 7.6 8.4 Yaeysuto eyeg 3 98 6.97 7.87 ae 7.73 Luk es L 16.2 17.6 Lv'8 18.3 18.3 (,wur/suor 9.2 12.1 8.1 qyuno9 :Aeq UP 6.78 8.12 cere 7.77 2U'8 wok 15.7 18.0 2t8 19.2 19.2 eTVINAaL s1do0jyEWI 10.6 15891 pu) 8.7LSAL I- 6.36 7.86 26 9 7.89 8L 9 990 15.1 17.9 65 9 18.3 18.3 7.9 C- 9.0 98 7.26 8.35 9 6 8.33 Cer 9 OL 16.5 18.5 18.5 * 8 19.3 19.3 (_ uu ayA09NaT *yuadinba quno9 :Aeg bb b's c'9 b's 2 6 SOL 1 83 6k 8 0 6 Lot L'8 aL /spuenoy)[2191 I- 9 9 s s 9 2 T'8 8 9 9 9 9 L'6 L s B F B 9 suloynsjew a9 0} yeuljuyquinn Tt 2e e pe St 9E Le 8E 6 < oF ueoW ENP SOT dnoin on OGM 000060457 Document--Sub ject to Protective or der JNJ 000060457 Ss; Oo oO ~ wv - xy Ns isa] et g 98 Top - 2 bP - 8 cep 6 Ib S Sb 9eb bb bey L cp }LID0}eWa :Aeq b nfea (%) bP beh - S 96 '9b 9 Lb 6b S 9b 6 8h S 8P 9 9pLb H 3say, I- MATERIAL Cornstarch Cornstarch Powder Powder Base 9 0 90 2b L 2b < 6S< eF 98 Hematolgic - Data - 8 T 6l O 8T Hemoglobin Hemoglobin 6 8T 6 LT a 8T m utqo[gwauoyeszjuoegbid! cr:Aeg 901 ( milions - 6'LT 9 6T 8 65 278 Test ) 0 8T bLt al H /3) sa 12.2 7.5 t- 8.45 St 7.80 2 91 6 ST 15.6 18.1 L St 2-92839 2 St L*sT UspfoD dapmog - penuos 9.5 Apnyg eyeq 98 9.0 - 99 L - TLL 16.2 19.6 brs 2-92839 6L L BL 7.5A (_ AyorxKo], AIGVL arm 6.48 Y junog bP Sr'8 - 10's 00 6 BS"8 15.2 18.2 29' 8 2-92839 Toseb's8 10.8 10.3 ayAsoryAaq 6.69 uone|EYyU /suotiyu) 8.1 6.35 8.15 S6 9 8.19 8b 86 9 9 ] 18.0 O L 2-9-28239 Sb'9 LL 9 aynoeqng Aeg-96 6.77 8.42 - 7.84 - OT 15.7 18.3 rs 18.8 o0r Oor (_ uw ayA04NV7 qunoyANI] :Aeq bP SL - s L 2'te 8 0T 8 6 T's 6 6 t'6 9 0T S Or | e}0. 382], /spuesnoy})TRIOL i 6'F ue 9 9 L 9 9 8 eb SL T'9 UL e'L L'9 yearuy aequnyn 16 26 6 b6 S6 96 L6 86 66 00L ueay Pap [ewiuy dnoay I-k = - 000060458 Document--Sub ject to Protective or der JNJ 000060458 Industrial BIO-TEST Laboratories, Inc. 32 98 Te? Ltt U'ep 0 9 2 86 U'bp - vob 6 26 Tes S*bP 31.190] Aeg 2 b' eld ante, (%) bP 2 05 TABLE VII continued continued 9 Lb - Lb 2 90 L 90 LD fy 1s9aL O 8 9 Subacute Inhalation Inhaltion Toxicity Study - Golden Syrian Hamsters Hamsters e re 2b 98 milions Count mm 2 et 8 02 T st - Concetraion Concentration Sut 9eT Day ulqo[Zway{uoyesapuge7y aseg 10.5 01/48)Ci :Aeq bb 6 02 44 6 LT 86 est SLI - 44 2 Lt 86 Tat S95 6.83 O st 8.27 9 ST 7.67 o'st 976037835 976037835 17.9 e ST 17.6 Sst dapmog 9.5- 5.8 YyIIsVAe}SAULOVDN 1.4 6.4 ayAsoay 6.2 sopeway9.1 yunoy 8.6 2 12.5 6.75 gt L 8.50 bb 8.35 se s 997766003377883355 -~ 18.3 89 2 20.8 BL L (gw :Aeg bE S9'8 8.22 S2'8 7.82 0s'8 976037835 Arg ys2L o 17.5 86 L 18.1 8 6.5 /suoljyiw) LSoL 6.87 19 9 8.27 95 9 7.88 s. 9 976037835 976037835 17.3 T1 9 18.6 91 9 9.5 8.4 98 6 6 9 9 OL b 9 S 2T bo - 8 8 9 6 L 6 9 8 :Aeq ayAr0q4NaTqunog vy B dt s Ol S 6 16 bet S*6 - 153 (,wu/spenoyi)[BIO] 9 S 6 b 8 2 or t- S*B 8 L o's 8's 9 8 z2 9 Qh O L S sS 9 Ue yewtuy. az9quin tst est <ST bsT SST 9ST LST 8ST 6ST Oot ueaW pap jeury dnoin II-L =- 000060459 Document--Sub ject to Protective or der JNJ 000060459 Industrial BIO-TEST LeboraterieIsnc,. 