## UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 

## 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION



## MEMORANDUM

Date: 6/29/2015

SUBJECT: Propyzamide (Pronamide): Data Evaluation Records (DERs) for EDSP Tier 1 Assays

PC Code: 101701



## Decision No.: 460658, 467265 

## DP Barcode: D398506

, D403721
D403723, D405597 

## Registration No.: NA
467267,470123



## Petition No.: NA



## Risk Assessment Type: NA



## TXR No.: 0056255



## MRID No.: See Table 

## Regulatory Action: NA



## Case No.: NA



## CAS No.: 23950-58-5

40 

## CFR: NA



## FROM: Greg Akerman, Ph.D.

# L:J~ 

# .IJc.-.___

Immediate Office

Health Effects Division (7509P)



## THROUGH: Jess Rowland

# ~~ Deputy Director

Health Effects Division



## TO: Jolene Trujillo Biologist/Chemical Review Manager

Risk Management and Implementation Branch V

Pesticide Re-evaluation Division (7505P)



## I. ACTION REQUESTED Ver.Apr. 2010



## The Pesticide Re-evaluation Division (PRD) of OPP has requested that the Health Effects

Division (HED) review the Endocrine Disruptor Screening Program (EDSP) Tier 1 assays
submitted in response to the agency's Test Order for propyzamide: Test Order# CON-101701-

37.

Page I of2

### Page 2 of 2 

## II. RESPONSE

Attached are the EDSP Tier 1 assay DERs for propyzamide.

III

. MRID Table

Chemical: Propyzamide (Pronamide) PC Code: 101701

Guideline Assay MRID

890.1100 Amphibian Metamorphosis Assay (Frog) 48619101

890.1150 Androgen Receptor Binding (Rat Prostate) 48619102

890.1200 Aromatase Assay (Human Recombinant) 48619103

890.1250 Estrogen Receptor Binding 48619104

890.1300 Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa

- 9903) 48619105

890.1350 Fish Short

- Term Reproduction 48619106

890.1400 Hershberger (Rat) 48673401

890.1450 Female Pubertal (Rat) 48673402

890.1500 Male Pubertal (Rat) 48688001

890.1550 Steroidogenesis (Human Cell Line

– H295R) 48619107

890.1600 Uterotrophic (Rat) 48619108

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԡԹՌԹԯԽՉՍՁՊԽՅԽՆՌ    ԢԭԞԡԭԟԹՊԻ ՇԼԽ  

ԬԢԠԡԡԹՌԹԭՇՁՆՌ  

ԢԭԞԪԯԦԡ   

ԢԭԞԤՍՁԼԽՄՁՆԽ   

      ԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊ ՈՀՇՋՁՋԞՋՋԹՑ
ԣՊՇԿ 

ԱԽՋՌԪԹՌԽՊՁԹՄ  ԭՊՇՆԹՅՁԼԽ ԭՍՊՁՌՑ
     

ԠՇՅՅՇՆՆԹՅԽ ԭՊՇՈՑՒԹՅՁԼԽ

ԠՀԽՅՁԻԹՄՆԹՅԽ ԦԲԭԞԠԼՁԻՀՄՇՊՇԫ
ՅԽՌՀՑՄԺՍՌՑՆՑՄԺԽ ՆՒԹՅՁԼԽ

 ԠԞ԰ՆԹՅԽԼՁԻՀՄՇՊՇԫ
ԼՁՅԽՌՀՑՄՈՊՇՈՑՆՑՄԺԽՆՒԹՅՁԼԽ

 ԠԞ԰ԫՇ

 ԰ՑՆՇՆՑՅՋԭՊՇՈՑՒԹՅՁԼԽ

 ԢԭԞԭԠԠՇԼԽ

ԭՊՁՅԹՊՑԯԽՎՁԽՏԽՊ ԧՇՀՆԪԹՊՌՇՆ ԡԹՌԽ 

԰ՌԹԾԾ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ

԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ
Ջ ԱԽՊՁ԰ԪՑԽՊՋ      ԡԹՌԽ 

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ

ԭՊՁՅԹՊՑԯԽՎՁԽՏԽՊ ԞՆԼՊԽՏ԰ԹՑԽՊ ԭՀԡ     ԡԹՌԽ 

ԟՁՇՄՇԿՁՋՌԢԭԞԬԭԭԢԣԢԡԢԯԟ

԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ ԢԼՏԹՊԼ԰ԻՇՄՄՇՆ ՆՇՄՇՆԿԽՊՏՁՌՀԢԭԞ ԡԹՌԽ 

ԱՇՐՁԻՇՄՇԿՁՋՌԢԭԞԬԭԭԢԣԢԡԢԯԟ 

ԞԼԼՁՌՁՇՆԹՄԯԽՎՁԽՏԽՊ ԠԹՌՀԽՊՁՆԽԞՍԺԽԽ       ԡԹՌԽ 

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԢԭԞԬԭԭԢԣԢԡԢԯԟ 

ԡԹՌԽԢՎԹՄՍԹՌՁՇՆԠՇՅՈՄԽՌԽԼ#ԼԼՅՅՑՑՑՑ%  Digitally signed by ANDREW

SAYER
DN: c=US, o=U.S. Government, ou=USEPA, ou=Staff,
cn=ANDREW SAYER,
dnQualifier=0000051409

Date: 2015.06.09 13:43:25

-04'00'

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԠԦԱԞԱԦԬԫ ԠՍՊՊՁԽԯԧԨԨԠՇԹԼՑԨԩԥՍՌԻՀՁՆՋՇՆԠԪԩԽՀՅԹՆԫԞԪ ԹՄՇՏՁՆՋՃՁԹՆԼԧԱՀՇՅԹՋ

ԭՊՇՆԹՅՁԼԽԱՀԽԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑՏՁՌՀՌՀԽԞԾՊՁԻԹՆԠ ՄԹՏԽԼԣՊՇԿ ԵԽՆՇՈՍՋՄԹԽՎՁՋ ԰ՌՍԼՑ

ՈԽՊԾՇՊՅԽԼԺՑԱՇՐՁԻՇՄՇԿՑԹՆԼԢՆՎՁՊՇՆՅԽՆՌԹՄԯԽՋԽԹՊԻՀԹՆԼԠՇՆՋՍՄՌՁ ՆԿԱՀԽԡՇՏԠՀԽՅՁԻԹՄԠՇՅՈԹՆՑԪՁԼՄԹՆԼ

ԪՁԻՀՁԿԹՆ  ԩԹԺՇՊԹՌՇՊՑ ՊԽՈՇՊՌ ՆՍՅԺԽՊ  ԰ՌՍԼՑ ՋՈՇՆՋՇՊԽ Լ ԺՑ ԡՇՏ ԞԿՊՇ԰ԻՁԽՆԻԽՋ ԩԩԠ

ԦՆԼՁԹՆԹՈՇՄՁՋԦՆԼՁԹՆԹ԰ՌՍԼՑԻՇՅՈՄԽՌԽԼ԰ԽՈՌԽՅԺԽՊ

ԫՇՌԽ ԱՀԽԲ԰ԢԭԞԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅ
Ԣԡ԰ԭԱՁԽՊՋԻՊԽԽՆՁՆԿԺԹՌՌԽՊՑՁՋԻՇՅՈՊՁՋԽԼՇԾԽՄԽՎԽՆ

ՋԻՊԽԽՆՁՆԿԹՋՋԹՑՋՁՆՌԽՆԼԽԼՌՇՁԼԽՆՌՁԾՑԹԻՀԽՅՁԻԹՄ0ՋՄՁՃԽՄՑԽՆԼՇԻ ՊՁՆԽԺՁՇԹԻՌՁՎՁՌՑՁԽՁՌՋՈՇՌԽՆՌՁԹՄՌՇՁՆՌԽՊԹԻՌՏՁՌՀ

ՌՀԽԽՋՌՊՇԿԽՆԹՆԼՊՇԿԽՆՇՊՌՀՑՊՇՁԼ
ԢԞՇՊԱՈԹՌՀՏԹՑՋԱՀԽՊ ՇԺՍՋՌՆԽՋՋՇԾՌՀԽԱՁԽՊԺԹՌՌԽՊՑՁՋԺԹՋԽԼՇՆ

ՌՀԽՋՌՊԽՆԿՌՀՋՇԾԽԹԻՀՁՆԼՁՎՁԼՍԹՄԹՋՋԹՑՌՇՁԼԽՆՌՁԾՑՈՇՌԽՆՌՁԹՄԽՆ ԼՇԻՊՁՆԽԺՁՇԹԻՌՁՎՁՌՑՏՁՌՀԻՇՅՈՄԽՅԽՆՌԹՊՑԽՆԼՈՇՁՆՌՋ

ՏՁՌՀՁՆՌՀԽԹՋՋԹՑՏՀԽՊԽԹՎԹՁՄԹԺՄԽԹՆԼՊԽԼՍՆԼԹՆԻՑԹԻՊՇՋՋՌՀԽԺԹՌՌԽՊՑԱՀՍՋՌՀԽՊԽՋՍՄՌՋՇԾԽԹԻՀՁՆԼՁՎՁԼՍԹՄ

ԹՋՋԹՑՋՀՇՍՄԼՆՇՌԺԽԻՇՆՋՁԼԽՊԽԼՁՆՁՋՇՄԹՌՁՇՆԺՍՌՊԹՌՀԽՊՋՀՇՍՄԼԺ ԽԻՇՆՋՁԼԽՊԽԼՁՆՌՀԽԻՇՆՌԽՐՌՇԾՇՌՀԽՊԹՋՋԹՑՋ

ՁՆՌՀԽԺԹՌՌԽՊՑԹՋՏԽՄՄԹՋԬՌՀԽՊ԰ԻՁԽՆՌՁԾՁԻԹՄՄՑԯԽՄԽՎԹՆՌԦՆԾՇՊՅԹ ՌՁՇՆ
Ԭ԰ԯԦԦՆՇՊԼԽՊՌՇԼԽՌԽՊՅՁՆԽՁԾԹԻՀԽՅՁԻԹՄ

ՀԹՋՌՀԽՈՇՌԽՆՌՁԹՄՌՇՁՆՌԽՊԹԻՌՏՁՌՀՌՀԽԢԞՇՊԱՈԹՌՀՏԹՑՋԹԴԽ ՁԿՀՌՇԾԢՎՁԼԽՆԻԽ
ԴՇԢԽՎԹՄՍԹՌՁՇՆՇԾԱՁԽՊ

ԹՋՋԹՑՊԽՋՍՄՌՋՁՆԻՇՅԺՁՆԹՌՁՇՆՏՁՌՀՌՀԽԾՁՆԼՁՆԿՋՁՆՌՀԽԬ԰ԯԦՋՀ ՇՍՄԼԺԽՍՆԼԽՊՌԹՃԽՆ
ՊԽԾԽՊՌՇՌՀԽԴՇԢ

ԡՇԻՍՅԽՆՌ

ԢԵԢԠԲԱԦԳԢ԰ԲԪԪԞԯԶ

ԱՀԽԼԹՑԹՋՋԹՑՇԾՈՊՇՆԹՅՁԼԽ
ԹՄՋՇՃՆՇՏՆԹՋՈՊՇՈՑՒԹՅՁԼԽ ՈՍՊՁՌՑՇՆԹՅՈՀՁԺՁԹՆՅԽՌԹՅՇՊՈՀՇՋՁՋՇԾ

ԞԾՊՁԻԹՆ ԻՄԹՏԽԼ ԾՊՇԿՋ ԵԽՆՇՈՍՋ ՄԹԽՎՁՋ  ՏԹՋ ԻՇՆԼՍԻՌԽԼ ՍՆԼԽՊ ԾՄՇՏՌՀՊՇՍԿՀ ԻՇՆԼՁՌՁՇՆՋ ԞՅՈՀՁԺՁԹՆ ՄԹՊՎԹԽ  ԹՌ

ԫՁԽՍՏՃՇՇՈԣԹԺԽՊ
ԫԣՋՌԹԿԽ
ՁՆԽԹԻՀՇԾՊԽՈՄՁԻԹՌԽՋ ՏԽՊԽԽՐՈՇՋԽԼՌՇՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋ

ՅԩԩԼՁՅԽՌՀՑՄԾՇՊՅԹՅՁԼԽԡԪԣԹՆԼՆՇՅՁՆԹՄՈՊՇՆԹՅՁԼԽԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾԹՆԼՅԿԹՁԩ

ԱՁՅԽՏԽՁԿՀՌԽԼԹՎԽՊԹԿԽ
ԱԴԞԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽ
ԩԬԮ ԻՇՆՌՊՇՄՋԹՆԼՅԿԹՁԩ

ԱՀԽՌԽՋՌՋՑՋՌԽՅՏԹՋՅԹՁՆՌԹՁՆԽԼԹՌՌՇոԠԹՆԼԹՈԥՇԾ ՌՇ

ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԹՄՄԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻ ՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄ

ԫՇՅՇՊՌԹՄՁՌՁԽՋՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇՄՋԱՀՊԽԽՌԹԼՈՇՄԽՋ
 ԼՁԽԼՁՆՌՀԽՄՇՏԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹՆԼ

ՌԹԼՈՇՄԽՋ
ԼՁԽԼՁՆՌՀԽՅՁԼՌՊԽԹՌՅԽՆՌԿՊՇՍՈԠՄՁՆՁԻԹՄՋՁԿՆ
Ռ ԹԼՈՇՄԽՋՊԽՋՌՁՆԿՇՆՌՀԽՋՍՊԾԹԻԽՏԽՊԽՇԺՋԽՊՎԽԼՁՆ

ՇՆԽՌՇՌՀՊԽԽՌԹԼՈՇՄԽՋՁՆԽԹԻՀՇԾՌՀԽԾՇՍՊՊԽՈՄՁԻԹՌԽՋՇԾՌՀԽՀՁԿ ՀԻՇՆԻԽՆՌՊԹՌՁՇՆԿՊՇՍՈՇՆԡԹՑՋԹՆԼՁՆՌՏՇ

ՌԹԼՈՇՄԽՋԹՌՌՀԽՄՇՏԻՇՆԻԽՆՌՊԹՌՁՇՆԹՆԼՇՆԽԹՌՌՀԽՅԽԼՁՍՅԻՇՆԻԽՆՌ ՊԹՌՁՇՆՇՆԡԹՑ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԭՊՇՆԹՅՁԼԽՋՁԿՆՁԾՁԻԹՆՌՄՑ
Ո ԼԽԻՊԽԹՋԽԼՆՇՊՅԹՄՁՒԽԼՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩԩԹՌԡԹՑ
 ԹՆԼԡԹՑ

ՊԽՄԹՌՁՎԽՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՌՌՀԽԱԴԞՅԿԹՁԩՄԽՎԽՄ԰ՁԿՆՁԾՁԻԹՆՌԼԽՄԹՑ
ՈՇԾՅԽԼՁԹՆ

ԫՁԽՍՏՃՇՇՈԣԹԺԽՊ
ԫԣԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽՏԹՋՇԺՋԽՊՎԽԼԹՌԡԹՑ
ՋՌԹԿԽԹՆԼԡԹՑ
ՋՌԹԿԽՋՁՆՌՀԽ

ԱԴԞՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԟԽՌՏԽԽՆՌԹԼՈՇՄԽՋՌՇՌԹ ՄՏԽՊԽԽՐԻՄՍԼԽԼԾՊՇՅՌՀԽ
ՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄՋԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԺԽԻԹՍՋԽՌՀ ԽՑԼԽՎԽՄՇՈԽԼՈԹՋՌՋՌԹԿԽՇՆՌՀԽԫԣՋԻԹՄԽ

ԱՀԽԽՐԻՄՍԼԽԼՌԹԼՈՇՄԽՋՏԽՊԽՋՈՊԽԹԼԹԻՊՇՋՋՊԽՈՄՁԻԹՌԽՌԹՆՃՋԹՆԼՌՀԽՊԽՏԹՋՆՇՈԹՌՌԽՊՆՇԾՌՀԽՁՊՇԻԻՍՊՊԽՆԻԽԹՋԹ

ԾՍՆԻՌՁՇՆՇԾՌՊԽԹՌՅԽՆՌԫՇՌԹԼՈՇՄԽՋԼԽՎԽՄՇՈԽԼԺԽՑՇՆԼԫԣՋՌԹԿԽՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԬՌՀԽՊ

ԹԾԾԽԻՌԽԼԡԹՑԽՆԼՈՇՁՆՌՋ
ԻՇՆՋՁԼԽՊՁՆԿԽՐԻՄՍՋՁՇՆՇԾԫԣ  ՁՆԼՁՎՁԼՍԹՄՋՁՆԻՄՍԼԽԼՋՁԿՆՁԾՁԻԹՆՌՊԽԼՍԻՌՁՇՆՋՁՆՏԽՌ

ՏԽՁԿՀՌ 
 ՇԾ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ Ո ԹՆԼ ԰Գԩ 
 ՇԾ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ Ո ԹՌ ԹՄՄ

ՈՊՇՆԹՅՁԼԽՌՊԽԹՌԽԼՄԽՎԽՄՋԹՆԼԹՊԽԼՍԻՌՁՇՆ
ՈՁՆԥԩԩԹՌ ՌՀԽՅԿԹՁԩՄԽՎԽՄԻՇՅՈԹՊԽԼՌՇՌՀԽ

ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ ԫՇ ԹՋՑՆԻՀՊՇՆՇՍՋ ԼԽՎԽՄՇՈՅԽՆՌ ՏԹՋ ՇԺՋԽՊՎԽԼ ՁՆ Թ ՆՑ ՌՊԽԹՌՅԽՆՌ ԿՊՇՍՈ ԪՁՄԼ ԾՇՄՄՁԻՍՄԹՊ ԻԽՄՄ

ՀՑՈԽՊՌՊՇՈՀՑՏԹՋԾՇՍՆԼՁՆԺՇՌՀԻՇՆՌՊՇՄՋԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԹՄՄԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼ

ԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄ

ԱՀԽՊԽՏԽՊԽՋԽՎԽՊԹՄԽՆԼՈՇՁՆՌՋԾՇՊՏՀՁԻՀՌՀԽՊԽՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌ
ՈԼՁԾԾԽՊԽՆԻԽՋԺԽՌՏԽԽՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼ

ՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈՋՁՆԻՄՍԼՁՆԿԡԹՑՏԽՌՏԽՁԿՀՌԹՆԼ԰ԳԩԹՋ ՏԽՄՄԹՋԡԹՑՏԽՌՏԽՁԿՀՌԥԩԩԹՆԼՆՇՊՅԹՄՁՒԽԼ

ԥԩԩԦՆՌՀԽՋԽՁՆՋՌԹՆԻԽՋՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈԽՐՀՁԺՁՌԽԼՀՁԿ ՀԽՊՎԹՄՍԽՋՌՀԹՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԿՊՇՍՈԲՈՇՆ

ԹՆԹՄՑՌՁԻԹՄՎԽՊՁԾՁԻԹՌՁՇՆՌՀԽԻՇՆԻԽՆՌՊԹՌՁՇՆՇԾՈՊՇՆԹՅՁԼԽՊԹՆԿԽԼ ՁՆՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՌԽՋՌ

ՁՆՁՌՁԹՌՁՇՆ
ԡԹՑԼՍԽՌՇՁՆՁՌՁԹՄԻՄՇԿԿՁՆԿՇԾՌՀԽՅՁՐՁՆԿԻԽՄՄ ԞԼԼՁՌՁՇՆԹՄՄՑՌՀԽՅԽԼՁՍՅԻՇՆԻԽՆՌՊԹՌՁՇՆՌՊԽԹՌՅԽՆՌԠԳՋ

ՋՄՁԿՀՌՄՑԽՐԻԽԽԼԽԼՊԽՈՇՊՌԽԼՄՑԼՍԽՌՇԼԽԻՊԽԹՋԽՋՁՆՎԽՋՋԽՄԻՇ ՆԻԽՆՌՊԹՌՁՇՆՋՇՆԡԹՑԞՄՄՇՌՀԽՊՈԽՊԾՇՊՅԹՆԻԽ

ԹՆԼՎԹՄՁԼՁՌՑԻՊՁՌԽՊՁԹՏԽՊԽՋԹՌՁՋԾՁԽԼՁՆՌՀՁՋՋՌՍԼՑ

ԱՀԽԹՋՋԹՑ ՋԹՌՁՋԾՁԽՋ ՌՀԽԢԡ԰ԭԱՁԽՊԱԽՋՌԬՊԼԽՊՊԽՉՍՁՊԽՅԽՆՌՋԾՇՊԹՆԞՅՈՀՁԺՁԹՆԪԽՌԹՅ ՇՊՈՀՇՋՁՋԞՋՋԹՑ
ԬԠ԰ԭԭ

ԤՍՁԼԽՄՁՆԽ

ԯԽՋՍՄՌՋ԰ՑՆՇՈՋՁՋ

ԱԽՋՌՇՊԿԹՆՁՋՅԫԣՋՌԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԫԣ

ԱԽՋՌՇՊԿԹՆՁՋՅՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՇՈՌՁՇՆԹՄԫՇՌԯ ԽՈՇՊՌԽԼ

ԱԽՋՌՌՑՈԽԾՄՇՏՌՀՊՇՍԿՀ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽ  ԰ՍՅՅԹՊՑ ՇԾ ԡԽՎԽՄՇՈՅԽՆՌԹՄ ԹՆԼ ԱՀՑՊՇՁԼ ԭԹՌՀՇՄՇԿՑԥՁՋՌՇՈԹ ՌՀՇՄՇԿՑ ԢԾԾԽԻՌՋ  

###  ՁՆ ՌՀԽ ԞՅՈՀՁԺՁԹՆ

ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ
ԞԪԞՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԱՊԽԹՌՅԽՆՌ


ՅԿԹՁԩ

#ԱԴԞՅԽԹՋՍՊԽԼ% ԫԣԡԽՎԽՄՇՈՅԽՆՌԹՄ

԰ՌԹԿԽ ԥՁՆԼԩՁՅԺ

ԩԽՆԿՌՀ  

### ԞՋՑՆԻՀՊՇՆՇՍՋ

ԡԽՎԽՄՇՈՅԽՆՌ ԱՀՑՊՇՁԼԤՊՇՋՋ

ԹՆԼ

ԥՁՋՌՇՈԹՌՀՇՄՇԿՑ

ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

 ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ

 ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ

 ԶԽՋ ԶԽՋ ԶԽՋ ԶԽՋ ԫՇ ԫՇ ԫՇ

 

###  Ԟ՟ՑԽՋՠՁՆԼՁԻԹՌԽՋԹՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆ ՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄՍՆՄԽՋՋ

ՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼ

 

###  ԱՀԽԻՊՁՌԽՊՁԹԾՇՊՋՁԿՆՁԾՁԻԹՆԻԽԹՊԽԼԽՋԻՊՁԺԽԼՁՆՌՀԽԯԽՎՁԽՏԽՊ0Ջ ԞՆԹՄՑՋՁՋԹՆԼ԰ՌԹՌՁՋՌՁԻԹՄԳԽՊՁԾՁԻԹՌՁՇՆՋԽԻՌՁՇՆՋՇԾ

ՌՀԽ ԡԢԯ  ԠՇՆԻՄՍՋՁՇՆՋ ՊԽԿԹՊԼՁՆԿ ՀՁՋՌՇՈԹՌՀՇՄՇԿՑ ՅԹՑ ԺԽ ՀԽԹՎՁՄՑ Տ ԽՁԿՀՌԽԼ ԺՑ ՌՀԽ ԽՐՈԽՊՌ ՇՈՁՆՁՇՆ ՇԾ Թ

ԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ

 

###  ԥՁՆԼՄՁՅԺՄԽՆԿՌՀՁՋՆՇՊՅԹՄՁՒԽԼՌՇՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰Գԩ

Ԧ ԪԞԱԢԯԦԞԩ԰ԞԫԡԪԢԱԥԬԡ԰ 

 ԤՍՁԼԽՄՁՆԽԣՇՄՄՇՏԽԼ  ԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼԾՇՄՄՇՏՁՆԿԿՍՁԼԽՄՁՆԽՋՇՍՌՄՁՆԽԼՁՆԲ԰ ԢԭԞԬԠ԰ԭԭ

ԱՀԽԾՇՄՄՇՏՁՆԿԼԽՎՁԹՌՁՇՆՋԾՊՇՅԬԠ԰ԭԭԹՆԼԬԢԠԡ 

ՏԽՊԽՆՇՌԽԼ

 ԱՀԽԠԳՊԹՆԿԽԼԾՊՇՅՌՇՁՆՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԱՀՁՋԽՐԻԽԽԼՋՌՀԽ

ՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁՇՆԠԳՇԾՆՇՅՇՊԽՌՀԹՆ

 ԫՇԼԽՌԹՁՄՋՈԽՊՌԹՁՆՁՆԿՌՇՈԹՊԽՆՌԹՄԹԻԻՄՁՅԹՌՁՇՆԽՅԺՊՑՇԻՍՄՌՍՊՁՆԿ ԾԽԽԼՁՆԿՇՊՈՊԽՌԽՋՌՀԽԹՄՌՀՏԽՊԽ

ՋՈԽԻՁԾՁԽԼ

 ԱՀԽԼՍՊԹՌՁՇՆՇԾՌՀԽԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԾՇՊՌՀԽՈԹՊԽՆՌԹՄԾՊՇԿՋԹՆԼԼԽՌԹՁՄՋՇՆՈԹՊԽՆՌԹՄԾԽԽԼՁՆԿԹՆԼՀԽԹՄՌՀ

ՏԽՊԽՆՇՌՋՈԽԻՁԾՁԽԼ

 ԱՀԽԽՅԺՊՑՇՋԽՄԽԻՌՁՇՆՅԽՌՀՇԼ
ԽԿԺԽՋՌՋՁՆԿՄԽՋՈԹՏՆՏԹՋՆՇՌՋ ՈԽԻՁԾՁԽԼ

 ԱՀԽՆՇՅՁՆԹՄԾՄՇՏՊԹՌԽ
ՅԩՅՁՆՏԹՋԿՊԽԹՌԽՊՌՀԹՆՊԽԻՇՅՅԽՆԼԽԼ ՅԩՅՁՆԺՍՌՌՀԽՎՇՄՍՅԽ

ՌՍՊՆՇՎԽՊՏԹՋԹԻԻԽՈՌԹԺՄԽ
ԻՇՅՈՄԽՌԽՎՇՄՍՅԽՌՍՊՆՇՎԽՊԽՎԽՊՑՀՇՍ ՊՋ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ   ԱՀԽՀԹՊԼՆԽՋՋՇԾՌՀԽԼՁՄՍՌՁՇՆՏԹՌԽՊ
ՅԿԩԹՋԠԹԠԬ  

### ԽՐԻԽԽԼԽԼՌՀԽՊԽԻՇՅՅԽՆԼԽԼՀԹՊԼՆԽՋՋ

ՇԾՅԿԩԹՋԠԹԠԬ  

### 

 ԱՀԽԻՇՆԻԽՆՌՊԹՌՁՇՆՇԾՈՊՇՆԹՅՁԼԽՊԹՆԿԽԼՁՆՌՀԽՅԿԹՁԩՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՌԽՋՌ

ՁՆՁՌՁԹՌՁՇՆ
ԡԹՑ

 ԱՀԽՊԽՎՁԽՏԽՊԹՆԼՋՌՍԼՑԹՍՌՀՇՊՋԼԽՌԽԻՌԽԼՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋ
ՈԺԽՌՏԽԽՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼ

ՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋԾՇՊՌՀԽԾՇՄՄՇՏՁՆԿԽՆԼՈՇՁՆՌՋԡԹՑՋԹՆԼՏԽՌ ՏԽՁԿՀՌԡԹՑ԰ԳԩԡԹՑԥԩԩ

ԹՆԼԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩԱՀԽՋՌՍԼՑԹՍՌՀՇՊՋԼՁԼՆՇՌԹԼԼՊԽՋՋԹՆ ՑՁՅՈԹԻՌՇԾՌՀԽՋԽԼՁԾԾԽՊԽՆԻԽՋՇՆ

ՌՀԽՋՌՍԼՑՏՀՁՄԽՌՀԽՊԽՎՁԽՏԽՊՆՇՌԽՋՌՀԹՌԾՇՊԹՄՄԹԾԾԽԻՌԽԼԽՆԼՈՇՁՆՌՋՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈՏԹՋ

ՈՊՇՅՇՌԽԼՊԽՄԹՌՁՎԽՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԿՊՇՍՈ

ԱՀԽՋԽԼԽՎՁԹՌՁՇՆՋԼՇՆՇՌՁՅՈԹԻՌՌՀԽԹԻԻԽՈՌԹԺՁՄՁՌՑՇԾՌՀԽՋՌՍԼՑ

 ԠՇՅՈՄՁԹՆԻԽ    ԰Ձ ԿՆԽԼ ԹՆԼ ԼԹՌԽԼ ԫՇ ԡԹՌԹ ԠՇՆԾՁԼԽՆՌՁԹՄՁՌՑ Ԥԩԭ ԹՆԼ ԮՍԹՄՁՌՑ ԞՋՋՍՊԹՆԻԽ

ՋՌԹՌԽՅԽՆՌՋՏԽՊԽՈՊՇՎՁԼԽԼԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼՁՆԻՇՅՈՄՁԹՆԻ ԽՏՁՌՀԲՆՁՌԽԼ

԰ՌԹՌԽՋ ԢՆՎՁՊՇՆՅԽՆՌԹՄ ԭՊՇՌԽԻՌՁՇՆ ԞԿԽՆԻՑ  ԭԽՋՌՁԻՁԼԽ ԭՊՇԿՊԹՅ Ջ ԤՇՇԼ

ԩԹԺՇՊԹՌՇՊՑ ԭՊԹԻՌՁԻԽ ԰ՌԹՆԼԹՊԼՋ ԣՁՆԹՄ ԯՍՄԽ 
 Ԡԣԯ ԭԹՊՌ  Տ ՁՌՀ ՌՀԽ

ԾՇՄՄՇՏՁՆԿԽՐԻԽՈՌՁՇՆՋՌՀԽՄԹՌԽՋՌՏԹՌԽՊԻՀԹՊԹԻՌԽՊՁՒԹՌՁՇՆՈԽՊԾՇՊՅԽԼՁՆԣԽԺՊՍԹՊՑ

ՏԹՋՆՇՌՈԽՊԾՇՊՅԽԼՁՆԹԻԻՇՊԼԹՆԻԽՌՇՌՀԽՋՌԹՌԽԼԤՇՇԼԩԹԺՇՊԹՌ ՇՊՑԭՊԹԻՌՁԻԽՋ

ԹՆԼՌՀԽՌԽՋՌՋՍԺՋՌԹՆԻԽՏԹՋՆՇՌԻՀԹՊԹԻՌԽՊՁՒԽԼԹԻԻՇՊԼՁՆԿՌՇՌՀԽՋ ՌԹՌԽԼԤՇՇԼ

ԩԹԺՇՊԹՌՇՊՑԭՊԹԻՌՁԻԽՋ

ԞԱԽՋՌԪԹՌԽՊՁԹՄ    ԭՊՇՆԹՅՁԼԽ

ԡԽՋԻՊՁՈՌՁՇՆ   ԴՀՁՌԽՈՇՏԼԽՊ

ԬԢԠԡՊԽԻՇՅՅԽՆԼՋԼԽՋԻՊՁԺՁՆԿՏԹՌԽՊՋՇՄՍԺՁՄՁՌՑՅԽՄՌՁՆԿԺՇՁՄՁՆԿՈՇ ՁՆՌՋՌԹԺՁՄՁՌՑՁՆՏԹՌԽՊԹՆԼՄՁԿՀՌՈԨԹԭՇՏ

ՇՊԨՇՏՎԹՈՇՊՈՊԽՋՋՍՊԽՇԾՌԽՋՌԻՇՅՈՇՍՆԼԽՐՈՁՊԹՌՁՇՆԼԹՌԽ

ԩՇՌԫՇԟԹՌԻՀԫՇ  ԵԤԯԱ԰ԫ
ԩՇՌ

ԭՍՊՁՌՑ     

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԦՅՈՍՊՁՌՁԽՋ     ԦՅՈՍՊՁՌՁԽՋՄՁՋՌԽԼՇՆ ՈԹԿԽՇԾԡԢԯ

԰ՌԹԺՁՄՁՌՑՇԾԠՇՅՈՇՍՆԼ ԯԽՄԹՌՁՎԽՄՑ ՋՌԹԺՄԽ ԼՍՊՁՆԿ ՌՀԽ ԼԹՑ ԽՐՈՇՋՍՊԽ ՈԽՊՁՇԼ ԺԹՋԽԼ ՇՆ ԱԴ Ԟ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏՀՁԻՀԹՎԽՊԹԿԽԼՌՇՇԾՆՇՅՁՆԹՄԥՇՏԽՎԽՊ ՌՀԽԠԳՁՆՌՀԽ

ՌՏՇՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԹՆԿԽԼԾՊՇՅՌՇ

԰ՌՇՊԹԿԽԠՇՆԼՁՌՁՇՆՋՇԾ

ԱԽՋՌԠՀԽՅՁԻԹՄՋ   ԫՇՌԯԽՈՇՊՌԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԟԱԽՋՌԬՊԿԹՆՁՋՅԱԹԺՄԽԤԽՆԽՊԹՄԦՆԾՇՊՅԹՌՁՇՆԞԺՇՍՌՌՀԽԱԽՋՌ԰ՈԽԻՁԽՋԹՆԼԭԹՊԽՆՌԹՄԠԹՊԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԽԻՁԽՋԻՇՅՅՇՆՆԹՅԽ ԞԾՊՁԻԹՆԻՄԹՏԽԼԾՊՇԿ ԢԭԞՊԽԻՇՅՅԽՆԼՋԞԾՊՁԻԹՆԻՄԹՏԽԼԾՊՇԿ ԵԽՆՇՈՍՋՄԹԽՎՁՋԴԽՋՌԽՊՆ#ԞԾՊՁԻԹ%ԻՄԹՏԽԼ ԾՊՇԿ԰ՁՄՍՊԹՆԹ
ԵԽՆՇՈՍՋՌՊՇՈՁԻԹՄՁՋՅԹՑԺԽ ՍՋԽԼԹՋԹՆԹՄՌԽՊՆԹՌԽՋՈԽԻՁԽՋ ՀՇՏԽՎԽՊԹՄՁՋՌ ՇԾԹՄՄՇԾՌՀԽՆԽԻԽՋՋԹՊՑՈՊՇՌՇԻՇՄԼԽՎՁԹՌՁՇՆՋՌՇ ԹԻԻՇՅՅՇԼԹՌԽՌՀՁՋՋՈԽԻՁԽՋՁՋՊԽԻՇՅՅԽՆԼԽԼ ԾՇՊՁՆԻՄՍՋՁՇՆՁՆՌՀԽՋՌՍԼՑՊԽՈՇՊՌԱՀԽԿՍՁԼԽՄՁՆԽ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹ ՍՋԽԼՌՇՋՍՈՈՇՊՌՌՀԽՊԽՄՁԹԺՁՄՁՌՑՇԾՌՀԽՌԽՋՌԺԽ

ՁԼԽՆՌՁԾՁԽԼ԰ՈԽԻՁԽՋՋԻՁԽՆՌՁԾՁԻՆԹՅԽ ԵԽՆՇՈՍՋՄԹԽՎՁՋ԰ՈԽԻՁԽՋՋՌՊԹՁՆ
ՁԾՋՌԹՌԽԼ ԫՇՌՋՌԹՌԽԼԴԽՊԽՈԹՊԽՆՌՋՅԹՁՆՌԹՁՆԽԼԹՋՁՆՀՇՍՋԽՋՌՇԻՃ!ԶԽՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՄԹՊՎԹԽ ՍՋԽԼ ՁՆ ՌՀԽ ԹՋՋԹՑԺԽԼԽՊՁՎԽԼԾՊՇՅՁՆՀՇՍՋԽԹԼՍՄՌՋ Բ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ
ԢԭԞ
ԠՇՊՊԽԻՌՁՇՆՋԹՆԼԠՄԹՊՁԾՁԻԹՌՁՇՆՋՇՆԱԽԻՀՆՁԻԹՄԞՋՈԽԻՌՋՇԾՌՀԽԱԽՋՌԤՍՁԼԽՄՁՆԽՋԾՇՊՌՀԽԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅԱՁԽՊԞՋՋԹՑՋ
ԬԠ԰ԭԭԱԽՋՌԤՍՁԼԽՄՁՆԽ԰ԽՊՁԽՋԪԹՊԻՀԬԾԾՁԻԽՇԾԠՀԽՅՁԻԹՄ԰ԹԾԽՌՑԹՆԼԭՇՄՄՍՌՁՇՆԭՊԽՎԽՆՌՁՇՆ
ԬԠ԰ԭԭԴԹՋՀՁՆԿՌՇՆԡԠՀՌՌՈՏՏՏԽՈԹԿՇՎԽՆԼՇՈՍԺՋԹՋՋԹՑՎԹՄՁԼԹՌՁՇՆԻՄԹՊՁԾՁԻԹՌՁՇՆԼՇԻՈԼԾԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԽՊԽՈԹՊԽՆՌԹՄԹԻԻՄՁՅԹՌՁՇՆԻՇՆԼՁՌՁՇՆՋՋԹՅԽԹՋԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԫՇՌԻՄԽԹՊՄՑՋՈԽԻՁԾՁԽԼ ԱՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌԹԼՈՇՄԽՋՏԽՊԽՅԹՁՆՌԹՁՆԽԼՍՆԼԽՊԾՄՇՏՌՀՊՇՍԿՀԻՇՆԼՁՌՁՇՆՋԹՌԹԼԽՆՋՁՌՑՌՀԹՌՏՇՍՄԼԹԾԾԽԻՌԼԽՎԽՄՇՈՅԽՆՌՌԹԼՈՇՄԽՋԩՍՆՌՁՄՌՀԽՑՊԽԹԻՀԽԼՌՀԽԹՈՈՊՇՈՊՁԹՌԽՌԽՋՌՋՁՒԽՋՌԹԿԽԞԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԾՇՊՈԹՊԽՆՌԹՄԾՊՇԿՋ
ՁԾԹՈՈՄՁԻԹԺՄԽԭԹՊԽՆՌՋ ՅԹՁՆՌԹՁՆԽԼ ԹՋԻՇՆՌՁՆՍՇՍՋ ՁՆՀՇՍՋԽԻՍՄՌՍՊԽՋԡԽՌԹՁՄՋՇՆՈԹՊԽՆՌԹՄԾԽԽԼՁՆԿ ԫՇՌՋՈԽԻՁԾՁԽԼԡԽՌԹՁՄՋՇՆՈԹՊԽՆՌԹՄՀԽԹՄՌՀ ԫՇՌՋՈԽԻՁԾՁԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԩԹՊՎԹՄ԰ԽՄԽԻՌՁՇՆԹՆԼԠԹՊԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԟԽՋՌՋՁՆԿՄԽՋՈԹՏՆ!ԫՇ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՌՀԽԺԽՋՌ- ՁՆԼՁՎՁԼՍԹՄՋՈԹՏՆՋՏՁՌՀԹՅՁՆՁՅՍՅՇԾ ՄԹՊՎԹԽՋՈԹՏՆԺԽԽՎԹՄՍԹՌԽԼՌՇՁԼԽՆՌՁԾՑՌՀԽ ԺԽՋՌՋՁՆԿՄԽՋՈԹՏՆԹՆԼՌՀԹՌՌՀԽՄԹՊՎԹԽՋԽՄԽԻՌԽԼ ԾՇՊՌԽՋՌՁՆԿՇՊՁԿՁՆԹՌԽԾՊՇՅՌՀԽԺԽՋՌՋՁՆԿՄԽՋՈԹՏՆ

ՁԽ ՌՀԽՋՈԹՏՆՋԹՊԽՆՇՌԻՇՅՁՐԽԼԫՍՅԺԽՊՇԾՋՈԹՏՆՋԽՎԹՄՍԹՌԽԼ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞԫՍՅԺԽՊՇԾԽԿԿՋՋԹՅՈՄԽԼՈԽՊՋՈԹՏՆԫԞ ԫԣՋՌԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԼԽԾՁՆՁՌՁՎԽՋՌՍԼՑԺԽ ՁՆՁՌՁԹՌԽԼՏՁՌՀՄԹՊՎԹԽԹՌԫՁԽՍՏՃՇՇՈ-ԣԹԺԽՊ ԫԣԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽ ԼԹՑՋ ՈՇՋՌԾԽՊՌՁՄՁՒԹՌՁՇՆԞԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԱԹԼՈՇՄԽՋՏԽՊԽԼԹՑՋՇՄԼԪԽԹՆՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆՁԾՊԽՈՇՊՌԽԼԫՇՌՊԽՈՇՊՌԽԼԯԹՆԿԽՇԾՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾՊԽՈՇՊՌԽԼԫՇՌՊԽՈՇՊՌԽԼԴԹՋՌՀԽՇՈՌՁՇՆԹՄՋՁՒԽՋԽՄԽԻՌՁՇՆՅԽՌՀՇԼՍՋԽԼ!ԫՇՌՋՈԽԻՁԾՁԽԼ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՄԹՊՎԹՄՋԽՄԽԻՌՁՇՆ ԱԹԼՈՇՄԽՋՏԽՊԽՊԹՆԼՇՅՄՑՋԽՄԽԻՌԽԼԹՆԼԻՀՇՋԽԾՇՊՌՀԽԹՋՋԹՑՁԾՌՀԽՑՏԽՊԽԫԣՋՌԹԿԽԩՇԹԼՁՆԿՊԹՌԽ
ՊԽԹՊՁՆԿԼԽՆՋՁՌՑ ՄԹՊՎԹԽԩԱՏԽՆՌՑՌԹԼՈՇՄԽՋՈԽՊՊԽՈՄՁԻԹՌԽՌԽՋՌ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՊԽԹՊՁՆԿ ԼԽՆՋՁՌՑ ՄՇԹԼՁՆԿ ՊԹՌԽ ՆՇՌ ԽՐԻԽԽԼ ԹՈՈՊՇՐՁՅԹՌԽՄՑ  ՄԹՊՎԹԽԩ ԻՍՄՌՍՊՁՆԿ ՋՑՋՌԽՅ ԾՇՊ ԾՄՇՏՌՀՊՇՍԿՀ ՋՑՋՌԽՅՋ ՇՊ  ՌԹԼՈՇՄԽՋԩ ՁՆ ՋՌԹՌՁԻՊԽՆԽՏԹՄ ԽՐՈՇՋՍՊԽՋՑՋՌԽՅՋԱՑՈԽՇԾԾՇՇԼ԰ԽՊԹԪՁԻՊՇՆն ԢԭԞՊԽԻՇՅՅԽՆԼՋ԰ԽՊԹԪՁԻՊՇՆ ն ՌՀՊՇՍԿՀՇՍՌ ՈՊԽԽՐՈՇՋՍՊԽ
ԹԾՌԽՊԫԣՋՌԹԿԽԹՆԼ ԼՍՊՁՆԿՌՀԽԽՆՌՁՊԽԼԼԽԾՁՆՁՌՁՎԽՋՌՍԼՑԦԾ ԹՆՇՌՀԽՊԼՁԽՌՁՋՍՋԽԼՌՀԽՋՌՍԼՑՊԽՈՇՊՌՋՀՇՍՄԼ ՈՊՇՎՁԼԽԹՆԹՄՑՋՁՋՇԾՁՇԼՁԼԽԻՇՆՌԽՆՌԹՆԼՈՇՌԽՆՌՁԹՄ ԻՇՆՌԹՅՁՆԹՆՌՋԹՆԼՌՀԽԼՁԽՌՋՀՇՍՄԼ ԼԽՅՇՆՋՌՊԹՌԽԽՉՍԹՄՈԽՊԾՇՊՅԹՆԻԽՌՇ԰ԽՊԹ

ԪՁԻՊՇՆ ն ԰ՇՍՊԻԽՇԾԾՇՇԼ԰ԽՊԹԪՁԻՊՇՆնԦՇԼՁԼԽԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆԼՁԽՌ
ՁԾՃՆՇՏՆՅԿՃԿ ԣՊԽՉՍԽՆԻՑՇԾԾԽԽԼՁՆԿՌՁՅԽՋԼԹՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾԽԽԼՁՆԿՇԻԻՍՊԹՌՄԽԹՋՌ

ՌՏՁԻԽՈԽՊԼԹՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆԾԽԽԼՁՆԿՊԽԿՁՅԽ ԣՇՄՄՇՏԽԼԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼԽԼՊԽԿՁՅԽ ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌԾՇՇԼՊԹՌՁՇՆՋԼՍՊՁՆԿՌՀԽ ՈՊԽԽՐՈՇՋՍՊԽՈԽՊՁՇԼԺԽՁՆԻՊԽԹՋԽԼԹՄՇՆԿՏՁՌՀ ՄԹՊՎԹՄԿՊՇՏՌՀՌՇԹՈՈՊՇՐՁՅԹՌԽՄՑ ՅԿՄԹՊՎԹԼԹՑԺՑՌԽՋՌՁՆՁՌՁԹՌՁՇՆԢԭԞԹՆԼ ԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌԾՇՇԼՊԹՌՁՇՆՋՁՆԻՊԽԹՋԽ ԾՊՇՅՅԿՄԹՊՎԹԼԹՑԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
԰ՌՍԼՑ ԡԹՑՌՇՅԿՄԹՊՎԹԼԹՑՁՆՌՀԽՄԹՋՌՏԽԽՃ ՇԾՌՀԽՌԽՋՌ
԰ՌՍԼՑԡԹՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԠԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԦՆԾՇՊՅԹՌՁՇՆՇՆՌՀԽԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԹՆԼԱԽՋՌԳԽՋՋԽՄԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱՑՈԽՇԾԽՐՈՇՋՍՊԽԣՄՇՏՌՀՊՇՍԿՀ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԾՄՇՏՌՀՊՇՍԿՀ

ՋՑՋՌԽՅԱՑՈԽՇԾԾՄՇՏՌՀՊՇՍԿՀԼՁՄՍՌՁՇՆՋՑՋՌԽՅ
ՁԾԹՈՈՄՁԻԹԺՄԽԠՇՆՌՁՆՍՇՍՋԾՄՇՏ ԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋՇՊ ԻՇՆՌՁՆՍՇՍՋԾՄՇՏՋԽՊՁԹՄԼՁՄՍՌԽՊՋԹՊԽ ՊԽԻՇՅՅԽՆԼԽԼ ԣՄՇՏՌՀՊՇՍԿՀՊԹՌԽ
ՁԾԹՈՈՄՁԻԹԺՄԽչՅԩՅՁՆ ԣՄՇՏՊԹՌԽՈՊՇՎՁԼԽԼԻՇՅՈՄԽՌԽՎՇՄՍՅԽՌՍՊՆՇՎԽՊԹՈՈՊՇՐՁՅԹՌԽՄՑԽՎԽՊՑՀՇՍՊՋ ԯԽԻՇՅՅԽՆԼԽԼԾՄՇՏՌՀՊՇՍԿՀՊԹՌԽՁՋ ՅԩՅՁՆ
ԻՇՅՈՄԽՌԽՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌԻԹ

ԽՎԽՊՑՀՊՋԞԼԼՁՌՁՇՆԹՄԿՍՁԼԹՆԻԽԾՇՊԹՉՍԹՌՁԻՌԽՋՌԼԽՋՁԿՆՁՋՄՇԻԹՌԽԼՁՆԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ԰ՈԽԻՁԹՄԠՇՆՋՁԼԽՊԹՌՁՇՆՋԾՇՊԠՇՆԼՍԻՌՁՆԿԞՉՍԹՌՁԻԩԹԺՇՊԹՌՇՊՑ԰ՌՍԼՁԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋ
ՁԾԹՈՈՄՁԻԹԺՄԽԞԻՇՆՌՁՆՍՇՍՋԾՄՇՏՋՑՊՁՆԿԽՈՍՅՈԼԽՄՁՎԽՊՑՋՑՋՌԽՅՍՋՁՆԿԿԹՋՌՁԿՀՌՋՑՊՁՆԿԽՋԼԽՄՁՎԽՊԽԼԹԻՇՆԻԽՆՌՊԹՌԽԼՌԽՋՌՋՍԺՋՌԹՆԻԽՋՌՇԻՃՋՇՄՍՌՁՇՆԹՌԹԼԽՋՁԿՆԹՌԽԼՊԹՌԽԾՊՇՅԹՋՌՇԻՃՎԽՋՋԽՄՌՇԹՋՌԹՁՆՄԽՋՋՋՌԽԽՄՅՁՐՁՆԿԻՀԹՅԺԽՊՏՀԽՊԽՁՌՏԹՋՅՁՐԽԼՏՁՌՀԼՁՄՍՌՁՇՆՏԹՌԽՊԱՀԽՌԽՋՌՋՇՄՍՌՁՇՆՏԹՋԿՊԹՎՁՌՑԾԽԼԾՊՇՅՌՀԽՅՁՐՁՆԿԻՀԹՅԺԽՊԹՆԼՋՈՄՁՌԽՉՍԹՄՄՑՌՇՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋ
ԻՇՆՌԹՁՆԽԼՁՆԹՌԽՅՈԽՊԹՌՍՊԽԻՇՆՌՊՇՄՄԽԼՏԹՌԽՊՌՊՇՍԿՀՎՁԹԹԱԽԾՄՇՆՅԹՆՁԾՇՄԼՏՁՌՀԱԽԾՄՇՆԼԽՄՁՎԽՊՑՌՍԺՁՆԿԹՌԹԾՄՇՏՊԹՌԽՇԾչՅՄՅՁՆԱՀՁՋԾՄՇՏՊԹՌԽՈՊՇՎՁԼԽԼԹԻՇՅՈՄԽՌԽՎՇՄՍՅԽՌՍՊՆՇՎԽՊԹՈՈՊՇՐՁՅԹՌԽՄՑԽՎԽՊՑՀՇՍՊՋԾՇՊԽԹԻՀՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄ ԯԽԻՇՅՅԽՆԼԽԼՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊ ԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋԪՁՐՁՆԿԻՀԹՅԺԽՊՁՋ ՊԽԻՇՅՅԽՆԼԽԼԺՍՌՆՇՌՊԽՉՍՁՊԽԼԞԽՊԹՌՁՇՆ ՁՋՆՇՌՊԽԻՇՅՅԽՆԼԽԼԾՇՊՅՁՐՁՆԿԞ ԼԽՅՇՆՋՌՊԹՌՁՇՆՌՀԹՌՌՀԽՌԽՋՌՋՇՄՍՌՁՇՆՁՋ ԻՇՅՈՄԽՌԽՄՑՅՁՐԽԼԺԽԾՇՊԽՁՆՌՊՇԼՍԻԽԼՁՆՌՇՌՀԽ ՌԽՋՌՋՑՋՌԽՅՁՋՊԽԻՇՅՅԽՆԼԽԼԱՀԽ ՊԽԻՇՅՅԽՆԼԽԼԾՄՇՏՋՈՄՁՌՌՁՆԿԹԻԻՍՊԹԻՑՁՋ

ՏՁՌՀՁՆԯԽՆԽՏԹՄՈԽՊՁՇԼԾՇՊՋՌԹՌՁԻՊԽՆԽՏԹՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԦԾՋՌԹՌՁԻՊԽՆԽՏԹՄՁՋՍՋԽԼԢԭԞՊԽԻՇՅՅԽՆԼՋ ՀՊՊԽՆԽՏԹՄՊԽՆԽՏԹՄՈԽՊՁՇԼՁՋ ՊԽԻՇՅՅԽՆԼԽԼՆՇՌՌՇԽՐԻԽԽԼՀՇՍՊՋԞԽՊԹՌՁՇՆ!ԫՇ ԢԭԞՊԽԻՇՅՅԽՆԼՋՅԹՁՆՌԹՁՆՁՆԿԼՁՋՋՇՄՎԽԼ ՇՐՑԿԽՆԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԹՁՊՋԹՌՍՊԹՌՁՇՆ

ՅԿԩ ԞԽՊԹՌՁՇՆՅԹՑԺԽՅԹՁՆՌԹՁՆԽԼ ՌՀՊՇՍԿՀԺՍԺԺՄԽՊՋԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՇՋԽՌ ԺՍԺԺՄԽՊՋԹՌՄԽՎԽՄՋՌՀԹՌԼՇՆՇՌԻԹՍՋԽՋՌՊԽՋՋ

ՇՆՌՀԽՌԹԼՈՇՄԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՇՍՊԻԽՇԾԼՁՄՍՌՁՇՆՏԹՌԽՊ ԡՁՄՍՌՁՇՆՏԹՌԽՊՏԹՋԩԹՃԽԥՍՊՇՆՏԹՌԽՊՋՍՈՈՄՁԽԼՌՇԱՀԽԡՇՏԠՀԽՅՁԻԹՄԠՇՅՈԹՆՑԺՑՌՀԽԠՁՌՑՇԾԪՁԼՄԹՆԼԴԹՌԽՊԱՊԽԹՌՅԽՆՌԭՄԹՆՌԴԹՌԽՊՏԹՋՇԺՌԹՁՆԽԼԾՊՇՅՌՀԽՍՈՈԽՊ԰ԹԿՁՆԹՏԟԹՑՇԾԩԹՃԽԥՍՊՇՆՇԾԾԴՀՁՌԽՋՌՇՆԽԭՇՁՆՌԹՆԼՏԹՋՄՁՅԽԼԹՆԼԾՄՇԻԻՍՄԹՌԽԼՏՁՌՀԾԽՊՊՁԻԻՀՄՇՊՁԼԽԴԹՌԽՊՏԹՋՈՍՅՈԽԼՌՇՌՀԽՄԹԺՇՊԹՌՇՊՑՈՊՁՇՊՌՇՅՍՆՁԻՁՈԹՄՌՊԽԹՌՅԽՆՌԾՇՊՀՍՅԹՆԻՇՆՋՍՅՈՌՁՇՆԭՊՁՇՊՌՇՍՋԽՁՆՌՀԽՄԹԺՇՊԹՌՇՊՑՏԹՌԽՊՏԹՋՋԹՆԼԾՁՄՌԽՊԽԼՈԥԹԼՂՍՋՌԽԼՏՁՌՀԠԬԻԹՊԺՇՆԾՁՄՌԽՊԽԼԹՆԼԲԳՁՊՊԹԼՁԹՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՆԹՌՍՊԹՄՇՊՊԽԻՇՆՋՌՁՌՍՌԽԼ ՏԹՌԽՊՁՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՆԹՌՍՊԹՄՏԹՌԽՊ ԺԽՋՌԽՊՁՄՁՒԽԼՏՁՌՀԲԳԹՆԼՌԽՋՌԽԼԾՇՊ ՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊ ՈՇՋՋՁԺՄԽԻՇՆՌԹՅՁՆԹՆՌՋՁՆԻՄՍԼՁՆԿՃՆՇՏՆ ՋՍԺՋՌՊԹՌԽՋՇԾՌՀԽՁՇԼՁՆԽՌՊԹՆՋՈՇՊՌԽՊՇԾՌՀԽ ՌՀՑՊՇՁԼԿՄԹՆԼ
ԽԿ ԾՄՍՇՊՁԼԽԻՀՄՇՊԹՌԽ ՈԽՊԻՀՄՇՊԹՌԽԬԢԠԡԹԻԻԽՈՌՋԹՆՑՏԹՌԽՊՁՆ ՏՀՁԻՀՌՀԽՌԽՋՌՋՈԽԻՁԽՋՋՀՇՏԻՇՆՌՊՇՄՋՍՊՎՁՎԹՄ ԹՌՄԽԹՋՌԹՋԿՇՇԼԹՋՁՆԼՁԻԹՌԽԼՁՆՌՀԽՌԽՋՌ

ԿՍՁԼԽՄՁՆԽԴԹՋԼՁՄՍՌՁՇՆՏԹՌԽՊԹՆԹՄՑՒԽԼԾՇՊՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊԻՇՆՌԹՅՁՆԹՆՌՋ!ԶԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԦՇԼՁԼԽՋՍՈՈՄԽՅԽՆՌԹՌՁՇՆՁՆՏԹՌԽՊ!ԫՇ  ԦԾՊԽԻՇՆՋՌՁՌՍՌԽԼՏԹՌԽՊՁՋՍՋԽԼՇՊՁԾ ԺԹԻՃԿՊՇՍՆԼՄԽՎԽՄՋՇԾՁՇԼՁԼԽՁՆՆԹՌՍՊԹՄՏԹՌԽՊ ԹՊԽՄԽՋՋՌՀԹՆսԿԩՁՇԼՁԼԽ ՋՍՈՈՄԽՅԽՆՌԹՌՁՇՆՁՋՊԽԻՇՅՅԽՆԼԽԼԱՀՁՋ ՋՍՈՈՄԽՅԽՆՌԹՌՁՇՆՁՋՁՆԹԼԼՁՌՁՇՆՌՇՌՀԽ ՊԽԻՇՅՅԽՆԼԽԼԼՁԽՌԹՊՑՋՇՍՊԻԽՇԾՁՇԼՁԼԽ ԽԿՁՆ԰ԽՊԹԪՁԻՊՇՆԱԽՋՌՎԽՋՋԽՄՌՑՈԽՅԹՌԽՊՁԹՄՋ ԤՄԹՋՋԹՉՍԹՊՁԹ ԢԭԞ ԹՆԼ ԬԢԠԡ ՊԽԻՇՅՅԽՆԼ ՌՀԹՌ ՏԹՌԽՊԻՇՆՌԹԻՌ ՈՇՊՌՁՇՆՋ ՇԾ ՌՀԽ ՋՑՋՌԽՅ ՆՇՌ ԻՇՅՈՊՇՅՁՋԽ ՌՀԽ ՋՌՍԼՑ 
ԽԿ ԹՄՄ ԿՄԹՋՋ ՎԽՋՋԽՄՋՇՊԿՄԹՋՋՎԽՋՋԽՄՋՏՁՌՀՋՌԹՁՆՄԽՋՋՋՌԽԽՄ ԾՊԹՅԽՋԹՊԽԹԻԻԽՈՌԹԺՄԽԽՐԹՅՈՄԽՋԱԽՋՌՎԽՋՋԽՄՋՁՒԽՐՐԻՅՏՁՌՀԹՌԽՋՌՋՇՄՍՌՁՇՆԼԽՈՌՀՇԾԻՅԣՁՄՄՎՇՄՍՅԽ+ԩԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋՇՆԽՐՈՇՋՍՊԽՋՑՋՌԽՅԫԞ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԴԹՌԽՊԮՍԹՄՁՌՑԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋՁՆՌՀԽԱԽՋՌ԰ՑՋՌԽՅԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԥԹՊԼՆԽՋՋ
ՅԿԩԹՋԠԹԠԬ ԴԽԽՃՄՑՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆ ԢԭԞՊԽԻՇՅՅԽՆԼՋՀԹՊԼՆԽՋՋՌՇ ՅԿԩԹՋԠԹԠԬ ՈԥԴԽԽՃՄՑՁՆԽԹԻՀՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈԥչ ՁՆՌԽՊՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌ ԼՁԾԾԽՊԽՆՌՁԹՄՋՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼԡՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ՅԿԩԴԽԽՃՄՑՁՆԽԹԻՀՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ԡԬ ՅԿԩ
 ԹՁՊՋԹՌՍՊԹՌՁՇՆԬԢԠԡ ՊԽԻՇՅՅԽՆԼՋԡԬԻՇՆԻԽՆՌՊԹՌՁՇՆ ՅԿԩ ԹՁՊՋԹՌՍՊԹՌՁՇՆԱԽՅՈԽՊԹՌՍՊԽ
ոԠ ԴԽԽՃՄՑՁՆԽԹԻՀՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌԽՅՈԽՊԹՌՍՊԽչ Շ Ԡ ՁՆՌԽՊՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌ ԼՁԾԾԽՊԽՆՌՁԹՄՋՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼ Շ ԠԦՇԼՁԼԽՅԿԩ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՉՍԹՌՁԻՁՇԼՁԼԽՊԹՆԿԽ -սԿԩ
ՋՍՈՈՄԽՅԽՆՌԹՄՁՇԼՁԼԽՋՀՇՍՄԼՆՇՌ
ԽՐԻԽԽԼսԿԩԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞՅՅՇՆՁԹՅԿԩ ԤԽՆԽՊԹՄՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋԾՇՊԾՊԽՉՍԽՆԻՑՇԾ ՅԽԹՋՍՊԽՅԽՆՌՋԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ՏԹՌԽՊՉՍԹՄՁՌՑՈԹՊԹՅԽՌԽՊՋԺԽՅԽԹՋՍՊԽԼՁՆԹ ԻՇՆՌՊՇՄԹՆԼԹՌՇՆԽՌԽՋՌՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆ ԹՌՄԽԹՋՌՏԽԽՃՄՑԦՆՋՌԹՌՁԻՊԽՆԽՏԹՄՋՑՋՌԽՅՋ ՏԹՌԽՊՉՍԹՄՁՌՑՈԹՊԹՅԽՌԽՊՋՁՆԻՄՍԼՁՆԿ ԹՅՅՇՆՁԹՋՀՇՍՄԼԺԽՅԽԹՋՍՊԽԼՂՍՋՌՈՊՁՇՊՌՇ ՊԽՆԽՏԹՄԦՆԹԼԼՁՌՁՇՆԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԡԬԺԽՅԽԹՋՍՊԽԼԹՌԽԹԻՀԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌ ՄԽԹՋՌՏԽԽՃՄՑԹՆԼՌՀԹՌՌԽՅՈԽՊԹՌՍՊԽԺԽ ՅԽԹՋՍՊԽԼԻՇՆՌՁՆՍՇՍՋՄՑԬԢԠԡ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԡԬԹՆԼՌԽՅՈԽՊԹՌՍՊԽԺԽ ՅԽԹՋՍՊԽԼԹՌՄԽԹՋՌՏԽԽՃՄՑԹՆԼՌՀԹՌՈԥԹՆԼ ՀԹՊԼՆԽՋՋԺԽՅԽԹՋՍՊԽԼԹՌՄԽԹՋՌԹՌՌՀԽ ԺԽԿՁՆՆՁՆԿԹՆԼԽՆԼՇԾՌՀԽՌԽՋՌԣՄՍՇՊՁԼԽՅԿԩԭԽՊԻՀՄՇՊԹՌԽԫՇՌՊԽՈՇՊՌԽԼԠՀՄՇՊԹՌԽԫՇՌՊԽՈՇՊՌԽԼԞՄՃԹՄՁՆՁՌՑ
ՅԿԩԹՋԠԹԠԬ ԴԽԽՃՄՑՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԠՇՆԼՍԻՌՁՎՁՌՑ
սՅՀՇՋԻՅ  ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾ ԡ԰ՌՍԼՑԡԽՋՁԿՆԹՆԼԞԼԼՁՌՁՇՆԹՄԢՐՈԽՊՁՅԽՆՌԹՄԠՇՆԼՁՌՁՇՆՋԱԹԺՄԽԯԹՆԿԽԣՁՆԼՁՆԿ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋ
ՁԾԞՈՈՄՁԻԹԺՄԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԹՊԹՆԿԽԾՁՆԼԽՊԻՇՆԼՍԻՌԽԼ!ԶԽՋԦԾՑԽՋՏՀԹՌՏԹՋՌՀԽՅԽՌՀՇԼԾՇՊԼԽՌԽՊՅՁՆՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽՊԹՆԿԽԾՁՆԼԽՊ!ԯԽԻՇՎԽՊՁԽՋԹՆԼՊԽՈՇՊՌԽԼՋՇՄՍԺՁՄՁՌՑ
ՅԿԩՇԾՌԽՋՌՅԹՌԽՊՁԹՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽ ՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊԼԽՅՇՆՋՌՊԹՌԽՋ ԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ
ԽԿ  ՅՇՊՌԹՄՁՌՑՏՀՁԻՀԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌ԰ՈԽԻՁԽՋ ԵԽՆՇՈՍՋՄԹԽՎՁՋԩՁԾԽՋՌԹԿԽԫԣԱԽՋՌԼՍՊԹՌՁՇՆՀՇՍՊՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԞՀՊՊԹՆԿԽԾՁՆԼԽՊՏԹՋԻՇՆԼՍԻՌԽԼՍՆԼԽՊՋՌԹՌՁԻԻՇՆԼՁՌՁՇՆՋԹՌՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾ
ՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌԹԼՈՇՄԽՋՏԽՊԽՊԹՆԼՇՅՄՑԹՋՋՁԿՆԽԼՌՇԹՌԽՋՌՎԽՋՋԽՄՈԽՊՊԽՈՄՁԻԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆԞԾՌԽՊՀՇՍՊՋՈՇՇՊՋՇՄՍԺՁՄՁՌՑՏԹՋՇԺՋԽՊՎԽԼԹՆԼՇՆՄՑԹՋՁՆԿՄԽՌԹԼՈՇՄԽԼՁԽԼԹՌՁՆՌՀԽՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԱՀԽՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԹՋԹՈՈՊՇՐՁՅԹՌԽՄՑՅԿԹՁԩԱԹԺՄԽԡԽԾՁՆՁՌՁՎԽ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՋՌԼՍՊԹՌՁՇՆԼԹՑՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌՀԽ ԼՍՊԹՌՁՇՆ ՇԾ ՌՀԽ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԼԹՑՋԪԽՌՀՇԼԾՇՊՋԽՄԽԻՌՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԯԹՆԿԽԾՁՆԼՁՆԿՋՌՍԼՁԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽ ՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊԼԽՅՇՆՋՌՊԹՌԽՋ ԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ
ԽԿ  ՅՇՊՌԹՄՁՌՑՏՀՁԻՀԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԯԽԾԽՊԽՆԻԽՋՌՍԼՑԻՁՌԹՌՁՇՆ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ԰ԽՈԹՊԹՌՁՇՆՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌՀԽ ՅԹՐՁՅՍՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՋԽՈԹՊԹՌՁՇՆ ԺԽ  ԹՆԼ ՌՀԽ ՅՁՆՁՅՍՅԺԽԫՍՅԺԽՊՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹՆԼԹԻՇՆՌՊՇՄՈՄՍՋՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄՁԾԹՈՈՊՇՈՊՁԹՌԽԞՊԽՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹԼՂՍՋՌԽԼԾՇՊՈՍՊՁՌՑ!ԶԽՋ ԦՆԼՁԻԹՌԽՌՀԽՌՑՈԽՇԾՎԹՄՍԽՋՈՊԽՋԽՆՌԽԼԾՇՊՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋ԰ՌՍԼՑԹՍՌՀՇՊՈՊԽՋԽՆՌԽԼՅԽԹՆՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋԡՍԽՌՇՀՁԿՀՎԹՊՁԹԺՁՄՁՌՑՊԽՎՁԽՏԽՊԻԹՄԻՍՄԹՌԽԼՌՁՅԽՏԽՁԿՀՌԽԼԹՎԽՊԹԿԽ
ԱԴԞԻՇՆԻԽՆՌՊԹՌՁՇՆՋԩՁՅՁՌՇԾՉՍԹՆՌՁԾՁԻԹՌՁՇՆ
ԩԬԮ ՅԿԹՁԩ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՇՊԻՀԽՅՁԻԹՄՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՄՇՏՌՀԽԩԬԮԹՆԹՄՑՋԽՋԺԽ ԻՇՆԼՍԻՌԽԼՇՆՌՀԽՋՌՇԻՃՋՇՄՍՌՁՇՆՋԩԽՎԽՄՇԾԼԽՌԽԻՌՁՇՆ
ԩԬԡ ԫՇՌՊԽՈՇՊՌԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԣՊԽՉՍԽՆԻՑՇԾՅԽԹՋՍՊԽՅԽՆՌ ԡԹՑՋԹՆԼ  ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌԽՋՌՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆ ԺԽՅԽԹՋՍՊԽԼՁՆՇՆԽՌԹՆՃԹՌԽԹԻՀՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԹՆԼԽՎԽՊՑՏԽԽՃ

ՌՀԽՊԽԹԾՌԽՊԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆԻՇՆՌՊՇՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽ  ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԽՍՋԽՇԾԹ ԻՇՆԻՍՊՊԽՆՌՋՇՄՎԽՆՌԻՇՆՌՊՇՄՏՀԽՆԹՋՇՄՍԺՁՄՁՒՁՆԿ ԹԿԽՆՌՁՋՍՋԽԼԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՈԽՊՌԽՋՌՁՌԽՅՌՊԽԹՌՅԽՆՌՄԽՎԽՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՄԹՊՎԹԽՈԽՊՌՊԽԹՌՅԽՆՌԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՊԽՈ ԴԹՋԹՋՇՄՎԽՆՌՍՋԽԼ!ԶԽՋ԰ՇՄՎԽՆՌՌՑՈԽ
ՁԾԹՈՈՄՁԻԹԺՄԽ ԡԪԣԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԪԹՐՁՅՍՅՋՇՄՎԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁԾԹՈՈՄՁԻԹԺՄԽՅԩԩ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՋՇՄՎԽՆՌՆՇՌԽՐԻԽԽԼ

ՅՄԩ ԬԢԠԡՊԽԻՇՅՅԽՆԼՋՌՀԹՌՋՇՄՎԽՆՌ ՀԹՎԽՆՇԽԾԾԽԻՌՇՆՋՍՊՎՁՎԹՄՆՇՊՈՊՇԼՍԻԽԹՆՑ ՇՌՀԽՊԹԼՎԽՊՋԽԽԾԾԽԻՌՋԹՆԼՌՀԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆ ՆՇՌԺԽԿՊԽԹՌԽՊՌՀԹՆՅՄԩ ԴԹՋԹՈՇՋՁՌՁՎԽԻՇՆՌՊՇՄՍՋԽԼ! ԫՇԭՇՋՁՌՁՎԽԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽ ԫԞԭՇՋՁՌՁՎԽԻՇՆՌՊՇՄԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՋՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԭՀՇՌՇՈԽՊՁՇԼՀՊՋՄՁԿՀՌՀՊՋԼԹՊՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈՀՇՌՇՈԽՊՁՇԼ

ՄՁԿՀՌԼԹՊՃԩՁԿՀՌՁՆՌԽՆՋՁՌՑԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽ ՄՍՐ ԢԭԞՊԽԻՇՅՅԽՆԼՋՄՁԿՀՌՁՆՌԽՆՋՁՌՑ-ԨՄՍՐ ԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԫԞ ԥՍՌԻՀՁՆՋՇՆԱԥ԰ՀՁՄՄԹԺԽԽՊԫԴՁՆՌԽՊԪԧԭՁԻՃԾՇՊԼԡԟ
ԞԻՍՌԽԹՆԼԻՀՊՇՆՁԻԽԾԾԽԻՌՋՇԾԻԹՊՊՁԽՊՋՇՄՎԽՆՌՋՁՆԹՉՍԹՌՁԻՇՊԿԹՆՁՋՅՋԞԻՊՁՌՁԻԹՄՊԽՎՁԽՏԯԽՎՁԽՏԞՉՍԹՌՁԻԱՇՐՁԻՇՄՇԿՑՈՈ- ԬԢԠԡ
ԤՍՁԼԹՆԻԽԡՇԻՍՅԽՆՌՇՆԞՉՍԹՌՁԻԱՇՐՁԻՁՌՑԱԽՋՌՁՆԿՇԾԡՁԾԾՁԻՍՄՌ԰ՍԺՋՌԹՆԻԽՋԹՆԼԪՁՐՌՍՊԽՋԢՆՎՁՊՇՆՅԽՆՌԹՄԥԽԹՄՌՀԹՆԼ԰ԹԾԽՌՑԭՍԺՄՁԻԹՌՁՇՆՋ԰ԽՊՁԽՋՇՆԱԽՋՌՁՆԿԹՆԼԞՋՋԽՋՋՅԽՆՌԫՇԭԹՊՁՋԣՊԹՆԻԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԱՊԽԹՌՅԽՆՌԠՇՆԻԽՆՌՊԹՌՁՇՆՋՁՆՌՀԽԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌԦԡԫՇՅՁՆԹՄԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԱԴԞԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՆԠԳ
ԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ ԫԞ԰ԽԽԯԽՎՁԽՏԽՊ0ՋԠՇՅՅԽՆՌՋ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՌԽՋՌՁՌԽՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՅԹՁՆՌԹՁՆԽԼԹՌԹԻՇԽԾԾՁԻՁԽՆՌՇԾ

