Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Farility Stu.d.y No. 4UO.SOIS 

Te.st Site lhference No. 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 of the Final Histopathology Report. 

Pmr Millar ..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 of the 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 of the 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 of the 

testes, the semmi:lrmus tubules of the testes were e\~ with respect to the:ir stage m the spamatogenic 

8/115 

Page 296 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadluy Stndy No. 4ll0581S 

Test Site Refermce 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 

number of animaJs 12 12 12 12 

ADRENAL CORTEX 

number examined 5 5 

ADRENAL MEDUU.A 

number examined 5 5 

BRAIN 

number examined 5 5 

CAECUM 

number examined 5 5 

COAGULATING GI.ANDS 

nwnberexamined 12 3 12 

COLON 

number examined 5 s 

DUODENUM 

number examined s 5 

EPmmYMIDES 

number examined 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.ologysummary incidence (OOld:inned) 

Male 

Dosage (mg/kg hw/day) 

numberofanil:nals 

HEART 

number eumined 

Focus(i) of myoc:ard.itis 

·minimal 

n.EUM 

nu.mbel" samined 

JEJUNUM 

number ez.amined 

lolr:dulndar hyaliae droplets 

-minimal 

-mild 

Total 

UDildenl. hydronephrosis 

-mild 

LIVER 

nwnb,er ez.amined 

lllllammatm.y cell focm(i) 

-minimal 

LUNGS 

number ea.mined 

Collgestion 

-moderate 

Foms(i) af mtra-alw:olar pinklhlid 

-mild. 

Pel'ir.lslcllbr -uc:1nr cell inlillratiml 

-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 (OECD 421.t 

Table 1: Histopathology summary incidence (continued) 

Male 

Dosage (mg/kg bw/day) 0 50 250 750 

number of animals 12 12 12 12 

LYMPH NODE. MANDIBUI.AR. 

number eumilled 5 5 

IDll'asinusal congestion/erythrophagocytosis 

present 1 1 

LYMPH NODE. MESENTERIC 

number examined 5 5 

IDll'asinusal eoagestion/erythrophagm:ytosis 

present 1 0 

MAMMARY GI.AND 

number eam.medl 10 3 12 

PAIICBEAS 

number examined! 1 

lnfamion 

-moderate 1 

PARATHYROID GI.ANDS 

numberealll.illed 5 5 

PITUITARY GLAND 

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) 

nwnber of aniimah 

RECTUM 

.number ea.mined 

SCIATIC NER.VE 

number ea.mined 

SEMINAi. VESICLES 

number ea.mined 

SPINAi. CORD, CERVICAL 

.nwnber ea.mined 

SPINAi. CORD, LUMBAR 

nwnberexamined 

SPINAi. cmm. TIIORACIC 

number ea.mined 

SPLEEN 

STONAOL GUNBUUll 

number examined 

STOMACH. NON-GIANDUI.AJI:. 

number ea.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:hology summaryhu:idenc:e (continued) 

Male 

Dosage (mg/kg hw/day) 

number of mimaJls 

TESTES 

nwnberenminedl 

Ouilateral germmal epithelid atroplly 

- minimal 

Bilateral FffDiDal epilhetial atnphy 

-moderate 

-severe 

Total 

THYMUS 

nwnbereum.medl 

Pad-morlem baemonrbage 

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 Site Referew::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/kg bw/day) 0 

12 

50 250 750 

numberofani!Dllls 12 12 12 

ADRENAL CORTEX 

numbermcamined 5 5 

ADRENAL MEDULLA 

number ea.mined 5 5 

BRAIN 

number era.mined 5 5 

CAECUM 

number ea.mined 5 5 

COLON 

numbereumined 5 5 

DUODENUM 

number ea.mined 5 5 

HEART 

number mcamined 5 5 

ILEUM 

number era.mined 5 5 

number ea.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/kg bw/day) 

number of animals 

KIDNEYS 

numbereamined 

Focus(i) of hsophilic (regeneratiag) tubules 

-mild 

Byaline cast(s) 

-minimal. 