98 0 0 - MATERIAL 0 U Powder Powder Base 00 stiydoseg 4:sA9ye,q90 Subacute Subacute Toxicity Inhalation Inhalation Study Golden Golden Syrian Hamsters Hamsters I- 0 0 0 Hematologic Hematologic Data Males 0 0 00 -1 aseg 14 98 0 Lymphocytes Lymphocytes 9 @ Monocytes Monocytes T it) Eosinophils Eosinophils :Aeq Neutrophils bP 0 0 0 86 0 -1 86 0 sed yoy T- 86 rd 0 84 0 S 86 0 2 44 0 if I0 [aD yo Japmog zaequiny) 14 :Aeq 14 0 14- 26 24 eyed yunog 4s97 5 98 86 0 - 0 2 0 ob 84 0 T 68 0 0 0 0 0a ee 0 0 20 20 T- 76 0 0 74 0 0 0 2 0 00 00 YI1esUu0D6 ds 12 ayAs0na7q 98 69 SB - 72 bL 98 2b 1 26 28 1 -TVIYALW 29 10 [enus9j1g LSaL :Aeg 3 by 91 28 61 81 6 28 0 0 06 28 352 16 18 I- 98 b8 98 58 OL 8 69 16 <8 98 0 15 98 st tI ~ 92 e neutrophils <l vz 81 g oI Lt ydounay neutrophils bP 8 et 08 bT ^' it o1 6I Ot SI 8 St 789, 6:ST I- vt eI bT T v2 ral 62 6 2 | <L jeuty azequny T @ bo S 9 L 8 6 ot uesyW = dnosn on 1.8 ayy y im up payejo) uaeq pap aaey spurg jewiuy = , - 000060460 Document--Subject to Protective Order 33 JNJ 000060460 34 Industrial BIQO-TEST LZ , Inc. 98 0 0 0 0 0 - - 0 0 00 stydoseg :AeqtPF 0 Q TABLE VIII continued 0 0 0 ) 00 say {- TEST MATERIAL MATERIAL Cornstarch Cornstarch Powder Base 0 0 0Q 98 if if T T b - - E 2 0 9T :Aeg (pazuny bp 9 U <0 t 4 0 tT T 0 60 Neutrophils stjydoursgsad ys9L -T Monocytes ) Lymphocytes Lymphocytes Lymphocytes t Monocytes l 2 Eosinophils Eosinophils aseg Day jsijoa9Q 82 76 0 4 t 0 - - 0 0 1 vo. Aspmog 24 23 zaquiny) $9) 82 60 - 40 83 0 0 t 0 Zz 0 3 1 1 A.0u0;, - 80 panuyos 18 yunog 17 34 79 0 0 0 0 02 0 0 3 10 YIESUODTTA 10 sAr0yqNeT] DIGVL 79 86 9L 08 bL 18 00 - 68 bL 4 6 08 IVNELW 29 15 PeI}Ua2z7IG LSUL 6868 68 67 8 6L 68 98 L9 58 1 89 e8 S*6L 15 soyA0duh] 669 I- 7 08 bE eb 6L 89 S8 98 eo 08 + 19 00 98 el te eT be st - - 8 $2 eI Lt 00 69.9 bP ve 91 st ol EL 0.4 SI 61 of 8T 1.6 0 28TYdornay2, ur poyejoy I- BI dt s9 9s 12 ras vr rat Le St 6 82 U9 q pewruy aquny 9 29 9 9 $9 99 Ly 99 69 OL ueow pop aAeYy = spueg jewruy dnoan = I-L 4 - 000060461 Document--Subject to Protective Order JNJ 000060461 35 Industrial BIO-TEST Laboratsries, Inc. a 0 0 0 TABLE VIII continued 0 0 00 stydoseg :1SA3,eLq 98 0 0 TEST MATERIAL MATERIAL Cornstarch Cornstarch Powder Base 0 0 T- Day Subacute Subacute Inhalation Toxicity Toxicity Study Golden Golden Syrian Hamsters 98 per 4 Differential Differential Leukocyte Leukocyte Count Number of Cells Neutrophils * Eosinophils bh 0 0 Test : 0 a Test Day 0 0 sxajwey Neutrophils44 1821 OU -1 T 0 I 0 t b if 2 0 0 ueyzAg 10 jo 20 bo 0 78 80 1 0 - t 0 0 0 uapjon 17 - 13saTeW- penuygos sa}yAD0Uupy Apnyg 13 43s9, eyeg 17 Q 83 87 0 0 0 0 0 U 01 13 0 0 0 I 0 0 0 0 0 0 0 jjA Ayorxoy 19 ATV. 98 8 79 63 <8 9 - 1 4 06 SL s8 b ae voRepyu JWFopyew 27 bP 06 08 48 98 18 9 +8 16 L8 bB < <8 16 sayA0dwhy]389 anoeqns 6 LL 73 87 28 v8 6L 28 18 e 98 S*18 Aeq-06 2.4 98 el 02 ut eT (a7 - 42 Or 9 vT 1.0 #5 847 -YIM the neutrophils neutrophils 02 et eI 6. Le 51 6 ral 91 S 9I UL the 189] payejo] I- @7 22 ST eT ST dt zl rat L2 bag PLT jewyu Tzt Z2I e2t bet set 921 L2t 821 62zT OET uean zaquny yuruy dnoan I-.L Uesq porp eaeYy spueg = - 000060462 Document--Subject to Protective Order JNJ 000060462 36 Industial BIO-TEST LetoraiorieIsnc,. 