### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Farility Stu.d.y 

### No. 4UO.SOIS 

### Te.st Site lhferenceNo. ISS-023 

### Report 

## Histopathology Phase Report PMDA hydrolyzed. to Pl,IA.: 

### Oral tGa1VBge) Keprod11mou/Developmeotal Tmicity Sctteniug 

### Test in the Rat 

### (OECD 421> P..IATERIALS 

### The study pathollogist was supplied 'With 

### the following study related 

### documents by the 

### test facility:

- Study Pim and amendments

- IndJividual 

### and SlmlJDalt}' animal necropsy 

### findings

- Indlividual ammaJ 

### histollogy reootds



### - Smmnuy of in-life 

### and :necropsy 

### findings ~ogieal 

### sec!liom, mmmted an glass slides, were 

### submitted by the Test Site (Histology) to the 

### study patbollogist. Seeticms from 

### all protocol required 

### tissues wme stained with 

### hilematm.ylin and 

## eom. In addition, m.h 

### sections of tes.1es 

### were taten mcl stained v.'llh 

### Periodic Acid 

### Schiff. Histological techmques were 

### periiomJ,ed by 

### tecbnicims at Propath 

### UK Ltd., Willow Court, Nethenvood R.oad, 

### Hereford HR2 6JU, UK. The number of 

### slides 

### and tllae da1e they 

### were received 

### are 

### :recomed in the 

### Study File. The quality of the 

### histological sections, 

### tisse acC!OUDtability, slide llabeling and 

### tissue placement were 

### good and comidered 

### adequate for the 

### purposes of

### the study. Arch 

### wing The mstopatbolo!Y raw data v;,j)Jj be 

### dispatclied to the 

### Test Facility fur arobiving as SO<lD 

### as 

### possible after the 

### completion of

### the study and issue 

### ofthe 

### Final 

### Histopathology Report.

PmrMillar

## ..u.maatc Ltd. - 

### 2.3...4.ng-1011 - CtJffjidmtial 

### 71115 

### Page 295

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlity Stady No. 4120SOIS Test Site RfflHDtt No. lS5-02J 

### Report 

## Histopathology Phase Report PMDA hydrelyzed to IJI.U.: Oral (Gavage) Reprodadion/Developmeotal Toxicity Screening Test 

### io the 

### Rat (OECD 421) l\llETHODS From the documentation supplied by 

### die test facility, a database exclusive to Study Reference No. 155-023 was ~ted OD the Roel..ee**~** system (Version 3_1). The smdy pathologist ezammed the tissue sections, by light microscopy, with full Jmo,wledge of the dosage g!!OUp to 

## wmch imlm.duals had been assigned, and recmded 

### his fi.nd:iugs by direct entry onto this database. Most his1opidhologiral findings weJrre graded 

### in seventy using a five point syslem of minimal,. mild, moder.i:te, marked 

### or selll!!l'e. Ocenmiall findmgs were reoorcled as 

### present 

### am- as unilateral or bibteral. In addition 

### to the routine evalution of the 

### testes, the seurinJ&mus bJ.buJes of the teS'les were evaluated with Iespect to their stage 

### in the 

### sperm.lb)genre cycle and the mteamy of the vmous 

### c:ell types present within the different stages. The tabJes oontm.ed 

### in this 

### eport 'Arere derived from the 155-023 database and were used by the study pathologist in the assessment ofthe histopathologieal findings. The study pathologist entered the macrmcopie data supplied by the test facility onto the Roel..ee system. 

### RESULTS Histopidhology findings are~m Table l and individual animal pathology findmgs are pRSeD1ed 

### in Table 2. 

### l\laff41SCOpic 

## Pathology

There 

### were no trea'lmmt-relatm findings. 

### All ofthe 

### histopathologial findings encountered were 

### considered to have 

### occmml spootmeomly 

### m post 

## monem. In particular 

### no cmrela:tmg lesions were found 

### to 

# expwn the greater than 

### control 

### nmm absolute and 

### relative kidney weights 

### in

### males given 250 

### or 750 mg/kg 

### bw/day, 

### mean absoluk 

### and relative**~** 

### weights 

### in the liver 

### of h.tales given 

### 250 or 750 mwkg bw/day 

### or the lower 

### than 

### oontrot seminal vesicle 

### mghts: 

### in males 

### given 750 mgi'kg 

### hw/day. 

### In addma.n to the 

### routine 

### evaluation 

### ofthe testes, 

### the 

### semmi:lrmus tubules 

### of the 

### testes were e\~ 

### with respect 

### to 

### the:ir 

### stage 

# mthe spamatogenic 8/115 

### Page 296

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fadluy Stndy No.4ll0581S Test SiteRefermce No. ISS-023 

### PMDA bydrel:,zed. to 

### Pl-IA: Oral tGavage) Reprodudion/Developmental

### Toxicity Screening 

### Test in the 

### Rat (OECD 421) 

### cycle and 

### the integrity of the various cell 

### types present within 

### the 

### ctiffercnt stages. No 

### treatment-related abnonmlities 

### were noted.

91115 

### Page 297

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Farilby Stady

### No. 41205015 Test Site R.nereatt No. 1S5-0l3 

### Report 

## Histopathology Phase Report PMDA hydrelyzetl to PA-IA: Oral (Gaw~) R.eprodm:tion!Defflopmeotal Toxicity Screeomg Test in the 

### Rat (OECD 411) 

### Table 1: Histopa:thologysummaryincid.enc:e Male



### Dosage(~bw/day) 0 50 250 750

numberofanimaJs 

### 12 12 12 12 ADRENAL CORTEX

numberexamined 5 5 ADRENAL MEDUU.A

numberexamined 5 5 BRAIN

numberexamined 5 5 CAECUM

numberexamined 5 5 COAGULATING GI.ANDS

nwnberexamined 

### 12 3 

### 12 COLON

numberexamined 5 

## s DUODENUM

numberexamined 

## s 5 EPmmYMIDES

numberexamined 

### 12 3 12 

### Bilateral bypospen111ia

-m:arlted 1 0 0 -severe 

### o, 1 0 Total 1 1 0 

### IDtratuhubr

### sperm. dellris

-mild 1 1 0 

### Jocal menGDUdear cell

### inliltratioo

-minimal 4 1 1



### 10/115 

### Page 298

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fariffly Stluly

### No. 4H05015 Test Site Refeftllce No.155-82J 

### Report 

## Histopathology Phase Report PMDA bydl'elyze,d 

### to Pt.IA: Oral (Gavage) Reprodu.ctiooJDevelopmental Toxicity Screeoiug Test in the Rat 

### (OBCD 421} 

### Table 1: Histopatb.ologysummaryincidence (OOld:inned) Male

Dosage 

### (mg/kghw/day)

numberofanil:nals HEART

numbereumined Focus(i) ofmyoc:ard.itis

·minimal n.EUM

nu.mbel" samined JEJUNUM

numberez.amined lolr:dulndarhyaliae droplets

-minimal 

### -mild Total UDildenl.

### hydronephrosis

-mild LIVER

nwnb,erez.amined 

### lllllammatm.ycellfocm(i)

-minimal LUNGS

number ea.mined Collgestion



### -moderate Foms(i) af

### mtra-alw:olarpinklhlid

-mild. Pel'ir.lslcllbr 

### -uc:1nrcellinlillratiml

-minimal 0 12 5 1 5 5 5 1 1 2 0 5 2 5 1 1 50 250 750 12 12 12

1 0 0 0 1 5 0 5 5 5 1 2 3 0 5 4 5 0 0 1



### 11/lH 

### Page 299

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Farilfty Study No. 41l0501S Test Sift

### Refereaa No. 155-023 

### Report 

## Histopathology Phase Report PMDA bydrelyzfll 

### to PUA: Oral (Gavage) Reprodudioo!Developmental Toxicity 

### Saeeumg Test in tie 

### Rat (OECD421.t 

### Table 1:Histopathologysummary

### incidence (continued) Male

Dosage 

### (mg/kgbw/day) 0 50 250 750



### numberofanimals 12 12 12 12 LYMPH NODE. MANDIBUI.AR.



### numbereumilled 5 5 

### IDll'asinusalcongestion/erythrophagocytosis

present 1 1 LYMPH NODE. MESENTERIC



### numberexamined 5 5 

### IDll'asinusal eoagestion/erythrophagm:ytosis

present 1 0 MAMMARY GI.AND



### numbeream.medl 10 3 12 PAIICBEAS



### numberexamined! 1 lnfamion



### -moderate 1 PARATHYROID GI.ANDS



### numberealll.illed 5 5 PITUITARYGLAND



### nwnberaammedl 12 3 12 

### cyst(s)

present l 0 0 PROSTATE GLAND 

### nwnberezammed 12 3 12 

### hals(i)mOD811111dear cell 

### hl6ltntioo

-mimmal 1 0 0 

### Fecal idammatitm



### -mwmal 

## z 0 0



### 121115 

### Page 300

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlify Stady 

### No. 41l0501S Test Site Refft'entt No. lSS-023 

### Report 

## Histopathology Phase Report PMDA bydrelyze41 to PMA: Oral (Gavage) Reprodm:tion.lDevelopmeotal Tmdcity Sc:reeoiug Test in the 

