Harlan Study Number: 41205015


### Appendix 15 (continued) Test Fadlity StadyNo. 4ll0501S Test Site Refeft>lltt No.155..023 Report


### Histopathology Phase Report

ftIDA hydrelyzed toPMA.: Oral {Gffl'Bge) Reproductiou/Devdopmeotal Tmrity Saeeoing Test io the Ra.t (OECD 421) Table:Z: 

### Individualanimalpathologyfindings 

### (c:ontinued)

GENERAL INFORMATION

MACROSCOPIC HNDINGS
MKROSCOPIC FINDINGS Animal No.: 38 Sex: Female Doselevel: 

### so mg/kg

### n/day
Death Day Number: 45.00 Start Date: 20-F'EB-2013 necropsystatos: SCHEDULED KILL
No abn.ormality detected

81!11J Page 369Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlily SbldyNo.41205015 Test ShRlferear:eNo.155-823 PMDA hydnly&d. toPMA.: Onl(Gmrage)**~** Tmidfy Scnea:iagTest la the Rat (OECDGl)

NACROSCOPICRNDINGS AniBlal. N'o.: 39 Su: lTemale Doselnel: 5Dmg/lsgbw/u,
DeathDayNllllllJer. 43.00 stutDate: 20-PEB-2013 necropsystatus: SCHEDULED KILL

Cydicll dilatiGlllpresent P1"MSlrusmorphologypresent No almonnalilies found in: MAMMARY GLAND,OVARJES.. PITUITAR.YGLAN'D, UTERINE CERVJX.

82/llS Page 370Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report Test FadlityStadyNo.41205015 Test SnReli!renftNo.155-823 PMDA ~toPMA: Oral(c-.p)**~** To.ucityScreeniagTest intlle llat (OECD421)

AnimlllNo.: 40 Sex: J'etnale DoseJevek 501Dg/kghw/drq
DeathDayNumber:43.00 Start Date: 20-FEB-2013 necropsystatwl: SCHEDULED KILL

83/llS Page 371

### Harlan Study Number: 41205015


### Appendix 15 (continued)

Test Fadffly StadyNo. 4UOS015 Test SnRefettnttNo. 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 Table2: Individualanimal patkologyfindings {continued)

GENERAi. iNFORMATION

J.IIJACROSCOPIC RNDVIGS

llllCROSCOP!C FINDINGS VAGINA ADimalNo.: 41 Sex: J'emale Doselevel: 50mg/kgbw/day
Death DayNumben 42.00 start Date: 20-FEB-2013 necropsystatus: SCHEDULED KJLL
No abnormality detected
Metoestmsmorphologypresent 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 StadyNo.41205815 Test Sh RefenunNo.155~...3 PMDA

### bydralJzed to PMA: Onl (Ga,,ap)**~** Tasidly Screening Test inthe Rat (OECD421)

Animal No.: 42 Sa:: l'emale DaseJent 

### sollllfllgn/u,
Death DayNumber: 42.00 start Date: 20-PEB-2013 necropsystatus: SCHEDULED KILL

85/J.15 Page 373Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

Test Fadlily Smd.yNo.41205015 Test Sift 

### Rmreace No. J.55.023 PMDAhydnlyzedtoPMA.: Onl(Gawlge)**~** Tcmdly ScreeningTest in die Rat (OECD421)

MACROSCOPIC FDIDINGS

MIOIOSCOPICJDIDDfGS Allilllal No.: 43 Sa: i'emale Dmelevel: 50mg/llgh/day
DeathDay Nam.hen 45.00 startDate: 20-PEB-2013 IK!CIOJISY statu: SCHEDULED KILL
No almormality detected
No tissues eamined

861115 Page 374Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilySndyNo.4llOSOIS Test Sile Refennft No.155-823 PMDA. bydNlyzed.toPM.A: Onl(Gavage)**~** Tmdmy Screening Test Indie Rat (OECDGl)

DeathDayNum.ben 45.00 Start Date: 20-PEB-2013 necropsystatus: SCHEDULED KILL

No tissues eamined

87/llS Page 375Harlan Study Number: 41205015


### Appendix 15 (continued)

Test Fadlity StudyNo.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 

### Table2: Individualaoimal.

### pathologyfindings (continued)

GENERAL INFORMATION

MACROSCOPIC FDmlNGS

MIC:ROSOOPIC PINDINGS Animal No.: 45 Ser. Female Doselevel: 50 mg/kghw /day
Death Day Num.beri 43.00 start Date: 20-FEB-2013 necropsystatus: SCHEDULED KJLL
No abnormality detected
No tiSSlles examined

