Harlan Study Number: 41205015 

Appendix 15 (continued) 

Test Fadlity Stady No. 4ll0501S 

Test Site Refeft>lltt No.155..023 

Report 

Histopathology Phase Report 

ftIDA hydrelyzed to PMA.: Oral {Gffl'Bge) Reproductiou/Devdopmeotal Tmrity Saeeoing Test io the 

Ra.t (OECD 421) 

Table :Z: Individual animal pathology findings (c:ontinued) 

GENERAL INFORMATION 

MACROSCOPIC HNDINGS 

MKROSCOPIC FINDINGS 

Animal No.: 38 

Sex: Female 

Dose level: so mg/kg n/day 

Death Day Number: 45.00 

Start Date: 20-F'EB-2013 

necropsy statos: SCHEDULED KILL 

No abn.ormality detected 

81!11J 

Page 369 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Sbldy No.41205015 

Test Sh Rlferear:e No.155-823 

PMDA hydnly&d. toPMA.: Onl(Gmrage) ~ Tmidfy Scnea:iag Test la the 

Rat (OECDGl) 

NACROSCOPICRNDINGS 

AniBlal. N'o.: 39 

Su: lTemale 

Dose lnel: 5Dmg/lsgbw/u, 

Death Day NllllllJer. 43.00 

stutDate: 20-PEB-2013 

necropsy status: SCHEDULED KILL 

Cydicll dilatiGlll present 

P1"MSlrus morphology present 

No almonnalilies found in: MAMMARY GLAND,OVARJES.. 

PITUITAR.YGLAN'D, UTERINE CERVJX. 

82/llS 

Page 370 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlity Stady No.41205015 

Test Sn Reli!renft No.155-823 

PMDA ~toPMA: Oral(c-.p) ~ To.ucityScreeniag Test intlle 

llat (OECD 421) 

Animlll No.: 40 

Sex: J'etnale 

Dose Jevek 501Dg/kghw/drq 

Death Day Number: 43.00 

Start Date: 20-FEB-2013 

necropsystatwl: SCHEDULED KILL 

83/llS 

Page 371 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadffly Stady No. 4UOS015 

Test Sn Refettntt No. 155-023 

Report 

Histopathology Phase Report 

PMDA hydnllyzed to PMA~ Oi"al (Gavage) Reproda.dion/Developmeotal To:dcity Screeoiug Test in tlile 

Rat (OECD Gil 

Table 2: Individual animal patkologyfindings {continued) 

GENERAi. iNFORMATION 

J.IIJACROSCOPIC RNDVIGS 

llllCROSCOP!C FINDINGS 

VAGINA 

ADimalNo.: 41 

Sex: J'emale 

Dose level: 50 mg/kg bw/day 

Death Day Numben 42.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED KJLL 

No abnormality detected 

Metoestms morphology present 

No abnormalities found in: MAMMARY GLAND, OVARIES, 

PITUITARY GLAND, UTERINE CERVIX. UTERUS. 

841115 

Page 372 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlity Stady No.41205815 

Test Sh Refenun No.155~...3 

PMDA bydralJzed to PMA: Onl (Ga,,ap) ~ Tasidly Screening Test in the 

Rat (OECD 421) 

Animal No.: 42 

Sa:: l'emale 

DaseJent sollllfllgn/u, 

Death Day Number: 42.00 

start Date: 20-PEB-2013 

necropsy status: SCHEDULED KILL 

85/J.15 

Page 373 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Smd.y No.41205015 

Test Sift Rmreace No. J.55.023 

PMDA hydnlyzed toPMA.: Onl (Gawlge) ~ Tcmdly Screening Test in die 

Rat (OECD 421) 

MACROSCOPIC FDIDINGS 

MIOIOSCOPIC JDIDDfGS 

Allilllal No.: 43 

Sa: i'emale 

Dmelevel: 50mg/llgh/day 

Death Day Nam.hen 45.00 

start Date: 20-PEB-2013 

IK!CIOJISY statu: SCHEDULED KILL 

No almormality detected 

No tissues eamined 

861115 

Page 374 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Sndy No.4llOSOIS 

Test Sile Refennft No.155-823 

PMDA. bydNlyzed. to PM.A: Onl(Gavage) ~ Tmdmy Screening Test In die 

Rat (OECDGl) 

Death Day Num.ben 45.00 

Start Date: 20-PEB-2013 

necropsy status: SCHEDULED KILL 

No tissues eamined 

87/llS 

Page 375 
Harlan Study Number: 41205015 

Appendix 15 (continued) 

Test Fadlity Study No. 41205815 

Ten Sitec Refereace No. 155-8"'-l 

Report 

Histopathology Phase Report 

PMDA hydrolyzed to PMA: Oral (Gavage) Reprochu:tioolDeftlopmental Tmidty Screening Test in the 

Rat (OECD 42U 

Table 2: Individual aoimal. pathology findings (continued) 

GENERAL INFORMATION 

MACROSCOPIC FDmlNGS 

MIC:ROSOOPIC PINDINGS 

Animal No.: 45 

Ser. Female 

Dose level: 50 mg/kg hw /day 

Death Day Num.beri 43.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED KJLL 

No abnormality detected 

No tiSSlles examined 

BIJlllJ 

Page 376 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadffl:y Shuly No. 41:205015 

Test Sin Referflltt No. 155-023 

Report 

Histopathology Phase Report 

Pfl.IDA hydnlyzed to PlllA: Oral •G11Yage) Reprodudioa!Development'al Toxicity Screeoiog Test in die 

R.at (OECD 421} 

Table 2: Individual aoimal patkologyfindiogs (couti.nued) 

GENERAL INFORMA.UON 

MACROSCOPIC FINDINGS 

MJCROSCOPIC FINDINGS 

Animal No.: 46 

Sex: llemale 

Dose level: SO mg/kg bw/day 

Death Day Number: 43.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED IOLL 

No abnormality detected 

No tiS31ile:s eaminecl 

891115 

Page 377 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Facility Stady No. 41:205015 

Test Site Reference No. 155-023 

Report 

Histopathology Phase Report 

Pl.IDA bydnlyzed to PMA: Oral (Ga-:,e) Repn>du.dioa/Deftlopmeotal Toxicity Screeoiug Test in the 

Rat (OECD 421) 

Table 2: Individual animal pathol.ogy:findings (continued) 

GENERAi. INFORMATION 

MACROSCOPIC RN'DINGS 

MICROSCOPIC FINDINGS 

VAGINA 

Animal No.: 47 

Sez: Female 

Dose level: 50 mg/kg hw/day 

Death Day Number: 44.00 

Start Date: 20-FEB-2013 

necropsy statm: SCHEDULED KJLL 

No abnormality detected 

Metoesm:is morphology present 

No abnormalities found in: MAMMARY GLAND, OVARIES, 

PITUITAR.Y GLAND, UTERINE CERVJX. UTERUS. 

90/115 

Page 378 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Sn.d.J' No.4120SDIS 

Test Sn Relenutt No.155-823 

PMDA. hydnlyzed. toPMA: Oral(Ga,,age) ~ Tazidty Screeaing Test in the 

Rat (OECDGl) 

I.IIACROSCOPIC RJIDIIIGS 

Animal No.: 48 

51111:: J'emale 

Due level: 50 mg/Jig tn, /day 

Deatll Day Nwnller: 44.00 

Start Date: 20-FEB-2013 

necropsy status: SCHEDULED KILL 

91/lJj 

Page 379 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Facility Stady No.4ll85015 

Test Sile .,_mft No. lSS-023 

PMDA. hydnl,-ltoPIIA: Oral (6-ge) ~ Tasidty Scneaiq Test in die 

:Rat (OECD 421) 

MACROSCOPIC FINDINGS 

Animal No.: 61 

Sa: Female 

Doseknrel: 250mg/ltgbw/day 

Death DayNumhen 44.00 

Start Date: 21-PEB-2013 

wropsy stabls: SCHEDULED KILL 

92/llS 

Page 380 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No. 41205815 

Test Site R.mnua No.155-023 

PMDA hydnlyzed toPMA: Onl(Gavap) ~ Tmicity Saeeaiag Test in die 

Rat (OECD 421) 

NACROSCOPICRNDIRGS 

MKROSCOPIC JINDIRG5 

Animal No.: 62 

Sa: Semale 

Dose level: 258 mg/kghw/my 

Deat:11 Day Nmnberi 46.00 

stut Date: 20-JEB-2013 

necropsy lltatus: SCHEDULED KILL 

No abnormality detected 

No tissues eamined 

91/lJj 

Page 381 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No.41205015 

Test Sile Rdenntt No.155-823 

PMDA. llydnllyzed. toPMA.: Oral (Gavap) ~ Tosidty Screeaia& Test in the 

Rat(OECD421) 

llfACROSCOPIC IIINDINGS 

Anilllal No.: 63 

Sa: Female 

Dueleftl: zsomg/Jign/my 

Death Day Number: 43.00 

Start Date: 20-PEB-2013 

necropsy status: SCHEDULED KILL 

94/lJj 

Page 382 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No. 4120SIDIS 

Test Site~ No. l55-02J 

PMDA hydnlyzed.toPMA: Oral(Glnage) ~ Tmicity Scrftuia& Test in die 

Rat (OECD 421) 

Animal No.: 64 

Sn: Female 

Dclse level: 258 mg/Ilg bw/,Jay 

Death Day Bumllen 44.00 

start DateJ 20-PEB-2013 

necropsy status: SCHEDULED KILL 

No abnormality detected 

9S/llS 

Page 383 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlby Smdy No.4ll8Hl5 

Test Site lhfHmff No.155-823 

PMDA hydnlyzedtoPMA.: Onl(Gaftge) ~hll Tmicity Screeniag Test in die 

Rat (OECD Cl) 

MICROSCOPIC RNDINGS 

Oelltb DayNmnben 44.00 

start Oldie: 20-J.IEB-2013 

necropsy stat.mi SCHEDULED KILL 

961115 

Page 384 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No. 4UOSOIS 

Test SiR RefenBft No.155-023 

RIDA hydrGlyzN toPMA: Oral (Gmiage) ~ Tasimy Screeoiag Test in tllr 

Rat (OECD 421} 

MAc:RDSc:OPIC RNDINGS 

ADilllal No.: 66 

Sa: hmale 

Daselnel: 250mg/Jlglrwfmy 

Dealb DayNumber: 42.00 

start Date: 20-FEB-2013 

necropsy st:aala1 SCHEDULED KILL 

9711l5 

Page 385 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlby Stady No.41305015 

Test Site Refereme No.155-023 

PMDA bydrolJzedtoPMA: Onl(ea-p) ~ Tmidty Screeaiq Testio the 

Rat (OECD 421) 

MACROSCOPIC RNDINGS 

ADmlal. No.: 67 

SB: .Fnulle 

Deselevel: 250 mg/lrglnr/uy 

Death DayNumben 45.00 

start Datei 20-FEB-2013 

necropsy statwl1 SCHEDULED Kll.l. 

98/llS 

Page 386 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadltty Stady No.41205015 

Test Site Relenan No.155-023 

Page 387 

PMDA hydnlyzetl toPMA: Oral(Gnap) ~ Tmidly Screening Test io thr 

Rat (OECD431) 

Death Day Number: 42..00 

Start Date: 20-PEB-2013 

necropsystatu.s1 SCHEDULED KILL 

991115 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No.41205015 

Test SIR~No.155-023 

PMDA hydnlyzed toPMA: Oral.(Gnage)~ Tasidty Screeaiag Tat in the 

Rat (OEa> 421) 

NKII.OSCOPIC JINDDIGS 

.Animal No.: 69 

Sm: Female 

Dose level: 250 mg/tlg'frw/my 

Death Day Nwnhen 44.00 

start Date: 20-JEB-2013 

necropsystatus1 SCHEDULED KD.L 

100/llJ 

Page 388 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlil:y Stady No.41205015 

Test Sift Ref•- No.155-823 

PMDA bydrolyzed.toPMA..: Onl (Ga9age) ~ Tmddty Seremiug Test in Ole 

Rat (OECD 421) 

MACROSCOPIC ANDINGS 

Animllll Na.: 78 

Smc l'emale 

Dose level: 250 mg/llgbw/day 

Death DayNwnlien 43.00 

start Date; 20-JEB-2013 

necropsy status: SCHEDULED KJLL 

No abnormality detected 

lDl/115 

Page 389 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadllly Stady No.41205015 

Test Sh Refennn No. l5S-023 

PMDA bydnl.,-1 toPMA: Oral(Glmlp) ~ Tmidty Sc:reenia& Test in die 

Rat (OECD 421) 

MACROSCOPIC FINDINGS 

l!OalOSCOPIC RJIDIRGS 

ADillllll No.: 71 

51111: Female 

Dmelnel: 258-c/llglnr/day 

Death Day Number: 44JlO 

start Date: 20-PEB-2013 

necropsy statllll: SCHEDULED KB.I. 