98 0 0 0 0 0 TABLE TABLE 0 0 00 stiudoseg:35h9]e,qPP it) 0 0 TEST MATERIAL MATERIAL Cornstarch Cornstarch Powder Base Base T- 0 Day Subacute Inhalation Inhalation Toxicity Toxicity Study Golden Syrian Syrian 98 9 T 0 Differential Differential Leukocyte Count Count Number of Cells Neutrophils Neutrophils Neutrophils T t U Day T S 0 Test Day I be Animal Neutrophilsaad Day ST I- 1 v4 rd 4 Z Q 0 2 t aseq uepadg syjap jo 98 0 0 9 80 0 0 9 0 0 0 Qo 4opmog uapjoy saquing) :Aeg 20 - be T T 0 77 0 0 00 00 0 0 sapeuag 2 2 Apnig yunog = 9b OT XI [- U 0 79 2 4 0 0 Qo t YDAuSUL0D eyeq - AWaVL Apoyxoy, TVINL uaoynneoyseqqun]g 2yD0jo;eEuay aTeynuhsozagyIyne17y6 LSAL 98 9L LL 8L 89 69 re) 2 tL 08 Tk 6 9L 16 bb L 08 ib 6L 28 68 +8 68 18 92 08 8 T- 69 vL <S 81 80 ee SL OL 02 98 272k Aeq-06 2.4 98 8I ee ez oT bE OT 2 61 LT 82 2 02 ayy with 2 Lt YM ra 9 8 the neutrophils neutrophils ee bl | oT LT 9 < with 189. UT prey) t- Le 2 Sh 91 bz 2 $2 o 82 el 8 22 ua q i pewruyaequinN 1 < ce 3 be SE oe Le gt 6 OF uraw a ey dnoin on s* pueg 000060463 Document--Subject to Protective Order JNJ 000060463 37 Induthial BIO-TEST Latoralories, Inc 98 0 - 0 - 0 0 0 0 0 00 sj1ydoseg:Aeqg bP 0 - 0 0 0 0 0 0 0 00 1891 T- 0 0 0 0 0 0 0 0 0 09 98 per 0 - Differential Diferntial Leukocyte Leukocyte Count Number of Cells Lymphocytes sxajuepy NeutrophilsNeutrophils 92 uethg Neutrophils vP qT - Test Test : 0 2 Test Day v 1 4S3], 44 t- 0 if C b S 0 c 0 15 0. . cA 9 jo 93 uapjon 19 - To 98 Q - 0 - 0 0 T 0 0 0 :Aeqg 6T'O) vb it) - T 0 0 0 0 0 0 0 sajewag sayf20u;- Apnyg 4soL 690 - penuos 90 T- 0 0 U 0 T 0 { 0 2 ) eyeq 95XxX] Ayorx], 25 PIV 98 s8 - 16 Ss s8 bL BL tL ae 08 t'08 96 uogepyu dySojewoy 25 98 1288 <te bP vB - 77 Or b8 L rae LL 6L ce aynoeqg sayAv0duhy 21 28 55 79 zs b9 S8 BL 9L SS 18 2Sh , Aeq-06 98 ST - L - oT Sz 8T 8 Te 61 1.6 sp the < L2 neutrophils neutrophils - 61 06 9T S2 SZ 2 LI 91 the 1s9L <'te [- st 82 02 bt of ST 81 be <h Lt peuy aquny 16 26 6 b6 56 96 L6 86 66 ool ueow == dnoan I-L 1.2 ayy YIM UL pafejo} Ua q parp BaeYy spueg pewyu = - 000060464 Document--Subject to Protective Order JNJ 000060464 38 Industual BIO-TEST Ladoratorues, Inc. 98 0 0 0 0 0 0 - 0 0 00 sjrydoseg :Aeq bP 0 0 0 0 0 0 - 0 0 00 Sal t- 0 0 Q 0 0 0 0 0 0 00 98 < Differential Differential Leukocyte Count ( Number Cells per per rophils :keq Test bb T Test Day T tT T Test : Test -1 rophilssad 86 Oe I- 0 t ra L 0 0 I 16 sjag jo 98 0 0 0 0 0 0 - 0 0 00 10 zaquiny) sa, 6 - ob 0 0 0 0 0 0 - it) it) 0o sopewia 14 23 14 gy I- 1 0 0 0 0 0 0 I 0 0 290 154 - qun0g 155 156 15 ayAv0NaT 98 v9 18 16 +3 $8 gL - Tk 8 St T'6L 27 I1B0[oyeWA} :Aeg by 8L 28 84 71 8 1 - +8 ra) 0 808 [eNuaszIg 22 29 2 I- 8 8 82 83 28 00 00 oL Te 28 3 17 2.8 98 ct Ot 9 bt It 6T - te Ut S2 0'8T ay} neutrophils neutrophils neutrophils 91 T 8T oT 62 - eT ST 8. L Lt YIM - the 159.L UT paleyo] I- SI ST OI 2 SI Sl L2 62 62 LT PST usaq Ist zS1 pemiuy zaquny= pewyu dnoan H-L <ST bST SST 9ST 4st 8ST 6ST o9T uesw pap a ey spueg = - 000060465 Document--Subject to Protective Order JNJ 000060465 < Induttial BIO-~TEST Leboreleries, Ine. b 98 L'Uy 2 . - O'bY L vy 2 18 9 6P < Sb 8 6 2p < <P :Aeq TEST (%) bP 8'8E b'LE b LE [LE S 6 < v2P L LE 6 LE l'2P 2 L 1v 6 < MATERIAL Inhalation Inhaltion Toxicity Study Golden Golden Syrian Hamsters Hamsters T Le TLE 8 9 < saojwepy uetwhg asegq 98 L'2z Test Day 2 12 0 12 6 12 2 22 8 22 Test Day 8 12 1epMog uspon 86 - 44 X Apnyg :Aeg - ...