ՎԹՊՁԹՌՁՇՆ
ԠԳ ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ ԫԞԱՊԽԹՌՅԽՆՌ ԱՊԽԹՌՅԽՆՌԱՊԽԹՌՅԽՆՌ ԞԺԺՊԽՎՁԹՌՁՇՆՋԠԳԠՇԽԾԾՁԻՁԽՆՌՇԾՎԹՊՁԹՌՁՇՆ ԢԬԺՋԽՊՎԹՌՁՇՆՋԟՁՇՄՇԿՁԻԹՄԢՆԼՈՇՁՆՌՋԡԹՑԫԣՋՌԹԿԽՏԽՌՏԽՁԿՀՌՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩԩՆՇՊՅԹՄՁՒԽԼԥԩԩ        ԡԹՑԫԣՋՌԹԿԽՏԽՌՏԽՁԿՀՌՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩԩՆՇՊՅԹՄՁՒԽԼԥԩԩՀՁՋՌՇՈԹՌՀՇՄՇԿՑ        ԡԹՁՄՑՅՇՊՌԹՄՁՌՑՋՍԺՄԽՌՀԹՄԽԾԾԽԻՌՋԴԽՊԽՊԹՏ
ՁՆԼՁՎՁԼՍԹՄԼԹՌԹՈՊՇՎՁԼԽԼ!ԶԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋՇԾՅՇՊՌԹՄՁՌՑԹՆԼԻՄՁՆՁԻԹՄՋՁԿՆՋՇԻԻՍՊԼԹՁՄՑԹՌԹՅՁՆՁՅՍՅՇՌՀԽՊՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽՊԽԻՇՅՅԽՆԼԽԼ ԹՋԾՇՄՄՇՏՋԫԣ ԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽ
ԡԹՑՋԹՆԼԹՆՑԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄՇՈՅԽ ՆՌՁՆԼՁԻԹՌԽԼԺՑՌԹԼՈՇՄԽՋՌՀԹՌԻԹՆՆՇՌԺԽԹՋՋՁԿՆԽԼԹՆԫԣՋՌԹԿԽ
ԡԹՑՋԹՆԼ ՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԡԹՑՋԹՆԼՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
ԡԹՑՋԹՆԼ ԺՇԼՑՏԽՁԿՀՌ
ՌԽՋՌՁՆՁՌՁԹՌՁՇՆԾՇՊՇՈՌՁՇՆԹՄՋՁՒԽԺԹՋԽԼՄԹ ՊՎԹՄՋԽՄԽԻՌՁՇՆԹՆԼՌՀՑՊՇՁԼ
ԿՄԹՆԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑ
ԡԹՑԫՇՌԽՌՀԽՀՁ ՋՌՇՈԹՌՀՇՄՇԿՑՋԽԻՌՁՇՆՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽԹՄՋՇՁՆԻՄՍԼԽՋՌՀՑՊՇՁԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑՇԺՋԽՊՎԹՌՁՇՆՋ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԦԦ ԯԢ԰ԲԩԱ԰ԞԫԡԡԦ԰ԠԲ԰԰ԦԬԫ

Ԟ ԯԽՋՍՄՌՋ

ԫՇՅՇՊՌԹՄՁՌՁԽՋՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇՄՋՇՊՌՊԽԹՌՅԽՆՌԿՊՇՍՈ ՋՇՆԡԹՑ
ԱԹԺՄԽԞՌՇՌԹՄՇԾՌԹԼՈՇՄԽՋ

ԼՁԽԼԺԽՌՏԽԽՆԡԹՑՋԹՆԼԱՀՊԽԽ
ԼՁԽԼՁՆՌՀԽՄՇՏԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹՆԼԾՁՎԽ
ԼՁԽԼՁՆՌՀԽ

ՁՆՌԽՊՅԽԼՁԹՌԽՌՊԽԹՌՅԽՆՌԿՊՇՍՈ

ԱԹԺՄԽԩԹՊՎԹՄԪՇՊՌԹՄՁՌՑՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ
ՅԿԹՁԩ

#ԱԴԞՅԽԹՋՍՊԽԼ% ԩԹՊՎԹՄԪՇՊՌԹՄՁՌՑ

ԡԹՑ  

### ԡԹՑ

Ն ԪՇՊՌԹՄՁՌՑ ԪՇՊՌԹՄՁՌՑ Ն ԪՇՊՌԹՄՁՌՑ ԪՇՊՌԹՄՁՌՑ 



### ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ      

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ      

      

      

      

 

###  ԰ԹՅՈՄԽՋՁՒԽԹՆԼԻՍՅՍՄԹՌՁՎԽՅՇՊՌԹՄՁՌՑՎԹՄՍԽՋԹՌԡԹՑՈՊՁՇՊՌՇ ՁՆՌԽՊՁՅՋԹԻՊՁԾՁԻԽ

 

###  ԠՍՅՍՄԹՌՁՎԽՅՇՊՌԹՄՁՌՑՇՆԡԹՑՁՋԺԹՋԽԼՇՆՌՀԽՆՍՅԺԽՊՇԾՌԹԼՈՇ ՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
Ն

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԪԽԼՁԹՆԡԹՑԫԣՋՌԹԿԽՊԹՆԿԽԼԾՊՇՅՁՆՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿ ՊՇՍՈՌՇՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԦՆԼՁՎՁԼՍԹՄՌԹԼՈՇՄԽՋՌԹԿԽՊԹՆԿԽԼԾՊՇՅՌՇ ԱԹԺՄԽ ԡԹՑՅԽԼՁԹՆԫԣՋՌԹԿԽՊԹՆԿԽԼԾՊՇՅ

ՁՆՌՀԽՀՁԿՀԽՋՌԿՊՇՍՈՌՇՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԱԹԺՄԽԩԹՊՎԹՄԡԽՎԽՄՇՈՅԽՆՌՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ -ԡԽՎԽՄՇՈՅԽՆՌԹՄ԰ՌԹԿԽԹՆԼԞՋՑՆԻՀՊՇՆՇՍՋԡԽՎԽՄՇՈՅԽՆՌ

ԱՊԽԹՌՅԽՆՌ
ՅԿԹՁԩ

#ԱԴԞՅԽԹՋՍՊԽԼ% ԡԽՎԽՄՇՈՅԽՆՌԹՄ԰ՌԹԿԽ

ԡԹՑ ԡԹՑ

Ն ԪԽԼՁԹՆ

԰ՌԹԿԽ ԞՋՑՆԻՀՊՇՆՇՍՋ Ն ԪԽԼՁԹՆ

԰ՌԹԿԽ ԞՋՑՆԻՀՊՇՆՇՍՋ

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ      

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ      

      

      

      

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԪԽԹՆԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩՊԹՆԿԽԼԾՊՇՅՁՆԻՇՆՌՊՇՄՋՌՇ ՁՆՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄ ԱԹԺՄԽ

 ԬՆԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩՎԹՄՍԽՋՊԹՆԿԽԼԾՊՇՅՁՆՌՀԽՆ ԽԿԹՌՁՎԽԻՇՆՌՊՇՄՌՇՁՆՌՀԽՀՁԿՀԽՋՌ

ՌՊԽԹՌՅԽՆՌԿՊՇՍՈ

ԱԹԺՄԽԩԹՊՎԹՄԡԽՎԽՄՇՈՅԽՆՌՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ -ԥՁՆԼԩՁՅԺԩԽՆԿՌՀ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ԱԴԞՅԽԹՋՍՊԽԼ% ԥՁՆԼԩՁՅԺԩԽՆԿՌՀ
ԥԩԩ

ԡԹՑ ԡԹՑ

Ն ԪԽԹՆ

ՅՅ չ԰ԡ ԥԩԩ

԰Գԩ  

### Ն ԪԽԹՆ

ՅՅ չ԰ԡ ԥԩԩ

԰Գԩ 



### ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ        

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ        

        

        

        

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԰ԡ 

### ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

 

### ԰ՍՅՅԹՊՑՊԽՋՍՄՌՋԾՇՊՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩԹՊԽՈՊԽՋԽՆՌԽԼՁՆՌՀԽՆԽՐՌՌԹԺՄԽ ԱԹԺՄԽ 

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԪԽԹՆ԰ԳԩՇՆԡԹՑՊԹՆԿԽԼԾՊՇՅՅՅՁՆՌՀԽՅԿԹՁԩԿՊՇ ՍՈՌՇՅՅՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԱԹԺՄԽԡԹՑՏԽՌՏԽՁԿՀՌՊԹՆԿԽԼԾՊՇՅԿՁՆՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄՌՇԿՁՆՌՀԽՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄ ԱԹԺՄԽ ԟՑԡԹՑ԰Գԩ
ՅՅԹՆԼՅԽԹՆՏԽՌՏԽՁԿՀՌ
ԿՏԽՊԽՀ ՁԿՀԽՋՌՁՆՌՀԽՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄԹՆԼՄՇՏԽՋՌՁՆՌՀԽՅԿԹՁԩԿՊՇՍՈԹՌՅՅԹՆԼ ԿՊԽՋՈԽԻՌՁՎԽՄՑ

ԱԹԺՄԽԩԹՊՎԹՄԤՊՇՏՌՀՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ԱԴԞ

ՅԽԹՋՍՊԽԼ% ԰ՆՇՍՌԳԽՆՌԩԽՆԿՌՀ
԰Գԩ ԟՇԼՑԴԽՁԿՀՌ 



### ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

Ն ԪԽԹՆ

ՅՅ չ԰ԡ Ն ԪԽԹՆ

ՅՅ չ԰ԡ Ն ԪԽԹՆ

Կ չ԰ԡ Ն ԪԽԹՆ

Կ չ԰ԡ

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ            

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ             

            

            

            

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԰ԡ 

### ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

 

###  ԞՄՋՇՊԽԾԽՊՊԽԼՌՇԹՋ՟ՏԽՌՏԽՁԿՀՌՠՁՆՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽ

ԫՇԿՄԹՆԼՍՄԹՊԹՌՊՇՈՀՑՇՊՀՑՈԽՊՌՊՇՈՀՑՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇ ՄԹՆԼՌՊԽԹՌՅԽՆՌՌԹԼՈՇՄԽՋ ԱԹԺՄԽ 

ԪՁՄԼ
ԿՊԹԼԽՌԹՄՄԻՇՄՍՅՆԹՊԻԽՄՄՋՄՁՆՁՆԿՌՀԽԾՇՄՄՁԻՄԽՋ
ԾՇՄՄՁԻՍՄԹՊԻԽՄՄՀՑՈԽՊՌՊՇՈՀՑՏԽՊԽՇԺՋԽՊՎԽԼՁՆԺՇՌՀ

ԻՇՆՌՊՇՄՋԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՏՁՌՀՌՀԽՆՍՅԺԽՊՇԾԹԾԾԽԻՌԽԼ ՁՆԼՁՎՁԼՍԹՄՋՊԹՆԿՁՆԿԾՊՇՅՁՆՌՀԽՄՇՏԽՋՌ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՌՇՁՆՌՀԽՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽԤՊՇՋՋԭԹՌՀՇՄՇԿՑԹՆԼԥՁՋՌՇՈԹՌՀՇՄՇԿՑՇԾՌՀԽԱՀՑՊՇՁԼԤՄԹ ՆԼՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ԱԴԞ

ՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 



### ԰ԽՎԽՊՁՌՑ ԱՀՑՊՇՁԼԤՄԹՆԼ

ԥՑՈԽՊՌՊՇՈՀՑ ԱՀՑՊՇՁԼԤՄԹՆԼ

ԞՌՊՇՈՀՑ ԣՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՌՊՇՈՀՑ ԣՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ         

        

        

        

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ         

        

        

        

         

        

        

        

         

        

        

        

         

        

        

        

 

###  ԱՀՑՊՇՁԼԿՄԹՆԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑԹՊԽԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽ

ԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ ԰ԽԽԬԢԠԡԫՇԾՇՊՊԽԾԽՊԽՆԻԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԞԼԼՁՌՁՇՆԹՄԱՀՑՊՇՁԼԤՄԹՆԼԥՁՋՌՇՈԹՌՀՇՄՇԿՑԬԺՋԽՊՎԹՌՁՇՆՋՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋԫԞԱՀՁՋՌԹԺՄԽՁՋՇՅՁՌՌԽԼԺԽԻԹՍՋԽԹԼԼՁՌՁՇՆԹՄՌՀՑՊՇՁԼԿՄԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑՇԺՋԽՊՎԹՌՁՇՆՋՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼԬՆԡԹՑՇՆԽՌՇՌՀՊԽԽՌԹԼՈՇՄԽՋՁՆԹՄՄԾՇՍՊՊԽՈՄՁԻԹՌԽՋՇԾՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԽՊԽՇԺՋԽՊՎԽԼՊԽՋՌՁՆԿՌՀԽՋՍՊԾԹԻԽԹՆԼՌՀՁՋԺԽՀԹՎՁՇՊՏԹՋՇԺՋԽՊՎԽԼՌՀՊՇՍԿՀԡԹՑԱԹԺՄԽԬՆԡԹՑՌՀԽՋԹՅԽՇԺՋԽՊՎԹՌՁՇՆՏԹՋՅԹԼԽԾՇՊՌՏՇՌԹԼՈՇՄԽՋՁՆՌՀԽՄՇՏԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹՆԼՇՆԽՁՆՌՀԽՅՁԼԼՄԽՌՊԽԹՌՅԽՆՌԿՊՇՍՈԦՌՁՋՆՇՌՊԽՈՇՊՌԽԼՁԾՌՀԽՋԽՇԺՋԽՊՎԹՌՁՇՆՋԻՇՆՌՁՆՍԽԼՌՀՊՇՍԿՀՌՇՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆԱԹԺՄԽԠՄՁՆՁԻԹՄ԰ՁԿՆՋՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ԱԴԞՅԽԹՋՍՊԽԼ%ԠՄՁՆՁԻԹՄ԰ՁԿՆՋԱՑՈԽՆԦՆԻՁԼԽՆԻԽԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄԞՄՄԹՈՈԽԹՊԽԼՆՇՊՅԹՄԹՆԼՀԽԹՄՌՀՑ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄԞՄՄԹՈՈԽԹՊԽԼՆՇՊՅԹՄԹՆԼՀԽԹՄՌՀՑՅԿԹՁԩ԰ԽԽԻՇՅՅԽՆՌՋԹԺՇՎԽՅԿԹՁԩ԰ԽԽԻՇՅՅԽՆՌՋԹԺՇՎԽՅԿԹՁԩ԰ԽԽԻՇՅՅԽՆՌՋԹԺՇՎԽԟԹՋԽԼՇՆՌՀԽՆՍՅԺԽՊՇԾՇԺՋԽՊՎԽԼՁՆԼՁՎՁԼՍԹՄՋՇՆԡԹՑՇՆՄՑԠՄՁՆՁԻԹՄՋՁԿՆՋՇԺՋԽՊՎԽԼՈՊՁՇՊՌՇԡԹՑԹՊԽՊԽՈՇՊՌԽԼՁՆՌՀԽՌԽՐՌ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԟ ԰ՌՍԼՑԞՍՌՀՇՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

԰ՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋԽՋՇԾՌՀԽԻՇՆՌՁՆՍՇՍՋԼԹՌԹՋԽՌՁՆԻՄՍԼՁՆԿՅԽԹՋ ՍՊԽՅԽՆՌՋՇԾԥԩԩՏԽՌՏԽՁԿՀՌԹՆԼ԰Գԩ

ՏԽՊԽԻՇՆԼՍԻՌԽԼՍՋՁՆԿՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌՁՆԹՋՌԽՈԼՇՏ ՆՅԹՆՆԽՊՁԾՌՀԽԼԹՌԹՏԽՊԽԻՇՆՋՁՋՌԽՆՌ

ՏՁՌՀ Թ ՅՇՆՇՌՇՆԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽ ԦԾ ՌՀԽՋԽ ԽՆԼՈՇՁՆՌՋ ՏԽՊԽ ԻՇՆՋՁՋՌԽՆՌ ՏՁՌՀ Թ ՅՇՆՇՌՇՆԽ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽ ՌՀԽ ԼԹՌԹ ՏԽՊԽ ԹՋՋԽՋՋԽԼ ԾՇՊ ՆՇՊՅԹՄՁՌՑ ՍՋՁՆԿ ԰ՀԹՈՁՊՇԴՁՄՃ0Ջ ՌԽՋՌ ԹՆԼ ԾՇՊ

ՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽՍՋՁՆԿԩԽՎԽՆԽ0ՋՌԽՋՌԴՀԽՆՆԽԻԽՋՋԹՊՑՌ ՊԹՆՋԾՇՊՅԹՌՁՇՆՋՏԽՊԽԹՈՈՄՁԽԼՌՇԹՌՌԽՅՈՌ

ՌՇՅԽԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՈԹՊԹՅԽՌՊՁԻՋՌԹՌՁՋՌՁԻՋԦԾԼԹՌԹՅԽՌ ՌՀԽՋԽԹՋՋՍՅՈՌՁՇՆՋԼԹՌԹՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿ

ԞԫԬԳԞԾՇՄՄՇՏԽԼՍՈԡՍՆՆԽՌՌ0ՋՌԽՋՌԦԾՌՀԽԼԹՌԹՏԽՊԽՆՇՊՅԹՄՄՑԼՁՋՌՊՁԺՍՌԽԼՏՁՌՀՀԽՌԽՊՇԿԽՆԽՇՍՋՎԹՊՁԹՆԻԽ

ՌՀԽ ԪԹՆՆԴՀՁՌՆԽՑԴՁՄԻՇՐՇՆ Բ ՌԽՋՌ ՏԹՋ ՍՋԽԼ ԦԾ ՆՇ ՆՇՊՅԹՄՁՒՁՆԿ ՌՊ ԹՆՋԾՇՊՅԹՌՁՇՆ ՏԹՋ ԾՇՍՆԼ ՌՀԽ

ԪԹՆՆԴՀՁՌՆԽՑԴՁՄԻՇՐՇՆԲՌԽՋՌՍՋՁՆԿԹԟՇՆԾԽՊՊՇՆՁԥՇՄՅԹԼՂՍՋՌՅԽՆՌ ՏԹՋՍՋԽԼ

ԡԹՑԴԽՌՏԽՁԿՀՌԹՆԼ԰ԳԩԺՇՌՀԽՐՀՁԺՁՌԽԼԹՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽԺ ՍՌԼՁԼՆՇՌՅԽԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾ

ՈԹՊԹՅԽՌՊՁԻ ՋՌԹՌՁՋՌՁԻՋ ԽՎԽՆԾՇՄՄՇՏՁՆԿ Թ ՊԹՆՃՌՊԹՆՋԾՇՊՅԹՌՁՇՆ ԹՆ Լ ԹՆԹՄՑՋԽՋՏԽՊԽ ԻՇՆԼՍԻՌԽԼ ՍՋՁՆԿՌՀԽ

ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԱԹԼՈՇՄԽՋՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄՀԹԼՋՁԿՆՁԾՁԻԹՆՌՄՑԿՊԽԹՌԽՊՏԽՌՏԽՁԿՀՌ
 Ո

ԹՆԼ԰Գԩ
 Ո ԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԼԹՌԹՏԽՊԽԻՇՅՈԹՊԽԼՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄՇՆՄՑ

ԟՇՌՀԿՊՇՏՌՀՈԹՊԹՅԽՌԽՊՋՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌԹՄՄՌՊԽԹՌՅ ԽՆՌՄԽՎԽՄՋՊԽՄԹՌՁՎԽՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԫՇՊՅԹՄՁՒԽԼԥԩԩՏԹՋՆՇՌՅՇՆՇՌՇՆՁԻԹՆԼՌՀԽՍՆՌՊԹՆՋԾՇՊՅԽԼԼԹՌԹՅԽՌ ՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՆՇՊՅԹՄՁՌՑԹՆԼ

ՀՇՅՇՋԻԽԼԹՋՌՁԻՁՌՑ ԫՇ ԼՁԾԾԽՊԽՆԻԽՋ ՏԽՊԽ ԼԽՌԽԻՌԽԼ ԺԽՌՏԽԽՆ ՌՀԽ ՆԽԿԹ ՌՁՎԽ ԹՆԼ ՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄՋ ԹՆԼ

ՆՇՊՅԹՄՁՒԽԼԥԩԩՏԹՋԻՇՅՈԹՊԽԼՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄՍՋՁՆԿԡՍՆՆԽՌՌ0ՋՌԽՋՌՆՇԼՁԾԾԽՊԽՆԻԽՋՏԽՊԽԼԽՌԽԻՌԽԼ

ԾՇՊԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩԟԹՋԽԼՇՆՌՀԽՅՍՄՌՁՉՍԹՆՌԹՄԧՇՆԻՃՀԽԽՊԽ ԱԽՊՈՋՌՊԹՌԽՋՌԫԣՋՌԹԿԽՇՆԡԹՑՏԹՋ

ԻՇՅՈԹՊԹԺՄԽԺԽՌՏԽԽՆՌՀԽՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԹՆԼՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ

ԟՇՌՀՏԽՌՏԽՁԿՀՌԹՆԼ԰ԳԩՇՆԡԹՑՀԹԼՆՇՆՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽՋ ԺՍՌՅԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՈԹՊԹՅԽՌՊՁԻ

ՋՌԹՌՁՋՌՁԻՋՏՁՌՀՇՍՌՌՀԽՆԽԽԼԾՇՊՌՊԹՆՋԾՇՊՅԹՌՁՇՆՋԟՇՌՀԽՆԼՈՇՁՆՌՋ ՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿԡՍՆՆԽՌՌ0ՋՌԽՋՌԞ

ՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՏԹՋԼԽՌԽԻՌԽԼԺԽՌՏԽԽՆՌՏՇԻՇՆՌՊՇՄՋԾՇՊՏԽ ՌՏԽՁԿՀՌ
ԿՊԽԹՌԽՊՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

Ո

ԹՆԼՌՊԽԹՌՅԽՆՌԼԹՌԹՏԽՊԽԻՇՅՈԹՊԽԼՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԠՇՆՎԽՊՋԽՄՑՆՇԼՁԾԾԽՊԽՆԻԽՋՏԽՊԽ

ԾՇՍՆԼԺԽՌՏԽԽՆՌՀԽԻՇՆՌՊՇՄՋԾՇՊ԰ԳԩԼԹՌԹԹՆԼՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՏ ԽՊԽԻՇՅՈԹՊԽԼՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ

ԠՇՅՈԹՊԹԺՄԽՌՇԡԹՑԺՇՌՀԿՊՇՏՌՀՈԹՊԹՅԽՌԽՊՋՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑ ՁՆՀՁԺՁՌԽԼԹՌԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՄԹՌՁՎԽ

ՌՇՌՀԽՁՊՊԽՋՈԽԻՌՁՎԽԻՇՆՌՊՇՄԫՇՊՅԹՄՁՒԽԼԥԩԩՇՆԡԹՑՏԹՋՅՇՆՇՌՇՆՁԻԹՆԼՏԹՋՌՀԽՊԽԾՇՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿ

ՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԱՊԽԹՌՅԽՆՌԼԹՌԹՏԽՊԽԻՇՅՈԹՊԽԼՌՇՌ ՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՋՌՀԽՊԽՏԹՋԹ

ՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽԺԽՌՏԽԽՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋ
ԿՊԽԹՌԽՊՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ Ո 

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԫՇՊՅԹՄՁՒԽԼԥԩԩՏԹՋՇՆՄՑՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌՌՀԽՀ ՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈ԰ՁՅՁՄԹՊՄՑԡԹՑ

ԫԣՋՌԹԿԽՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄՊԽՄԹՌՁՎԽՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ

 ԠԯԽՎՁԽՏԽՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

԰ՌԹՌՁՋՌՁԻԹՄԪԽՌՀՇԼՋ ԪՇՊՌԹՄՁՌՑՏԹՋՁՆՌՀԽԻՇՆՌՊՇՄՋԹՆԼՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹ ՆԼԼՁԼՆՇՌԽՐԻԽԽԼ

ՁՆՌՀԽՊԽՅԹՁՆՁՆԿՌՏՇՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԱՀԽՊԽԾՇՊԽՌՀԽՊԽՎՁԽՏ ԽՊՎՁՋՍԹՄՄՑԼԽՌԽՊՅՁՆԽԼՆՇՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌ

ՇՆՋՍՊՎՁՎԹՄԡԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽԼԹՌԹՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽ ՇՆԽՋՁԼԽԼԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌՊԽՆԼ

ՌԽՋՌՇՊՌՀԽՌՏՇՋՁԼԽԼԪԹՆՆԴՀՁՌՆԽՑԲԺԹՋԽԼՇՆԹՎՁՋՍԹՄԼԽՌԽՊՅՁ ՆԹՌՁՇՆՇԾՏՀԽՌՀԽՊՌՀԽԼԹՌԹՋՀՇՏԽԼԹ

ՅՇՆՇՌՇՆՁԻԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽԡԹՑՏԽՌՏԽՁԿՀՌԼԹՌԹԼՁԼՆՇ ՌԽՐՀՁԺՁՌԹՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽԹՆԼԼՁԼ

ՆՇՌՅԽԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՆՇՊՅԹՄՁՌՑԹՆԼՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆ ԻԽՌՀԽՊԽԾՇՊԽՌՀԽՑՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿ

ՌՀԽԪԹՆՆԴՀՁՌՆԽՑԲՌԽՋՌԡԹՑ԰ԳԩԼԹՌԹՏԽՊԽԹՆԹՄՑՒԽԼՏՁՌՀԡՍՆ ՆԽՌՌ0ՋՌԽՋՌԡԹՑԥԩԩԹՆԼՆՇՊՅԹՄՁՒԽԼ

ԥԩԩՋՀՇՏԽԼԹՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽԹՆԼՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽԧՇՆ ԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌ ԱԹԼՈՇՄԽՋՅԹՌՍՊՁՆԿԺԽՑՇՆԼԫԣՋՌԹԿԽԺՑԡԹՑՏԽՊԽԽՐԻՄՍԼԽԼԾՊ ՇՅԾՍՊՌՀԽՊԹՆԹՄՑՋՁՋՇԾԡԹՑ

ԽՆԼՈՇՁՆՌՋԱՀԽՊԽՏԹՋՆՇԹՈՈԹՊԽՆՌՈԹՌՌԽՊՆՌՇՌՀԽՇԻԻՍՊՊԽՆԻԽՇԾԫ ԣՋՌԹԿԽ  ՁՆԼՁՎՁԼՍԹՄՋԹԻՊՇՋՋՊԽՈՄՁԻԹՌԽՋ

ՇՊԹՅՇՆԿՌՊԽԹՌՅԽՆՌՋԺԽՌՏԽԽՆՌԹԼՈՇՄԽՋՌՇՌԹՄՏԽՊԽԽՐԻՄՍԼԽԼ ԾՊՇՅԽԹԻՀՇԾՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄՋԹՆԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԡԹՑՏ ԽՌՏԽՁԿՀՌ԰ԳԩԥԩԩԹՆԼՆՇՊՅԹՄՁՒԽԼ

ԥԩԩԼԹՌԹՏԽՊԽՆՇՌՅՇՆՇՌՇՆՁԻԺՍՌՌՀԽՑՅԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՈԹՊ ԹՅԽՌՊՁԻՋՌԹՌՁՋՌՁԻՋԹՆԼՏԽՊԽԹՆԹՄՑՒԽԼ

ՍՋՁՆԿԡՍՆՆԽՌՌ0ՋՌԽՋՌԫՇԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄՇՈՅԽՆՌՏԹՋՇԺՋԽՊՎԽԼ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋ

ՏԽՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌ Ո ԞՄՄԹՆԹՄՑՋԽՋՏԽՊԽԻՇՆԼՍԻՌԽԼՍՋՁՆԿ԰Ԟ԰ԳԽՊՋՁՇՆ

ԣՇՊԹՄՄԿՊՇՏՌՀԽՆԼՈՇՁՆՌՋԹՆԼՆՇՊՅԹՄՁՒԽԼԥԩԩՌՀԽՊԽՎՁԽՏԽՊԻՇՅՈԹՊԽԼՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄԼԹՌԹ

ՍՋՁՆԿԹՌՌԽՋՌԹՋՋՍՅՁՆԿՍՆԽՉՍԹՄՎԹՊՁԹՆԻԽՎՁԹԪՁԻՊՇՋՇԾՌԢՐԻԽՄ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ   ԠՇՆԻՄՍՋՁՇՆՋ

ԭՊՇՆԹՅՁԼԽԽՐՈՇՋՍՊԽԹՌՅԿԹՁԩՏԹՋԹՋՋՇԻՁԹՌԽԼՏՁՌՀՋՌԹՌՁՋՌՁ ԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋՇՆԡԹՑԹՆԼ

ԡԹՑԫԣՋՌԹԿԽ
ԹՆԼՋՌԹԿԽՋՊԽՋՈԽԻՌՁՎԽՄՑԹՆԼՇՆԡԹՑԹ ՆԼԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩ


ԹՆԼՊԽՋՈԽԻՌՁՎԽՄՑ
Ո ՏՀԽՆԻՇՅՈԹՊԽԼՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԡԹՑԹՆԼԡԹՑ԰ԳԩԹՆԼ

ԡԹՑԺՇԼՑՏԽՁԿՀՌՏԽՊԽԹՄՋՇՋՁԿՆՁԾՁԻԹՆՌՄՑՄՇՏԽՊՁՆՌԹԼՈՇՄԽՋԽՐ ՈՇՋԽԼԹՌՅԿԹՁԩԞՌՄՇՏԽՊՌՊԽԹՌՅԽՆՌ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾԹՆԼՅԿԹՁԩՇՆՄՑԡԹՑ԰ԳԩԹՆԼԡԹ ՑԺՇԼՑՏԽՁԿՀՌՏԽՊԽԹԾԾԽԻՌԽԼԹՆԼ

ՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑՄՇՏԽՊՌՀԹՆՁՆՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՋ
Ո

ԠՇՆՎԽՊՋԽՄՑԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩԡԹՑ԰ԳԩԹՆԼԡԹՑԹՆԼԡԹՑ ԺՇԼՑՏԽՁԿՀՌՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑ

ԿՊԽԹՌԽՊՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋՌՀԹՆՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ԰ՁՆԻ ԽՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋՏԽՊԽԿԽՆԽՊԹՄՄՑ

ՇԺՋԽՊՎԽԼՁՆՈՊՇՆԹՅՁԼԽՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՁՆՌՀԽՇՈՈՇՋՁՌԽԼՁՊԽԻՌՁՇ Ն ԽԿ ՌՊԽԹՌՅԽՆՌՊԽՄԹՌԽԼՁՆԻՊԽԹՋԽՁՆՋՌԽԹԼ

ՇԾԼԽԻՊԽԹՋԽՌՀԽՋՇՄՎԽՆՌԽԾԾԽԻՌՋԼՇՆՇՌԹՈՈԽԹՊՌՇՀԹՎԽՋՍԺՋՌԹՆ ՌՁՎԽՄՑՁՅՈԹԻՌԽԼՌՀԽՇՎԽՊԹՄՄՊԽՋՍՄՌՋՇՊ

ՁՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀԽՋՌՍԼՑԥՇՏԽՎԽՊՁՌՁՋՈՇՋՋՁԺՄԽՌՀԹՌՌՀԽ ՅԹԿՆՁՌՍԼԽՇԾԽԾԾԽԻՌՋՅԹՑՀԹՎԽԺԽԽՆԿՊԽԹՌԽՊ

ԹՌՌՀԽՀՁԿՀՌՊԽԹՌՅԽՆՌՄԽՎԽՄՁՆՌՀԽԹԺՋԽՆԻԽՇԾՌՀԽՋՇՄՎԽՆՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԡԽՎԽՄՇՈՅԽՆՌԹՄԹՆԼԱՀՑՊՇՁԼԤՊՇՋՋԭԹՌՀՇՄՇԿՑԥՁՋՌՇՈԹՌՀՇՄՇԿՑԢՆԼՈՇՁՆՌՋՁՆՌՀԽԞԪԞՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ԱԴԞՅԽԹՋՍՊԽԼ%ԫԣԡԽՎԽՄՇՈՅԽՆՌԹՄ԰ՌԹԿԽԥՁՆԼԩՁՅԺԩԽՆԿՌՀԞՋՑՆԻՀՊՇՆՇՍՋԡԽՎԽՄՇՈՅԽՆՌԱՀՑՊՇՁԼԤՊՇՋՋԹՆԼԥՁՋՌՇՈԹՌՀՇՄՇԿՑԡԹՑԡԹՑԡԹՑԡԹՑԡԹՑԡԹՑԡԹՑԪԽԼՁԹՆ ՈԪԽԼՁԹՆ ՈԡՁԾԾ ՈԡՁԾԾ ՈԡՁԾԾ ՈԡՁԾԾ ՈԱՊԽԹՌՅԽՆՌԯԽՄԹՌԽԼԢԾԾԽԻՌՋ!
ԶԽՋԫՇԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ  ԫԞ  ԫԞ  ԫԞ  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԫԞ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ  ԫԞ  ԫԞ   ԫԞ ԫԞ ԫԞ ԫԞ ԫՇ        ԫԞ ԫԞ ԫԞ ԫԞԫՇ       ԫԞ ԫԞ ԫԞ ԫԞԫՇ       ԫԞ ԫԞ ԫԞ ԫԞ ԫՇ԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԧՇՆԻՃՀԽԽՊԽ ԧՇՆԻՃՀԽԽՊԽ ԧՇՆԻՃՀԽԽՊԽ ԡՍՆՆԽՌՌ0Ջ ԫԞԫԞ ԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԡՁԾԾԡՁԾԾԽՊԽՆԻԽԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌ Ո ԥՁՆԼՄՁՅԺՄԽՆԿՌՀՁՋՆՇՊՅԹՄՁՒԽԼՌՇՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰Գԩ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽԤՊՇՏՌՀԢՆԼՈՇՁՆՌՋ  

### ՁՆՌՀԽԞԪԞՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ԱԴԞՅԽԹՋՍՊԽԼ% ԰ՆՇՍՌԳԽՆՌԩԽՆԿՌՀ ԟՇԼՑԴԽՁԿՀՌ

ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ  ԫԞ  ԫԞ  ԫԞ  ԫԞ

԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ        

   

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԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԪԹՆՆԴՀՁՌՆԽՑ ԡՍՆՆԽՌՌ0Ջ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ 

### ԡՁԾԾԽՊԽՆԻԽ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

###  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅՈ ԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄ

 

###  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄ ՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌ Ո 

 

### ԰ՁԿՆՁԾՁԻԹՆՌՄՑԼՁԾԾԽՊԽՆՌ
ՈԻՇՅՈԹՊԽԼՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇ ՄՈՍՋՁՆԿԹՌՌԽՋՌԹՋՋՍՅՁՆԿՍՆԽՉՍԹՄ

ՎԹՊՁԹՆԻԽՎՁԹԪՁԻՊՇՋՇԾՌԢՐԻԽՄ

Ԣ԰ՌՍԼՑԡԽԾՁԻՁԽՆԻՁԽՋ

ԱՀԽՊԽՏԽՊԽՌՏՇՅԹՂՇՊԼԽՎՁԹՌՁՇՆՋՁՆՌՀՁՋՋՌՍԼՑ

ԱՀԽԠԳՇԾՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԼՇՋԽՋԽՐԻԽԽԼԽԼՌՀԽՅԹՐՁՅՍՅԹԻ ԻԽՈՌԹԺՄԽ
ԹԻԻՇՊԼՁՆԿՌՇՌՀԽ

ԬԠ԰ԭԭԞԪԞՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹ

 ԱՀԽՊԽՏԽՊԽ ՋԽՎԽՊԹՄ ԽՆԼՈՇՁՆՌՋ ԾՇՊՏՀՁԻՀ ՌՀԽ ՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄ Ո ԽՊԾՇՊՅԹՆԻԽ ՋՁԿՆՁԾՁԻԹՆՌՄՑ 
Ո

ԽՐԻԽԽԼԽԼՌՀԹՌՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ
ՁԽԡԹՑՋԹՆԼՏԽՌ ՏԽՁԿՀՌԡԹՑ԰ԳԩԡԹՑԥԩԩԹՆԼԡԹՑ

ՆՇՊՅԹՄՁՒԽԼԥԩԩԣՇՊՅՇՋՌՇԾՌՀԽՋԽԽՆԼՈՇՁՆՌՋԹՌՊԽՆԼՌՇՏԹՊԼ ԹՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌ
 Ո 

ՏԹՋԼԽՌԽԻՌԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊ0ՋԹՆԹՄՑՋՁՋԹՆԼՌՀԽՊԽՎՁԽՏԽՊՁՋՆՇՌ ԻԽՊՌԹՁՆՁԾՌՀԽՋՇՄՎԽՆՌՁՆՌԽՊԾԽՊԽԼՏՁՌՀ

ԼԽՌԽԻՌՁՇՆՇԾՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋԼՍԽՌՇՌՀԽՌԽՋՌՅԹՌԽՊՁԹՄԹՄՇՆԽ



ԱՀԽՋԽԼԽՎՁԹՌՁՇՆՋԼՁԼՆՇՌՋՍԺՋՌԹՆՌՁՎԽՄՑՁՅՈԹԻՌՌՀԽՊԽՋՍՄՌՋՇՊՁՆ ՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀԽՋՌՍԼՑԞՄՄՇՌՀԽՊՎԹՄՁԼՁՌՑ

ԹՆԼՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹՏԽՊԽՅԽՌ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԣԯԽՎՁԽՏԽՊ0ՋԠՇՅՅԽՆՌՋ

ԱՀԽՊԽՎՁԽՏԽՊ0ՋԹՆԹՄՑՋԽՋՏԽՊԽԻՇՆԼՍԻՌԽԼԺՑԻՇՅՈԹՊՁՆԿՌՊԽԹՌՅԽՆՌԼԹՌԹՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՏՀԽՊԽԹՋ

ՌՀԽՋՌՍԼՑԹՍՌՀՇՊՋԻՇՅՈԹՊԽԼՌՊԽԹՌՅԽՆՌԼԹՌԹՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇ Մ
ԼՍԽՌՇՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋԺԽՌՏԽԽՆ

ՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՇՊՈՇՇՄԽԼԻՇՆՌՊՇՄԱՀԽՊԽՎՁԽՏ ԽՊԼԽՌԽԻՌԽԼՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋԺԽՌՏԽԽՆ

ՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋԾՇՊՌՀԽԾՇՄՄՇՏՁՆԿԽՆԼՈՇՁՆՌՋԡԹՑՋԹՆԼՏԽՌՏԽՁԿՀՌԡԹՑ԰ԳԩԡԹՑ

ԥԩԩԹՆԼԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩ

ԬՎԽՊՌՀԽԻՇՍՊՋԽՇԾՌՀԽԼԹՑՌԽՋՌՌՀԽԠԳՇԾՌՀԽՅԽԹՋՍՊԽԼՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԾՇՊԹՄՄՇԾՌՀԽՊԽՈՄՁԻԹՌԽ

ՌԹՆՃՋՊԹՆԿԽԼԾՊՇՅՌՇԱՀԽՄՇՏԻՇՆԻԽՆՌՊԹՌՁՇՆՏԹՋՌՀԽ ՇՆՄՑԻՇՆԻԽՆՌՊԹՌՁՇՆՄԽՎԽՄՌՀԹՌՀԹԼԠԳ

ՎԹՄՍԽՋՇԾՌՀԽՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋՌՀԹՌՏԽՊԽԱՀԽՅՁԼԻ ՇՆԻԽՆՌՊԹՌՁՇՆՄԽՎԽՄՀԹԼԠԳՎԹՄՍԽՋՌՀԹՌ

ՊԹՆԿԽԼԾՊՇՅՌՇՏՀՁՄԽՌՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆՀԹԼՌՀԽ ՀՁԿՀԽՋՌԠԳՎԹՄՍԽՋՇԾՌՇ

ԱՀԽՅՁԼԻՇՆԻԽՆՌՊԹՌՁՇՆՇՆՄՑՅՁՆՁՅԹՄՄՑԽՐԻԽԽԼԽԼԼՍԽՌՇՌՀԽԼԽ ԻՊԽԹՋԽՁՆՎԽՋՋԽՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇՆ

ՌԽՋՌԼԹՑԱՀԽԻՇՆԻԽՆՌՊԹՌՁՇՆՇԾՈՊՇՆԹՅՁԼԽՊԹՆԿԽԼՁՆ ՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՌԽՋՌ

ՁՆՁՌՁԹՌՁՇՆ
ԡԹՑԞՋԹՊԽՋՍՄՌԹՅՍԻՀՀՁԿՀԽՊԠԳՎԹՄՍԽՏԹՋԼԽ ՌԽՊՅՁՆԽԼԾՇՊՌՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆՏՀՁԻՀ

ՏԹՋՊԽՈՇՊՌԽԼՌՇԺԽԾՊՇՅՁՆՁՌՁԹՄԻՄՇԿԿՁՆԿՇԾՌՀԽՅՁՐՁՆԿԻԽՄՄԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԬՆԻԽՌՀԽՅՁՐՁՆԿԻԽՄՄՏԹՋԻՄԽԹՊԽԼ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ՁՆ ՌՀԽ ՀՁԿՀ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՄԽՎԽՄՋ ՊԽՌՍՊՆԽԼ ՌՇ ԹՆԼ  ՊԽՅԹՁՆԽԼ ԹՌ չ ՇԾ ՆՇՅՁՆԹՄ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ

ԱՀԽԾՇՄՄՇՏՁՆԿԹՆԹՄՑՌԽՋՏԽՊԽԼԽՌԽԻՌԽԼԼՍՊՁՆԿՌՀԽՈԽՊՁՇԼՁԻՋԻՊԽԽՆ ՁՆԿԹՆԹՄՑՋՁՋՇԾՌՀԽԼՁՄՍՌՁՇՆՏԹՌԽՊԻՀՄՇՊՁԼԽ

ՅԿԩՆՁՌՊԹՌԽ
ՅԿԫԩԺՇՊՇՆ
ՅԿԩԻԹՄԻՁՍ Յ
ՅԿԩՈՇՌԹՋՋՁՍՅ


ՅԿԩՅԹԿՆԽՋՁՍՅ
ՅԿԩՋՇԼՁՍՅ
ՅԿԩՋՍՄԾԹՌԽ
 ՅԿ԰ԩԹՆԼՒՁՆԻ
ՅԿԩ

ԫՇՈԽՋՌՁԻՁԼԽՋՇՊԭԠԟՋՏԽՊԽԼԽՌԽԻՌԽԼ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԦԦԦ ԯԢԣԢԯԢԫԠԢ԰

ԟԹՆՌՄԽԧԞԡՍՅՇՆՌԧԫԣՁՆԻՀԯԞԹՆԼԩՁՆԼԽՊԤ
 ԞՌՄԹՋՇԾԞԺՆՇՊՅԹՄՁՌՁԽՋԞԿՍՁԼԽԾՇՊՌՀԽ

ՈԽՊԾՇՊՅԹՆԻԽՇԾԣԢԱԞԵ

ԠՊՇՍՋԽԠ
ԡԽՌԽՊՅՁՆԹՌՁՇՆՇԾՈՍՊՁՌՑԹՆԼՇՊԦԼԽՆՌՁՌՑՇԾԭՊՇՆԹՅՁԼԽ
ԨԽՊԺԱԽԻՀՆՁԻԹՄԩՇՌԵԤԯ

Ա԰ԫ ԾՇՊ ՍՋԽ ՁՆ Թ ԰ՌՍԼՑ ԣԞԭԠ ԫՍՅԺԽՊ  ԡՇՏ ԞԿՊՇ԰ԻՁԽՆԻԽՋ ԩԩԠ

ԦՆԼՁԹՆԹՈՇՄՁՋԦՆԼՁԹՆԹ

ԥՇՄՄԹՆԼԽՊԪԹՆԼԴՇՄԾԽԡԞ
ԫՇՆՈԹՊԹՅԽՌՊՁԻ԰ՌԹՌՁՋՌՁԻԹՄ ԪԽՌՀՇԼՋԧՇՀՆԴՁՄԽՑԫԽՏԶՇՊՃ

ԫՁԽՍՏՃՇՇՈԭԡԹՆԼԣԹԺԽՊԧ
ԫՇՊՅԹՄԱԹԺՄԽՇԾԵԽՆՇՈՍՋՄ ԹԽՎՁՋ
ԡԹՍԼՁՆԤԹՊՄԹՆԼԭՍԺՄՁՋՀՁՆԿԫԽՏ

ԶՇՊՃ

ԭԹՊՊՁՋՀԠԣ
԰ՇՄՎԽՆՌՋՁՆԼՍՋՌՊՁԹՄԦՆԤՊԹՑՋՇՆԪԢԻ ՃՊՇՌՀԡԪԹՊՃԥԣԬՌՀՅԽՊԡԣԬՎԽՊԺԽՊԿԽՊ

ԠԤԹՆԼ԰ԽԹԺՇՊԿԤԱԽԼՁՌՇՊՋԨՁՊՃԬՌՀՅԽՊԽՆԻՑԻՄՇՈԽԼՁԹՇԾԻ ՀԽՅՁԻԹՄՌԽԻՀՆՇՄՇԿՑ  ԫԽՏԶՇՊՃԧՇՀՆ

ԴՁՄԽՑ԰ՇՆՋԦՆԻՈ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  ԞԭԭԢԫԡԦԵԦԬԲԱԭԲԱԬԣԯԢԳԦԢԴԢԯ0԰԰ԱԞԱԦ԰ԱԦԠԞԩԳԢԯԦԣԦԠԞԱԦԬԫ

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR01 ( 7-d wet weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.970 0.844 3.873 0.038 USE NON-PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.37 0.05 0.03 14.06 0.29, 0.46
Dose1 4 0.36 0.01 0.01 3.62 0.34, 0.38
Dose2 4 0.40 0.05 0.03 13.66 0.31, 0.49
Dose3 4 0.28 0.02 0.01 8.35 0.25, 0.32

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 0.36 0.33 0.44 . .

Dose1 0.36 0.35 0.38 96.78 3.22

Dose2 0.40 0.34 0.46 107.31 -7.31

Dose3 0.28 0.26 0.31 75.86 24.14

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 6.27 0.008

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 0.37 . 0.38 . . . . . .

Dose1 0.36 0.951 0.38 0.657 . . . . .

Dose2 0.40 0.664 0.38 0.692 0.533 . . . .

Dose3 0.28 0.021 0.28 0.005 0.073 0.007 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.07 0.028

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 0.36 . .

Dose1 0.36 1.000 0.500

Dose2 0.40 0.494 0.810

Dose3 0.28 0.067 0.046

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 6.27 0.008

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -0.37 . -0.35 . . . . . .

Dose1 -0.36 0.951 -0.35 0.820 . . . . .

Dose2 -0.40 0.664 -0.35 0.849 0.533 . . . .

Dose3 -0.28 0.021 -0.35 0.864 0.073 0.007 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.07 0.028

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -0.36 . .

Dose1 -0.36 1.000 0.500

Dose2 -0.40 0.494 0.190

Dose3 -0.28 0.067 0.954

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR02 ( 7-d stage (median) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.652 <.001 3.000 0.073 USE NON-PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 53.75 0.50 0.25 0.93 52.95, 54.55
Dose1 4 53.75 0.50 0.25 0.93 52.95, 54.55
Dose2 4 53.75 0.50 0.25 0.93 52.95, 54.55
Dose3 4 53.00 0.00 0.00 0.00 . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 54.00 53.00 54.00 . .

Dose1 54.00 53.00 54.00 100.00 0.00

Dose2 54.00 53.00 54.00 100.00 0.00

Dose3 53.00 53.00 53.00 98.60 1.40

***************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 6.43 0.093

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 54.00 . .

Dose1 54.00 1.000 0.500

Dose2 54.00 1.000 0.500

Dose3 53.00 0.102 0.025

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  test for amphib metamorph screen study - Propyzamide
ANALYSIS RESULTS FOR VARIABLE VAR03 ( 7-d sn-vent length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.903 0.090 0.855 0.491 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 15.55 1.07 0.53 6.86 13.85, 17.25
Dose1 4 15.89 0.47 0.24 2.98 15.13, 16.64
Dose2 4 15.79 0.93 0.46 5.86 14.32, 17.26
Dose3 4 14.00 0.71 0.35 5.04 12.87, 15.12

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 15.25 14.70 17.00 . .

Dose1 15.78 15.50 16.49 102.17 -2.17

Dose2 15.50 15.08 17.08 101.54 -1.54

Dose3 14.02 13.28 14.66 90.00 10.00

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 4.62 0.023

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 15.55 . 15.74 . . . . . .

Dose1 15.89 0.889 15.74 0.714 . . . . .

Dose2 15.79 0.954 15.74 0.749 0.998 . . . .

Dose3 14.00 0.051 14.00 0.012 0.031 0.041 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  3 8.93 0.030

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 15.25 . .

Dose1 15.78 0.678 0.718

Dose2 15.50 0.494 0.670

Dose3 14.02 0.067 0.025

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 4.62 0.023

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -15.55 . -15.31 . . . . . .

Dose1 -15.89 0.889 -15.31 0.746 . . . . .

Dose2 -15.79 0.954 -15.31 0.779 0.998 . . . .

Dose3 -14.00 0.051 -15.31 0.797 0.031 0.041 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 8.93 0.030

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -15.25 . .

Dose1 -15.78 0.678 0.282

Dose2 -15.50 0.494 0.330

Dose3 -14.02 0.067 0.975

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR04 ( 7-d hind-limb length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.844 0.011 0.843 0.496 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 2.02 0.21 0.11 10.63 1.68, 2.36
Dose1 4 2.02 0.12 0.06 5.72 1.84, 2.20
Dose2 4 2.00 0.22 0.11 11.05 1.64, 2.35
Dose3 4 1.72 0.13 0.06 7.46 1.51, 1.92

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1.93 1.88 2.34 . .

Dose1 2.02 1.88 2.16 100.00 0.00

Dose2 1.91 1.84 2.32 98.76 1.24

Dose3 1.71 1.58 1.86 84.90 15.10

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 2.85 0.082

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 2.02 . 2.02 . . . . . .

Dose1 2.02 1.000 2.02 0.583 . . . . .

Dose2 2.00 0.994 2.00 0.530 0.997 . . . .

Dose3 1.72 0.076 1.72 0.019 0.121 0.166 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 8.35 0.039

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1.93 . .

Dose1 2.02 0.780 0.668

Dose2 1.91 0.674 0.329

Dose3 1.71 0.067 0.007

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 2.85 0.082

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -2.02 . -1.94 . . . . . .

Dose1 -2.02 1.000 -1.94 0.821 . . . . .

Dose2 -2.00 0.994 -1.94 0.850 0.997 . . . .

Dose3 -1.72 0.076 -1.94 0.865 0.121 0.166 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 8.35 0.039

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1.93 . .

Dose1 -2.02 0.780 0.332

Dose2 -1.91 0.674 0.671

Dose3 -1.71 0.067 0.993

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide
ANALYSIS RESULTS FOR VARIABLE VAR05 ( 7-d norm hind-limb )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.929 0.232 0.666 0.589 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.13 0.01 0.00 4.65 0.12, 0.14
Dose1 4 0.13 0.00 0.00 3.44 0.12, 0.13
Dose2 4 0.13 0.01 0.00 5.30 0.12, 0.14
Dose3 4 0.12 0.00 0.00 2.65 0.12, 0.13

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 0.13 0.12 0.14 . .

Dose1 0.13 0.12 0.13 98.47 1.53

Dose2 0.12 0.12 0.14 97.79 2.21

Dose3 0.12 0.12 0.13 95.34 4.66

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 0.91 0.466

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 0.13 . 0.13 . . . . . .

Dose1 0.13 0.910 0.13 0.360 . . . . .

Dose2 0.13 0.786 0.13 0.292 0.995 . . . .

Dose3 0.12 0.292 0.12 0.085 0.705 0.830 . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  *****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 3.51 0.320

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 0.13 . .

Dose1 0.13 0.780 0.332

Dose2 0.12 0.346 0.170

Dose3 0.12 0.156 0.034

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences)

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 0.91 0.466

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -0.13 . -0.13 . . . . . .

Dose1 -0.13 0.910 -0.13 0.839 . . . . .

Dose2 -0.13 0.786 -0.13 0.867 0.995 . . . .

Dose3 -0.12 0.292 -0.13 0.881 0.705 0.830 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 3.51 0.320

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -0.13 . .

Dose1 -0.13 0.780 0.668

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Dose2 -0.12 0.346 0.830

Dose3 -0.12 0.156 0.966

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR06 ( 21-d stage (median) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.842 0.010 1.636 0.233 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 59.00 0.00 0.00 0.00 . , .
Dose1 4 59.25 0.50 0.25 0.84 58.45, 60.05
Dose2 4 59.00 0.82 0.41 1.38 57.70, 60.30
Dose3 4 57.25 0.50 0.25 0.87 56.45, 58.05

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 59.00 59.00 59.00 . .

Dose1 59.00 59.00 60.00 100.42 -0.42

Dose2 59.00 58.00 60.00 100.00 0.00

Dose3 57.00 57.00 58.00 97.03 2.97

***************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 10.24 0.017

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 59.00 . .

Dose1 59.00 0.478 0.841

Dose2 59.00 1.000 0.539

Dose3 57.00 0.049 0.008

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Jonckheere Dose3

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR07 ( 21-d wet weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.962 0.696 0.848 0.494 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.59 0.09 0.04 5.43 1.46, 1.73
Dose1 4 1.07 0.12 0.06 11.21 0.88, 1.26
Dose2 4 1.14 0.06 0.03 5.35 1.04, 1.23
Dose3 4 1.23 0.07 0.03 5.28 1.13, 1.34

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1.63 1.47 1.66 . .

Dose1 1.02 1.00 1.25 67.13 32.87

Dose2 1.12 1.09 1.22 71.22 28.78

Dose3 1.22 1.17 1.32 77.22 22.78

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 29.36 <.001

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 1.59 . 1.59 . . . . . .

Dose1 1.07 <.001 1.15 <.001 . . . . .

Dose2 1.14 <.001 1.15 <.001 0.714 . . . .

Dose3 1.23 <.001 1.15 <.001 0.088 0.431 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 10.62 0.014

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1.63 . .

Dose1 1.02 0.067 0.010

Dose2 1.12 0.067 0.039

Dose3 1.22 0.067 0.187

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose1 Jonckheere >highest dose (no sign. differences)

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 29.36 <.001

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -1.59 . -1.26 . . . . . .

Dose1 -1.07 <.001 -1.26 1.000 . . . . .

Dose2 -1.14 <.001 -1.26 1.000 0.714 . . . .

Dose3 -1.23 <.001 -1.26 1.000 0.088 0.431 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 10.62 0.014

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1.63 . .

Dose1 -1.02 0.067 0.990

Dose2 -1.12 0.067 0.961

Dose3 -1.22 0.067 0.813

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide
ANALYSIS RESULTS FOR VARIABLE VAR08 ( 21-d sn-vent length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.966 0.771 0.919 0.461 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 26.83 0.53 0.26 1.96 25.99, 27.66
Dose1 4 23.25 0.53 0.26 2.26 22.41, 24.09
Dose2 4 23.90 0.18 0.09 0.76 23.61, 24.19
Dose3 4 24.33 0.67 0.34 2.76 23.26, 25.39

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 26.95 26.10 27.30 . .

Dose1 23.10 22.80 24.00 86.67 13.33

Dose2 23.90 23.70 24.10 89.10 10.90

Dose3 24.25 23.60 25.20 90.68 9.32

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 37.80 <.001

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 26.83 . 26.83 . . . . . .

Dose1 23.25 <.001 23.83 <.001 . . . . .

Dose2 23.90 <.001 23.83 <.001 0.317 . . . .

Dose3 24.33 <.001 23.83 <.001 0.048 0.649 . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  *****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 11.49 0.009

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 26.95 . .

Dose1 23.10 0.067 0.010

Dose2 23.90 0.067 0.062

Dose3 24.25 0.067 0.227

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose1 Jonckheere >highest dose (no sign. differences)

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 37.80 <.001

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -26.83 . -24.58 . . . . . .

Dose1 -23.25 <.001 -24.58 1.000 . . . . .

Dose2 -23.90 <.001 -24.58 1.000 0.317 . . . .

Dose3 -24.33 <.001 -24.58 1.000 0.048 0.649 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 11.49 0.009

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -26.95 . .

Dose1 -23.10 0.067 0.990

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Dose2 -23.90 0.067 0.938

Dose3 -24.25 0.067 0.773

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide ANALYSIS RESULTS FOR VARIABLE VAR09 ( 21-d hind-limb length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.949 0.467 2.616 0.099 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 16.73 0.69 0.34 4.12 15.63, 17.82
Dose1 4 17.30 2.66 1.33 15.39 13.06, 21.54
Dose2 4 15.98 2.25 1.13 14.11 12.39, 19.56
Dose3 4 12.15 1.00 0.50 8.22 10.56, 13.74

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 16.90 15.80 17.30 . .

Dose1 17.40 14.10 20.30 103.44 -3.44

Dose2 15.10 14.40 19.30 95.52 4.48

Dose3 11.80 11.40 13.60 72.65 27.35

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 6.33 0.008

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 16.73 . 17.01 . . . . . .

Dose1 17.30 0.945 17.01 0.673 . . . . .

Dose2 15.98 0.891 15.98 0.367 0.744 . . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Dose3 12.15 0.011 12.15 0.003 0.009 0.054 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.07 0.028

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 16.90 . .

Dose1 17.40 0.889 0.614

Dose2 15.10 0.346 0.232

Dose3 11.80 0.067 0.003

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 6.33 0.008

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -16.73 . -15.54 . . . . . .

Dose1 -17.30 0.945 -15.54 0.880 . . . . .

Dose2 -15.98 0.891 -15.54 0.904 0.744 . . . .

Dose3 -12.15 0.011 -15.54 0.916 0.009 0.054 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.07 0.028

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Ctrl -16.90 . .

Dose1 -17.40 0.889 0.386

Dose2 -15.10 0.346 0.768

Dose3 -11.80 0.067 0.997

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

test for amphib metamorph screen study - Propyzamide
ANALYSIS RESULTS FOR VARIABLE VAR10 ( 21-d norm hind-limb )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric
analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.957 0.603 2.345 0.124 USE PARAMETRIC TESTS

*****************************************************************************

***

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.63 0.02 0.01 3.43 0.60, 0.66
Dose1 4 0.75 0.11 0.05 14.11 0.58, 0.92
Dose2 4 0.67 0.10 0.05 14.26 0.52, 0.82
Dose3 4 0.49 0.05 0.02 10.24 0.41, 0.57

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 0.63 0.61 0.66 . .

Dose1 0.77 0.61 0.85 119.05 -19.05

Dose2 0.64 0.60 0.81 106.35 -6.35

Dose3 0.47 0.45 0.56 77.38 22.62

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 8.30 0.003

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 0.63 . 0.69 . . . . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Dose1 0.75 0.111 0.69 0.916 . . . . .

Dose2 0.67 0.802 0.67 0.870 0.477 . . . .

Dose3 0.49 0.054 0.49 0.013 0.002 0.024 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.59 0.022

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 0.63 . .

Dose1 0.77 0.283 0.904

Dose2 0.64 1.000 0.587

Dose3 0.47 0.067 0.018

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose3

Jonckheere Dose3

*****************************************************************************

*** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

3 12 8.30 0.003

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -0.63 . -0.63 . . . . . .

Dose1 -0.75 0.111 -0.64 0.537 . . . . .

Dose2 -0.67 0.802 -0.64 0.571 0.477 . . . .

Dose3 -0.49 0.054 -0.64 0.589 0.002 0.024 . . .

*****************************************************************************

*** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

3 9.59 0.022

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  Level Median MannWhit p-value Jonckheere p-value

Ctrl -0.63 . .

Dose1 -0.77 0.283 0.096

Dose2 -0.64 1.000 0.413

Dose3 -0.47 0.067 0.982

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN

CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  

### ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϳtĞƚtĞŝŐŚƚ EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ Ϭ͘ϯϳϮΘϬρ Ϭ͘κεϯϳςρ

sĂƌŝĂŶĐĞ Ϭ͘ϬϬϮϳκϳΘκϳ Ϭ͘ϬϬϮϯΘεϳεκ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ς 

ƚ^ƚĂƚ Ͳϯ͘ϯϳρϭϮρϭΘκ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬϬϳκϳϯϳρ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů ϭ͘εκϯϭΘϬϮϳκ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘Ϭϭκεκϳκεε

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘κκςεϭϭΘκς 

ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϳ^s> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ ϭρ͘ρς ϭϳ͘ρϭϭϯϳρ

sĂƌŝĂŶĐĞ ϭ͘ϭϭϬςςςςςϳ Ϭ͘ϯϬϮϯρϳρςϮ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ρ 

ƚ^ƚĂƚ Ͳϯ͘ϮΘϯϭΘεϯϯϮ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬϭϬεϯΘςςϳ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů Ϯ͘ϬϭρϬκΘϯϳϮ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϬϮϭΘϳϳϯϯκ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘ρϳϬρΘϭΘϯρ 

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  

### ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϳ,>> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ Ϯ͘ϬϮ Ϯ͘Ϯϯ

sĂƌŝĂŶĐĞ Ϭ͘Ϭκςϭϯϯϯϯϯ Ϭ͘Ϭϯϳκςςςςϳ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ς 

ƚ^ƚĂƚ Ͳϭ͘κρϮςϬϬϯϳκ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬεΘϮϳϯεϭε 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů ϭ͘εκϯϭΘϬϮϳκ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϭεςρκϳΘϯϳ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘κκςεϭϭΘκς 

ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϳEŽƌŵĂůŝnjĞĚ,>> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ Ϭ͘ϭϮΘϳκϭκϬϭ Ϭ͘ϭϮςςρεϭεϮ

sĂƌŝĂŶĐĞ ϯ͘ρρϳϬϭͲϬρ Θ͘ςϭϭρϳͲϬρ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ρ 

ƚ^ƚĂƚ Ϭ͘ϯϳϳρϭρϯκΘ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϯςϬςκϮϮεϭ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů Ϯ͘ϬϭρϬκΘϯϳϮ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϳϮϭϮΘκρΘϭ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘ρϳϬρΘϭΘϯρ 

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  

### ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϮϭtĞƚtĞŝŐŚƚ EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ ϭ͘ρεκϳκκεϭΘ ϭ͘εΘϬϯΘϮςϳϯ

sĂƌŝĂŶĐĞ Ϭ͘ϬϬϳρϭϯΘρκ Ϭ͘ϬϮϮϯϳεϳϭϭ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ρ 

ƚ^ƚĂƚ Ͳκ͘κςϬΘΘϭρ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬϬϯϯϭϳρϮϭ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů Ϯ͘ϬϭρϬκΘϯϳϮ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϬϬςςϯρϬκϯ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘ρϳϬρΘϭΘϯρ   

ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϮϭ^s> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ Ϯς͘ΘϯρϬϯκϯκ Ϯϳ͘ςΘϬεκρϯρ

sĂƌŝĂŶĐĞ Ϭ͘ϮϳϭϯςρΘΘρ Ϭ͘ΘςεΘϬϳϳϯϮ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ρ 

ƚ^ƚĂƚ Ͳϭ͘ρΘϯϳϮϭκΘε 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬΘϳϬρϯΘεϯ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů Ϯ͘ϬϭρϬκΘϯϳϮ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϭϳκϭϬϳϳΘϳ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘ρϳϬρΘϭΘϯρ  

ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϮϭ,>> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ ϭς͘ϳϭϳρκΘϬΘ ϮϬ͘ϬΘΘϯϭεΘϭ

sĂƌŝĂŶĐĞ Ϭ͘κΘεϬϮϮϭςκ Ϭ͘ϳκεϬϬϯςϳϳ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ  

### KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ ς 

ƚ^ƚĂƚ Ͳς͘ϬρΘεϬεϳρ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬϬϬκρΘϭϯε 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů ϭ͘εκϯϭΘϬϮϳκ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϬϬϬεϭςϮϳϳ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘κκςεϭϭΘκς  

ƚͲdĞƐƚ͗dǁŽͲ^ĂŵƉůĞƐƐƵŵŝŶŐhŶĞƋƵĂůsĂƌŝĂŶĐĞƐ   ĂLJϮϭEŽƌŵĂůŝnjĞĚ,>> EĞŐŽŶƚƌŽů ^ŽůŽŶƚƌŽů

DĞĂŶ Ϭ͘ςϯϭκϭΘϳϯϭ Ϭ͘ϳϯϳϳςεϮϮΘ

sĂƌŝĂŶĐĞ Ϭ͘ϬϬϬρϳΘςϯς Ϭ͘ϬϬϮΘςϬρρ

KďƐĞƌǀĂƚŝŽŶƐ κ κ
,LJƉŽƚŚĞƐŝnjĞĚDĞĂŶŝĨĨĞƌĞŶĐĞ Ϭ 

ĚĨ κ 

ƚ^ƚĂƚ Ͳϯ͘ςϮςερϬΘΘρ 
W;dфсƚͿŽŶĞͲƚĂŝů Ϭ͘ϬϭϭϭϬεεϭρ 

ƚƌŝƚŝĐĂůŽŶĞͲƚĂŝů Ϯ͘ϭϯϭΘκςϳΘϮ 
W;dфсƚͿƚǁŽͲƚĂŝů Ϭ͘ϬϮϮϮϭεΘϯϭ

ƚƌŝƚŝĐĂůƚǁŽͲƚĂŝů Ϯ͘ϳϳςκκρϭϬρ 

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՊՇՆԹՅՁԼԽՌՇԞՅՈՀՁԺՁԹ ՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ՇԾ 

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE)

Study Type: OCSPP 890.1150, Androgen Receptor Binding (Rat Prostate Cytosol)

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619102)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Sandra Hastings Date: 2 / 14 /2012

Secondary Reviewer Signature: Michelle Sharpe

- Kass, M.S. Date: 2/20 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 2 / 27 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 2/27 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 battery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with

the E , A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE/ 101701 Androgen Receptor Binding (Rat Prostate Cytosol) (2012) I Page I of 13

OCSPP 890.1150/ OECD None



## Primary Reviewer: Patience Browne, Ph.D.



## Health Effects Division,

. Office of Pesticide**Progr~ms** 

## Secondary Reviewer: Greg Akerman, Ph

. D.



## Health Effects Division, Office of Pesticide Programs

# Signatu~ .e__.

# Date:~~ Signature:
e 

## Date:

# ~20ii2 Template version 08/2011



## DATA EVALUATION RECORD

STUDY TYPE: Androgen Receptor Binding (Rat Prostate Cytosol) ; OCSPP 890.1150



## PCCODE: 101701 

## DP BARCODE: D398506



## TXR#: 0056255 

## CAS No.: 23950-58-5



## TEST MATERIAL (PURITY): Pronamide (96

. 2% a.i.)



## SYNONYMS: Propyzamide; 3

, 5-dichloro-N-(1

, 1-dimethyl-2-propynyl)benzamide



## CITATION: LeBaron

, M.J.

, Schisler

, M

. R.

, and Visconti, N

. R. (2012)

. Evaluation of

Pronamide In An In Vitro Androgen Receptor Binding Assay. The Dow

Chemical Company

, Toxicology & 

## Environmental Research and Consulting,

Midland

, MI. Laboratory Project Study ID 111096

, January 3

, 2012. MRID

48619102. Unpublished.



## SPONSOR: Dow AgroSciences LLC

, 9330 Zionsville Rd., Indianapolis

, IN



## TEST ORDER#: CON-101701-37



## EXECUTIVE SUMMARY: In an androgen receptor (AR) binding assay (MRID 48619102)

,

v entral prostate cytosol from Sprague Dawley rats was used as the source of AR to conduct a competitive binding experiment, which was conducted to measure the binding of a single

concentration of [ 3 

## H]-R1881 (1 nM) in the presence of increasing concentrations ofpronamide ( 96.2 % purity; logarithmic increase from 10

- 1 0 

## to 10

- 3 

## M). Ethanol was used as a solvent at a
final concentration of < 3 %. No precipitation of pronamide was noted. The assay included

dexamethasone as a weak positive control, and Rl 881 as the ligand reference standard.

A saturation binding experiment was conducted to demonstrate that the AR in the rat prostate cytosol was present in reasonable numbers and was functioning with appropriate affinity for the

radio-labeled reference androgen (Rl 881) prior to conducting AR competitive binding

e xperiments. The saturation binding experiment was conducted in duplicate and summari z ed in a submitted stud y profile (MRID 48619102)

. In the saturation binding experiments

, the maximum binding capacity (Bm ax ) was 3.245 fmol/l 00 μg protein and the dissociation constant (Kd) 

## was 0.4641 nM ; both values were below the acceptable ranges determined in the validation studies.

The Scatchard plot showed a linear response across the concentrations of ligand added. Nonspecific binding as a percent of total binding was less than 20% across the entire

concentration range in the saturation binding assays (range 6.2-19.8%), with the exception of the high concentration (10 nM) in one assay, which was 24.6%.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 2 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## In the c ompetitive binding e xperiment

, the mean l og IC 50 

## s for R1881 and the weak positive control (dexamethasone) were

− 9.0 and

− 4.5 M, respectively. The mean relative binding affinity ( RBA ) for the weak positive control was 0.0034%. The solvent control responses indicated no drift in the study assay. All performance criteria were met, with the exception of the bottom (% binding) of R1881 in Assay #3, which was low (

− 3.6 versus

− 2.0). Spec ific [ 3 

## H] -R1881 binding in the presence of pronamide was >75% at all concentrations tested , therefore, a n IC 50 

## and RBA could not be calculated for pronamide.

Based on the results from the three runs, pronamide is classified as a Non -binder in the Androgen Receptor Binding Assay.

The assay satisfies the EDSP Tier 1 Test Order requirements for an Androgen Receptor Binding Assay (OCSPP 890.1150).

COMPLIANCE : Signed and dated GLP and Quality Assurance statements were provided.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 3 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : The Dow Chemical Company, Toxicology & Environmental Research and Consulting

Location: Midland, MI 48674 Study Director: Schisler, M.R.

Other Personnel: LeBaron, M.J. (Lead Scientist), Visconti, N.R.(Research Biologist), Gollapudi, B.B. (Technical reviewer) Study Period: June 16, 2011

– June 24, 2011



## 2

. Test substance : Pronamide

Description: Technical; powder white to off

- white

Source: DowAgroSciences LLC, Indianapolis, IN

Lot #: XG188R301, TSN003588

- 0004 ( expir y date : not reported ) Purity: 96.2 % Solubility : Soluble up to 30 mM in ethanol; insoluble in water Volatility : Not reported Stability: 2 years shelf life Storage conditions: 5°C to ambient

CAS #: 23950

- 58

- 5 Molecular weight: 256.1

Structure:



## 3

. Non

- labeled ligand : R1881

Supplier : Perkin

- Elmer, Boston, MA

Lot #: 614156 Purity: >97 %

CAS #: 965

- 93

- 5



## 4

. Radioactive ligand : [ 3 

## H]

- R1881

Supplier : Perkin

- Elmer, Boston, MA Catalog and Lot #: NET590250UC, Lot# 614814

Date of production: July 1, 2010

Date of use: June 6, 2011 to June 23, 2011 Radiochemical purity: >97 % Specific activity : 85.1 Ci /m mol

Concentration of stock : 1.0 m Ci/m L



## 5

. Positive control : Dexamethasone

Supplier : Sigma, St. Louis, MO

Lot # : BCBC9269 Purity: 98.9%

CAS # : 50

- 02

- 2



## 6

. Solvent/vehicle control : Ethanol

Justification for choice of

solvent : Not soluble in water

Final Concentration : <3%Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 4 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## B. METHODS

1. Preparation of Rat Ventral Prostate Cytosol : The rat ventral prostate tissue was purchased from Charles River Laboratories (Wilmington, MA). Male Sprague Dawley rats (number not reported) were castrated at approximately 90 days of age and euthanized approximately 24 hours later. The ventral prostat e tissues were collected and stored at approximately

− 80°C until use, and were processed as a batch and used for multiple studies.

The cytosol was prepared by adding low-salt TEDG buffer [0.01 M Tris, 1 mM sodium molybdate, 1.5 mM EDTA, 10% glycerol and 1 mM phenylmethylsulfonyl fluoride (PMSF) with dithiothreitol (DTT) ] at pH 7.4 to the ventral prostate tissues at 10 mL/g of tissue. The tissues were minced, homogenized on ice, and centrifuged for 30 min at 30,000 × g at 4°C. The supernatant was collecte d, pooled from all tissues, aliquoted (amounts not reported) and

stored at

− 80°C until used. Protein concentration of the cytosol prepared for this study was determined to be 6.566 mg/mL using the Pierce BCA method ( Thermo Scientific Pierce Research Lab, Rockford, IL)

.

2. Saturation Radioligand Binding Experiment : A saturation binding experiment measuring total and non-specific binding of [ 3 

## H] -R1881 was performed to demonstrate that the AR was present in reasonable concentrations and had the appropriate affinity for the R1881 ligand. The conditions for the saturation binding experiment are summarized in

Table 1.

TABLE 1. Summary of Conditions for Saturation Binding Experiment a


### Source of receptor Rat prostate cytosol
Concentration of radioligand (as se rial dilutions) 0.25

- 10 nM

Concentration of non

- labeled ligand (100X [radioligand]) 25

- 1000 nM
Optimization of receptor concentration Sufficient to bind 8.6

- 9.0% b 

### of radioligand

at 0.25 nM
Temperature ~2

- 8 oC

Incubation time ~16 hours
Composition of assay buffer (TEDG) Tris 10 mM (pH 7.4)

EDTA 1.5 mM
Glycerol 10%
Phenylmethylsulfonyl fluoride 1.0 mM

DTT 1.0 mM

a Data were not included in the study report, but are reported in the study profile (registrant ’s DER for MRID 48619102).

b As indicated in the guideline for acceptable assay performance the receptor concentration bound less than 25 to

35% of the radiolabeled R1881.



## On the day of the assay, the specific activity of the stock solution [ 3 

## H] -R1881 was not adjusted for decay over time, and serial dilutions in TEDG buffer were prepared to achieve the final concentrations in cytosol of 0.25, 0.5, 0.7, 1.0, 1.5, 2.5, 5.0, and 10.0 nM to determine total binding. To determine non-specific binding, solutions of non-labeled R1881

were prepa red in a similar manner to achieve concentrations that were 100-fold greater than each respective radiolabeled concentration, resulting in final concentrations in cytosol of 25, 50, 70, 100, 150, 250, 500, and 1000 nM. In the absence of cytosol, the radiation found inAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 5 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## 7.5, 15, 21, 30, or 45 μL of 10 nM [ 3 

## H] -R1881 and 7.5, 15, or 30 μL of 100 nM [ 3 

## H] -R1881 was measured. For each batch of cytosol, the optimal protein concentration was determined by calculating specific binding to differing amounts of protein per tube, using 0.25 nM radiolabeled R1881. The optimal protein concentration was determined to be 1.97 mg protein/assay tube, which resulted in the binding of 8.6-9.0% of the total radioactivity added. As indicated in the guideline for acceptable assay performance the receptor

concentration bound less than 25 to 35% of the radiolabeled R1881

. 