BIJlllJ Page 376Harlan Study Number: 41205015


### Appendix 15 (continued)

Test Fadffl:y ShulyNo.41:205015 Test SinReferflltt No. 155-023 Report


### Histopathology Phase Report
Pfl.IDA hydnlyzed to PlllA: Oral •G11Yage) Reprodudioa!Development'alToxicity Screeoiog Test in die R.at (OECD 421} Table

### 2: Individual

### aoimalpatkologyfindiogs (couti.nued)

GENERAL INFORMA.UON

MACROSCOPIC FINDINGS

MJCROSCOPIC FINDINGS Animal No.: 46 Sex: llemale Doselevel: SO mg/kgbw/day
Death Day Number: 43.00 start Date: 20-FEB-2013 necropsystatus: SCHEDULED IOLL
No abnormality detected
No tiS31ile:s eaminecl

891115 Page 377Harlan Study Number: 41205015


### Appendix 15 (continued)

TestFacility StadyNo.41:205015 Test SiteReference No. 155-023 Report


### Histopathology Phase Report
Pl.IDA bydnlyzedto PMA: Oral (Ga-:,e) Repn>du.dioa/Deftlopmeotal Toxicity Screeoiug Test in the Rat (OECD 421) Table2: Individualanimalpathol.ogy:findings (continued)

GENERAi. INFORMATION

MACROSCOPIC RN'DINGS

MICROSCOPIC FINDINGS VAGINA Animal No.: 47 Sez: Female Doselevel: 50mg/kghw/day
Death DayNumber: 44.00 StartDate: 20-FEB-2013 necropsystatm: 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 378Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlily

### Sn.d.J' No.4120SDIS Test SnRelenuttNo.155-823 PMDA. hydnlyzed. toPMA: Oral(Ga,,age)**~** Tazidty Screeaing Testin the Rat (OECDGl)

I.IIACROSCOPIC RJIDIIIGS AnimalNo.: 48 51111:: J'emale Duelevel: 50mg/Jigtn, 

### /day
Deatll Day Nwnller: 44.00 Start Date: 20-FEB-2013 necropsystatus: SCHEDULED KILL

91/lJj Page 379Harlan Study Number: 41205015 Report


## Appendix 15 (continued) Histopathology Phase Report

Test Facility StadyNo.4ll85015 Test Sile

# .,_mft No. lSS-023 PMDA. hydnl,-ltoPIIA: Oral (6-ge)**~** Tasidty ScneaiqTest in die :Rat (OECD421)

MACROSCOPIC FINDINGS AnimalNo.: 61 Sa: Female Doseknrel: 250mg/ltgbw/day
DeathDayNumhen44.00 Start Date: 21-PEB-2013 wropsystabls:SCHEDULED KILL

92/llS Page 380Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlilyStadyNo.41205815 Test Site R.mnuaNo.155-023 PMDA hydnlyzedtoPMA: Onl(Gavap)**~** Tmicity SaeeaiagTest in die Rat (OECD421)

NACROSCOPICRNDIRGS
MKROSCOPIC JINDIRG5 Animal No.: 62 Sa: Semale Doselevel: 258

### mg/kghw/my
Deat:11 DayNmnberi 46.00 stutDate: 20-JEB-2013 necropsylltatus: SCHEDULED KILL
Noabnormality detected
Notissues eamined

91/lJj Page 381Harlan 

### Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlilyStadyNo.41205015 Test SileRdennttNo.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 DayNumber: 43.00 Start Date: 20-PEB-2013 necropsystatus: SCHEDULED KILL

94/lJj Page 382Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilyStadyNo.4120SIDIS Test Site~No. l55-02J PMDAhydnlyzed.toPMA: Oral(Glnage)**~** Tmicity 

### Scrftuia& Test indie Rat (OECD421)

Animal No.: 64 Sn: Female Dclselevel: 258mg/Ilgbw/,Jay
Death DayBumllen 44.00 start DateJ 20-PEB-2013 necropsystatus: SCHEDULED KILL
No abnormality detected

9S/llS Page 383Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlbySmdyNo.4ll8Hl5 Test Site lhfHmffNo.155-823 PMDAhydnlyzedtoPMA.: Onl(Gaftge) ~hll Tmicity ScreeniagTest in die Rat (OECDCl)