- ...bb 3 8 02 333 ... ... s* <2 S 12 2222 2222 022 L'02 - ... 3s2] Yoarjsu0DFIVE ... *IVMELYW Auojpyeottryuxloy - I- 3 622 333 ... ... 022 22 2222 2222 Ltz 92-92323 LSA aynoeqs Aeqg-06 98 3 9S 333 aC sAeq ALD) vYV 3 LS 333333 159L LS 6S 22222 22222222 Ls 92-92323 LS 22222 22222 22222222 8s 92-92323 I- 9 9 29 19 19 19 22222 22222 29 09 92-92323 yeuty xaquin 22.2 Z 20.7 21.8 S 9 L 8 39.2 OT 92-923 39 yeuty dnoay on = - 000060466 Document--Subject to Protective Order JNJ 000060466 Industrial BYO-TEST Loboratrrizs, Ine c f 6" 98 <b 0b bb eb 9 <P - - T ep cb IP Lev Aeg 9 TEST %) bb : Cornstarch Cornstarch Powder Base < SE 2 00 8 9 < G LE b LE LE MATERIAL Inhalation Inhaltion Toxicity Study Golden Golden Syrian Hamsters Hamsters s 9t 8 SE 9 siajwepy uewAs aseg -1 saotpuy - 44 IepMmog 63 ... 61 ved 62 i 98 S'b2 S22 Day 4 p12 - Test $ - E? Test Day L 2e :Aeg bb 3 9 02 333292 6 02 - L 6T 6 02 5222 2222 02202 4saJ, yoaejsu05 61 63 Arq *TVIUELNW 62 I- 3 L te 33292 612 ... 222 Std 52222 2222 812 612 LSA. 64 98 3 09 333332922 9S ,, - - 52222222 22222 8S 8S 60 ... ... :38A9e]q... ...bb 3 SS 333292 Ls ,, LS 9S 52222222 22222 9S Lg T- 9 19 333332922 29 T9 b9 09 29 22222 29 c9 29 yeutyquinN 21.9 29 20.7 9 ... 99 dnoip I-L 000060467 Document--Subject to Protective Order 9 36.3 37.6 OL ueoWN perp pewpuy = - JNJ 000060467 x Industrial TEST Laboratories Inc. - ... ... -... - 8 86 - ... - ... ... ... ... -... - -... - -... - 0 9P tr - Day MCHC % 44 Test - 38.2 -1 / - " ... 37....5 Hamster Syrian Base Golden 86 , S*T2 22.5 Powder - Males Indices contiued Erythrocyte Study - MCHlugDay 44 602 Te 902 202 T'T2 002 002 02 9T2 202 20.6 Data Test X CMorAnTsEtRaIchL Inhaltion Hematolgic TABLE Toxicty Erythrocyte -1 ... ... 6* <2 22.9 TEST Subacte Day 86 - ... ... 56 - Day MCV u3 44 Test - - 57- -1 ' - - - - ... 62- AnimalNumber / - / - / - - " ... Group T Protected Document to Protective order JNJ 000060468 42 Industriel BIO-TEST Leloratries, Inc b U' 2 8 8 98 Teh cbr eb S p 2p T'bP 2p bp cP 1p 0 E? :Aeq 9 TEST (%) bv Cornstarch Cornstarch Powder Powder Base BE S LE c LE S*6E L Le L Le MATERIAL sagjmieyH T- Toxicity Toxicity Study Golden Syrian Syrian Hamsters TLE vse Tle viLe uetshg aseg Test 98 c* <e Test Day bed Tbe 0 9 22 b 22 Test : T* <2 - aospMmog - 86 - PIAVLIX Apnig - - sAeg vb- 3 3 23 8 02 9 12 S e2 2222 b 02 3222 Pte 3333 -- 1s9Z Yoare}suz0y Arg IVGLW uAoyyeoltxuoyy] - T- 3323 ee 0 <2 fe 2222 822 3222 G22 3333 LSaL ojneqg 98 333333232 8S LS ... ... ... ... 6S 22222222 SS 3222222 6S 333333 Aeqg-06 :Aeq bP 333333232 Ls 6S 4S], ... ... ... ... 6S 22222222 9S 3222222 8S 333333 T- 333333232 9 v9 ... ... ... ... 