1011115 

Page 390 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Ted Fadlily Stady No.4120!015 

Test~ Referenre Ne.155-023 

PMDA hydrtllyzedtoPMA.: Onl(Gaup) ~ Tadmy Scremiug Ted in die 

Ital (OECDGI) 

Ml£ROSCOPICJINDDfGS 

Anillull No.: 72 

Sa: Female 

Dose.level: 250mg/llglnr/day 

Death Day NIUllber: 46.00 

start Date: 20-FEB-2013 

oecropay status: SCHEDULED KILL 

No tisllles examined 

101/llS 

Page 391 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlity Stady No.4ll05015 

Test Se Refamn No.15S-023 

PMDA hydnlyzedtoPMA.: Onl.(Gtnage) ~ Tmidly Screening Testio die 

RBI (OECD 421) 

KIDNDS 

Death Day Rwnlier. 4.2..00 

start Date: 20-FEB-2013 

neaopsy status: SCHEDULED KILL 

Foc:m(i) ofhasophil:ic (regenerating) tubu1es - mild 

Hy.lline cast(s) - mmilllal 

Bi1atera] hydronephrasis- mild 

CoDpSl:ioD - mild 

L.ac:bdiGD prueDt 

EBlr.muldaDary haematopoiesis - mild 

Dec:nased cortical lymphocytes- mimma1 

Ro tissue available 

Regnssiug implantation site(s) pruent 

Mucification/)actatimi mcnphologypreseot 

Ro almormaliti.es found ins ADRENAL CORTEX.ADRENAL 

MEDULLA. BRAUf, CAECUM. COLOR, DUODENUM. HEART, 

II.E1JM. JEJUNUM, LUNGS. LYMPH RODE, MMfDIBULAR. 

LYMPH RODE. MESENTERIC. OVARIES, PARATHYROID 

GURUS. PITUITARY GLAND, RECTUM. SCIATIC NERVE. 

SPINAL meo. CERVJCAL SPINAL CORD, LUMBAR. SPINAL 

CORD. THORACIC. STOMACH. GLAKDULAR. STOMACH, 

ROR-GUMOOLAR. THYROID GI.ARDS. TRACHEA. UTERINE 

CEllVIJt. 

lfJ4/115 

Page 392 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlity Smly No.41205015 

Tm Site Refal!'Dft No.155-023 

PMDA hydnl.yzed to PMA.: Oral (Gawge) ~ Tmidty Screeniag Tmin die 

Rat (OECD 421) 

ADRERAI. NEDUUA 

MANMAJilYGLAIID 

PARATBD.Om GI.ANDS 

SPI.EEN 

1'IIYNUS 

O'l'ERU5 

VAGDIA. 

Death Day Number: 44.00 

start Date: 20-1£8-2013 

necropsy status: SCHEDULED KILL 

one section eamined 

Lactation present 

one sec:lioD eamined 

Edr:unerlullary baematopoiesi:s - mild 

Dec:nmed c:mtical lymphocytu -millimal 

bgressiogimplantation sit.e(s) present 

Mucifica.tion/la morphology present 

No abmmmlilies found in:.ADRENAL CORTEX. ADRENAL 

MEDULI.A. BR.AIN,CAECUM. COLOR, DUODENUM. HEAllT, 

11.EUM. )EJIDRJM, KIDNEYS, LIVER. LUNGS, LYMPH HOOE. 

MANDIBULAR.LYMPH NODE. MESENTERIC. OVARIES. 

P.ARATBYR.OID GLANDS, PITUITARY GLAND, RECTIJM, 

SCIATIC MEDE.SPINAL CORD, CER.VICAL. SPINAL CORD, 

WMBAJL SPINAL CORD, TIIORACIC. STOMACH. 

GU.NDUUR. STOMACH.RON-GUJD>ULAR. THYROID 

GU.NOS.. TllCHEA. URINARY BLADDER. UTERINE CERVIX. 

1051115 

Page 393 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Farility Stady No. 41:!0SOIS 

Test Site Reference No. 155-023 

Report 

Histopathology Phase Report 

PAIDA hydnlyzed to Pili: Oral (Ga,rage) R.eprodnc:tion/Developmental Toxicity Saeeoiug Test in the 

Ral (OECD 421) 

Taltle 2: Individual animal patbologyfiBdiop (continued) 

MA.CllOSCOPIC FINDINGS 

LUNGS (WITH BRONCHI) 

MICROSCOPIC PINDINGS 

LUNGS 

PITUITARY GLAND 

VAGINA 

Animal. No.: 87 

Sex: Female 

Dose level: 750 mg/kg bw/d.ay 

Death Day Number: 42.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED KJLL 

Redden.ed 

No abnormalities were found in any of the other tissues 

examined 

A.goml congestion and haemorrhage present (accounts for 

gross finding) 

ooly pars distalis on section 

Dioestrus :morphology present 

No abno.rmalilies found in: MAMMARY GIAND, OVARIES, 

UTERINE CERVOC UTERUS. 

1061115 

Page 394 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadlity Study No. 4llOS8lS 

Test Site llefermce No.155-0')..3 

Report Page 395 

Histopathology Phase Report 

ftIDA hydrolyzed to PMA~ Oral (Gavage) Reprodm:tionJDewlopmeotal Toxicity Screeuiug Test io the 

Rat (OECD 421} 

Table 2: Individual animal pathology findings (amtiuued) 

GENERAI.INJiORNA110N 

MACROSCOPIC RNDINGS 

MICROSCOPIC FINDINGS 

UVER 

NAMM.ARY GI.AND 

SPLEEN 

THDIUS 

O"l"EltUS 

VAGDIA 

Animal No.: 88 

Sex: Felllllle 

Dose level: 750 mg/kg bw/day 

Death Day Number: 42.00 

start Date: 20-FEB-2013 

necropsy stabu: SCHEDULED KlLL 

No abnormality detected 

Congestioo - mild 

lactation present 

Extramedullary haematopoiesis - minimal 

Decreased cortical lymphocytes - minimal 

Regressing implantation site(s) present 

Mucification/]actation morphology present 

No abnormalities found in: ADRENAL CORTEX. ADRENAL 

MEDULLA, BRAJN, CAECUM. COLON, DUODENUM, HEART, 

ILEUM. JEJUNUM, KllDNEYS, LUNGS, LYMPH NODE, 

MANDJBULAR. LYMPH NODE. MESENTERIC, OVARIES.. 

PARATHYROID GLANDS, PITUITARY GLAND, RECTUM, 

SCIATIC NERVE, SPINAL CORD, CERVICAL, SPINAL CORD, 

LUMBAR. SPINAL CORD, THORACIC, STOMACH, 

GLANDULAR. STOMACH, NON-<iLANDULAR. THYROID 

GLANDS. TRACHEA. URINARY BLADDER. UTERINE CERVIX. 

1071115 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Stady No.41205015 

Test Site Rd'HIIW! No.155-823 

PIIDA hydnlyzedtoPMA: Oral(G-ce)~ TasidtyScreeoing Test in tie 

Rat (OECD421) 

MACRGSa>PIC PDIDINGS 

Death Olly Numher. 43.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED KILL 

Lactation present 

one section aamimld 

EdrmulduDmy haematopoiesis - mild 

Decreased c:mtical lymphocytes- minimal 

RegnssiDg implantation site(s) present 

Muc:ificaticmJ)actatio morphology present 

No abnormaJitles found in: ADRENAL CORTEX. ADRENAL 

MEDULLA. BRAIN. CAECUM. COLON, DUODENUM.HEAllT, 

ILEUM. JEJUNUM, KIDNEYS, LIVER. LUNGS. LYMPH NODE. 

MANDIBULAR. LYMPH NODE. MESENTERIC, OVARIES. 

PARATBYROW GLANDS. PITUITARY GLAND. RECTUM. 

SCIATIC NEll\lE. SPINAL CORD. CERVICAL. SPINAL CORD, 

LUMBAR, SPINAL CORD. THORACIC. STOMACH. 

GU.JIDUI.AR. STOMACH. NON-GLANDULAR. THYROID 

GU.NOS. TRACHEA. URINARY BLADDER. UTERINE CERVIX. 

108/llS 

Page 396 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fadlfty Stnily No •. 41205015 

Test Site llefereutt No.155-023 

Report 

Histopathology Phase Report 

Pl-IDA hydnlyzed to PMA: Oral {Gavage) R.eprodadion/Developmeotal Toxicity Screening Test in the 

Rat (OECD 421) 

Table 2: Individual animal path.ologyfindings (continued) 

GENERAL DIFORHATION 

I.IIA.CllOSCOPICPINDINGS 

MK:ROSCOPIC FINDINGS 

NAMMAllY GI.AND 

PARATHYROID GIANDS 

SPLEEN 

THYMUS 

UTEJWS 

VAGINA 

Anim.al No.: 90 

Sex: Female 

Dose level: 750 mg/kg hw/day 

Death Day Number: 54.00 

Start Date: 20-FEB-2013 

necropsy statm: SCHEDULED KJLL 

No abnormality detected 

Lactation present 

one section examined 

Extramed.ullary haematopoiesis - minimal 

Decreased cortical lymphocytes - mild 

Regressing implantation site(s) present 

Mucificwon/lactation morphology present 

No abnormalities found in: ADRENAL CORTEX. ADRENAL 

MEDULLA. BRAJN, CAECUM, COLON, DUODENUM. HEART, 

ILEUM. JEJUNUM, KIDNEYS, LIVER. LUNGS, LYMPH NODE, 

MANDIBULAR. LYMPH NODE. MESENTERJC, OVARIES, 

PARATHYROID GLANDS, PITUITARY GLAND, RECTUM, 

SCIATIC NERVE, SPINAL CORD, CERVICAL. SPINAL CORD, 

LUMBAR. SPINAL mRD, THORACIC. STOMACH, 

GLANDULAR. STOMACH, NON-GLANDULAR. THYROID 

GLANDS, TRACHEA. URINARY BLADDER. UTERINE CERVIX. 

1091115 

Page 397 
Harlan Study Number: 41205015 

Appendix 15 ( continued) 

Test Fad&ly Stady No •. 41:205015 

Test Site Rffll'mtt No. 155-023 

Report Page 398 

Histopathology Phase Report 

PMDA hydnlyzed to Pl-IA: Oral (Gavage) Reprodllldioa/Developmemal Tmicity Screeamg Test in the 

Rat (OECD 4.'!l) 

Table :Z: Individual anhnal path.ologyliadi.ngs {continued) 

GENERAL INFORMATION 

MACllOSCOPIC FIWDINGS 

MJCROSCOPIC FINDINGS 

MDIMARYGUND 

DTERUS 

VAGINA 

Animal No.: 91 

Sex: Female 

Dose level: 750 mg/Ilg hw/day 

Death Day Number: 44.00 

Start Date: 20-FEB-2013 

necropsy status: SCHEDULED KJLL 

No abnormality detected 

Lactation present 

Regressing implantation site( s) present 

Mud:lkatiion/]actation morphology present 

No abn:onn:alities found in: OVARIES, PITUITARY GI.AND, 

UTERINE CER.VJX. 