### Rat (OECD 421> 

### Table 1: Histopa:thologysummaryio.ddenc:e (coBl:inoed) Ma.Je

Dosage (mg/kg

### bw/day)

nwnberofaniimah RECTUM



### .number ea.mined SCIATIC NER.VE



### numberea.mined SEMINAi.VESICLES



### numberea.mined SPINAi. CORD, CERVICAL



### .nwnber ea.mined SPINAi. CORD, LUMBAR



### nwnberexamined SPINAi.

## cmm. TIIORACIC



### numberea.mined SPLEEN
STONAOL GUNBUUll



### numberexamined STOMACH. NON-GIANDUI.AJI:.



### numberea.mined 0 12 5 5 12 5 

## s 5 5
5 

## s 50 250 750 12 12 12 5 5 3 12 5 

## s s 5 1 5 5



### 13/ll5 

### Page 301

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fariffly Stady 

### No. 4ll050IS Test Sift RefeHDtt 

### No. 155-02.l 

### Report 

## Histopathology Phase Report PMDA hydrolyzed 

### to 111,U.: 

### Oral (Gavage) Reprodac:tion/De¥dopmental Toxicity Screening 

### Test in the 

### Rat {OECD 42U 

### Table 1: Histopd:hologysummaryhu:idenc:e (continued) 

### Male

Dosage 

### (mg/kghw/day)

numberofmimaJls TESTES



### nwnberenminedl Ouilateral germmal 

### epithelid

### atroplly

- minimal Bilateral

## FffDiDal epilhetial atnphy



### -moderate -severe 

### Total THYMUS



### nwnbereum.medl Pad-morlembaemonrbage



### present THYRDm GI.ANDS



### nwnbereammed ORIIIABYBIADD!EB.



### numbereammed 0 12 12 1 1 0 1 

## s 2 

## s

5 50 250 750 12 12 12 3 0 0 1 l 12 2 0 0 0 

## s 1 

## s 5 3



### 141115 

### Page 302

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlily Study No. .:fllOSOIS Test SiteReferew::e No. ISS-023 

### Report 

## Histopathology Phase Report PMDA bydrolyze4 to 

### PMA: Oral (Gavage) Reprodudiou/Demopmental 

### Toxicity Screening Test in the Rat (OECD 421) 

### Table 

### 1: Histopathologysummary

### io.ddeuc:e (coutinued) female

Dosage 

### (mg/kgbw/day) 0 12 50 250 750 12 12 12 numberofani!Dllls ADRENAL CORTEX

numbermcamined 5 5 ADRENAL MEDULLA

numberea.mined 5 5 BRAIN

numberera.mined 5 5 CAECUM

numberea.mined 5 5 COLON

numbereumined 5 5 DUODENUM

numberea.mined 5 5 HEART

numbermcamined 5 5 ILEUM

numberera.mined 5 5 numberea.mined 5 5



### 151115 

### Page 303

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlity Stady 

### No. 41205015 Tat Site Reference No. l5S-02.3 

### Report 

## Histopathology Phase Report Pl.IDA hydnlyzed 

### to P!\IA: Oral 

### (Gavage) Reprod111fflOD!Developmeotal Tondty Sereeoiug Test in the 

### Rat (OECD 42U 

### Table 1: Histopafllologysummaryioddence (continued.) Female

Dosage 

### (mg/kgbw/day) numberofanimals KIDNEYS

numbereamined 

### Focus(i) of

### hsophilic (regeneratiag)tubules

-mild Byaline 

### cast(s)

-minimal. PapiUary 

### /medullarycalculi -minimal. Bilateral

### hyd.nmepllrosis

-mild numberelCaDl.ined Congestion



### -mild Extnmedulbry

### haemaloporesis

-minimal. LUNGS

numberexamined 

### Agcmal 

### congestion andhaemorrhage

present LYM:PB NODE, MANDIBULAR



### numbereamured LYMPH NODE, MESEN1'ERIC

numbere:ram.ined Apnal 

### congestionJha.emarrhage

u.milatenl 0 12 5 0 0 1 0 5 0 1 6 0 

## s s l SCI· 250 750 12 12 12

1 5 0 1 0 1 1 0 l 1 5 2 0 6 1 

## s 5 0



### 161115

### Page 304

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadffiy Stady 

### No. 41l05QIS Test Site Reference No. lS5-02J 

### Report 

## Histopathology Phase Report P:lIDA hydnlyzed to PMA: Oral (Gavagel lleprodadioa/Developmmtal Toxicity 

### Saeeniog Test in 

### the 

### Rat (OECD GU 

### Table 1: Histopa:lhology

### sommaryiuddenc:e (continued) Female



### Dosage (mg/kg bw/day)

number ofanimals MAMMARY GLAND



### numberelWllined Lactation



### present OVARIES



### number e,wnined PARATHYllOID GLANDS



### numbereamined PITUITAllYGI.AND 

### numbereamined RECTUM 

### numberexamined SCIATIC NEllVE



### numbeream.ined numbereamined SPINAL CORD, LUMBAR



### numbereamined SPINAL CORD,

## mouac

numberexamined 0 

### 12 12 11 

### 12 5 

### 12 

## s 5 5 

## s 

## s 50 250 750 

### 12 12 12 12 0 11 3 

### 12 5 3 

### 12 

## s 

## s 5 

## s 5 

### Page 305

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlity Study

### No. 41:205815 Test SiteRefft'flltt No. 155-823 

### Report 

## Histopathology Phase Report PIIDA bydrelyzed to Pl-IA: Oral (Gavagel R.epl'Odudioo/Devdopmental Toxicity Screening Test in the 

### Rat (OECD 421} 

### Table 

### 1: Histopatbology

### summaryiocideRce (continued)

Dosage (mg/kg llw/day)

number ofammaJs SPLEEN



### numbereumined Emam.edulbryhaematopoies:is

-minimal 

### -mild -moderate Total STOMAal. GLANDUI.All



### numbereamined STOMAal. NON-GLANDULAR



### numberexamined 

### THYMUS

numbeream.ined Decrnsedmmallymphocytes

-minimal -mild 

### Total numbereamlned TRACHEA



### numbereamined URINARY BIA.DOER



### numbeream.inedl 0 12 5 1 1 1 3 5 5 6 3 2 5 5 5 

### so zso 750 12 12 12 5 2 3 0 5 5 5 5 4 1 5 5 5 4



### 18/lH 

### Page 306

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Family StlulyNo. 41lOS.lS Test Site Refermce 

### No. 155-023 

### Report 

## Histopathology Phase Report PMDA.. hydNll.yzed to Pl\lA: OraliGavage) Reprodm:tioa/Developmental Toxicity Screening Test in the 

### Rat (OECD 4lU 

### Table 1: Histopathologysommaryim:idenc:e (continued) iemale

Dosage 

### (mg/kg 

### IN/day) 0 50 250 750



### number ofan:imaJs 12 l2 12 12 Dl'ElUNE CERVIX



### number examined 12 3 12 UTER.US



### numbereamined 12 3 12 Regressing 

### implantation site(s) 

### present 11 0 11 

### cydical dilation 

### present 0 1 0 VAGINA



### numbermi:amined 12 3 12 

### MucifkationJ'b.da.tim:lmorphology



### present 12 0 11 

### Dioestrusmarphology



### present 0 0 1 

### ProestnsmorpMlogy



### present 0 1 0 J.lllelaestnls· morpholoa



### present 0 2 0



### 191115 

### Page 307

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlily 

### Stady No. 41205015 Test Sn

### RefH'ftKe No. 155-023 

### Report 

## Histopathology Phase Report PlMDA bydrelyzed to Pr.IA: Oral (Gavage) R.eprodm:tio.n.lDnelopmental Toxicity Setteaing 

### Test in the 

### Rat (OECD 42U

GENERAL INPORMATION 

### MACROSCOPIC FINDINGS MICROSCOPIC FWDIN'GS 

### KIDNEYS LIVER 

### Table Z: 

### Individual 

### animalpathologyfindings Auimal No.: 1 

### Sex: Male Doselevel: Control Deatil Day Number: 43.00 Start Date: .20-P'EB-2013 

### necropsy status: SCHEDULED KJLL No abnormality detected Intnmbularhyaline 

### droplets - mild Inflammatory cell focus(i) - minimal LYMPH NODE. MANDIBULAR. 

### PARATIIYB.OID GI.ANDS PROSTATE GLAND Intra,sinualcongestion/eryl:hropbagocytosispresent one secti011 ezamiDed Focos[i) m011onuclear cell mfihation - minimal Focal inflammation - mmimal TESTES 

### THYMUS Unilateral germinal epithelial 

### atrophy- minimal Post-mortem haemorrhage present No abnormalities found im ADRENAL CORTEX. ADRENAL MEDULLA. BRAIN., CAECUM. COAGUIATING GLANDS. COLON, DUODENUM, EPIDIDYMIDES, HEART, ILEUM, JEJUNUM, LUNGS, LYMPH NODE, MESENTERIC. MAMMAltY GLAND, PARATHYROID GLANDS, PITUITARY GLAND, RECTUM. SCIATIC NERVE, SEMINALVESICLES, SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR, SPINAL CORD, THORACIC, SPLEEN, STOMACH, GLANDUIAR. STOMACH. NON-GLANDULAR. THYROID GLANDS, TRACHEA. URJNARY BLADDER..



### 20/115

### Page 308

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

TestFadlfty Shuly 

### No.4:UOSOIS Test S- 

### llda'attt

### No.155-82.l 

### PMDA. llydnlyzedtoPMA.: Oral(Gavace) ~ental Tnidty Scremiag Test in die 

### Rat (OECD421)

NACROKOPIC RNDDIGS IIIIICROSCOPIC RNDDIGS LIVER LDIPB NODE. NESENl'EIIC PITUITAJlYGU.ND SPI.EEII TIIYNUS Death DayNumben 43.00 

### start Date: 2C>-PEB-2013 necropsystabls: SCHEDULED KILL
lnftammatvlycell focus(i)- minimal 

### IDtrasimlsal c:cmgestion/erytbn,phagocytosispresent Cyst(s) 

### present 

### EKlramecluDaryhaematopoiem -minimal Post-mortem

### haemorrhage present No almormalil:in found

## mtADRENAL CORTEX.ADRENAL MEDUIJ.A. BRAIN. CAECUM, COAGUIATDIG GLANDS. COLON. DUODENUM, EPIDIDYMIDES, HEAltT, ILEUM, JEJUNUM,. KIDNEYS, LUNGS. LYMPH NODE, MANDIBULAR, MAMMARYGLAND,PARATHYROID GLANDS, PROSTATE GU.HD, RECTUM. SCIATIC NEKVE, SEMINAi. VESICLES. SPUUL a>RD, CERVICAL. SPINAL CORD, LUMBAR. SPINAL CORD. THORA.CIC, STOMACH. GLANDULAR. STOMACH, NON-GU.NDULAR. TESTES.THYROID GLANDS. 