9 22222222 9 9 29 333333 yewiuy asquN 23.0 ce 21.4 23.1 SE 9 < LE BE 37.7 Ov 3 3 3 dnozp on 000060469 Document--Subject to Protective Order JNJ 000060469 Iidushiol BIO-TEST Z , Ine. L S L 6 98 S SP - L cb - bP L t&ep C'bP dP ep 2b 8 <P :Aeg 8 TEST (%) vb p'9E - L le 9 OP 0 9E BLE 0 9 9f 6 9 <L'Le MATERIAL sajwepy Hematolgic Golden Inhalation Toxicity Study Golden LE Syrian Hamsters Hamsters 6 9 < 8 B8E c Le uewAg eseg -1 - 44 tapmog sotpuy 61 58 91 9yA014 eq 92 98 S he - Day - Tbe pe? 9 te 8 12 Test Day Pk? 58 (Br) :Aeqd by 2323 - 2 8 02 02 < T2 2222 T T2 T'Te 012 1891 Yoejsu0D 61 93 Arq I- 2323 L'te 2233 6 22 See 0 SZ 2222 22 <6?222 VTIALVN 62 9 , LSab 62 - 98 23233 - 222333 8S 8s ZS 22222 8S 95 8S 73 57 :48A9e]q (eH) bb 223322333 - 222333 SS - LG 6S 22222 6S 8S 8S T- 223322333 19 222333 29 c9 tL 22222 222 c9 9 yewIuy zequN 22.9 26 dnorp I-L 000060470 Document--Subject to Protective Order v6 96 L6 22222 222 00T ure parp yeury = - JNJ 000060470 Industrial TEST Laboratories Inc. - bt? 86 ... ... ... - ... - ... Day MCHC % 44 Test 37.4 -1 " 36....6 Hamster Syrian Base Golden 86 ... ... ... ... ... ... 23.0- - contiued Powder Females Indices study - MCH ag Day 44 ... / ... ... ... Erythrocyte Data Test XI ... ...21.0 Cornstach Toxicty TABLE Erythrocyte 22.8 MATERIL Inhaltion Hematolgic -1 ... / 22.8 TEST Subacte 86 - - ... - 59 Day Day MCV u3 44 Test | 58 -1 64 64 65 63 62 62 65 63 63 64 64 Animal Number / - / - Group II Protected Document to Protective order - > died Animal = - JNJ 000060471 Industrial BIO TEST LaboratoriIencs. 45 . @ D. Gross Pathologic Observations No treatment gross alterations were observed in any of the tissues and organs examined They consisted of the following Group Control 2 @ 2 2 2 T II Animal Number and Sex M 66 _ 67 92 94 110 140 Disposition Moribund Sacrifice Died Died Died Died Moribund Sacrifice Died Observation Carcass - Emaciated Right Ear - Inner ear infection Lung - Emphysematous Carcass ~- Emaciated Carcass - Emaciated Lung - Diffuse red discoloration Lung - Consolidated foci Carcass - Emaciated Lung - Diffuse red discoloration Carcass - Emaciated E. Histopathologic Findings The results of the histopathologic studies are presented in Tables XII and XIII The grading system and abbreviations used in these tables are as follows x Tissue present on slide and examined ou Tissue not present on slides 1 = Trace or minimal in severity 2 Mild in severity =3 Moderate in severity 4 Marked in severity 5 Extreme in severity p Lesion present not graded The pathologist's statement follows on the next page Protected Document to Protective order JNJ 000060472 Industrial TEST LaboratoriIencs. IBT No. 8562-09039 Johnson & Johnson ' 46 have completed a histopathological evaluation of a series of selected tissues lung kidneys liver and lymph nodes from hamsters of the control and II test groups of Study No. 8562-09039 No treatment changes were observed The lesions described were those of naturally occurring diseases or related to the method of sacrifice With regard to the latter there were varying degrees of capillary congestion and alveolar hemorrhage which occurred just prior to sacrifice in some animals In most instances these lesions were present among both the control and test animals The lesions are summarized in Table XII and individual data are presented in Table XII All tissues present on the slides and examined by light microscopy are also accounted for by sex and experi- mental group in Table XIII Those tissues which were absent were random in occurrence with regard