110/115 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadffly Stady No. 41205015 

Test Site Refereoa: No •. 155-923 

PMDA bydrolyzm to PMA.: Oral (Gavage) Reproductioa.lDefflOpmental Toxicity Screeoiug Test in the 

Rat (OECD 421) 

Table 2: Individual animal path.ology'findings { continued) 

GENERAL INFORMATION 

MACROSCOPIC FINDINGS 

MICROSCOPIC FINDINGS 

MAMMAllY GLAND 

UTERUS 

VAGINA 

Anilllal No.: 92 

Sex: Female 

Doselevel: 750mg/kgbw/day 

Death Day Number: 42.00 

start Date: 20-FEB-2013 

necropsy status: SCHEDULED KILL 

No abnormality detected 

Lactation present 

Regressing implantation site(s) present 

Mucffic:at:ionf]actation morphology present 

No abnormalities found in: OVARIES, PITUITARY GLAND, 

UTERINE CERVJX. 

Ptm1r Millar Assm:iaw Lid. - 21-A1lJ:-2011 - Co~mrl 111/llJ 

Page 399 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadffly Slad.y No.41205015 

Test Sile Referellft No.155-023 

PMDA.,...yzed. tePMA: Oral(G.n-ap) ~ To.sicity Screeoiq Teat in tile 

Rat (OECD 421) 

Animal No.: 93 

SB: Female 

Dose level: 750 mg/llghw/ay 

Death Day Nwn.her: 53.00 

Sbut Date; 20-JEB-2013 

necropsy status: SCHEDULED KU.I. 

Lac:tatiaD 

~ 

present 

implantation si.te(s) present 

Mucikation/]actation morphology present 

No ahnormalities fuund iDI OVARIES. PITUITARY GLAND, 

UTERINE CER.VJX. 

Page400 

1121115 
Harlan Study Number: 41205015 

Appendix 15 (continued) 

Test Fadlity Stutly No. 4llOS8lS 

Test Site Referftltt No. lSS-023 

Report 

Histopathology Phase Report 

PMDA bydrolyzetl to PMA: Oral (Gavage) ReprodudionJDevelopmeotal Toxicity Screeoiog Test .in the 

Rat (OECD 421) 

Table 2: Individual animal patllologyfindings (continued) 

GENERAL INFORMATION 

MACllOSCOPIC FINDDIGS 

MICROSCOPIC RNDDIGS 

MAMMARY GLAND 

UTERUS 

VA&INA. 

Animal No.: 94 

Sex: female 

Dose lent 750 mg/kg 'bw/day 

Death Day Number: 42.00 

start Date: .20-FEB-2013 

necropsy statwi: SCHEDULED IaLL 

No abnormality deteci:ed 

Lactation present 

Regressiog implantation site(s) present 

Muclfieation/Jactation morphology present 

No abno.rmal:iti.es found in: OVARIES, PITUITARY GI.AND, 

UTERINE CERVJX. 

1131115 

Page 401 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Sbrd.y No.41205015 

Test Sile Refeftace No.155-823 

PMDA. hydnllyzedtoPMA.: Oral(G ...... ) ~ Tmidly Scremilllg Test io tlte 

Rat (OECD 421) 

MACROSCOPIC RNDll!IGS 

Aldmlll No.: 95 

Su: Female 

Dmlelenl: 750 mg/llgbw/day 

Dea1h Day Number: 45.00 

Start Date: 20-FEB-2013 

necropsy status1 SCHEDULED KJLL 

Lactation present 

Regressing implantation site(s) present 

Muci:lic:ation/lcm morphology present 

No ahnmmal:ities found in: OVARIES. PITUITARY GLAND. 

UTERINE CEJMX. 

114/llS 

Page 402 
Harlan Study Number: 41205015 Report 

Appendix 15 ( continued) Histopathology Phase Report 

Test Fadlily Sm.dy No.41205015 

Test Site Refena£e No.155-82J 

PMDA hytlralyzedtoPMA: Oral (Gawge) ~ Tmidty Screenia& Test in tile 

Rat (OEC.D 421) 

NACROSCOPIC I.IDIDINGS 

Death Day Number: 43..00 

Start Date: 20-i:EB-2013 

necropry status: SCHEDULED DI.I. 

Lactalion 

~ 

present 

impl:mtltion site{s) present 

Mucificationfladation morphology present 

Na abnormalities found in: OVARIES. PITUITARY GLAND. 

UTERINE CEJmX 

1151115 

Page 403 
Harlan Study Number: 41205015 Report Page 404 

Appendix 16 Analytical Investigations 

1. METHOD OF ANALYSIS 

1.1 Summary 

The concentration of PMDA hydrolyzed to PMA in the test item formulations was determined 

by high performance liquid chromatography (HPLC) using an external standard technique. 

1.2 Samples 

The test item formulations were diluted with O.OlM orthophosphoric acid to give a final, 

theoretical test item concentration of approximately 0.01 mg/ml. 

1.3 Standards 

Standard solutions of test item were prepared in O.OlM orthophosphoric acid at a nominal 

concentration of 0.01 mg/ml. The standard solutions contained the equivalent amount of vehicle 

to that of the relevant standards. 

1.4 Procedure 

The standard and sample solutions were analysed by HPLC using the following conditions: 

HPLC 

Column 

Mobile phase 

Flow-rate 

UV detector 

wavelength 

Injection volume 

Retention time 

Agilent Technologies 1200, incorporating autosampler 

and workstation 

Sunfire 5μ C18 (150 x 4.6 mm id) 

O.OlM triethylamine (pH 2): methanol: acetonitrile (80:5:15 

v/v/v) 

0.8 ml/min 

210nm 

20 μ1 

-3.2 mins 
Harlan Study Number: 41205015 Report Page 405 

Appendix 16 (continued) Analytical Investigations 

1.5 Homogeneity Determinations 

The homogeneity determinations were performed under Harlan Laboratories Ltd. Study number 

41205014. 

1.6 Stability Determinations 

The stability determinations were performed under Harlan Laboratories Ltd. Study number 41205014. 

1. 7 Verification of Test Item Formulation Concentrations 

The test item formulations were sampled and analysed within three days of preparation. 
Harlan Study Number: 41205015 Report Page 406 

Appendix 16 (continued) Analytical Investigations 

2. RESULTS 

2.1 Verification of Concentration of Test Item Formulations 

Analysis Number 

1 

2 

3 

4 

5 

6 

ND = none detected 

- = not applicable 

Nominal Concentration 

(mg/ml) 

0 

5 

25 

75 

0 

5 

25 

75 

0 

5 

25 

75 

0 

5 

25 

75 

0 

5 

25 

75 

0 

5 

25 

75 

Concentration Found 

(mg/ml) ( expressed as % of nominal) 

ND -

5.04 101 

23.2 93 

71.6 95 

ND -

4.90 98 

26.1 104 

76.5 102 

ND -

5.54 111 

21.9 88 

80.3 107 

ND -

4.86 97 

26.1 105 

67.9 91 

ND -

5.31 106 

26.6 107 

80.5 107 

ND -

5.09 102 

24.9 100 

81.1 108 
Harlan Study Number: 41205015 Report Page 407 

Appendix 16 (continued) Analytical Investigations 

3. METHOD VALIDATION 

3.1 Linearity 

The linearity determinations were performed under Harlan Laboratories Ltd. Study number 41205014. 

3.2 Specificity 

The diluent solvent O.Olm orthophosphoric acid and a blank 1% CMC and 0.1% tween 80 (control) were 

analysed. The results are shown in the following table: 

Sample Concentration Found 

O.Olm orthophosphoric acid None detected 

1% CMC and 0.1% tween 80 (control) None detected 

Analysis of the solvent and a blank 1 % CMC and O .1 % tween 80 ( control) produced no signal that 

interfered with the signal due to the test item. 

3.3 Accuracy 

The accuracy determinations were performed under Harlan Laboratories Ltd. Study number 41205014. 

3.4 Conclusion 

The analytical method has been satisfactorily validated in terms of linearity, specificity and accuracy for 

the purposes of the study. 
Harlan Study Number: 41205015 Report Page408 

Appendix 16 (continued) Analytical Investigations 

Examples of the typical chromatography generated during this study are given below: 

Standard Solution 0.01 mg/ml 

' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 400 -------------------------c--- _____________________ 

1 

_________________________ 

1 

_________________________ r ________________________ _ 400 

300 - --- - - - - - - - ---- - - - - - --- - ; - - - - - - - - - - - - - - - - - - - - - - - - -1-------------------------i--~---------------------~--------------------------

! ! ! ~ ! 

300 

~: ..•...•... •••••···: I I I 200 

100 

' ' ' ' ' ' ' ' ' ' ' 0 --t-~~~~~~~~~~~~~~~~~-=.:/-"-----i~'~""'""'~~~~--''~~~~~~~~o 

0 2 3 4 5 

Minutes 

Control 

500 -,----~~~----:-::~,---,::-:-,-------,,-----,------=-c,..,,----~~----.~~~~~~-----.~~~~~~~-,--~~~~~~-,--500 

__ ~~~:.l~nal A, 2"'10 nm 

Retention Ti n-j'e 

400 I I I O -------------------------r-------------------------T--------------------------,--------------------------,-------------------------- 400 I I I I 

' ' ' ' ' ' ' ' ' I ' t 1 ' ' I 

I I l I 

I I 1 I 

I I I I 

300 -------------------------i.-------------------------+----------------- __ _, __________________________ , _________________________ _ I I I I 300 I I I I 

I I I I 

i I I I I 

I I I I 

I I I I 

I I I I 

I J I I 

I I I I 

200 -------------------------i-------------------------i------ ------------------!--------------------------:-------------------------- 200 

' ' ' ' ' ' ' ' ' ' r I I I 

100 , I I I -------------------------r-------------------------T---- --------------------,--------------------------,-------------------------- 100 ' ' 

0 

0 2 3 4 5 

Minutes 
Harlan Study Number: 41205015 Report Page409 

Appendix 16 ( continued) Analytical Investigations 

Examples of the typical chromatography generated during this study are given below: 

Test Item Formulation 5 mg/ml 

soo~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~soo 

__ ~:~:.l~nal A, 210 nm 

Retention Tiie 1 1 ' 

I I I L 

400 -------------------------r-------------------------,--------------------------,--------------------------,-------------------------- 400 I I I I 

' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 

300 -------------------------;-------------------------;------------------------- ;--19---- ----------------,--------------------------

! ! ! ro 

300 

·····················1············ I I I••·••·•••••••••• 

200 200 

100 

0 0 

0 2 3 4 5 

Minutes 

Test Item Formulation 75 mg/ml 

soo~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~soo 

VVVD: Signal A. 210 nm -- 715mg_m. 

Retention Tirrle 

' ' ' O ' I I I 

400- -------------------------:-------------------------;-------------------------:------------------------T---------- ------------:400 

300 - - - - - - - - - - - - - - - - - - - - - - - - - ~ - - - - - - - - - - - - - - - - - - - - - - - - - ~ - - - - - - - - - - - - - - - - - - - - - - - - - ~ - - ~-- - - - - - - - - - - - - - - - - - - - -!- -------------------------I-300 

: , : ro : 

i i ! n i >-

200- ------------ ------------: -------------------------1------------------------- :- - ----------------------:---------------------------200 

' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 100- -------------------------f-------------------------f-------------- - ----- - ~-- - - - - - - - - -------- - -- -- - -~------------------ - -- - - - - - - 100 

0 ,, 0 

0 2 3 4 5 

Minutes 
Harlan Study Number: 41205015 Report 

Appendix 17 Study Plan 

STUDY PLAN 

Test Substance 

Study Type 

Harlan Laboratories Project Number 

Proposed Experimental Starting Date 

Proposed Experimental Completion Date 

Proposed Draft Report Date 

Sponsor 

PMDA 

Oral (Gavage) Reproduction/Developmental 

Toxicity Screening Test in the Rat (OECD 421) 

41205015 

20 February 2013 

17 April 2013 

July 2013 

The American Chemistry Council 

PMDA Consortium 

700 2nd Street NE 

Wsshington DC 

20002 

UNITED STATES OF AMERICA 

FOR SPONSOR 

~l/4~ . ..................... ~~---· 1!)2~01~ DATE: ........ L~ ................. . 