MICROSCOPIC RNDINGS Oelltb DayNmnben 44.00 startOldie: 20-J.IEB-2013 necropsystat.mi SCHEDULED KILL

961115 Page 384Harlan Study Number: 41205015 Report


## Appendix 15 (continued) Histopathology Phase Report

Test FadlilyStadyNo.4UOSOIS Test SiRRefenBftNo.155-023 RIDAhydrGlyzN toPMA: Oral (Gmiage)**~** Tasimy Screeoiag Test intllr Rat (OECD421}

MAc:RDSc:OPIC RNDINGS ADilllal No.: 66 Sa: hmale Daselnel: 250mg/Jlglrwfmy
DealbDayNumber: 42.00 startDate: 20-FEB-2013 necropsyst:aala1 SCHEDULED KILL

9711l5 Page 385Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlbyStadyNo.41305015 Test SiteRefereme No.155-023 PMDAbydrolJzedtoPMA: Onl(ea-p)**~** Tmidty ScreeaiqTestio the Rat (OECD421)

MACROSCOPIC RNDINGS ADmlal. No.: 67 SB: .Fnulle Deselevel: 250

### mg/lrglnr/uy
Death DayNumben 45.00 start Datei 20-FEB-2013 necropsystatwl1 SCHEDULED Kll.l.

98/llS Page 386Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report Test FadlttyStadyNo.41205015 Test SiteRelenanNo.155-023 Page 387

PMDA hydnlyzetltoPMA: Oral(Gnap)**~** Tmidly ScreeningTestio thr Rat (OECD431)

DeathDay Number:42..00 Start Date: 20-PEB-2013 necropsystatu.s1 SCHEDULED KILL

991115Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilyStadyNo.41205015 Test SIR~No.155-023 PMDAhydnlyzedtoPMA: Oral.(Gnage)~ Tasidty ScreeaiagTat in the Rat (OEa>421)

NKII.OSCOPIC JINDDIGS .Animal No.: 69 Sm: Female Doselevel: 250 

### mg/tlg'frw/my
Death Day Nwnhen44.00 startDate: 20-JEB-2013 necropsystatus1 SCHEDULED KD.L

100/llJPage 388Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlil:y StadyNo.41205015 Test SiftRef•- No.155-823 PMDA bydrolyzed.toPMA..: Onl (Ga9age)**~** Tmddty SeremiugTest in Ole Rat (OECD421)

MACROSCOPIC ANDINGS Animllll Na.: 78 Smc l'emale Doselevel: 250 mg/llgbw/day
Death DayNwnlien43.00 start Date; 20-JEB-2013 necropsystatus: SCHEDULED KJLL
No abnormalitydetected

lDl/115 Page 389Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlllyStadyNo.41205015 Test ShRefennnNo. l5S-023 PMDA bydnl.,-1toPMA: Oral(Glmlp)**~** Tmidty

### Sc:reenia& Test in die Rat (OECD421)

MACROSCOPIC FINDINGS
l!OalOSCOPIC RJIDIRGS ADillllll No.: 71 51111: Female Dmelnel: 258-c/llglnr/day
DeathDayNumber: 44JlO start Date: 20-PEB-2013 necropsystatllll: SCHEDULED KB.I.

1011115 Page 390Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report Ted FadlilyStadyNo.4120!015 Test~ ReferenreNe.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
DeathDayNIUllber: 46.00 start Date: 20-FEB-2013 oecropay status: SCHEDULED KILL

No tisllles examined

101/llS Page 391Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlityStadyNo.4ll05015 Test SeRefamn No.15S-023 PMDA hydnlyzedtoPMA.: Onl.(Gtnage)**~** Tmidly ScreeningTestio die RBI (OECD421)

KIDNDS DeathDayRwnlier. 4.2..00 start Date: 20-FEB-2013 neaopsystatus: 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.muldaDaryhaematopoiesis
- mild Dec:nased corticallymphocytes- mimma1 Rotissue available Regnssiugimplantationsite(s) pruent Mucification/)actatimimcnphologypreseot Ro almormaliti.es found ins ADRENALCORTEX.ADRENAL MEDULLA. BRAUf,CAECUM. COLOR, DUODENUM. HEART, II.E1JM.