### TRACHEA. URINARYBLADDER.



### 111115 Page 309

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlity Stady 

### No. 4U0501S Test Site 

### Rfflrftlce No. 155-023 

### Report 

## Histopathology Phase Report ft.IDA bydrelyzetl 

### to PMA: 

### Oral (Gavagel Re,proda.rtiou/Developmeotal Toxicity 

### Screeuiug Test in the 

### Rat (OECD 421.1 

### Table 2: lndm.dual aniDlal patlmlogyfindings {continued)

GENERAL INFORMATION
MACROSCOPIC FINDINGS EPIDIDDUDES TESTES MICROSCOPIC FINDINGS EPIDIDYMIDES TESTES Animal No.: 3 

### Ser. Male Doselevel: Control Death Day Number: 43.00 

### start Date: 20-PEB-2013 

### necropsy status: SCHEDULED Kll.L Small Small Pl.ac:dd No abnormalities were found in 

### any ofthe othertissues examined 

### Bilateral hypospennia - marked (accounts for 

### gross finding) lntmubularsperm debris - mild Bi.lam-al germiml epithelial atrophy - moderate (accounts for gross finding) No abnormalme.s found in: .ADRENAL CORTEX. .ADRENAL MEDULLA. BRAllN, CAECUM. COAGULATING GLANDS. COLON, DUODENUM, HEART, ILEUM, JEJUNUM, KIDNEYS, UVER. LUNGS, LYMPH NODE, MANDmUl.AR. 

### LYMPH NODE, MESENTERIC. MAMMARY GLAND, PARATHYROID GLAMDS, PrrmTAJlYGLAMD, PROSTATE GLAND, RECTUM, SCIATIC NERVE. SEMINAL VESICLES, SPINAL CORD, CERVICAL.- SPINAL CORD, LUMBAR. SPINAL CORD, THORACC, SPLEEN, STOMACH. GLANDULAR. STOMACH, NON-GLANDULAR. TBYMUS, THYROID GLANDS, TRACHEA. URINARY BLADDER. 

### Page 310

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test 

### l'adlity Stady

### No.41205015 Test Site

### R.efat!llft No.155-023 PMDA 

### bJdnlJzed toPMA.: Onl(GaT.ge)**~** 

### Tmdcity Screening 

### Test in die 

### Rat (OECD421)

MACROSCOPIC RNDINGS
HEART PARATBYllOmGUNDS Dea1h Day Number: 43.00 Start Date: 20-PEB-2013 necropsystatus1 SCHEDULED KILL 

### No abnormality detected 

### POC11S(i) ofmyocarditls- minimal 

### one nction 

### mrammed No abnormalities found m:ADREN'ALCORTEX. ADRENAL MEDULLA. BRAJH. CAECUM. COAGULATING GLANDS. COLON. DUODENUM. EPIDIDYMIDES, ILEUM.JEJUNUM, KIDNEYS, 

### IJVER. LUNGS. LYMPH NODE, MANDIBULAR. LYMPH NODE. MESENTERIC. MAMMARY GLAND, PARATHYROm GLANDS, PITUfl"ARYGLAND, PROSTATE GLAND, RECTUM, SCATIC NEB.VE. SEMUIAL VESICLES, SPINAL CORD. CERVICAL, SPINAL CORD, WMBAR. SPINAL CORD. THORACIC. SPLEEN, STOMACH, GLANDULAJI:. STOMACH. NON-GLANDULAR. TESTES, THYMUS. THYROm GLANDS. TRACHEA. UR.IN.ARY BLADDER.



### 231115 

### Page 311

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlily 

### Stluly No. 41205015 Test Site Refennce No. ISS-0.23 

### Report 

## Histopathology Phase Report PMDA bydnlyzell

### to PMA: Oral (Gavage) Reprodw:tioDIDnelopmental Toxicity Sc:reeoiog Test in the 

### Rat (OECD 411) 

### Table 2: Individual animal 

### pathologyfiBdings 

### (c:ontianed)

GENERAL INFORMA110N
MACROSCOPIC FINDINGS LUNGS (WITH BRONCHI} MICROSCOPIC PIN'DINGS 

### KIDNEYS LUNGS MAMMAllY GI.AND SPLEEN Animal No.: 5 Sex: Male 

### Doselevel: Cootrol Death Day Number: 43.00 Start Date: 20-FEB-2013 necropsystatus: SCHEDULED KILL Reddened No abnormalimts 

### were foW1d in any of

### the othertissues examined lntratubuJarhyaline droplets • minimal Congestion - moderate (accounts 

### for gross finding) Focm(i) ofintra-alveolar pink fluid - mild No ti:!Slle available Extramedullaryhaematopoiesis - minimal No abnormalities found in: ADRENAL CORTEX. ADRENAL MEDULLA. BRAIN, CAECUM. COAGULATING GLANDS, COLON, DUODENUM, EPIDIDYMIDES, HEART, ILEUM, 

### JEJUNUM. LIVER. LYMPH NODE, MANDIBULAR. 

### LYMPH NODE. MESENTEJUC. PARATHYROID GLANDS, PITUJTARY GLAND, PROSTATE GLAND, RECTUM. SCIATIC NERVE. SEMJNAL VESICLES, SPINAL CORD, CERVICAL, SPINAL CORD, LUMBAR. SPINAL CORD, THORACIC. STOMACH, GLANDULAR. STOMACH, NON-GLANDULAR. TESTES, THYMUS, THYROID GLANDS, TRACHEA, URINARY BLADDER.



### 241115 

### Page 312

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlity 

### Shuly No. 4ll0581S Test Site

### Rftett11tt No. lSS-023 PMDA hydrolyzed to PMA: 

### On.I CGavage) R.ep:rodu.mon/Developmental Toxicity Saeening Test 

### in the 

### Rat (OECD 421) 

### Table 2: Individual animal patkologyfindings (coutiuued)

GENERAL INFORMATION
MACROSCOPIC F'DIDINGS MICROSCOPIC J'DlDINGS Animal No.: 6 Sex: Male 

### Dose lnel: COllb'cll Death Day Number: 43.00 

### start Date: 20-FEB-2013 necropsy status: SCHEDULED JOLL No abnormality detected No abnormality detected No abnormalities found in: COAGULATING GLANDS, EPIDJDYMIDES., MAMMARY GLAND, PITUITARY GLAND. PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 251115 

### Page 313

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlity Smdy 

### No.4120Si01S Test SiteRefeNDtt No. 155-823 

### Report 

## Histopathology Phase Report PMDA hydrolyzed to Pft.,IA: Oral (Gavage) Reprodudion!Deftlopmeotal To:d.c:ity Screeu:ing Test in 

### the 

### Rat (OECD 421J 

### Table2: lndmclual animal 

### patholoeYfindings 

### (continued)

GENERAl INFORMATION
MACROSCOPIC FINDINGS MKB.OSCOPIC ANDINGS EPIDIDYMIDES PROSTATE GLAND Animal No.: 7 Sex: Male 

### Dose level: 

### Control Death DayNumber: 43.00 SbrtDate: 20-FEB-2013 

### necropsy 

### status: SCHEDULED KJLL No abnormality detected Focal mcmonuclear cell infiltration - minimal Focal mllammation - minimal No abnormalities found im COAGULATING GLANDS, MAMMARY GLAND, PITUITARY GLAND, SEMINAL VESICLES, TESTES.



### 161115 

### Page 314

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test FadlilyStady

### No.41JOSOIS Test Site

### Refenlu:e Ne.155-823 PMDA 

### hydnl,-ItoPMA: Onl(GM'Bp)~Tmidty 

### Saeeoiog Test 

### in die 

### Rat (OECD Cl)

Death Day Number: 43.00 StartDate: 20-FEB-2013 

### necropsy 

### status: SCHEDULED DU.

No tissue available Ro 

### abnormalities found iD'I COAGULATING GLANDS, EPIDIDYMIDES. PITUITARY GI.ARD. PROSTATE GLAND, SEMINAL VESICLES, TESTES. 

### Page 315

17/JJj

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlily Stady 

### No. 41205015 Test Site RefeNDCe No. lSS-023 

### Report 

## Histopathology Phase Report J>i\.IDA hydrGlyzetl to J>i\.lA: Oral {Gavage) Reprodaction/Deftlopmeotal Toxicity Saeeoiog Test in the 

### Rat (OECD421} 

### Table 2: lndmdualanimal

### patkology:fiodings (continued)

GENERAL DIIFOl!lMATION
MACROSCOPIC FINDINGS MICROSCO.l'IC llINDINGS EPIDIDDUDES PITUITAllY GI.AND Anim:al No.: 9 Sele: Male Dose level: Ctmb'ol Death Day Number: 43.00 Start Date: 20-FEB-2013 necropsy 

### status: SCHEDULED KJLL No abnormality detected Focalmononuclear cellinfiltration - mmimal only pars distalis on section No abnormalities found in: COAGULATING GLANDS, MAMMARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 181115 

### Page 316

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlily Stady 

### No.4UOS'OIS Test Site Refettntt No. IS5-023 

### Report 

## Histopathology Phase Report RIDA hydnl,....

### to PMA: Oral 

### (Gavage) Reprodnctioa!Dewlopmeotal Toxicity Screeoiug 

### Test io the 

### Rat (OECD 421} 

### Table 2: Individual animal 

### patllologyfindings (continued)

GENERAL INFORMADON
MACROSCOPIC FINDINGS MICROSCOPIC RN'DINGS EPIDIDYMIDES Animal No.: 10 Sex: Male 

### Daselevel: Contnl Death Day Number: 43.00 

### Start Date 20-FEB-2013 

### o.ecropsy status: SCHEDULED KIILL No abnormality detected Foc:al mononuclearcell infiltration - minimal No abnormaltties found in: COAGULATING GLANDS, MAMMARY GLAND, PITUITAJlY GLAND, PROSTATE GLAND, SEMINAL VES]CLES, TESTES.