PapiUary /medullary calculi 

-minimal. 

Bilateral hyd.nmepllrosis 

-mild 

number elCaDl.ined 

Congestion 

-mild 

Extnmedulbry haemaloporesis 

-minimal. 

LUNGS 

number examined 

Agcmal congestion and haemorrhage 

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 of animals 

MAMMARY GLAND 

number elWllined 

Lactation 

present 

OVARIES 

number e,wnined 

PARATHYllOID GLANDS 

numbereamined 

PITUITAllY GI.AND 

number eamined 

RECTUM 

number examined 

SCIATIC NEllVE 

numbeream.ined 

numbereamined 

SPINAL CORD, LUMBAR 

numbereamined 

SPINAL CORD, mouac 

number examined 

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 Site Refft'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 summary iocideRce (continued) 

Dosage (mg/kg llw/day) 

number ofammaJs 

SPLEEN 

numbereumined 

Emam.edulbry haematopoies:is 

-minimal 

-mild 

-moderate 

Total 

STOMAal. GLANDUI.All 

numbereamined 

STOMAal. NON-GLANDULAR 

number examined 

THYMUS 

numbeream.ined 

Decrnsed mmallymphocytes 

-minimal 

-mild 

Total 

numbereamlned 

TRACHEA 

number eamined 

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 Stluly No. 41lOS.lS 

Test Site Refermce No. 155-023 

Report 

Histopathology Phase Report 

PMDA.. hydNll.yzed to Pl\lA: Oral iGavage) Reprodm:tioa/Developmental Toxicity Screening Test in the 

Rat (OECD 4lU 

Table 1: Histopathology sommaryim:idenc:e (continued) 

iemale 

Dosage (mg/kg IN/day) 0 50 250 750 

number of an: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 

number mi:amined 12 3 12 

MucifkationJ'b.da.tim:l morphology 

present 12 0 11 

Dioestrusmarphology 

present 0 0 1 

Proestns morpMlogy 

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 animal pathology findings 

Auimal No.: 1 

Sex: Male 

Dose level: Control 

Deatil Day Number: 43.00 

Start Date: .20-P'EB-2013 

necropsy status: SCHEDULED KJLL 

No abnormality detected 

Intnmbular hyaline droplets - mild 

Inflammatory cell focus(i) - minimal 

LYMPH NODE. MANDIBULAR. 

PARATIIYB.OID GI.ANDS 

PROSTATE GLAND 

Intra,sinual congestion/eryl:hropbagocytosis present 

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, SEMINAL VESICLES, 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 

Test Fadlfty Shuly No.4:UOSOIS 

Test S-llda'attt No.155-82.l 

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

Rat (OECD 421) 

NACROKOPIC RNDDIGS 

IIIIICROSCOPIC RNDDIGS 

LIVER 

LDIPB NODE. NESENl'EIIC 

PITUITAJlYGU.ND 

SPI.EEII 

TIIYNUS 

Death DayNumben 43.00 

start Date: 2C>-PEB-2013 

necropsy stabls: SCHEDULED KILL 

lnftammatvly cell focus(i)- minimal 

IDtrasimlsal c:cmgestion/erytbn,phagocytosis present 

Cyst(s) present 

EKlramecluDary haematopoiem -minimal 

Post-mortem haemorrhage present 

No almormalil:in found mt ADRENAL 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 

Dose level: 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 of the other tissues 

examined 

Bilateral hypospennia - marked (accounts for gross finding) 

lntmubular sperm 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, 

PrrmTAJlY GLAMD, 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 (OECD 421) 

MACROSCOPIC RNDINGS 

HEART 

PARATBYllOmGUNDS 

Dea1h Day Number: 43.00 

Start Date: 20-PEB-2013 

necropsystatus1 SCHEDULED KILL 

No abnormality detected 

POC11S(i) of myocarditls- 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 pathology fiBdings (c:ontianed) 