### JEJUNUM, LUNGS. LYMPH RODE, MMfDIBULAR. LYMPH RODE. MESENTERIC. OVARIES, PARATHYROID GURUS. PITUITARYGLAND, 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 392Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report

TestFadlitySmlyNo.41205015 Tm SiteRefal!'Dft No.155-023 PMDAhydnl.yzedto PMA.: Oral (Gawge)**~** Tmidty Screeniag Tmindie Rat (OECD421)

ADRERAI. NEDUUA MANMAJilYGLAIID PARATBD.Om GI.ANDS SPI.EEN 1'IIYNUS O'l'ERU5 VAGDIA. Death DayNumber:44.00 startDate: 20-1£8-2013 necropsystatus: SCHEDULED KILL

onesectioneamined Lactationpresent onesec:lioD eamined Edr:unerlullarybaematopoiesi:s
- mild Dec:nmedc:mticallymphocytu
- millimal bgressiogimplantation sit.e(s) present Mucifica.tion/lamorphologypresent No abmmmliliesfound 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. SPINALCORD, WMBAJL SPINAL CORD, TIIORACIC. STOMACH. GU.NDUUR. STOMACH.RON-GUJD>ULAR. THYROID GU.NOS.. TllCHEA.URINARY BLADDER. UTERINE CERVIX.

1051115 Page 393Harlan Study Number: 41205015


### Appendix 15 (continued)

Test Farility StadyNo.41:!0SOIS Test SiteReferenceNo. 155-023 Report


### Histopathology Phase Report

PAIDA hydnlyzed to Pili: Oral (Ga,rage) R.eprodnc:tion/Developmental Toxicity Saeeoiug Test in the Ral (OECD421) 

### Taltle2: Individual

### animalpatbologyfiBdiop(continued)

MA.CllOSCOPIC FINDINGS LUNGS (WITH BRONCHI)

MICROSCOPIC PINDINGS LUNGS PITUITARYGLAND VAGINA Animal. No.: 87 Sex: Female Dose level: 750 mg/kgbw/d.ay
Death Day Number: 42.00 start Date: 20-FEB-2013 necropsystatus: SCHEDULED KJLL
Redden.ed No abnormalities were found in any ofthe othertissues examined A.goml congestion and haemorrhage present (accounts for gross finding) ooly pars distalis on section Dioestrus :morphologypresent No abno.rmalilies found in:MAMMARY GIAND, OVARIES, UTERINE CERVOC UTERUS.

1061115 Page 394Harlan Study Number: 41205015


### Appendix 15 (continued) Test Fadlity StudyNo.4llOS8lS Test SitellefermceNo.155-0')..3 Report Page 395


### Histopathology Phase Report
ftIDA hydrolyzedto PMA~ Oral (Gavage) Reprodm:tionJDewlopmeotal Toxicity Screeuiug Test io the Rat (OECD 421} Table2: Individualanimal

### pathologyfindings 

### (amtiuued)

GENERAI.INJiORNA110N

MACROSCOPIC RNDINGS

MICROSCOPIC FINDINGS UVER NAMM.ARYGI.AND SPLEEN THDIUS O"l"EltUS VAGDIA Animal No.: 88 Sex: Felllllle Doselevel: 750mg/kgbw/day
Death Day Number: 42.00 start Date: 20-FEB-2013 necropsy stabu: SCHEDULED KlLL
No abnormality detected Congestioo
- mild lactationpresent Extramedullaryhaematopoiesis
- minimal Decreased corticallymphocytes
- minimal Regressingimplantation site(s) present Mucification/]actationmorphologypresent 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.

1071115Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilyStadyNo.41205015 Test Site Rd'HIIW! No.155-823 PIIDA hydnlyzedtoPMA: Oral(G-ce)~ TasidtyScreeoingTest intie Rat (OECD421)

MACRGSa>PICPDIDINGS Death OllyNumher. 43.00 start Date: 20-FEB-2013 necropsystatus: SCHEDULED KILL

Lactation present onesectionaamimld EdrmulduDmyhaematopoiesis
- mild Decreased c:mticallymphocytes- minimal RegnssiDg implantationsite(s) present Muc:ificaticmJ)actatio morphologypresent 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. PITUITARYGLAND. RECTUM. SCIATIC NEll\lE.SPINAL CORD. CERVICAL. SPINALCORD, LUMBAR, SPINAL CORD. THORACIC. STOMACH. GU.JIDUI.AR. STOMACH. NON-GLANDULAR. THYROID GU.NOS.TRACHEA. URINARY BLADDER. UTERINE CERVIX.