to experimental group and did not interfere with the above conclusions Reviewed and Approved Martin G. Robl M. Staff Pathologist Ph Za Gandin Gandin Donovan E. Gordon M. Ph D. Diplomate American College of Veterinary Pathologists Protected Document to Protective order JNJ 000060473 47 'Industrial BIO-TEST Laboratories, Inc. Day Subacute Ort OT iI-L of aoupiy Summary Histopathological Histopathological Histopatholgical Findings Findings Histopathological o't UT OT sajwey Histolgic Histolgic Findings Findings Aaa wn J 1 aa+a+i nN ra) ce aw ~~ ao man st eseg uepzAg Focal agregates agregates Multifocal Aapmog uaplon - Difuse intralveor agonal Not Nr M11 Oo Oo + a a T Focal sadeyosm AWTAXVL youes0g AAypomxiosy aoutaoeg Focal bronchilar hyperlasi -Sa[Nqn) -S9[N) jeurgy epithla cervial Lymphoid epithelia hyperlasi eyspdiaAy siajodemay soBeydszcew uoyepuy Subacute Lymphoid uy oBdeyszomay (WeuoBe) UT Uy jepoysnu 0 Teasqpiun 1.0 mesnteric eyuownsdaq SUOTyaID0A9 SUOTVaIDdA ) aBeysowy Lymphoid LSyumbphaociudte hyperlasi hyperlasi llyymmpphhaaddeennitiitss (jeuo8e)(JeuoBe) poiq uapey jeqpuida - 1.0 uapey 1-4 syneday sypedsy 1.11.1 stuiapeyduA; 2.0 Aary[npuivsxa sinuodahematopis Aeg-06 extramdulary laden hematopies hematop ies macrophages |e20) paye uy - macrophages sj opl jAue z jory u aq visejdzaiy eisda{y syi3uejoys ~ yuawdi yuatSyd snodeu sy04190u saeynqy 1.0 paz{esUTW, PazipersUIWE 206 hepatis laden laden sinuodal sinusiodal sinusiodal macrophages macrophagesyeog yesog jeog 0 aynoeqs proydwiy 1.5 pes04 aynoeq g yeo g pesos [np [eD04 pesojyn[ peso 1.0 [RDO Jeazqyun [B20 pezoypiq 4 mineralized 10 uEtAG sunq 000060474 Document--Subject to Protective Order 7 (2t4ayus) apou spou ydw^'q ydusy ABAYT sfaupry JNJ 000060474 48 Induthial BIO-TEST LaboratorweIsnc,. aderzsay apean H-L of Qousp Uy Amor NOmnta Foo i oa AA st se HO OO fm) fo] eco sajuiey adeaoy Histolgic Histologic Histologic d d d - Incidence Average Incidence Focal eseq uezikg dapmog uspjop sojewg intralveor - Focal - ago hemorrhan ge aga onal l N ) =m wa ome -- 7 Tea1S0joudyst epithla eysfdaAy cervicalpenuo? Ye suAOD Apnig ayiaseg sdSurpury TTX Ayoxoy jeurg Terminaly Terminaly FIMAVL epithelia sadeyoisw cervical Focal Lymphoid jo laden hyperplasia (yeuoBe) uaUN] hematopishematopis eBysroway AeTOYDU0IG mesnteric Lymphoid Aaewuns Lymphoid hyperlasi hyperlasi hyperlasi (jeuoze)(jeuode) Jo po[q yeaygideuapey sadeyosu . aydoapAy st ajod yewa uoyerzs o1d 1.0 jepiosnul uapey, SIy Zuepoy> syneday " uoyej ns a prolifeatn 15 Areynpawjx 1 extramduly macrophges eis[daAy stweldoyA prolifeaton prolifeaton macrophages prolifeaton proydwAy proyduhy jecoynpur [ed0s13(Ny mesntric payeuy extramedulary - 1.3 - UT duct proliferation [ed0} yonp 1.0 yuaewsid aliq yuawdi syorsau Aeqg-o6 macrophages [BO T sinuoidal macrophages aznoeqs multifocal hepatis cholangits cholangits cholangits macrophages macrophages jes0g [es0g yes0q 1.0 [e20g pes0g (2uaqesw) ansty, ([2}A4a9) 10 apou apou uedag sun] yduAy yduky ABAr] 000060475 Document--Subject to Protective Order JNJ 000060475 Industial BIO-TEST LaboratorieJsun,e. adeasy eprag Oo'LOL TEST MATERIAL MATERIAL 1I-L Of a juepyIu] 9 v Z 0 0 