### 19/llJ 

### Page 317

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test FadlilyStady

### No.41295015 Test SiteR.lfenna. 

### No.155""23 PMDA 

### llytlnlyzedtoPMA.: 

### Oral(G--.)**~** 

### Tnidty ScreeaiDg Test 

### in die 

### Rat 

### (OECDGI)

AllbHI Ila.: 11 Sa: Male Dose

### lent COlllrol Death])ayNumher: 43.00 

### start Date= 20-PEB-2013 necropsy

### status: SCHEDULED KILL

No almormalit)' 

### deteded No abnormalities found

## m: COAGULATING GLANDS, EPIDIDYMIDES, MAMMARY GLAND, PlTUITARY GLAND, PROSl"ATE GLAND, SEMINAL VESICLES, TESTES.



### 30/lll

### Page 318

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fariffly Stndy No. 41l0591S Test Site Referea~ No. 155-023 

### Report 

## Histopathology Phase Report PMDA hydrelyzed to 

### RIA: Oral(Gavage,J Reprodudioll/Devdopmeotal 

### Tmicity Screening Test in tbe 

### Rat (OECD 421) 

### Tale 2: Individual

### animal pathology

### findings (continued)

GDIERAI. INFORMATION
MACROSCOPIC FINDINGS I.IIICR.OSCOPIC RNDINGS EPIDIDYMIDES Animal No.: 12 

### Sex: 

### Male Dose

### level: Control Death Day Number: 43.00 

### start Date: 20-FEB-2013 

### necropsy status: SCHEDULED KILL No abnormality 

### detected Focal mcmonud.ear cell infiltration - minimal No abnormalities found in: COAGULATING GLANDS, MAMMARY GLAND, PITUITARY GLAND, PROSTATE GLAND, SEMINAL VESJCLES, TESTES.



### 311115 

### Page 319

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Farility Stndy 

### No •. 4llOSGIS Test Site Refereutt No. ISS-0"-3 

### Report 

## Histopathology Phase Report ft.IDA hydrelyzed 

### to PMA.: Oral 

### 4Gavage) Reprodadion/Developmental. Tmc:ity 

### Screening Test in 

### the 

### Rat (OECD 421.t 

### Table2: Individualanimalpathologyfindings {continued)

GENERAL INFORMATION
MACROSCOPIC PIJIDINGS MICROSCOPIC JINDINGS Animal No.: ZS Sex! Mal,e Dose level: 50 mg/Ilg bw 

### /day Death Day Number: 43,00 

### start Date: 20-FEB-2013 necropsy 

### status: SCHEDULED KILL No abnormality detected



### 32/llJ 

### Page 320

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Facilky StadyNo.4UOS81S Test Site Refenntt 

### No. 

### 155-023 PMDA hydrolyzed to RIA: Oral (Ga,,,age) ReprodadionlDevelopmeotal Tosi.city 

## Saeeomg Test 

### in the 

### Rat (OECD421} 

### Table 2: Individual 

### animal 

### pathologyfindings (c:oo:tmued)

GENERAi. INFOKIIIATION
MACROSCOPIC RJIDINGS NICROSCOPIC AliDJNGS Animal No.: 16 Sn: 

### Nale Dose level: 

### 50mg/kg

### bw/day Death Day Number: 43.00 start Date:: 20-FEB-2013 

### necropsy 

### status: SCHEDULED KILL No abnormality detected



### 33/115

### Page 321

### Harlan Study Number: 41205015 

## Appendix 15 (continued) TestFadlity Stady 

### No.41:!05015 Test Site Re-I~ No.155-023 

### Report 

## Histopathology Phase Report PMDA. hydrolyze4 to PUA.~ Oral (GDTI11e) Reproda.ctioa/Dewlopmental Tmkity Saeeoiug 

### Test in 

### the Rat (OECD421) 

### Table 2: Individual

### animal pathologyfindings (continued)

GENERAL INFORMA.UON
MACROSCOPIC FINDINGS LUNGS (WITH BRONCHI) MICROSCOPIC FINDINGS EPIDIDDIIDES PANCREAS Animal No.: 27 Sex: Jllak, Dose 

### level: SO mg/kgtn, 

## /day Death Day Number: 43.00 startDate120-FEB-2013 necropsy status: SCHEDULED KILL medianlobe: Mass Fibrous mass 7mm x 7mm x7mm No abnormalities were found in any of the othertissues examined Focal mooonudear ceU infiltration - miD.imal Infarction. - moderate (LUNGS (WITH BRONCHI}) (acco1:111ts for gross 

### 61:lding) No abnormalities found in: COAGULATING GLANDS, MAMMARYGLAND, PITUIT.AR.YGLAND, PROSTATE GLAND, SEMfflAL VESICLES, TESTES.



### 14/115 

### Page 322

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test 

### Fadlby StadyNo. 4llOSOIS Test 

### SiteReference No. ISS-0"...3 

### Report 

## Histopathology Phase Report ftIDA hydnilyzm to 

### PMA: Oral {Gavage) Reprodu.etioa/Developmeatal. 

### Toxicity Screening 

### Test in the 

### Rat 

### (OECD 431) 

### Table2: Individual animal patlmlogyfindings (continued)

GENERA.1. INPORMATION
MACROSCOPIC FINDINGS M.lCROSCOPIC RNDINGS Animal Ne.: 28 Sex: Male Doselevel: 50 mg/kghrw/day Death Day Number: 43.00 Start Date: 20-JEB-2013 necropsy 

### stams: SCHEDULED KILL No abnormality detected



### 351115 

### Page 323

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fa.ciffiy 

### Stady No. 41:lOSOIS 

### Test Site Ret'erence No.155.023 

### Report 

## Histopathology Phase Report SID.A. hydnlyzed 

### to Pl\•IA: Oral (Gavage) Reprodadioa!Developmeotal Toxicity ScreeDDII Test io tbe 

### Rat (OECD 421) 

### Table 2: 

### lndmdoalanimal

### pathologylindings (continued)

GENERAL INFORMATION 

### MACROSCOPIC FINDINGS

NJCROSCOPICFINDINGS TESTES Animal No.: 29 SR: 

### Male Dose

### level: 50 mg/kg

### bw/day Death Day Number: 43.00 Smrt Date: 20-FEB-2.013 

### necropsy status: SCHEDULED KJLL Small Small 

### Fl.aodd No abnormalities were found in 

### any ofthe other tissues 

### examined Bilatera:] hypospermia - severe (accounts for gross finding} 

### lntratubwar sperm debris - mild Bi1aterali germiDal epithelial 

### atrophy - severe (accounts for gross 6:nding} No abnormalities found in: COAGULATING GLANDS, MAMMARY GLAND, PITUITARY GLAND, PROSTATE GLAND, SEMINAL VESICLES.



### 361115 

### Page 324

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Facility Sm.tty No.4UOSOIS Test Site 

### R.mretKe No. 155-0"J 

### Report 

## Histopathology Phase Report PMDA hytlrelyzed to PUA: Oral 

### (Gavage) Reprodadion!Developmeotal Toncity Scll'ffaiug 

### Test in the 

### Rat (OECD 411) 

### Table 2: Individual animal 

### pathologyfimlinp: (continued)

GENERAL INFORMATION
MACROSCOPIC IIDIDINGS MICROSCOPIC FINDINGS Animal No.: 30 Sex: 

### Male 

### Dose kwel: 50 

### ml/klhw/day Death Day Number: 43.00 start Date: 20-FEB-2013 necropsy statwl: SCHEDULED KILL No abnormality detected



### 371115 

### Page 325

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Flldlily 

### StadyNo.41295815 Test Site

### Reference No.155-823 PMDAhydrulJ'ZNtoPMA: Oral(Gavap)**~** 

### Tozimy Screening Test in the 

### Rat (OECD 421)

MACROSCOPIC RNDINGS Animal No.: 31 Smc Male Doselevel: 50

### mg/lq:

## hw/da.f DeathDayNumlier. 43.00 

### start DDI 2CHEB-2Cl13 mcropsystam: SCHEDULED KJLL No abnormality detected

JBllIS 

### Page 326

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test 

### Fadltty StadyNo. 4UOSOIS Test Site R.eferew::e 

### No. lSS-023 

### Report 

## Histopathology Phase Report PMDA bydnlyzed to 

### PMA: Oral (Gavage) Reprodudion!Developmeotal 

### Tcmcity 

### Screeomg Test io the 

### Rat (OECD 421) 

### Table 2: Individual animal. 

### pa.tllologffindings (continued)

GENERAi. iNFORMATION
MACROSCOPIC PDIDINGS MJCROSCOPIC RNDINGS Animal No.: 32 Sex: Male Doselevel: 58 mg/kgbw/day Death Day Numhen 43.00 start Date: 20-FEB-2013 

### n«n>psy

### status: SCHEDULED KILL No abnormality detected

39!11J 

### Page 327

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadffiy Study 

### No. 41205015 Test SiteReference No.155-023 

### Report 

## Histopathology Phase Report Pfl.IDA hydrolyzed 

### to PMA: Oral 

### (Gavage) ReprodamonlDeftloJIDleofal TmkUy Saemiug Test io the Rat 

### (OECD 421) 

### Table 2: Individual aoiJDal 

### pathology

### findings {continued)

GENERAL INFORMATION
MACR.OSCOPIC FINDINGS MICROSCOPIC FINDINGS Animal No.: 33 

### SB: 

### Male Deselevel: SOmg/kgbw/day Death Day Number: 43.00 Start Date: 20-FEB-2013 necropsy statns: SCHEDULED KlLL No abnormality detected No tiSSlles enmined