## Cytosolic protein used in this assay was thawed fresh for this experiment at ~4°C and maintained at ~4°C during the binding assay. Each run contained three concur rent replicates at each concentration, resulting in the 72 samples depicted in Table 2.

TABLE 2. Saturation Binding Experiment Run a, b



### Total Binding Non

- Specific Binding Radioligand alone

Tubes 1

- 24 c 

### Tubes 25

- 48 d 

### Tubes 49

- 72 e


### [ 3 

### H]

- R1881

Final conc. (nM) [ 3 

### H]

- R1881 Final conc. (nM) R1881 Final conc. (nM) [ 3 

### H]

- R1881 Initial conc. (nM) [3H]

- R1881 (μL)

0.25 0.25 25 10 7.5

0.50 0.50 50 10 15

0.70 0.70 70 10 21

1.00 1.00 100 10 30

1.50 1.50 150 10 45

2.50 2.50 250 100 7.5

5.00 5.00 500 100 15

10.00 10.00 1000 100 30

a Data were not included in the study report, but are reported in the study profile (registrant’s DER for MRID 48619102).

b Each concentration was run in triplicate for a total of 72 samples.

c Tubes 1

- 24 contained 50 μL of triamcinolone acetonide and 7.5

- 45 μL [ 3 

### H]

- R1881. Samples were dried, and 300 μL of prostate cytosol were added.

d Tubes 25

- 48 contained 50 μL of triamcinolone acetonide and 7.5

- 45 μL [ 3 

### H]

- R1881. R1881 was added in a

100

- fold molar excess of [ 3 

### H]

- R1881 in a volume of 7.5

- 45 μL. Samples were dried, and 300 μL of prostate cytosol were added.

e Tubes 49

- 72 contained only 7.5, 15, 21, 30, or 45 μL of 10 nM [ 3 

### H]

- R1881 or 7.5, 15, or 30 μL of 100 nM
[ 3 

### H]

- R1881 without cytosol or other components to determine the total counts added.



## Following addition of triamcinolone acetonide, [ 3 

## H] -R1881, and/or R1881, the tubes were dried, dissolved in diluted prostate cytosol (300 μL), and incubated for approximately 16

hours at 2- 8°C. Samples were maintained at temperatures of ~4°C except during whole rack vortexing. To separate bound from free R1881, hydroxyapatite (HAP) slurry was added to each tube and vortexed once every 5 minutes for 20 minutes. The samples were then centrifuged, and the supernatant was aspirated and d iscarded. The samples were washed 3 times in 50 mM TRIS buffer. Following the last wash and decanting of the Tris buffer, pellets were then extracted by addition of 2 m L ethanol. The samples were vortexed 3 times at 5 minute intervals. Samples were maintained on ice at all times between vortexing. Each ethanol supernatant was then decanted into a scintillation vial, and the radiation was quantified by liquid scintillation counting. A total of 4 runs were performed on 2 batches of

c ytosol with similar r esults. For the batch of cytosol used for the competitive assay, 2 runs were performed rather than three runs as recommended in the test guideline; however, both runs had highly similar binding profiles.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 6 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## 3. Competitive Binding Experiment : A summary of the assay conditions for the c ompetitive binding e xperiment is included in Table 3.

TABLE 3. Summary of Conditions for Competitive Binding Experiment a


### Source of receptor Rat ventral prostate cytosol
Concentration of radioligand 1 nM
Optimization of receptor c oncentration Sufficient to bind 5.3

- 5.8 % of 1.0 nM radioligand b



### Concentration of test substance (as serial dilutions) 10

− 10 

### to 10

− 3 

### M
Incubation Temperature 4

- 8 oC

Incubation time Overnight
Composition of assay buffer Tris 0.01 M (pH 7.4)

EDTA 1.5 mM
Glycerol 10% (v/v)
Phenylmethylsulfonyl fluoride

with DTT 1 mM

Sodium molybdate 1 mM

Protease inhibitor 60 μM

a Data were obtained from page s 16, 20, and 21 of the study report.

b Data obtained from pages 39, 41 and 43 of the study report. Protein concentrations (μg/tube) were not reported

.



## The c ompetitive binding e xperiment was performed according to the protocol provided in

the EPA Test Guidelines OCSPP 890.1150. The c ompetitive binding e xperiment measures the binding of a single concentration of [ 3 

## H]

- R1881 (specific activity of 85.1 Ci/mmol) to the AR in the presence of increasing concentrations of a test substance.

Ethanol was used as the solvent vehicle, and the solubility of the test material in the vehicle and assay buffer was evaluated visually. No precipitation was noted.

It was reported that the results from the saturation binding experiment demonstrated that 6.566 mg/ml or 1.97 mg/assay tube of cytosolic protein contained enough receptor to bind no more than 10-15% of the [ 3 

## H] -R1881, and that non- specific binding met the guideline recommended value of <20%. In the competitive binding experiment, the amount of cytosolic protein used in the assay contains enough receptor to bind 5.3-5.8 % o f the [ 3 

## H]

- R1881.

Dilutions of the test substance, reference standard (R1881 ), weak positive control (dexamethasone), and solvent control (ethanol) were prepared to achieve the concentrations shown in Table 4. Each assay consisted of three independent runs on three different days, and each run contained duplicate blanks, and three replicates at each concentration of the solvent blank, NSB, reference standard, weak positive control, and test chemical resulting in a total of 77 samples per run. In addition, duplicate blanks followed by six replicates [ 3 

## H]

- R1881 only (for total binding calculations) were run the day before each analysis run (the day of preparation of sample tubes).Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 7 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



### TABLE 4

. Competitor F inal Molar (M) C oncentrations in Competitive Binding Assay a b



### Solvent Control Reference standard Weak positive control Test Chemical None Ethanol R1881 Dexamethasone Pronamide

Tubes 3

- 5 and 72

- 74 Tubes 6

- 2 3 and 7 5

- 7 7 c 

### Tubes 2 4

- 4 7 Tubes 48

- 71 Tubes 1

- 2

1×10

− 6 

### 1×10

− 3 

### 1×10

− 3



### 1×10

− 7 

### 1×10

− 4 

### 1×10

− 4



### 1×10

− 8 

### 1×10

− 5 

### 1×10

− 5



### 1×10

− 9 

### 1×10

− 6 

### 1×10

− 6



### 1×10

− 10 

### 1×10

− 7 

### 1×10

− 7



### 1×10

− 11 

### 1×10

− 8 

### 1×10

− 8



### -- 1×10

− 9 

### 1×10

− 9



### -- 1×10

− 10 

### 1×10

− 10



### a Data were obtained from pages 39

- 44 of the study report.

b Each concentration of each chemical was run in triplicate, plus duplicate blanks for a total of 77 tubes per run.

Tubes 3

- 77 contained 50 μL of triamcinolone acetonide and 30 μL [ 3 

### H]

- R1881. Samples were dried, and 300 μL of prostate cytosol were added. T ubes 3

- 77 also contained 10 μL of the solvent control, reference standard (non

- radiolabeled R1881), weak positive control, or test substance, with the exception of Tubes 6

- 8 and 75

- 77 that contained 30 μL of non

- radiolabeled R1881 (used to evaluate non

- spe cific binding). Six tubes analyzed the day prior to each run analysis contained only 30 μL of [ 3 

### H]

- R1881 to determine ligand activity.

c Tubes 6

- 8 and 75

- 77 were used to evaluate non

- specific binding by adding 100x of cold (non

- radiolabeled)

R1881.



## Sample tubes were stored overnight at 4-8°C in the dark to allow the reaction to reach equilibrium, bound R1881 was separated from free R1881 by washing with buffer and extraction with ethanol, followed by scintillation counting of bound [ 3 

## H] -R1881.

4. Da ta Analysis : The top and bottom of the curve, Hill slope, inhibition concentration (IC 50 

## ), and standard deviations were assessed using GraphPad Prism v. 5, and the data were graphed using a “one site binding” non- linear regression

.



## 5. Definitions

a. Classification of test material

If the data fit a 4 -parameter nonlinear regression model , the test chemical is classified as :

Binder : The average curve for the test chemical across runs crosses 50% of radioligand

bound.

Equivocal : The average lowest portion of curves across runs is between 50% and 75% radioligand binding ( i.e. radioligand displacement is at least 25% but less than 50%), or the curve falls outside the range for the weak positive control (

− 0.6 to

− 1.4).

Non

- Binder : The average lowest portion of curves across runs is greater than 75% activity ( i.e. less than 25% displacement of radioligand), or the data do not fit the model.

Untestable: If the test compound is not soluble above 1×10

− 6 

## M and the binding curve does not cross 50%, the ch emical is judged to be untestable.

b. Descriptors for receptor bindingAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 8 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## B max 

## : maximal binding capacity

K d 

## : dissociation constants

IC 50 

## : Concentration of the test substance at which 50% of radioligand is displaced from the AR by the competitor


## Relative Binding Affinity (RBA) : IC 50 

## of R1881 × 100 ÷ IC 50 

## of test substance

II. RESULTS

SATURATION BINDING EXPERIMENT : Saturation binding experiment parameters are presented in Table 5. The dissociation constant (K d 

## ) for [ 3 

## H] -R1881 was 0.4641, and

the estimated B
max 

## (nM) was 0.06392 for the batch of prostate cytosol that was used for this study. The K d 

## and the B
max 

## w ere below the range s reported in the EPA validation program (0.685-1.57 nM for K d 

## and 7-16 fmol/μg protein for B
max 

## ). Both runs provided similar

results and had goodness of fit (R 2 

## ) values of 0.9871 and 0.9937.

TABLE 5 . Saturation Binding Experiment of R

- 1881 with Androgen Receptor from Rat Prostate Cytosol a



### Parameter Run 1 b 

### Run 2 b 

### Run 3 b 

### Mean Runs 1

- 2 c



### R 2 

### (unweighted) 0.9937 0.9871 ND 0.9871

- 0.9937

B max 

### (nM) 0.06194 0.06590 ND 0.06392

B max 

### (fmol/100 μg protein) 3.146 3.343 ND 3.245

K d 

### (nM) 0.4359 0.4922 ND 0.4641

a Data were not included in the study report, but are reported as a separate validation report.

b Two saturation runs were performed for this batch of cytosol.

c The range of R 2 

### is reported and the mean is reported for the other parameters.

R 2 

### Goodness of fit for curve calculated for specific binding,

ND N ot determined



## Non -specific, specific, and total binding curves for [ 3 

## H] -R1881 to the androgen receptor are presented in Figure 1. The specific binding reached a plateau and the non-specific binding was generally less than 20% of total binding at all concentrations (range 6.2%-19.8%) except at the highest concentration (10 nM) in Run 1 (24.6%). Figure 2 is a Scatchard p lot that illustrates the binding of [ 3 

## H] -R1881 to the androgen receptor. The data fit results in a linear plot.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 9 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## FIGURE 1. Binding of [ 3 

## H] -R1881 to the Androgen Receptor during the Saturation Binding Experiment.

FIGURE 2. Scatchard Plot of the Bindi ng of [ 3 

## H] -R1881 to the Androgen Receptor.

B. COMPETITIVE BINDING EXPERIMENT : The results from the three c ompetitive binding experiments are summarized in Table 6 and shown graphically in Figures 3 and 4.

The estimated mean l og IC 50 

## for pronamide could not be determined as it did not result in 50% inhibition at any concentration. The estimated l og IC 50 

## s for R1881 and the weak positive control (dexamethasone) were

− 9.0 and

− 4.5 M , respectively . The mean RBA for the positive control was 0.0034 %. Confidence in these numbers is high due to the small variation. No precipitation of the test compound was visually observed at any concentration

tested ( ≤10

− 3 

## M). The solvent control responses indicated no drift in the study assay.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 10 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



### TABLE 6 . Competitive Binding Assay of Pronamide with A R from Rat Prostate Cytosol a



### Parameter Run 1 Run 2 Run 3 Mean b



### r 2 

### (unweighted) R1881 1.0000 1.0000 0.9981 0.9981

- 1.0000

Positive control 0.9996 0.9997 0.9956 0.9956

- 0.9997

Pronamide 0.8854 0.8600 0.1286 0.1286

- 0.8854
Log IC 50 

### (M) R1881

− 9.009

− 8.949

− 9.051

− 8.996

Positive control

− 4.576

− 4.525

− 4.467

− 4.522

Pronamide NA NA NA NA

IC 50 

### (M) R1881 9.803 × 10

− 10 

### 1.124 × 10

− 9 

### 8.902 × 10

− 10 

### 1.008 × 10

− 9



### Positive control 2.655 × 10

− 5 

### 2.988 × 10

− 5 

### 3.410 × 10

− 5 

### 3.004 × 10

− 5



### Pronamide NA NA NA NA
Log RBA c 

### Positive control

− 4 .4

− 4 .4

− 4 .6

− 4 .5

Pronamide NA NA NA NA
RBA (%) Positive control 0.0037 0.0038 0.0026 0.0034

Pronamide NA NA NA NA

a Data were obtained from page s 32

- 33 of the study report.

b The range is reported for r 2 

### ; the mean is reported for the remaining parameters.

c Calculated by the study reviewer.

NA Not applicable

r 2 

### Goodness of fit

RBA R elative binding affinityAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 11 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## F IGURE 3. Percentage R1881 Bound to the Androgen Receptor in the Presence of Radioinert R1881, Dexamethasone, and Pronamide (Assays 1 – 3).

Assay #1

Assay #2

Assay #3Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 12 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## F IGURE 4. Mean of Percentage R1881 Bound to the Androgen Receptor in the Presence of Pronamide from Three Assays.

C. PERFORMANCE CRITERIA : To ensure that the c ompetitive binding a ssay was functioning properly, each run was evaluated using the following criteria (Table 7) :

T ABLE 7. Criterion a 

### Tolerance Limit(s) b 

### Value Yes No Ligand depletion is minimal. The recommended r atio of total binding in the absence of competitor to total amount

of [ 3 

### H]

- R1881 added per assay tube. ≤15% 5.3

- 5.8% X

Pronamide Top (% binding) 80 to 115 95.2 to 98. 8 X

R1881 fitted curve parameters
Top (% binding) 82 to 114 96.7 to 1 00.9 X Bottom (% binding)

− 2.0 to 2.0

− 3.6 to

− 0.6 c 

### X Hill Slope

− 1.2 to

− 0.8

− 1.1 to

− 0.8 X Weak positive control (dexam e thasone ) fitted curve parameters
Top (% binding) 87 to 106 99.3 to 105.0 X Bottom (% binding)

− 12 to 1 2

− 1.8 to

− 1.1 X Hill Slope

− 1. 4 to

− 0. 6

− 1.0 to

− 0.9 X Saturation Binding Experiment K d 

### (nM) 0.685

- 1.57 0.4641 X

Non

- specific binding (%) ≤ 10.0 6. 65 to 6.88 d 

### X

a Data were obtained from page s 32

- 33 , 39, 41 and 43 of the study report.

b These values represent ranges from the validation study.

c In one run the calculated bottom of the curve was low (

− 3.6%); values were acceptable in the other two runs.

d Values reported for the three NSB tubes at the beginning of each run; does not includ e the three NSB tubes at

the end of the run.

NR Not reported



## Additionally, the curve for the reference material showed that increasing concentrations of unlabeled R1881 displaced [ 3 

## H] -R1881 in a manner consistent with one-site binding, as indicated by a H ill slope of

− 1.1 to

− 0.8. Examination across the runs indicated consistency of the Hill slope, placement along the X-axis, and top and bottom plateaus, except for one run which had a low bottom % binding for the reference material (R1881)

.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2012 ) / Page 13 of 13

PRONAMIDE / 101701 O CSPP 89 0.1150 / OECD None



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : Based on the combined responses in each of three independent androgen receptor binding assays, it was determined that pronamide treatment did not result in significant alterations in the binding o f the reference androgen (R1881) up to the assay limit concentration (1 mM, 10

− 3 

## M). The results of the in vitro androgen receptor binding assay using rat prostate cytosol indicate that, under the conditions of this study, pronamide was negative (non-binding) for androgen receptor binding.

B. AGENCY C OMMENTS : The results of the saturation binding experiment were not reported in the study report; however, summary saturation data including graphs showing specific, non-binding curves for [ 3 

## H] -R1881 to the androgen receptor were reported in a study profile (registrant’s DER for MRID 48619102). The maximum binding capacity (B
max 

## ) was 3.2 fmol/μg protein and the dissociation constant (K d 

## ) was 0.4641 nM. Both the

B max 

## and the K d 

## fell outside of the expected r ange of 7 to 16 fmol/μg protein (B
max 

## ) or 0.685 to 1.57 nM (K d 

## ). Only two saturation binding runs were performed instead of the

recommended three runs.

In the c ompetitive binding experiment, t he mean l og IC 50 

## s for R1881 and the weak positive control (de xamethasone) were

− 9.0 and

− 4.5 M, respectively. The mean RBA for the weak positive control was 0.0034%. The solvent control responses indicated no drift in the study assay. All performance criteria were met, with the exception of the bottom (% binding) of R1881 in Assay #3 which was low (

− 3.6 versus

− 2.0). Pronamide is classified as “non

binding” as specific radioligand binding was >75% at all concentrations tested. An IC 50 

## and RBA could not be calculated for pronamide.

C. STUDY DEFICIENCIES : The following deficienc ies were noted that are not considered to have had an adverse impact on the results, interpretation or conclusions of this study :

• Th e protein concentration (μg/tube) used in the assay was not reported and radioligand binding (5.3-5.8%) was lower than recommended in the test guidelines (10 -15%).

• The maximum binding capacity (B
max 

## ) and the dissociation constant (K d 

## ) in the saturation binding experiment fell outside of the expected ranges for these parameters

.

• Two runs of the saturation binding experiment were performed on the cytosol preparation used for the competitive binding experiment instead of the recommended three runs/cytosol preparation.

# DATA EVALUATION RECORD

PRONAMIDE ( PROPYZAMIDE )

Study Type: OCSPP 890.1200, Aromatase Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619103)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer : Signature: Rebecca L. Bryan, B.S. Date: 2 / 28 /2012

Secondary Reviewer : Signature:
David A. McEwen, B.S. Date: 3/01/ 2012

Program Manager: Signature: Jack D. Early, M.S. Date: 3 / 02 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 3 / 02 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 battery is based on the strengt hs of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).Aromatase (Human Recombinant) Assay (2012) I Page I of 12

PRONAMIDE I 101701 OCSPP 890.1200 I OECD None



## Primary Reviewer: Vincent Chen M.S.

# Signature:~ Health Effects Division (7509P) Date: e._y :rvA.J7-.VJ-5 

## Secondary Reviewer: Greg Akerman Ph.D. Signature:

7 

# -?c-.4

Risk Assessment Branch III, Health Effects Division (7509P) Date: G 

## /..J.r-/p--

Template version 08/2011



## DATA EVALUATION RECORD

STUDY TYPE: Aromatase (Human Recombinant); OCSPP 890.1200

PC CODE: 101701 DP BARCODE: 0398506

TXR: 0056255 CAS: 23950-58-5

TEST MATERIAL (PURITY): Pronamide (96.2% a.i

. )

SYNONYMS: RH-23315, Propyzamide

IUPAC: 3,5-dichloro-N-(1, 1-dimethylprop-2-ynyl)benzamide

CAS: 3

, 5-dichloro-N-(1

, l-dimethyl-2-propynyl)benzamide

CITATION: Coady, K.K. and Kan, H

. L. (2012) Evaluation of Pronamide in the Human

Recombinant Aromatase Assay. Toxicology & 

## Environmental Research and Consulting (The Dow Chemical Company [Midland

, MI 48674, USA]). Laboratory Study ID: 101012. 04 Jan 2012

. MRID 48619103. Unpublished.

SPONSOR: Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN

TEST ORDER: CON-101701-37

EXECUTIVE SUMMARY: In an in vitro 

## aromatase (CYP 19) assay (MRID 48619103), pronamide (96.2% a.i

., batch/lot# XG 1088R301) was incubated with human recombinant

aromatase and tritiated androstenedione**(1-~** 

## [ 3 

## H(N)]-androst-4-ene-3, 17-dione ([3H]ASDN)) in dimethyl sulfoxide (DMSO) at serial log concentrations of 10

- 10 

## to 10

- 3 

## M (or 10

- 33 

## M) for 15

minutes at 37 ° C to assess the potential of pronamide to inhibit aromatase activity. After completion of the first run
, the data were reviewed and precipitation of pronamide was observed

at the highest concentration tested (10

- 3 

## M). The highest concentration for the second and third

runs was set at the highest concentration that appeared to be soluble with mid-log concentrations (10- 33 

## M), to define the lower portion of the curve.

Aromatase activity was determined by measuring the amount of tritiated water produced at the

end of a 15-minute incubation for each concentration of chemical. Tritiated water was quantified using liquid scintillation counting (LSC). Three runs were conducted and each run included a full activity control

, a background activity control

, a positive control series (10- 10 

## to 10

- 5 

## M) using a known inhibitor ( 4-hydroxyandrostenedione; 4-0H ASDN)

, and the pronamide series (10

- 10 

### 10 

## 10

- 33 

## M) with 3 repetitions per concentration.

Aromatase activity in the full activity controls ranged from 0.244 to 0.493 nmol

· mgprotein

- 1

· min

- 1 for the three test runs, with a mean and standard deviation of 0

. 342±0.108Aromatase (Human Recombinant) Assay (2012 ) / Page 2 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## . Activity in the background controls ranged from 0.23 to 0.65% of the

full activity controls. The response of the full activity controls and background controls was acceptable.

Results for the positive control were generally within the recommended ranges for the top of the curve, bottom curve, Hill slope , log IC 50 

## , and coeffici ent of variation (CV) for replicates of each

concentration within runs. For 4- OH ASDN, the estimated log IC 50 

## averaged

− 7.30 M, and the Hill slope was

− 1.11.

For pronamide, aromatase activity averaged 0.343±0.112 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.222±0.029 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the highest successfully tested concentration ( 10

− 3.3 

## M). The data for pronamide were modeled, and the goodness of fit (R 2 

## ) values were 0.74-0.97. The average dose-r esponse curve indicated that the aromatase activity of the test material at concentrations ranging from 10

− 10 

## M to 10 −6 

## M was essentially equivalent to the activity observed in the full activity controls. However, pronamide reduced aromatase activity, on average, to approximately 74% at 10 −4 

## M and 62% at 10 −3.3 

## M. The average lowest portion of the response curve was between 50 and 75% activity (62% at

10

– 3.3 

## M pronamide), indicating that pronamide is an equivocal inhibitor of aromatase.

Based on the data from the average response curve, pronamide is classified as E quivocal for

aromatase inhibition in this assay

.

The assay satisfies the EDSP Tier 1 Test Order requirement s for an Aromatase a ssay (OCSPP 890.1200).

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, and Quality

Assurance statements were provided.Aromatase (Human Recombinant) Assay (2012 ) / Page 3 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test S ubstance : Pronamide Technical Description: White to Off

- white powder

Source: Dow AgroSciences LLC

Lot/Batch #: XG1088R301, TSN003588

- 0004 Purity: 96.2% a.i. Volatility: Not reported Storage C onditions: Ambient Stability: Not reported

Solvent : Dimethyl sulfoxide (DMSO) Solubility (in Test S olvent): Soluble in DMSO up to 0. 05 M Highest Concentration Tested: 10

− 3 M for first run; 10

− 3.3 M for R uns 2 and 3 Stock Solution Preparation Methodology: Dissolved the test material in DMSO

. Molecular W eight: 256.1 g/mol

CAS #: 23950

- 58

- 5

Structure:

Cl Cl O

N H CH 3

C
CH

CH 3



## 2. Non

- L abeled S ubstrate : Androstenedione (ASDN)

CAS # : 63

- 05

- 8

Source: Steraloids, Inc. (Cat. # A6030100)

Lot/Batch #: L1627 Purity: 95.36%



## 3

. Radiolabeled S ubstrate : 1

- β [ 3 H(N)]

- Androst

- 4

- ene

- 3,17

- dione ; ( [ 3 H] ASDN)

Source: Perkin Elmer Life and Analytical Sciences (Cat. # not reported)

Lot/Batch #: 3615304 Radiochemical Purity (Supplier): >97% Specific A ctivity: 20.7 Ci/mmol Radiochemical Purity (In

- Lab

D etermination): Not reported



## 4. Positive C ontrol : 4

- hydroxyandrostenedione (4

- OH ASDN)

CAS # : 566

- 48

- 3

Source: Sigma

- Aldrich (Cat. # F2552)

Lot/Batch #: 081K2133 Purity: 99.6%



## 5. Solvent (V ehicle C ontrol ) : Dimethyl Sulfoxide (DMSO)

Source: Sigma Aldrich (Cat. # D5879)

Lot/Batch #: 037K0766

Justification for C hoice of S olvent : DMSO is a Guideline recommended solvent Concentration (% of Total Volume in

A ssays) : 0.1% v/v



## 6. Test M icrosomes : Human recombinant aromatase ( CYP19 ) microsomes

Source : Gentest (Woburn, MA; Cat. # 456260)

Lot/Batch #: 54390

Protein C oncentration : Not reported, but determined each day of use Cytochrome C reductase activity: Not reported

Aromatase A ctivity: 2.8 pmol/min/pmol P450Aromatase (Human Recombinant) Assay (2012 ) / Page 4 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## B. METHODS

1. Assay C omponent s and Preparations : A mixture of non- labeled and radiolabeled
[ 3 

## H] -ASDN was prepared to result in a 2 μM ASDN solution with a predicted radioactive

content of 1.5 μCi/mL.

Test chemical(s) stock solutions were prepared such that the total volume of each test chemical formulation used per assay was no more than 1% v/v of the total assay volume. The report specified that DMSO was chosen because it was mentioned in the guideline as a preferred solvent and the test material was adequately soluble in this solvent at the specified

concentration.

A stock solution of the positive control substance, 4- OH ASDN, was formulated in DMSO

. Fresh serial dilutions of the stock solution were prepared each time the aromatase inhibition assay was conducted. Dilutions were prepared such that the target concent rations of the positive control substance (10

− 5 

## to 10

− 10 

## M; Table 4) were achieved by the addition of 20 μL of the dilution for a final assay volume of 2 mL.

Human recombinant microsomes were purchased from Gentest , and aliquoted into individual vials based on protein content. Microsomes were stored at approximately

− 80oC

until use.

Other assay components sodium phosphate buffer, propylene glycol, and NADPH are reported in Table 1.

T ABLE 1. Assay Components and Conditions

Assay Factor Values

S odium phosphate buffer (pH 7.4) 0.1M

Microsomal Protein 0.004 mg/mL

NADPH 6 mM

[ 3 H]ASDN 2 μ M Propylene Glycol 100 μL
Temperature 37°C

Incubation Time 15 min



## 2. Suitability Ass es s ments : The protein concentration in an aliquot of the microsomes was determined each day of use, and microsomes were diluted with phosphate buffer such that approximately 0.004 mg/mL protein was present in the final reaction solution. Aromatase activity of the microsomes was provided by the vendor as 2.8 pmol/min/pmol P450 for Lot

No. 54390. The minimum aromatase activity in the full activity control samples was

determined to be 0.257 nmol/mg

- protein/min, which was greater than the minimum acceptable aromatase activity of 0.10 nmol/mg- protein/min.

3. Aromatase A ssay : Ea ch assay run contained four tubes for the full enzyme activity and four tubes for the background activity controls. Two tubes of each control were run at the beginning of the assay, and two of each control were run at the end of the assay. A full

concent ration curve in duplicate for the positive control, and a full concentration curve in triplicate for the test substance were established. The aromatase assay was conducted according to the procedures described in OCSPP 890.1200 (Section h, pp. 9-10).Aromatase (Human Recombinant) Assay (2012 ) / Page 5 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## The amount of 3 

## H 2 

## O in the aqueous fraction was quantified for each assay tube by LSC, and aromatase activity was reported in units of nmol∙mg

- protein −1 

## ∙min −1



## .

4. Demonstration of P roficiency : No information was provided concerning proficiency testing.

a. Positive Control : Data were not provided.

(1) Initial Demonstration of Laboratory Proficiency : The positive control data (new/historical data for laboratory) were not reported in regards to the following criteria:

• Mean aromatase activity in the absence of an inhibitor was at least 0.1 nmol/mg

protein/min.

• Mean background control activity was ≤ 15% of the full activity control.

• Coefficient of variation (% CV) for replicates within each sample type and

concentration of 4- OH ASDN was <15%.

Performa nce criteria were reported for the test runs only (Table 2), and served as guidance in identifying runs that provided parameters in the preferred ranges.

(2) Demonstration of Proficiency of New Technician for Conducting Assay (when applicable) : Demonstration of proficiency by a new technician, if applicable, was not reported. The positive control data for slope, top and bottom percent, and log IC 50 

## met the criteria as listed in section (i) of OCSPP 890.1200, with the following exceptions: (i) Hill slope for Run 1 (– 1.5) was below the lower limit ( –1.2); and (ii) log IC 50 

## for Run 2 (–7.5)

and Run 3 (– 7.4) was below the lower limit ( –7.3).

TABLE 2. Performance Criteria for the Positive Control a

Parameter Lower Limit Criteria Upper Limit Criteria Actual Lower Limit Actual Upper Limit
Slope

− 1.2

− 0.8

– 1.5

– 0.84
Top (%) 90 110 99 110
Bottom (%)

− 5 +6

– 0.56 4.2
Log IC 50 (M)

− 7.3

− 7.0

– 7.5

– 7.2

a Data were obtained from page 29 of the study report.



## b. Proficiency C hemicals : Data were not provided.

T ABLE 3. Proficiency Chemicals

Compound CAS# Class Concentrations

Econazole 24169

- 02

- 6 Inhibitor Not reported

Fenarimol 60168

- 88

- 9 Inhibitor Not reported

Nitrofen 1836

- 75

- 5 Inhibitor Not reported

Atrazine 1912

- 24

- 9 Non

- inhibitor Not reported



## 5. Determination of Aromatase A ctivity with T est C hemical(s) : The response of aromatase activity to the presence of eight concentrations of pronamide per run, in triplicate, was tested during three independent runs. After completion of the first run, the da ta were reviewed and insolubility of pronamide was observed at the highest concentration tested (10

− 3 

## M). TheAromatase (Human Recombinant) Assay (2012 ) / Page 6 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## highest concentration for the second and third runs was set at the highest concentration that appeared to be soluble with mid-log concentrations (10

− 3.3 

## M) , to define the lower portion of

the curve. The lowest concentration tested was 10

− 10 

## M. The response of each full activity control within a run was between 96 to 106% of the average full activity, with the exception of two full activity control responses (86 and 112%) from the beginning of Run 3 that were outside of the guideline recommended range of 90 to 110%.

T ABLE 4. Test Chemical Study Design for each Test Run

Sample Type Repe titions (Tubes) Description Reference or Chemical (M)
Full Activity Control 4 All test components a plus solvent vehicle N/A Bkgd Activity Control 4 Same as above without NADPH N/A

4

- OH ASDN Conc 1 2 All test components plus 4

- OH ASDN 1×10

− 5

4

- OH ASDN Conc 2 2 All test components plus 4

- OH ASDN 1×10

− 6

4

- OH ASDN Conc 3 2 All test components plus 4

- OH ASDN 1×10

− 6.5

4

- OH ASDN Conc 4 2 All test components plus 4

- OH ASDN 1×10

− 7

4

- OH ASDN Conc 5 2 All test components plus 4

- OH ASDN 1×10

− 7.5

4

- OH ASDN Conc 6 2 All test components plus 4

- OH ASDN 1×10

− 8

4

- OH ASDN Conc 7 2 All test components plus 4

- OH ASDN 1×10

− 9

4

- OH ASDN Conc 8 2 All test components plus 4

- OH ASDN 1×10

− 10

Pronamide Conc 1 b 3 All test components plus test chemical 1×10

– 3 (or 1×10

– 3.3 ) b

Pronamide Conc 2 b 3 All test components plus pronamide 1×10

– 4

Pronamide Conc 3 b 3 All test components plus pronamide 1×10

– 5

Pronamide Conc 4 b 3 All test components plus pronamide 1×10

– 6

Pronamide Conc 5 b 3 All test components plus pronamide 1×10

– 7

Pronamide Conc 6 b 3 All test components plus pronamide 1×10

– 8

Pronamide Conc 7 b 3 All test components plus pronamide 1×10

– 9

Pronamide Conc 8 b 3 All test components plus pronamide 1×10

– 10

a The complete assay contained buffer, propylene glycol, microsomal protein, [ 3 H]ASDN, and NADPH

. b The highest concentration s tested were 1×10 –3 for Run 1, and 1×10 –3.3 for Runs 2 and 3.



## C. D ATA ANALYSIS

1. Raw D ata : Raw data were converted to aromatase activity (nmol/mg protein/min) and percent control for the positive control and t est chemical . The following raw data and calculated endpoints for each run were included in the report (Table 5).

T ABLE 5. Raw and Calculated Data

Raw/Calculated Data Included (X)
DPM/mL for each portion of extracted aqueous incubation mixture X Average DPM/mL for each aqueous portion (after extraction) X Total DPM for each aqueous portion (after extraction) X

The total DPM present in the assay tube at initiation X The percentage of substrate converted to product X Total DPM after extraction corrected for background X Aromatase activity expressed in nmol/mg protein/min X Average aromatase activity in the full activity control tubes X Percentage of control activity remaining in the presence of various inhibitor concentrations X

DPM Disintegrations per minute



## 2. S tatistical M ethods : Statistical analyses and graphical displays were conducted using Graph Pad Prism (Version 4.0, La Jolla, CA). Basic statistical analyses were performed on the data, which included means of replicates, standard deviation of the mean, relativeAromatase (Human Recombinant) Assay (2012 ) / Page 7 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## standard deviation, and coefficient of variation. The Hill slope and log IC 50 

## values across three independent runs were compared based on a one- way random effects analysis of variance, treating runs as random effects.

The response curve was fitted by nonlinear regres sion analysis. Model fits were carried out using a 4-parameter regression model. For each run, percent of full activity control were plotted versus logarithm (base 10) of the test chemical concentration or 4- OH ASDN concentration. Each run was plotted with the data’s best fit curve. Additionally, the average inhibition response curve across all runs was also plotted.

3. Interpretation of Results : Interpretation of the assay results was based on the average of three runs, using the categories presented in Table 6.

TABLE 6 . Interpretation of Results

Criteria Interpretation

Data fit 4

- parameter nonlinear regression

model Average curve across runs crossed 50% a Inhibitor
Average lowest portion of curves across runs is between 50% and 75% activity b Equivocal
Average lowest portion of curves across runs is greater than 75% activity b Non

- inhibitor

Data do not fit model

---

a Ordinarily, an inhibition curve will fall from 90% to 10% over 2 log units with a slope near

− 1. Unusually steep curves may indicate protein denaturing or solubility issues. If the slope of the curve is steeper than

− 2.0, the result is classified as equivocal.

b If the test compound was not soluble above 10

− 6 M and the inhibition curve does not cross 50%, the chemical is typically

determined to be untestable in the aromatase assay

.



## II

. RESULTS

A. CONTROL ACTIVITY : Aromatase activity in the full activity controls ranged from

0.244 to 0.493 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## for the three test runs, with a mean and standard

deviation of 0.342±0.108 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## . Activity in the background controls ranged from 0.23 to 0.65 % of the full activity controls. The response of each full activity control was generally between 90 to 110% of the average full activity. The response of the full activity controls and background controls were acceptable.

B. POSITIVE CONTROL : For the positive control substance (4

- OH ASDN ), a romatase activity averaged 0.351±0.125 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.003±0.002 nmol

∙ mg -protein -1



## ∙ min

− 1 

## at the highest tested concentration (10

− 5 

## M) . The mean aromatase activity of the positive control (expressed as % full control activity) for each concentration tested across all three runs is presented in Table 7, along

with the o verall standard deviation and % CV. Inhibition response curves for the positive control from each run and the average of all runs are shown in Figure 1. These results were generally within the recommended ranges for the top of the curve, bottom curve, Hill slope

, log IC 50 

## , and coefficient of variation for replicates of each concentration.Aromatase (Human Recombinant) Assay (2012 ) / Page 8 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



### TABLE 7 . Effect of Pronamide on Aromatase Activity (as percent of control) from Independent Runs a

Chemical Concen. ( Log M ) # Runs Overall Mean Overall SD Overall SEM Overall %CV

4

- OH ASDN (positive control) − 5 3 1.01 0.74 0.30 73.5

− 6 3 5.27 1.48 0.60 28.1

− 6.5 3 12.25 2.77 1.13 22.6

− 7 3 28.56 5.53 2.26 19.4

− 7.5 3 59.32 9.99 4.08 16.9

− 8 3 84.75 11.26 4.60 13.3

− 9 3 103.67 6.51 2.66 6.3

− 10 3 102.04 9.91 4.05 9.7

Pronamide

− 3 b 1 79.17 2.43 0.99 3.1

− 3.3 b 2 62.01 13.94 5.69 22.5

− 4 3 73.74 7.47 3.05 10.1

− 5 3 94.41 7.54 3.08 8.0

− 6 3 100.61 4.56 1.86 4.5

− 7 3 97.63 6.25 2.55 6.4

− 8 3 103.01 6.62 2.70 6.4

− 9 3 99.17 4.84 1.97 4.9

− 10 3 100.25 5.10 2.08 5.1

a Values were calculated by the reviewers based on data provided on pages 52

- 54

. b The highest concentrations tested were 1×10 –3 for Run 1, and 1×10 –3.3 for Runs 2 and 3.

SD Standard Deviation

SEM Standard Error of the Mean

CV Coefficient of VarianceAromatase (Human Recombinant) Assay (2012 ) / Page 9 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## FIGURE 1. Inhibition R esponse C urve s for 4

- OH ASDN

.

C. TEST SUBSTANCE : For pronamide , aromatase activity averaged 0.343±0.112 nmol

∙ mg

protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.222±0.029 nmol

∙ mg

protein

− 1



## ∙ min

− 1 

## at the highest successfully tested concentration (10

− 3.3 

## ) . The mean aromatase activity of pronamide (expressed as %full control activity) for each concentration

tested across all three runs is presented in Table 7 (above), along with the o verall standard

deviation and % CV. Inhibition response curves for pronamide from each run are shown in Fig ure 2, and the average inhibition response curve across all runs is shown in Figure 3. The overall %CV for the highest concentration (23%) exceeded the acceptable limit of 15%.Aromatase (Human Recombinant) Assay (2012 ) / Page 10 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## FIGURE 2. Inhibition R esponse C urves for Pronamide F rom E ach T est R un.

FIGURE 3. Mean I nhibition R esponse C urve for Pronamide

.Aromatase (Human Recombinant) Assay (2012 ) / Page 11 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## The data for pronamide were modeled , and the goodness of fit (R 2 

## ) values were 0.74-0.97.

For test material curves, the best fit Hill slope and log IC 50 

## values across three independent runs did not differ significantly. The average dose-response curve indicated that the aromatase activity of the test material at concentrations ranging from 10

− 10 

## M to 10 −6 

## M was essentially equivalent to the activity obse rved in the full activity controls. However, pronamide reduced aromatase activity, on average, to approximately 74% at 10 −4 

## M and

62 % at 10 −3 .3 

## M.

For positive control curves, the best fit Hill slope and log IC 50 

## values across three independent runs were significantly different.

The effect of the positive control on inhibition of aromatase activity is presented in Table 8.

For 4

- OH ASDN , t he estimated log IC 50 

## averaged

− 7.37 M and the slope was

− 1.11.

Confide nce in the mean log IC 50 

## for the positive control is high due to the small variation (< 3% CV ). Confidence in the mean slope is low due to the large variation (< 32% CV).

TABLE 8 . Effect of Pronamide on Aromatase Activity (as P ercent of C ontrol) F rom Independent Runs a

Chemical Run 1 Run 2 Run 3 Mean SD %CV
Log IC 50 (M)

Pronamide NA NA NA NA NA NA

4

- OH ASDN −7.20 −7.50 −7.40 −7.37 0.15 −2.07
Slope

Pronamide NA NA NA NA NA NA

4

- OH ASDN −1.50 −0.99 −0.84 −1.11 0.35 −31.17

a Data were provided on pages 27

- 28 of the study report. Mean, SD, and %CV were calculated by the reviewers based on

these data.

SD Standard Deviation

CV Coefficient of Variance

NA Not applicable. Values for pronamide were not suitable for modeling.



## Based on the data from the average response curve and the criteria listed above in Table 7, the results support the conclusion that pronamide is equivocal in the aromatase assay

.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS CONCLUSIONS : Based on the average of the three runs of the assay, the percent inhibition of aromatase at the highest concentration tested (1 x 10

− 3.3 

## M), was between 25% and 50% activity. Thus, pronamide is classified as having an “equivocal” ability to inhibit aromatase activity.

B. AGENCY COMMENTS : Aromatase activity in the full activity controls ranged from

0.244 to 0.493 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## for the three test runs, with a mean and standard

deviation of 0.342±0.108 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## . Activity in the background controls ranged from 0.23 to 0.65% of the full activity controls. The response of each full activity control was generally between 90 to 110% of the average full activity.

For the positive control substance (4- OH ASDN ), aromatase activity averaged 0.351±0.125

nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.003±0.002

nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the highest tested concentration (10

− 5 

## M ). These results wereAromatase (Human Recombinant) Assay (2012 ) / Page 12 of 12

PRONAMIDE / 101701 O CSPP 89 0. 1200 / OECD None



## generally within the recommended ranges for the top of the curve, bottom curve, Hill slope

, log IC 50 

## , and coefficient of variation for replicates of each concentration. The overall %CV for the highest concentration (21%) exceeded the acceptable limit of 15%.

For pronamide, aromatase activity averaged 0.343±0.112 nmol

∙ mg -p rotein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.222±0.029 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the highest successfully tested concentration (10

− 3.3 

## M ). The data for pronamide were modeled, and the goodness of fit (R 2 

## ) values were 0.74-0.97. The average dose-response curve indicated that the aromatase activity of the test material at concentrations ranging from 10

− 10



## M to 10 −6 

## M was essentially equivalent to the activity observed in the full activity controls. However, pronamide reduced aromatase activity, on average, to approximately 74% at 10 −4



## M and 62% at 10 −3.3 

## M.

For 4

- OH ASDN , the estimated log IC 50 

## averaged

− 7.37 M and the slope was

− 1.11.

The average lowest portion of the response curve was between 50 and 75% activity (62% at

10

– 3.3 

## M pronamide), indicating that pronamide is an equivocal inhibitor of aromatase

.

In general, CVs often exceeded the acceptable limit of 15% (Table 7) and limit confidence in assay results.

C. STUDY DEFICIENCIES : The following deficiencies were noted that are not considered to have had an adverse impact on the results, interpretation or conclusions of this study:

• Coefficients of variation often exceeded 15% (e.g. CVs of positive control concentrations exceeded 15% for 5 of 8 chemical concentrations and were reported up to 73.5%).

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE )

Study Type: OCSPP 890.1250, Estrogen Receptor Binding Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619104)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Rebecca L. Bryan, B.S. Date: 2/ 16 /2012

Secondary Reviewer Signature:
David A. McEwen, B.S. Date: 2/ 27 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 3 / 02 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 3 / 02 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathway s. The robustness of the Tier 1 battery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE/101701 Estrogen Receptor Binding (Rat Uterine Cytosol) (2012) I Page 1 of 13

OCSPP 890.1250/ OECD None



## Primary Reviewer: -=K=h=in"'--=0-=o-'--"-M-=·=D:....:..

__________ 

## Signature:

__ \£.;:::;'

# ~!\.~==·=;'!·'----- Health Effects Division Date:**----=LJ~_,,,'l.=--ct 1**  }_......

## z.-=-cc.:..::1~,.___ Secondary Reviewer: Greg Akerman, Ph.D. 

## Signature: ,/} 

# /-2=

Health Effects Division Date:

__ ,

# <o**"'- -'** **'Z-- =-.:..** **"f _,_I**  .:..... ' ,-

__ Template version 08/2011



## DATA EVALUATION RECORD

STUDY TYPE: Estrogen Receptor Binding Assay Using Rat Uterine Cytosol (ER-RUC);

OCSPP 890.1250



## PC CODE: 101701 

## DP BARCODE: D398506



## TXR#: 0056255 

## CAS No.: 23950-58-5



## TEST MATERIAL (PURITY): Pronamide (96.2% a.i.)



## SYNONYMS: Propyzamide ; KERBTM Technical ; 3

, 5-Dichloro-N-(1

, 1-dimethyl-2-

propyn y 1) benzamide



## CITATION: L e Baron

, M

. J.

, Schisler

, M

. R.

, and Visconti

, N.R. (2012). Evaluation of pronamide in an 

## in vitro estrogen receptor binding assay

. Toxicolog y &



### Environmental Research and Consulting

, The Dow Chemical Company

, Midland,

MI. Laboratory Study No. : 111125

, January 3

, 2012. MRID 48619104. Unpublished

.



## SPONSOR: Dow AgroSciences LLC

, 9330 Zionsville Road

, Indianapolis, 

## IN

TEST ORDER#: CON-101701-37



## EXECUTIVE SUMMARY: In an estrogen receptor (ER) binding assay (MRID 48619104)

, uterine cytosol from Sprague Dawley rats was used as the source of ER for a competitive binding experiment

, which was conducted to measure the binding of a single concentration of [3H]-17Pestradiol (1 nM) in the presence of increasing concentrations (10

- 1 0 

### to 10

- 3 

### M) of pronamide
(96.2 % purity) . E thanol was used as a vehicle at a final concentration of < 3%

. The assay
included 19-norethindrone as a weak positive control, octyltrietho x ysilane as a negative control

, and l 7P-estradiol as the natural ligand reference material.

A saturation binding experiment was conducted to demonstrate that the ER in the rat uterine cytosol was present in reasonable numbers and was functioning with appropriate affinity for the

radiolabeled reference estrogen prior to routinely conducting ER competitive binding experiments. In the saturation binding experiments

, the maximum binding capacity (B m ax) 

### was
59

. 28 fmol/100 μg prot e in and the dissociation constant (Kd) was 0.1032 nM; both within the

recommended range from the validation studies. The Scatchard plot showed a linear response

across the concentrations of ligand added

. Nonspecific binding was 

### I. 7%

- 8.6% of the total
binding

.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 2 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## In the c ompetitive binding experiment, pronamide did not inhibit specific binding of the natural ligand at concentrations up to 10 −3 

## M, but there was an apparent increase in specific binding of the [ 3 

## H]- 17β

- estradiol in each run at the highest pronamide concentration tested ( 10 −3 

## M). Across all three runs, specific radioligand binding averaged 95.7 – 98.2% at pronamide

concentration of 10 −10 

## to 10 −4 

## M, but average binding w as 121.4% at 10 −3 

## M of pronamide. An

IC 50 

## and relative binding affinity ( RBA ) were not calculated for pronamide because radioligand binding was not reduced to ≤ 50%.

The performance criteria were generally met for pronamide, and the reference compounds performed as expected in the assay. The negative control, octyltriethoxysilane, had no effect on binding, and the binding curves for 17β -estradiol and 19-norethindrone showed that increasing concentrations of each compound displaced [ 3 

## H]

- 17β -estradiol in a manner consistent with onesite binding. The mean l og IC 50 

## was −5.5 M for 19

- norethindrone and −8.9 M for 17β estradiol, and the mean RBA was 0.033% for 19-noirethindrone compared to the natural ligand.

Based on the results from the three runs, pronamide is classified as Not I nteractive in the Estrogen Receptor Binding Assay.

The assay satisf ies the EDSP Tier 1 Test Order requirement s for an E strogen R eceptor Binding assay (OCSPP 890.1250).

COMPLIANCE : Signed and dated Confidentiality. GLP and Quality Assurance statements

were pro vided.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 3 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology & Environmental Research and Consulting

Location: Dow Chemical Company, Midland, MI Study Director: M.R. Schisler

Other Personnel: M.J. LeBaron, Lead Scientist

N.R. V isconti, Research Biologist B.B. Gollapudi , Technical Reviewer Study Period: September 6, 2011 to January 3, 2012



## 2

. Test substance : Pronamide

Description: White to off

- white powder

Source: Dow AgroSciences LLC

, Indianapolis, IN

Lot/Batch #: XG1088R301, TSN003588

- 0004 Purity: 96.2 % Solubility: Soluble in ethanol up to 50 mM; insoluble in water Volatility: NR Stability: 2 years shelf life Storage conditions: 5 ° C to Ambient

CAS #: 23950

- 58

- 5 Molecular weight: 256.1

Structure:

Cl Cl O

N H CH 3

C
CH CH 3



## 3

. Non

- labeled ligand : 17 β

- estradiol

Supplier : Sigma, St. Louis, MO Catalog # : E8875

Batch #: 098K1372 Purity: 100 %

CAS #: 50

- 28

- 2



## 4

. Radioactive ligand : [ 3 

## H]

- 17 β

- estradiol

Supplier : Perkin

- Elmer, Boston, Massachusetts Catalog #: NET517001MC

Batch #: 639068 Radiochemical p urity: >97 % Specific activity : 162.9 Ci/mmol

Concentration of stock : 1.0 mCi/m L



## 5

. Positive control : 19

- norethindrone

Supplier: Sigma, St. Louis, MO Catalog # : N4128

Batch #: 030M1359 Purity: 99%

CAS #: 68

- 22

- 4Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 4 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## 6

. Negative control : Octyltriethoxysilane

Supplier: Sigma, St. Louis, MO Catalog # 440213

Batch #: 72596AMV Purity: 98.58%

CAS #: 2943

- 75

- 1



## 7

. Solvent/vehicle control : Ethanol

Justification for choice of

solvent : None reported.

Final Concentration : <3%



## B. METHODS

1. Preparation of R at U terine Cytosol (RUC) : Trimmed uterine tissue from 85 - to 100- day old female Crl:CD(SD) rats, which were ovariectomized approximately 7 -10 days prior to being euthanized, was purchased from Charles River (Wilmington, MA). The uteri were weighed, minced and homogenized in ice

- cold TEDG (Tris, EDTA, DTT, glycerol) + PMSF (phenylmethylsulfonyl fluoride) buffer, then centrifuged for 10 min at 2500 × g at 4oC. Supernatant was transferred and centrifuged for 60 minutes at 105,000 × g , discarding the resulting pellets. Protein concentration of the cytosol was determined to be 3.573 mg/mL using a protein kit compatible with DTT in the TEDG buffer (e.g., BioRad Protein Assay Kit). Cytosol was divided into aliquots (volume not reported) that were stored at

− 80 oC for up to 90 days until use.

2. Saturation (radioligand) B inding E xperiment : A saturation binding e xperiment measuring total and non-specific binding of [ 3 

## H] -17 β

- estradiol was reportedly performed to

demonstrate that the ER was present in reasonable concentrations and had the appropriate affinity for the native ligand. T he conditions for the saturation binding experiment are

summarized in Table 1. Each run included three replicates of each test substance at each concentration, resulting in the 72 samples depicted in Table 2.

TABLE 1 . Summary of Conditions for Saturation Binding Experiment a


### Source of receptor Rat uterine cytosol
Concentration of radioligand (as serial dilutions) 0.03

– 3.0 nM

Concentration of non

- labeled ligand (100X [radioligand]) 3.0

– 300 nM
Concentration of receptor Not Reported Sufficient to bind 40.77% of radioligand at 0.03nM b



### Temperature Not Reported 2

– 8 oC

Incubation time Not Reported 16 hours
Composition of assay buffer Tris Not Reported 10 mM (pH 7.4)

EDTA Not Reported 1.5 mM
Glycerol Not Reported 10%
Phenylmethylsulfonyl fluoride Not Reported 1mM

DTT Not Reported 1mMEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 5 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## 3. Competitive B inding E xperiment : A summary of the experiment conditions for the

c ompetitive bind ing e xperiment is presented in Table 3.

Tubes were incubated with gentle vortexing for 16 to 20 hours at 4-8 ° C. To separate bound from free estradiol, hydroxyapatite (HAP) slurry was added to each tube and vortexed (4 times at 5 minute intervals). Subsequently, the contents of each tube were washed three times as follows: TEDG +PMSF buffer was added, vortexed, centrifuged for 10 min at

1000 x g , and the supernatant decanted and discarded. Ethanol was added to the HAP pellet remaining in each tube to extract the bound [ 3 

## H] -17 β

- estradiol , followed by vortexing, and centrifugation for 10 min at 1000 × g . An aliquot of supernatant was radioassayed by liquid scintillation counting. The temperature was maintained at 4 -8 oC throughout the assay prior

to extraction with ethanol.

TABLE 3 . Summary of Conditions for Competitive Binding Experiment a


### Source of receptor Rat U terine C ytosol
Concentration of radioligand 1.0 nM

Concentration of receptor Sufficient to bind 6.89

- 7.57 % of radioligand
Concentration of test substance (as serial dilutions) 10

− 10 

### to 10

− 3 

### M
Temperature 4

- 8 ° C

Incubation time 16

- 20 hours
Composition of assay buffer Tris 10 mM

EDTA 1.5 mM
Glycerol 10%
Phenylmethylsulfonyl fluoride 1 mM

DTT 1 mM

a Data were obtained from page s 17, 21, 41, 43, and 45 of the study report.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 6 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## Solubility of pronamide in ethanol and assay buffer was evaluated visually and no precipitation was noted. On the day of the assay, the specific activity of the stock solution
[ 3 

## H] -17 β

- estradiol was not adjusted for decay over time, and diluted in TEDG + PMSF

buffer to achieve a final concentration of 1.0 nM. For each batch of cytosol, the optimal protein concentration was determined by testing serial amounts of protein per tube, using 1.0 nM radiolabeled estradiol, until a concentration was reached that bound 6.89-7.57 % of the total radioactivity added

. Serial dilutions of the test substance, positive control (19- norethindrone), negative control (octyltriethoxysilane), and reference material ( non- labeled 17β

- estradiol) were prepared to ach ieve the concentrations shown in Table 4 . E ach assay

co nsisted of three runs, and each run contained three replicates of each test substance at each

co ncentration, resulting in a total of 112 samples.

TABLE 4. Molar (M) concentrations in Co mpetitive Binding Assay Run a b



### Pronamide Positive control Negative control Reference Chemical

19

- norethindrone Octyltriethoxysilane Non

- labeled 17β

- estradiol

Tubes 83

- 106 c 

### Tubes 35

- 58 c 

### Tubes 59

- 82 c 

### Tubes 1

- 34 and 107

- 112 c



### 10

− 10 

### 10

− 8.5 

### 10

− 10 

### Solvent control or blank d



### 10

− 9 

### 10

− 7.5 

### 10

− 9 

### 10

− 11



### 10

− 8 

### 10

− 7 

### 10

− 8 

### 10

− 10



### 10

− 7 

### 10

− 6.5 

### 10

− 7 

### 10

− 9.5



### 10

− 6 

### 10

− 6 

### 10

− 6 

### 10

− 9



### 10

− 5 

### 10

− 5.5 

### 10

− 5 

### 10

− 8.5



### 10

− 4 

### 10

− 4.5 

### 10

− 4 

### 10

− 8



### 10

− 3 

### 10

− 4 

### 10

− 3 

### 10

− 7



### a Data were obtained from page s 41

- 42 of the study report.

b Each tube contains: 10μL of either the test substance, positive control, negative control, solvent control, or

non

- labeled 17β

- estradiol; 390 μL of TEDG + PMSF buffer with [ 3 

### H]

- 17β

- estradiol; and 100 μL of uterine cytosol (with ER), for a total of 500 μL.

c Each concentration of each chemical w as run in triplicate, for a total of 112 tubes per run.

d Solvent is ethanol in Tubes 11

- 13 and 107

- 109.



## C. D ATA ANALYSIS : For the competitive binding assay, GraphPad Prism was used to

generate nonlinear regression used to fit a curve (for 17β -estradiol, the positive control, and the test substance) to the Hill equation formula which incorporated IC 50 

## as a parameter to be

estimated. For parameters reported from the c 

## ompetitive binding e xperiment (l og IC 50 

## and RBA), m ean and standard deviation were calculated for each run and mean and standard error were calculated for the composite three runs.



## 1. Definitions

a. Classification of test material : Classification of the test material is based on the average of

three runs. Each run wa s first individually classified as follows:

Interactive = lowest point on the fitted curve within the range of the data is less than 50% (i.e., >50% of the radiolabeled estradiol has been displaced from the ER).Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 7 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## Not interactive = there are usable data points at or above 10

− 6 

## M and either the lowest point on the fitted response curve within the range of the data is above 75 % (i.e.,

<25 % of the radiolabeled estradiol has been displaced from the ER) or a binding curve cannot be fitted and the lowest average percent binding among concentration groups in the data is above 75%.

Equivocal up to the limit of concentrations tested = there are no data points at or above a

test chemical concentration of 10

− 6 

## M and either a binding curve can be fit but ≤50% of the radiolabeled estradiol has been displaced from the ER or a binding curve cannot be fit and the lowest average percent binding among concentration groups in the data is >50%.

Equivocal = A run is classified as equivocal if it does n ot fall into any of the categories

above.

The categorical classification of each run was assigned a numerical value as follows:

Run Classification Numerical Value

Interactive 2 Equivocal 1

Not interactive 0 Equivocal up to the limit of concentrations tested “missing”



## The values for each run were then averaged across runs and the chemical classified using the following ranges:

Test Material Classification Numerical Range

Interactive average ≥1.5 Equivocal 0.5 ≥ average <1.5

Not interactive average <0.5 Equivocal up to the limit of concentrations tested “missing”



## b. Descriptors for receptor binding :

Bmax: maximum specific binding number (fmol ER/100 μg cytosol protein) measures the concentration of active receptor sites

K d 

## : dissociation constant ( nM), measures the affinity of the receptor for its natural ligand

IC 50 

## : concentration of the test substance at which 50% of the radioligand is displaced from the receptor Relative Binding Affinity ( RBA % ): ( IC 50 

## of 17 β

- estradiol ÷ IC 50 

## of test substance) × 100Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 8 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## II. RESULTS

A. SATURATION BINDING EXPERIMENT : Data pertaining to the saturation binding experiment are in Table 5.

TABLE 5. Saturation Binding Experiment of 17 β

- E stradiol with Estrogen Receptor from Rat Uterine Cytosol a



### Parameter Run 1 b 

### Run 2 Run 3 Runs 1

- 3

R 2 

### (unweighted) 0.9617 N /A N /A N /A

B
max 

### (nM) 0.07097 N /A N /A N /A

B
max 

### (fmol/100 μg protein) 59.28 N /A N /A N /A

K d 

### (nM) 0.1032 N /A N /A N /AEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 9 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## B. COMPETITIVE BINDING EXPERIMENT : The results from the three c ompetitive binding experiments are summarized in Table 6 and presented graphically in Figures 1-3. Pronamide did not inhibit specific binding at concentrations up to 10

− 3 

## M in all three runs ; however, there was an apparent increase in specific binding of the natural ligand at the highest concentration of pronamide tested (10 −3 

## M) . At pronamide concentrations of 10 −10



## to 10 −4 

## M, the percent of total binding was 85.8 – 91.7% in Run 1, 97.9 – 101.3% in Run 2, and 96.8 – 103.2% in Run 3. However, at the high est concentration tested (10 −3 

## M), pronamide increase d specific binding to 101.4, 141.9, and 120.8% in Runs 1, 2, and 3, respectively. Across all three runs, specific binding averaged 95.7 – 98.2% at 10 −10 

## to 10 −4


## M of pronamide, and 121.4% at 10 −3 

## M. No explanation was provided regarding this apparent increase in specific binding. An IC 50 

## and RBA were not calculated for pronamide

as the minimum p ercent binding inhibition was ≥50%

.

The reference compound s performed as expected in the assay. Octyltriethoxysilane had no effect on binding of the radiolabeled ligand, and 17 β -estradiol and 19-norethindrone inhibited binding at the expected concentrations. The mean l og IC 50 

## was −5.5 M for

19-norethindrone and −8.9 M for 17 β -estradiol. The mean RBA was 0.033 % for

19-noirethindrone.

Confidence in these numbers is high due to the small variation. The solvent control responses indicated no drift in the study assay, and additional runs were unnecessary

. As pronamide had <25% inhibition of binding at concentrations up to 10

− 3 

## M in all three runs, it is classified as not interactive (0) in this assay (Table 7).Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 10 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



### TABLE 6. Competitive Binding Assay of Pronamide with Estrogen Receptor from Rat Uterine Cytosol a



### Parameter Run 1 b 

### Run 2 b 

### Run 3 b 

### Mean c



### r 2 

### (unweighted), 17 β

- estradiol 0.9974 0.9 990 0. 9997 0.9974

- 0.9997

19

- norethindrone 0.9995 0.9999 0.9997 0.9995

- 0.9999

Pronamide 0.8091 0.9943 0.9360 0.8091

- 0.9943 Log IC 50 

### (M), 17 β

- estradiol

− 8.9 17

− 8.9 48

− 8.9 42

− 8.9 36

19

- norethindrone

− 5. 459

− 5. 462

− 5.4 35

− 5.4 51

Pronamide NA NA NA NA

IC 50 

### (M), 17 β

- estradiol 1. 209 x 10

− 9 

### 1.1 27 x 10

− 9 

### 1.1 42 x 10

− 9 

### 1.159 x 10

− 9



### 19

- norethindrone 3.477 x 10

− 6 

### 3.448 x 10

− 6 

### 3.637 x 10

− 6 

### 3. 544 x 10

− 6



### Pronamide NA NA NA NA
Log RBA, 1 9

- norethindrone

− 3. 459

− 3. 486

− 3. 503

− 3. 485

Pronamide NA NA NA NA
RBA (%), 19

- norethindrone 0.03 5 0.03 3 0.03 1 0.03 3

Pronamide NA NA NA NA

a Data were obtained from pages 34

- 35 of the study report.

b The mean is reported for the concurrent replicates within each run.

c The range is reported for r 2 

### ; the mean is reported for all other parameters.

NA Not applicable

r 2 

### Goodness of fit

RBA R elative binding affinity

TABLE 7. Binding Classification of Pro namide with Estrogen Receptor a



### Run 1 2 3 Mean c 

### Binding Classification d


### Classification category value b 

### 0 0 0 0 Not interactive

a Data were obtained from page 35 of the study report.

b Classification category value: Interactive = 2; Equivocal = 1; Not interactive = 0; Equivocal up to the limit of concentrations tested (“missing”, i.e., not included in calculation of mean).

c Mean of three runs expressed to the tenths place

d Interactive = mean ≥1.5; Equivocal = 0.5≤ mean <1.5; Not interactive = mean <0.5



## F IGURE 3: Mean and Standard Error of the Mean for 3 Independent Assays - Relative ER Binding Activity for Pronamide.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 11 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## FIGURE 4. Percentage E2 Bound to the Estrogen Receptor in the Presence of Unlabeled E2, 19- Norethindrone or Octyltriethoxysilane

, Run 1

.

FIGURE 5. Percentage E2 Bound to the Estrogen Receptor in the Presence of Unlabeled E2, 19- Norethindrone or Octyltriethoxysilane

, Run 2

.

FIGURE 6. Percentage E2 Bound to the Estrogen Receptor in the Presence of Unlabeled E2, 19- Norethindrone or Octyltriethoxysilane, Run 3

.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 12 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## C. PERFORMANCE CRITERIA : To ensure that the competitive binding assay function ed properly, each run was evaluated using the following criteria (Table 8) :

TABLE 8. Criterion a 

### Tolerance Limit(s) Value Yes No

17 β

- estradiol fitted curve parameters
Log
e 

### residual SD ≤2.35

− 0.11 to 1.06 X Top (% binding) 94 to 111 99

- 101 X Bottom (% binding)

− 4 to 1

− 1.0 to

− 0. 1 X Hill Slope (log 10 

### (M)

− 1 

### )

− 1.1 to

− 0.7

− 1.0 to

− 0.98 X

Weak Positive control ( 19

- norethindrone ) fitted curve parameters b



### Log
e 

### residual SD NA

− 1.1 to 0.21 X Top (% binding) NA 99

- 100 X Bottom (% binding) NA

− 1. 2 to 0.6 X Hill Slope (log 10 

### (M)

− 1 

### ) NA

− 1. 1 to

− 0.98 X

Solvent concentration

Ethanol ≤3% <3% X Negative control (octyltriethoxysilane) does not displace

more than 25% of [ 3 

### H]

- 17 β

- estradiol from the ER on average across all concentrations ≤25% ≤17 % X

a Data were obtained from page 34 of the study report.

b The EPA Guideline does not define a set of tolerance limits for 19

- norethindrone. Acceptance criteria were only defined for norethynodrel, which cannot be obtained commercially. The values reported were considered acceptable as they show 19

- norethindrone to be an acceptable weak positive control.

NA Not appl icable



## Additionally, the curve for the reference material showed that increasing concentrations of unlabeled 17β

- estradiol displaced [ 3 

## H]

- 17β -estradiol in a manner consistent with one- site binding, as indicated by a H ill slope of

− 1.0 to

− 0.98.

Pronamide was tested over a concentration range that fully defined the top of t he curve. However, due to the apparent increase (>100%) in specific binding observed at the highest concentration of pronamide tested (10 −3 

## M), the percent binding at the top p lateau in Runs 1 and 2 (133.4 and 174.2%, respectively) w as not within 25 percentage points of the lowest concentration of the estradiol standard (97.5 and 96.7%, respectively). In Run 3, t he percent binding at the top plateau for pronamide (120.9%) was within 25 percentage points of the lowest concentration of the estradiol standard (98.1%). Examination across the runs indicated consistency of the Hill slope, placement along the X-axis, and top and bottom plateaus.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : Based on the combined responses in each of three independent estrogen receptor binding assays, it was determined that pronamide had no appreciable effect in the binding of the reference estrogen (radiolabeled 17β

- estradiol) at any concentration tested (up to 10 −3 

## M). The results of the in vitro estrogen receptor bindingEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2012 ) / Page 13 of 13

PRONAMIDE / 101701 O CSPP 89 0.1250 / OECD None



## assay using rat uterine cytosol indicate that, under the conditions of this study, pronamide was determined to be negative (not interactive) for estrogen receptor binding.

B. AGENCY COMMENTS : For the c ompetitive binding experiment, pronamide did not inhibit specific binding at concentrations up to 10 −3 

## M, but there was an apparent increase in specific binding of the [ 3 

## H]

- 17β

- estradiol in each run at the highest pronamide concentration

tested , 10 −3 

## M. Across all three runs, specific binding averaged 95.7 – 98.2% at 10 −10 

## to
10 −4 

## M of pronamide, and 121.4% at 10 −3 

## M. No explanation was provided regarding this apparent increase in speci fic binding. An IC 50 

## and RBA were not calculated for pronamide because the minimum percent binding inhibition was ≥50%

. As the minimum binding observed with pronamide was >75% at concentration s up to 10 −3 

## M across all runs, pronamide is classified as “no t interactive” under conditions of this assay.

The performance criteria were generally met for pronamide, and t he reference compound s performed as expected in the assay . The negative control, o ctyltriethoxysilane , had no effect on binding, and the binding curves for 17β -estradiol and 19-norethindrone showed that increasing concentrations of each compound displaced [ 3 

## H]

- 17β -estradiol in a manner consistent with one-site binding. T he mean l og IC 50 

## was

− 5.5 M for 19 -norethindrone and

− 8.9 M for 17 β

- estradiol , and the mean RBA was 0.033 % for 19 -noirethindrone compared to the natural ligand.

C. STUDY DEFICIENCIES: No ne.

# DATA EVALUATION RECORD

PRONAMIDE ( PROPYZAMIDE )

Study Type: OCSPP 890.1300, Estrogen Receptor Transcriptional Activation

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619105)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Michelle Sharpe

- Kass, M.S. Date: 2/15 /2012

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 2 / 29 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 3 / 02/ 2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 3 / 02 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The rob ustness of the Tier 1 battery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each

indiv idual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).

### PRONAMIDE/101701 Estrogen Receptor Transcriptional Activation (2012) I 

### Page I of 10

OCSPP 890.1300/ OECD 455



## Primary Reviewer: _K==h=in"""--=-0_..;:;o.i...=.;.M=

. =D-'-

. --------- 

## Health Effects Division Secondary Reviewer: Minerva Mercado, Ph.D.



## Health Effects Division

DATA EVALUATION RECORD

STUDY TYPE: Estrogen Receptor Transcriptional Activation (Human cell Line, HeLa-9903) ;
OCSPP 890.1300 ; OECD 455.



## PCCODE: 101701 

## DP BARCODE: D398506



## TXR#: 0056255 

## CAS No.: 23950-58-5



## TEST MATERIAL (PURITY): Propyzamide (96.2% a.i.)



## SYNONYMS: Pronamide ; 3,5-dichloro-N-(l, l-dimethyl-2-propynyl)benzamide



## CITATION: LeBaron

, M

. J

. ; Kan

, H.L. (2012) Evaluation of pronamide in an 

## in vitro

estrogen receptor transcriptional activation assay in human cell line

hERa-HeLa-9903. Toxicology & Environmental Research and Consulting, The

Dow Chemical Company, Midland, MI. Laboratory Report No

. : 101182

, January 4

, 2012

. MRID 48619105

. Unpublished.



## SPONSOR: Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, 

## IN

TEST ORDER# : CON-101701-37



## EXECUTIVE SUMMARY: In an estrogen receptor transcriptional activation assay (MRID
48619105), HeLa-9903 cells cultured 

## in vitro were exposed to pronamide (96.2% a.i.; Lot 

## # XG1088R301) at concentrations of 10

- 10 M to 10

- 3 5 

## M in DMSO (final concentration 0.1%). The experiments were performed using 96-well plates and each pronamide concentration was tested in triplicate (3 wells / plate). Cells were exposed to the test agent for approximately 24 hours to induce reporter (luciferase) gene products. Luciferase expression in response to activation of the estrogen

receptor was measured upon addition of a luciferase substrate and detection with a luminometer

w ith acceptable sensitivity.

Pronamide was tested up to the limit of solubility

, 10

- 4 

## M

. The mean RPCM ax for pronamide was
1.4 % for run 1

, 3.5 % for run 2 and 7.6% for run 3

, and the associated PCM ax values were 10

- 4

, 

## 10

- s, and 1 o

- s M, respectively. Performance criteria for the reference chemicals were met, with

the following exceptions: the Hill slope for l 7a-estradiol was slightly lower than expected in run
2

, and the log PCs o and log PC10 for l 7a-methyltestosterone were slightly lower than expected in

run 4

. These results indicate an increased sensitivity of the assay to weak agonists

. Because the

RPCM ax 

## < PC1 0 in three assay runs, pronamide was considered negative for estrogen receptor transcriptional activation in this test system.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 2 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## This assay satisfies the EDSP Tier 1 Test Order requirement for an Estrogen Receptor Transcriptional Activation assay (OCSPP 890.1300).

COMPLIANCE : Signed and dated GLP, Quality Assurance and Data Confidentiality

statements were provided.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 3 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Substance : Pronamide

Description: Technical, white to off

- white powder, MW 256.1

Source: Dow AgroSciences, LLC

Lot/Batch #: Lot # XG1088R301 Purity: 96.2 % Solubility : 0.1M in DMSO, insoluble in water Volatility : NR Stability: 2 years Storage conditions: Ambient
Vapor pressure : 4.97 Pa

CAS #: 23950

- 58

- 5

Structure :



## 2. Reference substances 17β

- estradiol (strong estrogen; positive control)

Supplier : Sigma, St Louis, MO Catalogue and Batch #: Cat# E

- 8875 Lot # 0 79K0131 Purity: 100%

CAS # : 50

- 28

- 2



## 17α

- estradiol (weak estrogen)

Supplier: Sigma, St Louis, MO Catalogue and Batch #: Cat # E8750 Lot # 029K4116 Purity: 

### ≥ 99.5 %

CAS # : 57

- 91

- 0



## Corticosterone (negative compound)

Supplier: Sigma, St Louis, MO Catalogue and Batch #: Cat# C

- 2505, Lot # 010M2010 Purity: 100 %

CAS # : 50

- 22

- 6



## 17α

- methyltestosterone (very weak agonist)

Supplier: Sigma, St Louis, MO Catalogue and Batch #: Cat # M

- 7252, Lot # 060M1543V Purity: 99 %

CAS # : 58

- 18

- 4



## 3. Vehicle(s)

Solvent: Dimethyl Sulfoxide; Sigma

- Aldrich, Cat # 276855, Lot # 68996LMV &

36296DM , Purity ≥ 99.9%

Solvent control (final conc e n tration ): 0.1%Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 4 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## B. METHODS

1. C ell C ulture : Stably

- transfected hERα

- HeLa -9903 cell s were obtained from the Japanes e Collection of Research Bioresources Cell Bank and were verified to be free of mycoplasma infection using RT PCR. Cells were maintained in Eagles Minimum Essential Medium without phenol red, supplemented with 60 mg/L kanamycin and 10% dextran- coated

charcoal

- treated fetal bovine serum (DCC

- FBS ; in -house prep: Lot # DCC-FBS 062410), in

an incubator under 5% CO 2 

## at 37oC. Upon reaching 75- 90% confluence, cells were

subcultured prior to exposure to the test material. Passages 6, 8 and 11 were used in the

ass ays reported in this study. DCC

- FBS was prepared at the performing laboratory using a protocol identical to that provided in the guideline.