STUDY DIRECTOR: N·K·~~~i······················ DATE: 

1 2 FEB 2013 

This study plan is issued without signature by the Study Direetor to enable changes to be made if necessary prior to 

authorisation. Sponsors should sign and return the document to Indicate approval and GLP authorisation will be 

confirmed by the Study Director's signature prior to the start of lhe study. 

Page 410 
Harlan Study Number: 41205015 Report Page 411 

Appendix 17 ( continued) Study Plan 

1. INTRODUCTION AND OBJECTIVES 

lhe purpose of this study is to generate initial information concerning the effects of the test 

substance on male and female reproductive perfonnance. such as gonodal fundion, mating 

behaviour. conceptiDn, development of the conceptus and parb.l"ition. The results of the study 

are believed to be of value in predicting the possible reprodUcttve toxicity of the test substance to 

man and estimation of the 'No Observed Effect level' (NOEL) for reproductiVe toxicity. 

The test method described is designed to be compatible with the following internationally 

accepted guidelines and recommendations: 

i) OECO Guidelines for Testing of Chemicals No 421 "Reproduction/developmental 

toxicity saeening test' (adopted 27.07.95) 

Where lesting is conducted in accordance with specific guidelines this Will be documented and 

reflected in the final repolt. 

Testing Will be per(Onned in mmplance With UK GLP standards (SChedufe 1, Good laboratory 

Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004J0994)). These regulations are 

in accordanee with GLP standards published as OECD Principles on Good laboratory Practice 

(revised 1997. ENVIMC/CHEM(98)17); and are in accordance with, and implement. the 

requirements of Directives 2004/9/EC and 2004/10/EC. 

lhese principles are compatible with Good Laboratory Practice regtdatiDns specified by 

regulatory aulholities 1hroughoul The European Community, The United states (EPA and FDA), 

and Japan (MHLW. MAFF and METI). 

The Principal Investigator wil be responsible for compliance with their national GLP regulations 

of work performed at 1he Test Site and data provided to 1he study Director for inclusion in the 

inal report 

2. RESPONSIBILITIES 

Study Director. 

Test Facilty: 

Pmjed No: 41205015 

NKDhinsa 

Harlan laboratories ltd. 

Shardlow Business Park 

Shardlow 

Derbyshire 

DE722GD 

Page2of17 
Harlan Study Number: 41205015 Report Page 412 

Appendix 17 ( continued) Study Plan 

Lead Quality Assurance: 

Study Pllases: 

Principal Investigator: 

Test Site: 

UK 

Harlan LabOratories ltd. Quality Assurance, ShardloW. UK 

Histology Processilg 

NFower 

Propath UK Limled 

Willow court 

Ne1helwood Road 

Hereford 

HR26JU 

UK 

Test Site Quality Assurance: AF International Consultancy. cambridgeshire, UK 

Study Phase: 

Principal Investigator: 

Test Site: 

Histopathology Examination 

To be conflnned by amendment to study plan 

To be confinned by amendment to study plan 

Test Site Quality Assurance: To be conflnned by amendment to study plan 

3. ANIMALS 

Specification 

Species: 

strain: 

SUb-strain: 

source or supply: 

Number: 

Body weight range: 

sex: 

Age: 

other: 

Pmjed ND: 41205015 

Rat 

Wisfar Han 111 

RccHan1U:W1ST 

Harlan Laboratories U.K. ltd., Oxon. UK 

12 animals per sex per group: 96 total 

Males: 272 to 393g at start of 1reatment 

Females: 175 to 247g at start of trea1ment 

Males and females 

Approximately 12 weeks at start of treatment 

Females must be nulliparous and non-pregnant 

Weight variation must not exceed :1: 20% of 1he mean weight 

for eill1er sex at start of treatment 

Page3of17 
Harlan Study Number: 41205015 Report Page 413 

Appendix 17 ( continued) Study Plan 

Justification 

Preferred species of choice as historically used for safety evaluation sludies and specified by 

appropriate regulatory authorities. 

4. ANIMAL HUSBANDRY 

Environment 

Environmental condltilofls will be maintained within the following target parameters: 

Target temperature: 

Target humidity: 

22 :t3 .. C 

50 to 60% 

Ughting: 

Ventilation: 

Twelve hours of continuous amficial light in each twenty-four hour period 

At least fifteen air changes per hour 

Animals wll be housed in accordance with the 'Code of Practice for the Housing and Care of 

Animals Used in Scientific Procedures' and in alignment with the United Kingdom Home Office 

recommendations and requirements. 

Housing 

Dunng the pre~pairing phase: 

Animals wHI be housed in groups of four by sex (when possible) in polypropylene cages with 

stainless steel mesh lids and furnished Will softwood flake bedding (Datesand Ltd., Cheshire, 

UK). 

Certificates of analysis for the bedding will be provided by the supplier. 

The bedding is considered not to cootain any contaminants that could reasonably be e~ed to 

affect the purpose or integrity of the study. 

During the pairing phase: 

Animals will be paired on a one rnale:one female basis Wittlin each dose group in polypropylene 

mating cages with stainless steel mesh lids and grid floofing suspended over polypropylene tray 

liners with absorbent paper. 

Project No: 41205015 Page4of17 
Harlan Study Number: 41205015 Report Page 414 

Appendix 17 ( continued) Study Plan 

Males wil be re-housed in their original pre-pairing cages. 

Females will be individually housed in solid Door polypropylene cages with stainless steel mesh 

lids and fi.lmiShed with soflwood lake bedding (Datesand Ltd .• Cheshire. UK) for the gestation, 

birth and ladation phases of the study. 

Diet and Water 

The animals will be provided with Rodent 2018C Teklad Global Certified Diet (Har1an 

Laboratories U.K. Ltd .• OXOn. UK) and tap water ad libitum. 

Drinking water is rootilely analysed (at least annualy) and certificates of analysis for cr1et will be 

, provided by the supplier. 

The diet and water are considered not to contain any contaminants that could reasonably be 

expected to affect the JJUIPOSe or integdy of the study 

5. AN.AL WELFARE 

Environmental Enrichment 

The animals wil be provided with enVirOnmental emidlment substances: wooden chew blocks 

and cardboard run tunnels (Datesand ltd .• Cheshire. UK) or suitable alternatives. 

certificates of analysis for the environmental enrichment substances will be provided by the 

supplier. 

These elllid1rnent lems are considered not to contain any contaminants that could reasonably 

be expected to affect 1he purpose or integrity of 1he study. 

Environmental enrichment wilt not be provided to animals during 1he mating phase or for females 

dumg the gestation and lactalion phases of the study. 

Pmjed ND: 41205015 Page5of17 
Harlan Study Number: 41205015 Report Page 415 

Appendix 17 ( continued) Study Plan 

Study Conduct 

The study was designed and will be conducted to cause the minimum suffering or distress to the 

animals consistent with the scientific objectives and in accordance With the Harlan Laboratories 

Ltd., Shardlow, UK policy on animal welfare and the requirements of the United Kingdom's 

Animals (Scientific Procedure) Act 1986. This study plan is subject to review and the conduct of 

the study may be retrospectiVely reviewed. as part of the Har1an Laboratories Ltd., Shardlow, UK 

Ethical Review Process. 

6. PRE-TEST PROCEDURES 

Acclimatisation Period 

At least five days prior to the start of treatment 

Allocation 

Animals will be alllocated to dose groups usilg a randomisation procedure to produce a 

homogeneous distribution of body weights across groups. 

Identification 

Each animal, selected at random, Will be uniquely identified Within the study by ear-punch and/or 

ta.ii mark. A colour-coded cage card will be prepared with def.ails of test substance, project 

number, dose level, sex, numbers of animals, route of administration and study Director 

responsible for the study. 

7. TEST SUBSTANCE AND EXPERIMENTAL PREPARATION 

Supply 

Pyromellilie dianhydride (PMDA) Will be supplied by the Sponsor with details of purtty and 

hazardous properties if known. The integnty of mta supplied relating to the identification, purity 

and stability of the test substance will be the responsibiity of the Sponsor. The hydrotysis product 

of PMDA is pyrometrltic anhydride (PMA) which is the test substance to be tested. 

Pro~tt No: 41205015 Page6of17 
Harlan Study Number: 41205015 Report Page 416 

Appendix 17 ( continued) Study Plan 

Storage 

Room temperature, in the dark. under nitrogen. 

Preparation 

The test substance will be suspended in 1% carboxyme!hyl cellulose and 0.1% Tween 80. The 

method of preparation will be documented in the study records. 

The frequency of test substance formulation will be dependent on known stability. The pH of 

each formulation mll be recorded. 

Analysis 

Details of identification of the test subs!ance Wil be supplied by the Sponsor. The test sl.lbstance 

formulations will be analysed for concentration. by Harlan Laboratmies Ltd .• Shardlow. UK 

Analyticat Services. Stability and homogeneity of the formulations have been previously 

determined in another study (Harlan Laboratories Ltd. Project Number 41205014). 

8. STUDY DESIGN 

Definitions 

Day 1 of the study is defined as the day the test substance is first administered to the animals. 

Day O of gestation is defined as the day a vaginal plUg is found (uncertain mating) or sperm is 

present in a vaginal smear (confirmed mating). 

Day O post partum is defined as the day of birth; that is, when parturition is recorded as 

complete. 

Administration 

Once daily, by oral gavage, throughout the treatment period (with the exception of females during 

parturition, if applicable), using a suitable dosing cannula attached to a graduated syringe. 

Dosing will be performed at a similar time each day wherever possible. 

Proj!ct No: 41205015 Page7of17 
Harlan Study Number: 41205015 Report Page 417 

Appendix 17 ( continued) Study Plan 

Dose Groups 

Foor dose groups each comprising 24 aninals (12 male and 12 female) will be dosed as follows: 

TREATMENT DURATION NEatOPSY 

OOSELEVEl. DAY 

GROUP VOLUME OF (mgflrg bwlday) (mlltg) TREATMENT Males Females 

Control 0 10 Upto8Weeb Day43 Day 5 postpartum 

low 50 10 Upto8Weeb Day43 Day 5 postpartum 

lnlermediale 250 10 Upto8Weeks Day43 Day 5 postpartum 

Hgh 750 10 Upto8Weeb Day43 Day 5 postpartum 

Dose levels will be based on a previous study (Hal1an Laboratories Ltd .• Project Number 

41205014). Conlrol animals will be treated wilh the vehicle alone and administered at the same 

dose volume as that of test animals. 

The volume of test and control substance administered to each animal wll be based on 1he most 

recenl body weight and adjusted acamHngly. 

c11rono1og1ca1 sequence or Study 

i) Groups of twelve male and twelVe female rats will be dosed according to dose group for 

tourteen days prior to pairing. 

ii) on Day 15. animals wiH be paired on a one male:one female basis wilhin each dose 

group for a maximum of rourteen days and smearing will commence. 

iii) At the end of the mating penod. males will be retumed to 1heir original cages and females 

wll be lransfened to individual cages wlh suitable nesting matelial. Dosing Will continue 

for both sexes dUring subsequent female gestmon and lactation phases. 

iV) Pregnant females are allowed to giVe bil1h and maintain their offspring IBltl Day 4 po:;t 

pa,tum. Evaluation of each ltter will be performed during this period. 

Projed No: 41205015 Page80l'17 
Harlan Study Number: 41205015 Report Page 418 

Appendix 17 ( continued) Study Plan 

v) on Day 5 post pa,tum all females and offspring wil be killed and examined 

macmscopicaly. Any females considered to be non-pregnant will be kiled on or after 

Day 25 post eoilUm. 

Yi) on Day 43 of Ile study. subjed: to confinnation of successful mating males are killed and 

examined macroscopically. 