108/llS Page 396Harlan Study Number: 41205015


### Appendix 15 (continued)

TestFadlfty StnilyNo•.41205015 Test Site llefereuttNo.155-023 Report


### Histopathology Phase Report

Pl-IDA hydnlyzed to PMA: Oral {Gavage) R.eprodadion/Developmeotal Toxicity Screening Test inthe Rat (OECD421) Table2: Individualanimalpath.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 Doselevel: 750 mg/kghw/day

Death DayNumber: 54.00 Start Date: 20-FEB-2013 necropsy statm: SCHEDULED KJLL
No abnormality detected
Lactationpresent one section examined Extramed.ullaryhaematopoiesis
- minimal Decreased corticallymphocytes
- mild Regressing implantation site(s) present Mucificwon/lactation morphologypresent 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 397Harlan Study Number: 41205015


### Appendix 15 (continued) Test Fad&ly StadyNo•. 41:205015 Test SiteRffll'mttNo. 155-023 Report Page 398


### Histopathology Phase Report
PMDA hydnlyzedto Pl-IA: Oral (Gavage) Reprodllldioa/DevelopmemalTmicity 

### Screeamg Test in the Rat (OECD4.'!l) 

### Table :Z: Individualanhnal

### path.ologyliadi.ngs {continued)

GENERAL INFORMATION

MACllOSCOPIC FIWDINGS

MJCROSCOPIC FINDINGS MDIMARYGUND DTERUS VAGINA Animal No.: 91 Sex: Female Doselevel: 750mg/Ilghw/day
Death DayNumber: 44.00 Start Date: 20-FEB-2013 necropsy status: SCHEDULED KJLL
No abnormality detected
Lactation present Regressing implantation site( s)present Mud:lkatiion/]actation morphologypresent No abn:onn:alities found in: OVARIES, PITUITARY GI.AND, UTERINE CER.VJX.

110/115Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report Test Fadffly StadyNo.41205015 Test Site Refereoa:No •. 155-923 PMDA bydrolyzmtoPMA.: Oral (Gavage) Reproductioa.lDefflOpmental Toxicity ScreeoiugTest in the Rat (OECD421) Table2: Individualanimalpath.ology'findings { continued)

GENERAL INFORMATION

MACROSCOPIC FINDINGS
MICROSCOPIC FINDINGS MAMMAllY GLAND UTERUS VAGINA Anilllal No.: 92 Sex: Female Doselevel: 750mg/kgbw/day

Death DayNumber: 42.00 start Date: 20-FEB-2013 necropsy status: SCHEDULED KILL

No abnormality detected
Lactationpresent Regressing implantation site(s) present Mucffic:at:ionf]actation morphologypresent No abnormalities found in: OVARIES, PITUITARY GLAND, UTERINE CERVJX.

Ptm1rMillarAssm:iawLid. - 21-A1lJ:-2011
- Co~mrl 111/llJPage 399Harlan Study Number: 41205015 Report


## Appendix 15 (continued) Histopathology Phase Report Test Fadffly Slad.yNo.41205015 Test SileReferellftNo.155-023 PMDA.,...yzed.tePMA: Oral(G.n-ap)**~** To.sicity ScreeoiqTeat intile Rat (OECD421)

Animal No.: 93 SB: Female Doselevel: 750 

### mg/llghw/ay
DeathDayNwn.her: 53.00 Sbut Date; 20-JEB-2013 necropsystatus: SCHEDULED KU.I.

Lac:tatiaDpresent**~** implantation si.te(s) present Mucikation/]actationmorphologypresent No ahnormalities fuund iDI OVARIES. PITUITARY GLAND, UTERINE CER.VJX. 

### Page400

1121115Harlan Study Number: 41205015


### Appendix 15 (continued)

TestFadlity StutlyNo. 4llOS8lS Test SiteReferftltt No. lSS-023 Report


### Histopathology Phase Report

PMDA bydrolyzetl to PMA: Oral (Gavage) ReprodudionJDevelopmeotal Toxicity Screeoiog Test .in the Rat (OECD 421) Table2: Individualanimalpatllologyfindings (continued)

GENERAL INFORMATION

MACllOSCOPIC FINDDIGS
MICROSCOPIC RNDDIGS MAMMARY GLAND UTERUS VA&INA. Animal No.: 94 Sex: female Dose lent 750 mg/kg'bw/day
DeathDay Number: 42.00 start Date: .20-FEB-2013 necropsystatwi: SCHEDULED IaLL
No abnormality deteci:ed
Lactationpresent Regressiog implantationsite(s) present Muclfieation/Jactation morphologypresent No abno.rmal:iti.es found in: OVARIES, PITUITARY GI.AND, UTERINE CERVJX.