2. Transcriptional Activation Assay s : For each test, cells were plated at a density of

1-1.5 × 10 4 

## cells /100 μL medium/well in a 96 well plate and allowed to attach for 3 hours.

The growth media was replaced with media containing serial log dilutions of pronamide in

DMSO (0.1% total final concentration ). Cells were incubated for approximately 24 hours at

ap proximately 37°C. Cytotoxicity was determined by the CellTiter96 Aqueous One Solution Cell Proliferation Assay Kit (Promega, Madison, WI). Transcriptional activation of the estrogen receptor was determined using Steady

- Glo® Luciferase Assay System (Prome ga, Madison, WI). The luminometer was able to detect linear responses down to 100 counts per second, and can detect ~5 cells in 100 μL of medium.

a. P reliminary T est : A preliminary test evaluating concentrations ranging from 10

− 3 .5 

## M to
10

− 9 

## M was conducted to determine the appropriate concentration range and to determine concentrations resulting in insolubility and/or cytotoxicity.

b. Proficiency Chemicals : L aboratory validation assay s with the 10 proficiency chemicals

was performed. These non-GLP unpublished experimental results were reported to have demonstrated laboratory proficiency, and are included in a separate report.

Compound CAS No. Concentration Range (M) Expected Response a Note s

Diethylstilbes t rol (DES) 56

- 53

- 1 10

− 14 to 10

− 8 Positive

--- 17α

- Ethynyl estradiol (EE) 57

- 63

- 6 10

− 14 to 10

− 8 Positive

--- Hexestrol 84

- 16

- 2 10

− 13 to 10

− 7 Positive

--- Genistein 446

- 72

- 0 10

− 12 to 10

− 5 Positive Cytotoxic at 0.01 b , 0.1, and 1 mM

Estrone 53

- 16

- 7 10

− 12 to 10

− 6 Positive

--- Butyl paraben 94

- 26

- 8 10

− 11 to 10

− 4 Positive Cytotoxic at 0.1 b and 1 mM

1,3,5

- Tris(4

- hydroxyphenyl)benzene c 15797

- 52

- 1 10

− 12 to 10

− 5 Positive Cytotoxic at 100μM. PC M ax approx. 50% of PC. Binds to hERα and has ER antagonistic activity
Dibutyl phthalate (DBP) 84

- 74

- 2 10

− 11 to 10

− 4 Negative d Cytotoxic at 1 mM

Atrazine 1912

- 24

- 9 10

− 11 to 10

− 4 Negative Cytotoxic at 1 mM b

Corticosterone 50

- 22

- 6 10

− 10 to 10

− 4 Negative If not cytotoxic at 1 mM, then that should be the highest tested concentration

a Positive = RPC M ax ≥10% of the response of the positive control in at least 2 of 2 (or 2 of 3) runs ; Negative = RPC Max fails to achieve at least 10% of the response of the positive control in 2 of 2 (or 2 of 3) runs

b Cytotoxicity is expected to be close to 80% at this concentration.

c Compound s e lected to challenge solubility and cytotoxicity

d DBP is negative for ERα mediated transcriptional activation, but may not be negative for non

- ERβ mediated transcriptional activation. A positive result would indicate that the system is detecting activity other than that due to pure ERα, and is therefore unacceptable.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 5 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## c. Reference Chemicals : To ensure th e stability of the response from the cell line, six concentrations of each of the following reference chemicals were included in each plate in the current assay, along with the test chemical :

Reference Chemical CAS No. Concentration R ange Class 17β

- estradiol 50

- 28

- 2 10

− 14 to 10

− 8 Strong estrogen

17α

- estradiol 57

- 91

- 0 10

− 12 to 10

− 6 Weak estrogen

Corticosterone 50

- 22

- 6 10

− 10 to 10

− 4 Negative compound

17α

- methyltestosterone 58

- 18

- 4 10

− 11 to 10

− 5 Very weak agonist



## 3. Data analysis : To obtain t he relative transcriptional activity to the 1 nM E2 positive control (PC) , the luminescence signals from the concurrent plate were analyzed by subtracting the

mean value of the vehicle control from each well value to norm alize the data ; each

normalized value was then divid ed by the mean value of the normalized PC. The resulting value was multiplied by 100 in order to ex press relative transcriptional activity as a percentage of the PC. Graph Pad Prism v. 5.0 ( GraphPad Software, Inc., La Jolla, CA) was

used to calculate t he EC 50 

## , PC 10 

## , PC 50 

## , RPC Max 

## , and PC Max 

## for pronamide when applicable.

T he test material was defined as negative for inducing estrogen receptor transcriptional

activation if the RPC Max 

## < PC 10 

## in at least 2 of 2 (or 2 of 3) runs. Log EC 50 

## and Hill slop e values are calculated only if a positive response is observed. Coefficients of variation (CV)

w ere calculated for the luminescence data triplicates. Concentrations showing >20% cytotoxicity or evidence of insolubility were excluded from analyses.

4. Definitions

EC 50 

## = concentration of agonist that induces a response halfway b etween the baseline (bottom) and maximum (top) response

PC 10 

## = concentration of a test chemical at which the response is 10% of the response induced by the positive control (E2 at 1 nM) in each plate

PC 50 

## = concentration of a test chemical at which the r esponse is 50% of the response induced by the positive control (E2 at 1 nM) in each plate

RPC Max 

## = maximum level of response induced by a test chemical, expressed as a percentage of the response induced by the positive control (1 nM E2) on the same plate

PC Max 

## = concentration of a test chemical inducing the RPC Max



## II. RESULTS

A. PRELIMINARY TEST : In order to identify a suitable top concentration for use in the transcriptional activation assays, preliminary cytotoxicity and precipitation assays were conducted. No cytotoxicity was observed at any concentration. Precipitation was observed

after 24 hours of treatment with 10

− 3.5 

## M pronamide. Based on these results, logarithmically increasing concentrations from 10

− 10 

## to 10

− 4 

## M were selected for the as say.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 6 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



### TABLE 1

. Preliminary T est for Solubility , C ytotoxicity , and Concentration

- Selection for Pronamide a

Concentration (M) % Viability Comments

10

− 3 .5 121.0 Precipitation observed after 24 hours treatment

10

− 4 138.7

10

− 5 130.2

10

− 6 139.1

10

− 7 160.2

10

− 8 133.9

10

− 9 120.2

E2 1nM 137.7

VC b 100.0

a Data were obtained from page 47 of the study report.

b VC = Vehicle control



## B. Positive and Negative Reference Chemicals

1. Proficiency Chemicals : The results of the proficiency test were not reported

TABLE 2 . Proficiency Chemicals a

Compound Expected R esponse Lab R esponse Diethylstilbes t rol Positive Positive

17α

- Ethynyl estradiol Positive Positive

Hexestrol Positive Positive

Genistein Positive Positive

Estrone Positive Positive
Butyl paraben Positive Positive

1, 3, 5

- Tris(4

- hydroxyphenyl)benzene Positive Positive
Dibutyl phthalate Negative Positive if PC 10 used as cutoff; negative if

PC 50 used as cut off b

Atrazine Negative Negative

Corticosterone Negative Negative

a Proficiency testing data were not included in the study report; instead, they were compiled in a separate proficiency/validation report.

b Dibutyl Phthalate induced a weakly positive response consistent with prior studies and the validation report forthis assay system. Classification based on PC 50 would be clearly negative for DBP; however, using the PC 10 calculation results in a positive response. Consistent assay performance for all the other proficiency chemicals, as well as QC parameters for each assay, indicated acceptable assay responsiveness.



## 2. Reference Chemicals : Values derived from the concentration response curve ( e.g ., l og PC 50, 

## log PC 10, 

## log EC 50, 

## Hill Slope) for the four concurrently run reference materials are

included in Table 3. The log PC 50 

## , l og PC 10

, 

## l og EC 50 

## and Hill Slope for the reference chemicals 17β

- estradiol, 17α

- estradiol, corticosterone and 17α

- methyltestosterone all performed within the acceptable range with the following exceptions: the Hill Slope for

17α

- estradiol was sli ghtly lower than the acceptable range in Run 2, and the log PC 50 

## and

l og PC 10 

## for 17α

- methyltestosterone were slightly lower than the acceptable range in Run 4.

For 17α

- methyltestosterone, the mean RPC Max 

## was 60.0% for the first run, 80.0% for the second run, and 109.4% for the fourth run. These results indicate an increased sensitivity to weak agonists.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 7 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



### TABLE 3. Performance Criteria for Reference Chemicals a

Reference Chemical

Parameter Acceptable Range Values Acceptable

Run 1 Run 2 Run 4 Yes No

17β

- estradiol
Log PC 50 − 11.4 to

− 10.1

− 10.6

− 10.6

− 11.0 X
Log PC 10 <

− 11

− 11.9

− 12.4

− 12.9 X
Log EC 50 − 11.3 to

− 10.1

− 10.5

− 10.7

− 11.2 X Hill Slope 0.7 to 1.5 1.0 1.4 0.7 X
Test range 10 −14 to 10 −8 M 10 −14 to 10 −8 M 10 −14 to 10 −8 M 10 −14 to 10 −8 M

17α

- estradiol
Log PC 50 − 9.6 to

− 8.1

− 8.7

− 9.0

− 9.4 X
Log PC 10 − 10.7 to

− 9.3

− 10.0

− 10.0

− 10.6 X
Log EC 50 − 9.6 to

− 8.4

− 8.7

− 8.9

− 9.0 X Hill Slope 0.9 to 2.0 1.0 0.7 1.0 X
Test range 10 −12 to 10 −6 M 10 −12 to 10 −6 M 10 −12 to 10 −6 M 10 −12 to 10 −6 M

Corticosterone
Test range 10 −10 to 10 −4 M 10 −10 to 10 −4 M 10 −10 to 10 −4 M 10 −10 to 10 −4 M X

17α

- methyltestosterone
Log PC 50 − 6.0 to

− 5.1

− 5.4

− 6.1

− 8.0 X b

Log PC 10 − 8.0 to

− 6.2

− 8.2

− 8.8

− 8.9 X b

Test range 10 −11 to 10 −5 M 10 −11 to 10 −5 M 10 −11 to 10 −5 M 10 −11 to 10 −5 M X

a Data were obtained from page 48 of the study report

. b Indicated these parameters were slightly out of the suggested range but the values indicated increased sensitivity of the

assay system (i.e. decreased log PC50 and logPC10 for 17α

- methyltestosterone).



## C. DEFINITIVE ASSAY

1. Vehicle and Positive Controls : Data for the vehicle and positive controls are included in

Table 4. The overall mean TA value, expressed as arbitrary light units, for the vehicle control was 1539.6 for the first assay, 3395.4 for the second assay and 2323.4 for the fourth

assay. The mean normalized value for the positive control was 11729.0 for the first assay, 19724.6 for the second assay and 14443.2 for the four th assay

. The PC 50 

## (50% of the maximum response) for E2 in this assay is 5864.5 for the first assay, 9862.3 for the second assay and 7221.6 for the fourth assay and the PC 10 

## (10% of the maximum response) is 1172.9 for the first assay, 1972.5 for the second assay and 1444.3 for the fourth assay

.

TABLE 4. Transcriptional Activation (TA) Response of Vehicle and Positive Control a

Sample Vehicle Control Positive Control b

Runs Mean SD Mean SD Fold Induction c

1 1539.6 244.4 11729.0 1251.0 7 .6

2 3395.4 598.3 19724.6 3250.5 5.8

4 2323.4 261.9 14443.2 1361.8 6.2

a Data were obtained from page 49 of the study report.

b Positive control was 17β

- estradiol (E2) at 1 nM.

c Fold

- induction = (mean TA of PC)/(mean TA of VC)



## 2. Test M ateria l : Relative (to the PC) transcriptional activation at each concentration of pronamide during the three assay runs is presented in Table 5. The concentration -response curves depicting fold induction of relative transcriptional activation is presented in Figur es 1-3. The mean RPC Max 

## for pronamide was 1.4% for the first assay, 3.5% for the second

assay , and 7.6% for the fourth assay, and the associated PC Max 

## values were 10

− 4 

## , 10

− 5 

## , and

10

− 5 

## M, respectively. Because the RPC Max 

## < PC 10 

## in all three valid runs, pronamide was considered negative for estrogen receptor transcriptional activation in this test system

.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 8 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



### TABLE 5. Relative Transcriptional Activation (RTA) of Pronamide a

Parameter RTA (mean ± SD); % of Positive Control (PC)

Run 1 Run 2 Run 4
Conc. (M) Mean SD Mean SD Mean SD

10 −3.5

− 0.1 3.2

-- -- -- -- 10 −4 1.4 0.7 1

. 0 2.1 5.6 4.5

10 −5 0.9 1.5 3.5 3.0 7.6 4.9

10 −6

− 0.9 0.3 1.2 2.5 3.7 4.0

10 −7

− 4.1 1.7 1.8 0.3 4 .2 1.9

10 −8

− 1.0 2.1

− 1.8 3.6 5.2 0.9

10 −9 0.0 2.1

− 0.6 4.1 1.7 0.3

10

− 10

-- -- 2.2 3. 8 3.1 2.4

Log EC 50 NA NA NA
Hill Slope NA NA NA

RPC Max 1.4% 3.5% 7.6%

PC Max 10 −4 10 −5 10 −5

PC 50 NA NA NA

PC 10 NA NA NA

a Data were obtained from page 50 of the study report.

NA = Not Applicable



## F IGURE 1. Fold Induction of Relative Transcription Activation (RTA) of Pronamide Compared to the Positive Control, Run 1

.Estrogen Receptor Transcriptional Activation ( 2012 ) / Page 9 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## F IGURE 2. Fold Induction of Relative Transcription Activation (RTA) of Pronamide Compared to the Positive Control, Run 2

.

F IGURE 3. Fold Induction of Relative Transcription Activation (RTA) of Pronamide Compared to the Positive Control, Run 3

.

3. Performance C riteria : The laboratory proficiency assays using the required reference compounds were not included in the study report and were not available to the reviewer.

The l og PC 50 

## , l og PC 10

, 

## l og EC 50 

## and Hill Slope for the reference chemicals 17β -estradiol,

17α

- estradiol , corticosterone and 17α

- methyltestosterone all performed within theEstrogen Receptor Transcriptional Activation ( 2012 ) / Page 10 of 10

PRONAMIDE / 101701 OCSPP 890.1300/ OECD 455



## acceptable range with the following exceptions: the Hill S lope for 17α

- estradiol was slightly lower than the acceptable range in Run 2, and the log PC 50 

## and l og PC 10 

## for 17α

methyltestos terone were slightly lower than the acceptable range in Run 4. These results indicate an increased sensitivity to weak agonists, and therefore do not negatively impact the validity of the study. Triplicate samples of the PC and the VC were included in ea ch plate, and the mean luciferase activity of the PC was greater than 4

- fold that of the mean vehicle control on each plate. The variability among raw data triplicates ( i.e ., luminescence intensity data) was minimal (CV less than 20%), indicating a reliab le PC 10 

## , and t he results were reproducible among runs.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS ’ CONCLUSIONS : Pronamide did not increase cytotoxicity at the concentrations tested. Based on the combined responses in each of three independent estrogen receptor transactivation assays, it was determined that pronamide treatment did not

result in ER -mediated transcriptional activation up to the highest acceptable concentration tested (10

− 4 

## M).

B. AGENCY COMMENTS : Pronamide was tested up to the limit of solubility, 10

− 4 

## M. The

mean RPC Max 

## was 1.4% for the first assay, 3.5% for the second assay and 7.6% for the fourth assay, and the associated PC Max 

## values were 10

− 4 

## , 10

− 5 

## , and 10

− 5 

## M, respectively. Performance criteria were met; the Log PC 50 

## , Log PC 10

, 

## Log EC 50 

## and Hill Slope for the reference chemicals 17β

- estradiol, 17α

- estradiol, corticosterone and 17α

- methyltestosterone all performed within the acceptable range with the following exceptions: the Hill Slope for

17α

- estradiol was slightly lower than the acceptable range in Run 2, and the log PC 50 

## and

l og PC 10 

## for 17α -methyltestosterone were slightly lower than the acceptable range in Run 4. These results indicate an increased sensitivity to weak agonists. Based on the results of this

ass ay, pronamide d id not interact with the human estrogen receptor to cause transcriptional activation under the conditions of this assay.

C. STUDY DEFICIENCIES : The following deficiency was noted:

• The proficiency chemicals were slightly outside of the acceptable range, but indicate increased sensitivity to weak agonists.

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SAYER
DN: c=US, o=U.S.
Government, ou=USEPA, ou=Staff, cn=ANDREW SAYER,
dnQualifier=0000051409

Date: 2015.06.09 13:53:51

-04'00'

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԴԹՊԽՀԹՅԪԹՋՋԹԻՀՍՋԽՌՌՋ԰ՍԺՅՁՌՌԽԼ ԺՑԡՇՏԠՀԽՅՁԻԹՄԠՇՅՈԹՆՑ԰ՌՍԼ ՑԫՇ ԧԹՆՍԹՊՑ



ԫՇՌԽ ԱՀԽԲ԰ԢԭԞԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅ
Ԣԡ԰ԭԱՁԽՊ ՋԻՊԽԽՆՁՆԿԺԹՌՌԽՊՑՁՋԻՇՅՈՊՁՋԽԼՇԾ

ԽՄԽՎԽՆՋԻՊԽԽՆՁՆԿԹՋՋԹՑՋՁՆՌԽՆԼԽԼՌՇՁԼԽՆՌՁԾՑԹԻՀԽՅՁԻԹՄ0ՋՄՁՃԽՄ ՑԽՆԼՇԻՊՁՆԽԺՁՇԹԻՌՁՎՁՌՑՁԽՁՌՋՈՇՌԽՆՌՁԹՄՌՇ

ՁՆՌԽՊԹԻՌՏՁՌՀՌՀԽԽՋՌՊՇԿԽՆԹՆԼՊՇԿԽՆՇՊՌՀՑՊՇՁԼ
ԢԞՇՊԱՈ ԹՌՀՏԹՑՋԱՀԽՊՇԺՍՋՌՆԽՋՋՇԾՌՀԽԱՁԽՊ

ԺԹՌՌԽՊՑՁՋԺԹՋԽԼՇՆՌՀԽՋՌՊԽՆԿՌՀՋՇԾԽԹԻՀՁՆԼՁՎՁԼՍԹՄԹՋՋԹՑՌՇՁ ԼԽՆՌՁԾՑՈՇՌԽՆՌՁԹՄԽՆԼՇԻՊՁՆԽԺՁՇԹԻՌՁՎՁՌՑՏՁՌՀ

ԻՇՅՈՄԽՅԽՆՌԹՊՑԽՆԼՈՇՁՆՌՋՏՁՌՀՁՆՌՀԽԹՋՋԹՑՏՀԽՊԽԹՎԹՁՄԹԺՄԽԹՆԼ ՊԽԼՍՆԼԹՆԻՑԹԻՊՇՋՋՌՀԽԺԹՌՌԽՊՑԱՀՍՋ

ՌՀԽՊԽՋՍՄՌՋՇԾԽԹԻՀՁՆԼՁՎՁԼՍԹՄԹՋՋԹՑՋՀՇՍՄԼՆՇՌԺԽԻՇՆՋՁԼԽՊԽԼՁՆՁՋՇՄԹՌՁՇՆԺՍՌՊԹՌՀԽՊՋՀՇՍՄԼԺԽԻՇՆՋՁԼԽՊԽԼ

ՁՆՌՀԽԻՇՆՌԽՐՌՇԾՇՌՀԽՊԹՋՋԹՑՋՁՆՌՀԽԺԹՌՌԽՊՑԹՋՏԽՄՄԹՋԬՌՀԽՊ ԰ԻՁԽՆՌՁԾՁԻԹՄՄՑԯԽՄԽՎԹՆՌԦՆԾՇՊՅԹՌՁՇՆ
Ԭ԰ԯԦ

ԦՆՇՊԼԽՊՌՇԼԽՌԽՊՅՁՆԽՁԾԹԻՀԽՅՁԻԹՄՀԹՋՌՀԽՈՇՌԽՆՌՁԹՄՌՇՁՆՌԽՊԹ ԻՌՏՁՌՀՌՀԽԢԞՇՊԱՈԹՌՀՏԹՑՋԹԴԽՁԿՀՌՇԾ

ԢՎՁԼԽՆԻԽ
ԴՇԢԽՎԹՄՍԹՌՁՇՆՇԾԱՁԽՊԹՋՋԹՑՊԽՋՍՄՌՋՁՆԻՇՅԺՁՆԹՌՁ ՇՆՏՁՌՀՌՀԽԾՁՆԼՁՆԿՋՁՆՌՀԽԬ԰ԯԦՋՀՇՍՄԼ

ԺԽՍՆԼԽՊՌԹՃԽՆ
ՊԽԾԽՊՌՇՌՀԽԴՇԢԡՇԻՍՅԽՆՌ

ԢԵԢԠԲԱԦԳԢ԰ԲԪԪԞԯԶ

ԱՀԽ ԼԹՑ ՋՀՇՊՌՌԽՊՅ ՊԽՈՊՇԼՍԻՌՁՇՆ ԹՋՋԹՑ ՇԾ ՈՊՇՆԹՅՁԼԽ 
ԹՄՋՇ ՃՆՇ ՏՆ ԹՋ ՈՊՇՈՑՒԹՅՁԼԽ  ՈՍՊՁՌՑ ՏՁՌՀ

ԾԹՌՀԽԹԼ ՅՁՆՆՇՏՋ ԭՁՅԽՈՀԹՄԽՋ ՈՊՇՅԽՄԹՋ  ՏԹՋ ԻՇՆԼՍԻՌԽԼ ՍՆԼԽՊ ԾՄՇՏՌՀՊՇՍԿՀ ԻՇՆԼՁՌՁՇՆՋ ԞԼՍՄՌ ԾՁՋՀ ՁՆ 

ՋՈԹՏՆՁՆԿ ԿՊՇՍՈՋ 
 ՅԹՄԽՋ ԹՆԼ  ԾԽՅԹՄԽՋ ՁՆ ԽԹԻՀ ԿՊՇՍՈ  ԿՊՇՍՈՋ ՌՊԽԹՌՅԽՆՌ ԻԹ   ՅՇՆՌՀՋ ՇՄԼ ՏԽՊԽ

ԽՐՈՇՋԽԼՌՇՈՊՇՆԹՅՁԼԽԹՌՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾ
ԻՇՆՌՊՇՄՋ ՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩ

ՅԽԹՆՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽԩԬԮ
ԻՇՆՌՊՇՄՋ ԹՆԼՅԿԹՁԩԱՀԽՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄԻՇՆՋՁՋՌԽԼՇԾԼՁՅԽՌՀՑՄԾՇՊՅԹՅՁԼԽ
ԡԪԣԹՌԹԾՁՆԹՄԻՇՆԻԽՆՌ ՊԹՌՁՇՆՇԾՅԩԩԱՀԽՌԽՋՌՋՑՋՌԽՅՏԹՋ

ՅԹՁՆՌԹՁՆԽԼ ԹՌ  ՌՇ  Շ 

### Ԡ ԹՆԼ Թ Ոԥ ՇԾ  ՌՇ   ԲՆՄԽՋՋ ՇՌՀԽՊՏՁՋԽ ՋՈԽԻՁԾՁԽԼ ԹՄՄ ՊԽՋ ՍՄՌՋ ԹՊԽ ՊԽՈՇՊՌԽԼ

ԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ

԰ՍՊՎՁՎԹՄ ՏԹՋ ՆՇՌ ԹԼՎԽՊՋԽՄՑ ԹԾԾԽԻՌԽԼ ԺՑ ՌՊԽԹՌՅԽՆՌ ԹՌ ՌՀԽ  Թ ՆԼ  ՅԿ ԹՁԩ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԱՀԽ ՀՁԿՀ

ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՌՊԽԹՌՅԽՆՌ 
 ՅԿ ԹՁԩ ՏԹՋ ՌԽՊՅՁՆԹՌԽԼ ՇՆ ԡԹՑ  Լ ՍԽ ՌՇ ՅՇՊԺՁԼՁՌՑ 
ՊԽՈՇՊՌԽԼ ԹՋ ՄՇՋՋ ՇԾ

ԽՉՍՁՄՁԺՊՁՍՅ ԹՆԼՄԽՌՀԹՊԿՑՊԽՋՍՄՌՁՆԿՁՆՌՀԽԹՋՋԽՋՋՅԽՆՌՇԾՇՆՄՑՌՏՇՌՊԽԹՌՅԽՆ ՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԱՀԽՊԹՌՁՇՆԹՄԽԾՇՊ

ՋԽՄԽԻՌՁՇՆՇԾՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՏԹՋՆՇՌՈՊՇՎՁԼԽԼ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԦՆ ՌՀԽ ՊԽՅԹՁՆՁՆԿ ՌՏՇ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ ՈՊՇՆԹՅՁԼԽ ԽՐՈՇՋՍՊԽ ՏԹՋ ՆՇՌ ԹՋՋՇԻՁԹՌԽԼ ՏՁՌՀ Թ ԼՁԾԾԽՊԽՆԻԽ ՁՆ ԺՇԼՑ

ՄԽՆԿՌՀՇՊԺՇԼՑՏԽՁԿՀՌԾՇՊԽՁՌՀԽՊՋԽՐԫՇԽԾԾԽԻՌՋՇՆՋԽԻՇՆԼԹՊՑՋ ԽՐԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋՇՊԻՄՁՆՁԻԹՄՋՁԿՆՋՇԾՌՇՐՁԻՁՌՑ

ՁԽ ԺԽՀԹՎՁՇՊԹՄԹՆԼՇՌՀԽՊՋՍԺՄԽՌՀԹՄԽԾԾԽԻՌՋՏԽՊԽՇԺՋԽՊՎԽԼԣԽԻՍՆ ԼՁՌՑՏԹՋՄՇՏԽՊԹՌՌՀԽՅԿԹՁԩ

ԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՈԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՊԽՄԹՌՁՎԽՌՇՌՀԽՆԽ ԿԹՌՁՎԽԻՇՆՌՊՇՄԣԽՊՌՁՄՁՌՑՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՄՇՏԽՊ

ՈԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԹՌՌՀԽՅԿԹՁԩԻՇՆԻԽՆՌՊԹ ՌՁՇՆԪԽԼՁԹՆՌՍԺԽՊԻՄԽՋԻՇՊԽՋՁՆՅԹՄԽԾՁՋՀ

ՏԽՊԽ  ԹՆԼ  ՁՆ ՌՀԽ  ԹՆԼ  ՅԿ ԹՁԩ ՌՊԽԹՌՅԽՆՌՋ ՊԽՋՈԽԻՌ ՁՎԽՄՑ ԻՇՅՈԹՊԽԼ ՌՇ  ՁՆ ՌՀԽ ՆԽԿԹՌՁՎԽ

ԻՇՆՌՊՇՄ
ՈԫՇՌՍԺԽՊԻՄԽՋՏԽՊԽՇԺՋԽՊՎԽԼՇՆԾԽՅԹՄԽԾՁՋՀԱՀԽՊԽՏԽՊԽՆՇԽԾԾԽԻՌՋՇՆՈՄԹՋՅԹՎՁՌԽՄՄՇԿԽՆՁՆ

ԳԱԤՇՊԿՇՆԹԼՇՋՇՅԹՌՁԻՁՆԼԽՐ
Ԥ԰ԦԭՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋՏԽՊԽՊԽՈՇՊՌԽԼՄՑՅԽԹՋՍՊԽԼԺՍՌՆՇՊԽՋՍՄՌՋՏԽՊԽ

ՈՊՇՎՁԼԽԼ

ԱՀԽՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋԽՋՁՆՅԹՄԽՋԹՋՋՇԻՁԹՌԽԼԽՐՈՇՋԽԼՌՇՈՊՇ ՆԹՅՁԼԽԹՌՅԿԹՁԩՁՆԻՄՍԼԽԼԼԽԻՊԽԹՋԽԼ

ՈՊՇՈՇՊՌՁՇՆՋ ՇԾ ՋՈԽՊՅԹՌՇՒՇԹ ՁՆԻՊԽԹՋԽԼ ՁՆՌԽՊՋՌՁՌՁԹՄ ԻԽՄՄ ՀՑՈԽՊՈՄ ԹՋՁԹ ԹՆԼ ՈՊՇՌԽՁՆԹԻԽՇՍՋ ԾՄՍՁԼ ԹՆԼ ՁՆԻՊԽԹՋԽԼ

ՌԽՋՌՁԻՍՄԹՊԼԽԿԽՆԽՊԹՌՁՇՆԹՌՌՀԽՅԿԹՁԩՄԽՎԽՄՌՀԽՊԽՏԽՊԽՆՇՌՊԽԹՌՅԽՆՌՊԽՄԹՌԽԼԽԾԾԽԻՌՋՁՆԾԽՅԹՄԽՋԱՏՇՇԾ

ՌՀԽՌԹՆՃՋՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՇՆԽՌԹՆՃՁՆՌՀԽՋՇՄՎԽՆՌԻ ՇՆՌՊՇՄԻՇՆՌԹՁՆԽԼՌՀՊԽԽՅԹՄԽՋԹՆԼՌՀՊԽԽԾԽՅԹՄԽՋ

ԼՍԽՌՇՅՁՋՋԽՐԽԼԾՁՋՀ

ԠՇՅՈԹՊՁՋՇՆՋԺԽՌՏԽԽՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈՋՊԽՎ ԽԹՄԽԼՆՇՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋ

Ո ԾՇՊԹՆՑԽՆԼՈՇՁՆՌԳԹՄՁԼՁՌՑԻՊՁՌԽՊՁԹԾՇՊՋՍՊՎՁՎԹՄ
ՋՇՄ ՎԽՆՌԻՇՆՌՊՇՄՇՆՄՑԹՆԼԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆԻՇՆՌԽՆՌ

ՁՆ ՌՀԽ ԬԠ԰ԭԭ  ԿՍՁԼԹՆԻԽ ՏԽՊԽ  ՆՇՌ ՅԽՌ ԺՍՌ ՌՀԽՋԽ ԼԽՎՁԹՌՁՇ ՆՋ ԼՁԼ ՆՇՌ ՋՍԺՋՌԹՆՌՁՎԽՄՑ ՁՅՈԹԻՌ ՌՀԽ

ՊԽՋՍՄՌՋՇՊՁՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀՁՋՋՌՍԼՑ

ԱՀՁՋ ԹՋՋԹՑ ՋԹՌՁՋԾՁԽՋ  ՌՀԽ Ԣԡ԰ԭ ԱՁԽՊ  ԱԽՋՌ ԬՊԼԽՊ ԾՇՊ Թ ԣՁՋՀ ԰ՀՇՊՌԱԽՊՅ ԯԽՈՊՇԼՍԻՌՁՇՆ ԞՋՋԹՑ 
ԬԠ԰ԭԭ

ԤՍՁԼԽՄՁՆԽ

ԯԽՋՍՄՌՋ԰ՑՆՇՈՋՁՋ

ԱԽՋՌՇՊԿԹՆՁՋՅԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ԻԹ ՅՇՆՌՀ
ՏԽԽՃՋ

ԪԽԹՆԺՇԼՑՏԽՁԿՀՌԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆՅԹՄԽԿ
Կ չՇԾՅԽԹՆԾԽՅԹՄԽԿ


ԿչՇԾՅԽԹՆ

ԪԽԹՆՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԫՇՌՅԽԹՋՍՊԽԼ

ԱԽՋՌՌՑՈԽԾՄՇՏՌՀՊՇՍԿՀԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢԾԾԽԻՌՋՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ
ԣ԰ԱԯԞՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԣԽԻՍՆԼՁՌՑԣԽՊՌ԰ՍԻԻԽՋՋԱՍԺԽՊԻՄԽ԰ԻՇՊԽԤ԰ԦԤՇՆԹԼԹՄԥՁՋՌՇԭՄԹՋՅԹԳԱԤԭՄԹՋՅԹԱԭՄԹՋՅԹԢԪԣԪԣԪԣԪԣԪԣԪԣԫՇ ԫՇԶԽՋԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫԞ ԫԞ ԫԞ ԫԞԶԽՋ ԶԽՋ ԶԽՋԫՇ ԫՇ ԫՇԶԽՋԫՇ ԫՇ ԫՇ ԫԞ ԫԞ ԫԞ ԫԞԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԢȕԽՋՌՊԹԼՁՇՄԣԣԽՅԹՄԽԣԽՊՌԣԽՊՌՁՄՁՒԹՌՁՇՆԤ԰ԦԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐԥՁՋՌՇԥՁՋՌՇՈԹՌՀՇՄՇԿՑԪԪԹՄԽԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԱԱԽՋՌՇՋՌԽՊՇՆԽԳԱԤԳՁՌԽՄՄՇԿԽՆՁՆ Ԟ՟ՑԽՋՠՁՆԼՁԻԹՌԽՋԹՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽ
ՈԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄՍՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼ  ԱՀԽԻՊՁՌԽՊՁԹԾՇՊՋՁԿՆՁԾՁԻԹՆԻԽԹՊԽԼԽՋԻՊՁԺԽԼՁՆՌՀԽԯԽՎՁԽՏԽՊ0ՋԞՆԹՄՑՋՁՋԹՆԼ԰ՌԹՌՁՋՌՁԻԹՄԳԽՊՁԾՁԻԹՌՁՇՆՋԽԻՌՁՇՆՋՇԾՌՀԽԡԢԯԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ ԱՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆՌՊԽԹՌՅԽՆՌՏԹՋՌԽՊՅՁՆԹՌԽԼՇՆԡԹՑԼՍԽՌՇՀՁԿՀՅՇՊԺՁԼՁՌՑ  ԱՀԽՈՎԹՄՍԽՏԹՋՍՋՁՆԿՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌՊԽՆԼՌԽՋՌԺՍՌՌՀԽԼԽԻՊԽԹՋԽՏԹՋԻՇՆՋՁԼԽՊԽԼՋՁԿՆՁԾՁԻԹՆՌԼՍԽՌՇՌՀԽՅԹԿՆՁՌՍԼԽԹՆԼԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋՁՎԽՈԹՌՌԽՊՆ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### Ԧ ԪԞԱԢԯԦԞԩ԰ԞԫԡԪԢԱԥԬԡ԰ 

ԤՍՁԼԽՄՁՆԽԣՇՄՄՇՏԽԼ  ԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼԹԻԻՇՊԼՁՆԿՌՇՌՀԽԲ԰ԢԭԞԬԠ԰ԭԭ ՟ԣՁՋՀ

԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՎԽԞՋՋԹՑՠԤՍՁԼԽՄՁՆԽԼԽՎՁԹՌՁՇՆՋԹՊԽՆՇՌԽԼ ԺԽՄՇՏ

 ԡՍԽՌՇՇՎԽՊՌՅՇՊԺՁԼՁՌՑՌՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՅԿԹՁԩ ՌՊԽԹՌՅԽՆՌՏԹՋՌԽՊՅՁՆԹՌԽԼՇՆ

ԡԹՑ  ԱՀԽՊԽԾՇՊԽ ՇՆՄՑ ՌՏՇ ԽՐՈՇՋՍՊԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ՏԽՊԽ ՋՌՍԼՁԽԼ ԱՀԽ ՇՆՄՑ ՊԹՌՁՇՆԹՄԽ ԾՇՊ

ՋԽՄԽԻՌՁՇՆ ՇԾ ՌՀԽ ՀՁԿՀԽՋՌ ՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ՏԹՋ ՄՁՋՌԽԼ ԹՋ ԻՇՆՋ ՍՄՌԹՌՁՇՆ ՏՁՌՀ ՌՀԽ ՋՌՍԼՑ

ՋՈՇՆՋՇՊԬԠ԰ԭԭ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆ ՈԽՊՅՁՌ  ՋՍՊՎՁՎԹՄ

ՍՈՌՇՌՀԽՄՁՅՁՌՇԾՋՇՄՍԺՁՄՁՌՑ

 ԱՀԽՋՍՊՎՁՎԹՄՎԹՄՁԼՁՌՑԻՊՁՌԽՊՁՇՆՇԾՏԹՋՆՇՌՅԽՌՁՆՌՀԽՋՇՄՎԽ ՆՌԻՇՆՌՊՇՄ

 ԱՀԽԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆԼՊՇՈՈԽԼԺԽՄՇՏՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼԹՄՄՈՊՇՆԹՅՁԼԽՌՊԽԹՌԽԼ

ԿՊՇՍՈՋ ՏՁՌՀ ՅՁՆՁՅԹ ՊԹՆԿՁՆԿ ԾՊՇՅ  ԬՆՄՑ ՊԹՆԿԽՋ ՏԽՊԽ ՊԽՈՇՊՌԽԼ ՋՇ ՌՀԽ ՊԽՎՁԽՏԽՊ

ԻՇՍՄԼՆՇՌԼԽՌԽՊՅՁՆԽՀՇՏՅԹՆՑՇՊԾՇՊՏՀՁԻՀԼԹՑՋԡԬԼՊՇՈՈԽԼԺԽՄՇ ՏՌՀԽՅՁՆՁՅՍՅԬԠ԰ԭԭ

ՊԽՉՍՁՊԽՅԽՆՌ

 ԱՏՇՇԾՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՌԹՆՃՋԹՆԼՇՆԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄՌԹՆՃՀԹԼՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋ

ԼՍԽՌՇՅՁՋՋԽՐԽԼԾՁՋՀԬԠ԰ԭԭՊԽԻՇՅՅԽՆԼՋՌՏՇՅԹՄԽՋԹՆԼ ԾՇՍՊԾԽՅԹՄԽՋՁՆԽԹԻՀ

ՌԹՆՃ

 ԦՆՁՌՁԹՄՅԹՄԽԹՆԼԾԽՅԹՄԽԾՁՋՀՏԽՁԿՀՌՋԽՐԻԽԽԼԽԼՌՀԽՊԽԻՇՅՅԽՆԼԽԼՅ ԹՐՁՅՍՅՎԹՊՁԹՌՁՇՆԹՊՇՍՆԼ

ՌՀԽ ՋԹՅՈՄԽ ՅԽԹՆ 
ՁԽ չ ՁՆՁՌՁԹՄ ՅԹՄԽ ԾՁՋՀ ՏԽՁԿՀՌՋ ՎԹՊՁԽԼ չ ԹՆԼ ՁՆՁՌՁԹՄ ԾԽՅԹՄԽ

ՏԽՁԿՀՌՋՎԹՊՁԽԼչՇԾՌՀԽՋԹՅՈՄԽՅԽԹՆ

 ԱՀԽ ՍՆՁՇՆՁՒԽԼ ԹՅՅՇՆՁԹ ԹՆԼ ՊԽՋՁԼՍԹՄ ԻՀՄՇՊՁՆԽ ՁՆ ՌՀԽ ՌԽՋՌ ՏԹՌԽՊ Տ ԽՊԽ ՆՇՌ ՊԽՈՇՊՌԽԼ ԱՀԽ

ԬԠ԰ԭԭՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹԽՋՌԹԺՄՁՋՀՅԹՐՁՅՍՅՄԽՎԽՄՋԾՇՊՌՀԽՋԽՎԹՄՍԽՋԹՆԼՁՌՁՋ

ՍՆԻՄԽԹՊՁԾՌՀԽՅԹՐՁՅՍՅՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋՏԽՊԽԽՐԻԽԽԼԽԼ

 ԬՆՌԽՋՌԡԹՑ ՌՀԽՅԹՐՁՅՍՅՌԽՅՈԽՊԹՌՍՊԽՏԹՋ ՊԽԻՇՊԼԽԼՌՇ ԺԽ ո ԠԾԹՄՄՁՆԿ ՇՍՌՋՁԼԽՌՀԽ

ՊԽՉՍՁՊԽԼՊԹՆԿԽՇԾչոԠ

ԱՀԽԼԽՎՁԹՌՁՇՆՋԼՇՆՇՌՋՍԺՋՌԹՆՌՁՎԽՄՑՁՅՈԹԻՌՌՀԽՊԽՋՍՄՌՋՇՊՁՆՌԽՈ ՊԽՌԹՌՁՇՆՇԾՌՀՁՋՋՌՍԼՑ

ԠՇՅՈՄՁԹՆԻԽ   ԰ՁԿՆԽԼԹՆԼԼԹՌԽԼԫՇԡԹՌԹԠՇՆԾՁԼԽՆՌՁԹՄՁՌՑԤԩԭԹՆԼԮՍԹՄՁՌՑԞՋ ՋՍՊԹՆԻԽՋՌԹՌԽՅԽՆՌՋ

ՏԽՊԽՈՊՇՎՁԼԽԼԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼՁՆԻՇՅՈՄՁԹՆԻԽՏՁՌՀԹՄՄ ՈԽՊՌՁՆԽՆՌԲ԰ԢԭԞ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԤՇՇԼ ԩԹԺՇՊԹՌՇՊՑԭՊԹԻՌՁԻԽ ՊԽԿՍՄԹՌՁՇՆՋՏՁՌՀՌՀԽԾՇՄՄՇՏՁՆԿ ԽՐԻԽՈՌՁ ՇՆՋ ՊՇՍՌՁՆԽ ԼՁՄՍՌՁՇՆ

ՏԹՌԽՊ ԹՆԼ ԾՇՇԼ ԻՇՆՌԹՅՁՆԹՆՌ ՋԻՊԽԽՆՁՆԿ ԹՆԹՄՑՋԽՋ ԾՇՊ ՈԽՋՌՁԻՁԼԽՋ ԭ ԠԟՋ ԹՆԼ ՌՇՐՁԻ

ՅԽՌԹՄՋ ԰ՁՆԻԽ ՌՀԽ ԹՆԹՄՑՋԽՋ ՏԽՊԽ ԻՇՆԼՍԻՌԽԼ ԾՇՄՄՇՏՁՆԿ ՋՌԹՆԼԹՊԼ ՎԹ ՄՁԼԹՌԽԼ ՅԽՌՀՇԼՋ

ՌՀԽՋԽԽՐԻԽՈՌՁՇՆՋՀԹԼՆՇՁՅՈԹԻՌՇՆՌՀԽՋՌՍԼՑՊԽՋՍՄՌՋ

Ԟ ԱԽՋՌԪԹՌԽՊՁԹՄ   ԭՊՇՆԹՅՁԼԽ

ԡԽՋԻՊՁՈՌՁՇՆ  ԞՈՀՑՋՁԻԹՄԼԽՋԻՊՁՈՌՁՇՆՏԹՋՆՇՌՈՊՇՎՁԼԽԼ

ԬԢԠԡՊԽԻՇՅՅԽՆԼՋԼԽՋԻՊՁԺՁՆԿՏԹՌԽՊՋՇՄՍԺՁՄՁՌՑՅԽՄՌՁՆԿԺՇ ՁՄՁՆԿՈՇՁՆՌՋՌԹԺՁՄՁՌՑՁՆՏԹՌԽՊԹՆԼՄՁԿՀՌՈԨԹ

ԭՇՏՇՊԨՇՏՎԹՈՇՊՈՊԽՋՋՍՊԽՇԾՌԽՋՌԻՇՅՈՇՍՆԼԽՐՈՁՊԹՌՁՇՆԼԹՌԽ

ԩՇՌԫՇԟԹՌԻՀԫՇ  ԵԤԯ

ԭՍՊՁՌՑ    

ԦՅՈՍՊՁՌՁԽՋ    ԫՇՌՊԽՈՇՊՌԽԼ

԰ՌԹԺՁՄՁՌՑՇԾ

ԠՇՅՈՇՍՆԼ  ԱՀԽՌԽՋՌՅԹՌԽՊՁԹՄՏԹՋՋՀՇՏՆՌՇԺԽԻՇՆՋՁՋՌԽՆՌ ՁՆՋՇՄՍՌՁՇՆՇՎԽՊՌ ՀԽՌԽՋՌՈԽՊՁՇԼ

ՏՁՌՀՅԽԹՆՅԽԹՋՍՊԽԼՊԽԻՇՎԽՊՁԽՋՊԹՆԿՁՆԿԾՊՇՅՇԾՆՇՅՁՆԹՄ

԰ՌՇՊԹԿԽԠՇՆԼՁՌՁՇՆՋՇԾ

ԱԽՋՌԠՀԽՅՁԻԹՄՋ  ԰ՌՇՊԽԼՁՆՌՀԽԼԹՊՃԹՌՊՇՇՅՌԽՅՈԽՊԹՌՍՊԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԟԱԽՋՌԬՊԿԹՆՁՋՅԱԹԺՄԽԤԽՆԽՊԹՄԦՆԾՇՊՅԹՌՁՇՆԞԺՇՍՌՌՀԽԱԽՋՌ԰ՈԽԻՁԽՋԹՆԼԞԻԻՄՁՅԹՌՁՇՆԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԽԻՁԽՋԻՇՅՅՇՆՆԹՅԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԢԭԞՊԽԻՇՅՅԽՆԼՋԾԹՌՀԽԹԼՅՁՆՆՇՏ
ԭՁՅԽՈՀԹՄԽՋ

ՈՊՇՅԽՄԹՋ԰ՈԽԻՁԽՋՋԻՁԽՆՌՁԾՁԻՆԹՅԽ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ԰ՈԽԻՁԽՋՋՌՊԹՁՆ
ՁԾՋՌԹՌԽԼԫՇՌՊԽՈՇՊՌԽԼԴԽՊԽԾՁՋՀՇԺՌԹՁՆԽԼԾՊՇՅԹՋՁՆԿՄԽՄԹԺՇՊԹՌՇՊՑՋՌՇԻՃ!ԶԽՋ ԦՆՀՇՍՋԽՄԹԺՇՊԹՌՇՊՑՋՌՇԻՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԾՊՇՅԹՋՁՆԿՄԽ

ՄԹԺՇՊԹՌՇՊՑՋՌՇԻՃԴԽՊԽԹԻԻՄՁՅԹՌՁՇՆԻՇՆԼՁՌՁՇՆՋՋԹՅԽԹՋԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԶԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԹԻԻՄՁՅԹՌԽԼՍՆԼԽՊ ՏԹՌԽՊՉՍԹՄՁՌՑԹՆԼՁՄՄՍՅՁՆԹՌՁՇՆԻՇՆԼՁՌՁՇՆՋՌՀԹՌԹՊԽ ՋՁՅՁՄԹՊՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԞԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԼԹՑՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՌՏՇՏԽԽՃ ԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԫՇՌԽՌՀԹՌՌՀԽԹԻԻՄՁՅԹՌՁՇՆ ՈԽՊՁՇԼՁՋԼՁԾԾԽՊԽՆՌԾՊՇՅՌՀԽՋՍԺՋԽՉՍԽՆՌՁՆՋՁՌՍ ՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՀԽԹՄՌՀԫՇՌՊԽԹՌՅԽՆՌՋԾՇՊԼՁՋԽԹՋԽՋՌԹՊՌՁՆԿՌՏՇՏԽԽՃՋՈՊՁՇՊՌՇՌՀԽՋՈԹՏՆՁՆԿՉՍԹՄՁԾՁԻԹՌՁՇՆ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՅՇՊՌԹՄՁՌՑԼՍՊՁՆԿՌՀԽ ԼԹՑՋՈՊՁՇՊՌՇՌՀԽՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽԺԽՄԽՋՋ ՌՀԹՆՇԾՌՀԽԻՍՄՌՍՊԽՈՇՈՍՄԹՌՁՇՆԦԾՅՇՊՌԹՄՁՌՑ ԼՍՊՁՆԿՌՀԽՋԽԼԹՑՋՁՋԿՊԽԹՌԽՊՌՀԹՆԢԭԞ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԾՁՋՀԺԽՊԽՂԽԻՌԽԼԦԾ ՅՇՊՌԹՄՁՌՑՁՋԺԽՌՏԽԽՆԢԭԞՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌԾՁՋՀԺԽՀԽՄԼԹՆՇՌՀԽՊԼԹՑՋԦԾՅՇՊՌԹՄՁՌՁԽՋ ԿՊԽԹՌԽՊՌՀԹՆՇԻԻՍՊԼՍՊՁՆԿՌՀՁՋԽՐՌԽՆԼԽԼ ԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽ

ԾՁՋՀՆՇՌԺԽՍՋԽԼԱՑՈԽՇԾԾՇՇԼԩՁՎԽԺՊՁՆԽՋՀՊՁՅՈՆԹՍՈՄՁՁ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԾԽԼԾՊՇՒԽՆԺՊՁՆԽ ՋՀՊՁՅՈՌՏՁԻԽՈԽՊԼԹՑՌՇՈՊՇՅՇՌԽԹԻՌՁՎԽ ՊԽՈՊՇԼՍԻՌՁՇՆԹՆԼՅԹՁՆՌԹՁՆԺՇԼՑԻՇՆԼՁՌՁՇՆ԰ՇՍՊԻԽՇԾԾՇՇԼԫՇՌՊԽՈՇՊՌԽԼԯԽՈՊԽՋԽՆՌԹՌՁՎԽՋԹՅՈՄԽՋՇԾՌՀԽԾՇՇԼՋՇՍՊԻԽՏԽՊԽՈԽՊՁՇԼՁԻԹՄՄՑԹՆԹՄՑՒԽԼԾՇՊՈԽՋՌՁԻՁԼԽՋԭԠԟՋԹՆԼՌՇՐՁԻՅԽՌԹՄՋԺՑԤԽՇԩԹԺՋԦՆԻԹՆԼԹՆԹՄՑՌԽՄԽՎԽՄՋՏԽՊԽԺԽՄՇՏԩԬԠՋՈԽԻՁԾՁԽԼԺՑԞ԰ԱԪ
ԣՊԽՉՍԽՆԻՑՇԾԾԽԽԼՁՆԿԱՏՇՌՁՅԽՋԼԹՑԡԽՌԹՁՄՋՇՆԾԽԽԼՁՆԿԫՇԼԽՌԹՁՄՋՇՆԹՅՇՍՆՌՏԽՊԽՈՊՇՎՁԼԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԣՁՋՀ԰ԽՄԽԻՌՁՇՆԹՆԼԭՊԽԢՐՈՇՋՍՊԽԭԽՊԾՇՊՅԹՆԻԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ԻԹՅՇՆՌՀՋ
ՏԽԽՃՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՊՇԼՍԻՌՁՎԽՄՑՅԹՌՍՊԽ ՋԽՐՍԹՄՄՑԼՁՅՇՊՈՀՁԻԾՁՋՀՅՇՆՌՀՋՇՄԼԪԽԹՆՏԽՁԿՀՌՇԾՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԿ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԹՋՍԺՋԹՅՈՄԽՇԾԾՁՋՀԺԽ ՏԽՁԿՀԽԼԺԽԾՇՊԽՌՀԽՌԽՋՌՌՇԽՋՌՁՅԹՌԽՌՀԽՅԽԹՆ ՏԽՁԿՀՌԾՇՊԽԹԻՀՋԽՐԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌՀԽ ՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՇԾԽԹԻՀԾՁՋՀՋԽՄԽԻՌԽԼԾՇՊՌՀԽ ՌԽՋՌԺԽՏՁՌՀՁՆչՇԾՌՀԽԽՋՌՁՅԹՌԽԼՅԽԹՆԾՇՊ

ԽԹԻՀՋԽՐԯԹՆԿԽՇԾՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԿԱՀԽՎԹՊՁԹՌՁՇՆՇԾՋԹՅՈՄԽՅԹՄԽԾՁՋՀՏԽՁԿՀՌՋՏԹՋչՇԾՌՀԽՅԽԹՆԽՐԻԽԽԼՁՆԿՌՀԽչՅԹՐՁՅՍՅՎԹՊՁԹՌՁՇՆՁՆՌՀԽԬԠ԰ԭԭԿՍՁԼԽՄՁՆԽԪԽԹՆՏԽՁԿՀՌՇԾԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼ ԯԹՆԿԽՇԾՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԿԱՀԽՊԹՆԿԽՇԾՋԹՅՈՄԽԾԽՅԹՄԽԾՁՋՀՏԽՁԿՀՌՋՏԹՋչՇԾՌՀԽՅԽԹՆԽՐԻԽԽԼՁՆԿՌՀԽչՅԹՐՁՅՍՅՎԹՊՁԹՌՁՇՆՁՆՌՀԽԬԠ԰ԭԭԿՍՁԼԽՄՁՆԽԪԽԹՆՄԽՆԿՌՀՇԾՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԫՇՌՊԽՈՇՊՌԽԼԪԽԹՆՄԽՆԿՌՀՇԾԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԫՇՌՊԽՈՇՊՌԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡՍՊԹՌՁՇՆՇԾՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽ ԼԹՑՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾԼԹՑՋԴԽՊԽՈՊԽԽՐՈՇՋՍՊԽԻՇՆԼՁՌՁՇՆՋՁԼԽՆՌՁԻԹՄՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԶԽՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՈՊԽԽՐՈՇՋՍՊԽԻՇՆԼՁՌՁՇՆՋ ՁՆԻՄՍԼՁՆԿՌԽՅՈԽՊԹՌՍՊԽՈՀՇՌՇՈԽՊՁՇԼԾԽԽԼՁՆԿԽՌԻ ԺԽՁԼԽՆՌՁԻԹՄՌՇԼԽԾՁՆՁՌՁՎԽՌԽՋՌԻՇՆԼՁՌՁՇՆՋԫՍՅԺԽՊՇԾՈՊԽԽՐՈՇՋՍՊԽՌԹՆՃՋ ԢՐՌՊԹՊԽՈՄՁԻԹՌԽՋՏԽՊԽԽՋՌԹԺՄՁՋՀԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԹԼԼՁՌՁՇՆԹՄՌԹՆՃՋՋԽՌՍՈԹՌ ՌՀԽԺԽԿՁՆՆՁՆԿՇԾՈՊԽԽՐՈՇՋՍՊԽՏՁՄՄԽՆՋՍՊԽՌՀԹՌ ՋՍԾԾՁԻՁԽՆՌՊԽՈՄՁԻԹՌԽՋՏՁՌՀՌՀԽԻՇՊՊԽԻՌՋԽՐՊԹՌՁՇԹՊԽ ԹՎԹՁՄԹԺՄԽԾՇՊՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԫՍՅԺԽՊՇԾՅԹՄԽՋՈԽՊՌԹՆՃ ԱՀՊԽԽՅԹՄԽԾՁՋՀՏԽՊԽՁՆԹԼՎԽՊՌԽՆՌՄՑԹԼԼԽԼՌՇՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՊԽՈՄՁԻԹՌԽՋԞԹՆԼԟԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՊԽՈՄՁԻԹՌԽԠԫՍՅԺԽՊՇԾԾԽՅԹՄԽՋՈԽՊՌԹՆՃ ԭՊԽԽՐՈՇՋՍՊԽԾԽԻՍՆԼՁՌՑԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՊԽՈՄՁԻԹՌԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՈՊԽԽՐՈՇՋՍՊԽԾԽԻՍՆԼՁՌՑՁՆ ԽԹԻՀՊԽՈՄՁԻԹՌԽ
ՌԹՆՃՋԽՄԽԻՌԽԼԾՇՊՍՋԽՁՆՌՀԽ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԹՌՄԽԹՋՌ ԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՊԽՈՄՁԻԹՌԽԼՍՊՁՆԿ ՌՀԽԼԹՑՋՈՊՁՇՊՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԫՍՅԺԽՊՇԾՋՈԹՏՆՋԼՍՊՁՆԿՈՊԽԽՐՈՇՋՍՊԽՌՏՇՌՁՅԽՋՁՆԼԹՑՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՋՈԹՏՆՁՆԿՇԻԻՍՊԹՌՄԽԹՋՌ ՌՏՁԻԽՁՆՌՀԽԼԹՑՋՈՊՁՇՊՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՈՊԽԽՐՈՇՋՍՊԽԣՁՋՀՏԽՊԽԾԽԼԹՅԽԹՋՍՊԽԼԹՅՇՍՆՌՇԾՄՁՎԽԺՊՁՆԽՋՀՊՁՅՈ ԞՊՌԽՅՁԹԠԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԦՆԾՇՊՅԹՌՁՇՆՇՆՌՀԽԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԹՆԼԱԽՋՌԳԽՋՋԽՄԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱՑՈԽՇԾԽՐՈՇՋՍՊԽԾՄՇՏՌՀՊՇՍԿՀ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԾՄՇՏՌՀՊՇՍԿՀ ՋՑՋՌԽՅԞՋՆՇՌԽԼՁՆՌՀԽԠՇՊՊԽԻՌՁՇՆՋԹՆԼ ԠՄԹՊՁԾՁԻԹՌՁՇՆՋԼՇԻՍՅԽՆՌ  ՌՀԽՍՋԽՇԾԹՋՌԹՌՁԻ ՊԽՆԽՏԹՄՋՑՋՌԽՅՁՋՆՇՌՊԽԻՇՅՅԽՆԼԽԼԾՇՊՌՀՁՋ

ԹՋՋԹՑԱՑՈԽՇԾԾՄՇՏՌՀՊՇՍԿՀԼՁՄՍՌՁՇՆՋՑՋՌԽՅԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋ ԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋՇՊ ԻՇՆՌՁՆՍՇՍՋԾՄՇՏՋԽՊՁԹՄԼՁՄՍՌԽՊՋԹՊԽ ՊԽԻՇՅՅԽՆԼԽԼ Բ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ
ԢԭԞ
ԠՇՊՊԽԻՌՁՇՆՋԹՆԼԠՄԹՊՁԾՁԻԹՌՁՇՆՋՇՆԱԽԻՀՆՁԻԹՄԞՋՈԽԻՌՋՇԾՌՀԽԱԽՋՌԤՍՁԼԽՄՁՆԽՋԾՇՊՌՀԽԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅԱՁԽՊԞՋՋԹՑՋ
ԬԠ԰ԭԭԱԽՋՌԤՍՁԼԽՄՁՆԽ԰ԽՊՁԽՋԪԹՊԻՀԬԾԾՁԻԽՇԾԠՀԽՅՁԻԹՄ԰ԹԾԽՌՑԹՆԼԭՇՄՄՍՌՁՇՆԭՊԽՎԽՆՌՁՇՆԬԠ԰ԭԭԴԹՋՀՁՆԿՌՇՆԡԠՀՌՌՈՏՏՏԽՈԹԿՇՎԽՆԼՇՈՍԺՋԹՋՋԹՑՎԹՄՁԼԹՌՁՇՆԻՄԹՊՁԾՁԻԹՌՁՇՆԼՇԻՈԼԾԞԼԼՁՌՁՇՆԹՄԿՍՁԼԹՆԻԽԾՇՊԹՉՍԹՌՁԻՌԽՋՌԼԽՋՁԿՆՁՋՄՇԻԹՌԽԼՁՆԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ԰ՈԽԻՁԹՄԠՇՆՋՁԼԽՊԹՌՁՇՆՋԾՇՊԠՇՆԼՍԻՌՁՆԿԞՉՍԹՌՁԻԩԹԺՇՊԹՌՇՊՑ԰ՌՍԼՁԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԣՄՇՏՌՀՊՇՍԿՀՊԹՌԽՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌՋԼԹՑ ԯԽԻՇՅՅԽՆԼԽԼԾՄՇՏՌՀՊՇՍԿՀՊԹՌԽՁՋ ՅԩՅՁՆ
ԩՀՊՇՊԹՌՄԽԹՋՌՌՇՌԹՄ ՎՇՄՍՅԽԽՐԻՀԹՆԿԽՋՈԽՊԼԹՑԡԽՌԹՁՄՋՇՆՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋԣՄՇՏՋՈՄՁՌՌՁՆԿԻՀԹՅԺԽՊՋՏԽՊԽՍՋԽԼԺԽՌՏԽԽՆՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋԢԹԻՀՅՁՐՁՆԿԾՄՇՏՋՈՄՁՌՌՁՆԿԻԽՄՄԼՁՎՁԼԽԼԽԹԻՀԩՎՇՄՍՅԽԾՇՍՊՏԹՑՋՊԽՋՍՄՌՁՆԿՁՆԻԹՅԩԼԽՄՁՎԽՊԽԼԽԹԻՀԻՑԻՄԽՌՇԽԹԻՀՇԾՌՀԽԿՄԹՋՋԹՉՍԹՊՁԹ ԯԽԻՇՅՅԽՆԼԽԼՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏ ՌՀՊՇՍԿՀՋՑՋՌԽՅՋԪՁՐՁՆԿԻՀԹՅԺԽՊՁՋ ՊԽԻՇՅՅԽՆԼԽԼԺՍՌՆՇՌՊԽՉՍՁՊԽԼԞԽՊԹՌՁՇՆՁՋ ՆՇՌՊԽԻՇՅՅԽՆԼԽԼԾՇՊՅՁՐՁՆԿԞ ԼԽՅՇՆՋՌՊԹՌՁՇՆՌՀԹՌՌՀԽՌԽՋՌՋՇՄՍՌՁՇՆՁՋ ԻՇՅՈՄԽՌԽՄՑՅՁՐԽԼԺԽԾՇՊԽՁՆՌՊՇԼՍԻԽԼՁՆՌՇՌՀԽ ՌԽՋՌՋՑՋՌԽՅՁՋՊԽԻՇՅՅԽՆԼԽԼԱՀԽ ՊԽԻՇՅՅԽՆԼԽԼԾՄՇՏՋՈՄՁՌՌՁՆԿԹԻԻՍՊԹԻՑՁՋՏՁՌՀՁՆ

ԞԽՊԹՌՁՇՆ!ԶԽՋ԰ՌԹՊՌԽԼՇՆԼԹՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹԽՊԹՌՁՇՆՁԾԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ

ՊԽԹԻՀԽՋ ՅԿԩ
 ՋԹՌՍՊԹՌՁՇՆԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՇՍՊԻԽՇԾԼՁՄՍՌՁՇՆՏԹՌԽՊԴԽՄՄՏԹՌԽՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՆԹՌՍՊԹՄՇՊՊԽԻՇՆՋՌՁՌՍՌԽԼ ՏԹՌԽՊՁՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՆԹՌՍՊԹՄՏԹՌԽՊ ԺԽՋՌԽՊՁՄՁՒԽԼՏՁՌՀԲԳԹՆԼՌԽՋՌԽԼԾՇՊ ՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊՈՇՋՋՁԺՄԽ ԻՇՆՌԹՅՁՆԹՆՌՋԬԢԠԡԹԻԻԽՈՌՋԹՆՑՏԹՌԽՊՁՆ ՏՀՁԻՀՌՀԽՌԽՋՌՋՈԽԻՁԽՋՋՀՇՏԻՇՆՌՊՇՄՋՍՊՎՁՎԹՄ ԹՌՄԽԹՋՌԹՋԿՇՇԼԹՋՁՆԼՁԻԹՌԽԼՁՆՌՀԽՌԽՋՌ

ԿՍՁԼԽՄՁՆԽԴԹՋԼՁՄՍՌՁՇՆՏԹՌԽՊԹՆԹՄՑՒԽԼԾՇՊՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊԻՇՆՌԹՅՁՆԹՆՌՋ!ԶԽՋԱՀԽՊԽՋՍՄՌՋՇԾՌՀԽԹՆԹՄՑՌՁԻԹՄՊԽՈՇՊՌՏԽՊԽՆՇՌՈՊՇՎՁԼԽԼԦՌՏԹՋՇՆՄՑՋՌԹՌԽԼՌՀԹՌՆՇՆԽՇԾՌՀԽՋԽԻՇՅՈՇՍՆԼՋՏԽՊԽԼԽՌԽԻՌԽԼԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԻՇՆՋՁԼԽՊԽԼՌՇԺԽՌՇՐՁԻԱԽՋՌՎԽՋՋԽՄՌՑՈԽՅԹՌԽՊՁԹՄՋ ԤՄԹՋՋԹՉՍԹՊՁԹ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՏԹՌԽՊ ԻՇՆՌԹԻՌՈՇՊՌՁՇՆՋՇԾՌՀԽՋՑՋՌԽՅՆՇՌ ԻՇՅՈՊՇՅՁՋԽՌՀԽՋՌՍԼՑ
ԽԿ ԹՄՄԿՄԹՋՋՎԽՋՋԽՄՋ ՇՊԿՄԹՋՋՎԽՋՋԽՄՋՏՁՌՀՋՌԹՁՆՄԽՋՋՋՌԽԽՄԾՊԹՅԽՋ ԹՊԽԹԻԻԽՈՌԹԺՄԽԽՐԹՅՈՄԽՋԱԽՋՌՎԽՋՋԽՄՋՁՒԽԩՐՐԻՅ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԩՌԽՋՌ ԻՀԹՅԺԽՊՋ
ԽԿՐՐԻՅԣՁՄՄՎՇՄՍՅԽԩ ԢԭԞՊԽԻՇՅՅԽՆԼՋԩՋՇՄՍՌՁՇՆՈԽՊՌԹՆՃԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՅԹՌԽՊՁԹՄ ԞԿԽԼԭԳԠՈՁՈԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԽԹԻՀՌԹՆՃԻՇՆՌԹՁՆ ՌՀՊԽԽՋԽՅՁԻՁՊԻՍՄԹՊՋՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՋԽԿ ԹԿԽԼԭԳԠՈՁՈԽԻՅՁՆՄԽՆԿՌՀՋՈՄՁՌ

ՄԽՆԿՌՀՏՁՋԽ԰ՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՋՁՒԽ ԠՍՌ ՄԽՆԿՌՀՏՁՋԽ ՌՇ ՈՊՇԼՍԻԽԹՊԻՀԽՋԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋՇՆԽՐՈՇՋՍՊԽՋՑՋՌԽՅ ԫՇԾՍՊՌՀԽՊԼԽՌԹՁՄՋՈՊՇՎՁԼԽԼԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԴԹՌԽՊԮՍԹՄՁՌՑԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋՁՆՌՀԽԱԽՋՌ԰ՑՋՌԽՅԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՅՈԽՊԹՌՍՊԽ
ոԠԠՇՆՌՁՆՍՇՍՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌԽՅՈԽՊԹՌՍՊԽչ Շ ԠՁՆՌԽՊ ՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌԼՁԾԾԽՊԽՆՌՁԹՄՋ ՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼ Շ ԠՈԥԡԹՁՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈԥՌՇԡՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ՅԿԩ 
 
 ԡԹՁՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ԡԬ ՅԿԩ
 ԹՁՊՋԹՌՍՊԹՌՁՇՆԱՇՌԹՄԹՄՃԹՄՁՆՁՌՑ
ՅԿԩԹՋԠԹԠԬ ԴԽԽՃՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՇՌԹՄԹՄՃԹՄՁՆՁՌՑ ՅԿԩ

ԹՋԠԹԠԬ ԥԹՊԼՆԽՋՋ#ՅԿԩԹՋԠԹԠԬ% ԴԽԽՃՄՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱՇՌԹՄՇՊԿԹՆՁԻԻԹՊԺՇՆ
ՅԿԩ ԪՇՆՌՀՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՇՌԹՄՇՊԿԹՆՁԻԻԹՊԺՇՆՁՆ ԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ ՅԿԩԲՆՁՇՆՁՒԽԼԹՅՅՇՆՁԹμԿԩ ԫԯ ԫԯ ԫԯ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՍՆՁՇՆՁՒԽԼԹՅՅՇՆՁԹՁՆ ՌՀԽԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ  μ ԿԩԯԽՋՁԼՍԹՄԻՀՄՇՊՁՆԽμԿԩ ԫԯ ԫԯ ԫԯ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՊԽՋՁԼՍԹՄԻՀՄՇՊՁՆԽՁՆ ԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ μ ԿԩԠՇՆԼՍԻՌԹՆԻԽ
սՅՀՇՋԻՅ ԴԽԽՃՄՑ ԤԽՆԽՊԹՄՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋԾՇՊԾՊԽՉՍԽՆԻՑՇԾ ՅԽԹՋՍՊԽՅԽՆՌՋԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ՌԽՅՈԽՊԹՌՍՊԽՈԥԹՆԼԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆԺԽ ՅԽԹՋՍՊԽԼՁՆԹՄՄՌԽՋՌՌԹՆՃՋԹՌՄԽԹՋՌՏԽԽՃՄՑԹՆԼ ՌՀԹՌՀԹՊԼՆԽՋՋԹՆԼԹՄՃԹՄՁՆՁՌՑԺԽՅԽԹՋՍՊԽԼՁՆ ԻՇՆՌՊՇՄՋԹՆԼՁՆՇՆԽՌԹՆՃԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՄԽԹՋՌՏԽԽՃՄՑԦՆԹԼԼՁՌՁՇՆ ԻՇՆՌՁՆՍՇՍՋՌԽՅՈԽՊԹՌՍՊԽՅՇՆՁՌՇՊՁՆԿՇԾԹՌՄԽԹՋՌ ՇՆԽՌԹՆՃՁՋԽՆԻՇՍՊԹԿԽԼԫԯԫՇՌՊԽՈՇՊՌԽԼԪԽԹՆՋՏԽՊԽԻԹՄԻՍՄԹՌԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊԹՋՌՀԽԹՎԽՊԹԿԽՇԾՌՀԽՅՁՆՁՅԹԹՆԼՅԹՐՁՅԹԾՇՊՌՀԽՊԹՆԿԽՋՈՊՇՎՁԼԽԼԹԻՊՇՋՋԻՇՆՌՊՇՄԹՆԼՌՊԽԹՌԽԼՄԽՎԽՄՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԡ԰ՌՍԼՑԡԽՋՁԿՆԹՆԼԞԼԼՁՌՁՇՆԹՄԢՐՈԽՊՁՅԽՆՌԹՄԠՇՆԼՁՌՁՇՆՋԱԹԺՄԽԯԹՆԿԽԣՁՆԼՁՆԿ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋ
ՁԾԞՈՈՄՁԻԹԺՄԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԹՊԹՆԿԽԾՁՆԼԽՊԻՇՆԼՍԻՌԽԼ!ԫՇ ԢԭԞՊԽԻՇՅՅԽՆԼՋԻՇՆԼՍԻՌՁՆԿԹՊԹՆԿԽԾՁՆԼԽՊՁԾ

ՀՇՍՊԩԠ  ԼԹՌԹԾՇՊՌՀԽԾԹՌՀԽԹԼՅՁՆՆՇՏԹՊԽ

ՍՆԹՎԹՁՄԹԺՄԽԦԾՑԽՋՏՀԹՌՏԹՋՌՀԽՅԽՌՀՇԼԾՇՊԼԽՌԽՊՅՁՆՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽՊԹՆԿԽԾՁՆԼԽՊ!ԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆԺԽՋԽՄԽԻՌԽԼԺԹՋԽԼՇՆՌՇՐՁԻՁՌՑԼԹՌԹ ԾՇՊՇՌՀԽՊԾՁՋՀՋՌՍԼՁԽՋՇՊՋՈԽԻՁԽՋՁԾԹՎԹՁՄԹԺՄԽ ԬՌՀԽՊՏՁՋԽԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽՌԽՋՌ ԻՇՅՈՇՍՆԼՇՊՅԿԩ
ՏՀՁԻՀԽՎԽՊՁՋՄՇՏԽՊՁՋ

ԹՈՈՊՇՈՊՁԹՌԽ԰ՈԽԻՁԽՋԫԞԩՁԾԽՋՌԹԿԽԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՊԹՆԿԽԾՁՆԼՁՆԿՌԽՋՌՋԺԽ ՈԽՊԾՇՊՅԽԼՏՁՌՀԾՁՋՀՇԾՋՁՅՁՄԹՊԹԿԽԹՆԼՋՁՒԽՌՇ ՌՀՇՋԽՌՀԹՌՏՇՍՄԼԺԽՍՌՁՄՁՒԽԼՁՆՌՀԽՌԽՋՌԱԽՋՌԼՍՊԹՌՁՇՆԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՀՇՍՊԽՐՈՇՋՍՊԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋԻՇՆԼՍԻՌՁՆԿԹՊԹՆԿԽԾՁՆԼԽՊՏՁՌՀ ԾՁՎԽՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋՈՄՍՋԹԻՇՆՌՊՇՄ
ՋՁՐՌՇՌԹՄ ՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՏՁՌՀԾՇՍՊԾԽՅԹՄԽՋԹՆԼՌՏՇ ՅԹՄԽՋՈԽՊԽՐՈՇՋՍՊԽՌԹՆՃ
ԾՁՋՀՌՇՌԹՄԱՀԽ ՆՍՅԺԽՊՇԾՅՇՊՌԹՄՁՌՁԽՋՌՀԹՌՇԻԻՍՊՅԹՑԺԽՍՋԽԼՌՇ ԼԽՎԽՄՇՈԹԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽԻՍՊՎԽ ԟԹՋԽԼՍՈՇՆՌՀԽՊԽՋՍՄՌՋՌՀԽՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆ ՌՀԹՌԼՇԽՋՆՇՌՊԽՋՍՄՌՁՆՁՆԻՊԽԹՋԽԼՅՇՊՌԹՄՁՌՑՇՊ ՋՁԿՆՋՇԾՇՎԽՊՌՅՇՊԺՁԼՁՌՑԻՇՅՈԹՊԽԼՌՇԻՇՆՌՊՇՄՋՇՊ ՌՀԽԼԽՊՁՎԽԼՀՊԩԠ  ՅԹՑԺԽՋԽՄԽԻՌԽԼԹՋ ՌՀԽՀՁԿՀԽՋՌԽՐՈՇՋՍՊԽԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԹՑ

ՌԽՋՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԡԽԾՁՆՁՌՁՎԽ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՋՌԼՍՊԹՌՁՇՆԼԹՑՋԡՍԽՌՇՋԻՀԽԼՍՄՁՆԿԻՇՆԾՄՁԻՌՋՌՀԽԽՐՈՇՋՍՊԽՏԹՋՅԹՁՆՌԹՁՆԽԼԾՇՊԹՈԽՊՁՇԼՇԾԼԹՑՋԹՋՇՈՈՇՋԽԼՌՇՌՀԽՋՌԹՆԼԹՊԼԼԹՑՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԼՍՊԹՌՁՇՆՇԾՌՀԽ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԼԹՑՋԪԽՌՀՇԼԾՇՊՋԽՄԽԻՌՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԟԹՋԽԼՇՆԻՇՆՋՍՄՌԹՌՁՇՆՏՁՌՀՋՈՇՆՋՇՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽ ՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊԼԽՅՇՆՋՌՊԹՌԽՋ ԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ
ԽԿՌՀԽ

ՀՇՍՊԩԠ  ՏՀՁԻՀԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌԯԽԾԽՊԽՆԻԽՋՌՍԼՑԻՁՌԹՌՁՇՆ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ԰ԽՈԹՊԹՌՁՇՆՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԱԽՆԾՇՄԼ ԢԭԞՋՍԿԿԽՋՌՋՌՀԹՌԹԻՇՆԻԽՆՌՊԹՌՁՇՆՋԽՈԹՊԹՌՁՇՆՇԾ ԺԽՌՏԽԽՆ
ՇՊՌՀՊԽԽԾՇՄԼԹՆԼ
ՇՊՌԽՆ ԾՇՄԼՁՋՋԻՁԽՆՌՁԾՁԻԹՄՄՑԹԻԻԽՈՌԹԺՄԽ  ԫՍՅԺԽՊՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԱՀԽՀՁԿՀԻՇՆԻԽՆՌՊԹՌՁՇՆՌՊԽԹՌՅԽՆՌՏԹՋՌԽՊՅՁՆԹՌԽԼՇՆԡԹՑԼՍԽՌՇՀՁԿՀՅՇՊՌԹՄՁՌՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹՆԼԹԻՇՆՌՊՇՄՈՄՍՋՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ՁԾԹՈՈՊՇՈՊՁԹՌԽԞՊԽՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹԼՂՍՋՌԽԼԾՇՊՈՍՊՁՌՑ!ԶԽՋ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԦՆԼՁԻԹՌԽՌՀԽՌՑՈԽՇԾՎԹՄՍԽՋՈՊԽՋԽՆՌԽԼԾՇՊՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋԪԽԹՆՅԽԹՋՍՊԽԼԞՎԽՊԹԿԽՊԽԻՇՎԽՊՁԽՋՊԹՆԿԽԼԾՊՇՅՌՇՇԾՆՇՅՁՆԹՄԩՁՅՁՌՇԾՉՍԹՆՌՁԾՁԻԹՌՁՇՆ
ԩԬԮ ՅԿԹՁԩԱՀԽԩԬԮԾՇՊՌՀԽԹՆԹՄՑՌՁԻՈԽՊՁՇԼԼԽՈԽՆԼԽԼՇՆՌՀԽՊԽԿՊԽՋՋՁՇՆԹՆԹՄՑՋՁՋՈԽՊԾՇՊՅԽԼՇՆՌՀԹՌԼԹՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՇՊԻՀԽՅՁԻԹՄՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՄՇՏՌՀԽԩԬԮԹՆԹՄՑՋԽՋԺԽ ԻՇՆԼՍԻՌԽԼՇՆՌՀԽՋՌՇԻՃՋՇՄՍՌՁՇՆՋԩԽՎԽՄՇԾԼԽՌԽԻՌՁՇՆ
ԩԬԡԫՇՌՊԽՈՇՊՌԽԼԣՊԽՉՍԽՆԻՑՇԾՅԽԹՋՍՊԽՅԽՆՌ ԼԹՑՋ  ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌԽՋՌՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆ ԺԽՅԽԹՋՍՊԽԼՈՊՁՇՊՌՇՌՀԽԹԼԼՁՌՁՇՆՇԾԾՁՋՀՁՆԹՄՄ ՌԹՆՃՋԹՆԼԹՌՄԽԹՋՌՏԽԽՃՄՑՌՀԽՊԽԹԾՌԽՊՁՆՌՏՇ ՊԽՈՄՁԻԹՌԽՋՈԽՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄԴԹՋՌՀԽՊԹՆԼՇՅՁՒԽԼԻՇՅՈՄԽՌԽԺՄՇԻՃԼԽՋՁԿՆՍՋԽԼ!ԶԽՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԹՄՄԾՁՋՀԺԽՊԹՆԼՇՅՄՑ ԹՋՋՁԿՆԽԼՌՇՌԹՆՃՋԼՍՊՁՆԿՈՊԽԽՐՈՇՋՍՊԽԱԹՆՃՋ ԹՊԽՌՀԽՆՊԹՆՃԽԼԹԻԻՇՊԼՁՆԿՌՇՈՊԽԽՐՈՇՋՍՊԽ ԾԽԻՍՆԼՁՌՑԹՆԼՌՀԽՌԹՆՃՋՏՁՌՀՌՀԽՀՁԿՀԽՋՌ ԾԽԻՍՆԼՁՌՑԹՊԽՊԹՆԼՇՅՄՑԹՋՋՁԿՆԽԼՌՇԹԼԽԾՁՆՁՌՁՎԽ ՌԽՋՌՌՊԽԹՌՅԽՆՌԹՆԼԺՄՇԻՃԾՁՊՋՌԢԹԻՀԺՄՇԻՃ ԻՇՆՌԹՁՆՋՇՆԽՊԽՈՄՁԻԹՌԽՇԾԽԹԻՀՌՊԽԹՌՅԽՆՌ ՁՆԻՄՍԼՁՆԿԻՇՆՌՊՇՄՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆԻՇՆՌՊՇՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԻՇՆԻՍՊՊԽՆՌ ՋՇՄՎԽՆՌԻՇՆՌՊՇՄՏՀԽՆԹՋՇՄՍԺՁՄՁՒՁՆԿԹԿԽՆՌՁՋՍՋԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՈԽՊՌԽՋՌՁՌԽՅՌՊԽԹՌՅԽՆՌՄԽՎԽՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՅԹՄԽԾՁՋՀՈԽՊՊԽՈՄՁԻԹՌԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋՏԽՊԽՍՋԽԼՁՆԻՇՆՌՊՇՄՌԹՆՃՋԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՌԹՆՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋՅԹՄԽՋՈԽՊՊԽՈՄՁԻԹՌԽ ԫՍՅԺԽՊՇԾԾԽՅԹՄԽԾՁՋՀՈԽՊՊԽՈՄՁԻԹՌԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋՏԽՊԽՍՋԽԼՁՆԻՇՆՌՊՇՄՌԹՆՃՋԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՌԹՆՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋԾԽՅԹՄԽՋՈԽՊՊԽՈՄՁԻԹՌԽԴԹՋԹՋՇՄՎԽՆՌՍՋԽԼ!ԶԽՋ԰ՇՄՎԽՆՌՌՑՈԽ
ՁԾԹՈՈՄՁԻԹԺՄԽ ԡԪԣԪԹՐՁՅՍՅՋՇՄՎԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՁԾԹՈՈՄՁԻԹԺՄԽՅԩԩ ԱՀԽՅԹՐՁՅՍՅՋՇՄՎԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀՁՋՋՌՍԼՑԽՐԻԽԽԼԽԼՌՀԽՅՄԩՊԽԻՇՅՅԽՆԼԽԼԺՑԢԭԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՋՇՄՎԽՆՌՆՇՌԽՐԻԽԽԼ

ՅՄԩ ԬԢԠԡՊԽԻՇՅՅԽՆԼՋՌՀԹՌՋՇՄՎԽՆՌ ՀԹՎԽՆՇԽԾԾԽԻՌՇՆՋՍՊՎՁՎԹՄՆՇՊՈՊՇԼՍԻԽԹՆՑՇՌՀԽՊ ԹԼՎԽՊՋԽԽԾԾԽԻՌՋԹՆԼՌՀԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆՆՇՌԺԽ ԿՊԽԹՌԽՊՌՀԹՆՅՄԩ ԴԹՋԹՈՇՋՁՌՁՎԽԻՇՆՌՊՇՄՍՋԽԼ! ԫՇԥՍՌԻՀՁՆՋՇՆԱԥ԰ՀՁՄՄԹԺԽԽՊԫԴՁՆՌԽՊԪԧԭՁԻՃԾՇՊԼԡԟ
ԞԻՍՌԽԹՆԼԻՀՊՇՆՁԻԽԾԾԽԻՌՋՇԾԻԹՊՊՁԽՊՋՇՄՎԽՆՌՋՁՆԹՉՍԹՌՁԻՇՊԿԹՆՁՋՅՋԞԻՊՁՌՁԻԹՄՊԽՎՁԽՏԯԽՎՁԽՏԞՉՍԹՌՁԻԱՇՐՁԻՇՄՇԿՑՈՈ-ՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ ԫԞՋ
ՁԾ ԫԞՀՊՋՄՁԿՀՌՀՊՋԼԹՊՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈՀՇՌՇՈԽՊՁՇԼ
ՄՁԿՀՌԼԹՊՃԹԻԽ ՌՇՄՍՐԩՁԿՀՌՏԹՋՈՊՇՎՁԼԽԼԺՑ԰ՑՄՎԹՆՁԹԬՃՌՊՇՆնԾՄՍՇՊԽՋԻԽՆՌԺՍՄԺՋԹՆԼՁՆՌԽՆՋՁՌՑՏԹՋՅԽԹՋՍՊԽԼՏՁՌՀԹԳԴԯՄՁԿՀՌՅԽՌԽՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՄՁԿՀՌՁՆՌԽՆՋՁՌՑ-ՄՍՐ ԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽ԰ՌՇԻՃՋՇՄՍՌՁՇՆՏԹՋՇԺՋԽՊՎԽԼՌՇԺԽԻՄԽԹՊԹՆԼՑԽՄՄՇՏՏՁՌՀՆՇՎՁՋՁԺՄԽՍՆԼՁՋՋՇՄՎԽԼՌԽՋՌՋՍԺՋՌԹՆԻԽԾՇՄՄՇՏՁՆԿՈՊԽՈԹՊԹՌՁՇՆԱՀՊՇՍԿՀՇՍՌՌՀԽՋՌՍԼՑՈԽՊՁՇԼԹՄՄԽՐՈՇՋՍՊԽՋՇՄՍՌՁՇՆՋՏԽՊԽՇԺՋԽՊՎԽԼՌՇԺԽԻՄԽԹՊԹՆԼԻՇՄՇՊՄԽՋՋՍՅԽՆՌՇՆԞՉՍԹՌՁԻԱՇՐՁԻՁՌՑԱԽՋՌՁՆԿՇԾԡՁԾԾՁԻՍՄՌ԰ՍԺՋՌԹՆԻԽՋԹՆԼԪՁՐՌՍՊԽՋԢՆՎՁՊՇՆՅԽՆՌԹՄԥԽԹՄՌՀԹՆԼ԰ԹԾԽՌՑԭՍԺՄՁԻԹՌՁՇՆՋ԰ԽՊՁԽՋՇՆԱԽՋՌՁՆԿԹՆԼՆԻԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԱՊԽԹՌՅԽՆՌԠՇՆԻԽՆՌՊԹՌՁՇՆՋՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌԦԡԫՇՅՁՆԹՄԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՋՍՊԽԼԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՆԠԳ
ԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԠՇՆՌՊՇՄ
ԼՁՄՍՌՁՇՆՏԹՌԽՊՇՆՄՑԩԬԮԫԞ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌԽՋՌ ՁՌԽՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԺԽ ՅԹՁՆՌԹՁՆԽԼ ԹՌ Թ ԻՇԽԾԾՁԻՁԽՆՌ ՇԾ ՎԹՊՁԹՌՁՇՆ 
ԠԳ ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄԩԬԮԫԞԱՊԽԹՌՅԽՆՌԱՊԽԹՌՅԽՆՌԱՊԽԹՌՅԽՆՌԞԺԺՊԽՎՁԹՌՁՇՆՋԠԳԠՇԽԾԾՁԻՁԽՆՌՇԾՎԹՊՁԹՌՁՇՆԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽԢԬԺՋԽՊՎԹՌՁՇՆՋԟՁՇՄՇԿՁԻԹՄԢՆԼՈՇՁՆՌՋԢՆԼՈՇՁՆՌՋ ՁՆԻՄՍԼԽԼԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՒԹՌՁՇՆ ՋՍԻԻԽՋՋ ՋՍՊՎՁՎԹՄ ՊԹՌԽՋՏԽՁԿՀՌ ՆՍՈՌՁԹՄ ՌՍԺԽՊԻՄԽ ՋԻՇՊԽԳԱԤ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԹՆԼԤ԰Ԧ ԰ԽՐ ՋՌԽՊՇՁԼՋ ՏԽՊԽ ՊԽՈՇՊՌԽԼՄՑ ՅԽԹՋՍՊԽԼ ԺՍՌ ՆՇ ՊԽՋՍՄՌՋ ՏԽՊԽ ՈՊՇՎՁԼԽԼ ԰ԽԻՇՆԼԹՊՑ ՋԽՐ ԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋ ԹՆԼԺԽՀԹՎՁՇՊԹՄԻՄՁՆՁԻԹՄՋՁԿՆՋՏԽՊԽՊԽՈՇՊՌԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԴԽՊԽՊԹՏ
ՁՆԼՁՎՁԼՍԹՄԼԹՌԹՈՊՇՎՁԼԽԼ!ԶԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋՇԾՋՍՊՎՁՎԹՄԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄ ՁՒԹՌՁՇՆՋՍԻԻԽՋՋՋԽԻՇՆԼԹՊՑՋԽՐԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼՇՌՀԽՊԻՄՁՆՁ ԻԹՄՋՁԿՆՋՇԻԻՍՊԹՌՄԽԹՋՌԼԹՁՄՑԞՌ ՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆ
ԡԹՑԹԼԼՁՌՁՇՆԹՄՇԺՋԽՊՎԹՌՁՇՆՋՁՆԻՄՍԼԽԺՇԼՑՏԽՁԿՀՌԹՆԼՄԽՆԿՌՀՆՍՈՌՁԹՄՌՍԺԽՊԻՄԽՋԻՇՊԽԿՇՆԹԼԹՄՋՌԹԿՁՆԿԹՆԼ ՀՁՋՌՇՈԹՌՀՇՄՇԿՑՈՄԹՋՅԹ
ՎՁՌԽՄՄՇԿԽՆՁՆԹՆԼՈՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋ
ՌԽՋՌՇՋՌԽՊՇՆԽԹՆԼȕ ԽՋՌՊԹԼՁՇՄՁԾՅԽԹՋՍՊԽԼԤՇՆԹԼՇՋՇՅԹՌՁԻՁՆԼԽՐ
Ԥ԰ԦՁՋԻԹՄԻՍՄԹ ՌԽԼՍՋՁՆԿԹՊԹՌՁՇՇԾԿՇՆԹԼՏԽՁԿՀՌ ՌՇԺՇԼՑՏԽՁԿՀՌ
ԿՇՆԹԼՏԽՁԿՀՌՌՇՌՀԽՆԽԹՊԽՋՌՅԿԺՇԼՑՏԽՁԿՀ ՌՁՆՅԿՐԹՌՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆ ԠՄՁՆՁԻԹՄՋՁԿՆՋՇԾՇՎԽՊՌՌՇՐՁԻՁՌՑՅԹՑՁՆԻՄՍԼԽ
ԺՍՌԹՊԽՆՇՌՄՁՅՁՌ ԽԼՌՇՀԽՅՇՊՊՀԹԿԽԻԽՋՋԹՌՁՇՆՇԾԾԽԽԼՁՆԿԹՆԼՇՌՀԽՊԹԺՆՇՊՅԹՄԺԽՀԹՎՁՇՊԦԦԯԢ԰ԲԩԱ԰ԞԫԡԡԦ԰ԠԲ԰԰ԦԬԫԞԯԽՋՍՄՌՋԱՀՊՇՍԿՀՇՍՌՌՀԽՌԽՋՌՆՇՅԹՄԽՅՇՊՌԹՄՁՌՁԽՋՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՅԹՄԽՋՍՊՎՁՎԹՄՏԹՋՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԣԽՅԹՄԽՋՍՊՎՁՎԹՄՏԹՋՁՆԺՇՌՀԻՇՆՌՊՇՄԿՊՇՍՈՋԹՆԼՏԹՋԹՆԼՊԽՋՈԽԻՌՁՎԽՄՑԹՌՌՀԽԹՆԼՅԿԹՁԩՄԽՎԽՄՋԱՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՏԹՋՌԽՊՅՁՆԹՌԽԼՇՆԡԹՑԼՍԽՌՇՀՁԿՀՅՇՊԺՁԼՁՌՑՁՆԻՄՍԼՁՆԿՄԽՌՀԹՊԿՑԹՆԼՄՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅԞՄՄԾՁՋՀՁՆՌՀՁՋՌՊԽԹՌՅԽՆՌԿՊՇՍՈՏԽՊԽԽՍՌՀԹՆՁՒԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԞԼՍՄՌԣՁՋՀ԰ՍՊՎՁՎԹՄՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԪԹՄԽՋԣԽՅԹՄԽՋՆ԰ՍՊՎՁՎՁՆԿ԰ՍՊՎՁՎԹՄԫ԰ՍՊՎՁՎՁՆԿ԰ՍՊՎՁՎԹՄԠՇՆՌՊՇՄ
ԩԬԮ     ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄԩԬԮ                    ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽԪԽԹՆՅԹՄԽԺՇԼՑՏԽՁԿՀՌՏԹՋԹՆԼԿԹՆԼՅԽԹՆԾԽՅԹՄԽԺՇԼՑՏԽՁԿՀՌՏԹՋԹՆԼԿՁՆՌՀԽԻՇՆՌՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑԪԽԹՆՅԹՄԽՄԽՆԿՌՀՏԹՋԹՆԼՅՅԹՆԼՅԽԹՆԾԽՅԹՄԽՄԽՆԿՌՀՏԹՋԹՆԼՅՅՁՆՌՀԽԻՇՆՌՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑԪԹՄԽՎԹՄՍԽՋԽՐԻՄՍԼԽՅԽԹՋՍՊԽՅԽՆՌՋՇԾԾՁՋՀՁՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋՌՀԹՌՏԽՊԽՅՁՋՁԼԽՆՌՁԾՁԽԼԹՋԾԽՅԹՄԽԾՁՋՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԱՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՏԹՋՌԽՊՅՁՆԹՌԽԼԹՌԡԹՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽ԰ՁՒԽԹՌԱԽՋՌԱԽՊՅՁՆԹՌՁՇՆՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԟՇԼՑԴԽՁԿՀՌԩԽՆԿՌՀԪԹՄԽՋԣԽՅԹՄԽՋԪԹՄԽՋԣԽՅԹՄԽՋՆԪԽԹՆԿչ԰ԡՆԪԽԹՆԿչ԰ԡՆԪԽԹՆՅՅչ԰ԡՆԪԽԹՆՅՅչ԰ԡԠՇՆՌՊՇՄ
ԩԬԮ            ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄԩԬԮ                                 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽ԰ԡ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ ԰ԹՅՈՄԽՋՁՒԽ
ՆՊԽՈՊԽՋԽՆՌՋՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԪԽԹՆԾԽԻՍՆԼՁՌՑՎԹՄՍԽՋՏԽՊԽԹՆԼԽԿԿՋԾԽՅԹՄ ԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑԹՆԼԾԽՊՌՁՄՁՒԹՌՁՇՆ

ՋՍԻԻԽՋՋՏԹՋ ԹՆԼՁՆՌՀԽԻՇՆՌՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼ

ԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ

ԱԹԺՄԽԣԽԻՍՆԼՁՌՑԹՆԼԣԽՊՌՁՄՁՒԹՌՁՇՆ԰ՍԻԻԽՋՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ  ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԣԽԻՍՆԼՁՌՑ  ԣԽՊՌՁՄՁՒԹՌՁՇՆ԰ՍԻԻԽՋՋ 

ԪԽԹՆ չ԰ԡ ԪԽԹՆ
 չ԰ԡ

ԠՇՆՌՊՇՄ
ԩԬԮ    

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ    

    

    

 ԫԞ ԫԞ ԫԞ ԫԞ

ԫԞ

ԫՇՌԹՈՈՄՁԻԹԺՄԽ

  ԣԽԻՍՆԼՁՌՑՁՋԻԹՄԻՍՄԹՌԽԼԹՋՌՀԽՆՍՅԺԽՊՇԾԽԿԿՋՈԽՊՋՍՊՎՁՎՁՆԿԾԽ ՅԹՄԽՈԽՊՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՈԽՊՊԽՈՄՁԻԹՌԽ

  ԣԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋ
ՁՋԻԹՄ ԻՍՄԹՌԽԼԹՋՌՀԽՆՍՅԺԽՊՇԾԽՅԺՊՑ ՇՋԼՁՎՁԼԽԼԺՑՌՀԽՆՍՅԺԽՊՇԾԽԿԿՋՅՍՄՌՁՈՄՁԽԼԺՑ

ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԪԽԼՁԹՆՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՋՏԽՊԽԹՆԼՁՆՌՀԽԻՇՆՌ ՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆ

ՅԽԹՋՍՊԽԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑԱՀԽՋԽՎԹՄՍԽՋԽՐԻՄՍԼԽՅԽԹՋՍՊԽՅԽՆՌՋՇԾ

ԾՁՋՀՁՆՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋՌՀԹՌՏԽՊԽՅՁՋՁԼԽՆՌՁԾՁ ԽԼԹՋԾԽՅԹՄԽԾՁՋՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԫՇ

ՌՍԺԽՊԻՄԽՋՏԽՊԽՇԺՋԽՊՎԽԼՇՆԾԽՅԹՄԽԾՁՋՀ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԫՍՈՌՁԹՄԱՍԺԽՊԻՄԽ԰ԻՇՊԽՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԼՁԹՆԱՍԺԽՊԻՄԽ

԰ԻՇՊԽ Ն ԪԽԼՁԹՆԱՍԺԽՊԻՄԽ

԰ԻՇՊԽ

ԠՇՆՌՊՇՄ
ԩԬԮ    

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ    

    

    

 ԫԞ ԫԞ ԫԞ ԫԞ

ԫԞ

ԫՇՌԹՈՈՄՁԻԹԺՄԽ

԰ԹՅՈՄԽՋՁՒԽ
ՆՊԽՈՊԽՋԽՆՌՋՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ

 ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԪԽԹՆՅԹՄԽԤ԰ԦՏԹՋԹՆԼԹՆԼՅԽԹՆԾԽՅԹՄԽԤ԰ԦՏԹՋԹՆԼ

ՁՆՌՀԽԻՇՆՌՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼ ԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋ

ՊԽՋՈԽԻՌՁՎԽՄՑԪԹՄԽՎԹՄՍԽՋԽՐԻՄՍԼԽՅԽԹՋՍՊԽՅԽՆՌՋՇԾԾՁՋՀՁՆՌՀԽՆ ԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄՋՌՀԹՌՏԽՊԽ

ՅՁՋՁԼԽՆՌՁԾՁԽԼԹՋԾԽՅԹՄԽԾՁՋՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐ
Ԥ԰ԦՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԹՆԤ԰Ԧ 

 չ԰ԡ Ն ԪԽԹՆԤ԰Ԧ 

 չ԰ԡ

ԠՇՆՌՊՇՄ
ԩԬԮ      

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ      

      

      

 ԫԞ   ԫԞ  

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 ԤՇՆԹԼՇՋՇՅԹՌՁԻՁՆԼԽՐ
ՁՋԻԹՄԻՍՄԹՌԽԼԹՋԿՇՆԹԼՏԽՁԿՀՌ
ՌՇՌՀԽ ՆԽԹՊԽՋՌՅԿԺՇԼՑՏԽՁԿՀՌ
ՅԿՐ

԰ԹՅՈՄԽՋՁՒԽ
ՆՊԽՈՊԽՋԽՆՌՋՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ

 ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԪԽԼՁԹՆՅԹՄԽԿՇՆԹԼԹՄՋՌԹԿԽՏԹՋԹՆԼԹՆԼՅԽԼՁԹՆԾԽՅԹՄԽ ԿՇՆԹԼԹՄՋՌԹԿԽՏԹՋԹՆԼՁՆ

ՌՀԽԻՇՆՌՊՇՄՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼԹՆԼ ՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԼՁԹՆ԰ՌԹԿԽ  Ն ԪԽԼՁԹՆ԰ՌԹԿԽ 

ԠՇՆՌՊՇՄ
ԩԬԮ    

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ    

    

    

 ԫԞ  ԫԞ 

ԫԞ

ԫՇՌԹՈՈՄՁԻԹԺՄԽ

  ԱՀԽ ԿՍՁԼԽՄՁՆԽ ՊԽԻՇՅՅԽՆԼՋ ՌՀԽ ԾՇՄՄՇՏՁՆԿ ԿՇՆԹԼԹՄ ՋՌԹԿՁՆԿ ՋԻԹՄԽ Ծ ՇՊ ՅԹՄԽ ԾԹՌՀԽԹԼ ՅՁՆՆՇՏ ՍՆԼԽՎԽՄՇՈԽԼ ԽԹՊՄՑ

ՋՈԽՊՅԹՌՇԿԽՆՁԻՅՁԼՋՈԽՊՅԹՌՇԿԽՆՁԻՄԹՌԽՋՈԽՊՅԹՌՇԿԽՆՁԻՋՈԽ ՆՌ

  ԱՀԽ ԿՍՁԼԽՄՁՆԽ ՊԽԻՇՅՅԽՆԼՋ ՌՀԽ ԾՇՄՄՇՏՁՆԿ ԿՇՆԹԼԹՄ ՋՌԹԿՁՆԿ ՋԻԹՄԽ Ծ ՇՊ ԾԽՅԹՄԽ ԾԹՌՀԽԹԼ ՅՁՆՆՇՏ ՍՆԼԽՎԽՄՇՈԽԼ ԽԹՊՄՑ

ԼԽՎԽՄՇՈՅԽՆՌՅՁԼԼԽՎԽՄՇՈՅԽՆՌՄԹՌԽԼԽՎԽՄՇՈՅԽՆՌՄԹՌԽԼԽՎԽՄՇՈՅԽՆՌՀՑԼՊԹՌԽԼՈՇՋՌՇՎՍՄԹՌՇՊՑ

԰ԹՅՈՄԽՋՁՒԽ
ՆՊԽՈՊԽՋԽՆՌՋՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ

 ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԪՁՆՁՅԹՄՌԽՋՌՁԻՍՄԹՊԼԽԿԽՆԽՊԹՌՁՇՆՏԹՋՆՇՌԽԼՁՆՇԾՇԾԹՆ ԼՇԾՅԹՄԽՋՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՋՈԽԻՌՁՎԽՄՑԻՇՅՈԹՊԽ ԼՌՇՆՇՆԽՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԣՇՍՊ

ՅԹՄԽՋՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՀԹԼԹՄՌԽՊԽԼՈՊՇՈՇՊՌՁ ՇՆՋՇԾՋՈԽՊՅԹՌՇՒՇԹՇՊՋՈԽՊՅԹՌՇԻՑՌԽՋ

ՅՁՆՁՅԹՄՌՇՅՇԼԽՊԹՌԽԻՇՅՈԹՊԽԼՌՇՆՇՆԽՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՄԽՎԽՄԹՆԼՇՆՄՑ

ՅՁՆՁՅԹՄՁՆԻՁԼԽՆՌՏԹՋՇԺՋԽՊՎԽԼՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԞՋՁՆԿՄԽ ՅԹՄԽՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈ

ՀԹԼՌՀԽՈՊԽՋԽՆԻԽՇԾՌԽՋՌՁՋՇՎԹԻՇՅՈԹՊԽԼՌՇՆՇՆԽՁՆՌՀԽՇՌՀԽՊՌՊԽԹՌԽԼՄԽՎԽՄԹՆԼԻՇՆՌՊՇՄՋ԰ՁՐՅԹՄԽՋ

ԼՁՋՈՄԹՑԽԼՅՁՄԼՌՇՅՇԼԽՊԹՌԽՁՆՌԽՊՋՌՁՌՁԹՄԻԽՄՄՀՑՈԽՊՌՊՇՈՀՑՀՑՈԽՊՈՄԹՋՁԹԻՇՅՈԹՊԽԼՌՇԾՇՍՊՅՁՆՁՅԹՄՁՆԻՁԼԽՆՌՋ

ԽԹԻՀՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՄԽՎԽՄԹՆԼՇՆՄՑ ՇՆԽՁՆԻՁԼԽՆՌՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ

ԟԹՋԽԼՇՆՌՀԽՋԽԾՁՆԼՁՆԿՋՌՀԽՊԽՏԹՋՋՇՅԽԽՎՁԼԽՆԻԽԾՇՊՈՊՇՆԹՅՁԼԽ ՊԽՄԹՌԽԼՀՁՋՌՇՄՇԿՁԻԹՄԽԾԾԽԻՌՋՁՆՅԹՄԽ

ԾԹՌՀԽԹԼՅՁՆՆՇՏՋԹՌՌՀԽՅԿԹՁԩՄԽՎԽՄ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԞՋՄՁԿՀՌՄՑԿՊԽԹՌԽՊՈՊՇՈՇՊՌՁՇՆՇԾԾԽՅԹՄԽՋ
ՇԾՋՀՇՏԽԼՅՁՄԼՁՆԻՊԽԹՋԽԼՇՇԻՑՌԽԹՌՊԽՋՁԹԹՌՌՀԽՅԿ

ԹՁԩՄԽՎԽՄԻՇՅՈԹՊԽԼՌՇՇԾԹՆԼՇԾՁՆՌՀԽՋՇՄՎԽՆՌԻՇ ՆՌՊՇՄԹՆԼՅԿԹՁԩՄԽՎԽՄՋ

ՊԽՋՈԽԻՌՁՎԽՄՑՌՀԽՊԽՏԹՋՇԾՋՀՇՏՁՆԿՅՁՆՁՅԹՄՇՇԻՑՌԽԹՌՊԽՋՁԹ ՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԪՁՆՁՅԹՄԼԽԻՊԽԹՋԽԼ

ՑՇՄՃԾՇՊՅԹՌՁՇՆՏԹՋՈՊԽՋԽՆՌՁՆՇՆԽՇԾԾԽՅԹՄԽՋՁՆՌՀԽՅԿԹ ՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԻՇՅՈԹՊԽԼՌՇՆՇՆԽ

ՁՆՌՀԽԻՇՆՌՊՇՄՋԹՆԼՄՇՏԽՊԽՐՈՇՋՍՊԽՄԽՎԽՄԪՁՆՁՅԹՄՇՊՅՁՄԼԿՊԹՆՍ ՄՇՅԹՌՇՍՋՁՆԾՄԹՅՅԹՌՁՇՆՏԹՋՈՊԽՋԽՆՌՁՆՇՆԽ

ՁՆԼՁՎՁԼՍԹՄԽԹԻՀԾՊՇՅՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼՌՀԽՅԿԹՁԩՄԽՎԽՄԻՇՅՈԹՊԽԼՌՇՌՀՊԽԽՁՆԻՁԼԽՆՌՋՇԾ

ՅՁՆՁՅԹՄԿՊԹՆՍՄՇՅԹՌՇՍՋՁՆԾՄԹՅՅԹՌՁՇՆԹՌՌՀԽՅԿԹՁԩՄԽՎԽՄ ԱՀԽՋՌՍԼՑԹՍՌՀՇՊԻՇՆԻՄՍԼԽԼՌՀԹՌՌՀԽՊԽՏԹՋ

ՆՇՁՆԼՁԻԹՌՁՇՆՇԾԹՈՊՇՆԹՅՁԼԽՊԽՄԹՌԽԼԽԾԾԽԻՌՇՆՌՀԽՀՁՋՌՇՄՇԿՁԻԹՄ ԾՁՆԼՁՆԿՋՇԾԾԽՅԹՄԽԾԹՌՀԽԹԼՅՁՆՆՇՏՋՁՆՌՀՁՋ

ՋՌՍԼՑ

ԱԹԺՄԽԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑՁՆԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼ

ԭՊՇՈՇՊՌՁՇՆՇԾ

԰ՈԽՊՅԹՌՇԿՇՆՁԹ ԭՊԽՋԽՆԻԽՇԾ

ԱԽՋՌՁՋԬՎԹ ԦՆԻՊԽԹՋԽԼ

ԱԽՋՌՁԻՍՄԹՊ

ԡԽԿԽՆԽՊԹՌՁՇՆ ԦՆՌԽՊՋՌՁՌՁԹՄԠԽՄՄ

ԥՑՈԽՊՌՊՇՈՀՑ

ԥՑՈԽՊՈՄԹՋՁԹ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԠՇՆՌՊՇՄ
ԩԬԮ         

        

        

        

        

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԩԬԮ         

        

        

        

        

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼ

ԭՊՇՈՇՊՌՁՇՆՇԾ

԰ՈԽՊՅԹՌՇԿՇՆՁԹ ԭՊԽՋԽՆԻԽՇԾ

ԱԽՋՌՁՋԬՎԹ ԦՆԻՊԽԹՋԽԼ

ԱԽՋՌՁԻՍՄԹՊ

ԡԽԿԽՆԽՊԹՌՁՇՆ ԦՆՌԽՊՋՌՁՌՁԹՄԠԽՄՄ

ԥՑՈԽՊՌՊՇՈՀՑ

ԥՑՈԽՊՈՄԹՋՁԹ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

         

        

        

        

        

         

        

        

        

        

  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

  ԤՇՆԹԼԹՄՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋՌՁԻՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՆՁՅԹՄ

ԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽ ՄՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԞԼԼՁՌՁՇՆԹՄԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑԬԺՋԽՊՎԹՌՁՇՆՋՁՆԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԡԽԻՊԽԹՋԽԼԭՊՇՈՇՊՌՁՇՆՇԾ԰ՈԽՊՅԹՌՇԿՇՆՁԹԦՆԻՊԽԹՋԽԼԳԹՋԻՍՄԹՊՇՊԦՆՌԽՊՋՌՁՌՁԹՄԭՊՇՌԽՁՆԹԻԽՇՍՋԣՄՍՁԼԞՋՑՆԻՀՊՇՆՇՍՋԤՇՆԹԼԡԽՎԽՄՇՈՅԽՆՌԞՄՌԽՊԽԼԭՊՇՈՇՊՌՁՇՆՋՇԾ԰ՈԽՊՅԹՌՇԻՑՌԽՋՇՊ԰ՈԽՊՅԹՌՁԼՋԤՊԹՆՍՄՇՅԹՌՇՍՋԦՆԾՄԹՅՅԹՌՁՇՆՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽԠՇՆՌՊՇՄ
ԩԬԮ                                                  ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ                                                                                                     ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԡԽԻՊԽԹՋԽԼԭՊՇՈՇՊՌՁՇՆՇԾ԰ՈԽՊՅԹՌՇԿՇՆՁԹԦՆԻՊԽԹՋԽԼԳԹՋԻՍՄԹՊՇՊԦՆՌԽՊՋՌՁՌՁԹՄԭՊՇՌԽՁՆԹԻԽՇՍՋԣՄՍՁԼԞՋՑՆԻՀՊՇՆՇՍՋԤՇՆԹԼԡԽՎԽՄՇՈՅԽՆՌԞՄՌԽՊԽԼԭՊՇՈՇՊՌՁՇՆՋՇԾ԰ՈԽՊՅԹՌՇԻՑՌԽՋՇՊ԰ՈԽՊՅԹՌՁԼՋԤՊԹՆՍՄՇՅԹՌՇՍՋԦՆԾՄԹՅՅԹՌՁՇՆՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽ                                                   ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԤՇՆԹԼԹՄՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋՌՁԻՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՆՁՅԹՄԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑՁՆԣԽՅԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼԬՇԻՑՌԽ

ԞՌՊԽՋՁԹ ԭԽՊՁԾՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

ԥՑՈԽՊՌՊՇՈՀՑ ԡԽԻՊԽԹՋԽԼԶՇՄՃ

ԣՇՊՅԹՌՁՇՆ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԠՇՆՌՊՇՄ
ԩԬԮ       

      

      

      

      

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ       

      

      

      

      

       

      

      

      

      

       

      

      

      

      

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼԬՇԻՑՌԽ

ԞՌՊԽՋՁԹ ԭԽՊՁԾՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

ԥՑՈԽՊՌՊՇՈՀՑ ԡԽԻՊԽԹՋԽԼԶՇՄՃ

ԣՇՊՅԹՌՁՇՆ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

  ԤՇՆԹԼԹՄՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋՌՁԻՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՆՁՅԹՄ

ԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽ ՄՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԱԹԺՄԽԞԼԼՁՌՁՇՆԹՄԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑԬԺՋԽՊՎԹՌՁՇՆՋՁՆԣԽՅ ԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋ

ՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋ ՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆՌԽՊՋՌՁՌՁԹՄԣՁԺՊՇՋՁՋ ԢԿԿԡԽԺՊՁՋՁՆ

ԬՎՁԼՍԻՌ ԤՊԹՆՍՄՇՅԹՌՇՍՋ

ԦՆԾՄԹՅՅԹՌՁՇՆ ԡԽԻՊԽԹՋԽԼԭՇՋՌ

ԬՎՍՄԹՌՇՊՑԣՇՄՄՁԻՄԽՋ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԠՇՆՌՊՇՄ

ԩԬԮ         

        

        

        

        

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ

ԩԬԮ         

        

        

        

        

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋ ՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆՌԽՊՋՌՁՌՁԹՄԣՁԺՊՇՋՁՋ ԢԿԿԡԽԺՊՁՋՁՆ

ԬՎՁԼՍԻՌ ԤՊԹՆՍՄՇՅԹՌՇՍՋ

ԦՆԾՄԹՅՅԹՌՁՇՆ ԡԽԻՊԽԹՋԽԼԭՇՋՌ

ԬՎՍՄԹՌՇՊՑԣՇՄՄՁԻՄԽՋ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

         

        

        

        

        

         

        

        

        

        

  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

  ԤՇՆԹԼԹՄ ՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋՌՁԻ ՇԺՋԽՊՎԹՌՁՇՆՋ ԹՊԽ ԿՊԹԼԽԼ- ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌ ՊԽՅԹՊՃԹԺՄԽ ԪՁՆՁՅԹՄ

ԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽ ՄՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԪԽԹՆ ՅԹՄԽ ԳԱԤ ՏԹՋ    ԹՆԼ  ՆԿՅԩ ԹՆԼ ԾԽՅԹՄԽ ԳԱԤ Տ ԹՋ Ր  

###  Ր 



### 

Ր  

### ԹՆԼ Ր  

###  ՆԿՅԩ ՁՆ ՌՀԽ ԻՇՆՌՊՇՄ ՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄ ԹՆԼ ՅԽԹՆՅԽԹՋՍՊԽԼ   ԹՆԼ  ՅԿ

ԹՁԩ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ ՊԽՋՈԽԻՌՁՎԽՄՑ ԪԹՄԽ ՎԹՄՍԽՋ ԽՐԻՄՍԼԽ ՅԽԹՋ ՍՊԽՅԽՆՌՋ ՇԾ ԾՁՋՀ ՁՆ ՌՀԽ ՆԽԿԹՌՁՎԽ ԹՆԼ

ՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄՋ ՌՀԹՌ ՏԽՊԽ ՅՁՋՁԼԽՆՌՁԾՁԽԼ ԹՋ ԾԽՅԹՄԽ ԾՁՋՀ ԹՌ ՌԽՋՌ  ՁՆՁՌՁԹՌՁՇՆ ԰ՌԽՊՇՁԼ ՄԽՎԽՄՋ ՏԽՊԽ ՊԽՈՇՊՌԽԼՄՑ

ՅԽԹՋՍՊԽԼԾՊՇՅՈՄԹՋՅԹՋԹՅՈՄԽՋԺՍՌՌՀԽՊԽՋՍՄՌՋՏԽՊԽՆՇՌՈՊՇՎՁԼԽԼ ՁՆՌՀԽՋՌՍԼՑՊԽՈՇՊՌ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԭՄԹՋՅԹԳՁՌԽՄՄՇԿԽՆՁՆՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ 

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԭՄԹՋՅԹԳՁՌԽՄՄՇԿԽՆՁՆ
ԳԱԤ

ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԹՆ

ՆԿՅԩ

ՈՄԹՋՅԹ չ԰ԡ Ն ԪԽԹՆ

ՆԿՅԩ

ՈՄԹՋՅԹ չ԰ԡ

ԠՇՆՌՊՇՄ
ԩԬԮ     Ր   Ր 

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ     Ր   Ր 

     Ր   Ր 

     Ր   Ր 

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԰ԡ ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

԰ԹՅՈՄԽՋՁՒԽ
ՆՊԽՈՊԽՋԽՆՌՋՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ

 ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԭՄԹՋՅԹ԰ԽՐ԰ՌԽՊՇՁԼՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՀՁՋՌԹԺՄԽՁՋՇՅՁՌՌԽԼԺԽԻԹՍՋԽՊԽՋՍՄՌՋԾՇՊՈՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼԫՇԹԺՆՇՊՅԹՄՇԺՋԽՊՎԹՌՁՇՆՋՁՆԺԽՀԹՎՁՇՊՇՊԹՈՈԽԹՊԹՆԻԽՁՆԻՄՍԼՁՆԿՋԽԻՇՆԼԹՊՑՋԽՐԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋՏԽՊԽՆՇՌԽԼՁՆՌՀԽԻՇՆՌՊՇՄՋՇՊԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋԺՑՌՀԽՋՌՍԼՑԹՍՌՀՇՊԩԽՌՀԹՊԿՑԹՆԼՄՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅՇԺՋԽՊՎԽԼԹՌՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆՄԽԼՌՇՌՀԽՌԽՊՅՁՆԹՌՁՇՆՇԾՌՀՁՋԿՊՇՍՈԹՌՋՌՍԼՑԡԹՑԱԹԺՄԽ԰ԽԻՇՆԼԹՊՑ԰ԽՐԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼԠՄՁՆՁԻԹՄ԰ՁԿՆՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%԰ԽԻՇՆԼԹՊՑ԰ԽՐԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼԠՄՁՆՁԻԹՄ԰ՁԿՆՋԪԹՄԽՋԣԽՅԹՄԽՋԱՑՈԽՆԦՆԻՁԼԽՆԻԽԱՑՈԽՆԦՆԻՁԼԽՆԻԽԠՇՆՌՊՇՄ
ԩԬԮԫՇՆԽՊԽՈՇՊՌԽԼ   ԫՇՆԽՊԽՈՇՊՌԽԼ  ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮԫՇՆԽՊԽՈՇՊՌԽԼ   ԫՇՆԽՊԽՈՇՊՌԽԼ  ԫՇՆԽՊԽՈՇՊՌԽԼ   ԫՇՆԽՊԽՈՇՊՌԽԼ  ԫՇՆԽՊԽՈՇՊՌԽԼ   ԩՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅՇՆԡԹՑՋ  ԩԽՌՀԹՊԿՑ   ԩԽՌՀԹՊԿՑ  ԫԞԩՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅ ԩՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅ ԦՆԻՁԼԽՆԻԽՁՋԽՋՌՁՅԹՌԽԼԺԹՋԽԼՇՆԼԹՌԹՈՊՇՎՁԼԽԼԺՑՊԽՈՄՁԻԹՌԽՊԹՌՀԽՊՌՀԹՆԺՑՁՆԼՁՎՁԼՍԹՄԾՁՋՀԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԟ ԰ՌՍԼՑԞՍՌՀՇՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

ԱՀԽՋՌՍԼՑԹՍՌՀՇՊԹՆԹՄՑՒԽԼՋՍՊՎՁՎԹՄՏԽՁԿՀՌՌՍԺԽՊԻՄԽՋԻՇՊԽԤ԰Ԧ ԾԽՊՌՁՄՁՌՑ
ԽԿԿՋՌՀԹՌՏԽՊԽԾԽՊՌՁՄԽ

ԾԽԻՍՆԼՁՌՑ
ԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑԹՆԼԳԱԤԡԹՌԹԾՇՊԿՊ ՇՏՌՀՌՍԺԽՊԻՄԽՋԻՇՊԽԤ԰ԦԹՆԼ

ԳԱԤՏԽՊԽԹՆԹՄՑՒԽԼՋԽՈԹՊԹՌԽՄՑԺՑՋԽՐԣՇՊԹՄՄՈԹՊԹՅԽՌԽՊՋՌՀԽՆԽԿ ԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈՋ

ՏԽՊԽԻՇՅՈԹՊԽԼՍՋՁՆԿԹՌԱԽՋՌ Į ՆՇԼՁԾԾԽՊԽՆԻԽՏԹՋԼԽՌԽԻՌԽԼԾՇՊԹՆՑԽՆԼՈՇՁՆՌՋՇՌՊԽԹՌՅԽ ՆՌ

ԿՊՇՍՈՋՏԽՊԽԻՇՅՈԹՊԽԼՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ

ԡԽՋԻՊՁՈՌՁՎԽՋՌԹՌՁՋՌՁԻՋ
ՅԽԹՆՋՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆԽՌԻՏԽՊԽԼԽ ՌԽՊՅՁՆԽԼԾՇՊԽԹԻՀԽՆԼՈՇՁՆՌ԰ՁԿՆՁԾՁԻԹՆՌ

ԽԾԾԽԻՌՋՏԽՊԽԼԽՌԽԻՌԽԼԾՇՊՈԹՆԼԹՆԹՄՑՋԽՋՏԽՊԽԻՇՆԼՍԻՌԽԼՍՋ ՁՆԿԠԢԱԦ԰ TM ԳԽՊՋՁՇՆ

ԢԾԾԽԻՌՋՇՆՋՍՊՎՁՎԹՄՏԽՊԽԼԽՌԽՊՅՁՆԽԼՍՋՁՆԿԹԣՁՋՀԽՊ0ՋԽՐԹԻՌՌԽՋՌ 
ՏՁՌՀԟՇՆԾԽՊՊՇՆՁԥՇՄՅԹԼՂՍՋՌՅԽՆՌ

ԡԹՌԹՏԽՊԽՌԽՋՌԽԼՌՇԻՇՆԾՁՊՅՆՇՊՅԹՄՁՌՑՍՋՁՆԿ԰ՀԹՈՁՊՇԴՁՄՃ0ՋՌԽՋՌ ԹՆԼՌՇԻՇՆԾՁՊՅՀՇՅՇԿԽՆԽՁՌՑՇԾ

ՎԹՊՁԹՆԻԽՋՍՋՁՆԿԟԹՊՌՄԽՌՌ0ՋՌԽՋՌ Į ԡԹՌԹՌՀԹՌՋԹՌՁՋԾՁԽԼՌՀԽՋԽԹՋՋՍՅՈՌՁՇՆՋԺՍՌԼՁԼՆՇՌԽՐՀՁԺ ՁՌԹ

ՅՇՆՇՌՇՆՁԻՌՊԽՆԼՏԽՊԽԻՇՅՈԹՊԽԼՍՋՁՆԿԡՍՆՆԽՌՌ0ՋՌԽՋՌԱՀԽՆՇՆՈԹՊ ԹՅԽՌՊՁԻԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌ

ՏԹՋՍՋԽԼՏՀԽՆԼԹՌԹԼՁԼՆՇՌՅԽԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՆՇՊՅԹՄՁՌՑԹՆԼՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽՋՇՊԾՇՊ

ԼԹՌԹՏՀՁԻՀՏԽՊԽԼԽՌԽՊՅՁՆԽԼՌՇԺԽԽՅՈՁՊՁԻԹՄՄՑՅՇՆՇՌՇՆՁԻԱՀԽՋԽՅ ԽՌՀՇԼՋԹՈՈԽԹՊՌՇԺԽԻՇՆՋՁՋՌԽՆՌ

ՏՁՌՀՌՀԽՅԽՌՀՇԼՋՊԽԻՇՅՅԽՆԼԽԼՁՆՌՀԽԬԠ԰ԭԭԿՍՁԼԽՄՁՆԽ

ԞԼՍՄՌՋՍՊՎՁՎԹՄՏԹՋՆՇՌՋՁԿՆՁԾՁԻԹՆՌՄՑԼՁԾԾԽՊԽՆՌԻՇՅՈԹՊԽԼՌՇՌՀԽ ՈՇՇՄԽԼԻՇՆՌՊՇՄՋ
Ո ԣՁՋՀԽՊ0ՋԢՐԹԻՌ

ՌԽՋՌԾՇՊՅԹՄԽՋԾԽՅԹՄԽՋՇՊԻՇՅԺՁՆԽԼՋԽՐԽՋԱՀԽՊԽՏԽՊԽՋՌԹՌՁՋՌՁ ԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌՊԽԼՍԻՌՁՇՆՋԼԽՌԽԻՌԽԼ

ԾՇՊԾԽՊՌՁՄՁՌՑԹՆԼԾԽԻՍՆԼՁՌՑԻՇՅՈԹՊԽԼՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ
ՈԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԹՌՌՀԽ

ՅԿԹՁԩՄԽՎԽՄԱՀԽՊԽՏԽՊԽՆՇՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋԼԽՌԽԻՌԽԼ ԾՇՊԹՆՑՊԽՅԹՁՆՁՆԿԽՆԼՈՇՁՆՌՊԽՄԹՌՁՎԽՌՇ

ՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄ
Ո ԡՍՆՆԽՌՌ0ՋՇՊԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԞՄՌՀՇՍԿՀՆՇՌԹՆԹՄՑՒԽԼ

ՋՌԹՌՁՋՌՁԻԹՄՄՑՌՀԽՋՌՍԼՑԹՍՌՀՇՊՆՇՌԽԼՈՇՌԽՆՌՁԹՄՄՑԻՇՆԻԽՆՌՊԹՌՁՇՆ ՊԽՄԹՌԽԼՄԽՋՁՇՆՋՁՆԻՄՍԼՁՆԿԼԽԻՊԽԹՋԽԼ

ՈՊՇՈՇՊՌՁՇՆՋՇԾՋՈԽՊՅԹՌՇՒՇԹՁՆԻՊԽԹՋԽԼՁՆՌԽՊՋՌՁՌՁԹՄՈՊՇՌԽՁՆԹԻԽՇՍ ՋԾՄՍՁԼՁՆՌԽՊՋՌՁՌՁԹՄԻԽՄՄՀՑՈԽՊՈՄԹՋՁԹԹՆԼ

ՁՆԻՊԽԹՋԽԼՌԽՋՌՁԻՍՄԹՊԼԽԿԽՆԽՊԹՌՁՇՆԹՌՌՀԽՅԿԹՁԩՄԽՎԽՄԱ ՀԽՊԽՏԽՊԽՆՇՇԺՎՁՇՍՋՌՊԽԹՌՅԽՆՌՊԽՄԹՌԽԼ

ՄԽՋՁՇՆՋՈՊԽՋԽՆՌՁՆԾԽՅԹՄԽԾՁՋՀԱՀԽՋՌՍԼՑԹՍՌՀՇՊԼՁԼՆՇՌՊԽՈՇՊՌ ՇԺՋԽՊՎՁՆԿԹՆՑՆՇՌԹԺՄԽԻՄՁՆՁԻԹՄՋՁԿՆՋՇՊ

ԺԽՀԹՎՁՇՊԹՄԽԾԾԽԻՌՋՁՆԻՄՍԼՁՆԿՋԽԻՇՆԼԹՊՑՋԽՐՍԹՄԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋ ԱՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՄՑՇԺՋԽՊՎԽԼ

ՌՀԽՈՊԽՋԽՆԻԽՇԾՌՀԽԼՇՊՋԹՄՆԹՈԽՈԹԼՁՆՅԹՄԽՋԹՆԼԻՇՄՄԽԻՌԽԼՈՄԹՋ ՅԹՋԹՅՈՄԽՋԾՇՊՅԽԹՋՍՊԽՅԽՆՌՇԾ

ՋԽՐՋՌԽՊՇՁԼՋԺՍՌՊԽՋՍՄՌՋՇԾՌՀԽՋԽԹՆԹՄՑՋԽՋՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼՁ ՆՌՀԽՋՌՍԼՑ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### Ԡ ԯԽՎՁԽՏԽՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

԰ՌԹՌՁՋՌՁԻԹՄԪԽՌՀՇԼՋ ԱՀԽՊԽՎՁԽՏԽՊՎՁՋՍԹՄՄՑԹՋՋԽՋՋԽԼՋՍՊՎՁՎԹՄ
ՅՇՊՌԹՄՁՌՑԼԹՌԹԣԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՌՑ

ՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՅԹՄԽՈՄԹՋՅԹԳԱԤԹՆԼԾԽՅԹՄԽՄԽՆԿՌՀՏԽՊԽԻՇ ՆՋՁՋՌԽՆՌՏՁՌՀԹՅՇՆՇՌՇՆՁԻ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽԹՆԼՏԽՊԽՌՀԽՊԽԾՇՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽԧՇ ՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌՊԽՆԼՌԽՋՌԱՀԽ

ՊԽՅԹՁՆՁՆԿԽՆԼՈՇՁՆՌՋՏԽՁԿՀՌՅԹՄԽՄԽՆԿՌՀԾԽՅԹՄԽՈՄԹՋՅԹԳԱԤԹՆ ԼԤ԰ԦԼԹՌԹՏԽՊԽՆՇՌԻՇՆՋՁՋՌԽՆՌ

ՏՁՌՀԹՅՇՆՇՌՇՆՁԻԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽԞՄՄԼԹՌԹՏԽՊԽՌԽՋՌԽԼԾ ՇՊՆՇՊՅԹՄՁՌՑՍՋՁՆԿ԰ՀԹՈՁՊՇԴՁՄՃՋՌԽՋՌ

ԹՆԼԾՇՊՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽՍՋՁՆԿԩԽՎԽՆԽ0ՋՌԽՋՌ
԰Ԟ԰ ԱՀԽՋԽԼԹՌԹՅԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾ

ՆՇՊՅԹՄՁՌՑԹՆԼՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽԹՆԼՏԽՊԽՌՀԽՊԽԾՇՊԽԹՆԹՄՑՒ ԽԼՍՋՁՆԿՌՀԽՈԹՊԹՅԽՌՊՁԻԡՍՆՆԽՌՌ0Ջ

ՌԽՋՌ

ԫՇՋՍՊՎՁՎՁՆԿԾԽՅԹՄԽՋՏԽՊԽԾՇՍՆԼՌՇՀԹՎԽՌՍԺԽՊԻՄԽՋԹՆԼՋԽՐՋՌԽՊՇ ՁԼՋՏԽՊԽՆՇՌՅԽԹՋՍՊԽԼԲՆՄԽՋՋ

ՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋՏԽՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆ ՁԾՁԻԹՆՌԹՌՈԱՀԽՊԽՎՁԽՏԽՊ0Ջ

ԹՆԹՄՑՋՁՋՏԹՋԻՇՆԼՍԻՌԽԼՍՋՁՆԿ԰Ԟ԰ԱՀԽՊԽՎՁԽՏԽՊԹԼԼՁՌՁՇՆԹՄՄՑ ԻՇՅՈԹՊԽԼՌՀԽՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌ

ԻՇՆՌՊՇՄԿՊՇՍՈՋԾՇՊԹՄՄԽՆԼՈՇՁՆՌՋՍՋՁՆԿԹՌՏՇՋՁԼԽԼ԰ՌՍԼԽՆՌ0ՋՌ ՌԽՋՌՁՆԢՐԻԽՄՆՇՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋ

ԺԽՌՏԽԽՆՌՀԽԻՇՆՌՊՇՄՋՏԽՊԽԼԽՌԽԻՌԽԼ
Ո ԱՀԽՊԽՎՁԽՏԽՊԻՇՅՈԹ ՊԽԼԹՄՄՈՊՇՆԹՅՁԼԽՌՊԽԹՌԽԼԿՊՇՍՈՋ

ՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ

ԠՇՆԻՄՍՋՁՇՆՋ ԣԽՊՌՁՄՁՌՑՋՀՇՏԽԼԹՋՁԿՆՁԾՁԻԹՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆԼԽՈԽՆԼԽՆՌՊԽԼՍԻՌՁ ՇՆ
ՈԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹՇԾԹՌՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄԻՇՅՈԹՊԽԼ ՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԣԽԻՍՆԼՁՌՑ

ԾՇՄՄՇՏԽԼԹԻՇՆԻԽՆՌՊԹՌՁՇՆԼԽՈԽՆԼԽՆՌՊԽԼՍԻՌՁՇՆՇԾԹՆԼԹՌ ՌՀԽԹՆԼՅԿԹՁԩ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋՊԽՋՈԽԻՌՁՎԽՄՑՀՇՏԽՎԽՊՌՀԽՋԽՊԽԼՍԻՌՁՇՆՋՏԽՊԽՆՇՌ ՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌ
ՈԹՆԼ

ՈՊԽՋՈԽԻՌՁՎԽՄՑԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԱՀԽՊԽԼՍԻՌՁՇՆԹՌՌ ՀԽՅԿԹՁԩԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋ

ԻՇՆՋՁԼԽՊԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊՌՇԺԽԺՁՇՄՇԿՁԻԹՄՄՑՊԽՄԽՎԹՆՌԼՍԽՌՇՌ ՀԽՅԹԿՆՁՌՍԼԽՇԾԽԾԾԽԻՌԹՆԼՌՀԽ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋՁՎԽՈԹՌՌԽՊՆԞԼԼՁՌՁՇՆԹՄՄՑՅԹՄԽՌՍԺԽՊԻՄԽՋ ԻՇՊԽՋՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑԿՊԽԹՌԽՊ

ՈԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԺՑՁՆՌՀԽՅԿԹՁԩՌՊԽ ԹՌՅԽՆՌԿՊՇՍՈԹՆԼԺՑԹՌՌՀԽ

ՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԱՀԽՊԽՏԽՊԽՊԽԼՍԻԽԼՈՊՇՈՇՊՌՁՇՆՋՇ ԾՋՈԽՊՅԹՌՇՒՇԹՁՆԻՊԽԹՋԽԼՌԽՋՌՁԻՍՄԹՊ

ԼԽԿԽՆԽՊԹՌՁՇՆԹՆԼՁՆԻՊԽԹՋԽԼՁՆԻՁԼԽՆՌՋՇԾՁՆՌԽՊՋՌՁՌՁԹՄՈՊՇՌԽՁՆԹԻ ԽՇՍՋԾՄՍՁԼԹՆԼՁՆՌԽՊՋՌՁՌՁԹՄԻԽՄՄՀՑՈԽՊՈՄԹՋՁԹ

ԹՌՌՀԽՅԿԹՁԩՄԽՎԽՄՊԽՄԹՌՁՎԽՌՇՌՀԽԻՇՆՌՊՇՄԿՊՇՍՈՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢՆԼՈՇՁՆՌՋԾՇՊԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋՁՆՌՀԽԣ԰ԱԯԞՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԱՍԺԽՊԻՄԽ԰ԻՇՊԽԤ԰ԦԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿԹՆԼԥՁՋՌՇԭՄԹՋՅԹԳԱԤԭՄԹՋՅԹԱԭՄԹՋՅԹԢԪԽԼՁԹՆՈԡՁԾԾՈԢԾԾԽԻՌ!ԶԽՋԫՇԡՁԾԾՈԡՁԾԾՈԡՁԾԾԭԠՇՆՌՊՇՄ
ԩԬԮ ԫԞ  ԫԞ ԫԞ  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ    ԫՇ   ԫԞ ԫԞ ԫԞ ԫԞ  ԫՇ   ԫԞ ԫԞ ԫԞ ԫԞ  ԶԽՋ   ԫԞ ԫԞ ԫԞ ԫԞԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ ԡՍՆՆԽՌՌ0ՋԫԞ ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԫԞԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԡՁԾԾԡՁԾԾԽՊԽՆԻԽԢȕԽՋՌՊԹԼՁՇՄԤ԰ԦԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐԥՁՋՌՇԥՁՋՌՇՈԹՌՀՇՄՇԿՑԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԱԱԽՋՌՇՋՌԽՊՇՆԽԳԱԤԳՁՌԽՄՄՇԿԽՆՁՆ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՆԼՈԽՊԻԽՆՌ
ԼՁԾԾԽՊԽՆԻԽՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈ ԠՇՅՈԹՊՁՋՇՆՋՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՊԽԺԹՋԽԼՇՆԹՌՏՇՋՁԼԽԼ԰ՌՍԼԽՆՌ0ՋՌՌԽՋՌԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԱԹԺՄԽԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢՆԼՈՇՁՆՌՋԾՇՊԣԽՅԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋՁՆՌՀԽԣ԰ԱԯԞՏՁՌՀԭՊՇՆԹՅՁԼԽԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԣԽԻՍՆԼՁՌՑԣԽՊՌ԰ՍԻԻԽՋՋԱՍԺԽՊԻՄԽ԰ԻՇՊԽԤ԰ԦԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿԹՆԼԥՁՋՌՇԭՄԹՋՅԹԳԱԤԭՄԹՋՅԹԱԭՄԹՋՅԹԢԡՁԾԾՈԡՁԾԾՈԪԽԼՁԹՆՈԡՁԾԾՈԢԾԾԽԻՌ!ԶԽՋԫՇԡՁԾԾՈԡՁԾԾՈԡՁԾԾԭԠՇՆՌՊՇՄ
ԩԬԮ ԫԞ  ԫԞ  ԫԞ  ԫԞ ԫԞ  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄԩԬԮ     ԫԞ   ԫՇ   ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ   ԫՇ   ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ   ԫՇ   ԫԞ ԫԞ ԫԞ ԫԞԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԫԞ ԡՍՆՆԽՌՌ0Ջ ԫԞ ԡՍՆՆԽՌՌ0Ջ ԫԞ ԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԡՁԾԾԡՁԾԾԽՊԽՆԻԽԢȕԽՋՌՊԹԼՁՇՄԣԽՊՌԣԽՊՌՁՄՁՒԹՌՁՇՆԤ԰ԦԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐԥՁՋՌՇԥՁՋՌՇՈԹՌՀՇՄՇԿՑԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԱԱԽՋՌՇՋՌԽՊՇՆԽԳԱԤԳՁՌԽՄՄՇԿԽՆՁՆ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՆԼՈԽՊԻԽՆՌ
ԼՁԾԾԽՊԽՆԻԽՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈ ԠՇՅՈԹՊՁՋՇՆՋՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՊԽԺԹՋԽԼՇՆԹՌՏՇՋՁԼԽԼ԰ՌՍԼԽՆՌ0ՋՌՌԽՋՌԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱԹԺՄԽԤՊՇՏՌՀԢՆԼՈՇՁՆՌՋ  

### ՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ
ԣ԰ԱԯԞՏՁՌՀԭՊՇՆԹՅՁ ԼԽ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԟՇԼՑԴԽՁԿՀՌ ԩԽՆԿՌՀ

ԪԹՄԽՋ ԣԽՅԹՄԽՋ ԪԹՄԽՋ ԣԽՅԹՄԽՋ

ԡՁԾԾ Ո  ԡՁԾԾ Ո  ԡՁԾԾ Ո  ԡՁԾԾ Ո 

ԠՇՆՌՊՇՄ
ԩԬԮ  ԫԞ  ԫԞ  ԫԞ  ԫԞ

԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ԩԬԮ        

        

        

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ ԡՁԾԾԽՊԽՆԻԽ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ

  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼՈԽՊԻԽՆՌ
ԼՁԾԾԽՊԽՆԻԽՋԹՊԽՊԽՈՇՊՌ ԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊ

ԻՇՆՌՊՇՄ

  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈ

  ԠՇՅՈԹՊՁՋՇՆՋՌՇՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՊԽԺԹՋԽԼՇՆԹՌՏՇՋՁԼԽԼ԰Ռ ՍԼԽՆՌ0ՋՌՌԽՋՌ

ԩԬԮՅԿԹՁԩ
ԹՎԽՊԹԿԽՎԹՄՍԽ



### ԡ ԰ՌՍԼՑԡԽԾՁԻՁԽՆԻՁԽՋ

ԱՀԽՊԽՏԽՊԽԹՆՍՅԺԽՊՇԾԼԽՎՁԹՌՁՇՆՋԼԽՋԻՊՁԺԽԼՁՆ԰ԽԻՌՁՇՆԦԪԹՌԽՊ ՁԹՄՋԹՆԼԪԽՌՀՇԼՋՇԾՌՀՁՋԡԢԯ

ՊԽԿԹՊԼՁՆԿՌՀԽՆՍՅԺԽՊՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹՆԼԾԹՁՄՍՊԽՌՇՊԽՈՇ ՊՌԻԽՊՌԹՁՆՏԹՌԽՊԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋԞՄՇՆԿ

ՏՁՌՀՌՀԽՋԽԼԽՎՁԹՌՁՇՆՋՋԽՎԽՊԹՄՎԹՄՁԼՁՌՑԹՆԼՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁ ԹՊԽԿԹՊԼՁՆԿՋՍՊՎՁՎԹՄԾԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋ

ՌԽՅՈԽՊԹՌՍՊԽԹՆԼԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆԻՇՆՌԽՆՌ
ՋՈԽԻՁԾՁԽԼԺՑՌՀԽԬԠ԰ ԭԭԿՍՁԼԽՄՁՆԽՏԽՊԽՆՇՌ

ՅԽՌԾՇՊՌՀՁՋՋՌՍԼՑ

 ԱՀԽՋՍՊՎՁՎԹՄՎԹՄՁԼՁՌՑԻՊՁՌԽՊՁՇՆՇԾՏԹՋՆՇՌՅԽՌՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԞՎԽՊԹԿԽՋՍՊՎՁՎԹՄՁՆՌՀԽ

ՋՇՄՎԽՆՌԻՇՆՌՊՇՄՏԹՋԞՎԽՊԹԿԽՋՍՊՎՁՎԹՄՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊ ՇՄՏԹՋԱՀԽՀՁԿՀԽՋՌ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՏԹՋՆՇՅՁՆԹՄՄՑՅԿԹՁԩՏՁՌՀԹՅԽԹՆՅԽԹՋՍՊԽԼ ԻՇՆԻԽՆՌՊԹՌՁՇՆՇԾՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԱՀՁՋՀՁԿՀԽՋՌՄԽՎԽՄՊԽՋՍՄՌԽԼՁՆՅՇՊԺՁԼՁՌՑԹՆԼՌԽՊՅՁՆԹՌՁՇՆՇԾՌՀՁ ՋՄԽՎԽՄԾՊՇՅՌՀԽՋՌՍԼՑՇՆԡԹՑԞ

ՊԹՆԿԽԾՁՆԼՁՆԿՋՌՍԼՑՏԹՋՆՇՌՊԽՈՇՊՌԽԼ

 ԱՏՇՇԾՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՌԹՆՃՋԹՆԼՇՆԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄՀԹԼ ՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋԬԠ԰ԭԭ

ՊԽԻՇՅՅԽՆԼՋՌՏՇՅԹՄԽՋԹՆԼԾՇՍՊԾԽՅԹՄԽՋՁՆԽԹԻՀՌԹՆՃԱՀ ԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌՀԹՌ

ԹՄՄԽՆԼՈՇՁՆՌՋՏԽՊԽԹԼՂՍՋՌԽԼԾՇՊՌՀԽՊԽԼՍԻԽԼՆՍՅԺԽՊՇԾԾԽՅԹՄԽՋ

 ԡՁՋՋՇՄՎԽԼՇՐՑԿԽՆԼՊՇՈՈԽԼԺԽՄՇՏՁՆՌՀԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄԹՆԼԺ ՇՌՀՈՊՇՆԹՅՁԼԽՌՊԽԹՌԽԼՄԽՎԽՄՋ

ՏՁՌՀՅՁՆՁՅԹՊԹՆԿՁՆԿԾՊՇՅ

 ԦՆՁՌՁԹՄՅԹՄԽԹՆԼԾԽՅԹՄԽԾՁՋՀՏԽՁԿՀՌՋԽՐԻԽԽԼԽԼՌՀԽՊԽԻՇՅՅԽՆԼԽԼՅ ԹՐՁՅՍՅՎԹՊՁԹՌՁՇՆԹՊՇՍՆԼՌՀԽ

ՋԹՅՈՄԽՅԽԹՆ
ՁԽչՁՆՁՌՁԹՄՅԹՄԽԾՁՋՀՏԽՁԿՀՌՋՎԹՊՁԽԼչ ԹՆԼՁՆՁՌՁԹՄԾԽՅԹՄԽՏԽՁԿՀՌՋՎԹՊՁԽԼ

չՇԾՌՀԽՋԹՅՈՄԽՅԽԹՆ

 ԱՀԽՍՆՁՇՆՁՒԽԼԹՅՅՇՆՁԹԹՆԼՊԽՋՁԼՍԹՄԻՀՄՇՊՁՆԽՁՆՌՀԽՌԽՋՌՏԹՌԽՊՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼԱՀԽԬԠ԰ԭԭ

ՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹԽՋՌԹԺՄՁՋՀՅԹՐՁՅՍՅՄԽՎԽՄՋԾՇՊՌՀԽՋ ԽՎԹՄՍԽՋԹՆԼՁՌՁՋՍՆԻՄԽԹՊՁԾՌՀԽ

ՅԹՐՁՅՍՅՄՁՅՁՌՋՏԽՊԽԽՐԻԽԽԼԽԼ

 ԬՆՌԽՋՌԡԹՑՌՀԽՅԹՐՁՅՍՅՌԽՅՈԽՊԹՌՍՊԽՏԹՋՊԽԻՇՊԼԽԼՌՇԺԽո ԠԾԹՄՄՁՆԿՇՍՌՋՁԼԽՌՀԽՊԽՉՍՁՊԽԼ

ՊԹՆԿԽՇԾչոԠ

ԱՀԽՋԽԼԽՎՁԹՌՁՇՆՋԼՇՆՇՌՋՍԺՋՌԹՆՌՁՎԽՄՑՁՅՈԹԻՌՌՀԽՊԽՋՍՄՌՋՇՊՁՆՌ ԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀՁՋՋՌՍԼՑ

Ԣ ԯԽՎՁԽՏԽՊ0ՋԠՇՅՅԽՆՌՋ

ԱՀԽՋՌՍԼՑԹՍՌՀՇՊ0ՋԹՆԹՄՑՋՁՋԻՇՅՈԹՊՁՆԿՈՊՇՆԹՅՁԼԽՌՊԽԹՌԽԼԻՇՆԼՁՌՁ ՇՆՋՌՇՌՀԽՈՇՇՄԽԼԻՇՆՌՊՇՄՊԽՎԽԹՄԽԼ

ՋՇՅԽԼՁԾԾԽՊԽՆԻԽՋԻՇՅՈԹՊԽԼՌՇՌՀԽՊԽՋՍՄՌՋՇԾՌՀԽՊԽՎՁԽՏԽՊ0ՋԹՆԹՄՑՋՁՋԺԹՋԽԼՇՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ

ԱՀԽՇՆՄՑՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋԼԽՌԽԻՌԽԼԺՑՌՀԽՋՌՍԼՑԹՍՌՀՇՊ0ՋԹՆԹ ՄՑՋՁՋՏԽՊԽԾՇՊԾԽՊՌՁՄՁՌՑԹՆԼԾԽԻՍՆԼՁՌՑԹՌ

ՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄԱՀԽՊԽՎՁԽՏԽՊ0ՋԹՆԹՄՑՋՁՋԼԽՌԽ ԻՌԽԼՌՀԽՋԽԽԾԾԽԻՌՋԹՆԼԾՍՊՌՀԽՊԼԽՌԽԻՌԽԼ

ՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌՋ
ՈՇՆՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽԟՇՌՀՌՀԽՋ ՌՍԼՑԹՍՌՀՇՊԹՆԼՌՀԽՊԽՎՁԽՏԽՊԹԿՊԽԽԼ

ՌՀԹՌՀՁՋՌՇՈԹՌՀՇՄՇԿՁԻԹՄԽԾԾԽԻՌՋՏԽՊԽՇԺՋԽՊՎԽԼՁՆՅԹՄԽԾՁՋՀԹՌՌՀ ԽՅԿԹՁԩՄԽՎԽՄ

ԱՀԽՊԽՏԽՊԽԾՇՍՊԽՆԼՈՇՁՆՌՋԽՐՀՁԺՁՌՁՆԿԹՅՇՆՇՌՇՆՁԻԻՇՆԻԽՆՌՊԹՌՁՇՆ ՊԽՋՈՇՆՋԽՏՀՁԻՀԹՄՋՇՋԹՌՁՋԾՁԽԼ

ՈԹՊԹՅԽՌՊՁԻԹՋՋՍՅՈՌՁՇՆՋ ՁԽ ԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՌՑՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽԹՆԼՅԹՄԽԳԱԤԱՀԽ ԬԠ԰ԭԭ

ԿՍՁԼԹՆԻԽՊԽԻՇՅՅԽՆԼՋՍՋԽՇԾՌՀԽՆՇՆՈԹՊԹՅԽՌՊՁԻԧՇՆԻՃՀԽԽ ՊԽԱԽՊՈՋՌՊԹՌԽՋՌՌՇԼԽՌԽԻՌ

ՌՊԽԹՌՅԽՆՌՊԽՄԹՌԽԼԽԾԾԽԻՌՋԾՇՊԹՆՑՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽՏՀՁՄԽՌՀԽ ՀՁՋՌՇՊՁԻԹՄԢԣԢԡՅԽՌՀՇԼՋՍԿԿԽՋՌՋՍՋԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ՇԾԴՁՄՄՁԹՅ0ՋՌԽՋՌՏՀԽՆՈԹՊԹՅԽՌՊՁԻԹՋՋՍՅՈՌՁՇՆՋԹՊԽՋԹՌՁՋԾՁԽԼԣՇՊՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽԹՆԼՅԹՄԽԳԱԤ