GENERAL INFORMA110N 

MACROSCOPIC FINDINGS 

LUNGS (WITH BRONCHI} 

MICROSCOPIC PIN'DINGS 

KIDNEYS 

LUNGS 

MAMMAllY GI.AND 

SPLEEN 

Animal No.: 5 

Sex: Male 

Dose level: Cootrol 

Death Day Number: 43.00 

Start Date: 20-FEB-2013 

necropsy status: SCHEDULED KILL 

Reddened 

No abnormalimts were foW1d in any of the other tissues 

examined 

lntratubuJar hyaline droplets • minimal 

Congestion - moderate (accounts for gross finding) 

Focm(i) of intra-alveolar pink fluid - mild 

No ti:!Slle available 

Extramedullary haematopoiesis - 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 patkology findings (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 Site RefeNDtt 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 

Table 2: lndmclual animal patholoeY findings (continued) 

GENERAl INFORMATION 

MACROSCOPIC FINDINGS 

MKB.OSCOPIC ANDINGS 

EPIDIDYMIDES 

PROSTATE GLAND 

Animal No.: 7 

Sex: Male 

Dose level: Control 

Death Day Number: 43.00 

Sbrt Date: 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 Fadlily Stady 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 

Start Date: 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 (OECD 421} 

Table 2: lndmdual animal 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 

Focal mononuclear cell infiltration - 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 patllology findings (continued) 

GENERAL INFORMADON 

MACROSCOPIC FINDINGS 

MICROSCOPIC RN'DINGS 

EPIDIDYMIDES 

Animal No.: 10 

Sex: Male 

Dase level: Contnl 

Death Day Number: 43.00 

Start Date 20-FEB-2013 

o.ecropsy status: SCHEDULED KIILL 

No abnormality detected 

Foc:al mononuclear cell 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 Fadlily Stady No. 41295015 

Test Site R.lfenna. No.155""23 

PMDA llytlnlyzed toPMA.: Oral(G--.) ~ Tnidty ScreeaiDg Test in die 

Rat (OECDGI) 

AllbHI Ila.: 11 

Sa: Male 

Dose lent COlllrol 

Death])ay Numher: 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 

Table 2: Individual animal pathology findings {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) His to pathology Phase Report 

Test Facilky Stady No. 4UOS81S 

Test Site Refenntt No. 155-023 

PMDA hydrolyzed to RIA: Oral (Ga,,,age) ReprodadionlDevelopmeotal Tosi.city Saeeomg Test in the 

Rat (OECD 421} 

Table 2: Individual animal pathology findings (c:oo:tmued) 

GENERAi. INFOKIIIATION 

MACROSCOPIC RJIDINGS 

NICROSCOPIC AliDJNGS 

Animal No.: 16 

Sn: Nale 

Dose level: 50 mg/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) 

Test Fadlity 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 (OECD 421) 

Table 2: Individual animal pathology findings (continued) 

GENERAL INFORMA.UON 

MACROSCOPIC FINDINGS 

LUNGS (WITH BRONCHI) 

MICROSCOPIC FINDINGS 

EPIDIDDIIDES 

PANCREAS 

Animal No.: 27 

Sex: Jllak, 

Dose level: SO mg/kg tn, /day 

Death Day Number: 43.00 

startDate120-FEB-2013 

necropsy status: SCHEDULED KILL 

median lobe: Mass Fibrous mass 7mm x 7mm x7mm 

No abnormalities were found in any of the other tissues 

examined 

Focal mooonudear ceU infiltration - miD.imal 

Infarction. - moderate (LUNGS (WITH BRONCHI}) (acco1:111ts 

for gross 61:lding) 

No abnormalities found in: COAGULATING GLANDS, 

MAMMARY GLAND, PITUIT.AR.YGLAND, PROSTATE GLAND, 

SEMfflAL VESICLES, TESTES. 