1131115 Page 401Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilySbrd.yNo.41205015 Test SileRefeftace No.155-823 PMDA. hydnllyzedtoPMA.: Oral(G ...... )**~** Tmidly Scremilllg Test iotlte Rat (OECD421)

MACROSCOPICRNDll!IGS Aldmlll No.: 95 Su: Female Dmlelenl: 750mg/llgbw/day
Dea1hDayNumber: 45.00 Start Date: 20-FEB-2013 necropsystatus1 SCHEDULED KJLL

Lactationpresent Regressingimplantation site(s) present Muci:lic:ation/lcmmorphologypresent No ahnmmal:ities found in: OVARIES. PITUITARY GLAND. UTERINE CEJMX.

114/llS Page 402Harlan Study Number: 41205015 Report


### Appendix 15 (continued) Histopathology Phase Report TestFadlilySm.dyNo.41205015 Test SiteRefena£eNo.155-82J PMDAhytlralyzedtoPMA: Oral (Gawge)**~** Tmidty

### Screenia& Test intile Rat (OEC.D 421)

NACROSCOPIC I.IDIDINGS DeathDay Number: 43..00 StartDate: 20-i:EB-2013 necroprystatus: SCHEDULED DI.I.

Lactalionpresent**~** impl:mtltion site{s) present Mucificationfladationmorphologypresent Na abnormalitiesfound in: OVARIES. PITUITARY GLAND. UTERINE CEJmX

1151115 Page 403Harlan 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 ofapproximately 0.01 mg/ml. 

### 1.3 Standards Standard solutions of test item were prepared in O.OlM orthophosphoric acid at a nominal concentration of0.01 mg/ml. The standard solutions contained the equivalent amount ofvehicle to that ofthe 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 minsHarlan 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 ofpreparation.

### Harlan Study Number: 41205015 

### Report Page 406


### Appendix 16 (continued) Analytical Investigations 2. RESULTS 2.1 Verification of Concentration ofTest 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 % 

### ofnominal)

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 108Harlan 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 ofthe study.Harlan Study Number: 

### 41205015 Report 

### Page408


### Appendix 16 (continued) Analytical Investigations Examples ofthe 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 MinutesHarlan Study Number: 41205015 Report 

### Page409


### Appendix 16 (continued) Analytical Investigations Examples ofthe 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 MinutesHarlan 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 410Harlan 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 

### ofvalue in predicting the possible reprodUcttve toxicity of

### the 

### test substance 

### to man and estimation 

### ofthe 

### 'No 

### Observed Effectlevel' (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 inthe 

### 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. 

### TestFacilty:

Pmjed

### No: 41205015 

### NKDhinsa 

### Harlan laboratories 

### ltd. Shardlow Business Park Shardlow Derbyshire DE722GD Page2of17Harlan Study Number: 41205015 Report Page 412


### Appendix 17 (continued) Study Plan

Lead 

### QualityAssurance: 

## 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 

### QualityAssurance: To 

### be conflnned 

### by amendment to study plan 

### 3. ANIMALS 

### Specification Species: 

## strain: SUb-strain: 

## source or supply: 

### Number: Bodyweight 

### range: 

## sex: Age: 

### other:

Pmjed

### ND: 41205015 

### Rat Wisfar 

### Han111 

### RccHan1U:W1ST Harlan Laboratories U.K. ltd., 

## Oxon. UK 

### 12 animals 

### per sex 

### per

### group: 96total 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% 

### of1he mean weight 

### for 

### eill1er 

### sex at 

### start of

## treatment Page3of17Harlan 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 

### Page4of17Harlan 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 adlibitum. Drinking water is rootilely 

### analysed (at 

### least annualy) and 

### certificates of 

### analysis for 

## cr1et will 

### be

, provided bythe supplier. The 

### diet 

### and water 

### are 

### considered not 

### to contain 

### any 

### contaminants that could 

### reasonably be 

### expected

### to affect

### the

## JJUIPOSe orintegdy of

## the study 

### 5. AN.ALWELFARE 

### 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 orintegrity of

### 1he 

### study. Environmental enrichment 

### wilt 

## not be provided 

## to animals during 

### 1he mating 

### phase orfor females 

### dumg the gestation 

### and lactalion phases

### of

### the study.

Pmjed ND: 41205015 Page5of17Harlan 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 priorto the start oftreatment 