sayjue] ade13say Histolgic Histologic Histologic Findings oT o'2 aseg uetshg sajewag Focal Focal [esZojydt suoaADUOITW SsUOyeADZTW snoeuyajzod paztjeuIUT pazieAvuTW YIAeSUOTDsevrity - AapmMog uapjop mineralzd L < b 2T -~ sduipry penuo> Apmg aylse System 2 sevrity peury :[9A7 speulwxg - tubular casts sapnq) Sa[Nqn, Jeazpiun uy Ul minmal sevrity yo ansodxgazoquny yeaszqjun qezaliq - sjseo sevrity sevrity pue Aaewuins dnoin sulpry - - siozydau sioxydau aejnq) Aeq-06 12190[9/7s se[nq) aernqy [e904 [vo0g [e204 [eroj t an [e0g Tezae Tq [e0 4 Ays a9s Ayjtenas Ajlia ul s Aj a s Aylag es apead ou aNsij, waysig up ut uy ul 10 pewyuW py ayespoul payew auijyxa yuased sXaupry Suipeay uedAO == == = AN mew = A 000060476 Document--Subject to Protective Order 49 JNJ 000060476 ; Ss ca oO = wurn ~ 3 &g wy oO of 62 82 xx 92 92 $2 xx d d d 4 ' Mo- a KX = K b2 - RX EZ = TEST MATERIAL KX Syrlan Inhalation - OZ Toxicty = Gl l s4ajsuae Individual Histopahlogical Ut H HU XX 45678910 welads 45678910 Saye 45678910 * ~ - Wl uapjog X ~ at X X agregates Apmg tt DYp4IVS Of macrophages dd intralveoar jeuy 6 . 8B te2{Bojyds}4 XX 2 Males d 17 KX KX -~ KX 23 i K . d X. 4 YY KX - I -2 XX 2 intralveoar 9 d penyarpu XX S dd xX I xX b&b I anoeqngAeg-ps ek XX et U a - KX <-2 d - Ut XY --, ^ spjuaeydA, - epsday toysaBuos pue dno 1y2ao7] X X jo yoanye (euoBe) X payeuy - X I[euy uy Buo0d jeaoy (jeuo8e) yuamSyd eyuonscd01q eBysowy -deyasouy Apeuyw, ops yeo0y syaqp peoy aeporze [BIO] peso] [NW fer0q (qeuodr)asnyig (1eu08e)aynoeqng poyq pesog uapel pyodwiy aynseqn S]ulsayxo * UP apou ueda Bunq ydud^'q(Te24.9) Padpjyse 000060477 Document--Subject to Protective Order JNJ 000060477 51 Induttial BIO-TEST 4 , Ina. 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Xx det X tot gFt xX et TEST t x BbT flamsters Subacute x 2bU x Individual x Indivdual GEC 125 Findgs LEL SEL asegq uepsks X SEL X X X extramedulary extram-edulary ZET hepatis sduypy Apnig TET necrotic aysvegnecrotic OFT Multifocal peayTojds Focal yews 621 B2T yyy Lz pignet ladentublar X X nephrosi SpZzT nephrosi <Z0 2z1 TZU X - x 1 L xX 138 X X KX X MW 1-2 x x xy x KX xX xX xX xX xX X 2-1 Aaeypnwax pazyeoup Pazyeuj pue dnoan 1 9409 ta quiny: sduyp y uapey ayoesd3u_ ~ syoaydu syoaydu UP Uy [ea}qjun BUC} feaspeyq sanodxgpemyu sjaodewary sadeyoseu SU04;]29D. a12NOD0A;UI 3yBop peoy jaepoI0za4u spyeday yeoyH| spyeday yuamAyd aeynqy feaytpun aepnqy e498 saynq sagny PEIP s{ t NW jesoy pesog [es0y f1q jeo04 yu yesoy Puno] (etyaucq-4>e2}) jeupUY wedag, ydwuhy spou a@Ay] shaupy y 000060480 Document--Subject to Protective Order JNJ 000060480 Iudushial BIO-TEST Laboratories, Ine. 54 09 x x 65 xX xX 8S xX Tt xX 5 xX 2-1 XxX 95 X xX S$ x x U $5 & Mo <S MATERIAL Subacute Inhalation MXM - Syrian Syrian IS X KX OS X KX Individual Individual and OF X LE X Females I X Control t Number Findings 32 jesySopd, necrotic sdurpz extramdulary extramedulary extramedulary hepatis aoypares vacuolation cytoplasmichydrophic cytoplasmic youry duct prolife- tublar nephrosi penysipu 35 --" --" --" Sh --"--"--"--"--"--" Cb fe Ih OF GE BE LE : X SE 37 KX --"--"--"--"--"--" 1 t X-KX X C KX KX 1 X oC X KX KX KX { KX Ut KX ( KX 1 X XK Li X rf X @-1 . 