### 40ll15 

### Page 328

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadliiy Stady

### No•. 4ll054>1S Test Site RefeNDtt 

### No. 155-023 

### Report 

## Histopathology Phase Report PflIDA 

### hydnlJZH. to PMA: Oral (Gavage) lleprodactimtlDevelopmeutal Toxidty Saeeniag Test in 

### the 

### Rat (OECD 4ll) 

### Table 

### 2: IDdmdloal 

### animal padmlogyfindings {coolinued)

GENERAL INFORMATION
MACllOSCOPIC RNDINGS MICROSCO.PIC FIXDINGS Animal No.: 34 Ser. Male 

### Doselevel: SOmg/kgbw/day Death Day Number: 43.00 

### start Date: 20-FEB-2013 necropsy

### status: SCHEDULED KllLL No abnormality detected No tiSSlles examined



### 411115 

### Page 329

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Facilily

## SladJ' No.41JO!OIS Test Sile 

### Refenace 

### Ne. 155-01.l PIIDA hydnl:,zedtoPMA: Oral(Glmlge) 

### R~ TOJlidty Screening 

### Test in die 

### Rat 

### (OECD421)

N.ACROSCOPIC RNDIRGS 

### Animal No.: 35 Sa: Male 

### Do•lenl: 50-c/llgbw/day Death Day Number. 43.00 Slut Daliel: 20-PEB-2013 

### necropsy st:atm1 SCHEDULED KJLL

No 

### almmmality detected No 

### abaormalitia found 

### m= COAGULATING GLANDS, EPIDIDYMIDES, MAMMARY GLAND, PITUlTARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 42/llj 

### Page 330

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fariliey Stady No.4ll0501S 

### Test SiteRe.f'erence No. 

### 155-023 

### Report Page 331 

## Histopathology Phase Report PIIDA hydrolyzed 

### to PAIA: Oral 

### (Ga,,age} R.eprodudioalDevelopmental Toxicity Screening Test in 

### the Rat 

### (OECD Gl) 

### Table2: ladividuaJ animal 

### pathologyfindings {amtinued)

GENERAL INFORMATION
NACROSC:OPIC FINDINGS MICROSCOPIC RNDINGS Animal No.:: 36 Sex: Male Dose 

### level: 5D 

### mg/kg

## n/day Death Day Number: 43.00 

### Start Date: 20-FEB-2013 necropsy

### status: SCHEDULED KJLL No abnormality detected No tissues examined



### 4;111;

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlity 

### StadyNo. 4llOSOlS Test Site Refer-.::e No. lSS-023 

### Report 

## Histopathology Phase Report PMDA 

### bydnlyzed to PM.A: 

### Oral iGavage) Reprodl!ldioa/Developmeotal Toncity Sc:reeoiug Test in the 

### Rat (OECD 421) 

### Table2: Individual animal pathologyfindings (continued)

GENERAL INPORMA.UON
MACROSCOP!IC FDlDINGS MICROSCOP!IC JINDINGS Animal No.: 49 Sex: Male Dose level: 250 

### mg/kg'bw/day Death 

### Day Number: 43.00 

### start Date1 20-FEB-2013 necropsy

### status: SCHEDULED KILL No abnormality detected No tiS311es examined



### 44/115 

### Page 332

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlicy .Stady 

### No.4ll058IS Test Site Rl'fereutt No. ISS-0"-3 

### Report 

## Histopathology Phase Report Pl-IDA bydnlyzed 

### to Pl-IA: Oral 

### (Gavage> Repro~talToxicity Screening Test in the 

### Rat (OECD GI} 

### Table2: Individual anboal pa:tllologyfindings 

### (continued)

GENERAL INPORMA'l10N
MACROSCOPIC FINDINGS MICROSCOPIC JDlDINGS A.Dim.al No.: 50 Sex: Male Dose

### level: 250 

### mg/Ilgbw 

### /day Death Day Number: 43.00 Start Dare: 2(1-FEB-ZO 13 necropsy 

### status: SCHEDULED KILL 

### No abnormality detected No tissues examined

451115 

### Page 333

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlhy 

### Shuly No.4U05015 Test SileReferem:e No. 

### 155-023 

### Report 

## Histopathology Phase Report Pl-IDA bydnlyzed.

### to Pl\lA: Onl (Gangel Reprodumoa/Dffdopmmtal Toxkity Scremiog Test in die 

### Rat (OECD 43U 

### Table2: Individual animal

### path.ologyfindings (continued)

GENERAL U&ORMATION 

### MACROSCOPICF'INDDIIGS J.IIJCR.OSCOPIC ANDDfGS Animal No.: 51 Sex: 

### Male Dose

### level: 2:50 mg/Ilg

### bw 

### /day Death Day Numben 43.00 

### start Date: 20-P'EB-2013 

### necropsy 

### status: SCHEDULED Kl1LL No abnormality detected



### 46/lJj 

### Page 334

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Farilliy Stady 

### No.4UOSOIS Test Site Raereace No. 155-023 

### Report 

## Histopathology Phase Report PMDA hydrelyzed to PMA: Oral (Gava.g,e) 

### Reprodadion!Developmental Tou:ity Sc:reeniog Test in the 

### Rat (OECD 421> 

### Table2: Individual

### animal pathologJfindings 

### (continued)

GDIEU.l. lNFORMAUON'
MACROSCOPIC JDmINGS MICROSCOPIC FDIDIN'GS Auimail No.: 52 SB: Male Doselevel: 250 mg/q

### bw/day Death Day Number: 43.00 Start Date: 20-FEB-2013 necropsy 

### status: SCHEDULED KllLL No abnormality detected No tissues eumined



### 47/115 

### Page 335

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadffly Stady 

### No. 4U050lS Test Site Refffftltt No. lSS-023 

### Report 

## Histopathology Phase Report RIDA hyd£elyzed to PlfA.: Oral (Gavage) Reprodadion/Developmeotal Toxicity Screening Test in the Rat (OECD 421) 

### Table 2: Individual

### animal pathologyfindi.np {couti.Bued)

GENERAL INFORMATION
MACROSCOPIC FINDINGS MICROSCOPIC RNDDfGS Animal No.: 53 Sele: Male 

### Doselevel: 250mg/kglnr/day Death Day Number: 43.00 Start Date: 20-FEB-2013 

### necropsy status: SCHEDULED Kl!LL No abnormality 

### detected No tismes examined



### PDrMillar ..h.sociates: 

### Ud. - 21-.4.ttg-2013 - Cimftdenttal 

### 481115 

### Page 336

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fadlity StadyNo.41205015 Test Sh:Refereaft

### No.155-823 PMDAbydnlyzed

### toPUA: Oral (Gtmtp)**~** 

### Tmdty 

## Scremilllc Test in die 

### Rat (OECD421)

AllilDal No.: 54, Sa: Male 

### Dmelenl: 250-c/llglnr/day Death DayNumber: 43.00 

### start Date: 20-PEB-2Cl13 necropsy 

### status: SCHEDULED KILL



### 491115 

### Page 337

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report TestFadlity StudyNo.41JUD15 Test Site Rdenace 

### No. lS5-023 

### PMDA .,...,._.toPMA: Oral.(Gavage)**~** 

### Tmddty Screming 

### Test in die 

### Rat (OECDGl)

&ENERAL INFORMATION Animal No.: 55 Sa: Male DNe

### level: 250 mg/llglrw/day Deatb DayNumben 43..00 Start Date: 20-JEB-2013 necropsystat.us: SCHEDULED KILL



### 50/115 

### Page 338

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Family 

### Study No. 41205815 Test Site Rrferentt No. ISS-023 

### Report 

## Histopathology Phase Report PMDA hydnlyzed 

### to PMA: Oral 

### (Gavage) ReprodactionJDefflopmmbd Toxicity Screening Test in the 

### Rat (OECD 4?1) 

### Ta'ble 2: Individual 

### animalpat.hologyfindings (matinued)

GENERAL llftl'ORMA110Ji
MACROSCOPIC FINDINGS

MICROSCOPIC ANDINGS KIDNEYS Animal No.: 56 Sa: Male 

### Doselevel: ZSOmg/kgbw/day Death Day Number: 43.00 

### Start Date: 20-FEB-2013 

### n.ecropsy status: SCHEDULED JDLL lm:reased Pelvic Space left Fluid Filled

### left No abnormalities were foWJd in 

### any ofthe othertissues examined Unilateralhydronepbrosis - mild (accounts for gross findi~



### 511115 

### Page 339

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test FadHly StmlyNo.41205015 Test Site