### Allocation Animals will 

### be alllocated to dose groups usilg a randomisation procedure to produce a homogeneous distribution ofbody 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 

### ofthe test substance will 

### be the responsibiity ofthe Sponsor. 

### The hydrotysis product of PMDA is pyrometrltic anhydride (PMA) 

### which is the test substance to 

### be tested.
Pro~tt

### No: 41205015 Page6of17Harlan 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 ofthe 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 

### ofthe 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 offemales during parturition, 

### if applicable), using a suitable dosing cannula attached 

### to a graduated syringe. Dosing 

### will 

### be performed at a similartime each 

### day wherever possible.
Proj!ct

### No: 41205015 Page7of17Harlan Study Number: 41205015 Report Page 417


### Appendix 17 (continued) Study Plan Dose 

### Groups Foor

### dose groups each comprising 24 aninals (12 

### male and 12female) 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 priorto 

### pairing. ii) 

## on Day 15. 

### animals wiH 

### be paired on a one male:one 

### female basis wilhin each dose 

### group for a maximum ofrourteen 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 

### ltterwill 

### be 

### performed during this 

### period.

Projed

### No: 41205015 Page80l'17Harlan 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

### posteoilUm. 

### Yi) 

# on Day 43 of 

### Ile study. subjed: 

### to confinnation ofsuccessful 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.. 

### Bodyweights 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

### postcoilUm 

### and body weights 

### tor females which giVe birth will 

### be recorded on Days 1 

### and 4 

## postpartum. Bodyweights 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 Page9of17Harlan 

### 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 ifa 

## treatmentrelated 

### effect 

### is suspected. 

## atthe 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 

### ofa vaginal 

### plug orspenn 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 ofpairing 

### ii) 

### Date of mating 

### iii) Date of 

### parturition Project No: 

### 41205015 Page10of17Harlan StudyNumber: 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 

### ofoffspring 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 

### ofthe stomach. 

### The corpora lutea of

### all ovaries from 

### al cohabited adultfemales 

### 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 Page11of17Harlan Study Number: 41205015


### Appendix 17 (continued)

Epididymides 

### ovaries Pituitary (postfixation) 

### 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 Bouinsfluid then transfem!d

### to 70% Industrial Methylated Spirils (IMS) approximately48 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 of17Harlan 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 orapoptotic 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 

## sentto the 

### study Director. 

### 10. EVALUATION OF DATA Where considered 

### appropriate, quantitative 

### data will 

### be subjected to slaflstical analysis 

### to detect 

### lie signlicance of intergroup differencesfrom control; statistical significance Will 

### be aehieved at a 

### level of

### p<0.05. 

### statistical analysis wil beperformed 

## as follows: Metald 9afstic:a1Analysis If p,1!1i11i11ay test is nat Parmlll!ller Pn!limira

### r Tl!Slt signilii::ant Ifpl!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,stest lilr ln!nd. I'no band. Male BadyWeg,tGain 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 

### Page13of17Harlan Study Number: 41205015 Report Page 423


### Appendix 17 (continued)

Female

### Pwe-Pam,g BodyWeight Gllin

Pro)!cl: No: 41205015 

### Study Plan

an:ler of iransforms**~** DunnetsorstudentT Test will be log. squse-mot. and 'Milney 'U' test. rank-on:ller. If ihe log and
~·1ransfimTls fail. the 1'311'1l-an:llerwift be used.

One-way analysis of variaooe Kruskal-Wallis test fdio-d bythe follawed by Dunnett'stest IM'arm-Whilney 

### v test

Page 14 of17Harlan 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 QualityAssurance. 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 ofthe results where relevant A draft 

### report 

### will be sent 

## to the Sponsor 

### for review 

### and mmments 

### before issUe 

### ofthe 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 

## atthe 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 Page15of17Harlan 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). Flrbemethodezum makroskopischen NachWeis von lrnplantaUonsstelen am uterus 