14/115 

Page 322 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadlby Stady No. 4llOSOIS 

Test Site Reference 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) 

Table 2: Individual animal patlmlogyfindings (continued) 

GENERA.1. INPORMATION 

MACROSCOPIC FINDINGS 

M.lCROSCOPIC RNDINGS 

Animal Ne.: 28 

Sex: Male 

Dose level: 50 mg/kg hrw/day 

Death Day Number: 43.00 

Start Date: 20-JEB-2013 

necropsy stams: SCHEDULED KILL 

No abnormality detected 

351115 

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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: lndmdoal animal 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.a odd 

No abnormalities were found in any of the 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 pathology fimlinp: (continued) 

GENERAL INFORMATION 

MACROSCOPIC IIDIDINGS 

MICROSCOPIC FINDINGS 

Animal No.: 30 

Sex: Male 

Dose kwel: 50 ml/kl hw/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 Stady No. 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 

Dose level: 50 mg/lq: hw/da.f 

Death Day Numlier. 43.00 

start DDI 2CHEB-2Cl13 

mcropsystam: SCHEDULED KJLL 

No abnormality detected 

JBllIS 

Page 326 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadltty Stady No. 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.tllologf findings (continued) 

GENERAi. iNFORMATION 

MACROSCOPIC PDIDINGS 

MJCROSCOPIC RNDINGS 

Animal No.: 32 

Sex: Male 

Dose level: 58 mg/kg bw/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 Site Reference 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 padmlogy findings {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 

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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 (OECD 421) 

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 Site Re.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) 

Table 2: ladividuaJ animal pathology findings {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 Stady No. 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) 

Table 2: Individual animal pathology findings (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~tal Toxicity Screening Test in the 

Rat (OECD GI} 

Table 2: Individual anboal pa:tllologyfindings (continued) 

GENERAL INPORMA'l10N 

MACROSCOPIC FINDINGS 

MICROSCOPIC JDlDINGS 

A.Dim.al No.: 50 

Sex: Male 

Dose level: 250 mg/Ilg bw /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 Sile Referem: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 

Table 2: 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> 

Table 2: Individual animal pathologJ findings (continued) 

GDIEU.l. lNFORMAUON' 

MACROSCOPIC JDmINGS 

MICROSCOPIC FDIDIN'GS 

Auimail No.: 52 

SB: Male 

Dose level: 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 

PDr Millar ..h.sociates: Ud. - 21-.4.ttg-2013 - Cimftdenttal 481115 

Page 336 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlity Stady No.41205015 

Test Sh :Refereaft No.155-823 

PMDAbydnlyzed to PUA: Oral (Gtmtp) ~ Tmdty Scremilllc Test in die 

Rat (OECD421) 

AllilDal No.: 54, 

Sa: Male 

Dmelenl: 250-c/llglnr/day 

Death Day Number: 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 

Test Fadlity Study No.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 Day Numben 43..00 

Start Date: 20-JEB-2013 

necropsy stat.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 animal pat.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 of the other tissues 

examined 

Unilateral hydronepbrosis - mild (accounts for gross 

fin di~ 

511115 

Page 339 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test FadHly Stmly No. 41205015 

Test Site Reference No.155-023 

PMDA hydnlyzed.to PMA: Oral(ea-p) ~ Tmidty Saeea:iag Test in Die 

Rat (OECD 421) 

MACROSCOPIC IIINDDIIGS 

Allilllal No.: 57 

Sa: Male 

Dose level: 258 mg/lrgbw/ay 

Death Day Number. 43.00 

start Date: 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 Stady No. 41:!0SDIS 

Test Site lt.denott No •. lS5-02J 

PMDA hydrelyzed to PMA: Oral {GlWBge) lt.eprodudion/Developmeotal Toxicity Saeeoiog Test in die 

Rat (OECD 421) 

Table 2: 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 (OECD 421) 

Animal No.: 59 

Su: Male 

DDSe len:1: 258 mg/Ilg n /day 

Death. Day Nmnhen 43.00 

start DateiJ 20-FEB-2013 

necropsy status: SCHEDULED mt. 