9. OBSERVATIONS 

Morbiditylltorlatity Inspection 

Twice daily. early and late dUring the working penod. 

Clinical Observations 

Individual clinical obsemdions will be performed immediately before dosing, up to 30 minutes 

aner dosing and one hour after dosing. An additional observation will be made five hours after 

dosing dumg Ile nonnal working week (not at weekends or m public holidays). Al obsefValions 

wiB be recorded.. 

Body weights 

Individual body weights will be recorded for males on Day 1 and then weekly until tennination. 

Individual body weights will also be recorded at terminal kill. 

For females. individual body weights wll be rec:oo:led m Day 1 and then weekly unto pamg. 

During Ille mating phase. females will be weighed daily until mating is confinned (this data may 

be presented in the final report only if required).. Mated females Will be weighed on Day o. 7. 14 

and 20 post coilUm and body weights tor females which giVe birth will be recorded on Days 1 and 

4 postpartum. Body weights wll also be recorded at terminal kiB. 

Females with no evidence of mating will be weighed daily until termination. This data will not be 

reported. 

Pfojed No: 41205015 Page9of17 
Harlan Study Number: 41205015 Report Page 419 

Appendix 17 ( continued) Study Plan 

Food Consumption 

Male food consumption will be recorded weekly prior to and after pairing. Female food 

cmstnnption will be recorded weekly prior to pairing. Weekly food efficiency (body weight 

gain/food intake) wil be calculated for males and females prior to pairing and for males after the 

mating phase. Food consumptions wil not be performed during the pairing phase. 

Food consumption for mated females will be recorded on Days 0-7. 7-14 and 14-20 post coitum. 

Food consumptions for females with live llters wiR be recorded between Days 1-4 postpartum. 

Water Consmnption 

Monitored daily by ViSUal i1spedion or water bottles. Measurement will be initiated if a treatmentrelated effect is suspected. at the discretion of 1he Study Di'edor. 

Mating 

Animals will be paired on a one male:one female basis Within each dose group for up to fourteen 

days (animals will be placed together in mating cages). 

The stage of oestrus will be recorded during 1his period for all females via vaginal smear. 

Smearing of individual females wll be discontinued when a vaginal plug or spenn are found in 

the vaginal smear. 

On confimation of mating. males will be re-housed in lleir original cages and females Wil be 

individually housed in sold floor cages. Uncertain mated females wiD continue to be housed wflh 

1he male until mating is confirmed by 1he presence of a vaginal plug or spenn in a vaginal smear 

or 1he fourteen day mating period is complete. 

Pregnancy and Parturition 

For each pregnant female 1he foloWing wil be recorded: 

i} Date of pairing 

ii) Date of mating 

iii) Date of parturition 

Project No: 41205015 Page10of17 
Harlan Study Number: 41205015 Report Page420 

Appendix 17 ( continued) Study Plan 

Utter Data 

Offspring will be individually idenflfied within each litter by tattoo on Day 1 of lactation. 

For each litter the folowing wiU be recorded: 

i) Number of offspring bom 

ii} Number of offspring alive recorded daily 

iii} sex of olfspling on Day 1 and 4 postpartum 

iv) Results of Ile surface righting assessments on Day 1 postpartum 

v) Clnical condiliOn of offspring from birth to Day 5 postpartum 

Vi) Individual offspring weights on Day 1 and 4 post partum (litter weights wil be calculated 

retrospectively from offspring weights) 

Post Monem Studies 

Post mortem studies will be perfonned on animals found dead or killed in extremis during the 

study and ma all adul animalS killed by intravenous overdose of sodium pentobarbitone followed 

by exsanguination at termination. Offspring Will be killed by intracardiac overdose of sodium 

pentobarbitone. 

Gross Examination 

Full external and internal examination of all animals inducing offspring. In Ile adult animalS, 

special attention will be paid to Ile gaslnHltestinal tract with macroscopic examination of Ile 

mucosa of the stomach. 

The corpora lutea of all ovaries from al cohabited adult females wil be counted at necropsy. 

The uterine implantalion sites from al eohabitated adult females wil be counted. The procedure 

may be enhanced using the tedtniqUe proposed by 5alewski (1964). 

Organ Weights 

The followlng mgans wil be kimmed free from fat and weighed at terminal kilt 

PfDjed No: 41205015 Page11of17 
Harlan Study Number: 41205015 

Appendix 17 ( continued) 

Epididymides 

ovaries 

Pituitary (post fixation) 

Prostate 

Seminal vesicles 

Spleen 

Testes 

Histopathology 

Report 

Study Plan 

Liver 

Kidneys 

Heart 

Thymus 

Brain 

Adrenals 

Thyroid/parathyroid (post fixation) 

Page 421 

Samples of the folloWing tissues will be preserved, from all animals. in buffered 10% formalin 

except where stated and despatched to the histology processing Test Site: 

Epididymides+ 

Gross lesions 

ovaries 

Pituitary 

Prostate 

Seminal vesides 

Coagulating gland 

Testes+ 

Mammary gland 

uterus with Cervix 

Vagina 

• Preserved m Bouins fluid then transfem!d to 70% 

Industrial Methylated Spirils (IMS) approximately 48 

hours later 

The rollloWing additional tissues will be preserved from 5 males and 5 females surviVing to 

scheduled saaifice from each treatment group, in buffered 10% and despatched to the histology 

processing Test Site: 

Liver 

Duodenum 

lcetJm 

Colon 

Kidneys 

Lungs 

Heart 

lbymus 

Lymph nodes (mabmlibulaf and mesenteric) 

Proj!ct No: 41205015 

Stomach 

Jejenum 

Caecum 

Rectum 

Urinary bladder 

Trachea 

Spleen 

Adrenals 

Sciatic nerve 

Page 12 of17 
Harlan Study Number: 41205015 Report 

Appendix 17 ( continued) Study Plan 

Brain (including cerebrum. cerebellum and pons) Thyroidfpara1hyroid 

Spinal cord (cervical. mid-1horacic and lumbar) 

Page 422 

Initially. al tissues listed from any decedents. any animals failing to produce a pregnancy and all 

cootml and high dose animals will be routinely processed to paraffin wax. sectioned and stained 

Wilh Haematoxylin and EOSin. Gross lesions will also be processed.. In addition. sections of 

testes will also be stained wi1h Periodic Acid-Schiff (PAS) stain. 

Detailed qualitative examination of 1he testes will be made for all control and high dose males, 

taking into account 1he tubular stages of 1he spennatogenic cycle. The examination wil be 

conducted in order to identify treatment-related effects such as missing germ cell layers or types, 

retained spermatids. muffinudeated or apoptotic germ cells and sloughing of spennatogenic cells 

into the lumen. Arty eel-or slage-specifidly of testicular findings will be noted. 

Prepared sides Will be sent to the histopalhology examination Test Site for histopathology 

examinations by the Pathologist acting as 1he Principal Investigator for this study. whereupon 

special slaining techniques may be used, where appropriate. A peer review of the histopathology 

examlnal:ions will also be included in lhis phase of the study. 

The study Pathologist will infOrm 1he Study Director of any treatment-related changes. Where 

trealment-related lesions are seen in the high dose group, histology processing and 

histopathological examinations Will be extended to al animals from the remaining dose groups. 

on completion, a histopa1hological examination phase report Will be sent to the study Director. 

10. EVALUATION OF DATA 

Where considered appropriate, quantitative data will be subjected to slaflstical analysis to detect 

lie signlicance of intergroup differences from control; statistical significance Will be aehieved at a 

level of p<0.05. statistical analysis wil be performed as follows: 

Metal d 9afstic:a1Analysis 

If p,1!1i11i11ay test is nat 

Parmlll!ller Pn!limira r Tl!Slt signilii::ant If pl!l!llinnwytest is !iigl1il-,t 

AirMllnfia Slaiail:al' Rll:flag9 Ws 1lest b- Hamagmlil!.ty. 0.-, analJ!;isdva'ialme CII' Kruslial-Wah test falk-.:1 by 

T1a1Slbnns 1111! data 1D ..__ One-War analysis d Shide,s test lilr ln!nd. I' no band. 

Male BadyWeg,t Gain nannality ... --- Qmmame. Then --1est this .. be ranr-cl by the steel 

lmmagmeil)' will t:re used. 1he .... trend. If nat applicallle. test. If unsuilable, by lhe MamAojed No: 41205015 Page13of17 
Harlan Study Number: 41205015 Report Page 423 

Appendix 17 ( continued) 

Female Pwe-Pam,g Body Weight 

Gllin 

Pro)!cl: No: 41205015 

Study Plan 

an:ler of iransforms ~ Dunnets or student T Test 

will be log. squse-mot. and 

'Milney 'U' test. 

rank-on:ller. If ihe log and 

~· 1ransfimTls fail. the 

1'311'1l-an:ller wift be used. 

One-way analysis of variaooe Kruskal-Wallis test fdio-d by the 

follawed by Dunnett's test IM'arm-Whilney v test 

Page 14 of17 
Harlan Study Number: 41205015 Report Page424 

Appendix 17 ( continued) Study Plan 

11. QUALITY ASSURANCE 

The study plan wil be reviewed for GLP compliance and the final report will be audited by Harlan 

L.aboralortes ltd .• Shan:llow. UK Quality Assurance Unit. Study phases will be inspected as 

detennined by Harlan Laboratories Ltd .• Shardlow. UK Quality Assurance Unit. 

The Test Site(s) quamy assurance should inspect ~ work according to their own 

SOPs. reporting any inspediDn resuls prornpUy in Wfffing to the Principal Investigator, Test Site 

management study Director. Test Facility management and lead quality assurance. 

12. STUDY PLAN AMENDMENTS AND DEVIATIONS 

Amendments to 1he study plan wil be made only by completion of an amendment to study plan 

approved by the study Director and Sponsor. 

The Pmdpal Investigator will document deviations to the study plan. acknoWledge and report 

them to the study Director and Sponsor. 

Deviations to the study plan will be documented and acknoWledged by the study Director. 

13. REPORT 

Any phase report or data provided by a Principal Investigator should include a signed statement 

of GLP compliance and a quality assurance slatement signed by a representaUve of Test Site 

Quality Assurance. 

A 1UI report cootanng a desaiption of the test substance and detailed description of the 

e,ipenmenlal procedu'es will be presented. The report will contain obselYations. discussion and 

intelpretation of the results where relevant A draft report will be sent to the Sponsor for review 

and mmments before issUe of the final report. 

14. ARCHIVE 

At the request of the Sponsor, and will the exception of unprocessed wet tissue samples, all 

ongm data induding tissue '*>cks and tissue slides generated at the histology processing Test 

Sile and all dala generated at the Test Facility. induding the 1inal report and the histopathoklgy 

examination phase report, will be retained in the Harlan Laboratories ltd .• Shardlow, UK archives 

Pmjed No: 41205015 Page15of17 
Harlan Study Number: 41205015 Report Page425 

Appendix 17 ( continued) Study Plan 

fOr ten years. after wtlidl instructions Wil be sought as to 'bther retention or disposal. 

Unprocessed wet tissue samples will be retained in these archives for two years prior to disposal. 

15. REFERENCE 

salewsld E (1964). Flrbemethode zum makroskopischen NachWeis von lrnplantaUonsstelen am 

uterus der Ratte. Naunyn - Schmiedebergs Arch Exp Path Phannacol 247 367. 

Pnljed No: 41205015 Page16of17 
Harlan Study Number: 41205015 Report 

Appendix 17 ( continued) Study Plan 

Appendix. 1 Reproductive Indices 

Malin lndeX = Number of animals maled x 100 

g Number of animats paired 

Pregnancy Index = Number of pregnant females x 100 

Number of animals mated 

Parturition Index = Number of females delvenng live offspring x 100 

Number of pregnant females 

Live Binh Index = Number of offspring alive on Day 1 x 100 

Number of offspring born 

Viability Index = Number of offspling alive on Day 4 x 100 

Number of offspring alive on Day 1 

Pre-implantation loss= Number of corpora lutea-number of implantations x 100 

Number of corpora IUtea 

Post-implantation loss= Number of implantations-total number of offspring born x 100 

Number of implantations 

% Male offspri (sex Ratio) = Number of male offspring x 100 

ng Total number of offspring 

Page426 

Projed No: 41205015 Page17of17 
Harlan Study Number: 41205015 Report 

Appendix 17 ( continued) Study Plan 

HARLAN LABORATORIES LTD. 