### der 

### Ratte. Naunyn - Schmiedebergs 

### Arch Exp Path Phannacol 247 367.

Pnljed

### No: 41205015 Page16of17Harlan Study Number: 41205015 Report


### Appendix 17 (continued) Study Plan Appendix. 

### 1 Reproductive Indices Malin 

### lndeX = 

### Number 

### ofanimals maled x 100 

### g Number 

### of animats

### paired 

### PregnancyIndex = 

### Numberof

### pregnant

### females x 100 Number 

### of animals

### mated Parturition Index 

## = Number

### of

### females delvenng liveoffspring 

### x 100 Number 

### ofpregnant 

### females Live 

### Binh Index 

## = Numberofoffspring aliveon 

### Day 1 x 100 Number

### of 

### offspring

### born Viability Index 

## = Number ofoffsplingaliveon 

### Day 4 x 100 Number 

### ofoffspring alive on Day 1 

### Pre-implantation

### loss= Numberof 

### corpora lutea-number

### of implantations 

### x 100 Numberof

### corpora IUtea Post-implantation

### loss= Numberof implantations- total number

### ofoffspring

### born x 100 

### Number of implantations


### % Male offspri 

### (sex Ratio) 

### = Numberof

### male offspring x 100 ng Total number

### ofoffspring Page426

Projed No: 41205015 Page17of17Harlan 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•tSite 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 1Harlan 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 ofthe 

### test 1ubltmnce. PAGE 1 T•tlubetance 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 ofthe study.

AUTHORISED FOR 

### HARLAN LABORATORIES L TO BY:

APPROVED FOR SPONSOR BY: Project Number: 41206015 (Amendment No.2) Page1of1 

### Page428Harlan 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 

### ofthe 

### 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) 

## 25 JUL 

## 2013 DATE: ......................................
DATE:
....

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

# ~.:.J.:..!.~..........

Page1 of1 Page 429Harlan Study Number: 41205015 Report 

## Appendix 18 Histology Processing Phase Test Site Quality Assurance Statement

Facility:

Audit Date: QUALITYASSURANCE 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 ofthe OECD Principles ofGood 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'heMgitsters, 'l'he 014 Grainfiam, (Jeorge

### Lane. fludcden, Canms f'Et9 5:XN Page 430

### Harlan Study 

### Number: 41205015 Report 

### Appendix 19 Histology Processing Phase Test Site Statement ofCompliance 

# •• 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 ofthe Histology phase ofthis study and confirm that it 

### was conducted in compliance with the UK Principles ofGood 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 431Harlan Study Number: 41205015 Report 

## Appendix 20 Histology Processing Phase Test Site Statement ofGLP Compliance 

# 'nH) Department 

# C ofHeslth

THE DEPARTMENT OFIIEALTR OFTHE GOVERNMENT OFTBE UNITED KINGDOM GOOD LABORATORY PRACTICE STATDIENT OFCOMPLIANCE 

### 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 atthe above test 

### facility 

### as part

### ofthe UK GLPCompliance

### Programme. At 

### the 

### time ofinspection 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 ofAnalysis ofDiet Used Teklad Certified Global 18% Protein Rodent Diet 

# 2018C Certificate ofAnalysis
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 433Harlan 

### Study Number: 41205015 Report Page 434


### Appendix 21 (continued) Certificates ofAnalysis ofDiet 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 312013 

### 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...ttlffllhd9 M!MaofHartln l...tlortortas. lnc.02008--rlol.lnc. Harlan Laboratories · PO Box 44220 Madison, WI e37444220 800 ·483 ·5523 • www.ha~an.com Paga 2of2Harlan Study Number: 41205015 Report Page 435


### Appendix 21 (continued) Certificates ofAnalysis ofDiet 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 apraHldan • '11 .....r

### rnolltur9""" 

## -06'00' ·s..-dlltl'orlle
___ _rlo,lorl'CIII ---70-120% Page 1of2Harlan Study Number: 41205015 Report Page 436


### Appendix 21 (continued) Certificates ofAnalysis ofDiet Used 

## Teklad Certified Global 18% Protein Rodent Diet 

# 2018C Batch Number 

### 201SC-101112MB Certificate Number 12-N12252 Date of Manufacture October 11 12012 Expiry Date Ju!X 81 2013 

### 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 Propham 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. ofAnimals 

### 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. ofAnimals 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 ofAnalysis ofthe Test Item 

# Lonza

Lanza NMllnD Lid No.2111, Eutl>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>lplrydate 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 

# ----- Whiteto 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 441Harlan Study Number: 41205015 Report


### Appendix 25 (continued) Certificate ofAnalysis ofthe 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 otprotecl9d data and la signed electronlcaHy In ~lancewllh 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

Plgelof2Harlan Study Number: 41205015 Report 

### Appendix 26 Monitoring Authority Statement ofGLP 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 Shardlow 

### 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