541115 

Page 342 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Tat Family Smdy No.4ll05D15 

Tat Sile Refeftnft No.155-023 

PMDA bydnlped. toPMA: Onl(Glmlge) ~ Toiddty Screeoiu& Tat in tile 

Rat (OECD 421) 

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 Site Rmre-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) 

Table 2: lndMdual animal patkologyfi.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 

lntratubular hyaline droplets - mild 

Inflammatory cell focus(i) - mimmal 

lntrasinnsal c:.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} 

Table 2: 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 

lmlammatory cell 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 Millar b.wciates Ltd. -11-.4ug-1011 - Confirlminal 571115 

Page 345 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadffly Study No. 4llOSOlS 

Test Site Reference 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/kg bw /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 

Extramedullary haematopoiesill - 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. MAMMARY GLAND, 

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 Stady No. 41205015 

Test Site Kdenace No. 155-023 

Report 

Histopathology Phase Report 

PMDA hydrolyzed to PAIA: Oral iG-.e) KeprodnctioD!Developmeotal Toxicity Screeaiug Test iD the 

Kat (OECD CU 

Table 2: IDdiriduaJ aohnal pathology findings {c:ontinued) 

GENERAL INFOllMATION 

MACROSCOPIC FINDINGS 

MICROSCOPIC RNDINGS 

KIDNEYS 

TESTES 

Animal No.: 76 

Ser. Male 

Dose level: 750 mg/kg bw /day 

Death Day Nwnben 43,00 

Start Date. 20-FEB-2013 

necropsy status, SCHEDULED KJLL 

No abnormality detected 

lntratubular hyaline 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 Stady No.41205015 

Test Site Relenace No. lSS-823 

PMDA bydralyzed.to PMA.: Oral (G1m1p) ~ Tmddty Screeniag Test in die 

Rat (OECD 421) 

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 

IDtratubular hyaline droplets - minimal 

Inflammatory cel focus{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. SPINAL CORD, TIIORACIC. SPLEEN, 

STOMACH. GUJIDULA.R.. STOMACH. NON-GLANDULAR.. 

TESTES. nmtom GU.NOS. TRACHEA. 

60/J.Jj 

Page 348 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Facility Stady No.412U015 

Test Sile Refereaft No. lSS-023 

PMD.A hydnlpmtoPMA.: Oral.(Ga-ce) ~ Ttmdty Screening Test in die 

Rat (OECD 421) 

IIIICIIOSCOPIC '.PDIIDINGS 

AniBlal No.: 78 

Sm; Male 

Dose level: 758 mg/Jlgbw/day 

Death Day Nwnberi 43.00 

start Datet 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 (OECD 421) 

Death Day Bwnher: 43.00 

Start Date= 20--PEB-2013 

necropsy status: SCHEDULED KILL 

Unil.amalpnnmal epithelial 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 Day Number: 43,00 

start Date-: 20-FEB-2013 

necropsy status: SCHEDULED KJLL 

No almormal:ily detected 

only pars 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 Shuly No. 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 pathology findings (am.tinned) 

GENERAi. iNFORMATION 

MACROSCOPIC FINDINGS 

MICROSCOPIC FINDINGS 

Animal No.: 82 

Sex: Nale 

Dose level: 750 mg/kg lnr /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 Site Refermtt 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 

Table 2: Individual animal 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 Stady No. 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) 

Tahle 2: Individual animal 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 Stady No.41205815 

Test Site Rmnu.ce No.155-023 

PMDA hydrolyzed toPMA: Oral (Gnage) ~ Ta.deity Screening Test in tile 

Rat (OECD 421) 