### Reference No.155-023 PMDA hydnlyzed.to

### PMA: Oral(ea-p)**~** 

### Tmidty Saeea:iag 

### Test in Die 

### Rat (OECD421)

MACROSCOPIC IIINDDIIGS Allilllal No.: 57 Sa: Male Dose

### level: 258 

### mg/lrgbw/ay Death DayNumber. 43.00 

### startDate: 20-FEB-2013 DIICl'OJISY 

### status: SCHEDULED KJLL No abnormality detected No tissues examined

52/llS 

### Page 340

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Farility 

### StadyNo.41:!0SDIS 

### Test Sitelt.denott No •. lS5-02J PMDA hydrelyzed to PMA: Oral 

### {GlWBge) lt.eprodudion/DevelopmeotalToxicity Saeeoiog 

### Test 

### in die 

### Rat (OECD421) 

### Table2: lndividoalaoi:mal pathology

### findings (conti.maed)

GENERAL INFORMATION
MACROSCOPIC FINDINGS MICROSCOPIC FINDINGS 

### Animal No.: 

### 58 SB: Male 

### Doselevel: ZSOmg/kgbw/day Death Day Number: 43.00 

### start Date: 20-FEB-2013 

### necropsy status: SCHEDULED KILL No abnormality detected



### 53111.5 

### Page 341

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily Stady 

### No.41285015 Test Site~

### No.155-023 PMDA llydnlyzed. to PMA: Onl(Glnraae) 

### ~tat Tmdcity Screeaiug Test 

### in die 

### Rat (OECD421)
Animal No.: 59 Su: Male DDSe len:1: 258 mg/Ilg

## n /day Death. DayNmnhen43.00 

### startDateiJ 20-FEB-2013 necropsystatus: SCHEDULED mt.



### 541115 

### Page 342

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

TatFamily Smdy

### No.4ll05D15 Tat Sile

### Refeftnft No.155-023 PMDA bydnlped.toPMA: Onl(Glmlge)**~** 

### Toiddty 

## Screeoiu& Tat in

### tile 

### Rat (OECD421)

Death 

### Oaf Number: 43.cJO Slut Daile: 20-F'EB-2013 

### necn,psy

### status: SCHEDULED KILL No 

### abaonmJity detec.ted

551115 

### Page 343

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fariluy Study

### No.41205015 Tm 

### SiteRmre-nc:e No. lSS.OlJ 

### Report 

## Histopathology Phase Report PMDA 

### hydrolyzed to PM:A: Oral tGavage) R.q,rodudion/Developmeotal Toxicity Screening Tm in the 

### Rat 

### (OECD 421) 

### Table2: lndMdual animalpatkologyfi.odings 

### {continued) Animal No.: 73 Sex: Male Dose level: 750 

### mg/kgn/day GENERAL INFORMATION
MACROSCOPIC FINDINGS MKROSCOPIC FINDINGS KIDNEYS LIVER LYMPH NODE. MANDIB'UU.R PARATBYROmGIANDS UJiUNAJlYBIADDER Death Day Number: 43.00 start Date1 20-FEB-2013 necropsy status: SCHEDULED KJLL No abnormality detected lntratubularhyaline 

### droplets - mild Inflammatory cell focus(i) - mimmal lntrasinnsalc:.angestion/erytbrophagocytosis present one section 

### 9Ullned No tissue available No abno.rmalities found in: ADRENAL CORTEX. ADRENAL MEDULLA, BRAIN, CAECUM, COAGULATING GLANDS, COLON. DUODENUM, EPIDIDYMIDES, HEART, ILEUM, 

### JEJUNUM, LUNGS, LYMPH NODE, MESENTERIC, MAMMARY GLAND, P.AJIATHYROID GLANDS, PITUITARY GI.AND, PROSTATE GLAND, RECTUM, SCIATIC NERVE, SEMINAL VESICLES, SPINAL CORD, CERVICAL, SPINAL CORD, LUMBAR. SPINAL CORD, THORACIC, SPLEEN, STOMACH, GLANDULAR. STOMACH, NON._(jLANDUUR. TESTES, THYMUS, THYROID GLANDS, TRACHEA.



### 561115 

### Page 344

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlity Stady No. 4UOSOIS Test Site 

### RefereJKe No. ISS..023 

### Report 

## Histopathology Phase Report Pl.IDA hydrolyzed 

### to Pl\lA: 

### Oral (Gavage) Reprochu:tiou/Developmeotal Toxicity 

### Screening Test in the 

### Rat (OECD 42:1} 

### Table2: lndividuaJI 

### animal pathology

### findings (continued)

GENERAL INFORMATION
MACllOSC:OPIC n:NDINGS MICROSCOPIC P'DfDINGS UYER A.oiliDal. No.: 74 Sex: Male Dose level: 750 

### mg/kgbw/day Death Day Number: 43.00 

### start Date: 20-FEB-2013 necropsy status: SCHEDULED KJLL No abnormality detected lmlammatorycell focus(i) - 

### :minim.al No abnormalities found in: ADRENAL CORTEX. ADRENAL MEDULLA. BRAJN, CAECUM, COAGULATING GLANDS, COLON, DUODENUM, EPIDIDYMJDES, HEART, ILEUM, 

### JEJUNUM, KIDNEYS, LUNGS, LYMPH NODE, MANDIBULAR. LYMPH NODE.. MESENTEJUC, MAMMARY GLAND, PARATHYROID GLANDS, PITUITARY GLAND, PROSTATE GLAND, RECTUM, SCIATIC NERVE, SEMINAL VESICLES, SPINAL CORD. CERVICAL. SPINAL CORD, LUMBAR. SPINAL CORD, THORAac. SPLEEN, STOMACH. GLANDULAR. STOMACH, NON-GLANDULAR. TESTES. THYMUS, THYROID GLANDS, TRACHEA. URINARY BLADDER.

Ptliflr

### Millarb.wciates Ltd. -11-.4ug-1011 - Confirlminal 

### 571115 

### Page 345

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadffly Study No.4llOSOlS Test SiteReference No. 155-023 

### Report 

## Histopathology Phase Report PMDA bydnlyzed to PMA: Oral 

### (G-age) Reprodndioa!Developmeotal Toxicity Screening Test iD the 

### Rat (OECD 421) 

### Table 2: Individual aoilOal pafllol.ogyfindings (continued)

GENERAL INFORMATION
NACllOSCOPIC FINDINGS MICROSCOPIC FINDINGS LIVER PARATHYB.Om GI.ANDS SPLEEN Anilllal No.: 75 Sex: Male Dose level: 750 

### mg/kgbw 

### /d:q Death Day Number: 43.00 

### start Date: 20-FEB-2013 necropsy 

### status: SCHEDULED KILL No abnormality detected mflammatory cell focus{i) - minimal one section 

### exam.med Extramedullaryhaematopoiesill - minimal No abnormalities found in: ADRENAL CORTEX. ADRENAL MEDULLA. BR.Ail'f, CAECUM, COAGUIATING GLANDS. COLON., DUODENUM, EPIDIDYMJDES, HEART, ILEUM, JEJUNUM. KIDNEYS, LUNGS, LYMPH NODE, MANDIBULAR.. LYMPH NODE. MESENTERIC. MAMMARYGLAND, PARATHYROID GLANDS, PITUITARY GLAND, PROSTATE GLAND, RECTUM, SCIATIC NERVE, SEMINAL VESICLES, SPINAL CORD, CERVICAL. SPINAL CORD, LUMBAR. SPINAL CORD, THORACJC, STOMACH, GLANDULAR. STOMACH, NON-GLANDULAR, TESTES, THYMUS, THYROID GLANDS, TRACHEA. UlUNARY BLADDER.



### 581115 

### Page 346

### Harlan Study Number: 41205015 

## Appendix 15 (continued) Test Fadlily 

### StadyNo. 41205015 Test Site Kdenace No. 155-023 

### Report 

## Histopathology Phase Report PMDA hydrolyzed to PAIA: OraliG-.e) KeprodnctioD!Developmeotal Toxicity Screeaiug Test iD the Kat (OECD CU 

### Table2: IDdiriduaJ aohnal

### pathologyfindings {c:ontinued)

GENERAL INFOllMATION
MACROSCOPIC FINDINGS MICROSCOPIC RNDINGS KIDNEYS TESTES Animal No.: 76 Ser. Male Doselevel: 750 mg/kgbw 

## /day Death Day Nwnben 43,00 Start Date. 20-FEB-2013 necropsy

### status, SCHEDULED KJLL No abnormality detected lntratubularhyaline droplets - mild Unilateral germinal epithelial atrophy- minimal No abnormalities found in: ADRENAL CORTEX. ADRENAL MEDULLA. BRAJN, CAECUM, COAGULATING GLANDS, COLOM, DUODENUM, EPIDIDYMJDES, HEART, ILEUM, 

### JEJUNUM. LIVER. LUNGS, LYMPH NODE, MANDIBULAR. LYMPH NODE, MESENTEJUC, MAMMARY GLAND, PARATHYROID GLANDS, PITUITARY GLAND, PROSTATE GLAND, RECTUM, SCIATIC NIEKV& SEMINAL VESICLES, SPINAL CORD, CERVICAL, SPINAL CORD, LUMBAA. SPINAL CORD, THORACIC, SPLEEN, STOMACH. GLANDULAR. STOMACH, NON-GIANDUIAR.THYMUS, THYROID GLANDS, TRACHEA, URINARY BLADDER.

S9111J 

### Page 347

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fa.dlhy StadyNo.41205015 Test Site

### Relenace No. lSS-823 PMDA bydralyzed.to PMA.: Oral 

### (G1m1p)**~** 

### Tmddty Screeniag Test in 

### die 

### Rat (OECD421)

MM:llOSCOPIC FINDINGS 

### Allmllll. Ra.: 77 Sa: 

### Nale Due left): 750

## mc/llg&w/my Deatlt Day 

### Numhen 43.00 Start Date: 20-PEB-2013 IHICIDpsJ' 

### status: SCHEDULED KILL No abn.onnality det8cted POCII mODODuclear eel i1lfiltration - mmimal IDtratubularhyaline 

### droplets - minimal Inflammatory 

### celfocus{i) - minimal 

### PerinsC'ular mCIDODUdear eel infiltration - mmimal one section

### u:amined Pmt-martmn

### haemormappnsent No tissu a.vai1alile No 

### abnonmlities found iD:ADRDfALCOR.TEX. ADRENAL MEDULLA. BRAIN.CAECUM, COAGULATING GLANDS. COLON. DUODENUM. HEART. ILEUM, 

### JEJUNUM. LYMPH NODE.MANDIBULAR. LYMPH NODE, MESENTERIC. MAMMARY GLAND, PARATHYROID GLANDS. PlTUITAllY GUJID, PROSTATE GLA.JID, 

### RECTDM. SCIA11CNEllVE. SEMINAL VESICLES, SPINAL CORD. CEJtVICAL. SPDl'AL CORD. LUMBAR. SPINALCORD, TIIORACIC. SPLEEN, STOMACH. GUJIDULA.R.. STOMACH. NON-GLANDULAR.. 