ԺՇՌՀՌԽՋՌՋՊԽՋՍՄՌԽԼՁՆՌՀԽՋԹՅԽԻՇՆԻՄՍՋՁՇՆՋԥՇՏԽՎԽՊԾՇՊԾԽՊՌՁ ՄՁՌՑԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԼԽՌԽԻՌԽԼԹ

ՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌԹՌՌՀԽՅԿԹՁԩԻՇՆԻԽՆՌՊԹՌՁՇՆՏՀԽՆԴՁՄՄ ՁԹՅ0ՋՌԽՋՌԼՁԼՆՇՌԹՆԼԾՇՊԾԽԻՍՆԼՁՌՑ

ԴՁՄՄՁԹՅ0ՋՌԽՋՌԼԽՌԽԻՌԽԼԹՋՁԿՆՁԾՁԻԹՆՌԽԾԾԽԻՌԹՌՌՀԽՅԿԹՁ ԩԻՇՆԻԽՆՌՊԹՌՁՇՆՏՀԽՆԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹԼՁԼՆՇՌ

ԞՄՋՇՇԾՆՇՌԽՁՆՌՀՁՋՋՌՍԼՑՁՋՌՀԹՌՌՀԽՋՌԹՌՁՋՌՁԻԹՄՋՁԿՆՁԾՁԻԹՆԻԽ ՇԾՌՀԽՅԹՄԽՌՍԺԽՊԻՄԽՊԽՋՍՄՌՋԼԽՈԽՆԼՋՇՆ

ՏՀԽՌՀԽՊՌՀԽԼԹՌԹՁՋՂՍԼԿԽԼՌՇԾՇՄՄՇՏԹՅՇՆՇՌՇՆՁԻՌՊԽՆԼԱՀԽՊԽՎՁԽՏԽՊԺԽՄՁԽՎԽԼԹՌՊԽՆԼՏԹՋՈՊԽՋԽՆՌ

ԹՆԼՊԽՈՇՊՌԽԼՌՀԽՊԽՋՍՄՌՋԾՊՇՅՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԹԻԻՇ ՊԼՁՆԿՄՑԦԾԡՍՆՆԽՌՌ0ՋՌԽՋՌՁՋՍՋԽԼԾՇՊ

ՌՀԽԹՆԹՄՑՋՁՋՌՀԽՁՆԻՊԽԹՋԽՋՁՆՌՀԽՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԹՊԽՆՇՌՋՌԹ ՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌ
ՈԹՆԼ

ՈԾՇՊՌՀԽԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՋՈԽ ԻՌՁՎԽՄՑ

ԱՏՇՇԾՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՌԹՆՃՋԹՆԼՇՆԽՋՇՄՎԽՆՌԻՇՆՌՊՇՄՀԹԼ ՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋԼՍԽՌՇ

ՅՁՋՁԼԽՆՌՁԾՁԻԹՌՁՇՆՇԾՅԹՄԽԾՁՋՀԹՌՋՌՍԼՑՁՆՁՌՁԹՌՁՇՆԯԽՋՍՄՌՋՈՊԽ ՋԽՆՌԽԼՁՆՌՀՁՋԡԢԯԽՐԻՄՍԼԽՌՀԽՋԽԾՁՋՀԾՊՇՅ

ՋՍՅՅԹՊՑՋՌԹՌՁՋՌՁԻՋԹՆԼՋՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋՁՋԦՆԻՄՍԼՁՆԿՌՀԽՋԽԾՁ ՋՀՁՆՌՀԽՋՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋՁՋԾՇՊՌՀԽՅԹՄԽ

ԽՆԼՈՇՁՆՌՋԼՇԽՋՄԽԹԼՌՇՋՄՁԿՀՌՄՑԼՁԾԾԽՊԽՆՌԻՇՆԻՄՍՋՁՇՆՋԾՇՊՌՏՇԽ ՆԼՈՇՁՆՌՋ
ԾՇՊՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՌՀԽ

ՁՆԻՊԽԹՋԽԹՌՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆԺԽԻՇՅԽՋՆ ՇՆՋՁԿՆՁԾՁԻԹՆՌ
ՈԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹԱՀԽԽԾԾԽԻՌԹՌՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԻՇՆԻԽՆՌՊ ԹՌՁՇՆՊԽՅԹՁՆՋՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌ

ԞՆԼ
ԾՇՊՅԹՄԽՄԽՆԿՌՀԹՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌՁՆԻՊԽԹՋԽՇ ԾՁՋԼԽՌԽԻՌԽԼԹՌՌՀԽՅԿԹՁԩ

ՌՊԽԹՌՅԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՈԡՍՆՆԽՌՌ0ՋԱՀԽՁՆԻՊԽԹՋԽԹՌՅԿԹՁԩՊԽՅԹՁՆՋՆՇՆՋՁԿՆՁԾՁԻԹՆՌ

ԱՀԽՋԽԼՁԾԾԽՊԽՆԻԽՋԹՊԽՋՄՁԿՀՌԹՆԼՋՀՇՍՄԼՆՇՌՋՍԺՋՌԹՆՌՁԹՄՄՑԹՄՌԽՊ ՌՀԽՁՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀԽՋՌՍԼՑՊԽՋՍՄՌՋ

԰ՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋՁՋՇԾՌՀԽՅԹՄԽՋՈԽԻՁԾՁԻԽՆԼՈՇՁՆՌՋՁՆԻՄՍԼՁՆԿԼ ԹՌԹԾՊՇՅՌՀԽՅՁՋՋԽՐԽԼՅԹՄԽՋՁՋ

ՈՊԽՋԽՆՌԽԼԹՌՌՀԽԽՆԼՇԾՌՀԽՋՌԹՌՁՋՌՁԻԹՄՊԽՋՍՄՌՋՁՆԞՈՈԽՆԼՁՐԦ

ԟԽԻԹՍՋԽՀՁԿՀՎԹՊՁԹԺՁՄՁՌՑՁՆՌՀԽԽՆԼՈՇՁՆՌՅԹՃԽՋՅԹՄԽԳԱԤՊԽՋՍՄՌՋ ԼՁԾԾՁԻՍՄՌՌՇՁՆՌԽՊՈՊԽՌՌՀՁՋԽՆԼՈՇՁՆՌՁՋ

ՈՊԽՋԽՆՌԽԼԿՊԹՈՀՁԻԹՄՄՑՁՆՌՀԽԺՇՐՈՄՇՌՋԺԽՄՇՏԦՆԻՄՍԼՁՆԿՇՊԽՐԻՄՍ ԼՁՆԿՌՀԽՅՁՋՋԽՐԽԼՅԹՄԽԾՁՋՀՁՆՌՀԽ

ՆԽԿԹՌՁՎԽԹՆԼՋՇՄՎԽՆՌԻՇՆՌՊՇՄԿՊՇՍՈՋԼՇԽՋՆՇՌԻՀԹՆԿԽՌՀԽՁՆՌԽՊՈՊ ԽՌԹՌՁՇՆՇԾՌՀԽԽՆԼՈՇՁՆՌ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

# Pronamide, Male Vtg Excluding Mis-sexed Males

NC SC 0.094 1.1 0 1000 2000 3000vtg

conc



# Pronamide, Male Vtg Including Mis-sexed Males

NC SC 0.094 1.1 0 1000 2000 3000vtg

conc

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### ԦԦԦ ԯԢԣԢԯԢԫԠԢ԰

ԞՆՃՄԽՑԤԱԧԽՆՋԽՆԨԪԨԹՀՄԪԡԨՇՊՌԽԧԧԹՆԼԪԹՃՑՆԽ ՆԢԞԡԽՋԻՊՁՈՌՁՇՆԹՆԼԽՎԹՄՍԹՌՁՇՆՇԾ

ԹՋՀՇՊՌՌԽՊՅՊԽՈՊՇԼՍԻՌՁՇՆՌԽՋՌՏՁՌՀՌՀԽԾԹՌՀԽԹԼՅՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ ԢՆՎՁՊՇՆԱՇՐՁԻՇՄԠՀԽՅ



ԞԭԥԞԞԴԴԞԴԭԠԣ԰ՌԹՆԼԹՊԼԪԽՌՀՇԼՋԾՇՊՌՀԽԢՐԹՅՁՆԹՌՁՇՆՇԾ ԴԹՌԽՊԹՆԼԴԹՋՌԽՏԹՌԽՊՌՀԢԼՁՌՁՇՆ

ԴԹՋՀՁՆԿՌՇՆԡԠ

Ԟ԰ԱԪԠՇՅՅՁՌՌԽԽԢՇՆԟՁՇՄՇԿՁԻԹՄԢԾԾԽԻՌՋԹՆԼԢՆՎՁՊՇՆՅԽՆ ՌԹՄԣԹՌԽ԰ՌԹՆԼԹՊԼԤՍՁԼԽԾՇՊԠՇՆԼՍԻՌՁՆԿ

ԢԹՊՄՑԩՁԾԽ԰ՌԹԿԽԱՇՐՁԻՁՌՑԱԽՋՌՋՏՁՌՀԣՁՋՀԽՋԞ԰ԱԪԡԽՋՁԿՆԹՌՁՇՆԢ ԞՅԽՊՁԻԹՆ԰ՇԻՁԽՌՑԾՇՊԱԽՋՌՁՆԿԹՆԼ

ԪԹՌԽՊՁԹՄՋԟԹՊՊԥԹՊԺՇՊԡՊՁՎԽԭԬԟՇՐԠԴԽՋՌԠՇՆՋՀՇՀՇԻՃԽ ՆԭԽՆՆՋՑՄՎԹՆՁԹ

ԣՄԽՁՋԻՀԽՊԪԹՊՃԢԳԹՄՁԼԹՌՁՇՆՇԾՌՀԽԞՆԹՄՑՌՁԻԹՄԪԽՌՀՇԼԾՇՊՌՀԽԡԽՌԽՊՅՁՆԹՌՁՇՆՇԾԱԽՋՌՇՋՌԽՊՇՆԽԹՆԼԢՋՌՊԹԼՁՇՄՁՆ

԰ԽՊՍՅ԰ՅՁՌՀԽՊՋԳՁՋԻՁԽՆՌ԰ՌՍԼՑԫՍՅԺԽՊԣՁՆԹՄՊԽՈՇՊՌԼԹՌ ԽԧԹՆՍԹՊՑ

ԦՎԽՋԪՁԻՀԹԽՄԠԢԱԦ԰ԠՇՅՈՊԽՀԽՆՋՁՎԽԢՆՎՁՊՇՆՅԽՆՌԹՄԱՇՐՁԻՁՌ ՑԦՆԾՇՊՅԹՌՁՇՆ԰ՑՋՌԽՅ ԱԪ 

### ԲՋԽՊ0ՋԤՍՁԼԽ

ԱՁԼԽՈՇՇՄ԰ԻՁԽՆՌՁԾՁԻ԰ՇԾՌՏԹՊԽԪԻԨՁՆՄԽՑՎՁՄՄԽԠԹՄՁԾՇՊՆՁԹ

ԪՇՍՆՌԡԦԹՆԼԴԞԟՊՍՆԿՋԞՋՁՅՈՄՁԾՁԽԼԼՇՋՁՆԿԹՈՈԹՊԹ ՌՍՋԾՇՊԾՁՋՀՌՇՐՁԻՇՄՇԿՑՋՌՍԼՁԽՋԴԹՌԽՊ

ԯԽՋԽԹՊԻՀ

԰ՈՊԹԿՍԽԧԟԪԽԹՋՍՊԽՅԽՆՌՇԾՈՇՄՄՍՌԹՆՌՌՇՐՁԻՁՌՑՌՇԾՁՋՀ ԟՁՇԹՋՋԹՑՅԽՌՀՇԼՋԾՇՊԹԻՍՌԽՌՇՐՁԻՁՌՑԴԹՌԽՊ

ԯԽՋ

ԬԢԠԡԤՍՁԼԽՄՁՆԽԾՇՊԱԽՋՌՁՆԿՇԾԠՀԽՅՁԻԹՄՋ ԡԹՈՀՆՁԹՅԹԿՆԹ ԯԽՈՊՇԼՍԻՌՁՇՆԱԽՋՌԤՍՁԼԽՄՁՆԽ

ԞԼՇՈՌԽԼ԰ԽՈՌԽՅԺԽՊ

ԬԢԠԡ
ԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑԬԢԠԡԤՍՁԼԽՄՁՆԽ ԾՇՊՌՀԽՌԽՋՌՁՆԿԠՀԽՅՁԻԹՄՋԱԽՋՌԫՇ

ԭԹՊՁՋԣՊԹՆԻԽՈՈ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  

### Բ԰ԢԭԞԠԣԯԭԹՊՌԣԽԼԽՊԹՄԦՆՋԽԻՌՁԻՁԼԽԣՍՆԿՁԻՁԼ ԽԹՆԼԯՇԼԽՆՌՁԻՁԼԽԞԻՌԤՇՇԼԩԹԺՇՊԹՌՇՊՑ

ԭՊԹԻՌՁԻԽՋ԰ՌԹՆԼԹՊԼՋԣՁՆԹՄԯՍՄԽԬԾԾՁԻԽՇԾՌՀԽԣԽԼԽՊԹՄԯԽԿՁՋՌԽՊ ԫԹՌՁՇՆԹՄԞՊԻՀՁՎԽՋԹՆԼԯԽԻՇՊԼՋ

ԞԼՅՁՆՁՋՌՊԹՌՁՇՆԲ԰ԤՇՎԽՊՆՅԽՆՌԭՊՁՆՌՁՆԿԬԾԾՁԻԽԴԹՋՀՁՆԿՌՇՆԡ Ԡ

Բ԰ԢԭԞԬԾԾՁԻԽՇԾԭՊԽՎԽՆՌՁՇՆԭԽՋՌՁԻՁԼԽՋԹՆԼԱՇՐՁԻ԰ՍԺՋՌԹՆԻԽՋԢԻՇՄՇԿՁԻԹՄԢԾԾԽԻՌՋԤՍՁԼԽՄՁՆԽԬԭԭԱ԰

԰ՈԽԻՁԹՄԠՇՆՋՁԼԽՊԹՌՁՇՆԾՇՊԠՇՆԼՍԻՌՁՆԿԞՉՍԹՌՁԻԩԹԺՇՊԹՌՇ ՊՑ԰ՌՍԼՁԽՋ՟ԭՍԺՄՁԻԡՊԹԾՌՠԢԭԞԠ

ԞՈՊՁՄԲ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑԴԹՋՀՁՆԿՌ ՇՆԡԠ

԰ՅՁՌՀԽՊՋԳՁՋԻՁԽՆՌ԰ՌՍԼՑԫՇԭԹԿԽ

Բ԰ԢԭԞ԰ՀՇՊՌՌԽՊՅՅԽՌՀՇԼՋԾՇՊԽՋՌՁՅԹՌՁՆԿՌՀԽԻՀՊՇՆՁԻՌ ՇՐՁԻՁՌՑՇԾԽԾԾՄՍԽՆՌՋԹՆԼՊԽԻԽՁՎՁՆԿՏԹՌԽՊՋՌՇ

ՅԹՊՁՆԽԹՆԼԽՋՌՍԹՊՁՆԽՇՊԿԹՆՁՋՅՋԱՀՁՊԼԽԼՁՌՁՇՆԬԾԾՁԻԽՇԾԴԹՌԽՊ Բ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ

ԴԹՋՀՁՆԿՌՇՆԡԠԢԭԞԯ

Բ԰ԢԭԞԬԾԾՁԻԽՇԾԭՊԽՎԽՆՌՁՇՆԭԽՋՌՁԻՁԼԽՋԹՆԼԱՇՐՁԻ԰ՍԺՋՌԹՆԻԽՋԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿ

ԭՊՇԿՊԹՅԱԽՋՌԤՍՁԼԽՄՁՆԽԬԭԭԱ԰ԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍ ԻՌՁՇՆԞՋՋԹՑԢԭԞԠ

ԬԻՌՇԺԽՊԲ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑԴԹՋՀՁՆԿՌՇՆ ԡԠԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԞԭԭԢԫԡԦԵԦԬԲԱԭԲԱԬԣԯԢԳԦԢԴԢԯ0԰԰ԱԞԱԦ԰ԱԦԠԞԩԳԢԯԦԣԦԠԞԱԦԬԫԠՇՆՌՊՇՄԠՇՅՈԹՊՁՋՇՆՋԪՇՊՌ
ԹՄՄ ԪՇՊՌ
ՅԹՄԽ ԪՇՊՌ
ԾԽՅԹՄԽ ԣԽԻՍՆԼՁՌՑ ԣԽՊՌԫԽԿԠՇՆՌՊՇՄԞՎԽՊԹԿԽ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄԞՎԽՊԹԿԽՌՌԽՋՌՈՎԹՄՍԽԴՌ
ԹՄՄՅԹՄԽՋԴՌ
ՅԹՄԽԽՐԻՄՍԼՁՆԿՅՁՋՋԽՐԽԼ ԩԽՆԿՌՀ
ԹՄՄՅԹՄԽՋԩԽՆԿՌՀ
ՅԹՄԽԽՐԻՄՍԼՁՆԿՅՁՋՋԽՐԽԼ ԴՌ
ԾԽՅԹՄԽ ԩԽՆԿՌՀ
ԾԽՅԹՄԽԫԽԿԠՇՆՌՊՇՄ    ԞՎԽՊԹԿԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՊՇՆԹՅՁԼԽԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽοԾԠՇՆՌՊՇՄԠՇՅՈԹՊՁՋՇՆՋ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ    ԞՎԽՊԹԿԽՌՌԽՋՌՈՎԹՄՍԽԤ԰Ԧ
ԹՄՄՅԹՄԽՋԤ԰Ԧ
ՅԹՄԽԽՐԻՄՍԼՁՆԿՅՁՋՋԽՐԽԼ Ԥ԰Ԧ
ԾԽՅԹՄԽԱՍԺԽՊԻՄԽ
ԹՄՄՅԹՄԽԱՍԺԽՊԻՄԽ
ՅԹՄԽԽՐԻՄՍԼՁՆԿՅՁՋՋԽՐԽԼԳԱԤ
ԹՄՄՅԹՄԽՋԳԱԤ
ՅԹՄԽԽՐԻՄՍԼՁՆԿՅՁՋՋԽՐԽԼ ԳԱԤ
ԣԽՅԹՄԽԫԽԿԠՇՆՌՊՇՄ     ԞՎԽՊԹԿԽ ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ      ԞՎԽՊԹԿԽ ՌՌԽՋՌՈՎԹՄՍԽ  ՌՌԽՋՌՋԹՊԽՋՁԼԽԼ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ԳԽՊՁԾՁԻԹՌՁՇՆՇԾԞՆԹՄՑՌՁԻԹՄԳԹՊՁԹՌՁՇՆ   

ԫՇՅՁՆԹՄ ԪԽԹՋՍՊԽԼ

ԠՇՆԻԽՆՌՊԹՌՁՇՆ
ՅԿԹՁԩ ԱՁՅԽ
ԡԹՑ ԠՇՆԻԽՆՌՊԹՌՁՇՆ
ՅԿԹՁԩ  ԯԽՈ ԯԽՈ ԞՎԿ

ԫԽԿԹՌՁՎԽԹՆԼ԰ՇՄՎԽՆՌԠՇՆՌՊՇՄ    

   

   

   

     ԪԽԹՆ 

԰ՌԹՆԼԹՊԼԡԽՎ 

ԠԳ
  

    

   

   

   

     ԪԽԹՆ 

԰ՌԹՆԼԹՊԼԡԽՎ 

ԠԳ
  

    

  

    

   

   

     ԪԽԹՆ 

԰ՌԹՆԼԹՊԼԡԽՎ 

ԠԳ
  

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ԳԽՊՁԾՁԻԹՌՁՇՆՇԾԞՆԹՄՑՌՁԻԹՄԳԹՊՁԹՌՁՇՆ   

ԫՇՅՁՆԹՄ ԪԽԹՋՍՊԽԼ

ԠՇՆԻԽՆՌՊԹՌՁՇՆ
ՅԿԹՁԩ ԱՁՅԽ
ԡԹՑ ԠՇՆԻԽՆՌՊԹՌՁՇՆ
ՅԿԹՁԩ  ԯԽՈ ԯԽՈ ԞՎԿ

    

   

     

 

 

 

   ԪԽԹՆ 

԰ՌԹՆԼԹՊԼԡԽՎ 

ԠԳ
 

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR01 ( F body weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.841 0.028 1.419 0.291 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.32 0.05 0.03 4.02 1.24, 1.41
Dose1 4 1.38 0.16 0.08 11.88 1.12, 1.64
Dose2 4 1.37 0.16 0.08 11.52 1.12, 1.62

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1.34 1.24 1.36 . .

Dose1 1.44 1.13 1.49 104.08 -4.08

Dose2 1.40 1.15 1.52 103.59 -3.59

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.19 0.829

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 1.32 . 1.36 . . . . . .

Dose1 1.38 0.799 1.36 0.722 . . . . .

Dose2 1.37 0.839 1.36 0.756 0.997 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.88 0.390

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1.34 . .

Dose1 1.44 0.346 0.876

Dose2 1.40 0.346 0.847

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Numerator df Denominator df F-stat P-value

2 9 0.19 0.829

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -1.32 . -1.32 . . . . . .

Dose1 -1.38 0.799 -1.37 0.362 . . . . .

Dose2 -1.37 0.839 -1.37 0.386 0.997 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.88 0.390

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1.34 . .

Dose1 -1.44 0.346 0.124

Dose2 -1.40 0.346 0.153

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR02 ( M body weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.916 0.253 0.189 0.831 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 2.64 0.48 0.24 18.18 1.88, 3.41
Dose1 4 3.13 0.42 0.21 13.39 2.46, 3.79
Dose2 4 3.03 0.45 0.22 14.80 2.32, 3.74

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 2.62 2.14 3.20 . .

Dose1 3.13 2.62 3.62 118.22 -18.22

Dose2 2.97 2.55 3.63 114.58 -14.58

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.28 0.323

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 2.64 . 2.93 . . . . . .

Dose1 3.13 0.272 2.93 0.877 . . . . .

Dose2 3.03 0.408 2.93 0.901 0.951 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.58 0.276

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 2.62 . .

Dose1 3.13 0.235 0.926

Dose2 2.97 0.346 0.847

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.28 0.323

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -2.64 . -2.64 . . . . . .

Dose1 -3.13 0.272 -3.08 0.122 . . . . .

Dose2 -3.03 0.408 -3.08 0.130 0.951 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.58 0.276

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -2.62 . .

Dose1 -3.13 0.235 0.074

Dose2 -2.97 0.346 0.153

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR03 ( F body length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.911 0.219 1.775 0.224 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 49.68 0.42 0.21 0.85 49.01, 50.36
Dose1 4 49.16 0.70 0.35 1.42 48.05, 50.26
Dose2 4 49.08 1.33 0.66 2.71 46.96, 51.19

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 49.78 49.11 50.06 . .

Dose1 49.26 48.24 49.87 98.94 1.06

Dose2 49.54 47.16 50.07 98.78 1.22

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.54 0.602

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 49.68 . 49.68 . . . . . .

Dose1 49.16 0.634 49.16 0.256 . . . . .

Dose2 49.08 0.555 49.08 0.233 0.991 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.51 0.469

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 49.78 . .

Dose1 49.26 0.235 0.074

Dose2 49.54 0.889 0.255

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.54 0.602

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -49.68 . -49.30 . . . . . .

Dose1 -49.16 0.634 -49.30 0.800 . . . . .

Dose2 -49.08 0.555 -49.30 0.830 0.991 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.51 0.469

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -49.78 . .

Dose1 -49.26 0.235 0.926

Dose2 -49.54 0.889 0.745

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR04 ( M body length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.971 0.917 0.176 0.841 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 59.77 2.64 1.32 4.42 55.57, 63.98
Dose1 4 63.77 2.17 1.09 3.41 60.31, 67.23
Dose2 4 61.67 2.95 1.47 4.78 56.98, 66.36

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 58.80 57.86 63.63 . .

Dose1 64.52 60.59 65.45 106.68 -6.68

Dose2 62.76 57.33 63.84 103.17 -3.17

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Numerator df Denominator df F-stat P-value

2 9 2.35 0.151

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 59.77 . 61.77 . . . . . .

Dose1 63.77 0.102 61.77 0.908 . . . . .

Dose2 61.67 0.510 61.67 0.921 0.517 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.50 0.105

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 58.80 . .

Dose1 64.52 0.103 0.978

Dose2 62.76 0.678 0.721

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 2.35 0.151

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -59.77 . -59.77 . . . . . .

Dose1 -63.77 0.102 -62.72 0.085 . . . . .

Dose2 -61.67 0.510 -62.72 0.091 0.517 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.50 0.105

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -58.80 . .

Dose1 -64.52 0.103 0.022

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose2 -62.76 0.678 0.279

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR05 ( F vitellogenin (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.955 0.718 3.687 0.068 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1158044 376768.3 188384.1 32.53 558521.6, 1757566
Dose1 4 1021250 148782.8 74391.41 14.57 784503.6, 1257997
Dose2 4 1062088 309213.6 154606.8 29.11 570060.2, 1554116

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1199186 753299.0 1480506 . .

Dose1 1043868 838713.0 1158553 88.19 11.81

Dose2 1014884 750273.0 1468312 91.71 8.29

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.23 0.801

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 1158044 . 1158044 . . . . . .

Dose1 1021250 0.743 1041669 0.351 . . . . .

Dose2 1062088 0.860 1041669 0.375 0.979 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 0.62 0.735

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1199186 . .

Dose1 1043868 0.889 0.386

Dose2 1014884 0.494 0.232

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.23 0.801

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -1158044 . -1080461 . . . . . .

Dose1-1021250 0.743 -1080461 0.729 . . . . .

Dose2-1062088 0.860 -1080461 0.763 0.979 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 0.62 0.735

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1199186 . .

Dose1 -1043868 0.889 0.614

Dose2 -1014884 0.494 0.768

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR06 ( M vitellogenin (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.907 0.196 2.712 0.120 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 786.00 851.85 425.92 108.38 -569.48, 2141.48
Dose1 4 434.25 618.14 309.07 142.35 -549.35, 1417.85
Dose2 4 239.50 271.42 135.71 113.33 -192.39, 671.39

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 581.00 95.00 1887.00 . .

Dose1 187.00 14.00 1349.00 55.25 44.75

Dose2 121.00 71.00 645.00 30.47 69.53

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.78 0.487

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 786.00 . 786.00 . . . . . .

Dose1 434.25 0.657 434.25 0.268 . . . . .

Dose2 239.50 0.398 239.50 0.158 0.900 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.13 0.569

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 581.00 . .

Dose1 187.00 0.678 0.282

Dose2 121.00 0.346 0.170

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 0.78 0.487

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -786.00 . -486.58 . . . . . .

Dose1 -434.25 0.657 -486.58 0.822 . . . . .

Dose2 -239.50 0.398 -486.58 0.851 0.900 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.13 0.569

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Level Median MannWhit p-value Jonckheere p-value

Ctrl -581.00 . .

Dose1 -187.00 0.678 0.718

Dose2 -121.00 0.346 0.830

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR07 ( F GSI )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.938 0.478 0.154 0.859 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 15.28 1.74 0.87 11.39 12.51, 18.04
Dose1 4 15.37 1.78 0.89 11.57 12.54, 18.20
Dose2 4 13.59 1.54 0.77 11.32 11.14, 16.03

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 15.34 13.26 17.17 . .

Dose1 15.78 12.97 16.95 100.62 -0.62

Dose2 13.44 11.89 15.57 88.94 11.06

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.41 0.292

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 15.28 . 15.32 . . . . . .

Dose1 15.37 0.995 15.32 0.600 . . . . .

Dose2 13.59 0.312 13.59 0.120 0.338 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.35 0.309

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 15.34 . .

Dose1 15.78 1.000 0.500

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose2 13.44 0.235 0.094

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.41 0.292

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -15.28 . -14.74 . . . . . .

Dose1 -15.37 0.995 -14.74 0.753 . . . . .

Dose2 -13.59 0.312 -14.74 0.786 0.338 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.35 0.309

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -15.34 . .

Dose1 -15.78 1.000 0.500

Dose2 -13.44 0.235 0.906

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR08 ( M GSI )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.954 0.702 1.814 0.218 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.61 0.32 0.16 19.63 1.11, 2.11
Dose1 4 1.29 0.12 0.06 9.56 1.09, 1.48
Dose2 4 1.40 0.36 0.18 25.92 0.82, 1.98

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1.59 1.26 2.00 . .

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose1 1.29 1.14 1.44 79.97 20.03

Dose2 1.35 1.03 1.88 87.11 12.89

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.30 0.320

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 1.61 . 1.61 . . . . . .

Dose1 1.29 0.244 1.35 0.133 . . . . .

Dose2 1.40 0.514 1.35 0.142 0.841 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.42 0.298

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1.59 . .

Dose1 1.29 0.235 0.074

Dose2 1.35 0.346 0.121

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.30 0.320

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -1.61 . -1.43 . . . . . .

Dose1 -1.29 0.244 -1.43 0.869 . . . . .

Dose2 -1.40 0.514 -1.43 0.894 0.841 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.42 0.298

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1.59 . .

Dose1 -1.29 0.235 0.926

Dose2 -1.35 0.346 0.879

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR09 ( F tubercle score (median) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

. . . . NO DATA FOR TEST

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.00 0.00 0.00 . . , .
Dose1 4 0.00 0.00 0.00 . . , .
Dose2 4 0.00 0.00 0.00 . . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 0.00 0.00 0.00 . .

Dose1 0.00 0.00 0.00 . .

Dose2 0.00 0.00 0.00 . .

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

. . . 9 . . . . . . .

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 0.00 . . . . . . . .

Dose1 0.00 . . . . . . . .

Dose2 0.00 . . . . . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 0.00 1.000

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Level Median MannWhit p-value Jonckheere p-value

Ctrl 0.00 . .

Dose1 0.00 1.000 .

Dose2 0.00 1.000 .

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose1

Jonckheere Dose1

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

. . . 9 . . . . . . .

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 0.00 . . . . . . . .

Dose1 0.00 . . . . . . . .

Dose2 0.00 . . . . . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 0.00 1.000

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 0.00 . .

Dose1 0.00 1.000 .

Dose2 0.00 1.000 .

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

Williams Dose1

Jonckheere Dose1

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded
ANALYSIS RESULTS FOR VARIABLE VAR10 ( M tubercle score (median) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.976 0.962 0.758 0.496 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 29.00 2.80 1.40 9.65 24.55, 33.45

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose1 4 33.50 1.87 0.94 5.58 30.52, 36.48
Dose2 4 33.63 3.73 1.86 11.09 27.69, 39.56

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 29.75 25.00 31.50 . .

Dose1 33.75 31.00 35.50 115.52 -15.52

Dose2 32.50 30.50 39.00 115.95 -15.95

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.30 0.084

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 29.00 . 32.04 . . . . . .

Dose1 33.50 0.097 32.04 0.955 . . . . .

Dose2 33.63 0.089 32.04 0.967 0.998 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 5.81 0.055

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 29.75 . .

Dose1 33.75 0.103 0.978

Dose2 32.50 0.103 0.961

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.30 0.084

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -29.00 . -29.00 . . . . . .

Dose1 -33.50 0.097 -33.50 0.032 . . . . .

Dose2 -33.63 0.089 -33.63 0.031 0.998 . . . .

********************************************************************************

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 5.81 0.055

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -29.75 . .

Dose1 -33.75 0.103 0.022

Dose2 -32.50 0.103 0.039

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

Williams Dose1

Jonckheere Dose1

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR11 ( fecundity )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.911 0.220 1.797 0.220 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 21.04 10.63 5.31 50.50 4.13, 37.95
Dose1 4 16.88 2.54 1.27 15.04 12.84, 20.92
Dose2 4 10.26 6.49 3.24 63.19 -0.06, 20.58

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 17.87 12.30 36.12 . .

Dose1 17.77 13.15 18.84 80.23 19.77

Dose2 8.94 3.89 19.28 48.78 51.22

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 2.20 0.167

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 21.04 . 21.04 . . . . . .

Dose1 16.88 0.651 16.88 0.265 . . . . .

Dose2 10.26 0.117 10.26 0.041 0.442 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  2 3.04 0.219

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 17.87 . .

Dose1 17.77 0.889 0.386

Dose2 8.94 0.156 0.054

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2 Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 2.20 0.167

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -21.04 . -16.06 . . . . . .

Dose1 -16.88 0.651 -16.06 0.887 . . . . .

Dose2 -10.26 0.117 -16.06 0.910 0.442 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 3.04 0.219

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -17.87 . .

Dose1 -17.77 0.889 0.614

Dose2 -8.94 0.156 0.946

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR12 ( fertility )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.828 0.020 2.840 0.111 USE PARAMETRIC TESTS

********************************************************************************

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 96.78 1.20 0.60 1.24 94.86, 98.69
Dose1 4 94.60 2.95 1.47 3.12 89.91, 99.29
Dose2 4 92.30 5.35 2.67 5.80 83.79, 100.81

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 97.00 95.20 97.90 . .

Dose1 95.60 90.30 96.90 97.75 2.25

Dose2 94.70 84.30 95.50 95.38 4.62

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 96.78 . 96.78 . . . . . .

Dose1 94.60 0.616 94.60 0.247 . . . . .

Dose2 92.30 0.190 92.30 0.070 0.651 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.89 0.087

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 97.00 . .

Dose1 95.60 0.283 0.096

Dose2 94.70 0.103 0.012

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences)

Jonckheere Dose2

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -96.78 . -94.56 . . . . . .

Dose1 -94.60 0.616 -94.56 0.869 . . . . .

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose2 -92.30 0.190 -94.56 0.894 0.651 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.89 0.087

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -97.00 . .

Dose1 -95.60 0.283 0.904

Dose2 -94.70 0.103 0.988

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR13 ( F testosterone (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.828 0.020 2.840 0.111 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 0 . . . . . , .
Dose1 0 . . . . . , .
Dose2 0 . . . . . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl . . . . .

Dose1 . . . . .

Dose2 . . . . .

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR14 ( M testosterone (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.828 0.020 2.840 0.111 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 0 . . . . . , .
Dose1 0 . . . . . , .
Dose2 0 . . . . . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl . . . . .

Dose1 . . . . .

Dose2 . . . . .

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose1 . . .

Dose2 . . .

Jonckheere Dose1

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR15 ( F 17b-estradiol (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.828 0.020 2.840 0.111 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 0 . . . . . , .
Dose1 0 . . . . . , .
Dose2 0 . . . . . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl . . . . .

Dose1 . . . . .

Dose2 . . . . .

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

Pronamide FSTRA 101701 48619106 Mis-sexed Males Excluded ANALYSIS RESULTS FOR VARIABLE VAR16 ( M 17b-estradiol (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.828 0.020 2.840 0.111 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 0 . . . . . , .
Dose1 0 . . . . . , .
Dose2 0 . . . . . , .

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl . . . . .

Dose1 . . . . .

Dose2 . . . . .

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.55 0.264

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl . . .

Dose1 . . .

Dose2 . . .

Jonckheere Dose1

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Pronamide FSTRA 101701 48619106 Mis-sexed Males Included ANALYSIS RESULTS FOR VARIABLE VAR02 ( M body weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.957 0.743 0.050 0.952 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 2.52 0.32 0.16 12.65 2.01, 3.02
Dose1 4 3.13 0.42 0.21 13.39 2.46, 3.79
Dose2 4 3.03 0.45 0.22 14.80 2.32, 3.74

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 2.56 2.14 2.81 . .

Dose1 3.13 2.62 3.62 124.24 -24.24

Dose2 2.97 2.55 3.63 120.42 -20.42

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 2.70 0.120

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 2.52 . 2.89 . . . . . .

Dose1 3.13 0.102 2.89 0.941 . . . . .

Dose2 3.03 0.173 2.89 0.955 0.938 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.31 0.116

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 2.56 . .

Dose1 3.13 0.156 0.958

Dose2 2.97 0.156 0.928

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Numerator df Denominator df F-stat P-value

2 9 2.70 0.120

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -2.52 . -2.52 . . . . . .

Dose1 -3.13 0.102 -3.08 0.045 . . . . .

Dose2 -3.03 0.173 -3.08 0.048 0.938 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.31 0.116

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -2.56 . .

Dose1 -3.13 0.156 0.042

Dose2 -2.97 0.156 0.072

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

Williams Dose1 Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Included
ANALYSIS RESULTS FOR VARIABLE VAR04 ( M body length (mm) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.909 0.209 0.609 0.565 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 59.46 1.68 0.84 2.82 56.79, 62.12
Dose1 4 63.77 2.17 1.09 3.41 60.31, 67.23
Dose2 4 61.67 2.95 1.47 4.78 56.98, 66.36

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 58.84 58.28 61.87 . .

Dose1 64.52 60.59 65.45 107.25 -7.25

Dose2 62.76 57.33 63.84 103.72 -3.72

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.44 0.078

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 59.46 . 61.63 . . . . . .

Dose1 63.77 0.049 61.63 0.940 . . . . .

Dose2 61.67 0.343 61.63 0.955 0.442 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 5.12 0.077

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 58.84 . .

Dose1 64.52 0.103 0.978

Dose2 62.76 0.346 0.810

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.44 0.078

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -59.46 . -59.46 . . . . . .

Dose1 -63.77 0.049 -62.72 0.046 . . . . .

Dose2 -61.67 0.343 -62.72 0.048 0.442 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 5.12 0.077

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -58.84 . .

Dose1 -64.52 0.103 0.022

Dose2 -62.76 0.346 0.190

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Williams Dose1 Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Included ANALYSIS RESULTS FOR VARIABLE VAR06 ( M vitellogenin (ng/mL) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.903 0.176 1.254 0.331 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 936.25 749.44 374.72 80.05 -256.27, 2128.77
Dose1 4 434.25 618.14 309.07 142.35 -549.35, 1417.85
Dose2 4 239.50 271.42 135.71 113.33 -192.39, 671.39

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 881.50 95.00 1887.00 . .

Dose1 187.00 14.00 1349.00 46.38 53.62

Dose2 121.00 71.00 645.00 25.58 74.42

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.52 0.269

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 936.25 . 936.25 . . . . . .

Dose1 434.25 0.404 434.25 0.151 . . . . .

Dose2 239.50 0.210 239.50 0.078 0.886 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.94 0.379

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 881.50 . .

Dose1 187.00 0.494 0.193

Dose2 121.00 0.235 0.106

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  ******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.52 0.269

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -936.25 . -536.67 . . . . . .

Dose1 -434.25 0.404 -536.67 0.889 . . . . .

Dose2 -239.50 0.210 -536.67 0.912 0.886 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 1.94 0.379

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -881.50 . .

Dose1 -187.00 0.494 0.807

Dose2 -121.00 0.235 0.894

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Included
ANALYSIS RESULTS FOR VARIABLE VAR08 ( M GSI )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.915 0.251 1.536 0.267 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.61 0.38 0.19 23.45 1.01, 2.20
Dose1 4 1.29 0.12 0.06 9.56 1.09, 1.48
Dose2 4 1.40 0.36 0.18 25.92 0.82, 1.98

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 1.51 1.26 2.14 . .

Dose1 1.29 1.14 1.44 80.22 19.78

Dose2 1.35 1.03 1.88 87.38 12.62

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Numerator df Denominator df F-stat P-value

2 9 1.07 0.382

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 1.61 . 1.61 . . . . . .

Dose1 1.29 0.299 1.35 0.159 . . . . .

Dose2 1.40 0.574 1.35 0.169 0.862 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.42 0.298

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 1.51 . .

Dose1 1.29 0.235 0.074

Dose2 1.35 0.346 0.121

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 1.07 0.382

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -1.61 . -1.43 . . . . . .

Dose1 -1.29 0.299 -1.43 0.851 . . . . .

Dose2 -1.40 0.574 -1.43 0.878 0.862 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 2.42 0.298

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -1.51 . .

Dose1 -1.29 0.235 0.926

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Dose2 -1.35 0.346 0.879

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

Pronamide FSTRA 101701 48619106 Mis-sexed Males Included
ANALYSIS RESULTS FOR VARIABLE VAR10 ( M tubercle score (median) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals -- alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) -- alpha-level=0.05 Use parametric analyses if neither test rejected, otherwise non-parametric analyses. Shapiro-Wilks Shapiro-Wilks Levenes Levenes Conclusion

Test Stat P-value Test Stat P-value

0.958 0.757 1.240 0.335 USE PARAMETRIC TESTS

********************************************************************************

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 28.63 3.15 1.57 10.99 23.62, 33.63
Dose1 4 33.50 1.87 0.94 5.58 30.52, 36.48
Dose2 4 33.63 3.73 1.86 11.09 27.69, 39.56

Level Median Min Max %of Control(means) %Reduction(means)

Ctrl 29.00 25.00 31.50 . .

Dose1 33.75 31.00 35.50 117.03 -17.03

Dose2 32.50 30.50 39.00 117.47 -17.47

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.57 0.072

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing negative trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl 28.63 . 31.92 . . . . . .

Dose1 33.50 0.084 31.92 0.960 . . . . .

Dose2 33.63 0.077 31.92 0.971 0.998 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.72 0.094

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing negative trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl 29.00 . .

Dose1 33.75 0.125 0.970

Dose2 32.50 0.156 0.938

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹ ՑՏՁՌՀԭՊՇՆԹՅՁԼԽ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽ  ο Ծ  Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

******************************************************************************** PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Analysis of Variance (ANOVA) - overall F-test

Numerator df Denominator df F-stat P-value

2 9 3.57 0.072

Dunnett - testing each trt mean signif. different than control Williams - test assumes dose-response relationship, testing INCREASING trend Tukey - two-sided tests, all possible comparisons, not used for NOEC or LOEC

Level Mean Dunnett Isotonic Williams Tukey p-values
p-value mean p-value Dose1 Dose2 Dose3 Dose4 Dose5

Ctrl -28.63 . -28.63 . . . . . .

Dose1 -33.50 0.084 -33.50 0.028 . . . . .

Dose2 -33.63 0.077 -33.63 0.027 0.998 . . . .

******************************************************************************** NON-PARAMETRIC ANALYSES - use alpha-level=0.05 for all tests Kruskal-Wallis test - equality among treatment groups
Degrees of Freedom TestStat P-value

2 4.72 0.094

MannWhit - testing each trt median signif. different from control Jonckheere - test assumes dose-response relationship, testing INCREASING trend

Level Median MannWhit p-value Jonckheere p-value

Ctrl -29.00 . .

Dose1 -33.75 0.125 0.030

Dose2 -32.50 0.156 0.062

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL

Williams Dose1 Jonckheere >highest dose (no sign. differences)

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE)

Study Type: O CSPP 890.1400, In vivo Hershberger Assay

EPA Contract No. EP10H001452 Task Assignment No. 3-14-2012 (MRID 48673401)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer: Signature: Michelle Sharpe

- Kass, M.S. Date: 8 /21/ 2012

Secondary Reviewer : Signature: Scott D. Studenberg, Ph.D., D.A.B.T. Date: 8/29 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 9 / 04 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 9 / 04 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 bat tery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE /101701



## Primary Reviewer:**_Kh_in~O~o~M~·~D~·-------­** 

## Health Effects Division Secondary Reviewer: Greg Akerman, Ph.D.

Health Effects Division In vivo Hershberger Assay (2012)/ Page 1 of 17

OCSPP 890.1400/ OECD 441



## Signature:

# _l=**-~=·=·** 

# ,.....----
Date:

## c./z.."t/1.o\~ Signature: 

# * Oii ,A-:==

Date:**c../~lt.:r** Template version 10/2011



## DATA EVALUATION RECORD

STUDY TYPE: Jn Vivo 

## Hershberger Assay (Rat) ; OCSPP 890.1400; OECD 441

PCCODE: 101701 DP BARCODE: D403721

TXR#: 0056255 CAS No: 23950-58-5

TEST MATERIAL (PURITY): Pronamide (95.7% a.i.)

SYNONYMS: Propyzamide, 3,5-Dichloro-N-(l, 1-dimethyl-2-propynyl)benzamide

CITATION: Marty, M.S., Marshall, V.A., Zhang, F

. (2012). Pronamide Technical: Hershberger Assay in Castrated Adult Male Crl : CD(SD) Rats. Toxicology &



## Environmental Research and Consulting

, Midland, MI. Laboratory Report No

. 101010, June 22

, 2012. MRID 48673401. Unpublished.

SPONSOR: Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268

TEST ORDER#: CON -101701-37

EXECUTIVE SUMMARY: In a Hershberger Assay (MRID 48673401) screening for androgenic activity

, pronamide (95.7% purity, Lot# TA0788R301

, TSN003588-0002) in

0.5% aqueous methylcellulose (MC) was administered daily via oral gavage to groups of seven, 55-day old

, castrated male Crl : CD(SD) rats at dose levels of 0 (vehicle), 40, 200 or 1000 (limit
dose) mg / kg / day. The test included an androgenic positive control group consisting of seven castrated rats exposed orally to the vehicle control plus 0.4 mg / kg / day of testosterone propionate (TP) by s.c. injection.

To screen for potential anti-androgenic activity

, pronamide (95 .7 % a.i

. ) in 0.5% MC was administered daily via oral gavage to groups of seven, 55-day old, castrated male Crl:CD(SD)

rats at dose levels of 0 (vehicle), 40, 200 or 1000 mg / kg / day, in conjunction with a daily dose of

TP at 0.4 mg / kg / day by s.c

. injection. The anti-androgenic positive control group consisted of

seven castrated rats exposed to 3 mg/kg / day flutamide (FT) in com oil by oral gavage and 0.4

mg / kg / day TP by s

. c. injection. The positive control animals for the androgen agonist assay served as the anti-androgenic negative controls.

For both components of the assay, body weights and food consumption were determined daily.

The animals were dosed for 10 consecutive days and terminated approximately 24 hours after the

final dose administration

. At necropsy, the five androgen-dependent tissues, adrenal glands, kidneys, and liver were collected and weighed. Blood was collected for measurement of serumI n v ivo Hershberger Assay (2012) / Page 2 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## testosterone, and livers from control group and the 200 and 1000 mg/kg/day groups were collected for microsomal analysis of testosterone metabolism.

All rodents survived until termination with the exception of one rat in the 1000 mg/kg/day group,

which was found dead on Day 11 from an apparent gavage dosing error. There were no

treatment

- related clinical signs in animals dosed at ≤ 200 mg/kg/day in either assay. In the 1000 mg/kg/day group , the only treatment -related observation was perineal (urine) soiling in three

animals in the androgenic portion of the study over Days 3-8 and in one animal in the antiandrogenic portion of the study during Days 7- 10.

In the androgen agonist assay, there were no treatment

- related effects on body weights in any dose group, or on body weight gain in the low- and mid -dose groups. In the high- dose group, body weight gains were decreased by 79% for Days 1-4, 47% for Days 1-7 and 20% for Day 1-
11. However, after inspection of individual body weights, with particular attention to the rat

which died on Day 11 due to a g avage error (effects observed beginning on Day 2), that had a negative body weight gain over Days 1-4 and gained only 11 grams by Day 7, it is clear that this

animal drove the low response. Food consumption in this group was also decreased ( p<0.05) by 27% during Days 1-4. In the mid -dose group, food consumption was decreased (p<0.05) by 11% during Days 1-4, but was increased (p<0.05) by 9% for Days 4-7. Absolute liver weights were increased (p<0.05) in the mid - and high-dose groups by 56% a nd 125%, respectively , and adrenal gland weights were also increased (p<0.05) by 35% in the high -dose group. There were no other pronamide- related effects in the androgen assay. T here were no statistically significant weight increases in androgen -depende nt tissue weight s at up to the limit dose (1,000 mg/kg/day). Animals in the positive control (vehicle + TP) group had accessory sex organ weight increases (p<0.05) as follows: 446% in Cowper’s glands; 71% in glans penis; 187% in levator ani

bulbocavernos us muscle complex ( LABC) ; 533% in ventral prostate; and 1211% in the seminal vesicles with coagulating glands.

In the anti-androgen assay, body weights were decreased (p<0.05) by 11% and 9% on Days 7 and 11, respectively, in the high- dose group , but there were no treatment

- related effects on body weight at the mid - or low-dose . Body weight gains were initially decreased by 40% in the mid

dose group, but were not significantly different over the entire study (Days 1-11). In the highdose group, body weight gains were decreased (<0.05) by 77% and 71% for Days 1-4 and 1-7, respectively, and by 38% over Days 1-11. Food consumption was also decreased (p<0.05) by 10-32% over the entire study in the high-dose group, and by 6-14% in the positive FT+TP control group. As in the androgenic assay, absolute liver weights were increased (p<0.05) in a dose-dependent manner by 49 and 102% in the mid- and high- dose groups, respectively, and adrenal gland weights were increased (p<0.05) by 59% in the high-dose group. No significant weight changes were observed in accessory sex tissues in the low -dose group or in the Cowper’s gland and glans penis in the mid- and high-dose groups. However, dose- dependent decreases (p<0.05) in weight were observed in the LABC (↓ 22% and ↓51%) , ventral prostate (↓24% and ↓50%) and seminal vesicles (↓35% and ↓42%) in the mid - and high- dose groups. In addition, animals in the positive control (FT+TP) group had the expected decreases (p<0.05) in accessory sex organ weight as follows: 58% in Cowper’s glands; 25% in glans penis; 57% in LABC; 74% in ventral prostate; and 81% in seminal vesicles with coagulating glands. There were dosedependent decreases observed in three androgen-dependent tissues.

Percent CVs for the vehicle contr ol and the high-dose groups for both assays were compared to the performance criteria in the Guidelines. In the androgenic assay, all %CV values were lessI n v ivo Hershberger Assay (2012) / Page 3 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## than the maximum permissible values. In the anti

- androgenic assay, the following values were

greate r than the maximum permissible values: Cowper’s glands in the high-dose group (CV

42% vs. 35% maximum ); LABC in the low- , mid - and high- dose grou ps (CV 21-29% vs. 20%

maximum ); v entral prostate in the mid - and high-dose groups (CV 4 1-44% vs. 40% maximum ) ; and s eminal vesicles in the mid

- dose group (CV 45% vs. 40% maximum ). Although CV values for numerous accessory sex tissues were above the allowable maximum values, t hese deviations do not interfere with the interpretation of the study as there was a significant effect in three target

tissues in the anti

- androgenic assay

.

The results of the microsomal assay indicate that pronamide treatment can induce the liver enzymes responsible for testosterone metabolism, which could possibly result in reduced

test osterone levels and subsequent decreases in the weights of androgen sensitive tissues. However, the serum testosterone data from the anti-androgen assay do not clearly support this conclusion. Although there was an apparent 50% decrease (not significant, NS) in serum testosterone levels in the high -dose group, there was also an apparent 14% increase (NS) in

serum testosterone in the mid -dose group, which also showed significant decreases in weights of androgen sensitive tissues. The utility of the available serum testosterone data is limited due to the large within -group variability (CVs 47-89%).

Pronamide was negative for androgenic activity in the Hershberger assay as no statistically significant increases in organ weights were seen in two or more of the five androgen sensitive tissues in the androgen agonist assay. However, pronamide was positive for anti-androgenicity in the Hershberger assay as statistically significant decreases in organ weights were seen in three of the five androgen sensitive tissues in the androgen antagonist assay.

The assay satisfies the EDSP Tier 1 Test Order requirement s for a Hershberger assay (OCSPP 890.1400).

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, and Quality

Assurance statements were provided.I n v ivo Hershberger Assay (2012) / Page 4 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology & Environmental Research and Consulting

Location: Midland, MI Study Director: Marshall, V.A.

Other Personnel: Marty, M.S., Lead Scientist Zhang, F., Research Scientist Study Period: February 23, 2010

- June 2 2 , 2012



## 2. Test Substance : Pronamide

Description: Off

- white powder

Source: Dow AgroSciences, LLC, Indianapolis, IN (Cat # not reported )

Lot/Batch #: TA0788R301, TSN003588

- 0002 (No expiration date; test substance

recertification

- August 19, 2011 Purity: 95.7 % Stability: The stability of pronamide in 0.5% aqueous cellulose at 0.250, 2.50 and 250 mg/ml was determined in a previous study : ≤ 12 days

C AS #: 23950

- 58

- 5

Structure:



### Cl Cl O

N H CH 3



### CH 3 

### CH



## 3

. Reference Androgen : Testosterone propionate (TP)

Supplier : Sigma

- Aldrich (St. Louis, MO)

Lot/Batch #: Lot # and Expiration date were not provided Purity: ≥ 98 %

CAS #: 57

- 85

- 2



## 4. Reference Anti

- androgen : Flutamide (FT)

Supplier: Sigma

- Aldrich (St. Louis, MO)

Lot/Batch #: Lot # and Expiration date were not provided Purity: ≥ 99%

CAS #: 13311

- 84

- 7



## 5

. Solvent/Vehicle Control : Aqueous methylcellulose ( MC; Methocel TM 

## )

Supplier : Not provided

Lot/Batch #: Not provided Rationale (if other than water) : Not provided

Final concentration : 0.5%I n v ivo Hershberger Assay (2012) / Page 5 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## 6

. Test Animals : Species: Rat (males only)

Strain: Crl:CD (SD) Age/weight at dose initiation: Post

- natal day (PND) 55 / 194

- 256 .4 g Source : Charles River, Raleigh, NC Housing: 2

- 3 /cage, stainless steel cages, wire mesh floor suspended over absorbent

paper Diet: LabDiet Certified Rodent Diet #5002 , ad libitum Phytoestrogen content not reported

Water: Tap Water ad libitum

Environmental conditions: Temperature: Humidity: Air changes: Photoperiod: 22 ± 3 oC

40

- 70 %

12

- 15 /hr

12 hrs light/ 12 hrs dark Acclimation period: 10 days post

- castration



## B. STUDY DESIGN

1. In

- life D ates : Start: July 4/5, 2010 End: July 14/15, 2010

2. Study Design : In a Hershberger Assay conducted to screen for potential androgenic activity, the test substance was administered in 0.5% aqueous MC daily via oral gavage to

castrated male rats , which also received a s.c. injection of corn oil. The positive control group received the vehicle plus TP (0.4 mg/kg/day) in corn oil by s.c. Positive androgenic activity is defined as a significant increase in two or more target organ weights compared to the vehicle control. Negative control groups for androgenic activity consisted of 0.5% aqueous MC alone and 0.5% aqueous MC with an s.c. injection of corn oil only.

To screen for the potential anti

- androgenic activity, the test substance was also administered daily via oral gavage to castrated male rat s in conjunction with a daily dose of TP (0.4 mg/kg/day) by s.c. injection. A positive control group received flutamide (FT ) at 3 mg/kg/day in corn oil by oral gavage plus TP at 0.4 mg/kg/day by s.c. injection.

Anti

- androgenic activity is indicated by a statistically significant decrease in two or more target organ weights of the treated groups (test substance + TP) compared to the negative control. For anti-androgenic test, the negative control (vehicle control + TP) was the same group of animals that served as the positive control in the androgenic assay

. For both assays, the animals were dosed for 10 consecutive days and necropsied approximately 24 hours after the final dose administration for organ weight measurements.

3. Study Schedule : Rats were castrated at Charles River Laboratories at 45 days of age and

received by the test laboratory at 49 or 50 days of age. The dose administration period was

from PND 55 through PND 64, which allowed 10 days after castration for recovery and regression of acc essory sex organ weights prior to initiation of dosing. Rats were euthanized on PND 65 approximately 24 hours after the last dose and necropsied for organ weight measurements.

4. Animal Assignment : Animals were assigned, stratified by body weight, to the test groups noted in Table 1. Statistical analysis indicated that there were no significant differences in group means at study initiation. Furthermore, the body weight of each animal was within

20% of the overall mean.I n v ivo Hershberger Assay (2012) / Page 6 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



### TABLE 1. Study D esign a



### Test group Dose (mg/kg/day) # of Males
Androgen Agonist Assay
Vehicle control (no s.c. injection) 0 7

Vehicle control

, negative control b 

### 0 7

Low ( Pronamide) b 

### 40 7
Mid (Pronamide) b 

### 200 7
High (Pronamide ) b 

### 1000 7
Positive control (Vehicle + TP c 

### ) 0 + 0.4 7

Anti

- Androgen Assay
Low (Pronamide + TP c 

### ) 40 + 0.4 7
Mid (Pronamide + TP c 

### ) 200 + 0.4 7
High (Pronamide + TP c 

### ) 1000 + 0.4 7

Flutamide d 

### + TP, positive control 3 + 0.4 7

a Data were obtained from page 17 of the study report.

b Gavage administration of test compound plus s.c. administration of corn oil vehicle.

c Testosterone propionate administered by s.c. in corn oil.

d The animals in the positive control group for the androgenic assay also served as the negative control group for

the anti

- androgenic a ssay.

e Administered in corn oil by oral gavage.



## 5. Dose Selection Rationale : The dose levels were selected based on the results from a range

finding study that was included in the report. Five castrated male rats/dose group were administered pronamide in 0.5% aqueous methylcellulose by oral gavage in a two

- phase

range -finding study. The first phase consisted of dose levels of 0, 25, 100, 250, and 500 mg/kg/day, and the second phase included hi gher dose levels of 0, 600, 800, and 1000 mg/kg/day. The second phase was added due to the lack of clear, treatment

- related body weight effects in the first phase of the range -finding study. Because the high -dose level of 1000 mg/kg/day pronamide was well tolerated in study animals and produced an approximate 10% decrease in body weights after administration of 10 daily doses by

gavage
, it was selected as the high dose in the Hershberger assay.

6. (a) Dose Preparation : Pronamide technical was admini stered as a suspension in 0.5 %

aqueous MC at a dose volume of 10 mL/kg body weight. F T was administered in corn oil at a dose volume of 5 mL/kg body weight. The TP dosing solution w as prepared in laboratory grade stripped corn oil and administered at a dose volume of 0.5 mL /kg to achieve the targeted dose (0.4 mg/kg). Dosing solutions were prepared in accordance with established stability limits. Dose volumes were adjusted daily based on body weights. Homogeneity

and dose confirmation analyses were det ermined pre -exposure on all pronamide technical

dose solutions from the first mix.

( b) Dose Analysis :

Results

Homogeneity (% RSD ): 0.2-0.9%I n v ivo Hershberger Assay (2012) / Page 7 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## Stability: Not T ested (Stability was determined previously as ≤ 12 days for pronamide in

0.5% METHOCELTM a t concentrations of 0.25-250 mg/ mL. 1



## Concentration (% of nominal): 97.7-100.1%

The analytical data indicated that the mixing procedure was adequate , and that the variation between nominal and actual dosage to the animals was acceptable.

7. Dosage A dminis tration : Test formulations were administered to the animals daily by oral gavage ( 10 mL/kg) for 10 days. TP was given via s.c. injection at 0.5 mL/kg and FT was administered by oral gavage at 5 mL/kg. Dose volumes were adjusted daily based on the concurrent body weight measurement.

8. Statistics : Body weights, body weight gains, organ weights (absolute), testosterone levels, testosterone metabolites (excluding estrone), and f eed consumption were evaluated by Bartlett’s test (α = 0.01) for equality of variances. Based on the outcome of Bartlett's test, a parametric or non

- parametric analysis of variance (ANOVA) was performed. Variables that required transformation prior to analysis included DHT and estradiol, which were log transformed, and 6-alpha-hydroxytestosterone and 16- beta -hydroxytestosterone, which were square root transformed. If the ANOVA was significant at α = 0.05, analysis by two -sided (body weights/gains, liver, kidney and adrenal weights; testosterone metabolites (excluding estrone) or one- sided Dunnett's test ( androgen

- sensitive tissue weights and testosterone levels) (α = 0.05) or the Wilcoxon Rank

- Sum test (α = 0.05) with Bonferroni's correction was performed, respectively. A coefficient of variation (CV) was calculated for the control organ weights and compared with acceptance criteria provided in the OECD test guideline.

The statistical analyses were considered adequate by the reviewers

.

C. METHODS

1. Cl inical Examinations : Cage -side checks for mortality, moribundity, and clinical signs of toxicity were conducted twice daily , and a hand- held examination was conducted once daily approximately one hour after dosing . Detailed physical examinations were performed prior to initiation of dosing and at termination.

2. Body Weight : Animals were weighed at randomization, study initiation and daily throughout the dosing period.

3. Food Consumption : Food consumption was measured for each cage by subtracting the amount of food remaining in the cage from the amount supplied. Values were reported as group mean daily food consumption (g/animal/day) for the following intervals: Days 1 -4, 4- 7, and 7-11.

1 

### Dryzga, M. D. and Yano, B. L. (2005). Pronamide Technical: 28

- Day Dermal Toxicity Study in F344/DuCrl Rats.

Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.I n v ivo Hershberger Assay (2012) / Page 8 of 17

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## 4. Serum Hormone Measurements : At study termination (Day 11 ) , each animal was

anesthetized with isoflurane/O 2 

## , and blood was collected via cardiac puncture for serum hormone analyses. The initial quantitative analyses of t estosterone were conducted by liquid chromatography/positive atmospheric pressure photoioniz ation tandem mass spectrometry (LC/APPI

- MS/MS). Secondary analyses of samples from the anti-androgen assay (TP control group, and low- , mid - and high-doses + TP groups) were determined by radioimmunoassay (RIA) with the Coat-A-Count total Testosterone RIA kit (Siemens Diagnostics, California) conducted at AniLytics Incorporated (Gaithersburg, MD).

5. Dissection and Measurement of Tissue and Organ Weights : On PND 65 (approximately 24 hours after the final administration of the test substance) , all surviving animals were

euthanized by decapitation following anesthesia with isoflurane/O 2 

## , exsanguinated, and subjected to a gross necropsy. The five mandatory androgen-dependent organs (ventral prostate, seminal vesicles, levator ani -bulbocavernous muscl e complex [ LABC ], Cowper’s gland, and glans penis) were excised, trimmed free of adhering tissue, and weighed fresh (unfixed) according to the standard operating procedures detailed in the U.S. EPA Guideline (OCSPP 890.1400). Additionally, the liver, kidn eys, and adrenals were weighed , and all tissues were prepared for microscopic examination

.

6. Microsomal Preparation and Testosterone Metabolite F ormation : To evaluate testosterone metabolizing capacity, microsome s were isolated from liver tissue of control and pronamide-treated animals (200 and 1000 mg/kg/day groups). Frozen samples were homogenized in a Tris-buffered KCl solution containing EDTA and an antioxidant. Samples were centrifuged to pellet ize microsomes

, and resultant pellets were resusp ended in a pyrophosphate solution to remove nucleic acid polymers and re centrifuged. Pelleted

microsomes were then suspended in a Tris -buffered 20% glycerol solution containing an antioxidant. Microsomes were aliquoted in multiple cryo

- tubes and stored a t -80 ° C until

used. Rat liver microsomes (1 mg/m L) were incubated for 30 minutes with testosterone (0.25 mM) in the presence of cofactor NADPH (1 mM) in 0.1 M phosphate buffer, pH 7.3 at

37 ° C. The reaction was stopped by transferring the vials to ice and adding 10% kill solution (2% formic acid in CH 3 

## CN). The supernatant was analyzed for hydroxylated testosterone metabolites and androstenedione by LC/MS- MS. Other potential metabolites were quantified by a method developed in house (not reported)

II. RESULTS

A. OBSERVATIONS

1. Mortality : All rodents survived until schedule sacrifice with the exception of one rat (animal #5049) in the 1000 mg/kg/day group, which was found dead on Day 11 prior to the scheduled necropsy. Necropsy revealed clotted bloo d in the thoracic cavity and the visceral and parietal pleura had adhesions of fibrin and clotted blood which were consistent with a gavage dosing error. Organ weights were not collected and tissues were not preserved from this animal, because its death w as deemed unrelated to pronamide treatment.I n v ivo Hershberger Assay (2012) / Page 9 of 17

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## 2. Clinical S igns of Toxicity : O ne animal in the 1000 mg/kg/day group, which was found

dead on Day 11, began showing clinical signs of toxicity on Day 2 . Clinical observations

over the Days 3-10 (excluding Days 7 and 9) includ ed uncoordinated gait, splayed hind limbs, soft/limp muscle tension, decreased, activity, urine perineal soilin g, perioral/perioc u lar/perinasal red soiling, dehydration and labored respiration without mouth breathing. These observations were considered secondary to an apparent error during gavage dosing. The only t reatment -related observation occurred in selected high -dose

animals , which consisted of perineal (urine) soiling seen in three animal s in the androgenic portion of the study over Days 3-8, and one animal in the anti-androgenic portion of the study during Days 7-10.

B. BODY WEIGHT AND WEIGHT GAIN : Body weight and body weight gain data for the androgen agonist assay are presented in Table 2. There were no differences in bod y weights of the pronamide treated groups compared to the control. However, b ody weight gains were

decreased (p<0.05) by 7 8 % for Days 1-4 and by 47% for Days 1-7 in the high- dose group

, although the overall body weight grain (Day 1- 11) for the high-dose group was comparable

to the control. As expected, the positive TP control group had an overall increase in b ody weight gain of 23% compared to the control.

TABLE 2

. Group Mean Body Weights and Cumulative Body Weight Gains (g) in the Androgen Agonist Assay a



### Study Day # Dose (mg/kg/day)

Vehicle

Control Positive Control

Vehicle + TP (0.4) Pronamide (40) Pronamide (200) Pronamide (1000)

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD

1 7 223.9 8.5 7 221.3 12.9 7 225.5 7.1 7 229.5 12.6 7 225.7 5.4

4 7 241.6 11.1 7 246.6 15.7 7 244.7 9.1 7 240.2 15.4 7 229.5 11.1

7 7 262.3 14.1 7 271.2 18.3 7 266.0 11.7 7 267.8 19.7 7 246.0 12.2

11 7 290.7 18.8 7 303.6 19.1 7 293.8 15.8 7 298.5 21.6 6 279.3 16.7

B WG (Days 1

- 4) 7 17.8 3.7 7 25.2* (↑42) 5.2 7 19.2 3.5 7 10.6 7.1 7 3. 9 * (↓7 8 ) 8.7

B WG (Days 1

- 7) 7 38.4 7.0 7 49.9* (↑ 30) 10.3 7 40.4 6.5 7 38.3 8.2 7 20.3* (↓47) 8.6

BWG (Days 1

- 11) 7 66.9 12.4 7 82.2* (↑23) 12.5 7 68.3 10.8 7 69.0 9.8 6 53.6 13.5

a D ata were obtained from Table 4 on pages 48

- 49 and Table 5 on pages 53

- 54 of the study report. Percent

differences from vehicle controls

, calculated by the reviewers , a re included in parentheses.

N Number of animals in the group

SD Standard Deviation

* Significantly different from controls at p<0.05



## Body weight and body weight gain data for the anti

- androgen assay are presented in Table 3. Body weights in the low- and mid-dose groups were comparable to the TP control, but

bo dy weigh t s in the high-dose group were decreased (p<0.05) by 11% and 9% on Days 7 and 11, respectively. Initially (Days 1 -4), b ody weight gains were decreased by 38 and 77%

in the mid - and high-dose groups, and the reduction in weight grain was maintained in the high

- dose group , in which the overall (Days 1-11) weight grain was reduced by 38% compared to the control.I n v ivo Hershberger Assay (2012) / Page 10 of 17

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### TABLE 3

. Group Mean Body Weights and Cumulative Body Weight Gains (g) in the Anti

- Androgen Assay a



### Study Day # Dose (mg/kg/day)

Vehicle Control

+ TP (0.4) Positive Control

TP + F T (0.4 + 3) Pronamide + TP ( 40 + 0.4) Pronamide + TP (2 0 0 + 0.4) Pronamide + TP (1000 + 0.4)

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD

1 7 221.3 12.9 7 223.6 11.5 7 225.2 9.8 7 223.5 11.8 7 226.5 6.7

4 7 246.6 15.7 7 243.4 7.9 7 249.4 11.2 7 239.2 11.6 7 232.3 11.6

7 7 271.2 18.3 7 265.8 12.6 7 276.2 13.7 7 268.8 14.6 7 241.1* (↓11) 16.6

11 7 303.6 19.1 7 293.7 14.4 7 306.4 17.0 7 301.3 16.3 7 277.7* (↓9) 14.9

Body Weight Gain (Days 1

- 4) 7 25.2 5.2 7 19.8 10.0 7 24.2 3.1 7 15.7* (↓ 38 ) 4.0 7 5.8* (↓77) 9.9

Body Weight

Gain (Days 1

- 7) 7 49.9 10.3 7 42.2 7.5 7 50.9 5.4 7 45.3 8.3 7 14.6* (↓62% ) 15.6

Body Weight

Gain (Days 1

- 11) 7 82.2 12.5 7 70.0 9.2 7 81.1 9.3 7 77.8 11.0 7 51.2* (↓38) 14.3

a Data were obtained fro m Table 4 on pages 50

- 51 and Table 5 on pages 55

- 56 of the study report. Percent

differences from negative controls

, calculated by the reviewers , a re included in parentheses.

N Number of animals in the group

SD Standard Deviation

* Significantly different from controls at p<0.05



## C. FOOD CONSUMPTION : Food consumption data for the androgen ic assay are presented

in Table 4. In the mid -dose group, food consumption was decreased (p<0.05) by 11% during Days 1-4, but was increased (p<0.05) by 9% for Days 4-7. In the high -dose group, food consumption was decreased (p<0.05) by 27% during Days 1-4. Food consumption was increased (p<0.05) in the positive control group on Days 4- 7 (↑9%) and Days 7- 11 (↑8 %).

TABLE 4. Food Consumption (g/animal/day) in the Androgen Agonist Assay a



### Study Day

Interval Dose (mg/kg/day)

Vehicle Control Positive Control

Vehicle + TP (0.4) Pronamide (40) Pronamide (200) Pronamide (1000)

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD

1

- 4 7 19.8 0.9 7 20.9 0.2 7 20.3 0.7 7 17.7* (↓11) 1.8 7 14.5* (↓27) 1.6

4

- 7 7 20.6 0.9 7 22.5* (↑9) 0.9 7 21.7 0.7 7 22.5* (↑9) 1.6 7 19.6 0.8

7

- 11 7 21.4 1.0 7 23.2* (↑8) 1.1 7 21.8 1.3 7 22.2 1.6 7 20.1 3.2

a Data were obtained from page s 58 and 59 of the study report. Percent differences from vehicle controls, calculated by the reviewers, are included in parentheses.

N Number of animals in the group

SD Standard Deviation

* Significantly different from controls at p<0.05I n v ivo Hershberger Assay (2012) / Page 11 of 17

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## Food consumption data for the anti-androgen assay are presented in Table 5. In t he low

dose group, food consumption was decreased (p<0.05) by 3% during Days 1-4. In the high

dose group, food consumption was decreased (p<0.05) by 32% for Days 1-4, 25% for Days 4-7, and 10% for Days 7-11. Food consumption was also decreased (p<0.05) i n the positive

control (FT+TP) group on Days 1- 4 (↓6%), Days 4- 7 (↓13%), and Days 7- 11 (↓14%).

TABLE 5. Food Consumption (g/animal/day) in the Anti

- Androgen Agonist Assay a



### Study Day

Interval Dose (mg/kg/day)

Vehicle Control +

TP (0.4) Positive Control

TP + F T (0.4 + 3) Pronamide + TP (40 + 0.4) Pronamide + TP (200 + 0.4) Pronamide + TP (1000 + 0.4)

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD

1

- 4 7 20.9 0.2 7 19.7* (↓6) 0.9 7 20.2* (↓3) 0.4 7 18.8 1.7 7 14.3* (↓32) 2.8

4

- 7 7 22.5 0.9 7 19.5* (↓13) 0.9 7 22.5 0.5 7 23.2 1.4 7 16.9* (↓25) 1.7

7

- 11 7 23.2 1.1 7 19.9* (↓14) 0.7 7 22.2 0.6 7 22.6 1.0 7 20.9* (↓10) 0.4

a Da ta were obtained from page s 60 and 61 of the study report. Percent differences from negative controls, calculated by the reviewers, are included in parentheses.

N Number of animals in the group

SD Standard Deviation

* Significantly different from controls at p<0.05



## D. ORGAN WEIGHTS : Weights for the accessory sex organs, adrenal glands, kidneys, and liver from the androgen agonist assay are presented in Table 6. Absolute liver weights w ere increased (p<0.05) by 56 and 125% in the mid

- and high

- dose groups , respectively , and

a drenal gl and weight w as increased (p<0.05) by 35% in the high

- dose group

. No differences were observed in kidney weights, and the weights of all androgen- sensitive tissues in the pronamide- treatment groups were similar to the control.

Rats in the positive contr ol (vehicle + TP) group had accessory sex organ weight increases (p<0.05) as follows: 446% in Cowper’s glands; 71% in glans penis ; 187% in LABC; 533 % in ventral prostate; and 1211% in the seminal vesicles with coagulating glands

.