AMENDMENT TO STUDY PLAN 

Amendment Number: One 

Study Type: 

Oral (Gavage) Reproduction/Developmental Toxicity SCINning 

Teat In the Rat 

Test Item: 

Harlan Laboratories Project Number: 

Sponsor: 

Amendments: 

REASON FOR CHANGE 

PMDA 

41205015 

The American Chemistry Councll 

PMDA Consortium 

700 2nc:I Street NE 

Washington DC 

20002 

UNITED STATES OF AMERICA 

This amendment has been issued to conflnn the name and addreu of the hlstopathology examination test 

site and a typographical error noted on Page 12. 

Paga 3 RESPON81BILfflE8 

StudyPhMe: 

Principal lnvMtlgator: 

Teat Site: 

T•t Site Quallty Assurance: 

Paga 12 Hl9topathology 

Hlstopathology Examination 

Peter Miiiar 

Pater Miiiar Associates Ltd. 

3 Queen Charlotte Lana 

Edinburgh 

SCOTLAND 

EH88AY 

Quality Assurance, Peter MOiar Associates Ltd, Scotland 

The spelling for 'Lymph nodes (mandibular and rnaenteric)' has hereby been corrected 

This amendment does not affect the purpose or Integrity of the study. 

AUTHORISED FOR 

HARLAN LABORATORIES LTD BY: ··~·-················ 

N K Dhln18 MSc BSc (Hons) 

STUDY DIRECTOR 

2 5 FEB 2013 DATE: ........ .-.................. .. 

Page427 

APPROVED FOR SPONSOR BY: ~~lck.2~~ 

Project Number: 41205015 (Amendment No.1) Page 1 of 1 
Harlan Study Number: 41205015 Report 

Appendix 17 ( continued) Study Plan 

HARLAN LABORATORIES LTD. 

AMENDMENT TO STUDY PLAN 

Amendment Number: Two 

StudyType: 

Ori! (Glvage) ReprocluCUon/Developmental Toxicity Screening 

Teet In the Riii (OECD 421) 

TNt Subttllnce: 

H1rl1n LaborelorlN Project Number: 

Sponeor: 

Amendments: 

RIAION FOR CHANGE 

PMDA 

41205015 

The Amlrlclln Chemistry Council 

PMDA Consortium 

700 2nd Street NE 

Washington DC 

20oo2 

UNITED STATES OF AMERICA 

Thll amendment hes been iaaued to clWlge the name of the test 1ubltmnce. 

PAGE 1 T•t lubetance 

At the requat of the Sponsor, the test aubltlnce name h• been changed from 'PMDA' to 'PMDA 

hydrolynd to PMA'. 

Thia emendment does not affect the purpose or l'*9rtty of the study. 

AUTHORISED FOR 

HARLAN LABORATORIES L TO BY: 

APPROVED FOR SPONSOR BY: 

Project Number: 41206015 (Amendment No.2) Page1of1 

Page428 
Harlan Study Number: 41205015 Report 

Appendix 17 ( continued) Study Plan 

HARLAN LABORATORIES LTD. 

AMENDMENT TO STUDY PLAN 

AMENDMENT NUMBER: Three 

STUDY TYPE: 01'111 (Gavage) Repn,ductlonlDevlopmentll TOJClclty Scraenlng Teat In 

the Rat (OECO 421) 

TEST ITEM: 

HARLAN LABORATORIES 

LTD. PROJECT NUMBER: 

SPONSOR: 

AMENDMENT: 

RIIPONIIBLl!PIRSONNEL 

PMDA hydrolyzed to PMA 

41205015 

The American Chemlltry Council 

PMDA Consortium 

700 2nd Street NE 

W..hlngton DC 

20002 

UNITED STATES OF AMERICA 

Due to the l'Hfgnatlon of the current Study Director, a new Study Director ha been appointed: 

Exllllng Study Director: NKDhlnu NIW study Dlnlctor: J s Dun• 

Thll lCtion does not affect the purpose or lntagrltv of the study. 

PREPARED FOR HARLAN 

LABORATORIES LTD. BY: 

REPLACEMENT STUDY 

DIRECTOR: 

APPROVED BY MANAGEMENT: 

APPROVED FOR SPONSOR BY: 

N"K--iii,;i.i ...... . Study DlnlctDr 

j'~~~i ........... .. 

New y Director 

Projlet Number: 41205015 (Amlndment 3) 

2 5 JUL 2013 

DATE: ..................................... . 

DATE: .... ll.JP.1JD1t ..... 

DATE: ...... ~.:.J.:..!.~ ......... . 

Page1 of1 

Page 429 
Harlan Study Number: 41205015 Report 

Appendix 18 Histology Processing Phase Test Site Quality Assurance Statement 

Facility: 

Audit Date: 

QUALITY ASSURANCE STATEMENT 

Propath UK Ltd 

Willow Court 

Netherwood Road 

Hereford HR2 6JU 

4th & 5th March 2013 

Authenticated Copy 

Signature~ 

· Date 6 -6·1'3 · 

Reported to 

Propath management 12111 March 2013 

Scope: Histology laboratory facilities (Organisation, training records, 

jpp f.lewrlpjip.o.i;Jt CV$...~~v~:w.~QA}~ 

processes (sample receipt, tissue trimming, embedding, 

sectioning, staining and cover-slipping, correlation) were 

inspected for compliance with the requirements of the OECD 

Principles of Good Laboratory Practice 1997 Revision 

(ENV/MC/CHEM(98)17} and the United Kingdom GLP 

'.Regulations 1999, Statutory1nstruments 1999, No. 3106 as 

amended. 

Signed: _ ___.A:("-',..;..... '\i_·_-v<...-,_=!ZJ ..... ··---'--,l~-"'----

Anne Fox 

AF International Consultancy 

AF INTERNATIONAL CONSULTANCY 

4 ·'l'he Mgitsters, 'l'he 014 Grain fiam, (Jeorge Lane. fludcden, Canms f'Et9 5:XN 

Page 430 
Harlan Study Number: 41205015 Report 

Appendix 19 Histology Processing Phase Test Site Statement of Compliance 

•• PROPATH·-

Speclahsts 1n hlstopathology 

Propath UK Umlted 

Willow Court, Netherwood Road 

Hereford HR2 6JU 

United Kingdom 

OLP COMPLIANCE STATEMENT FOR HISTOLOGY 

AT PROPATH UK LIMITED 

STUDY/PROJECT NUMBER 41205015 

DATE: 07 June2013 

T +44 (0) l432 354 052 

F +44 (0) 1432 352 340 

E enquiries@propoth.co.uk 

W www.propoth.co.uk 

I, the undersigned, accept responsibility for the validity of the Histology phase of this study and confirm 

that it was conducted in compliance with the UK Principles of Good Laboratory Practice (The United 

Kingdom OLP Regulations 1999), Statutory Instrument No. 3106 as amended by the Good Laboratory 

Practice (Codification Amendment Etc) Regulations 2004 Statutory Instrument No. 994. These are in 

accordance with the Organisation for Economic Co-operation and Development (OECD) Principles of 

Good Laboratory Practice (1997) (ENV /MC/CHEM (98) 17) 

PRINCIPAL INVESTIGATOR: 

~sv""'-...,._~~ 

Nicola Fower 

Deputy Laboratory Manager 

Propoth 1, accredited by the UK Medicines and Heoltt,care products Regulatory Agency 

Registered in England and Wales number: 3224075 VAT registration number: 893 5802 85 

Page 431 
Harlan Study Number: 41205015 Report 

Appendix 20 Histology Processing Phase Test Site Statement of GLP Compliance 

'nH) Department C ofHeslth 

THE DEPARTMENT OFIIEALTR OF THE GOVERNMENT 

OFTBE UNITED KINGDOM 

GOOD LABORATORY PRACTICE 

STATDIENT OF COMPLIANCE 

IN A.CCOIIDANCE WITH DlRECl'IVE 2004IM'.C 

TISTFACILl'l'Y 

Propath UK Limited 

Willow Court 

Nethenrood Road 

Hereford 

BR26JU 

27June20ll 

Histology proceaing 

Page 432 

A general :inspecCion for compliance with the Principles of Good LaboralOly Pracdce 

was cattied out at the above test facility as part of the UK GLP Compliance Programme. 

At the time of inspection no deviations were found of sufflcieat magnitude to affect 

the validity of non-clinical studies performed at these facilities • 

Dr. Andrew J .. Gray 

Bead, UK GLPMOllftartalA'lltherlly • 
Harlan Study Number: 41205015 Report 

Appendix 21 Certificates of Analysis of Diet Used 

Teklad Certified Global 18% Protein Rodent Diet 

2018C 

Certificate of Analysis 

11.2 

18.4 

6.76 

3.34 "' 

5.28 "' 

0.95 "' 

0.69 "' 

0.23 "' 

0.2 "' 

0;611,' 'II, "'

0.41 

$'1:31 ~'fug(tcg "' 

otal Viable Count 

t.ilesopt,ilic Spores 

Salmonella 

Coliforms, 

E.coli 

Fungal Spores .·· 

tibiotic Acti · 

Data entered by: 

86.6 ,,11:u· 

197.2 

14.5 •. 

67.0 

nd 

0.3 

0.3 

0.16 

0.07 

.nd 

nd 

15.3 

nd 

nd 

nd 

nd 

nd 

lid 

nd 

rid 

1.1 

Rebecca Porter 

2012.10.0314:53:23 

-05'00' 

ncl·l'oMdelaelld(,..Dlede-onlrrft. DI.) 

mg/kg 

riio.'kili 

mg/kg 

n,g/kQ 

mg/kg 

·(1111/l!g 

mg/kg 

mg/kg 

mg/kg 

mg/kg 

mg/kg 

n,g/kQ 

mg/kg 

.mg/kg . =:./ 

cru,g 

cfulg 

cru,g 

17.0 

4.0 

2,0 

4.0 

0.7 

0.4 

0.1 

0.15 

0.5 

0.25 

,.o-; 

80.0 

. • :!3.0 

100.0 

8.0 

50.0 

IJrNH alhtrwll1 ltmled rua,ta an 11111 Clrtillcall ar. expretNd on a 'e1 rwcei¥ed' maillure bllil 

•s.o-lllll'<>rllo-rlOlldun-

-•llrPCllllondRNld,-.. 70-120% 

Batch Number 2018C-090612MB 

Certificate Number 12-N10433 

Date of Manufacture __ Se=p,..te;;.;.m""be""r....;6 ... 2;;;;.;0'"'1;;;;.2 __ 

13.0 

20.0 

7.0 

6.0 

7.0 

1.3 

1.1 

0.3 

0.35 

1.1 

0.65 

90.0 

160.0 

. 20',0· . 

350.0 

.20.0 

150.0 

100.0 

5.0 

0.5 

1.0 

0.4 

3.0 

0.1 

40.0 

0.1 

0.02 

0.1 

0.05 

0.5 

5,0 · 

100,000.0 

10,000.0 

0.0 

5.0 

0.0 

200.0 

0.0 

Expiry Date ____ J_un_e'""'3;.:,., _20"-1=3 __ _ 

0.01% 

o.5% 

0.1% 

100mg/kg 

825 mg/kg 

100mg/kg 

0.06% 

. 800mg/kg 

0.02% 

0.5 mg/kg 

0.02 

0.025 

0.005 

0.025 

0.03 

15-30 

0.03 

o.~ 

0.03 

0.02 

0.05 

0.05 

<10 CIU/g 

nfln 25g. 