### TESTES. 

### nmtomGU.NOS. TRACHEA.

60/J.Jj 

### Page 348

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

TestFacility 

### StadyNo.412U015 Test Sile Refereaft 

### No. lSS-023 PMD.A 

### hydnlpmtoPMA.: Oral.(Ga-ce)**~** 

### Ttmdty Screening Test in 

### die 

### Rat (OECD421)

IIIICIIOSCOPIC '.PDIIDINGS AniBlal No.: 78 Sm; 

### Male Dose

### level: 758 

### mg/Jlgbw/day Death DayNwnberi 43.00 

### startDatet 20-FEB-2013 

### necropsy statm1 SCHEDULED Kll.L

No abnormality dmt:tecl No almmmaJities 

### found in: COAGULATIKG GLANDS, EPIDIDYMIDES. MAMMARY GLAND. PITIJITARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 611115 

### Page 349

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fadlily Stady

### No.41215815 Test Site ihferetlft

### No.155-823 PMDA hytlnlyzedtePMA: Onl(Gavage)**~** 

### Tomdty Screening 

### Test in 

### tile 

### Rat (OECD421)

DeathDayBwnher: 43.00 Start Date= 20--PEB-2013 necropsy

### status: SCHEDULED KILL


### Unil.amalpnnmalepithelial 

### atrophy- minimal No abnormalities found iD;: COAGULATING GLANDS, EPIDIDYMIDES. MAMMAILYGLAHD, PITUITARY GLAND, PROSFATE GLAND, SEMINAL VESICLES.



### 62/lJj 

### Page 350

### Harlan Study Number: 41205015 

### Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlity Study No. 41205815 Test Site RefeHDtt 

### No. 155-023 Pl-IDA hydrolyzed to 

### PMA: Oral 

### {Gavage) R.eprod1U:tion}evelopmeotal 

### Toxicity Screening 

### Test in the 

### ht(OECD421) 

### Table Z: 

### Individual animal 

### patllology

### findings (continued)

GENERAL INFORMATION
MACROSCOPIC FINDINGS MICROSCOPIC JDIDINGS Pl11JIT.AllY GI.AIID Aubnal No.: 80 

### Sex: Male 

### Doselevel:: 750mg/llgbw/day Death DayNumber: 43,00 start Date-: 20-FEB-2013 

### necropsy 

### status: SCHEDULED KJLL No almormal:ily detected onlypars distalis on section No abnormalities found in: COAGULATING GLANDS, EPIDJDYMIDES, MAMMARY GLAND, PROSTATE GLAND, SEMINAL VESJCLES, TESTES.



### 6Jl1H 

### Page 351

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Farility 

### ShulyNo.4UOSOLS Test Site Reference No.155-023 

### Report 

## Histopathology Phase Report Pl\IDA bydnlyzed 

### to PMA.: Oral 

### (Gavage) R.eprodaction!Developmeotal Tmicity 

### Screming Test in 

### the Rat (OECD 4ll) 

### Ta'ble 2: Individual aoi.mal 

### patkology

### 6ndiags 

### {c:ootinued)

MACROSCOPIC FINDINGS MICROSCOPIC P'IXDINGS 

### Animal No.: 

### 81 Sex: Male Dose 

### level~ 750 

### mg/kgbw/day Death Day Number: 43.00 

### start Date: 20-FEB-2013 

### necropsy status: SCHEDULED Jal.L No abnormality detected No abnormality detected No abnormalities found in: COAGULATING GLANDS, EPIDIDYMIDES, MAMMARY GLAND, PITUITARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.

641115 

### Page 352

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlity Study

### No.41205815 Test Site 

### Refenm:e No. 155-023 PftIDA 

### hydrolyzed. to 

### Pl\.fA.: Oral (Ga,rage) Reprodu.dioDIDevelopmeotal 

### Toxicity Saeeoiug Test in the Rat 

### (OECD 421) 

### Table 2: Individual animal 

### pathologyfindings (am.tinned)

GENERAi. iNFORMATION
MACROSCOPIC FINDINGS MICROSCOPIC FINDINGS Animal No.: 82 Sex: 

### Nale Dose level: 750 mg/kglnr 

## /day Death Day Number: 43.00 Sblirt Date: 20-FEB-2013 necropsy 

### status: SCHEDULED KJLL No abnormality detected No abnormality detected No abnormalities found in; COAGULATING GLANDS, EPIDIDYMIDES, MAMMARY GLAND, PITUITARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 651115 

### Page 353

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test 

### Fadffly Stady

### No.4ll0501S Test SiteRefermtt No. ISS-023 

### Report 

## Histopathology Phase Report Pl-IDA hydnlyzed to 

### PMA: Oral (Ga,rage) Reprudadiml/Developmeotal Toxicity Screening Test io 

### the 

### Rat (OECD Gll 

### Table2: Individualanimal

### pathologyfimlings (cootiBued)

GENERAi. iNFORMATION
MACROSCOPIC FDilDINGS MKR.OSCOPIC J'INDINGS Animal Na.: 83 

### Sex: 

### Male Doselevel~ 750mg/kghw/day Deai'h Day Nwnben 43.00 

### start Date: 20-FEB-2.013 

### necropsy status: SCHEDULED KJLL No abnormality detected No abnormality detected No abnormalities found in: COAGULATING GLANDS, EPIDJDYMIDES, MAMMARY GLAND, PmnTARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 66/11.5 

### Page 354

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Tat Fadlby StadyNo.41205015 Test Site Refereutt 

### No. 155-023 ft.IDA hydnlyzed to PMA: Oral (Gavage) Reprodtu:tioll/Denlopmeotal Toxkity Screening Test in the 

### Rat (OECD 421) 

### Tahle2: Individualanimal 

### pathology

### findings (continued)

GENERAL INFORMATION
NACROSCOPIC PDlDINGS MJCROSOOPIC FINDINGS Animal No.: 84 SelC: Male 

### Doselevel: 750mg/kgbw/day Death Day Number: 43.00 

### Start Date: 2CHEB-2013 

### necropsy 

### status: SCHEDULED KJLL No abnormality detected No abnormality detected No abnormalities found in: COAGULATING GLANDS, EPIDIDYMIDES, MAMMARY GLAND, PlTUITARY GLAND, PROSTATE GLAND, SEMINAL VESICLES, TESTES.



### 671115 

### Page 355

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily

### StadyNo.41205815 Test Site Rmnu.ce 

### No.155-023 PMDA hydrolyzed toPMA: Oral 

### (Gnage)**~** 

### Ta.deity Screening Test 

### in tile 

### Rat (OECD421)

GEIIERAJ. INPOIUU.1'10N Death DayNumber: 43.00 

### startDate: 20-PEB-2013 nec:rupsystatus: SCHEDULED KILL

Lactationpresent -secti.onexamined 

### Exl:nmeduDary haematopoiesis - 

### moderate Dec:nued cortical

### lymphoqrb,s- mild No tillSll.e avaBable RegressiDg implmtation 

### site(s) present 

### Mucificd:ion/)ac:tation morphology

### pnstmt No alm.mm:dities 

### foUDd in:ADRERAL COJlTEX. ADRENAL MEDULLA. BUD'f,CAECUM. COLON. DUODENUM. HE.AllT, ILEUM. )EJUNUM. ICIDffEYS. 

### LIVER. LUNGS. LYMPH NODE, MANDIBULAR.LYMPH NODE. MESENT£RIC, OVARIES. PARATBYJt.Om GLANDS, ffltDT.AltY GLAND, REcnJM,. SCIATIC REDE.SPINAL CORD, CERVICAL, SPINAi.CORD, LUMBAR. SPINAL CORD, 'fflORACIC. STOMA.CH. 

### GU.KDUIAR. STOMACH. HON-GLANDULAR. THYROm 

### GU.KOS. TRACHEA. trrElUNE CERVDL



### 68/llS 

### Page 356

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily SbulyNo.4UOS815 Test SiteRefeftnce No. 155-823 PMDA. 

### •ydralyzed 

### toPMA: Oral (Ga,,age) 

### Rep~ 

### Ta:ddty Screeuiug 

### Tat in Ole 

### Rat (OECD421)

Delltb DayNumber: 43.00 StartDate: 20-FEB-2013 

### necropsy stafm1 SCHEDULED KILL

Lactation

### pruent 

### ane secticmeumimld Deaeased corticallymphocytes- minima) Regressing implantation site(s) 

### pruent Mucmcation.J)ad:ation morpho)ogypresmt No almmmalities found iDI ADRERALCOJLTEX. ADRENAL MEDUJJ.A. BRAIN. CAECUM. COLON, DUODEHUM,HEAllT, 

### B..EUM. JEJUNUM, 

### DDNEYS. LIVER. LUNGS. LYMPH NODE. MANDIBUUR.LYMPH NODE. MESENTERIC, OVA.RIES. PARATHYROID GLANDS, PITUITAltY GLAND, REC'l1JM, SCIATIC NEKVE.SPINAL CORD, CERVICAL SPINAi.CORD, LUMBAR.SPINAL CORD, THORACIC. SPLEEN, STOMACH. GLANDULAR. SMMACH. NON-GLANDULAR. THYROID GI.A.NOS. TRACHEA. U11INAltYBLADDER. UTERINE CE:R.VIX.