GEIIERAJ. INPOIUU.1'10N 

Death DayNumber: 43.00 

start Date: 20-PEB-2013 

nec:rupsystatus: SCHEDULED KILL 

Lactation present 

-secti.on examined 

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 Sbuly No.4UOS815 

Test Site Refeftnce No. 155-823 

PMDA. •ydralyzed toPMA: Oral (Ga,,age) Rep~ Ta:ddty Screeuiug Tat in Ole 

Rat (OECD 421) 

Delltb Day Number: 43.00 

Start Date: 20-FEB-2013 

necropsy stafm1 SCHEDULED KILL 

Lactation pruent 

ane secticmeumimld 

Deaeased cortical lymphocytes- 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 (OECD 421) 

NlalOSCOPIC RJIDINGS 

Animal No.: 15 

Sa: Female 

Dose level: Caatrol 

Death Day Nwnben 43.00 

St.ut Date: 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 Site Reference No.1SS-02J 

Report 

Histopathology Phase Report 

MIDA hydrelyzed to Pl-IA.: Oral (Gavage) Reprodamon/Developmeotal Tcmcity Screeoiug Test in the 

Rat (OECD 421) 

Table 2: Individual animal pathology findings (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 

IJllllllAllY BIADDEll 

UTERUS 

VAGINA 

Deatn DayNumben 42.00 

stut Date: 2CH1EB-2013 

necrop.sy stat.mi SCHEDULED Kill 

Papillm.y/med.ulwy calculi - minimal 

I.ac:tdion present 

Dec:naed cortical lymphocytes- minimal 

No tissue anilallle 

Regressing implantation site(s) present 

Mm:ifiationJ]actation morphology 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 

Extrammulmy baematopoiesis - minimal 

Lactation pnseat 

one secl:icm examined 

Exl:nmedulluy baematopoiesis - mild 

Del:'l'Nllld cortical lympboc:yta -minimal 

Regressing implantation site(s] pnseat 

Mucikation/)ad:ation morphology 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 

Test Fadlily Study No.41205815 

Ten Sile Rdi!naft No.155-823 

PMDA~toPIU.: Oral(Gwtage)R~ Tozicity Screeaiq Ten in tile 

Rat (OECD 421) 

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/)actation morphology 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 Day Number: 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 

Test Fadlity 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 Day Nwnhen 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 

start Date: 21-PEB-2013 

necropsy statu: SCHEDULED KILL 

No abnormality detected 

Lac:talian pruent 

RtignmiDg implantation 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 

PMDA hydnlyzedtoPMA: Onl.(G.,...) ~ Tasidty Screeoing Test in die 

Rid (OECD 421) 

Death Day Number: 44.00 

start Date: 20-PEB-2013 

necropsy status: SCHEDULED Kll.L 

Lactatkm present 

lkgrusiDg implantation site(s:) preseat 

Muci&c:ation/lacon morphology present: 

Bo abnormalities found in: OVARIES.. Pn'UITARY GLAND, 

UTERINE CEJmX. 

781115 

Page 366 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No.4U05115 

Test Site :.ferellft No.155-023 

PMDA llydntl,-d toPMA.: Oral(Gaff&e.l ~ Tmidty Screeaiag Test in die 

Rat (OECD421) 

Death Day Nmnilm 45.00 

Start Date: 20-PEB-2013 

necropsy atabul: 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 Saeeoiag Te.st ia die 

Rat (OECD 421) 

NICROSCOJIIC JINDIRGS 

Allilllal llo.: 37 

Sa: Female 

DoseJevel: 50...,.hw/day 

Death DayNumlien 44.00 

start Date! 20-PEB-2013 

necropsy status: SCHEDULED KILL 

lm::reued Pemc Space 

No abnormalities were Cmmd inmy of the othertmues 

eumined 

Papilluy/meduDalJ' cak:uli- minimal 

ll1ateral hydranephmsis - mid (accounts ror gross finding) 

80/llS 

Page 368