10 cl'ulg 

ng in 1/g 

nfln 10g 

na 

Data checked by: 

2012.10.25 

~~.\IA C. }l,.,..ti.( .. -.... 19:36:24 

-05'00' 

Page 1 of2 

Page 433 
Harlan Study Number: 41205015 Report Page 434 

Appendix 21 ( continued) Certificates of Analysis of Diet Used 

Teklad Certified Global 18% Protein Rodent Diet 

• 

Batch Number 2018C-090612MB 

2018C Certificate Number 12-N10433 

Date of Manufacture Sel!!ember6, 2012 

Expiry Date June 31 2013 

Multi-Residue Screen 

Level LOD Level LOD Lave! LOD 

nd 0.02 lprodlone nd 0.2 

nd Chlordane nd 0.07 Procymldone nd 

nd DDT nd 0.03 inclozolin .nd 

Bromophos nd 0.05 nd 0.02 

arbophenothlon nd ·0,07 n.d 0.03 

Chlorfenvlnphos nd 0.1 nd 0.05 

hlorpyrlfos • nd ·a.04 nd 0.02 Chlorpropham .. •' 

.:nd ·o.s 

Chlorpyrlfos Methyl nd 0.05 nd 0.02 Etridlazole nd 0.1 

Demeton-S-Methyl nd. 0.1 nd 0.03 Fenarlinol nd 0;08 

Dlazlnon nd 0.05 nd 0.08 Metalaxyt nd 0.2 

Dlchlorvos nd 0.06 · nd ·0.02· etribuzln nd 0.2 

Dimethoate nd 0.1 nd nd 0.2 

Ethlon nd 0.07 nd nd 0.3 

Ethc,pyrophos nd 0.05 nd 0.2 

Etrimfol nd· 0.05 nd. . 0-3. 

Fenchlorphos nd 0.1 nd 0.1 

Fennrothlon nd 0.08 Blfenthrln nd 0.1 nd\: 1.,0: 

Fenthion nd 0.08 Cyfluthrln nd 0.1 nd 0.07 

Fonophos nd 0.03 lamda Cyhalothrln nd 0.1 nd 0.2 

Heptenophos nd 0.1 Cypennethrln nd 0.1 nd 0.1 

Ml!ilathion, i': .. nd 0.05 i:>eltamethrln nd 0.1 nd 0.03 

Methamidophos nd 0.2 Fenvalerate nd 0.1 

Mettlldathlon .·• nd . 0.1 FIUcythl'.lnate nd 0.1 

Mevlnphos nd 0.05 Permethrln nd 0.5 

Omathoate nd 0.1 effuthriri;. nd 0.05 Cadusafos nd' O.OG 

Parathion nd 0.03 Chlorothalonll nd 0.2 

Parathion M$1!1yl nd 0.03 Chlorthakfimethyl nd' 0.06 

Phosalone nd 0.1 Chlorthlon nd 0.05 

Phosmet nd 0.1 m:t 0.1 Dlchlofluanld . nd. O.OG 

Phosphamldon nd 0.06 nd 0.1 Dlcofol nd 0.1 

Plrlmlph~~· .. ,,.nd 0~05 nd· 0,1 l)lphenylaml"9 . net,;, 0.1 

Qulnalphos nd 0.05 nd 0.1 Methoxychlor nd 0.08 

Tolck!foa~ nd 0.05 nd OJ el'ldlmeth~kn . l'ld 0,05 

Trlazo hos nd 0.05 nd 0.1 Pentachlorobenzene (PCB) nd 0.5 

etradlfori:. . nd 0.05 

ebuconazole nd 0.3 

harlanTM .... Helping you do research better Hartin, Hlr1an ubcnlorin, Helping JOU do NIH.n:ih better, Md ... 

Hamn klgoare ltad...tt lffllhd9 M!MaofHartln l...tlortortas. 

lnc.02008--rlol.lnc. 

Harlan Laboratories · PO Box 44220 Madison, WI e37444220 800 ·483 · 5523 • www.ha~an.com Paga 2of 2 
Harlan Study Number: 41205015 Report Page 435 

Appendix 21 (continued) Certificates of Analysis of Diet Used 

Teklad Certified Global 18% Protein Rodent Diet 

Batch Number 201BC-101112MB 

2018C Certificate Number ____ 12_-N_1_2_25_2 ___ _ 

Date of Manufacture ____ o __ cto __be.....__r .... 11 ..... __ 20_1_2 __ 

ExpicyDa~------'J_u~ly~8~,2~0~13"---

Certificate of Analysis 

ActlonUmlta 

11.4 13.0 

18.1 II(, 17.0 20.0 0.1111, 

7.ff " 4.0 7.0 Review 0.01'11, 

3.34 II(, 2.0 e.o 0.511(, 

4.98 " 4.0 7.0 0.1'11, 

0.89 II(, 0.7 1.3 100m;lkg 

0.83 " 0.4 1.1 82& mg/kg 

0.2 .. 0.1 0.3 100 mg/kg 

0.2 'II, 0.15 0.35 0.08'11, 

0.81 II(, 0.5 1.1 800 mg/kg 

0.4 'II, 0.25 0.65 

74.32 mg/kg 40.0 90.0 

87.4 mg/kg 80.0 160.0 

12.83 mg/kg 8.0 20.0 

228.3 100.0 350.0 

14.1 8.0 20.0 

74.8 50.0 150.0 

nd 100.0 

0.38 5.0 

0.33 0.5 0.02 

0.18 1.0 0.025 

0.08 0.4 0.005 

0.08 mg/kg 3.0 0.025 

nd mg/kg 0.1 o.oa 

18.1 mg/kg 40.0 15-30 

nd mg/kg 0.1 o.oa 

nd mg/kg 0.02 0.02 

nd mg/kg 0.1 o.oa 

nd mg/kg 0.05 0.02 

nd 0.5 0.05 

nd 5.0 0.05 

nd 

nd 0.01 

nd 

100,000.0 

10,000.0 

0.0 

c:fulg 5.0 

cru,g 0.0 

c:fulg 200.0 

0.0 na 

Data entered by: Data checked by: 

Rebecca Porter hirlan .. -~ 2012.11.30 2012.12.0314:05:00 

-()6'00' ~.tM,, U. ]'lw.cA/J,-.., 23:46:06 

nd·N--(-tlleclo-iml,Dlj 

Unlnl alhlrMle ,lllld ruull on 11111 ceJtillc:ale are apraHld an • '11 .....r rnolltur9""" ·s..-dlltl'orlle ___ -06'00' 

_rlo,lorl'CIII ---70-120% Page 1 of2 
Harlan Study Number: 41205015 Report Page 436 

Appendix 21 ( continued) Certificates of Analysis of Diet Used 

Teklad Certified Global 18% Protein Rodent Diet 

2018C 

Batch Number 201SC-101112MB 

Certificate Number 12-N12252 

Date of Manufacture October 111 2012 

Expiry Date Ju!X 812013 

Multi-Residue Screen 

Level LOD Level LOD 

Acephate nd 0.1 

Azlnphoa Methyl nd 0.2 

Bromophos Ethyl nd 0.08 

Bromophoa nd 0.05 nd 0.02 

Carbophenolhkm nd 0.07 nd 0.03 

Chlorfenvlnphos nd 0.1 nd 0.05 

Chlorpyrlfol nd 0,04 nd 0.02 Chlorpropham nd 0.5 

Chlorpyrifos Methyl nd 0.05 nd 0.02 Etrldlazole nd 0.1 

Demeton-S-Melhyl nd 0.1 nd 0.03 Fenartmol nd 0.08 

Dlazinon nd 0.05 nd 0.08 Metalaxyl nd 0.2 

Dlchlorvoa nd 0.08 nd 0.02 Metrlbuzln nd 0.2 

Dlrnethoate nd 0.1 0.05 Pirlmlcarb nd 0.2 

Ethlon · nd 0.07 0.05. Propachlor nd 0.3 

Ethopyrophos nd 0.05 0.05 Prop ham nd 0.2 

Etrlmfos nd 0.05 Proplconazole nd 0.3 

Fenchlorphos nd 0.1 Propyzamlde nd 0.1 

Fenltrothlon nd 0.08 labendazole nd 1.0 

Fen1hion nd 0.06 olyfluanld nd 0.07 

Fonophos nd 0.03 Triadlmefon nd 0.2 

Heptenophos nd 0.1 Trladlmanol nd 0.1 

Malathion nd O.OD Trlflurann nd 0.03 

Methamldophos nd 0.2 Fenvalerate nd 0.1 

Melhldathlon nd 0.1 Flucythrtnate nd 0.1 

Mevlnphos nd 0.05 Permethrln nd 0.5 

Omethoeta nd 0.1 efluthrlri nd 0.05 Cadueafoa nd O.OD 

Parathion nd 0.03 Chlorothalonll nd 0.2 

Parathion Methyl nd 0.03 Chlorthal-dlmethyl nd 0.05 

Phosalone nd 0.1 Chlorthlon nd 0.05 

Phosmat nd 0.1 nd 0.1 . Dlchlofluanld nd 0.05 

Phosphamldon nd 0.06 nd 0.1 Dlcofol nd 0.1 

Plrimlphos Methyl nd 0.05 nd 0.1 Dlphenylamlne nd 0.1 

Quinalphos nd 0.05 nd 0.1 Methoxychlor nd 0.08 

Tolclofos Methyl nd 0.05 nd 0.1 Pendimethalln nd 0.06 

Trlazo hos nd 0.05 nd 0.1 Pentachlorobenzene (PCB) nd 0.5 

Tetradlfon ncl 0.05 

ebuconazole nd 0.3 

harlanTM ... Helping you do research better ---~Holpng,OUdollNIIOhllolfor,ondlhl 

-1ogo .. -...i--o1H1111n-... 

lno.02IJDl-n Lallomarill, me. 

Hllllan Labomaries • PO Box ~220 · MadilOll, WI 53744-4220 • 800 · 483 · 5523 · www.harlan.com Page 2 of 2 
Harlan Study Number: 41205015 Report Page 437 

Appendix 22 Normal Ranges for Reproductive Parameters in the Pregnant and Lactating 

Female Wistar HanTM:RccHanTM: WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. 

November 2011 

APPROXIMATE AGE: Fourteen to Nineteen weeks 

UPDATED: 

Range . No. of Animals 

MATING & GESTATION 

Pre-Coital Interval (Days) 1 - 5 209 

(2) (1) 

Gestation Lengths (Days) 21.8 - 23.5 213 

(22.7) (0.4) 

FOOD CONSUMPTIONS (g/rat/day) 

Gestation Days O - 7 15 - 23 208 

(19) (2) 

Gestation Days 7 - 14 17 - 25 208 

(21) (2) 

Gestation Days 14 - 20 19 - 27 206 

(23) (2) 

Lactation Days 1 - 4 18 - 36 196 

(27) (4) 

BODY WEIGHT CHANGE (g) 

Gestation Days O - 7 13 - 35 208 

(24) (5) 

Gestation Days 7 - 14 16 - 36 180 

(26) (5) 

Gestation Days 14 - 20 44 - 81 179 

(63) (9) 

Lactation Days 1 - 4 -3 - 24 209 

(10) (7) 

CORPORA LUTEA & 

IMPLANTATIONS 

Corpora Lutea (Number) 10 - 19 208 

(15) (2) 

Implantations (Number) 9 - 18 208 

(13) (2) 

Pre-Implantation loss(%) 0 - 27 200 

(8) (10) 

Post-Implantation loss(%) 0 - 24 207 

(7) (8) 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41205015 Report Page 438 

Appendix 23 Normal Ranges for Offspring Parameters in the Wistar HanTM: RccHanTM: 

WIST Strain Rat 

SUPPLIER: 

UPDATED: 

Harlan Laboratories U.K. Ltd. 