The guideline performa nce criteria for the androgenic assay were met for the control and high

- dose groups

.I n v ivo Hershberger Assay (2012) / Page 12 of 17

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### TABLE 6

. Accessory Sex Organ Weights from Androgen Agonist Assay in Sprague Dawley Rats a



### Organ Dose (mg/kg/day)

Vehicle Control

(Methocel with corn oil) 

### Positive Control

Vehicle + TP (0.4) Pronamide (40) Pronamide (200) Pronamide (1000)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Liver (g) 7 11.2 1.2 11 7 12.3 1.5 12 7 12.7 1.3 10 7 17.5* 

### (↑56) 2.3 13 6 25.2* 

### (↑125) 2.4 10

Adrenal glands (g) 7 0.061 4 0.006 10 7 0.0542 0.010 18 7 0.0610 0.005 8 7 0.0692 0.007 10 6 0.0826* 

### (↑35) 0.015 18

Kidneys (g) 7 1.9 0.144 8 7 2.0177 0.224 11 7 2.1147 0.175 8 7 2.1203 0.2 5 6 1 2 6 2.1011 0.164 8
Cowper’s glands (g) 7 0.0056 0.002 29 6 0.0316* 

### (↑464) 0.00 8

6 27 7 0.0060 0.001 23 7 0.0056 0.001 20 6 0.0030 0.001 47

Glans penis (g) 6 0.052 0.005 10 6 0.0890* 

### (↑71) 0.014 16 6 0.0529 0.006 11 7 0.0566 0.00 8 14 6 0.0557 0.012 22

LABC (g) 7 0.1393 0. 0 20

6 15 7 0.4002* 

### (↑187) 0.033 8 7 0.1379 0.031 23 7 0.1392 0.037 27 6 0.1136 0.025 22

Ventral prostate (g) 7 0.0246 0.007 29 6 0.1556* 

### (↑533) 0.021 13 7 0. 0184 0.006 34 7 0.0193 0.008 41 4 0.0154 0.007 44

Seminal

vesicles (g) b 7 0.0317 0.006 17 7 0.4155 * (↑1211) 0.033 8 7 0.0335 0.007 20 7 0.0326 0.010 29 6 0.0322 0.006 17

a Data were obtained from Table 7 on pages 63

- 64 of the study report. Percent differences from vehicle controls

, calculated by the reviewers, are included in parentheses.

b Seminal vesicles with coagulating glands.

N Number of animals in the group

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05



## Weights for the accessory sex organs, adrenal glands, kidneys, and liver from the antiandrogen assay are presented in Table 7. As seen in the androgenic assay, absolute liver weights were increased (p<0.05) in the mid- and high-dose groups by 49 and 102%, respectively, and adrenal gland weight was increased (p<0.05) by 59% in the high-dose group. No differences were observed in kidney weights for any groups and the weights of all androgen

- sensitive tissues in the low -dose + TP group similar were to the TP control. In

the mid -dose +TP group, the following decreases (p<0.05) occurred in three of the five androgen sensitive tissues: 22% in the LABC, 24% in ventral prostate, and 35% in seminal

vesicles with coagulating gland. Decreases (p<0.05) in weight f rom the same three tissues

were also observed in the high- dose + TP group: 51% in LABC, 50% in ventral prostate

, and 42% in the seminal vesicles with coagulating glands. The decrease in weights for these

three tissues was dose-dependent.

Rats in the positive control (FT+TP) group had the expected decreases (p<0.05) in accessory sex organ weight as follows: 58% in Cowper’s glands; 25% in glans penis; 57% in LABC; 74% in ventral prostate; and 81% in seminal vesicles with coagulating glands.

The guideline performance criteria for the anti

- androgen assay were met for the control group and for the glans penis and seminal vesicles in the high-dose group. However, the maximum permissible CV values specified in the Guideline were exceeded in the mid -dose

+ T P group for the LABC (21% vs. 20% allowable), ventral prostate (44% vs. 40% allowable), and seminal vesicles (45% vs. 40% allowable), and in the high-dose + TP groupI n v ivo Hershberger Assay (2012) / Page 13 of 17

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## for the Cowper’s gland (42% vs. 35% allowable), the LABC (29% vs. 20% allowable), and ventral prostate (41% vs. 40% allowable).

TABLE 7

. Accessory Sex Organ Weights from Anti

- Androgen Assay in Sprague Dawley Rats a



### Organ Dose (mg/kg/day)
Negative Control

Vehicle + TP ( 0.4) Positive Control

TP + F T (0.4 + 3) Pronamide + TP (40 + 0.4) Pronamide + TP (200 + 0.4) Pronamide + TP (1000 + 0.4)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Liver (g ) 7 12.3 1.5 12 7 12.0 1.2 10 7 13.3 1.2 9 7 18.3* 

### (↑49) 1.9 10 7 24.8* 

### (↑102) 2.1 8

Adrenal glands (g) 7 0.0542 0.010 18 7 0.0610 0.008 12 7 0.0564 0.011 19 7 0.0627 0.008 12 7 0.0861* 

### (↑59) 0.010 11

Kidneys (g) 7 2.0177 0.224 11 7 1.9225 0.177 9 7 2.1151 0.215 10 7 2.1523 0.090 4 7 2.0569 0.170 8

Cowper’s glands (g) 6 0.0316 0.009 27 7 0.0134* 

### (↓58) 0.005 38 7 0.0313 0.006 20 7 0.0279 0.008 27 7 0.0228 0.0 096 42 b

Glans penis (g) 6 0.0890 0.014 16 7 0.0670* 

### (↓25) 0.012 17 7 0.0897 0.011 12 7 0.0786 0.011 15 7 0.0796 0.0115 14

LABC (g) 7 0.4002 0.033 8 7 0.1715* 

### (↓57) 0.044 26 7 0.361 9 0.080 22 b 7 0.3116* 

### (↓22) 0.065 21 b 7 0.1976* 

### (↓51) 0.058 29 b

Ventral prostate (g) 7 0.1556 0.021 13 7 0.0399* 

### (↓74) 0.017 43 7 0.1532 0.022 14 7 0. 1182 * 

### (↓24) 0.05 2 44 b 7 0.0785* 

### (↓50) 0.032 41 b

Seminal

vesicles (g ) b 7 0.4155 0.033 8 7 0.0801* 

### (↓81) 0.048 60 7 0.3785 0.103 27 7 0.2712* 

### (↓35) 0.123 45 b 7 0.2399* 

### (↓42) 0.087 36

a Data were obtained from Table 7 on pages 65

- 66 of the study report. Percent differences from negative controls, calculated by the reviewers, are included in parentheses.

b CV values exceed the maximum allowable for the anti

- androgenic assay specified in Guideline 890.1400.

c Seminal vesicles with coagulating glands.

N Number of animals in the group

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05



## E. SERUM HORMONE CONCENTRATIONS : Serum testosterone data (as determined by RIA) for the anti

- androgen assay are presented in Table 8. Although there were no significant changes in serum testosterone, the high level of variability in the data (CVs 47- 89%) and application of exogenous TP may have masked any treatment

- related effects. Average testosterone concentration was increased by 47 and 14% for the low- and mid-dose groups and decreased by 50% in the high- dose group.I n v ivo Hershberger Assay (2012) / Page 14 of 17

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### TABLE 8

. Hormone Measurement in the Anti

- Androgen Assay a



### Hormone Dose (mg/kg/day)

Vehicle Control +

TP (0.4) Pronamide + TP (40 + 0.4) Pronamide + TP (200 + 0.4) Pronamide + TP (1000 + 0.4)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Serum

Testosterone

(ng/mL) 7 0.36 0.18 50 7 0.53 

### (↑47) 0.25 47 7 0.41
( 

### ↑14) 0.26 63 7 0.18 

### (↓50) 0.16 89

a Data were obtained from page 68 of the study report. 

### Percent differences from negative controls, calculated by the reviewers, are included in parentheses.

N Number of animals in the group

SD Standard Deviation

CV Coefficient of Variation



## F. TESTOSTERONE METABOL ITE FORMATION : The quantities of hydroxylated testosterone metabolites produced by liver microsom es in vitro are shown in Table 9. The microsomes were obtained from the control, mid-dose and high-dose groups for the androgenic assay.

The hydroxylation of testosterone in the 16β

- position was the most sensitive to treatment, based on the >2600% increase in this metabolite following p ronamide treatment . In addition, there were significant dose-dependent increases in 6α -OHT (105 and 375%) and 6β

- OHT (89 and 92%) at both dose levels . 16α

- OHT was also significantly increased at the mid -dose level (118%), but not at the high- dose; this b iphasic response has been reported previously and may be due to an increase in CYP2B1 with a concurrent decrease in CYP2C11. In contrast, the formation of DHT and estradiol were decreased significantly (75- 80%) at both doses of pronamide.I n v ivo Hershberger Assay (2012) / Page 15 of 17

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### TABLE 9. Testosterone Metabolite Formation from Liver Microsomes from the Androgen Assay in Sprague Dawley Rats a



### Testosterone Metabolites (pmol/min/mg microsomal protein) Dose (mg/kg/day)

Vehicle Control Pronamide (200) Pronamide (1000)

Mean SD Mean SD Mean SD

2 α

- hydroxytestosterone ( 2 α

- OHT ) 275.1 129.0 214.1 47.1 261.4 49.1

6α

- hydroxytestosterone ( 6 α

- OHT ) b 21.0 7.9 43.1* 

### (↑105) 4.3 99.8* 

### (↑375) 21.2

6 β

- hydroxytestosterone ( 6 β

- OHT ) 488.5 286.3 922.0* 

### (↑89) 127.5 936.0 * 

### (↑92) 171.3

7 α

- hydroxy

- testosterone ( 7 α

- OHT ) 61.8 16.4 70.1 16.5 149.2 * (↑141) 37.5

16α

- hydroxytestosterone ( 16 α

- OHT ) 141.0 143.1 307.3* 

### (↑118) 112.6 253.3 50.1

16 β

- hydroxytestosterone ( 16 β

- OHT ) b 7.1 2.7 198.0* 

### (↑2689) 27.8 249.0* 

### (↑3407) 41.4

Androgen 84.2 57.1 115.2 30.2 105.5 19.2
Dihydrotestosterone (DHT) 837.7 533.8 165. 6 * 

### (↓80) 100.9 199.2* 

### (↓76) 87.5

Estradiol 882.9 548. 6 181.8* 

### (↓79) 117.5 223.7* 

### (↓75) 103.3

a Data were obtained from Table s 3 and 4 on pages 33

- 34 of the study report. Percent differences from controls, calculated by the reviewers, are included in parentheses.

b Analysis was performed on square root transformed data.

SD Standard Deviation

* Significantly different from controls at p<0.05



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR’S CONCLUSIONS : Based on the lack of significant, treatment

- related increases in two accessory sex tissue weights in the androgenic portion of the assay, pronamide at doses ≤ 1000 mg/kg/day was deemed negative for androgenic activity in the Hershberger assay. Based on sig nificant decreases in three accessory sexual tissue weights in the anti-androgenic portion of the assay, the mid- and high- dose levels of pronamide were deemed positive for anti-androgenic potential. H owever, the significant increase in liver weight, appa rent decrease in serum testosterone level, increased testosterone metabolism using hepatic microsomes from pronamide- treated animals, and lack of direct interaction with the androgen receptor indicate that the apparent anti -androgenic response was due to enhanced testosterone metabolism, resulting in decreased accessory sexual tissue weights. These data will require careful consideration in the pronamide weight-of-evidence (WoE)

assessment for anti

- androgenicity. There were no effects on androgen

- sensitiv e endpoints at 40 mg/kg/day pronamide.

B. AGENCY COMMENTS : All animals survived until scheduled sacrifice on Day 11, with the exception of one rat in the high

- dose group, which was found dead on Day 11. Based on clinical signs and necropsy data, this de ath was the result of an apparent gavage error that likely occurred early during the study (Day 2). There were no treatment

- related clinical signs in animals dosed at ≤200 mg/kg/day in either assay , and the only clinical sign observed in the high-dose groups was periodic perineal (urine) soiling in three animals from the androgenic assay and in one animal from the anti- androgenic assay

.I n v ivo Hershberger Assay (2012) / Page 16 of 17

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## In the androgen agonist assay, mean body weights of all pronamide- treated animals were similar to the control on Days 1, 4, 7 and 11 (sacrifice). In the high-dose group, b ody weight gains were decreased by 79% for Days 1-4 and 47% for Days 1-7. However, after inspection of individual body weights, with particular attention to the rat which died on Day 11 due to a gavage error (effects were seen beginning on Day 2), it is clear that this animal drove the low response as it lost weight over Days 1-4 and gained only 11 grams by D ay 7.

When this animal wa s excluded from analysis, the overall body weight grain (Days 1-11) for the high-dose group was similar to the control. Food consumption in the high- dose

group was initially decreased (p<0.05) during Days 1-4, but not at the later intervals. In the

mid -dose group, food consumption was slightly decreased (p<0.05) during Days 1-4, but

was then slightly increased f or Days 4-7. Absolute liver w eights were increased (p<0.05) in

a dose- dependent manner in the mid - and high-dose groups, and a drenal gland weights were also increased (p<0.05) in the high

- dose group

. There were no treatment

- related effects on weight of any of the accessory sex organs at dose levels up to 1000 mg/kg/day. Animals in the positive TP control group showed the expected increases (p <0.05) in accessory sex organ weights.

In the anti-androgen assay, body weights were decreased (p<0.05) on Days 7 and 11 in the high

- dose group , but not in the mid- or low- dose groups . Body weight gains were also initially decreased in the mid -dose group, but weight grains recovered by Day 11. In the high

- dose group

, body weight gains were decreased (p<0.05) at all intervals as was food consumption. Food consumption was also decreased (p<0.05) in the positive control group

at all intervals

. As in th e androgenic assay, absolute liver weights were increased (p<0.05) in a dose-dependent manner in the mid- and high-dose groups, and adrenal gland weights were increased (p<0.05) in the high-dose group. No significant weight changes were

observed in access ory sex tissues in the low-dose group or in the Cowper’s gland and glans penis in the mid - and high-dose groups. However, dose- dependent decreases (p< 0.05) in weight were observed in the LABC, ventral prostate and seminal vesicles in the mid - and high -dose groups. In addition, animals in the positive TP+FT control group showed the expected increases (p<0.05) in accessory sex organ weights. There were significant, dosedependent decreases in three androgen -dependent tissues.

Percent CVs for the vehicle control and the high-dose treatment groups for both assays were compared to the performance criteria in the Guidelines. In the androgenic assay, all %CV values were less than the maximum permissible values. In the anti

- androgenic assay, the following values were greater than the maximum permissible values: Cowper’s glands in

the high -dose group (CV - 42%, maximum permissible - 35%); LABC in the low-, mid - and high -dose groups – 21- 29%, maximum permissible

– 20%); v entral prostate in the mid - and high

- dose groups (CV = 44% and 41%,respectively, maximum permissible 40%); and

Seminal vesicles in the mid -dose group (CV

– 45%, maximum permissible – 40%). These deviations do not interfere with the interpretation of the study as there was a significant effect in three target tissues in the anti

- androgenic assay.

The results of the microsomal assay support the conclusion that treatment with pronamide

indu ces metabolic enzymes responsible for testosterone metabolism, which could possibly result in reduced testosterone levels and subsequent decreases in the weights of androgen

sensitive tissues. However, the serum testosterone data from the anti- androgen as say do notI n v ivo Hershberger Assay (2012) / Page 17 of 17

PRONAMIDE /101701 O CSPP 89 0.1400 / OECD 441



## clearly support this conclusion. Although there was an apparent 50% decrease (NS) in

serum testosterone levels in the high

- dose group , there was also an apparent 14% increase (NS) in serum testosterone in the mid -dose group, which also showed s ignificant decreases in weights of androgen sensitive tissues. Due to the large within-group variability (CVs 47- 89%), the utility of the serum testosterone data is limited.

Pronamide was administered at up to the limit dose (1000 mg/kg/day) ; at this do se, large

increases were observed in liver (102- 125%) and adrenal (35

- 59%) weight s, and a 38% decrease in body weight gain was observed in the anti- androgen assay

.

Pronamide was negative for androgenic activity in the Hershberger assay as no statistically significant increases in organ weights were seen in two or more of the five androgensensitive tissues in the androgen agonist assay. However, pronamide was positive for antiandrogenicity in the Hershberger assay as statistically significant decreases in organ weights were seen in three of the five androgen sensitive tissues in the androgen antagonist assay.

C. STUDY DEFICIENCIES : None

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE)

Study Type: O CSPP 890.1450, Female Pubertal Assay

EPA Contract No. EP10H001452 Task Assignment No. 3-14-2012 (MRID 48673402)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer: Signature: Michelle Sharpe

- Kass, M.S. Date: 8 /21/2012

Secondary Reviewer : Signature: Scott D. Studenberg, Ph.D., D.A.B.T. Date: 8/27 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 8/30/ 2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 8/30 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 bat tery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE I 101701 Female Pubertal Assay (2012) I Page 1 of 16

OCSPP 890.1450/ OECD None



## DATA EVALUATION RECORD

STUDY TYPE: Female Pubertal Assay; OCSPP 890.1450; OECD None.



## PC CODE: 101701 

## DP BARCODE: D403723



## TXR#: 0056255 

## CAS No: 23950-58-5



## TEST MATERIAL (PURITY): Pronamide (96.2%

. a.i

. )



## SYNONYMS: 3,5-dichloro-N-(1, l-dimethyl-2-propynyl)benzamide; Propyzamide



## CITATION: Marty, M.S., Zablonty

, C.L.

, Stebbins, K.E. (2012). Pronamide: Pubertal Development and Thyroid Function in Intact Juvenile/Peripubertal Female Crl:CD(SD) Rats. Toxicology & 

## Environmental Research and Consulting,
Midland, MI. Laboratory Report No.: 111080

, June 21, 2012. MRID

48673402. Unpublished.



## SPONSOR: Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN



## TEST ORDER#: CON-101701-37



## EXECUTIVE SUMMARY: In a Female Pubertal Assay (MRID 48673402), 16 Crl:CR(SD)

rats / dose group were treated daily via oral gavage with pronamide (96.2% purity, Lot#

XG1088R301

, TSN003588-0004) in 0.5% aqueous methylcellulose at doses ofO (vehicle), 25,
100, or 300 mg/kg/day from post-natal day (PND) 22 to 42

. Animals were examined for vaginal opening (VO) daily beginning on PND 22

, and age and weight at day of attainment were recorded. Following sacrifice on PND 42

, blood was collected for clinical chemistry and

hormone analyses; total thyroxine (T 4) 

## and thyroid stimulating hormone (TSH) levels were determined using a chemiluminescent immunoassay or a radioimmunioassay (RIA). Adrenal,
liver, pituitary, thyroid, and urogenital organs were collected and weighed, and microscopic

examinations were performed on the ovaries

, uterus, adrenal, thyroid, and kidneys.

All rats survived the 21-day test period with the exception of one animal in the mid-dose group. This animal appeared dehydrated

, had urine soiling, soft feces, decreased activity, and partially

closed eye lids on PND 23

, and died spontaneously on PND 24

. Tissues from this animal were moderately autolytic at necropsy and the probable cause of death could not be determined.

Given the lack of a dose-response relationship and previous toxicity data for pronamide, this

death was not considered treatment related.

No treatment-related effects were observed on body weight, body weight gain, age or weight of

at VO at any dose. Three high-dose animals failed to achieve VO by PND 42; however, all otherFemale Pubertal Assay ( 2012 ) / Page 2 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## study animals achieved VO during the monitoring period. Decreased body weights/body weight gains may have contributed to the delays in VO because each of three affected animals weighed 19-38% less on PND 34 than the mean control body weight at the time of VO ( i.e. , ≤88.2 g vs. 109.3 g).

Administration of pronamide did not change the day of first estrus compared to the control group. Animals exhibited similar cycle lengths and regularity. The majority of females in the 300 mg/kg/day group were in diestrus at necropsy.

There were dose -de pendent increases in all liver weight s at mid and high doses . At 100 mg/kg/day, absolute, adjusted and relative liver weights were increased by 13-18%, with only the increase in relative weight being significant (p<0.05); however, at 300 mg/kg/day, all li ver weights were increased (p<0.05) by 53-58%. Relative kidney weights were significantly increased at 100 and 300 mg/kg/day (6% and 7%, respectively); however, neither absolute nor adjusted kidney weights were affected . Given the minimal change in absolute weights and the lack of associated histopathological changes in the kidney, the toxicological significance of the increase in kidney weights is unclear. For the thyroid, both absolute and adjusted weights were significantly increased by 16

- 18% in the mi d-dose and by 26-28% in the high -dose groups.

Th ese increase s in thyroid weight are consistent with the observed increase s in serum TSH levels

and are considered treatment related. There were dose-dependent decreases (p ≤ 0.05) in serum

T 4 

## concentrations at all dose levels of pronamide (↓25, 42, and 48%) and corresponding

increases in serum TSH concentrations at all doses [↑69% (NS), low dose; ↑123 and 338% in the

mid - and high-dose groups, respectively].

In addition to the changes in thyroid weight and hormone levels at the high dose , there were

treatment

- related decreases (p<0.05) in follicular colloid area (Grades 2-3) and increases in follicular cell height (Grades 3 -4), compared to the control a s well as the low - and mid-dose groups. The combination of these thyroid effects indicates a change in thyroid function in response to treatment with pronamide.

Pronamide treatment also had a significant effect on adrenal histology. In both the mid - and high -dose groups, there was a very slight increase in hypertrophy of the zona fasciculate region and an increase in cortex vacuolization, with the incidence of both effects increasing with dose. No significant differences were observed in the ovaries or uterus, although at the high-dose the ovaries of several animals (4/16) were slightly juvenile in appearance and there was a slight decrease in uterus size for 2/16 animals. These findings in the ovaries and uterus were almost exclusively associated with the three high -dose animals that did not attain VO during the study.

Based on the l arge increase s in liver weight (53-58%) and the histological changes noted in the adrenal glands at 300 mg/kg/day, the high-dose used in this study was considered an appropriate

concentration to challenge the animals

.

Th e assay satisfies the EDSP Tier 1 Test Order requirement s for a Female Pubertal Assay (OCSPP 890.1450).

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, and Quality

Assurance statements were provided.Female Pubertal Assay ( 2012 ) / Page 3 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology& Environmental Research and Consulting

Location: Midland, Michigan Study Director: Zablotny, C.L

Other Personnel: Woolhiser, M.R.; Manager Marty, M.S. ; Lead Scientist Stebbins, K.E. ; Pathologist Mahan, H.M

. ; Quality Assurance Gallagher, K.H. ; A nimal t echnician Passage, J.K. ; Reproductive technologist Lawson, M.A.; Pathology data Perala, A.W. ; A nalytical analyses Hall, B.K.; Document management Lacher, J.W.; Laboratory Veterinarian McFadden, L.G.; Statistical a nalyses Study Period: June 27, 2011 to June 21, 2012



## 2

. Test S ubstance : Pronamide

Description: Not reported

Source: Dow AgroSciences, LLC, Indianapolis, IN

Lot/Batch #: XG1088R301, TSN003588

- 0004 (Expiration date not reported) Purity : 96.2 % Stability: Not reported

CAS #: 23950

- 58

- 5

Structure:



### Cl Cl O

N H CH 3



### CH 3 

### CH



## 3

. Vehicle : Aqueous Methylcellulose ( 0.5% )

4

. Test A nimals : Species: Rat

Strain: Crl:CD(SD Age/Weight at Study Initiation: PND 22 / 39.0 to 62.2 g females only

Source: Charles River (Portage, MI) Housing: 2 /cage, plastic solid bottom cages with heat

- treated laboratory grade , aspen wood shavings

Diet: Teklad Diet #2016, Harlan Laboratories

, ad libitum Phytoestrogen content <325 μg of genistein equivalents/gram diet

Water: Deionized water

, ad libitum

Environmental

Conditions: Temperature: Humidity: Air changes: Photoperiod: 22 ± 1 °C

40

- 70 %

12

- 15 /hr

12 hrs light/ 12 hrs dark



## B. ST UDY DESIGN

1. In -L ife D ates : Start: July 1 , 2011 End: July 22, 2011Female Pubertal Assay ( 2012 ) / Page 4 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## 2. Mating : Time

- mated pregnant dams were received from the supplier such that they would

all reach gestation day (GD) 21 on the same day; however, litters born on either gestation day 21 or 22 were used for the pubertal assay. Litters with more than 10 pups were standardized by culling on PND 4 to 10 pups per litter.

3. Animal A ssignment : Offspring were weaned on PND 21 and weighed. Animals were assigned such that mean body weights and variances for all groups were similar, to the test groups noted in Table 1. Littermates were not assigned to the same treatment group.

TABLE 1. Study Design a


### Test group Dose (mg/kg/day) # of Fem ales

Control 0 16

Low 25 16

Middle 100 16 High 300 16

a Data were obtained from page 18 of the study report.



## 4. Dose S election Rationale : The dose levels were selected based on the results from a screening study, a dietary study, a probe study, and a Hershberger assay. In a screening study, rats were treated for 3 days by oral gavage with pronamide doses of 0, 25, 100 or

400 mg/kg/day in 0.5% methylcellulose 1 

## . Liver -to body weight ratios were increased in both sexes at the high dose. In a 2 -week dietary study, pronamide was found to be an inducer of cytochrome P450 enzymes at 239.3 mg/kg/day 2



## . In a probe study, male rats were given 0 to 1000 mg/kg/day pronamide by gavage for 15 days from PND 30-44. Terminal body weights were decreased by 12 -15% at pronamide doses ≥ 600 mg/kg/day without a strong dose-response relationship 3 

## . There were marked increases in absolute and relative liver weights at doses ≥ 10 0 mg/kg/day, which partially masked body weight decreases. In the uterotrophic assay 4 

## , groups of 6 immature female rat s were exposed to 0, 25, 100 or 400 mg/kg/day pronamide from PND 19-21. There were significant decreases in terminal body weights at all doses of pronamide. Body weight gains in pronamide- treated animals were

decreased ; however, there were no treatment -r elated effects on wet or blotted uterine weights at any dose level.

Based on the probe study a high dose of 300 mg/kg/day was selected for the female pubertal

assay as this dose was expected to cause a statistically significant reduction in terminal body weight gain relative to the control animals, but not exceed a 10% change in terminal body weight.

1 

### Deckert, F. W. and Steigerwalt, R. B. (1979). KERBTM: Screening for hepatic enzyme induction via in vitro para

nitroanisole demethylation after 3 day oral pretreatment of rats. Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.

2 

### Harada, T. (1996). Propyzamide: Hepatic drug

- metabolizing enzyme induction study in mice and rats. Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.

3 

### Marty, M. S., Marshall, V. A., and Zhang, F. (In progress). Pronamide: Hershberger assay in castrated adult male Crl:CD(SD) rat. Report of Toxicology & Environmental Researc h and Consulting, The Dow Chemical Company, Midland, Michigan

4 

### Marty, M. S., Brooks, K. J., and Jeong, YC. (2011). Pronamide: Uterotrophic assay in the immature females Crl:CD(SD) rat. Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.Female Pubertal Assay ( 2012 ) / Page 5 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## 5. Dose P reparation and Analysis : Dose formulations were prepared by mixing appropriate amounts of test substance with 0.5% aqueous methylcellulose. Homogeneity (top, middle, bottom) and achieved concentrations were tested for the low- and high-dose formulations, but only two samples were collected for the mid

- dose for mulation. The stability of pronamide in 0.5% aqueous methylcellulose at 0.250, 2.50 and 250 mg/ml was determined in a previous study for 12 days 5



## .

Results of D ose Analysis

Homogeneity (%CV) : 1.4% - 4.1%

Stability: No data provided

Concentration: 93.6 - 97.3%

The analytical data indicated that the mixing procedure was adequate and that the variation between nominal and actual dosage to the animals was acceptable.

6. Dosage A dministration : All doses were administered once daily by gavage, from PND 22 through PND 42, in a volume of 4.0 mL/kg of body weight. Dosing was performed at approximately the same time daily. Dose volume was adjusted daily based on individual body weights.

7. Statistics : The following statistical analyses were performed. Statistical significance was reported when p<0.05. The analyses were considered appropriate.

Parameter Statistical test
Initial Body weight, body weight gain (Except PND 22

- 25) clinical chemistries (except alanine aminotransferase), mean cycle length, body weight at VO, age at first estrus, organ weights, organ

- to

- body weight ratios (liver, kidney, adrenal, and pituitary

we ights, and serum hormones. Homogeneous data sets were analyzed using a two

way analysis of variance (ANOVA) with block and

treatment as main ef f ects , followed by pairwise comparisons using Dunnett’s two

- tailed t tests.

Body weight at VO and organ weights ( t hyroid , ovaries, uterus) Homogeneous data sets were analyzed using a two

way analysis of covariance (ANCOVA) with PND 21 body weight as the covariable, followed by pairwise comparisons using Dunnett’s two

- tailed t

tests. Cycling status and percent cycling regularly Chi

- square analysis, followed by a Fisher’s exact
test with a Bonferroni

- Holm adjustment, if significant

BWG from PND 22

- 25, alanine aminotransferase

, and age at VO. Bartlett's test, followed by nonparametric Kruskal

Wallis test and a Wilcoxon rank

- sum test with a

Bonefforoni

- Holm adjustment for multiple comparisons to control

5 

### Dryzga, M. D., and Yano, B. L. (2005). Pronamide Technical: 28

- Day dermal toxicity

, study in F344/DuCrl rats. Report of Toxicology & Environmental Research and

, Consulting, The Dow Chemical Company, Midland, Michigan.Female Pubertal Assay ( 2012 ) / Page 6 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## C. METHODS

1. Mortality and C linical Examinations : All animals were examined at least twice daily after dosing for mortality and moribundity. Clinical examinations were conducted after dosing.

2. Body W eight : Animals were weighed daily prior to dosing, and body weights were statistically analyzed and reported for PND 21, 22, 25, 28, 32, 35, and 42. Body weight gains were also analyzed over the associated intervals beginning with PND 22 -25, as wel l as for the overall dosing period (PND 22-42).

3. Vaginal O pening (VO) : Beginning on PND 22 , all animals were examined daily for onset

of VO

. The appearance of a small “pin hole”, a vaginal thread, and complete vaginal opening were recorded. Age and weight on the day of completion of VO were recorded. However, if any animal within any group showed incomplete opening (persistent pin holes and/or threads) for greater than 3 days, a separate second analysis was conducted using the age at which incomplete opening was first observed. Examination of the females was continued daily until VO was present or until euthanasia.

4. Estr o us C yclicity : Beginning on the day of VO , and up to and including the day of necropsy, daily vaginal smears were obtained and evaluated for the presence of leukocytes, nucleated epithelial cells, or cornified epithelial cells. The vaginal smears were classified as

dies trus (predominance of leukocytes mixed with some cornified epithelial cells), proestrus (predominance of clumps of round, nucleated epithelial cells), or estrus (predominance of cornified epithelial cells). The age at first vaginal estrus was recorded.

5. Sacrifice and Pathology : On the afternoon of PND 41, rats were transferred to thenecropsy holding area to avoid transport on the day of necropsy, so as not to induce stressrelated responses in other animals which may affect hormone measurements. Al l surviving

animals were sacrificed by sedation with isoflurane followed by exsanguination on PND 42 approximately 2 hours post-dosing , and all necropsies were completed by 1300 hours. Blood from the trunk of the animals was collected immediately into serum separation tubes, processed by centrifugation , and stored at

− 80 ° C for subsequent hormone and clinical chemistry evaluations.

a. Hormone Analysis : TSH levels were determined by RIA , and total T 4 

## concentrations were determined by chemiluminescent immunoassay, at W IL Research Laboratories, LLC in accordance with GLP requirements. Samples were assayed in duplicate with multiple quality control samples

.

b. Clinical C hemistry : The following CHECKE D (X) parameters were examined.Female Pubertal Assay ( 2012 ) / Page 7 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None

ELECTROLYTES OTHER

X Calcium X Albumin

X Chloride X Creatinine*

Magnesium X Urea nitrogen*

X Phosphorus X Total cholesterol

X Potassium X Globulins

X Sodium Glucose

ENZYMES X Total bilirubin

X Alkaline phosphatase (AL P ) Total protein

Cholinesterase (ChE) Triglycerides

Creatine phosphokinase Serum protein electrophoresis

Lactic acid dehydrogenase (LDH) X A/G ratio

X Alanine aminotransferase (ALT/also SGPT)

X Aspartate aminotransferase (AST/also SGOT)

Sorbitol dehydrogenase (SDH)

X Gamma glutamyl transferase (GGT)

Glutamate dehydrogenase

* Recommended for the pubertal assay in female rats based on Guideline 890.1 45 0.



## c. Organ W eights and Histopathology : The following CHECKED (X) tissues were collected and weighed. The (XX) organs, in addition, were subjected to histological

examination

UROGENITAL OTHER

X X Ovaries ( paired, without oviducts) * + X X Thyroid * +

X X Uterus* + X Liver *

X X Kidneys (paired)*+ X X Adrenals (paired) *

X Pituitary *

* Weights required based on Guideline 890.1 4 50

+ Histopathological examination required based on Guideline 890.1 4 50



## All organs collected, except the thyroid/trachea and uterus were weighed prior to fixation.

Paired organs (kidneys, adrenals, and ovaries) were weighed together. The uterus and cervix were separated from the vagina and weighed , and the uterus was re weighed following

removal of the fluid in the lumen (blotted weight)

.

The ovaries and uterus were fixed in 10% buffered formalin and stored in 70% ethanol prior to embedding. The thyroid (with parathyroid) and kidneys were fixed in 10% buffered formalin for at least 24 hrs. Following fixation

, the thyroid w as dissected fro m the trachea.

All collected tissues were routinely processed into paraffin blocks, sectioned, stained with hematoxylin and eosin, and examined microscopically.

One animal died on PND 24 prior to the scheduled necropsy. It was necropsied on the same day, and similar procedures were followed to examine for gross lesions, but no blood collection, recording of terminal body and organ weights, or histopathological examination

was conducted.Female Pubertal Assay ( 2012 ) / Page 8 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## II. RESULTS

A. MORTALITY : All rats survived the 21- day test period with the exception of one animal

in the mid -dose (100 mg/kg/day) group. This animal appeared dehydrated, had urine soiling, soft feces, decreased activity and partially closed eye lids on PND 23, and died spontaneously on PND 24. Tissues from this animal were moderately autolytic at necropsy and the probable cause of death could not be determined. All other rats survived until

scheduled sacrifice.

B. CLINICAL SIGNS OF TOXICITY : No treatment

- related clinical signs of toxicity were observed in animals for any dose groups. Clinical observations were limited to the mid -dose animal that died on PND 24 and one high-dose animal that exhibited urine soiling on PND 25 only.

C. GENERAL GROWTH AND VAGINAL OPENING : Body weights, body weight gains,

and age an d weight at day of attainment of VO are presented in Table 2. No treatment

related effects were observed on body weights, body weight gains, age of attainment of VO or weight at day of attainment at any dose. Females in the 300 mg/kg/day group gained

96.0 g from PND 22 -42 compared with 100.6 g in the control group during this interval; therefore, the high-dose animals weighed 95.4% of mean control body weight on PND 42. After adjustment for increased liver weight, terminal body weight and body weight gains in the high-dose group were 94.6 and 91.7% of control values, respectively, which more accurately reflected the overall growth differences.

The mean age at VO for the control animals was PND 33.8 (adjusted value 33.7); whereas

, the pronamide- treat ed animals ranged from PND 34.3-35.8 (adjusted values 34.3-35.8). Three high

- dose animals failed to achieve VO by PND 42 ( A nimal s #7192, #7194, and #7195), whereas all other study animals achieved VO during the monitoring p eriod

.

The mean age at VO, bo dy weight at VO, and final body weight in the control group were within the acceptable range of the performance criteria provided in the Guideline (890.1450).Female Pubertal Assay ( 2012 ) / Page 9 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



### TABLE 2

. General Growth and Vaginal Opening (VO) a

Parameter

Evaluated Vehicle Control Pronamide (25 mg/kg/day) Pronamide (100 mg/kg/day) Pronamide (300 mg/kg/day)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)
Initial body weight (PND 22; g) U 16 51.05 6.09 11.93 16 50.78 6.41 12.62 16 51.19 5.20 10.16 16 51.16 5.67 11.09

Body weight at vaginal opening (g) U 16 109.28 10.98 10.05 16 107.56 13.76 12.79 15 109.01 14.23 13.06 13 110.79 14.31 12.91

A 16 109.76 2.741 NA 16 108.40 2.744 NA 15 108.92 2.826 NA 13 109.27 3.053 NA

Final body weight (g) U 16 151.66 13.30 8.77 16 143.29 16.21 11.31 15 147.94 17.78 12.02 16 147.19 21.43 14.56

A 16 151.77 3.428 NA 16 143.91 3.429 NA 15 147.26 3.542 NA 16 147.10 3.428 NA
Final body weight (% of control) U NA NA NA NA NA 94.5 10.07 11.3 NA 97.5 11.7 12.0 NA 97.1 14.1 14.6

A NA NA N A NA NR NR NR NR NR NR NR NR NR NR NR NR
Body weight gain (final

– initial; g) U 16 100.61 10.69 10.63 16 92.51 13.85 14.97 15 96.46 15.08 15.63 16 96.03 17.54 18.26

A NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR
Age at vaginal opening (PND) U 16 33.8 1.5 4.4 16 34.3 1.4 3.9 15 34.3 1.6 4.6 16 35.8 4.1 11.4

A 16 33.7 0.41 NA 16 34.3 0.41 NA 15 34.3 0.43 NA 16 35.8 0.59 NA
Proportion unopened (#/N) 0 NA 0 NA 0 NA 3 NA

a Data were obtained from page 55 of the study report . Percent differences from controls, calculated by the reviewers, are included in parentheses.

U Unadjusted for body weight on PND 22

A Adjusted for body weight on PND 22

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

NA Not applicable

NR Not Required as part of the test guideline



## D. ORGAN WEIGHTS : Organ weights at necropsy are presented in Table 3. T here were significant increase s (p<0.05) in absolute, adjusted and relative liver weight s (↑53

- 58%) at 300 mg/kg/day and there was a significant increase of 18% in relative liver weight at 100 mg/kg/day. Increases of 13-14% (NS) were also observed in absolute and adjusted liver weights at 100 mg/kg/day. All liver weights at 25 mg/kg/day were similar to the control. Relative kidney weights were increased (p<0.05) by 6 and 7%, respectively, at 100 and 300 mg/kg/day ; however , neither absolute nor adjusted k idney weights were statistically

different from controls at these dose levels. Both absolute and adjusted thyroid weights

were dose-dependently increased (p<0.05) in the mid -and high- dose groups by 16 -18% and

26- 28%, respectively. There were no other sig nificant, treatment

- related effects on organ weights at any dose of pronamide.

The unadjusted values for all organ weights in the control group were within the acceptable range of the performance criteria provided in the Guideline (890.1450).Female Pubertal Assay ( 2012 ) / Page 10 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



### TABLE 3

. Organ Weights at Necropsy a

Organ Vehicle Control Pronamide (25 mg/kg/day) Pronamide (100 mg/kg/day) Pronamide (300 mg/kg/day)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Liver (g) U 16 6.89 0.81 11.68 16 6.69 0.94 14.13 15 7.86 (↑14) 1.31 16.69 16 10.59 * (↑54) 1.77 16.73

A 16 6.90 0.294 NA 16 6.71 0.295 NA 15 7.83 (↑13) 0.304 NA 16 10.58 * (↑53) 0.294 NA

R 16 4.5 4 0.28 6.25 16 4.66 0.37 7.93 15 5.29 * (↑18) 0.33 6 .28 16 7.18 * (↑ 58 ) 0.52 7.28

Kidneys (g) U 16 1.28 0.12 9.66 16 1.26 0.1 6 12.49 15 1.33 0.18 13.44 16 1.34 0.22 16.05

A 16 1.29 0.038 NA 16 1.26 0.038 NA 15 1.33 0.03 9 NA 16 1.34 0.038 NA

R 16 0.85 0.06 7.31 16 0.88 0.04 4.75 15 0.90 * (↑6) 0.05 6.07 16 0.91 * (↑7) 0.07 7.21

Pituitary (mg) U 16 8.1 0.9 11.3 16 7.2 1.1 15.2 15 7.3 1.1 14.8 16 7.6 1.6 21.1

A 16 8.1 0.29 NA 16 7.2 0.29 NA 15 7.3 0.30 NA 16 7.6 0.29 NA

R 16 5.3 0.7 13.4 16 5.0 0.5 10.3 15 4.9 0.6 12.6 16 5.1 0.7 12.9

Adrenals (mg) U 16 38.7 8.3 21.4 16 37.8 7.1 18.9 15 41.7 4.8 11.6 16 41.9 7.7 18.4

A 16 38.7 1.63 NA 16 38.0 1.63 NA 15 41.5 1.69 NA 16 41.9 1.63 NA

R 16 25.5 4.9 19.2 16 26.4 4.1 15.7 15 28.3 2.6 9.2 16 28.5 3.5 12.4

Ovaries (mg) U 16 57.4 8.6 15.0 16 57.0 9.6 16.8 15 57.2 9.6 16.7 16 54.5 17.9 32.8

A 16 57.5 2.92 NA 16 57.2 2.93 NA 15 57.0 3.02 NA 16 54.5 2.92 NA

Uterus, wet (mg) U 16 333.5 120.4 36.1 16 279.8 158.9 56.8 15 271.7 105.3 38.8 16 265.7 109.4 41.2

A 16 333.8 30.80 NA 16 281.5 30.81 NA 15 269.9 31.82 NA 16 265.4 30.80 NA

Uterus,

blotted (mg) U 16 307.1 63.7 20.7 16 249.1 92.8 37.3 15 245.0 73.7 30.1 16 254.5 97.2 38.2

A 16 307.2 20.60 NA 16 249.9 20.61 NA 15 244.1 21.29 NA 16 254.4 20.60 NA

Thyroid,

fi xed (mg) U 16 8.7 1.5 17.2 15 8.9 1.4 15.8 15 10.3 * (↑18) 2.0 19.9 16 11.1 * (↑28) 1.9 17.1

A 16 8.8 0.39 NA 15 8.9 0.40 NA 15 10.2 * (↑16) 0.40 NA 16 11.1 * (↑26) 0.39 NA

a Data were obtained from page 58 of the study report . Percent differences from controls, calculated by the reviewers, are included in parentheses.

U Unadjusted for body weight on PND 22

A Adjusted for body weight on PND 22

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

R Organ

- to

- body weight ratio (relative to body weight)

* Significantly different from controls at p<0.05.



## E. ESTROUS CYCLICITY : Estr ous cycle data are provided in Table 4. Administration of pronamide did not change the day of first estrus compared to the vehicle control group. The mean age at first estrus was PND 34.5 in control animals compared with PND 35.4, 34.7, and 35.0 in the 25, 100 and 300 mg/kg/day pronamide grou ps, respectively. The age at vaginal estrus excluded values from the three high- dose animals that failed to achieve VO. Animals exhibited similar cycle lengths and regularity. The majority of females in the 300 mg/kg/day group were in diestrus at necrop sy.Female Pubertal Assay ( 2012 ) / Page 11 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



### TABLE 4

. Estrous Cyclicity a

Treatment Groups N Mean A ge at

F irst V aginal

E strus (PND) Mean C ycle

L ength (days) b Cycling (%) Regularly

C ycling

(%) Cycle S tatus at N ecropsy (# F emales)

Diestrus Proestrus Estrus Not

C ycling

Vehicle Control 16 34.5 4.7 (n=15) 93.8 93.8 7 2 7 0

Pronamide (25 mg/kg/day) 16 35.4 4.9 (n=13) 100.0 81.3 13 0 3 0

Pronamide (100 mg/kg/day) 15 34.7 4.9 (n=12) 86.7 80.0 14 1 0 0

Pronamide (300 mg/kg/day) 13 35.0 5.4 (n=10) 84.6 69.2 9 0 4 0

a Data were obtained from page 56 of the study report . Percent differences from controls, calculated by the reviewers, are included in parentheses.

b Cycle length was determined only for regularly cycling animals; the actual number of regularly cycling animals in each group is shown in parentheses.

N Number of animals



## F. CLINICAL CHEMISTRY AND HORMONE LEVELS : Mean hormone and clinical chemistry levels are presented in Table 5. Rats administered 3 00 mg/kg/day had a treatment

related lower mean alkaline phosphatase activity (p≤0.05) . Rats administered 100 or 300 mg/kg / day had treatment -related higher mean phosphorus concentrations, which is a nonadverse effect as there were no corresponding histopathological alterations in the kidne ys of rats administered 300 mg/kg/day. R ats administered 300 mg/kg/day had a statistically significant higher mean albumin concentration.

There were dose- dependent decreases (p <0.05) in serum T 4 

## at all dose levels of pronamide and corresponding increases in serum TSH , which were significant f or the 100 and 300 mg/kg/day dose groups. In the 25, 100 and 300 mg/kg/day groups, s erum T 4 

## levels were

decreased by 25, 42, and 48% , respectively , and serum TSH levels were increased by 69, 123 and 338%, respectively.

The results for serum T 4 

## in the control group were within the acceptable range of the performance criteria provided in the Guideline (890.1450 ).Female Pubertal Assay ( 2012 ) / Page 12 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



### TABLE 5

. Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control Pronamide (25 mg/kg/day) Pronamide (100 mg/kg/day) Pronamide (300 mg/kg/day)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Hormones

Serum T4,

Total (μg/dL) 16 4.02 0.77 19.11 16 3.02* ( ↓ 25) 0.36 11.92 15 2.34* ( ↓ 42) 0.40 17.03 16 2.09* ( ↓ 48) 0.20 9.74

Serum TSH (ng/mL) 16 2.6 1.2 45.5 16 4.4 (↑69) 4.7 107.1 15 5.8* (↑123) 2.1 37.1 16 11.4* (↑338) 4.1 35.7

Clinical Chemistry

Creatinine (μmol/L) 16 0.14 0.05 35.6 16 0.18 0.04 22.2 15 0.17 0.06 34.3 16 0.16 0.05 32.8

Serum urea nitrogen (mg/dL) 16 15 2 17 16 15 3 18 15 15 3 21 16 15 3 17

Alkaline phosphatase (μ/L) 16 260 56 22 16 233 52 22 15 224 42 19 16 207* ( ↓ 20) 47 23

ALT (μ/L) 16 48 10 22 16 51 6 12 15 52 8 15 16 54 14 26
AST (μ/L) 16 96 7 8 16 96 15 16 15 100 12 12 16 98 14 15
GGT (μ/L) 16 1.5 0.0 0.0 16 1.7 0.6 35.6 15 1.7 0.5 32.0 16 1.8 0.7 38.6

Albumin (g/dL) 16 4.2 0.3 6.1 16 4.2 0.2 3.7 15 4.3 0.1 2.8 16 4.4* (↑5) 0.2 3.5

A/G Ratio 16 3.4 0.3 8.8 16 3.4 0.5 15.9 15 3.6 0.5 13.9 16 3.5 0.5 14.4

Cholesterol (mg/dL) 16 87 17 20 16 88 18 21 15 84 18 21 16 88 20 23

Globulin (g/dL) 16 1.3 0.1 8.6 16 1.3 0.2 13.5 15 1.2 0.2 13.9 16 1.3 0.2 14.7

Total

bilirubin (mg/dL) 16 0.05 0.00 0.00 16 0.05 0.00 0.00 15 0.05 0.00 0.00 16 0.05 0.00 0.00

Total protein (g/dL) 16 5.5 0.3 5.6 16 5.5 0.2 2.9 15 5.6 0.2 3.5 16 5.7 0.3 5.3

Sodium (mmol/L) 16 143 1 1 16 143 1 1 15 143 2 1 16 143 2 1

Potassium (mmol/L) 16 4.9 0.4 7.5 16 4.9 0.4 7.3 15 5.1 0.5 8.9 16 4.9 0.5 9.2

Chloride (mmol/L) 16 100 1 1 16 100 2 2 15 100 2 2 16 100 2 2

Calcium (mg/dL) 16 11.3 0.3 3.1 16 11.4 0.4 3.2 15 11.5 0.4 3.1 16 11.5 0.4 3.3

Phosph orus (mg/dL) 16 8.8 0.7 7.7 16 8.9 0.6 6.7 15 9.5* (↑8) 0.7 7.8 16 9.6* (↑9) 0.9 9.1

a Data were obtained from page 57 of the study report . Percent differences from controls, calculated by the reviewers, are included in parentheses.

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from con trols at p<0.05.Female Pubertal Assay ( 2012 ) / Page 13 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## G. HISTOPATHOLOGY : No treatment

- related gross pathological alterations were observed

at necropsy. The incidence s of histopathological findings of the thyroid gland are presented

in Table 6. Rats administered 300 mg/kg/day pronamide had treatment -related (p<0.05)

decreases in follicular colloid area ( Grades 2-3) compared to the control and the low- and

mid

- dose animals (Grades 3 -5 ). Follicular cell height was also increased (p<0.05 ; Grades 3-4) in the 300 mg/kg/day group compared to the vehicle control and the other pronamidetreatment groups (Grades 1 -3).

TABLE 6

. Incidence of Histopathological Lesions of the Thyroid Gland a

Treatment Groups Parameter Evaluated

Colloid Area Follicular Cell Height

Grade b Incidence Grade Incidence

O E O E

Vehicle Control 1 0 16 1 7 16

2 0 16 2 7 16

3 2 16 3 2 16

4 7 16 4 0 16

5 7 16 5 0 16

Pronamide (25 mg/kg/day) 1 0 16 1 5 16

2 0 16 2 9 16

3 2 16 3 2 16

4 9 16 4 0 16

5 5 16 5 0 16

Pronamide (100 mg/kg/day) 1 0 15 1 2 15

2 0 15 2 7 15

3 6 15 3 6 15

4 7 15 4 0 15

5 2 15 5 0 15

Pronamide (300 mg/kg/day) 1 0 16 1 0* 16

2 7* 16 2 0* 16

3 9* 16 3 9* 16

4 0 16 4 7* 16

5 0 16 5 0 16

a Data were obtained from page 64 of the study report.

b Thyroid histopathology is graded 1- 5 Follicular cell height, 1 = lowest, 5 = highest, and colloid area, 1 = most colloid

5 = least colloid

. See OECD No. 82 for reference.

O N umber O bserved

E N umber Examined

* Significantly different from controls at p. < 0.05



## The incidence of histopathological findings of the ovaries, uterus, and kidneys are presented

in Table 7. There were no treatment -related findings in the kidneys, and n o significant

differences were observed in the ovaries or uterus, although at the high-dose, the ovaries of several animals (4/16) were slightly juvenile in appearance and there was a slight decrease

in uterus size for 2/16 animals. However, a significant effect was observed on adrenal histology in both the mid- and high-dose groups. There was a very slight increase in hypertrophy of the zona fasciculate region and an increase in cortex vacu oli zation , with the incidence of both effects increasing with dose.Female Pubertal Assay ( 2012 ) / Page 14 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



### TABLE 7

. Incidence of Histopathological Lesions of the Ovaries, Uterus and Kidney s a

Findings Dose Level (mg/kg/day)

Vehicle Control Pronamide (25) Pronamide (100) Pronamide (300)

# Obs. # Exam. # Obs. # Exam. # Obs. # Exam. # Obs. # Exam.

Ovaries

Within Normal Limits 16 16 16 16 15 15 12 16

Juvenile Appearance (slight) 0 16 0 16 0 15 4 16

Uterus

Within Normal Limits 16 16 16 16 15 15 14 16 Decreased size (slight) 0 16 0 16 0 15 2 16
Kidney

Within normal limits 2 16

-- 0

-- 0 5 16 Degeneration; tubule; focal (very slight) 1 16

-- 0

-- 0 0 16

Degeneration; tubule; multifocal (very slight) 12 16

-- 0

-- 0 11 16

Cyst; cortex; tubule; focal 1 16

-- 0

-- 0 1 16
Inflammation; chronic; interstitium; multifocal (very slight) 2 16

-- 0

-- 0 1 16

Adrenal Glands

Within normal limits 12 16 10 16 2 15 0 16 Hypertrophy; zona fasciculate; (very slight) 0 16 1 16 5* 15 12* 16

Vacuolization; increased; cortex (very slight) 4 16 5 16 12* 15 16* 16

a Data were obtained from page 65 of the study report.

* Treatment

- related



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS’ CONCLUSIONS : Based on the lack of significant changes in puberty onset, estrous cycle and reproductive organ weights, there was little evidence of

altered estrogen stat us in this study, although three females in the 300 mg/kg/ day group exhibited delayed development (delayed VO). Decreased T 4 

## , increased TSH, increased thyroid weights and altered t hyroid histopathology (300 mg/kg/day only) suggest altered thyroid function at 100 and 300 mg/kg/ day. Given the increase in relative liver weights at 100 and 300 mg/kg/day and previous mode-of-action work, it is likely that pronamide is enhancing T 4 

## clearance and thereby stimulating the hypothalamic

- pituitary -thyroid axis.

There were stress

- mediated changes in adrenal histopathology at both the mid-and high-dose of pronamide. There was no evidence of endocrine activity for pronamide at 25 mg/kg /day.

B. AGENCY COMMENTS : All rats survi ved the 21-day test period with the exception of

one animal in the mid -dose group. This animal appeared dehydrated, had urine soiling, soft feces, decreased activity and partially closed eye lids on PND 23 , and died spontaneously on

PND 24. Tissues from this animal were moderately autolytic at necropsy , and the probable cause of death could not be determined. Given the lack of a dose-response relationship and previous toxicity data for pronamide, this death was not considered treatment related

.

No tr eatment -related effects were observed on body weights, body weight gains, age of attainment of VO or weight at day of attainment at any dose. Three high- dose animals failed to achieve VO by PND 42 ; whereas

, all other study animals achieved VO during the monitoring period. Decreased body weights/body weight gains may have contributed to theFemale Pubertal Assay ( 2012 ) / Page 15 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## delays in VO because the three affected animals weighed 19 -38% less on PND 34 than the mean control body weight at the time of VO.

Administration of pronamide did not change the day of first estrus compared to the vehicle control group. Animals exhibited similar cycle lengths and regularity. The majority of females in the 300 mg/kg/day group were in diestrus at necropsy.

T here were dose

- dependent increase s in all liver weight parameters at 100 and 300 mg/kg/day, with the increases being significant for all liver weight parameters at 300 mg/kg/day and for relative liver weight at 100 mg/kg/day . Relative kidney weights were

also significantly increased at 100 and 300 mg/kg/day; however, neither absolute nor adjusted kidney weights were statistically different. Given the minimal change in absolute weights and the lack of associated histopathological changes in the kidney, the toxi cological significance of the increase in kidney weights is unclear. For thyroid, both absolute and adjusted weights were significantly increased in the mid -and high- dose groups in a dosedependent manner . Th ese increase s in thyroid weight are consistent with the observed

increase s in serum TSH levels and are considered treatment related. There were no other significant, treatment -related on organ weights at any dose of pronamide.

There were dose- dependent decreases (p≤0.05) in serum T 4 

## at all dose le vels of pronamide and corresponding increases in serum TSH at all doses, with the increases being significant

at the mid - and high-dose levels. At 25, 100 and 300 mg/kg/day, s erum T 4 

## levels were

decreased by 25, 42 and 48%, respectively, and serum TSH levels were increased by 69 (NS), 123 and 338% respectively. Although serum T 4 

## levels were significantly decreased at

25 mg/kg/day, the effect is not considered toxicologically significant because there was no significant increase in TSH or thyroid we ights , and no altered histopathology at this dose

level.

In addition, at the 300 mg/kg/day dose, there were treatment

- related (p<0.05) decreases in

follicular colloid area (G rade s 2- 3) and increases in f ollicular cell height (G rade s 3-4), compared to th e control as well as the low- and mid- dose group s. The combination of these thyroid effects indicates a change in thyroid function in response to treatment with pronamide.

Pronamide treatment also had a significant effect on adrenal histology. In both t he mid - and high -dose groups, there was a very slight increase in hypertrophy of the zona fasciculate region and an increase in cortex vacuolization, with the incidence of both effects increasing

with dose. N o significant differences were observed in the ovaries or uterus, although at the high

- dose, the ovaries of several animals (4/16) were slightly juvenile in appearance and there was a slight decrease in uterus size for 2/16 animals. These findings in the ovaries and uterus were almost exclusively associated with the three high -dose animals that did not attain VO during the study.

The large increases in liver weight (53 -58%) and the histological changes noted in the adrenal glands of the animals in the 300 mg/kg/day group indicate that the high -dose was an adequate level to challenge the animals

.Female Pubertal Assay ( 2012 ) / Page 16 of 16

PRONAMIDE / 101701 O CSPP 89 0. 1 45 0/ OECD None



## C. STUDY DEFICIENCIES : The following deficiencies were noted that were not considered

to have had an adverse impact on the results, interpretation, or conclusions of this study:

• No C ertificate of Analysis was provided f or pronamide.

• The photoperiod was 12 hrs light/12 hrs dark instead of the Guideline recommendation of 14 hrs light/10 hrs dark.

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE)

Study Type: O CSPP 890.1500, Male Pubertal Assay

EPA Contract No. EP10H001452 Task Assignment No. 3-28-2012 (MRID 48688001)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Rebecca L. Bryan, B.S. Date: 10/ 19 /2012

Secondary Reviewer Signature: Scott D. Studenberg, Ph.D., D.A.B.T. Date: 10/ 2 4 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 10/ 2 9 /2012

Quality Assurance: Signature:

Jack D. Early, M.S. Date: 10/ 2 9 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS

- Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 battery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).

### PRONAMIDE 

### I 101701 Male Pubertal Assay (2012) I 

### Page 1 of 

### 19

OCSPP 890.1500 I 

### OECD None



## DATA EVALUATION RECORD

STUDY TYPE: Male Pubertal Assay ; OCSPP 890.1500



## PC CODE: 101701 

## DP BARCODE: D405597



## TXR#: 0056255 

## CAS No: 23950-58-5



## TEST MATERIAL (PURITY): Pronamide (96

. 2%

. a.i

. )



## SYNONYMS: 3

, 5-dichloro-N-(l

, l-dimethyl-2-propynyl)benzamide ; Propyzamide



## CITATION: Marty

, M.S

., Andrus, 

## A.K

., Thomas

, J. 

## (2012)

. Pronamide: Pubertal Development and Thyroid Function in Intact Juvenile / Peripubertal Male Cr! : CD(SD) Rats. Toxicology and Environmental Research and Consulting

, The

Dow Chemical Company

, Midland

, MI. Laboratory Project Study ID No .: 111081 ; August 31

, 2012. MRID 48688001. Unpublished

.



## SPONSOR: Dow AgroSciences LLC, 9330 Zionsville Road

, Indianapolis

, Indiana



## TEST ORDER#: CON-101701-37



## EXECUTIVE SUMMARY: In two Male Pubertal Assays (MRID 48688001 )

, 15 or 16 Sprague Dawley Crl : CD(SD) male rats / dose group were treated daily via oral gavage with pronamide (96.2 % purit y, Lot No

. XG 1088R301) in 0.5 % aqueous methylcellulose from postnatal day (PND) 23 to 53

. The test doses included 0 (vehicle)

, 25, 100, and 300 mg / kg/day for Study 1 and 0 (vehicle)

, 2.5

, 10

, and 25 mg / kg / day for Study 2. Animals were examined for preputial separation (PPS) daily beginning on PND 30

, and age and body weight on the day of

attainment was recorded. Following sacrifice on PND 53

, blood was collected for clinical chemistry and hormone analyses. Total serum testosterone

, thyroxine (T4), and th y roid stimulating hormone (TSH) levels were analyzed by radioimmunoassay or chemiluminescent immunoassay. Liver

, pituitary

, adrenal and urogenital organs were weighed and examined macroscopically

, and microscopic examinations were performed on the testes

, epididymides

, th y roid

, and kidneys.

All animals survived until scheduled termination. No treatment-related clinical signs of toxicity

were observed in animals for any dose groups. During Study 1

, the terminal body weights were significantly decreased by 11-12% for the 100 and 300 mg/kg / day dose groups
, indicating overt

to x icit y at these dose levels

. Therefore

, the male pubertal assay was repeated with lower pronamide doses ( :S 25 mg / kg / day)

. For inter-study comparison, the data from the 25 mg/kg / day

group from Study 1 was included in the study report; however, detailed data from the 100 or 300

mg / kg / day groups were not reported.Male P ubertal Assay (2012) / Page 2 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## In the 25 mg/kg/day group in Study 1, two animals did not achieve PPS. T erminal body weights were decreased by 7% , and body weight gain for PND 23 to 53 w as decreased by 11% (no

statistical analyses were conducted for Study 1 data) . Adjustment for liver weight did not affect terminal body weight or body weight gain . The age at PPS was delayed by 4.7 days, compared

to the control, and this increase is considered treatment

- related and biologically relevant, as body weight at PPS was also increased by 9%

. Relative liver weight was increased by 11% and absolute pituitary weight w as decreased by 14%. Absolute thyroid weight w as increased by 7%,

but w as within historical control range

, an d not considered treatment related. The absolute weights of the seminal vesicle + coagulating glands (with and without fluid) were decreased by 38% and 26%, respectively, compared to the control. Absolute ventral prostate, dorsolateral prostate, and leva tor ani-bulbocavernosus muscle complex ( LABC) weights were also decreased by 25, 23, and 20%, respectively, and a bsolute weights for the left and right epididymides were

decrease d by 11% and 12%, respectively. Serum testosterone was increased by 86%; however, the control testosterone value was atypically low compared to the historical control range, and the difference was reported as incidental. T 4 

## concentration was decreased by 32% and TSH was increased by 46%. Cholesterol levels w ere also decreased by 14%, but there were no doserelated effects for the other measured clinical chemistry parameters. There were no dose

- related effects on the weights of kidneys, adrenals, or testis. No treatment

- related changes were observed in the histopathology of the thyroid, right testes, right epididymides, or kidneys.

In Study 2, no treatment-related effects were observed on body weight, body weight gain, or age and weight at PPS at any dose of pronamide (up to 25 mg/kg/day; high dose). There were increases (p ≤0.05) in absolute, adjusted and relative liver weights (↑10

- 14%) at 25 mg/kg/day. Absolute and adjusted thyroid weights at 10 and 25 mg/kg/day were increased (not significant, NS) by 5 and 12%, respectively. There were no significant, treatment- related effects on kidneys, adrenals or accessory sex tissue weights at any dose of pronamide. However, minor decreases of 4-6% (NS) were noted in four of the androgen sensitive tissues in the 25 mg/kg/day group , with

no effect on serum testosterone concentration

. Serum T 4 

## concentrations in the 10 and 25 mg/kg/day dose groups were decreased (p ≤ 0.05) by 13 and 23%, respectively. In addition,

serum TSH was increased by 25% (NS) and 62% (p ≤ 0.05) at 10 and 25 mg/kg/day, respectively. Thyroid histopathology showed a slightly higher incidence of taller follicular epithelial cells (Grade 4) with corresponding smaller colloid areas (G rade 2) at the high dose compared to control (5 to 1, respectively). Serum albumin was increased (p ≤ 0.05) by 5% and cholesterol was decreased (p ≤ 0.05) by 15% at 25 mg/kg/day, with n o dose- related effects for the other clinical chemistry parameters. No treatment

- related changes were observed in the histopathology of the right testes, right epididymides, or kidneys.

The effects observe d in both studies on T 4 

## and TSH concentrations, and thyroid histopathology in Study 2, indicate a change in thyroid function in response to treatment with pronamide at

25 mg/kg/day. Although the 25 mg/kg/day dose group tested in Study 2 did not reproduce the effects on age and body weight at PPS, or accessory sex tissue weights observed at 25 mg/kg/day during Study 1, liver weight changes at 25 mg/kg/day were consistent between both studies.

The 25 mg/kg/day dose (Study 1 low dose; Study 2 high dose) was considered an adequate high dose based on the ≥10% increase in liver weights in Study 2, and because the next highest

- tested dose (100 mg/kg/day) yielded >10% decreases in terminal body weight in Study 1.Male P ubertal Assay (2012) / Page 3 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## Th e assay satisfies the EDSP Tier 1 Test Order requirements for a Male Pubertal Assay (OCSPP 890.1500).

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, and Quality

Assurance statements were provided.Male P ubertal Assay (2012) / Page 4 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology and Environmental Research and Consulting

Location: Midland, MI. Study Director: A.K. Andrus

Other Personnel: M.S. Marty, Lead Scientist J.Thomas, Pathologist Study Period: July 1, 2011 to August 31, 2012



## 2

. Test S ubstance : Pronamide ( P ropyzamide)

Description: Not reported (CoA not provided)

Source: Dow AgroSciences, LLC, Indianapolis, IN

Lot #: XG1088R301, TSN003588

- 0004 (Expiration date not reported) Purity: 96.2% Stability: Not reported

CAS #: 23950

- 58

- 5

Structure:



### Cl Cl O

N H CH 3



### CH 3 

### CH



## 3

. V ehicle : Aqueous Methylcellulose (0.5%)

4

. Test A nimals : Species:

Rat (males only)

Strain: Sprague Dawley Crl:CD(SD) Age/Weight at Study

Initiation:

PND 23/ 37.4

– 64.9 g Source: Charles River Laboratories, Inc., Portage, MI Housing: 2 animals/cage in plastic solid bottom cages with heat

- treated, aspen wood shavings (Harlan Laboratories, Inc., Indianapolis, IN)

Diet: T eklad D iet #2016 (Harlan Laboratories, Inc. ), ad libitum

Total genistein equivalents < 325 μg/g diet

Water: Deionized water, ad libitum

Environmental

Conditions: Temperature: Humidity: Air changes: Photoperiod: 22 ±1 °C (with a permissible excursion of ± 3)

40

– 70 %

10– 15 times/hr

12

- hr light/ dark (with exception of unverified dates June 7 and June

29

- July 10, 2011)



## B. STUDY DESIGN

1. In -L ife D ates : Study 1: Start: July 2 -3, 2011 End: August 1-2, 2011 Study 2: Start: February 27-28, 2012 End: March 28-29, 2012Male P ubertal Assay (2012) / Page 5 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## 2. Mating : Time -mated pregnant nulliparous dams were received from the supplier on

G estation D ay 5-10 and allowed to deliver their pups naturally . Litters with more than 10 pups were standardized by culling on PND 4 to 10 pups per litter with equal numbers of

males and females whenever possible.

3. Animal A ssignment : Animals were weaned on PND 21 and weighed. Animals were assigned to dose groups such that the mean body weights (and variances) were similar

among t he test groups noted in Table 1, and the assignment of littermates to the same

treatment group was avoided. During Study 1, overt toxicity occurred at 100 and 300 mg/kg/day based on decreased terminal body weights (↓11

- 12%) . A second test, Study 2,

was conducted at lower test concentrations.

TABLE 1. Study Design a


### Test group Dose (mg/kg/day) # of Males
Study 1

Control 0 15

Low 25 15

Mid 100 b 

### 15 High 300 b 

### 15 Study 2

Control 0 16

Low 2.5 16

Mid 10 16 High 25 16

a Data were obtained from page 21 of the study report.

b Results for the 100 and 300 mg/kg/day dose groups were not included with this report.



## 4. Dose S election Rationale : The dose levels were selected based on the results from a screening study, a dietary study, a probe study, a Hershberger assay and an uterotrophic

assay . In a screening study, rats were treated for 3 days by oral gavage with pronamide doses of 0, 25, 100 or 400 mg/kg/day in 0.5% methylcellulose 1 

## . Liver

- to body weight ratios were increased in both sexes at the high dose. In a 2-week dietary study, pronamide was found to be an inducer of cytochrome P450 enzymes at 239.3 mg/kg/day 2 

## . In a probe study, male rats were given 0 to 1000 mg/kg/day pronamide by gavage for 15 days from PND 30- 44 (48673401.DER). T ermina l body weights were decreased by 12 -15% at pronamide doses ≥600 mg/kg/day without a strong dose -response relationship. There were marked increases in absolute and relative liver weights at doses ≥100 mg/kg/day, which partially masked body weight decreases . In the uterotrophic assay (48619108.DER), groups of 6 immature female rats were exposed to 0, 25, 100 or 400 mg/kg/day pronamide from PND 19-21. There were significant decreases in terminal body weights at all doses of pronamide. Body weight gains in pronamide- treated animals were decreased; however, there were no

treatment

- related effects on wet or blotted uterine weights at any dose level.

1 Deckert, F. W. and Steigerwalt, R. B. (1979). KERBTM: Screening for hepatic enzyme induction via in vitro para

- nitroanisole demethylation after 3 day oral pretreatment of rats. Report of Toxicology & Environmental Research and Consulting, The Dow

Chemical Company, Midland, Michigan.

2 Harada, T. (1996). Propyzamide: Hepatic drug

- metabolizing enzyme induction study in mice and rats. Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.Male P ubertal Assay (2012) / Page 6 of 19

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## Based on the probe study a high dose of 300 mg/kg/day was selected for S tudy 1 of the male pubertal assay as this dose was expected to cause a statistically significant reduction in terminal body weight gain relative to the control animals, but not exceed a 10% change in terminal body weight.

However, overt toxicity occurred during Study 1 based on reductions of 1 1-12 % in terminal body weight at 100 and 300 mg/kg/day, compared to the control. The test concentrations

were reduced during Study 2 and included 2.5, 10, and 25 mg/kg/day dose groups

. Data

from the 25 mg/kg/day dose group of Study 1 are also included in the results.

5. Dose P reparation and Analysis : Dose formulations were prepared by mixing appropriate amounts of test substance with 0.5% aqueous methylcellulose. Homogeneity (top, middle, bottom) and achieved concentrations were tested for the low- and high-dose formulations. The stability of pronamide in 0.5% aqueous methylcellulose at 0.250, 2.50 and 250 mg/mL was determined in a previous study for 12 days 3



## .

Results of D ose Analysis

Homogeneity (% R.S.D. ): 1.3 to 1.5%

Stability: S table for ≥ 12 days (data not provided)

Concentration (% nominal): 93.0 to 102.8%

The analytical data indicated that the mixing procedure was adequate and that the variation between nominal and actual dosage to the animals was acceptable.

6. Dosage A dministration : All doses were administered once daily by gavag e, from PND 23 through PND 53, in a volume of 4 mL/kg of body weight. Dose volumes were adjusted based on the individual daily body weights.

7. Statistics : Mean values were presented with st andard deviations and coefficient of

variation. The following statistical scheme was used:

Classification Procedure



### B ody weight

B ody weight gain

C linical chemistries

A ge at PPS

B ody weight at PPS

O rgan weights

O rgan

- to

- body weight ratios (liver, kidney, adrenal and pituitary weights)

S erum hormones A Bartlett’s test was conducted to check for homogeneity of variance (p=0.01).

Two

- way analysis of variance (ANOVA) with block and treatment as main effects was performed.

When significant dose effects were determined in the

two

- way ANOVA at p = 0.05, then individual dose groups were compared to controls with Dunnett's test at p = 0.05 (experiment

- wise error).

3 Dryzga, M. D., and Yano, B. L. (2005). Pronamide Technical: 28

- Day dermal toxicity, study in F344/DuCrl rats. Report of Toxicology & Environmental Research and, Consulting, The Dow Chemical Company, Midland, Michigan.Male P ubertal Assay (2012) / Page 7 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None

Classification Procedure



### A ge and body weight at PPS

O rgan weights A Bartlett’s test was c onducted to check for homogeneity of variance (p=0.01).

Analysis of covariance (ANCOVA) was conducted with body weight on PND 23 as the covariate.

When the dose effect was significant at p = 0.05, least square means with a Dunnett’s correction was us ed to determine differences (experiment wise p = 0.05).

When the ANCOVA was not statistically significant, a Dunnett’s test was performed. Specific histopathologic observations Pair

- wise Chi

- square test with Yates' continuity correction (alpha = 0.05, two

- sided)



## Statistical outliers were identified by a sequential test (p = 0.02). Outliers and questionable data points (i.e., values due to technical errors) were excluded only for documented scientifically sound reasons. Histopathology results were not subjected t o outlier tests. The statistical analyses were considered adequate.

C. METHODS

1. Mortality and C linical Examinations : All animals were examined cage

- side at least twice daily for mortality, morbundity, availability of food/water, and clinical abnormalities

. In addition, c linical , hand- held e xaminations with each animal were conducted daily post-dose.

2. Body W eight : Animals were weighed prior to allocation to dose groups (PND 21) and daily prior to dosing. Body weights determined prior to dosing on PND 53 were used as the terminal body weights. Body weights were statistically analyzed on PND 21, 23, 26, 30, 37, 42, 45, and 53; body weight gains were statistically analyzed beginning with the PND 23-26

interval , followed by subsequent intervals, in addition to the entire dosing period (PND 23- 53). Body weights and body weight gains were adjusted for liver weights to remove the contribution of the pronamide- induced increases in liver weights.

3. Preput ial Separation (PPS) : Beginning on PND 30 , all animals were examined daily for

onset of PPS . Age and weight on the day of completion of PPS were recorded. Examination for the onset of puberty ceased with acquisition or on PND 53 if PPS was not yet acqui red . If PPS was not acquired by PND 53, then PND 54 is used for the calculation of mean age of puberty onset.

4. Sacrifice and Pathology : A nimals were moved to the necropsy holding room on the afternoon of PND 52. All surviving animals were anesthetized with 5% isoflurane approximately 2 hours after the final dose (starting at approximately 0800 hours) on

PND 53. Blood was collected immediately into serum separation tubes after cardiac puncture. Blood samples for hormone analysis were kept on ice, or refrigerated

, until centrifugation , and stored at

− 80°C until subsequent hormone evaluations. Animals were euthanized by exsanguination, followed by decapitation.

Groups were counter- balanced d uring necropsy, and necropsies were completed by

1300 hours. A complete necropsy was performed on all animals.Male P ubertal Assay (2012) / Page 8 of 19

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## a. Hormone Analysis : Samples were sent on dry ice to WIL Research Laboratories, LLC (Ashland, OH) for analysis. TSH concentration s were ana lyzed by radioimmunoassay, and chemiluminescent immunoassays were used for total T 4 

## and testosterone analyses

.

b. Clinical C hemistry : The following CHECKED (X) parameters were examined.