### 69/lJj 

### Page 357

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily Stady

### No.41285815 Test Sib~

### No.155-t23 

### PMDA hydlr..,_.toPMA: Oral.(Gavage')**~** 

### Tmdty Screeaillg 

### Test io die 

### Rat (OECD421)

NlalOSCOPICRJIDINGS Animal No.: 15 Sa: 

### Female Dose level: 

### Caatrol Death Day Nwnben 43.00 St.utDate: 20-iEB-2013 

### necropsy 

### status: SCHEDULED KILL



### Dec:Rued cortical 

### lymphocytn- mild Mw:ificdion/Jactation morphology

### present No 

### abnmmalilia found int LUNGS, MAMMARY GLAND, OVARIES, PITUITARY GLAND. UTERINE CERVIX. UTERUS.



### 70/llj 

### Page 358

### Harlan Study Number: 41205015 

## Appendix 15 (continued)

Test Fadlhy Stwly 

### No. 4Il0501S Test SiteReference No.1SS-02J 

### Report 

## Histopathology Phase Report MIDA hydrelyzed 

### to Pl-IA.: Oral 

### (Gavage) Reprodamon/Developmeotal Tcmcity Screeoiug Test in the 

### Rat (OECD 421) 

### Table2: Individual animal 

### pathologyfindings (continued) Animal No.: 16 GENERALINFORMAnON
MACROSCOPIC FINDINGS MICROSCOPIC FINDINGS LYMl'B NODE, MESENTERIC MA.MI.IIAllY GLAND PARATHYROm GLANDS 

### SPLEEN UTERUS VAGINA Sex: Female Dose 

### level: Control Death Day Number: 45.00 

### start Date: .20-FEB-2013 

### necropsy status: SCHEDULED KILL No abnormality detected Agonal conge:monjhaemorrha.ge um.lateral Lactation present one section examined E:xtr.u:nedullacy haematopoiesis - minimal Regressing implantation site[s) present Mw:ification/laetation morphology present No abnormalities found in: ADRENAL CORTEX. ADRENAL MEDULLA. BRAIN, CAECUM, COLON, DUODENUM, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, LYMPH NODE, MANDIBULAR. OVARIES, PARATHYROID GLANDS, PITUITARY GLAND, RECTUM, SCIATIC NERVE, SPINAL CORD, CERVJCAL. SPINAL CORD, LUMBAR. SPINAL CORD, THORACIC, STOMACH. GLANDULAR. STOMACH, NONGLANDULAR. THYMUS, THYROID GLANDS, TRACHEA. URINARY BLADDER. UTERINE CERVIX.



### 711115 

### Page 359

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fac:ility Stady

### No.4128S815 Test Site Rlfennft

### No.155-023 PMDA bydrelyzed toPMA: Onl(Gawge) ~eatal 

### Tmicity 

## Screeoia& Test in

### the 

### Rat (OECD Cl)

MACR.OSCOPIC FDD>IRGS MK:llOSCOPIC JINDIRGS 

### KIDNEYS MANMARYGUND TIIYMDS IJllllllAllYBIADDEll UTERUS VAGINA Deatn DayNumben 42.00 stut Date: 2CH1EB-2013 

### necrop.sy stat.mi SCHEDULED Kill
Papillm.y/med.ulwycalculi - minimal I.ac:tdion present Dec:naed 

### corticallymphocytes- minimal No tissue anilallle Regressingimplantation 

### site(s) present Mm:ifiationJ]actationmorphology

### present No 

### ahmmmlities fOUDd iD:ADREl'fAL CORTEX. ADRENAL MEDULLA. BRAIN.CAECUM.. COLON. DUODENUM.HEART, ILEUM. JEJUNUM, 

### LIVER. LUNGS. LYMPH NODE. MARDIBUlAR.LYMPH NODE. MESENTERIC. OVARIES. P.All'l'BYROID GLANDS, PITUITARY GLAND, RECTIJM. SCIATIC NERVE. SPINAL CORD. CERVICAL, SPINAL CORD, LUMBAR.SPINAL CORD, THORACIC. SPLEEN, STOMACH. GI.A.NDULU. STOMACH. NON-GLANDULAR. THYROID GI.A.NOS. 

### TRACHEA. UTElUNE CERVIX.

72/JIS 

### Page 360

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily Stady

### No.4128SDl5 Test Sile lhfenace

### No. lSS-823 PMDA 

### bydnlyzed.toPMA.: Onl 

### (Gffll'BP)**~** 

### Tozieity 

### Screeoiug Test in the :a.(OECD421)

Death DayNwnber. 45.00 Start Date: 2CHIEB-2013 

### necropsy status: SCHEDULED KILL 

### Extrammulmybaematopoiesis - minimal Lactation

### pnseat onesecl:icm 

### examined Exl:nmedulluy

### baematopoiesis - mild 

### Del:'l'Nllld corticallympboc:yta - minimal Regressing implantation 

### site(s] 

### pnseat Mucikation/)ad:ationmorphology

### present Na llmormalil:ies found iD:ADRENAL COllTEX.ADRENAL MEDULLA. BRADl,CAECUM. COLON, DUODENUM. HEAltT, 

### H.EUM. JEJUBUM. KJDNEYS, LUNGS, LYMPH NODE. MAJIDIBDLAR,LYMPH NODE. MESENTERIC. OVARIES. PARATIIYROID GI.ARDS, PITUITAR.YGLAND, RECTIJM, SCIATIC NERVE.SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR.SPINAL CORD. THORACIC. STOMACH. GLANDULAR. STOMACH.NON-GLANDULAR. THYROID GI.ANDS. 

### TRACHEA. URINAR.YBLADDER. UTERINE CERVIX.



### 7Jl1Jj 

### Page 361

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

TestFadlilyStudy

### No.41205815 Ten Sile 

### Rdi!naft

### No.155-823 PMDA~toPIU.: Oral(Gwtage)R~Tozicity Screeaiq 

### Ten in 

### tile 

### Rat 

### (OECD421)

MXROSOOPIC llDIDBfGS Death Day NWII.Hl'l 45,00 

### start Date: 20-JEB-2013 

### D1C1UJ1S1 statmr. SCHEDULED Kll.L

I.ac:bdicm

### present Regressing implantation sit.e(s) present 

### Mudiation/)actationmorphology

### present No almonmlitia found in: OVARIES. PITUITARY GLAND, U1'DINE CElMX.



### 741115 

### Page 362

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fadliiy Stady

### Ne.41205815 Test S-ReferlllCe

### No.155-823 PMDA 

### hydrolyzed. 

### to PMA: Onl (Gimp) Repndadioa/Deftlopmeotal Tcmdty 

### Screening Test 

### in

### die 

### lbl (OECDGl)

Death DayNumber: 42.00 Start Date: 20-FEB-ZO 13 necrop1ystatus1 SCHEDULED KILL

Lactaticm

### present ~implantationde(s)

### present 

### Mucification/lad:ation morphology present No ahnormalities 

### found im OVARIES, PITUlTARY GLAND, UTERINE CEIMX.

75/llS 

### Page 363

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

TestFadlity Smdy

### No.41205015 Test Site Refermn 

### No. 155-823 PMDA. 

### hydnlyzed to

### PM.A.: Onl(Gaw&e)**~** 

### Tmidty 

### Saeeaiag Test in die 

### Rat (OECD GI)

Death DayNwnhen 43.00 Start Date: 20-:FEB-2013 

### necropsy 

### status: SCHEDULED DU.

Lac:bdion

### pnsent aa)ypars dmalis 

### u section RepessiDg implantation 

### site(s) 

### pnsent Mucificaticm/]actation morphology pnsmt No ahnmmaJ:ities fouml inJ OVARIES, UTERINE CERVIX.



### 76/llS 

### Page 364

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlity SbMly 

### No.4ll05815 Test Sile 

### Refa:mn No.155-823 PMDA. hydnlyzed.toPMA: Onl(Ga9ap)**~** 

### Tosidly Screeniq 

### Test in Ole 

### Rat 

### (OECD421)

NACIIOSC:OPIC FINDINGS Death Day Number: 44.00 

### startDate: 21-PEB-2013 necropsy 

### statu: SCHEDULED KILL No abnormality detected Lac:talian

### pruent RtignmiDgimplantation 

### site(s) present 

### Muciflc:atirm/lonmorpbologypnsent No alla.ormalities found iD1 OVARIES, PITUITARY GLAND. UTERINE CEJmX.



### 771115 

### Page 365

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test Fadlily Smd.y No.41205815 Test Sile Rtferimft 

### No.155-G23 PMDAhydnlyzedtoPMA: Onl.(G.,...)**~** 

### Tasidty Screeoing 

### Test in die 

### Rid 

### (OECD421)

Death DayNumber: 44.00 

### start Date: 20-PEB-2013 

### necropsy status: SCHEDULED Kll.L

Lactatkm

### present lkgrusiDgimplantation 

### site(s:) preseat 

### Muci&c:ation/laconmorphology

### present: Boabnormalities found in: OVARIES.. Pn'UITARY GLAND, UTERINE CEJmX.



### 781115 

### Page 366

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report

Test 

### FadlilyStadyNo.4U05115 Test Site :.ferellft

### No.155-023 PMDA llydntl,-dtoPMA.: 

### Oral(Gaff&e.l**~** 

### Tmidty Screeaiag Test in

### die 

### Rat (OECD421)

Death Day Nmnilm 45.00 Start Date: 20-PEB-2013 

### necropsyatabul: SCHEDULED KILL

Lactation pnsent RegreaiDg implantation site(s) pnsent M1K:i&c:at.ionJ]actation morpbologypnsent No 

### almormaiilies 

### fcnmd in: OVARIES, PITUITARY GLAND, UTERINE CEJlVIX.



### 791115 

### Page 367

### Harlan Study Number: 41205015 Report 

## Appendix 15 (continued) Histopathology Phase Report Test Fadlily Stady

### No.41205'015 Test Site

### Rlfenuft Ne. 

### ISS-823 

### PMDAhJdnlpedtoPMA: Onl{Gtnage)**~** 

### Tmidly SaeeoiagTe.st ia 

### die Rat (OECD421)

NICROSCOJIIC JINDIRGS Allilllal llo.: 37 Sa: 

### Female DoseJevel: 

### 50...,.hw/day DeathDayNumlien 44.00 

### start Date! 20-PEB-2013 necropsy

### status: SCHEDULED KILL lm::reued 

### Pemc Space No abnormalities were 

### Cmmd inmyof the 

### othertmues eumined Papilluy/meduDalJ' cak:uli- minimal ll1ateral hydranephmsis - mid (accounts

# ror gross finding)



### 80/llS 

### Page 368