2-1 X xX 1 : ea FE X xX : nephrosi < < 1-2 I tr. xX 2< X X ii TE X X Aaeynpowsjxasyajod)emay SUON>2910a;u su013a.9UI; snoareuyjod stopryAu pazyersu dpuseydojAuoPeTONIA pue dnoay '[2a q wequn sduypuy spneday -vjyoad - yanp ansodxg peujy spo29u e}q syPopwig aydoapAy jesoy [Ro04 p[esNosW) yen0g uones pazieoup sjozydou eysoaydu Uy Dj Uy} yeaqgyun TeABYIQ - szejnqy aejynqz - - 8]82 yerog jesaypun yesoq Peza7]qqeosog saynq) peog BayNAny jeso0g aeynq) {e-ayqun TeBIG adAY] shaupy 000060481 Document--Sub ject to Protective or der JNJ 000060481 Industial BIO-TEST Laboratories, Inc. 55 Subacute aseq Indivdual Histopahlgica 34 36 - X X X X adYyzIG 39 TX AyaxoL yeusy F1GVL IVALYN Yopejyu PPP PP P Aeg-og 9 x 6$ $$ 46 NEN 99 SS RR BS Es MR continued tS KK 0S Study Sacrifice Golden UF - {oaHjiusotgopath4olg2ical Control <b is XX tb KK Ob 1 GE KR Bf Ze RK OC sr KR be 1 < < XX 2< Te YY 1 I ' . BOOM MOM MOK T XX KX KK KX t KK X KK KX KX P ~*~ me < x xm x= ~ ~~ x Xx X X X . xx ~ XX X - X pezysauw X X X eistda4y X uoy)saduos ^ oansodxg x x X pue3Jae7 X XX reupay, 70 Yapel X X {eo0y X yuamd uy ^ x x X X X 1 pes04 pes0g szaqop X xhq ploydury apou apou uedig Suny yduhy(yeat43) ydwiy(2}431Uuasw) 000060482 Document--Subject to Protective Order JNJ 000060482 Iudustial BIO-TEST LatoratorieIsnc,. 56 x ORL x GLT x - dd GAT xX x LLU X xX GLE xX xX SLU X X BLT X xX TEST MATERIAL xX Subacute K K Subacute Inhalation X OLE XK X Individual x d X sajureg Individual Histopathological Histopathological x LIT x d x 151 156 158 170 Number 156 X X 154 UWapyaH FIT K X Findgs - XX X congestion sduypy Apwg 290 XK d X TIC X xX congestion Aypoxg Boyes bronchiolar lumen congestion OFT x X yeurs GSE 1 X X X pesZoydj macrophages BSE uoPepyu;inhaled seLSt x penyAlpu amoeqng ' x GSI SGT xX Aeg-og X xX BST X EST xX X X 251 X d X IST saBeydoseu pue dnoip spea ] ra quiny S U[puyg ansodag jo vopsaBuos uoysaBues Uy uaWNy sayeBs8e pa eya (euo8e) per y sp Ppaz er ujyw Wosaye uy -adhy pewyu 2}80/}8H jes0q (jeuoBy) esnyiq (yeuode) FAQOP Ro ; aepoy 2u sg pesog 1epOsAye Ap eu i szay, po lq aynorq s oy suo4q pesog spaq p proydwi4eyseyd peap apou punoy (yespa)y uesio funy ydwiq peuy 000060483 Document--Subject to Protective Order JNJ 000060483 Industrial BIO-TEST LaboratorieIsnc,. 57 SajsweRy Findings uetZAg 153 X A8pmog uapjopn - - hyper- YDAesUIED Apnig BIYPAKS X WX Ayp>yxo, peuy ATVL 1YVNAL voye;uy extramedulary aynoeqg penyaqpu Aeg-06 OBT GLE BLT LLU 9ZT SLT b2i CLE Subacute (ZU Individual Individual 891 156 156 ek SIL HIE COT Z9E 191 O91 6ST BST 1-2 9ST SST BSE 1-2 2ST IST 96 x - KX - X X MATERIAL KX Inhalation X X Histopathological XX X 158 xX X X X X - x X I xX xX X X I x x X -2 X X X X X X X X X X Xx - xX X X 1 XxX x Xx I 2-1 xX XX X xX xX = ~OAD - dnoin ansodxy1 -adAy T2Fopfqys ydushy eyseyd steajodway uoqe.tazypord uopesayod soBeydsur syHBurjoys FEro;pa yesazqun aynseqg teaoyq snosau yuoHyd UP yonp s7TIq ;HwW a]TIq ; szeyngy aeynqy quGAuDo pesoqe peap pesog fes04 jesog jes0q jesog [esog peru punoy spou apou uwdig ydudy(2y4aqus01) ydwdq-0aysea})([epyouag 4ary] skoupry p4ewpuy 000060484 Document--Subject to Protective Order JNJ 000060484