November 2011 

OFFSPRING DATA 

SURVIVAL INDICES(%) 

Live Birth Indices 

Viability on Day 4 

LITTER SIZE 

Litter size at birth 

Litter size at Day 1 

Litter size at Day 4 

LITTER WEIGHT (g) 

Litter weight at Day 1 

Litter weight at Day 4 

SEX RATIOS 

% Males at Day 1 

% Males at Day 4 

OFFSPRING BODY WEIGHTS (g) 

Male body Weights at Day 1 

Male body Weights at Day 4 

Female body Weights at Day 1 

Female body Weight at Day 4 

DEVELOPMENTAL & REFLEX 

MARKERS 

Surface Righting (%) 

• Range = mean ± 2 standard deviations 

AGE: 0 - 4 Days 

Range . 

97 - (100) 

92 -

(99) 

7 - (12) 

8 -

(12) 

7 - (12) 

48.2 - (70.6) 

71.0 -

(101.3) 

24 - (50) 

24 -

(50) 

4.8 - (5.9) 

6.6 - (8.7) 

4.6 - (5.7) 

6.5 - (8.3) 

61.9 - (87.5) 

(values in brackets indicate group mean and standard deviation respectively) 

No. of Animals 

100 214 

(1) 

100 214 

(4) 

17 213 

(3) 

17 210 

(2) 

17 209 

(2) 

93.1 209 

(11.2) 

131.7 208 

(15.2) 

76 203 

(13) 

76 203 

(13) 

7.0 208 

(0.5) 

10.8 209 

(1.0) 

6.7 206 

(0.5) 

10.1 200 

(0.9) 

100.0 213 

(12.8) 
Harlan Study Number: 41205015 Report Page 439 

Appendix 24 Normal Ranges for Absolute and Body Weight-Relative Organ Weight 

Values in the Wistar HanTM:RccHanTM: WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. 

November 2011 

APPROXIMATE AGE: Eighteen to Twenty Weeks 

UPDATED: 

ABSOLUTE WEIGHT (g) RELATIVE TO TERMINAL BODY 

WEIGHT(%) MALE ORGAN WEIGHTS No.of No.of Range (g)* Animals Range(%)* Animals 

Adrenals 0.0420 - 0.0809 140 0.0104 - 0.0210 150 

(0.0614) (0.0097) (0.0157) (0.0027) 

Brain 1.8435 - 2.1774 150 0.4340 - 0.5724 151 

(2.0105) (0.0835) (0.5032) (0.0346) 

Epididymides 1.1566 - 1.6432 222 0.2896 - 0.4105 210 

(1.3999) (0.1216) (0.3501) (0.0302) 

Heart 1.0013 - 1.4852 139 0.2562 - 0.3723 143 

(1.2433) (0.1210) (0.3142) (0.0290) 

Kidneys 1.8425 - 2.7070 162 0.4519 - 0.6867 174 

(2.2747) (0.2161) (0.5693) (0.0587) 

Liver 10.0646 - 15.2853 163 2.7634 - 3.5536 163 

(12.6750) (1.3052) (3.1585) (0.1975) 

Pituitary 0.0074 - 0.0120 78 0.0020 - 0.0029 73 

(0.0097) (0.0012) (0.0025) (0.0002) 

Prostate 0.3731 - 0.7418 85 0.0925 - 0.1918 89 

(0.5575) (0.0922) (0.1421) (0.0248) 

Seminal vesicles 1.5821 - 2.7187 87 0.3940 - 0.6642 84 

(2.1504) (0.2841) (0.5291) (0.0676) 

Spleen 0.5302 - 0.8397 150 0.1361 - 0.2054 151 

(0.6850) (0.0774) (0.1708) (0.0173) 

Testes 3.0354 - 4.2231 224 0.7534 - 1.0558 213 

(3.6292) (0.2969) (0.9046) (0.0756) 

Thymus 0.2866 - 0.6494 149 0.0749 - 0.1634 151 

(0.4680) (0.0907) (0.1191) (0.0221) 

Thyroid/Parathyroid 0.0107 - 0.0286 159 0.0029 - 0.0070 157 

(0.0196) (0.0045) (0.0049) (0.0010) 

• Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41205015 Report Page 440 

Appendix 24 (continued) Normal Ranges for Absolute and Body Weight-Relative Organ 

Weight Values in the Wistar HanTM:RccHanTM:WIST Strain 

Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. APPROXIMATE AGE: Eighteen Weeks 

UPDATED: November 2011 

ABSOLUTE WEIGHT (g) RELATIVE TO TERMINAL 

LACTATING FEMALE ORGAN BODY WEIGHT(%) 

WEIGHTS Range (g)° No.of Range(%)* No.of 

Animals Animals 

Adrenals 0.0654 - 0.1085 132 0.0259 - 0.0407 133 

(0.0870) (0.0108) (0.0333) (0.0037) 

Brain 1.7469 - 1.9906 130 0.6378 - 0.7871 137 

(1.8687) (0.0609) (0.7125) (0.0373) 

Heart 0.7786 - 1.1823 128 0.3065 - 0.4480 127 

(0.9805) (0.1009) (0.3772) (0.0354) 

Kidneys 1.2887 - 1.7435 139 0.4980 - 0.6713 150 

(1.5161) (0.1137) (0.5846) (0.0433) 

Liver 8.5995 - 12.9085 147 3.5429 - 4.6890 145 

(10.7540) (1.0772) (4.1159) (0.2865) 

Ovaries 0.0822 - 0.1410 134 0.0336 - 0.0519 131 

(0.1116) (0.0147) (0.0427) (0.0046) 

Pituitary 0.0109 - 0.0171 69 0.0042 - 0.0066 71 

(0.0140) (0.0015) (0.0054) (0.0006) 

Spleen 0.4475 - 0.7611 124 0.1797 - 0.2755 121 

(0.6043) (0.0784) (0.2276) (0.0240) 

Thymus 0.1497 - 0.3320 134 0.0607 - 0.1201 128 

(0.2409) (0.0456) (0.0904) (0.0148) 

Thyroid/Parathyroid 0.0095 - 0.0226 136 0.0037 - 0.0085 134 

(0.0160) (0.0033) (0.0061) (0.0012) 

• Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41205015 Report 

Appendix 25 Certificate of Analysis of the Test Item 

Lonza 

Lanza NMllnD Lid 

No.2111, Eut l>awel Aallll 

NMjlng a........1nc1u11ry Pllk 

Nanjlllg, a.. 

Paml cade 210047 

TII + 88 25 51138 8388 

FIX+ 88 25 5838 8399 

Certttlcllte of Anelyale 

Subllance name 

Abbr9vlatlon 

Fonnula 

Material 

Sample 

Batch 

CUltomer batch 

Pyrofflelll1lc dlMhydllde crpt. 

PMDAcrCA 

C10H20e 

200173 

1511107 

NJC1207029 

CASnumber 

Specification 

Production date 

E>lplry date 

Analyala date 

[89-32-71 

N5-08119PB.1 

2ChlUL-2012 

UhlAN-2014 

25-JUL-2012 

Manufacturing site 

Comment 

Lanza Nanjing Ltd, No.201, East Dewel Road, Nanjing Chemical lndualry Park, Nanjing, Ctn, Tel+ 

88 25 5838 8388, Fax + 88 25 5838 8399 

Remark 

Teat Result Unit 

Appearance Cryatala ----- Cryatala 

N5V015156A.111/CNGZ-15158.1 

Colour White ----- White to off-white 

N5V015158A.1/11CNGZ-15158.1 

Aaaay (HPLC) 99.94 "l.wlw >-99.50 

N5-G8119PK.1/1/CNGZ-18118.1 

TMA(HPLC) 0.02 %wlw <a0.20 

N6-08119PQ.1/1/CNGZ-18118.1 

Melling point 287.3 •c 288.0 - 287.5 

N5-08119PA.1/1/CNGZ-18114.1 

Fretacld(fflr.) 0.05 %w/w <•0.60 

N5-081181B.1/1/CNGZ-18121.1 

Particle size fraction > 500p'II 0.3 %wlw c-6.0 

N5-08119PM.1/1/CNGZ-18135.2 

Parltcle IIZe fraction >81111rn 98.4 %w/w -95.0 

N5-08119PM.1 /1/CNGZ-18135.2 

Insoluble Matter 2.9 IAQlo <•15.0 

N5-08118PB.1/1/CNGZ-18122.1 

MtJie of Repoff 37.5 • 28.0-41.0 

N5-08119PD.1/1/CNGZ-18138.1 

Al c0.1 IAQlo <•1.0 

N5-08119PG.1/1 

Ca c0.3 IAQlo <•1.0 

N5-08119PG.1/1 

Co c0.1 IAQlo <•1,0 

N5-08119PG.1/1 

Cu c0.1 l,lg/g <•1.0 

N5-08119PG.111 

Fe c0.1 l,lg/g <•1.0 

N5-08119PG.1/1 

K c0.1 IAQlo c-1.0 

N5-08119PG.1/1 

"""1ed an: Nlrfnl, 15-AUQ-IIG12 lll:&1:18 UTCtt I0:130878 Pqe1oll 

Page 441 
Harlan Study Number: 41205015 Report 

Appendix 25 ( continued) Certificate of Analysis of the Test Item 

Substance name 

Abbreviation 

Tm 

Mg 

N5-06119PG.1/1 

Na 

N5-06119PG.1/1 

NI 

N5-06119PG.1/1 

Sn 

N5-08119PG.1/1 

Zn 

N5-06119PG.1/1 

Cr 

N5-06119PG.1/1 

Mn 

N5-06119PG.1/1 

SI 

N5-06119PG.1/1 

,-.Y (1H-NMA) 

N5-06119PH.1/1 

Forthelm: 

Carny Vang 

08-AU0-2012 

QC Supervlaor 

BllCII releued by: 

SlmuelXu 

06-AUG-2012 

QAManaaer 

Continued Certlbte of Analyala 

Pyromelllltc cllMhydltde Cl'J8I. 

PIIDAcrCA 

1511107 

NJC1207029 

Producllon date 

Expiry date 

Analysla date 

....... 

<0.1 

<0.1 

<0.1 

<0.1 

<0.1 

<0.1 

<0.1 

<0.1 

99.72 

Unit 

l,IGlg 

l,IGlg 

1,11119 

l,IGlg 

l,IGlg 

l,IGlg 

l,IGlg 

l,IGlg 

"loW/w 

Thie Clfllflcale la the output ot protecl9d data and la signed electronlcaHy In ~lance wllh the law. 

Pllnlld on:~ 15-AUG-2012 08:51 :18 UTCt8 1):130871 

20-JUL-2012 

18-JAN-2014 

2~UL-2012 

<•1.0 

<•1.0 

<•1.0 

-1.0 

<•1.0 

<•1.0 

<•1.0 

<•1.0 

>-99.50 

Page442 

n 

Plgelof2 
Harlan Study Number: 41205015 Report 

Appendix 26 Monitoring Authority Statement of GLP Compliance 

, n-;, Department 

C ofHealth 

THE DEPARTMENT OF HEALTH OF THE GOVERNMENT 

OF THE UNITED KINGDOM 

GOOD LABORATORY PRACTICE 

STATEMENT OF COMPLIANCE 

IN ACCORDANCE WITH DIRECTIVE 2004/9/EC 

TEST FACILITY 

Harlan Laboratories Ltd 

Shardlow Business Park 

London Road 

Shard low 

Derby 

DE722GD 

DATE OF INSPECTION 

10 July2012 

TEST TYPE(S) 

Analytlcal/Cllnlcal 

Chemistry 

Environmental Toxicity 

Environmental Fate 

Mutagenlclty 

Phys/Chem. Teats 

Toxicology 

An inspection for compliance with the Principles of Good Laboratory Practice was 

carried out at the above test facility as part of the UK Good Laboratory Practice 

Compliance Monitoring Programme. 

This statement confirms that. on the date of i11ue, the UK Good Laboratory 

Practice Monitoring Authority were satisfied that the above test facility was 

operating in compliance with the OECO Principles of Good Laboratory Practice. 

This statement constitutes a Good Laboratory Practice Instrument (as defined in the 

UK Good Laboratory Practice Regulations 1999). 

Page443