ELECTROLYTES OTHER

X Calcium X Albumin

X Chloride X Creatinine*

Magnesium X Urea nitrogen*

X Phosphorus X Total cholesterol

X Potassium X Globulins

X Sodium Glucose

ENZYMES X Total bilirubin

X Alkaline phosphatase ( ALP/also ALK) X Total protein

Cholinesterase (ChE) Triglycerides

Creatine phosphokinase Serum protein electrophoresis

Lactic acid dehydrogenase (LDH) X A/G ratio

X Alanine aminotransferase (ALT/also SGPT)

X Aspartate aminotransferase (AST/also SGOT)

Sorbitol dehydrogenase (SDH)

X Gamma glutamyl transferase (GGT)

Glutamate dehydrogenase

* Recommended for the pubertal assay in male rats based on G uideline 890.15 0 0.



## c. Organ W eights and Histopathology : The following CHECKED (X) tissues were collected and weighed . The (XX) organs, in addition, were subjec ted to histological

examination.

UROGENITAL OTHER

XX Testes (left and right separately) * + XX Thyroid * +

XX Epididymides (left and right separately) * + X Liver *

X Seminal vesicle plus coagulating glands (with and without fluid) * X Adrenals (paired) *

X Ventral prostate * X Pituitary *

X Dorsolateral prostate *

X Levator ani

- bulbocavernosus (LABC) muscle complex *

XX Kidneys (paired) * +

* Weights required based on G uideline 890.1500

+ Histopathological examination required based on G uideline 890.1500



## All organs except the thyroid/trachea and pituitary were weighed pri or to fixation. The paired kidneys and adrenals were weighed together. The seminal vesicle with coagulating glands was weighed. After each side was cut sagittally to allow removal of the fluid in the

lumen (blotted weight) , the seminal vesicle was weighed again.

Th e gross lesions, adrenals, dorsolateral prostate, kidney s, levator ani -bulbocavernosus muscle, liver, pituitary, seminal vesicle with coagulating glands, thyroid , and ventra l prostate were fixed in 10% phosphate-buffered formalin prior to embedding. After fixation, the thyroid was dissected from the trachea and weighed. All collected tissues were routinelyMale P ubertal Assay (2012) / Page 9 of 19

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## processed into paraffin blocks, sectioned, stained with hematoxylin and eosin, and examined microscopically.

The testes and epididymides were placed in Bouin’s fixative for 24–72 hours, rinsed with 50% ethanol, and stored in 70% ethanol prior to embedment in paraffin. For the qualitative assessment of the spermatogenesis stages, a cross

- section from the center of the testes was embedded in paraffin, and stained with PAS/hematoxylin. The histopathological examination of the testes included a qualitative assessment of the stages of spermatogenesis; a qualitative assessment of the relationships between spermatagonia, spermatocytes, spermatids, and spermatozoa seen in cross sections of the seminiferous tubules; and identification of any degenerative changes ( e.g., vacuolation of the germinal epithelium, a preponderance of Sertoli cells, sperm stasis, inflammatory changes, mineralization, and fibrosis). Examination of the intact epididymis included the caput, corpus, and cauda, accomplished by evaluation of a longitudinal section, and was conducted in order to identify such lesions as sperm granulomas, leukocytic infiltration (inflammation), aberrant cell types within the lumen, or the absence of clear cells in the cauda epididymal epithelium.

Two sections of each of the two lobes of the thyroid were examined and evaluated for follicular cell height and colloid area. A 5 -point grading scale (1 = shorte st/smallest; 5 = tallest/largest) was used, and the thyroids were evaluated relative to photomicrographs supplied by the U.S. EPA. Other histopathological findings were graded as very slight, slight, moderate, or severe.

For Study 1, the thyroid, right t estes , and right epididymis of the control and 25 mg/kg/day groups and the right and left kidneys from the control animals were processed for histopathology findings. For Study 2, right and left kidneys, right testes, and right epididymis of the control and 25 mg/kg/day groups were processed for histopathology findings. The thyroids from all dose groups were processed in Study 2.

II. RESULTS

A. MORTALITY : All animals survived until scheduled termination

.

B. CLINICAL SIGNS OF TOXICITY : No treatment

- related clinical signs of toxicity were observed in animals for any dose groups. At 25 mg/kg/day in Study 1, one animal had dermatitis (PND 53) and one animal had a muzzle laceration (PND 32 -34). These

observati ons were considered isolate d and not related to treatment

.

C. GENERAL GROWTH AND PREPUTIAL SEPARATION : Body weight, body weight gain, age of attainment of PPS, and weight at day of PPS are presented in Table s 2a and 2b for Study 1 and 2, respectively

.

In the 25 mg/kg/day group in Study 1, two animals did not achieve PPS, and b ody weight at

PND 23 w as increased by 11% compared to control. T erminal body weights were decreased by 7% , but were within the historical range , and b ody weight gain for PND 23 to

53 w as decreased by 11%. T he terminal body weights adjusted for liver weights were decreased by 7% , and body weight gains adjusted for liver weights were decreased (p<0.05) by 11%. The age at PPS was increased by 4.7 days compared to the control, and b odyMale P ubertal Assay (2012) / Page 10 of 19

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## weight at PPS was increased by 9 %. However, the data for age at PPS, and body weight at

PPS for Study 1 were not statistically analyzed.

In Study 2, no treatment- related effec ts were observed on body weight, body weight gain, or age and weight at PPS at any dose

.

The mean age at PPS, body weight at PPS, weanling weight, and final body weight in the control group were within the acceptable range of the performance criteria provided in the Guideline; however, the % CV for weight at PPS (Study 2) and final body weight s ( Studies 1 and 2) were outside the acceptable range, as follows: 8.47 % CV fo r weight at PPS in Study 2 (maximum 7.57%), 10.33% CV for final body weight in Study 1 (maximum 7.47%)

and 8.74 % CV for final body weight in S tudy 2 (maximum 7.47%).

TABLE 2a. Study 1 General Growth and Preputial Separation (PPS) a

Parameter Evaluated Vehicle Control Pronamide (25 mg/kg/day)

N Mean SD N Mean SD
Initial body weight (PND 23; g) U 15 50.5 8.4 15 56.1 (↑11) 5.2

Body weight at PPS (g) U 15 195.8 14.8 13 212.9 (↑9) 18.3

A 15 NR NR 13 NR NR

Final body weight (PND 53; g) U 15 273.1 28.2 15 254.9 (↓7) 29.3

A 15 NR NR 15 NR NR

L 15 273.1 27.0 15 254.4 (↓7) 27.4

Body weight gain (final

– initial; g) U 15 222.6 23.4 15 198.7 (↓11) 27.2

A 15 NR NR 15 NR NR

L 15 222.6 22.3 15 198.3* (↓11) 25.3

Age at PPS (PND) U 15 43.4 2.2 15 48.1 (↑11) 3.2

A 15 NR NR 15 NR NR

Proportion unseparated (#/N) 0/15 2/15

a Data were obtained from Table s 7, 9, 11, and 13 on pages 65, 67, 69, and 71 of the study report. No statistical analysis was performed. Percent differences from controls, calculated by the reviewers, are included in parentheses.

SD Standard deviation

U Unadjusted for body weight on PND 23

A Adjusted for body weight on PND 23

L Adjusted for liver weights

N Number of animals examined

NR Not reportedMale P ubertal Assay (2012) / Page 11 of 19

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### TABLE 2 b

. Study 2 General Growth and Preputial Separation (PPS) a

Parameter Evaluated Vehicle Control Pronamide ( 2.5 mg/kg/day) Pronamide ( 10 mg/kg/day) Pronamide ( 25 mg/kg/day)

N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%)
Initial body weight (PND 23; g) U 16 56.5 4.84 8.57 16 56.0 4.16 7.44 16 56.1 4.01 7.15 16 56.31 4.92 8.74

Body weight at PPS (g) U 16 201.6 17.1 8.47 16 198.8 10.7 5.38 16 198.1 20.0 10.1 16 204.7 15.7 7.68

A 16 201.2 3.66 NA 16 199.2 3.66 NA 16 198.3 3.66 NA 16 204.6 3.66 NA

Final body weight (PND 53; g) U 16 286.3 25.0 8.74 16 281.5 20.0 7.11 16 285.1 20.2 7.07 16 275.9 28.5 10.3

A 16 285.4 4.34 NA 16 282.4 4.34 NA 16 285.6 4.34 NA 16 275.5 4.34 NA

L 16 286.3 23. 6 NR 16 281.9 18.9 NR 16 284.7 19.0 NR 16 274.6 27.0 NR
Final body weight (% of control) U 16 NA NA NA 16 98.3 7.0 7.1 16 99.6 7.0 7.1 16 96.4 9.9 10.3

A 16 NA NA NA 16 NR NR NR 16 NR NR NR 16 NR NR NR

Body weight gain (final

– initial; g) U 16 229.9 21.2 9.21 16 225.6 18.0 7.96 16 229.0 18.5 8.07 16 219.6 25.1 11.4

A 16 NR NR NR 16 NR NR NR 16 NR NR NR 16 NR NR NR

L 16 229.9 19.7 NR 16 226.0 16.9 NR 16 228.6 17.3 NR 16 218.3 23.6 NR

Age at PPS (PND) U 16 43.2 1.3 3 16 43.1 1.5 3.4 16 43.2 1.6 3.6 16 44.3 1.7 3.8

A 16 43.2 0.32 NA 16 43.0 0.32 NA 16 43.2 0.32 NA 16 44.3 0.32 NA

Proportion unseparated (#/N) 0/16 0/16 0/16 0/16

a Data were obtained from Table s 12 and 14 on page s 70 and 72 of the study report.

b Standard deviation (SD) reported for unadjusted values and standard error of the mean (SE) reported for adjusted values.

U Unadjusted for body weight on PND 23

A Adjusted for body weight on PND 23

L Adjusted for liver weights

N Number of animals examined

CV Coefficient of Variation

NA Not applicable

NR Not reported



## D. ORGAN WEIGHTS : Organ weights at necropsy from Studies 1 and 2 are presented in

Table s 3 a and 3b , respectively.

In S tudy 1, organ weights were not statistically analyzed. However, r elative liver weight

was increased by 11 % and absolute pituitary weights were decreased by 14 % at 25 mg/kg/day . In addition, the absolute weight s of the seminal vesicle + coagulating glands (with and without fluid) were decreased by 38% and 26% , respectively . Absolute v entral

prostate , dorsolateral prostate, and LABC weights were also decreased by 25%, 23%, and 20%, respectively. Absolute weights for the left and right epididymides were decreased by 11% and 12%, respectively. Absolute thyroid weights were inc reased by 7%, but were within historical control range. There were no dose- related effec ts on the weights of kidneys, adrenals , or test es.

In S tudy 2, there were significant increases (p ≤ 0.05) in absolute, adjusted and relative liver weights (↑10 -14%) at 25 mg/kg/day. All liver weights at 2.5 and 10 mg/kg/day were similar to the control. Absolute and adjusted thyroid weights at 10 and 25 mg/kg/day wereincreased (NS) by 5 and 12%, respectively. There were no other significant, treatmentrelated effects on organ weights at any dose of pronamide. However, minor decreases of 4

- 6% (NS) were noted in four of the androgen sensitive tissues.

The unadjusted values for all organ weights in the control group were within the acceptable range of the performance criteria provided in the Guideline (890.1500) with the followingMale P ubertal Assay (2012) / Page 12 of 19

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## exceptions: (i) CV for seminal vesicles in Study 1 (32.78%; maximum 21.06 %) ; ( ii) mean thyroid weight in S tudy 1 (11.5 mg; acceptable range 14 -26 mg); (iii ) mean kidney weight in Study 1 (1.97 g; acceptable range 2.242-3.050 g); (iv) mean thyroid weight in Study 2 (11.3 mg; acceptable range 14 -26 mg); and (v) mean kidney weight in Study 2 (1.93 g; acceptable range 2.242 -3.050 g)

TABLE 3a. Study 1 Organ Weights at Necropsy a

Organ Vehicle Control Pronamide (25 mg/kg/day)

N Mean SD N Mean SD

Liver (g) U 15 12.19 1.33 15 12.63 2.06

R 15 4.46 0.23 15 4.93 (↑11) 0.31
Kidneys (g) U 15 1.97 0.22 15 1.92 0.23

R 15 0.72 0.04 15 0.75 0.02 Pituitary (mg) U 15 10.0 1.1 15 8.6 ( ↓ 14) 1.2

R 15 3.7 0.3 15 3.4 0.2

Adrenals (mg) U 15 45.0 5.1 15 42.4 6.3

R 15 16.5 1.7 15 16.8 2.6 Seminal vesicles + coagulating glands, with fluid (mg) U 15 467.3 153.2 15 288.6 (↓38) 102.0

Seminal vesicles + coagulating glands, without fluid (mg) U 15 222.8 54.8 15 165.1 (↓26) 48.5

Ventral prostate (mg) U 15 222.2 38.3 15 167.0 (↓25) 42.5
Dorsolateral prostate (mg) U 15 169.0 28.1 15 130.5 (↓23) 33.9

LABC (mg) U 15 487.0 74.5 15 388.0 (↓20) 85.5
Epididymis, left (mg) U 15 209.9 22.0 15 185.8 (↓11) 27.2 Epididymis, right (mg) U 15 216.1 25.4 15 189.8 (↓12) 26.7
Testis, left (mg) U 15 1435.9 172.8 15 1359.9 192.7 Testis, right (mg) U 15 1438.7 147.9 15 1356

. 2 192.9
Thyroid, fixed (mg) U 15 11.5 1.9 15 12.3 (↑7) 2.0

a Data were obtained from Table 17 on pages 78

- 79 of the study report

. Adjusted organ weights were not reported. No statistical analysis was performed. Percent differences from Text Tables 6

- 9 on pages 42

- 46 are included in parentheses. The pituitary percent difference was calculated by the reviewers.

SD Standard deviation

U Unadjusted for body weight on PND 23

R Organ

- to

- body weight ratio (relative to body weight , g/100g bodyweight )

N Number of animals examined



### TABLE 3 b

. Study 2 Organ Weights at Necropsy a

Organ Vehicle Control Pronamide ( 2.5 mg/kg/day) Pronamide ( 10 mg/kg/day) Pronamide ( 25 mg/kg/day)

N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%)

Liver (g) U 16 13.2 1.61 12.2 16 12.8 1.25 9.79 16 13.6 1.34 9.82 16 14.5* (↑ 10) 1.75 12.0

A 16 13.1 0.31 NA 16 12.9 0.31 NA 16 13.6 0.31 NA 16 14.5* (↑ 10) 0.3 1 NA

R 16 4.60 0.25 5.4 16 4.54 0.2 4.46 16 4.77 0.25 5.31 16 5.26* (↑ 14) 0.31 5.88

Kidneys (g) U 16 1.93 0.21 10.7 16 1.95 0.23 11.7 16 2.02 0.15 7.61 16 1.98 0.22 10.9

A 16 1.92 0.04 NA 16 1.96 0.04 NA 16 2.02 0.04 NA 16 1.98 0.04 NA

R 16 0.67 0.03 4.86 16 0.69 0.05 7.39 16 0.71 0.05 7.4 16 0.72 0.06 7.73 Pituitary (mg) U 16 10.1 0.7 7.4 16 10.0 1.3 13.3 16 9.5 0.7 7.8 16 9.7 1.5 15.1

A 16 10.1 0.27 NA 16 10.0 0.27 NA 16 9.5 0.27 NA 16 9.7 0.27 NA

R 16 3.6 0.4 10.1 16 3.5 0.4 11.4 16 3.4 0.3 8.8 16 3.5 0.3 9.5Male P ubertal Assay (2012) / Page 13 of 19

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### TABLE 3 b

. Study 2 Organ Weights at Necropsy a

Organ Vehicle Control Pronamide ( 2.5 mg/kg/day) Pronamide ( 10 mg/kg/day) Pronamide ( 25 mg/kg/day)

N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%) N Mean SD/

SE b CV (%)

Adrenals (mg) U 16 43.3 6.1 14.2 16 40.7 9.3 22.8 16 42.8 7.3 17.2 16 42.0 5.9 14.1

A 16 43.2 1.83 NA 16 40.8 1.83 NA 16 42.8 1.83 NA 16 42.0 1.83 NA

R 16 15.1 2.1 13.6 16 14.4 3 20.5 16 15 2.2 14.7 16 15.3 2.3 15

Seminal vesicles + coagulating glands, with fluid (mg) U 16 625.7 91.5 14.6 16 627.6 136 21.6 16 604.8 121 19.9 16 599.9 (↓4) 161 26.8

A 16 623.3 31.0 NA 16 629.8 31.0 NA 16 606.0 31.0 NA 16 598.9 31.0 NA

Seminal vesicles + coagulating glands, without fluid (mg) U 16 342 70.2 20.5 16 333.7 56.2 16.8 15 319.6 49.6 15.5 16 319.9 (↓6) 64.1 20

A 16 341.8 15.3 NA 16 334.1 15.3 NA 1 5 319.5 15.7 NA 16 319.9 15.2 NA Ventral prostate (mg) U 16 227.9 38.6 16.9 16 220.7 39.3 17.8 16 212.7 29.5 13.9 16 213.1 (↓6) 45.9 21.6

A 16 227.2 9.32 NA 16 221.4 9.32 NA 16 213.0 9.31 NA 16 212.8 9.31 NA
Dorsolateral prostate (mg) U 16 154 24.1 15.6 16 157.2 30.2 19.2 16 144.7 27.3 18.9 16 147 (↓5) 33.6 22.8

A 16 153.1 6.27 NA 16 158.0 6.27 NA 16 145.2 6.27 NA 16 146.6 6.27 NA

LABC (mg) U 16 517.8 50.5 9.8 16 536.7 70.9 13.2 16 512.5 59.3 11.6 16 497.7 (↓4) 100 20.1

A 16 515.6 15.7 NA 16 538.7 15.7 NA 16 513.6 15.7 NA 16 496.8 15.7 NA Epididymis, left (mg) U 16 211.9 16.8 7.9 16 212.5 27.2 12.8 1 5 217.6 17.1 7.8 16 211.4 19.3 9.2

A 16 211.6 5.04 NA 16 212.8 5.04 NA 1 5 217.6 5.20 NA 16 211.3 5.04 NA
Epididymis, right (mg) U 16 212.1 20.6 9.7 16 217.8 28.4 13.0 16 218.2 15.2 7 16 204 21.4 10.5

A 16 211.7 5.30 NA 16 218.1 5.30 NA 16 218.4 5.29 NA 16 203.8 5.29 NA
Testis, left (mg) U 16 1429 87.6 6.1 16 1443 74.9 5.2 16 1449 122.3 8.4 1 5 1415 106.4 7.5

A 16 1426 24.4 NA 16 1443 24.4 NA 16 1448 24.4 NA 1 5 1418 25.3 NA
Testis, right (mg) U 16 1453 130 8.9 16 1465 93.2 6.4 16 1457 109.5 7.5 16 1427 97.2 6.8

A 16 1450 26.0 NA 16 1467 26.0 NA 16 1458 26.0 NA 16 1426 26.0 NA Thyroid, fixed (mg) U 16 11.3 2 17.3 16 11.3 1.9 16.5 16 11.9 (↑5) 1.8 15.1 16 12.6 (↑12) 2.1 16.2

A 16 11.3 0.48 NA 16 11.3 0.48 NA 16 11.9 (↑5) 0.48 NA 16 12.6 (↑12) 0.48 NA

a Data were obtained from Table 18 on page s 80 -82 of the study report . Percent differences from Text Tables 6 and 9 on pages 42 and 46 are included in parentheses.

b Standard deviation (SD) reported for unadjusted values and standard error of the mean (SE) reported for adjusted values.

U Unadjusted for body weight on PND 2 3

A Adjusted for body weight on PND 2 3

R Organ

- to

- body weight r atio (relative to body weight)

N Number of animals examined

NA Not applicable

CV Coefficient of Variation

* Significantly different from controls at p ≤ 0.05.



## E. CLINICAL CHEMISTRY AND HORMONE LEVELS : Mean hormone and c linical chemistry concentration s for Studies 1 and 2 are presented in Table s 4a and 4b , respectively.

In Study 1, data for hormone and clinical chemistry concentrations were not statistically analyzed . Serum testosterone at 25 mg/kg/day was increased by 86% ; however, the control testosterone value was atypically low compared to the historical contro l range, and the difference was reported as incidental. At 25 mg/kg/day, T 4 

## was decreased by 32% and TSH was increased by 46%. No clinical chemistry changes were observed

, except for a 14%

decrease in cholesterol at 25 mg/kg/day.Male P ubertal Assay (2012) / Page 14 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## In Study 2, no dose-dependent treatment effects were observed on serum testosterone.
However, s erum T 4 

## concentrations in the 10 and 25 mg/kg/day dose groups were significantly decreased (p ≤ 0.05) by 13 and 23%, respectively , and s erum TSH was increased by 25% (NS) and 62% (p≤0.05) at 10 and 25 mg/kg/day, respectively. At 25 mg/kg/day,

albumin was increased (p ≤ 0.05) by 5% and cholesterol was decreased (p ≤ 0.05) by 15%. No

dose- related effects were observed f or the other measured clinical chemistry parameters.

Historical control values were not provided for either the hormone or clinical chemistry

parameters.

The mean serum T 4 

## and TSH in the control group were within the acceptable range of the performance criteria provided in the Guideline; however, the mean testosterone (Study 2)

was 4.368 ng/mL was outside the acceptable range (0.260-3.96 ng/mL) and the 74.14% CV for TSH ( S tudy 1) was outside the accept able range (maximum 58.29%).

TABLE 4 a

. Study 1 Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control Pronamide (25 mg/kg/day)

N Mean SD N Mean SD

Hormones

Serum T 4 , Total (μg/dL) 15 5.40 0.441 15 3.65 (↓32) 0.474

Serum TSH (ng/mL) 15 9.09 6.74 15 13.26 (↑46) 5.48

Serum testosterone (ng/mL) 15 2.47 1.10 15 4.59 (↑86) 3.89
Clinical Chemistry Urea nitrogen (mg/dL) 15 15 2 15 14 2
ALT (U/L) 15 54 8 15 55 7
ALP (U/L) 15 286 46 15 293 56
AST (U/L) 15 86 9 15 92 13

Total protein (g/dL) 15 5.4 0.1 15 5.3 0.2 Albumin (g/dL) 15 3.8 0.1 15 3.9 0.1
Globulin (g/dL) 15 1.6 0.1 15 1.4 0.2 Albumin/ globulin ratio 15 2.4 0.3 15 2.8 0.3 Cholesterol (mg/dL) 15 88 15 15 76 (↓14 ) 16
Total bilirubin (mg/dL) 15 0.05 0.00 15 0.05 0.00 Creatinine (μmol/L) 15 0.1 0.0 15 0.1 0.0
GGT (U/L) 15 1.5 0.0 15 1.5 0.0 Calcium (mg/dL) 15 11.1 0.2 15 10.9 0.3
Phosphorus (mg/dL) 15 8.7 0.7 15 8.6 0.6
Sodium (mmol/L) 15 143 2 15 144 1
Potassium (mmol/L) 15 5.4 0.2 15 5.3 0.4
Chloride (mmol/L) 15 102 1 15 103 1

a Data were obtained from Table 15 on page s 73

- 75 of the study report. No statistical analysis was performed. Percent differences from controls, calculated by the reviewers, are included in parentheses.

N Number of animals examined

SD Standard Deviation

CV Coefficient of VariationMale P ubertal Assay (2012) / Page 15 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



### TABLE 4b. Study 2 Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control Pronamide ( 2.5 mg/kg/day) Pronamide ( 1 0 mg/kg/day) Pronamide (25 mg/kg/day)

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Hormones

Serum T 4 , Total (μg/dL) 16 5.04 0.479 9.51 16 4.95 0.653 13.2 16 4.36* (↓ 13) 0.656 15.0 16 3.86* (↓ 23) 0.414 10.7

Serum TSH (ng/mL) 16 10.6 4.07 38.3 16 10.8 4.51 41.7 16 13.2 (↑25) b 6.67 50.5 16 17.2* (↑ 62) 7.73 45.0

Serum testosterone (ng/mL) 16 4.37 2.13 48.9 16 3.4 1.70 50.0 16 4.16 2.32 56.0 16 4.86 2.30 47.3

Clinical Chemistry

Creatinine (μmol/L) 16 0.2 0 0 16 0.2 0 0 16 0.2 0 22.8 16 0.2 0 22.2

Serum urea nitrogen (mg/dL) 16 16 2 11 16 14 2 12 16 15 2 14 16 15 2 12

Alkaline phosphatase (μ/L) 16 325 49 15 16 314 57 18 16 317 45 14 16 300 49 16

ALT (μ/L) 16 47 7 15 16 48 6 12 16 51 9 17 16 52 8 15
AST (μ/L) 16 104 17 16 16 108 15 14 16 108 19 17 16 108 14 13
GGT (μ/L) 16 1.5 0 0 16 1.5 0 0 16 1.5 0 0 16 1.5 0 0

Albumin (g/dL) 16 4 0.2 3.8 16 4 0.1 3.2 16 4.1 0.2 4.4 16 4.2* (↑ 5) 0.1 3.1

A/G Ratio 16 2.7 0.3 10.9 16 2.8 0.3 9.9 16 3.1 0.4 12.2 16 3.4 0.5 13.5

Cholesterol (mg/dL) 16 88 11 12 16 88 11 13 16 84 14 16 16 75* (↓ 15 ) 12 16

Globulin (g/dL) 16 1.5 0.1 9.9 16 1.5 0.1 8.3 16 1.3 0.1 10.1 16 1.3 0.2 12.6

Total bilirubin (mg/dL) 16 0.05 0 0 16 0.05 0 0 16 0.05 0 0 16 0.05 0 0

Total protein (g/dL) 16 5.5 0.2 4.1 16 5.5 0.2 3.1 16 5.4 0.2 3.4 16 5.5 0.2 3.9

Sodium (mmol/L) 16 145 1 1 16 145 1 1 16 145 2 1 16 145 1 1

Potassium (mmol/L) 16 5.3 0.3 6.1 16 5.2 0.3 5.3 16 5.3 0.3 6.1 16 5.2 0.4 8.5

Chloride (mmol/L) 16 99 1 1 16 100 1 1 16 100 1 1 16 100 1 1

Calcium (mg/dL) 16 11.4 0.3 2.6 16 11.3 0.3 2.8 16 11.5 0.3 2.5 16 11.2 0.2 2.1 Phosphorus (mg/dL) 16 8.8 0.7 7.4 16 8.9 0.5 5.8 16 9.2 0.8 8.2 16 8.8 0.5 5.5

a Data were obtained from Table 16 on pages 76 and 77 of the study report. Percent differences from controls, calculated by the reviewers, are included in parentheses.

b Not significant

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p ≤ 0.05.



## F. GROSS PATHOLOGY : No treatment -related effects were observed on gross pathology. Diagnoses of inflammation in the neck (one animal, Study 1, 25 mg/kg/day) and hiatal hernia (one animal, Study 1, 25 mg/kg/day, and three animals, Study 2, 2.5, 10 and 25 mg/kg/day) were considered to be unassociated with exposure.

G. HISTOPATHOLOGY : The incidences of h istopathological findings of the thyroid gland

for Studies 1 and 2 are presented below in Table 5. In Study 1, no significant treatment

related changes in thyroid histopathology were observed

. In Study 2, there was a slightly higher incidence of taller follicular epithelial cells ( Grade 4) with corresponding smallerMale P ubertal Assay (2012) / Page 16 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## colloid areas ( Grade 2) in the 25 mg/kg/day group compared to the controls (5 to 1, respectively, for each comparison ).

TABLE 5. Thyroid Gland Follicular Cell Height and Colloid Area a



### Treatment Groups Parameter Evaluated

Colloid Area Follicular Cell Height

Grade b 

### Incidence Grade Incidence

Observed Examined Observed Examined

Study 1

Vehicle Control 1 0 15 1 0 15

2 1 15 2 10 15

3 4 15 3 4 15

4 10 15 4 1 15

5 0 15 5 0 15

Pronamide (25 mg/kg/day) 1 0 15 1 1 15

2 1 15 2 9 15

3 4 15 3 4 15

4 9 15 4 1 15

5 1 15 5 0 15

Study 2

Vehicle Control 1 0 16 1 0 16

2 1 16 2 9 16

3 6 16 3 6 16

4 9 16 4 1 16

5 0 16 5 0 16

Pronamide (2.5 mg/kg/day) 1 0 16 1 0 16

2 1 16 2 12 16

3 3 16 3 3 16

4 12 16 4 1 16

5 0 16 5 0 16

Pronamide (10 mg/kg/day) 1 0 16 1 1 16

2 2 16 2 8 16

3 5 16 3 5 16

4 8 16 4 2 16

5 1 16 5 0 16

Pronamide (25 mg/kg/day) 1 0 16 1 0 16

2 5 16 2 7 16

3 4 16 3 4 16

4 7 16 4 5 16

5 0 16 5 0 16

a Data were obtained from Table s 21 and 22 on page s 93 and 94 of the study report.

b Thy roid histopathology is graded 1

– 5. Follicular cell height: 1 = lowest, 5 = highest; and Colloid area: 1 = most colloid, 5 =

least colloid.



## The incidence of histopathological findings of the testes, epididymides and kidneys for Studies 1 and 2 are presented in Table 6. No treatment

- related findings were observed in the right testes

, right epididymides , or kidneys at any pronamide dose.

Immature spermatic elements were noted in the right epididymis for both studies; however,

these effects were not dose -dependent and are consistent with the juvenile age of the

animals.Male P ubertal Assay (2012) / Page 17 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



### TABLE 6. Incidence of Histopathological Lesions of the Testes, Epididymides and Kidney a

Findings Dose Level (mg/kg/day)

Vehicle Control Pronamide (25)

# Observed # Examined # Observed # Examined

Study 1

Testes

Within Normal Limits 15 15 15 15
Epididymides

Within Normal Limits 0 15 0 15
Decreased spermatic elements, slight 0 15 2 15
Immature spermatic elements, very slight 15 15 14 15

Immature spermatic elements, slight 0 15 1 15

Study 2

Testes

Within Normal Limits 16 16 15 16
Degeneration, seminiferous tubule, multifocal, very slight 0 16 1 16

Multinucleated spermatids, s eminiferous tubule, focal, very slight 0 16 1 16

Epididymides

Within Normal Limits 0 16 0 16
Aggregates of mononuclear cells, focal, very slight 1 16 0 16
Immature spermatic elements, very slight 16 16 16 16
Kidney

Within Normal Limits 1 16 1 16 Cyst, cortex, unilateral 1 16 1 16 Cyst, medulla, unilateral 1 16 2 16 Degeneration, tubule, focal, very slight 14 16 15 16
Dilatation, tubule, focal, very slight 3 16 2 16 Dilatation, tubule, multifocal, very slight 1 16 0 16
Inflammation, subacute to chronic, interstitum; focal, very slight 6 16 5 16

Inflammation, subacute to chronic, interstitum; multifocal, very slight 4 16 1 16

a Data were obtained f rom Tables 23 and 24 on page s 95

- 97 of the study report.



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : There was an indication of potential antiandrogenic effects at 25 mg/kg/day pronamide in Study 1 (delayed age and increased body weight at PPS , and decreased weight of androgen- sensitive tissues and epididymal weights), which was not reproducible in Study 2. Decreases in body weight and body weight gain also were seen in Study 1, but not in Study 2. In Study 2, there was evidence of potential thyroid perturbations at 25 mg/kg/day, including decreased T 4 

## , incre ased TSH and thyroid histopathology. Although consistent changes in thyroid hormones (T 4 

## and TSH) were seen in Study 1, there was no associated thyroid histopathology, thereby indicating a lack of sustained changes in thyroid function. In addition, previous pronamide mode-ofaction studies have shown hepatic enzyme induction and enhanced testosterone metabolism and thyroxine metabolism/clearance, which support an indirect mode- of

- action for effects on androgen and thyroid-sensitive endpoints. There were no effects on androgen- or thyroid -sensitive endpoints at pronamide doses <10 mg/kg/day.Male P ubertal Assay (2012) / Page 18 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## B. AGENCY COMMENTS : All animals survi ved until scheduled termination. No

treatment -related clinical signs of toxicity were observed in animals for any dose groups. During Study 1, t erminal body weights were significantly decreased by 11 -12% for the 100

and 300 mg/kg/day pronamide dose groups. Therefore, a repeated male pubertal development al assay was conducted with pronamide at 0, 2.5, 10, and 25 mg/kg/day (Study 2). The data from the 25 mg/kg/day group from Study 1 were reported f or com parison with data from Study 2; however, detailed data from the 100 and 300 mg/kg/day groups was not reported.

In the 25 mg/kg/day group from Study 1, two animals did not achieve P PS. Terminal body weights for this group were decreased by 7% , compared to control, but were within the historical range , and body weight gains for PND 23 to 53 were decreased by 11%. When adjusted for liver weight, the terminal body weights and body weight gains were decreased by 7 and 11% (p<0.05), respectively . The age at PPS was delayed by 4.7 days, compared to

the control, and is considered treatment

- related and biologically relevant as b ody weight at PPS was increased by 9% in the 25 mg/kg/day group compared to the control. Relative liver weight was increased by 11% and absolute pituitary weights were decreased by 14%. Although statistical analyses were not report, decreases of 11 to 38% were observed in the absolute weigh ts of the seminal vesicle + coagulating glands (with and without fluid), absolute ventral prostate, dorsolateral prostate, and LABC, and absolute left and right epididymides

. Absolute t hyroid weights were increased by 7%, but were within historical

contro l ran ge , and the effect was not considered treatment related. There were no dose

related effects on the weights of kidneys, adrenals, or testis. Serum testosterone in the

25 mg/kg/day animals was increased by 86% compared to the control; however, the con trol testosterone value was atypically low compared to the historical control range. Mean T 4 

## was decreased by 32% and mean TSH was increased by 46%. No clinical chemistry parameters were affected

, except for mean cholesterol th at was decreased by 14%. No

treatment -related changes in histopathology for thyroid, right testes, right epididymides, or kidneys were observed in the 25 mg/kg/day group.

In Study 2, no treatment-related effects were observed on body weight, body weight gain, or age and weight at PPS at any dose of pronamide. S ignificant increases (p ≤ 0.05) were observed in absolute, adjusted and relative liver weights (↑10

- 14%) in the 25 mg/kg/day

group . All liver weights at pronamide doses of 2.5 and 10 mg/kg/day were similar to control. Absolute and adjusted thyroid weights at 10 and 25 mg/kg/day were increased (NS) by 5 and 12%, respectively. There were no other significant, treatment- related effects on organ weights at any dose of pronamide. However, minor decreases of 4

- 6% (NS) werenoted in four of the androgen sensitive tissues in the 25 mg/kg/day group. No dosedependent treatment effects were observed on serum testosterone. Mean serum T 4 

## concentrations in the 10 and 25 mg/kg/day dose groups were decreased (p ≤ 0.05) by 13 and 23%, resp ectively

, and mean serum TSH in the 25 mg/kg/day group was increased (p ≤ 0.05) by 62%. For t hyroid histopathology, there was a slightly higher incidence of taller follicular epithelial cells ( Grade 4) with corresponding smaller colloid areas (G rade 2) in the 25 mg/kg/day group compared to control (5 to 1, respectively). Also at 25 mg/kg/day

, albumin was increased (p ≤ 0.05) by 5% and cholesterol was decreased (p ≤ 0.05) by 15%. No

dose- related effects were observed for the other measured clinical chemistry parameters. No significant treatment

- related changes were observed in the histopathology for the right testes, right epididymides, or kidneys.Male P ubertal Assay (2012) / Page 19 of 19

PRONAMIDE / 101701 O CSPP 89 0. 1 500 / OECD None



## The effects observed in both studies on T 4 

## and TSH levels , and thyroid histopathology in Study 2, indicate a change in thyroid function in response to treatment with pronamide at
25 mg/kg/day . Although the 25 mg/kg/day dose group in Study 2 did not reproduce the effects on age and body weight at PPS, or accessory sex tissue weights observed in the 25 mg/kg/day group from Study 1

, the liver weight changes at 25 mg/kg/day were consistent

between both studies. The reviewers agree with the study investigator conclusion that despite the poor reproducibility between the first and second male pubertal study regarding

t he effects observed in the 25 mg/kg/day animals, the findings should be considered.

Based on the >10% decreased in terminal body weight at 100 mg/kg/day in Study 1 and the ≥10% increase in liver weight at 25 mg/kg/day in Study 2

, an adequate dose for testing was

reached at 25 mg/kg/day.

C. STUDY DEFICIENCIES : The following deficiencies were noted that are not considered

to have had an adverse impact on the results, interpretation or conclusions of this study:

• Total genistein -equivalent content of the laboratory diet (Teklad Diet #2016) was reported as <325 μ g/g; Guideline states that the content should be ≤ 300 μ g/g.

• A 12:12 hour light:dark photoperiod was used instead of a 14:10 hour period.

• A CoA for pronamide was not included in the study report.

• Control CV for Study 2 body weight at PPS (8.47% ) exceeded the performance criteria (maximum 7.57%)

• Control C V for Study 1 final body weight (10.33% ) exceeded the performance criteria (maximum 7.47%)

• Control CV for S tudy 2 final body weight (8.74% ) exceeded the performance criteria (maximum 7.47%)

• Control CV for Study 1 seminal vesicles (32.78% ) exceeded the performance criteria (maximum 21.06%)

• Control m ean for Study 1 thyroid weight (11.5 mg ) was below the performance criteria (acceptable range 14

- 26 mg)

• Control m ean for Study 2 thyroid weight (11.3 mg ) was below the performance criteria (acceptable range 14

- 26 mg)

• Control m ean for Study 1 kidney weight ( 1.97 g ) was below the performance criteria (acceptable range 2.242-3.050 g)

• Control m ean for Study 2 kidney weight ( 1.93 g ) was below the performance criteria (acceptable range 2.242 -3.050 g)

• Control CV for Study 1 TSH (74.17% ) exceeded the performance criteria (maximum

58.29 %)

• Control m ean for Study 2 testo sterone (4.368 ng/mL ) exceeded the performance criteria ( maximum 3.96 ng/mL).

# DATA EVALUATION RECORD

PRONAMIDE (PROPYZAMIDE )

Study Type: O CSPP 890.1550, Steroidogenesis Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619107)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer : Signature:
Ronnie J. Bever Jr., Ph.D., D.A.B.T. Date: 2 / 16 /201 2

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 2 / 28 /201 2

Program Manager: Signature: Jack D. Early, M.S. Date: 3 / 02 /201 2

Quality Assurance: Signature: Jack D. Early, M.S. Date: 3 / 02 /201 2

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS -Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 battery is based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with

the E , A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE I 101701



## Primary Reviewer: =Kh=in;;:......::0--=o'""--"-'M"""'.=D;...:..

_______ _ 

## Health Effects Division Secondary Reviewer: John Liccione, Ph

. D.



## Health Effects Division Steroidogenesis Assay (2011) I Page I of 13

OCSPP 890.1550/ OECD None



## Signature: ---"-=-"------ 

## Date:**~'-j;:~-'-4----=-"-='"---** 

## S i gnat u re:**--,,,;,.p;-_~--....,c--** 

## Da te:**----¥+-=-"-#~'---**



## DATA EVALUATION RECORD

STUDY TYPE: Steroidogenesis Assay (H295R Cells); OCSPP 890.1550



## PC CODE: 101701 

## DP BARCODE: D398506



## TXR#: 0056255 

## CAS No.: 23950-58-5



## TEST MATERIAL (PURITY): Pronamide (96.2% a.i.)



## SYNONYMS: 3

, 5-dichloro-N-(1

, l-dimethyl-2-propynyl)benzamide; Propyzamide



## CITATION: LeBaron

, M.J. ; Kan

, H.L; Perala

, A.W

. (2011) Evaluation ofpronamide in

the 

## in vitro steroidogenesis assay

. Toxicology & 

## Environmental Research

and Consulting, The Dow Chemical Company

, Midland, Ml. Laboratory StudyNo.: 101181

, December20

, 2011. MRID48619107

. Unpublished.



## SPONSOR: Dow AgroSciences LLC

, 9330 Zionsville Road

, Indianapolis

, IN



## TESTORDER#: CON-101701-37



## EXECUTIVE SUMMARY: In a steroidogenesis assay (MRID 48619107)

, H295R cells

cultured 

## in vitro in 24-well plates were incubated with pronamide (96.2% purity

, Lot#

XG 1088R301) at serial log concentrations of 10

- 1 0 

## to 10

- 4 

## M for 48 hours in triplicate for three
independent experiments

. Dimethyl sulfoxide (DMSO) was used as the vehicle

, at a final

concentration in the assay of 0.1 %.

Testosterone and estradiol levels were measured using LC-APPi-MS/MS. A Quality Control
(QC) plate was run concurrently with each independent run of a test chemical plate to

demonstrate that the assa y responded properly to positive control agents at two concentration

levels. The positive controls included a known inhibitor (prochloraz) and a known inducer
(forskolin) of estradiol and testosterone production.

Guideline acceptability recommendations and requirements were generally met

, including adequate production of testosterone and estradiol, acceptable reproducibility (low %CV), and appropriate induction and inhibition with positive controls

. Departures from the Guideline

included : (i) the required concentration for estradiol (25 pg / mL) was not met in in Run 1 for the

solvent control (SC) well (22.1

- 24.3 pg / mL); (ii) two runs were slightly outside the criteria for prochloraz inhibition of estradiol production (0

. 6-fold vs 0.5-fold); and (iii) the between plate

CV in the SC was 33

. 5% for testosterone

, rather than ::; 30%. As the positive controls approximated the expected responses on both testosterone and estradiol concentrations, theseSteroidogenesis Assay ( 2011 ) / Page 2 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## departures from Guideline recommendations were considered minor and were not expected to affect the scientific integrity of these studie s.

Precipitation of pronamide and cyto toxicity w ere not reported at any concentration. No effect

was observed on testosterone concentration s. Decreases (p≤0.05) of 20% in testosterone levels

relative to DMSO

- treated cells were observed in Run 2 at the lowest concentration and in Run 5 at 1 μM. These effects were neither concentration -dependent nor reproducible.

A treatment

- related effect was observed on estradiol concentration s. A decrease (p≤0.05) of 10% was noted at 1 μM in one run, but this effect was neither concentration-dependent nor reproducible. However, reproducible increases (p≤0.05) were noted at the highest concentration (100 μM), with estradiol concentrations increased 1.2-, 1.4-, and 1.9-fold that observed in the

DMSO t reated cells in the three runs.

Based on the hormone responses in each of the three independent runs, pronamide treatment resulted in statistically significant and reproducible increases in estradiol production. Pronamide treatment did not result in statistically significant and reproducible alterations in testosterone production.

Th e assay satisfies the EDSP Tier 1 Test Order requirement s for a Steroidogenesis Assay (OCSPP 890.1550).

COMPLIANCE : Signed and dated GLP Compliance, Quality Assurance, and Data Confidentiality statements were provided.Steroidogenesis Assay ( 2011 ) / Page 3 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology & Environmental Research and Consulting

Location: Midland, MI Study Director: H. L. Kan

Other Personnel: M. J. LeBaron, lead scientist A. W. Perala, analytical chemist B. B. Gollapudi, technical reviewer Study Period: Not provided



## 2

. Test S ubstance : Pronamide

Description: White to off

- white powder

Lot # (expiration date): XG1088R301 (not provided) Purity: 9 6.2 % Solubility: Soluble in DMSO up to 0.1 M; insoluble in water
Vapor pressure : 4.97 Pa Stability: 2 year shelf life Storage conditions: Ambient

CAS #: 23950

- 58

- 5 Molecular weight: 256.1

Structure:



## 3

. Positive C ontrol : Forskolin

Description (molecular weight) : White powder (410.50)

Source: Sigma

- Aldrich (St. Louis, MO)

Batch # ( expiration d ate) : 097K50653 ( not provided ) Purity: 99 % Solubility (in s olvent): Soluble in DMSO up to 0.01 M Storage conditions: Ambient

CAS #: 66575

- 29

- 9



## 4. Negative C ontrol : Prochloraz

Description (molecular weight): Off

- w hite powder (376.67)

Source: Sigma

- Aldrich (St. Louis, MO)

Batch # (expiration date): SZE 6220X ( not provided ) Purity: 99.1 % Solubility (in solvent): Soluble in DMSO up to 0.01 M Storage conditions: Ambient

CAS #: 6 7747

- 09

- 5Steroidogenesis Assay ( 2011 ) / Page 4 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## 5

. Solvent/ V ehicle C ontrol : Dimethyl Sulfoxide ( DMSO )

Description (molecular weight) : Clear liquid (78.13)

Source: Sigma

- Aldrich (St. Louis, MO)

Lot # (expiration date): 38096HK and 108K0186 ( n ot provided ) Purity: >99 .9 % Storage conditions: Ambient

CAS #: 67

- 68

- 5

Justification for choice of

solvent: Not provided. DMSO is a Guideline recommended solvent in which pronamide is reasonably soluble

. Final concentration in assay : 0.1 % v/v



## 6

. Stock Medium : Dulbecco’s modified Eagle’s medium/ Ham’s F12 nutrient

mixture

Source: Sigma

- Aldrich ( St. Louis, MO )

Lot # (expiration date): RNBB 0035 ( not provided )

Sodium bicarbonate : C omponent of stock medium

Nu

- Serum : 2.5%, BD Biosciences ; L ot # 81515 ; t ested for background hormone concentrations by performing laboratory

ITS+ premix: BD Biosciences; Lot # 75382 Other components: 2.5 mM L

- glutamine (Life Technologies, GIBCO, Grand Island, New York), and penicillin/streptomycin (25 IU/m L /25 μ g/m L ) (GIBCO).



## 7. Test Cells : H295R human adrenocortical carcinoma cells (ATCC CLR -2128; Batch # not provided) at passage 5.5 – 7.5 were incubated in the stock medium. Incubation conditions were at approximately 37 °C with 5% CO 2 

## for approximately 24 hours prior to exposure.

The following performance criteria were met (indicated by an “x”):

X Cell passage identifier . Cell Passage # : 5 .5

– 7 .5

X Cells frozen down at passage 5

X Frozen cells cultured for 4 additional passages

X Total number of passages does not exceed 10



## B. METHODS

1. Pre -T est Information

a. Hormone Assay Interference Test : A separate chemical interference assay was not performed, as LC/APPI -MS/MS was used along with internal spike-in controls to measure extraction and quantitation efficiency.

b. Hormone Extraction : Briefly, s tandards and samples were vortexed with methylene chloride containing both testosterone and estradiol internal standards, and the resulting organic phases w ere transferred to clean vials. The aliquots were evaporated to dryness, and

the final residue in each vial was deriva tized with dansyl chloride. Samples were subjected

to LC/APPI

- MS/MS analysis.Steroidogenesis Assay ( 2011 ) / Page 5 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## c. Laboratory Proficiency Test : The Sponsor stated that Laboratory proficiency assays were performed to optimize and validate the H295R steroidogenesis assay. These non- GLP, unpublished experimental results with positive control chemicals demonstrated laboratory proficiency and validation and are reported separately (data not presented and report not cited).

2. Test Solutions : Pronamide, forskolin, and prochloraz w ere dissolved in DMSO and diluted

1 :1000 in the final treatment medium. When added to the cell culture plates, these dilutions yie lded final concentrations of 1 μM and 10 μM for forskolin, 0.1 μM and 1 μ M for prochloraz, and 10

− 4 

## , 10

− 5 

## , 10

− 6 

## , 10

− 7 

## , 10

− 8 

## , 10

− 9 

## , and 10

− 10 

## M for pronamide. The selected concentrations of the test material in the dosing solutions used for the treatment in a definitive assay (generally the first assay) were verified analytically. The f inal

concentration of DMSO in the medium was held constant at 0.1 % (v/v).

3. Cell Plating and P reincubation : Cells were maintained in the stock medium described

above. The hormone concentrations in undiluted Nu- Serum were 974 p g/mL for testosterone and 681 pg/mL for estradiol. H295R cells were grown for five passages, frozen in liquid nitrogen, then thawed and cultured for five to seven additional passages prior to use in the assay. The cells were plated into wells of a 24

- well cell culture plate at a density of approximately 200,000 – 300,000 cells in 1 mL (50 – 60% confluency). The cells were then placed into an incubator (approximately 37 °C /5% CO 2 

## ) for approximately 24 hours prior to chemical exposure. After a 24 -hour pre- incubation, the cells were checked microscopically for good attachment and proper morphology.

4. Exposure : The medium was removed from the cells and replaced with 1 mL of medium containing concentrations of pronamide (or solvent) in triplicate, according to the schematic presented in Table 1.

TABLE 1

. Dosing Schematic for the Exposure of H295R Cells to Pronamide (Final Concentrations in M). a

1 2 3 4 5 6

A DMSO DMSO DMSO 10

− 7 10

− 7 10

− 7

B 10

− 4 10

− 4 10

− 4 10

− 8 10

− 8 10

− 8

C 10

− 5 10

− 5 10

− 5 10

− 9 10

− 9 10

− 9

D 10

− 6 10

− 6 10

− 6 10

− 10 10

− 10 10

− 10

a Data were obtained from page s 1 7 and 18 of the study report.



## A concurrent QC plate was included with each of the three independent runs of the test chemical plates to demonstrate the assay’s response to forskolin (an inducer of testosterone and estradiol production) and prochloraz (an inhibitor of testosterone and estradiol production). The QC plate was prepared and dosed in the same manner with either forskolin or prochloraz, according to the schematic presented in Table 2.Steroidogenesis Assay ( 2011 ) / Page 6 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None

TABLE 2

. Dosing S chematic for the QC P late for P ositive C ontrols ( F inal C oncentrations in μM). a

1 2 3 4 5 6

A Blank b Blank Blank Blank + methanol c Blank + methanol Blank + methanol

B DMSO DMSO DMSO DMSO + methanol DMSO + methanol DMSO + methanol

C Forskolin 1 μM Forskolin 1 μM Forskolin 1 μM Prochloraz 0.1 μM Prochloraz 0.1 μM Prochloraz 0.1 μM

D Forskolin 10 μM Forskolin 10 μM Forskolin 10 μM Prochloraz 1 μM Prochloraz 1 μM Prochloraz 1 μM

a Data were obtained from page 1 6 of the study report.

b Blank wells received medium only.

c Methanol (MeOH) was added after the exposure was terminated and the medium was removed.



## Following dosing, the plates were incubated for approximately 48 hours under the conditions previously described. After the incubation period, t wo aliquots of medium were

collected and frozen at

− 80°C until further processing.

5. Cell V iability/ Cytotoxicity A ssay : The cell viability/cytotoxicity testing was conducted in the QC plate and in the test chemical exposure plate immediately after termination of the exposure experiments. In addition to viability/cytotoxicity testing, cells were checked for the degree of confluence, homogeneity from well- to -well, and any signs of cytotoxicity or altered morphology. A subjective parallel visual assessment of each well was conducted. The CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Madison Wisconsin, Cat# G3580) was used for assessment of cell viability testing, as per manufacturer’s instructions. This cell proliferation assay kit is a colorimetric modified MTT cell viability

assay
, contain ing a tetrazolium compound [3-(4,5- dimethylthiazol -2- yl)

- 5(3

- carboxymethoxyphenyl)-2- (4 -sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES). The quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of viable cells in culture. The minimum cell viability required per well was ≥80%; wells with lower viability were excluded in the final data analysis.

6. Hormone M easurement S ystem : The concentration of each hormone (testosterone and estradiol) was evaluated in triplicate in the culture medium . Hormones were extracted from the samples with methylene chloride, deriv a tized with dansyl chloride , and analyzed by

LC

- APPI

- MS/MS. The lower limit of quantification (LLQ) for this measurement system was 25 pg/ml for testosterone and 10 pg/ml for estradiol.

The following performance criteria were met (indicated by an “x”) :

X Method detection limit (100 pg/mL testosterone; 10 pg/mL estradiol)

X Spiked sample recovery acceptable for two concentrations of testosterone and estradiol (mean measured amount from triplicate samples within 30% of nominal concentration)

NA Hormone cross

- reac tivity (antibody

- based assays only; ≤30% of basal production of the respective hormone)

X Solvent control within 75% range below maximum response on standard curve

NA Test compound tested for interference with measurement system



## C. DATA ANALYSIS : To evaluate the relative increase or decrease of hormone production after test chemical exposure, the results were normalized to the mean SC value for each assay and results were expressed as fold

- change relative to the SC in each exposure plate.

All data were expressed as mean ± standard deviation (SD) and concentrations that exhibited cytotoxicity ≥20% were omitted from further evaluation. Relative changes were

calculated as follows:Steroidogenesis Assay ( 2011 ) / Page 7 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## Relative Change = hormone concentration in each well ÷ mean h ormone c oncentration of solvent (vehicle) control

Prior to conducting statistical analyses, the assumptions of normality and variance homogeneity were evaluated. Homogeneity of variance were evaluated by Bartlett’s test and normality by Shapiro-Wilk’s test at alpha = 0.01. If the data were not homogeneous or normally distributed, then the data were transformed to approximate homogeneity or a normal distribution. If the data were homogeneous and approximately normally distributed, differences between chemical treatments and SC were analyzed using a param etric analysis of variance followed by Dunnett’s test, if significant. If the data were not homogeneous or normally distributed, a non- parametric test was used (Kruskal Wallis) and if significant, was followed by the Wilcoxon rank sum test with a Bonferroni- Holm correction. Differences were considered significant at p ≤ 0.05. These statistical analyses were considered appropriate.

II. RESULTS

A. TEST COMPOUND : Precipitation of pronamide was not reported at any concentration.

C ytotoxicity was not observed at any tested concentration

. The %CVs were 4.0–10.2 % for

absolute testosterone concentrations in the solvent control replicate wells within a plate

. The %CVs were 3.1-4.8% for absolute estradiol concentrations in the solvent control replicate wells within a plate

. The between plate CVs for solvent controls w ere 34.1 % for

testosterone and 26.0 % for estradiol. The inter

- and intraplate variability was within the guideline recommendation of ≤30%, except for the between plate CV for tes tosterone which was slightly high.

No e ffect was observed on testosterone levels (Table 3). Decreases (p≤0.05) of 20% in

testosterone levels relative to DMSO

- treated cells were observed in Run 2 at the lowest concentration and in Run 5 at 1 μM. These ef fects were neither concentration -dependent nor reproducible. The effects on testosterone and estradiol are illustrated in Figures 1 and 2.

An effect was observed on estradiol levels. A decrease (p≤0.05) of 10% was noted at 1 μM,

but this effect was neit her concentration-dependent nor reproducible. However, reproducible increases (p≤0.05) were noted at the highest concentration (100 μM), where
estradiol levels were determined to be 1.2-, 1.4-, and 1.9-fold that observed in the DMSO

treated cells in the three runs.

The Sponsor stated that Run 3 was analyzed, but not included for data analysis due to an insufficient inhibition of E2 production in response to 1 μM prochloraz, i.e., the assay varied considerably from the quality control criteria. Run 4 was not included for analysis as one of the replicate cell culture wells for 1 μM pronamide administration was contaminated, hence the samples were not analyzed.Steroidogenesis Assay ( 2011 ) / Page 8 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None

TABLE 3

. Mean (±SD) Hormone Concentrations Following Treatment with Pronamide f or 48 Hours. a

Nominal

Concentration (μM) Run 1 Run 2 Run 5 Run 1 Run 2 Run 5 Mean ± SD Statistical Significance b

Testosterone (pg/mL) Fold Difference

DMSO 913.3 634.3 460.3

— — — — — — 0.0001 893.3 527.0 426.3 1.0 0.8 0.9 0.9 0.1 Run 2

0.001 914.0 627.0 475.7 1.0 1.0 1.0 1.0 0.0

— 0.01 847.3 558.3 427.3 0.9 0.9 0.9 0.9 0.0

— 0.1 931.3 577.0 465.3 1.0 0.9 1.0 1.0 0.1

— 1 944.7 636.7 370.3 1.0 1.0 0.8 0.9 0.1 Run 5

10 785.3 548.7 404.0 0.9 0.9 0.9 0.9 0.0

— 100 1010.0 648.3 486.0 1.1 1.0 1.1 1.1 0.0

— Estradiol (pg/mL) Fold Difference

DMSO 23.1 33.0 39.6

— — — — — — 0.0001 24.4 35.3 36.3 1.1 1.1 0.9 1.0 0.1

— 0.001 25.4 34.1 38.5 1.1 1.0 1.0 1.0 0.1

— 0.01 24.2 34.1 37.4 1.0 1.0 0.9 1.0 0.1

— 0.1 23.6 34.5 38.3 1.0 1.0 1.0 1.0 0.0

— 1 22.6 32.4 34.5 1.0 1.0 0.9 0.9 0.1 Run 5

10 24.6 33.4 37.6 1.1 1.0 0.9 1.0 0.1

— 100 43.5 45.9 47.6 1.9 1.4 1.2 1.5 0.4 Runs 1, 2, 5

a Data were obtained from page 31 of the study report. The lower limit of quantification (LLQ) was 25 pg/mL for

testosterone and 10 pg/mL for estradiol.

b p ≤ 0.05Steroidogenesis Assay ( 2011 ) / Page 9 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## F IGURE 1. Change in Testosterone P roduction Relative to Pronamide C oncentration.Steroidogenesis Assay ( 2011 ) / Page 10 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## F IGURE 2. Change in Estradiol Production Relative to Pronamide Concentration.

B. CYTOTOXICITY : Pronamide was not cytotoxic to the H295R cells (Table 4 ). Via bility in each run ranged from 103 –140% relative to solvent controls. In the quality control plate, viability in each run ranged from 91–142% relative to the SC , except in the methanol- treated

cells which had viabilities of 17.7–23.7%.Steroidogenesis Assay ( 2011 ) / Page 11 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



### TABLE 4 . Mean (±SD) MTT Cell Viability Results after Treatment with Forskolin, Prochloraz, or Pronamide for 48 Hours. a



### Compound Concen tration ( μ M) Cell Viability

Mean SD

Media NA 95.0 4.56

Media + Methanol NA 20.0 3.21

DMSO + Methanol NA 20.1 1.89

Forskolin 1 128.3 15.02

Forskolin 10 116.0 10.54

Prochloraz 0.1 104.7 1.95

Prochloraz 1 102.8 7.18

Pronamide 0.0001 118.1 8.50

Pronamide 0.001 115.0 6.27

Pronamide 0.01 112.1 0.93

Pronamide 0.1 104.8 2.08

Pronamide 1 118.4 4.51

Pronamide 10 115.7 6.30

Pronamide 100 131.3 7.17

a Values were calculated by the reviewers from data obtained from page 43 of the study report.



## C. QC PLATE : The hormone concentrations after exposure to the reference chemicals, SC, and blank samples, as well as the fold difference change relative to SC (individual and mean ± SD) for the three assay runs are presented in Table 5. The minimum basal hormone production levels (500 pg/mL for testosterone, 40 pg/mL for estradiol) were met in both blank and SC wells for testosterone, except in Run 5 for the SC well (433 pg/mL). The required concentration for estradiol was only met in in Run 5 for the SC well; other e stradiol concentrations ranged from 26.7–39.2 pg/mL. Forskolin at 10 μM induced testosterone an average of 3.1-fold and estradiol 18-fold over the SC. Prochloraz at 1 μM inhibited concentrations of testosterone and estradiol by 0.3- to 0.6- fold compared to SC. Two runs were slightly outside the criteria for prochloraz inhibition of estradiol production (0.6-fold vs 0.5-fold). Criteria for the QC plate were generally met for induction and inhibition.

The variability (%CV) between the runs (calculated by the reviewer) based on the absolute

hormone concentrations in the SC were 33.5% for testosterone and 26.6 % for estradiol ; the

CV for testosterone was slightly greater than the guideline criteria of ≤30% for the assays. The %CVs within each run for the QC plates were 4.2-9.0 % for testosterone and 3.1-5.9 % for estradiol, which were within the guideline criteria (≤30%).Steroidogenesis Assay ( 2011 ) / Page 12 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



### TABLE 5 . Mean (±SD) Hormone Concentrations Following T reatment with Forskolin or Prochloraz for

48 Hours. a

Concentration (μM) Run 1 Run 2 Run 5 Run 1 Run 2 Run 5 Mean ± SD
Testosterone (pg/mL) Fold Difference (Relative to DMSO)

Blank 1240 691 543

— — — — — DMSO 840 575 433

— — — — — 1 μM Forskolin 1680 1233 964 2.0 2.1 2.2 2.1 0.1
10 μM Forskolin 2750 1620 1333 3.3 2.8 3.1 3.1 0.2
0.1 μM Prochloraz 578 357 385 0.7 0.6 0.9 0.7 0.1
1 μM Prochloraz 252 165 132 0.3 0.3 0.3 0.3 0.0
Estradiol (pg/mL) Fold Difference (Relative to DMSO)

Blank 26.8 33.2 39.2

— — — — — DMSO 26.7 34.6 45.6

— — — — — 1 μM Forskolin 383.0 312.0 259.0 14.3 9.0 5.7 9.7 4.3 10 μM Forskolin 687.0 612.0 483.0 25.7 17.7 10.6 18.0 7.6
0.1 μM Prochloraz 22.9 24.9 33.1 0.9 0.7 0.7 0.8 0.1
1 μM Prochloraz 13.5 20.7 28.5 0.5 0.6 0.6 0.6 0.1

a Data were obtained from page s 32 of the study report. The lower limit of quantification (LLQ) was 25 pg/mL for

testosterone and 10 pg/mL for estradiol. ALQ indicates the concentration was above the limit of quantification (>2000 pg/mL).



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : It was concluded that pronamide treatment resulted in a statistically significant increase in estradiol production at the assay limit concentration of 100 μM (10

− 4 

## M), while no effects on estradiol production were seen at lower concentrations. There were no effects on testosterone production at any concentration of pronamide. The slight increases in estradiol production (1.2-fold, 1.4-fold, and 1.9- fold) did not reproducibly meet the 1.5-fold cut-off criteria established in the validation program for this assay and hence was not interpreted to be biologically relevant.

B. AGENCY COMMENTS : Guideline acceptability recommendations and requirements

were generally met for the following: lack of cytotoxicity, adequate production of testosterone, acceptable reproducibility (low %CV), and appropriate induction and inhibition with positive controls. Departures from the Guideline included: (i) the required

co ncentration for estradiol (25 pg/mL) was not met in in Run 1 for the SC well (22.1–24.3 pg/mL) ; (ii) two runs were slightly outside the criteria for prochloraz inhibition of estradiol production (0.6-fold vs 0.5-fold); and ( iii ) the between plate CV in the SC was 33.5% for

testosterone rather than ≤30% . As the positive controls approximated the expected responses on both testosterone and estradiol concentrations, these departures from Guideline recommendations were considered minor and were not expected to affect the scientific integrity of these studies.

Precipitation of pronamide was not reported at any concentration. Cytotoxicity was not observed at any tested concentration. The %CVs were 4.0 –10.2% for absolute testosterone concentrations in the solvent control replicate wells within a plate. The %CVs were 3.1- 4.8% for absolute estradiol concentrations in the solvent control replicate wells within a plate. The between plate CVs for solvent controls were 34.1% for testosterone and 26.0%

for estradio l.Steroidogenesis Assay ( 2011 ) / Page 13 of 13

PRONAMIDE / 101701 O CSPP 89 0. 1550/ OECD None



## No effect was observed on testosterone levels. Decreases (p≤0.05) of 20% in testosterone

levels relative to DMSO

- treated cells were observed in Run 2 at the lowest concentration and in Run 5 at 1 μM. These effects were neither concentration -dependent nor reproducible.

An effect was observed on estradiol levels. A decrease (p≤0.05) of 10% was noted at 1 μM,

but this effect was neither concentration -dependent nor reproducible. However, reproducible increases (p≤0.05) were noted at the highest con centration (100 μM), where estradiol levels were determined to be 1.2-, 1.4-, and 1.9-fold that observed in the DMSO

treated cells in the three runs.

C. STUDY DEFICIENCIES : The following deficiencies were noted that are not considered to have had an adverse impact on the results, interpretation or conclusions of this study:

• Stability of pronamide in the test system was not reported.

• There were minor departures from the Guideline: (i) the required concentration for estradiol (25 pg/mL) was not met in in Run 1 for the SC well (22.1–24.3 pg/mL); (ii) two runs were slightly outside the criteria for prochloraz inhibition of estradiol production (0.6-fold vs 0.5- fold); and (iii) the between plate CV in the SC was 33.5%

for testosterone rather than ≤30%.

• Pr oficiency assays 2 and 3 found that the EC-50 concentrations for testosterone with the inhibitor prochloraz were 0.58 μM and 0.26 μM respectively (expected range is 0.01 – 0.1)

# DATA EVALUATION RECORD

PRONAMIDE ( PROPYZAMIDE)

Study Type: O CSPP 890.1600, In V ivo Uterotrophic Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-19-2012 (MRID 48619108)

Prepared for

Health Effects Division Office of Pesticide Programs U.S. Environmental Protection Agency 2777 South Crystal Drive

Arlington, VA 22202

Prepared by

CSS

- Dynamac Corporation 1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Rebecca L. Bryan, B.S. Date: 2 / 15 /201 2

Secondary Reviewer Signature:
Ronnie J. Bever Jr., Ph.D., D.A.B.T. Date: 2/27/2012

Program Manager: Signature: Jack D. Early, M.S. Date: 2/ 27 /2012

Quality Assurance: Signature:

Jack D. Early, M.S. Date: 2/ 27 /2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by CSS -Dynamac Corporation personnel

.

## The US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 screening battery is comprised of eleven screening assays intended to identify a chemical’s likely endocrine bioactivity, i.e., its potential to interact with the estrogen, androgen, or thyroid (E, A, or T) pathways. The robustness of the Tier 1 battery i s based on the strengths of each individual assay to identify potential endocrine bioactivity with complementary endpoints within the assay, where available, and redundancy across the battery. Thus, the results of each individual assay should not be considered in isolation but rather should be considered in the context of other assays in the battery as well as Other Scientifically Relevant Information (OSRI). In order to determine if a chemical has the potential to interact with the E, A or T pathways, a Weight of Evidence (WoE) evaluation of Tier 1 assay results, in combination with the findings in the OSRI, should be undertaken (refer to the WoE Document).PRONAMIDE/101701 In Vivo Uterotrophic Assay (2011) I Page I of9

OCSPP 890.1600/ OECD 440



## DATA EVALUATION RECORD

STUDY TYPE: Uterotrophic Assay (Rat); OCSPP 890.1600; OECD 440

PCCODE: 101701 DP BARCODE: D398506

TXR#: 0056255 CAS#: 23950-58-5

TEST MATERIAL (PURITY): Propyzamide (96.2% a.i.)

SYNONYMS: Pronamide; KERBTM Technical ; 3

, 5-Dichloro-N-(l

, 1-dimethyl-2- propynyl)benzamide

CITATION: Marty

, M.S.

, Brooks

, K.J. and Jeong, Y

. C. (2011). Pronamide: Uterotrophic

assay in the immature female CrL:CD(SD) rat. Toxicology & 

## Environmental

Research and Consulting

, The Dow Chemical Company, Midland, MI. Laboratory Project Study ID: 101145, October 19

, 2011. MRID 48619108. Unpublished.

SPONSOR: Dow AgroSciences LLC

, 9330 Zionsville Road

, Indianapolis

, IN

TEST ORDER#: CON-101701-37

EXECUTIVE SUMMARY: In a uterotrophic assay (MRID 48619108) conducted to screen for potential estrogenic activity

, pronamide (96.2% a.i., lot# XG 1088R301) in 0.5% aqueous methylcellulose was administered daily via oral gavage to groups of 6 immature female

, Sprague-Dawley rats at dose levels of 0 (vehicle)

, 25, 100

, or 400 mg / kg / day on postnatal days (PND) 19-21. A positive control group was treated with 17a-ethynyl estradiol (EE) in com oil by gavage at a dose level of 10 μg / kg / day. All animals were terminated and necropsied approximately 24 hours after the final dose on PND 22 to determine wet and blotted uterine weights

.

All animals survived until scheduled termination. No clinical signs of toxicity were observed in

animals for any pronamide treated groups
, and no precocious vaginal opening was observed in

the pronamide-treated females. The body weights and overall body weight gain were decreased

in all pronamide-treated groups. Body weights were decreased (p < 0.05) at 25 mg/kg / day 

# O 11 %, Day 4)

, 100 mg / kg / day (l 7-8%, Days 3-4), and 400mg / kg / day(l10-25%

, Days 2-4). Overall body weight gains were also decreased (p < 0.05) for the 25

, 100 and 400 mg / kg / day groups by

58

, 38

, and 112%

, respectively. Uterine weights in the pronamide-treated groups were comparable to the controls. Absolute wet and blotted uteru s weights for the positive control EE

group were increased (p < 0.05) by 797% and 423%

, respectively

, as expected.In Vivo Uterotrophic Assay ( 2011) / Page 2 of 9

PRO N AMIDE / 101701 O CS PP 8 9 0. 1600/ OECD 440



## Dosing for the assay (high dose of 400 mg/kg/day) was adequate based on decreased body weight observed at all doses.

No statistically significant changes were seen in uterine weight in this assay. Pronamide is negative in the uterotrophic assay.

The assay satisfies the EDSP Tier 1 Test Order requirements for an Uterotrophic assay (OCSPP 890.1600).

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, and Quality Assurance statements were provided.In Vivo Uterotrophic Assay ( 2011) / Page 3 of 9

PRO N AMIDE / 101701 O CS PP 8 9 0. 1600/ OECD 440



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Toxicology & Environmental Research and Consulting

Location: Midland, MI Study Director: K. J. Brooks

Other Personnel: M. S. Marty , l ead s cientist J. A. Wachner, animal technician H. M. Mahan, quality assurance L. G. McFadden, data analyses J. W. Lacher, laboratory veterinarian J. R. McFadden, analytical analyses

Study Period: Not provided



## 2

. Test S ubstance : Pronamide

Description: Molecular weight = 256.1 g/mol

Source: Dow AgroSciences LLC (Indianapolis, IN)

Lot #: XG1088R301 , TSN 003588

- 0004 Purity: 96.2 % Stability: Stable in 0.5% methylcellulose for up to 12 days; temperature of stability determination not reported

CAS #: 23950

- 58

- 5

Structure:

Cl Cl O

N H CH 3

C
CH CH 3



## 3

. Reference E strogen : 17α

- ethynyl estradiol (EE)

Supplier : Sigma Aldrich (St. Louis, MO)

Lot #: 028K1411 Purity: 98 %

CAS # : 57

- 63

- 6



## 4 a

. Solvent/ V ehicle C ontrol

for Test Chemical : Methylcellulose

Supplier : The Dow Chemical Company (Midland, MI)

Lot #: WD14012N13 Rationale (if other than water) : Selected due to the solubility properties of the test substance and lack of toxicity

Final concentration : 0.5% aqueous



## 4b. Solvent/Vehicle Control

for Positive Control : Corn Oil

Supplier: Sigma Aldrich (St. Louis, MO)

Lot #: MKBC6753 Rationale (if other than water): Selected due to the solubility properties of the test substance without estrogenicity or toxicity

Final concentration: Not applicableIn Vivo Uterotrophic Assay ( 2011) / Page 4 of 9

PRO N AMIDE / 101701 O CS PP 8 9 0. 1600/ OECD 440



## 5

. Test A nimals : Species: Rats (immature , female only )

Strain: Sprague

- Dawley (Crl:CD[SD]) Age/weight at dose initiation : Post

- natal day (PND) 19; 41.5

- 49.0 g Source: Charles River Laboratories (Portage, MI)

Housin g: Rats were housed 6 per cage in solid bottom cages with paper pulp bedding with low phytoestrogen content (7089 Tekland Diamond Soft bedding, Harlan Laboratories, Inc., Indianapolis, IN )

Diet : Teklad Diet # 2016 (Harlan Laboratories, Inc., Indianapolis, IN) , a d libitum ( low phytoestrogen rodent diet, total genistein equivalents <325 μg/g )

Water: Tap water, ad libitum

Environmental conditions: Temperature: Humidity: Air changes: Photoperiod: 22 ± 3 oC

40

- 70 %

12

- 15 times /hour (average) 12 hrs light/12 hrs dark Acclimation period: 8 days ; immature females housed with their dam



## B. METHODS

1. In -L ife D ates : Dates not provided

2. Study Design : Following a n 8-day acclimation period, intact, immature female rats were administered the test substance by oral gavage once daily from PND 19 -21. A positive control group of six rats were given 17 α

- ethynyl estradiol (EE) daily by gavage at 10 μg/kg/day. Rats were euthanized approximately 24 hours after the last dose and necropsied for uterine weight measurements.

3. Animal A ssignment : Animals were randomly assigned, stratified by body weight, to the test groups noted in Table 1 using a computer program designed to increase the probability of uniform group mean weights and standard deviations on Day 1. Statistical analysis indicated that there were no significant differences in group means at study initiation.

T ABLE 1. Study Design a



### Test G roup Dose (mg/kg/day) # of Females b



### Estrogen A gonist A ssay
Vehicle C ontrol 0 6

Low 25 6

Mid 1 00 6 High 4 00 6

17 α

- ethynyl estradiol (EE), R eference

E strogen 10 μ g/kg/day 6

a Data were obtained from Text Table 1 on page 15 of the study report.



## 4. Dose Selection Rationale : In a screening study examin ing hepatic enzyme induction, rats (6/sex/dose) were treated for 3 days by oral gavage with pronamide at doses of 0, 25, 100 or 400 mg/kg/day in 0.5% methylcellulose. Liver

- to -body weight ratios were increased in both sexes at the high dose and in vitro p-nitroanisole O- demethylase activity was increased at doses of 100 and 400 mg/kg/day pronamide. In a 2

- week dietary study in Crl:CD rats, pronamide was found to be a mixed inducer of cytochrome P450 enzymes at 239 mg/kg/day. Liver weights, microsomal protein levels

, and microsomal enzyme activities

were increased. M ale rats were administered the test substance via gavage at doses of 0, 25, 100, 250, 500, 600, 800 or 1000 mg/kg/day for 15 days from PND 30 . Decreased bodyIn Vivo Uterotrophic Assay ( 2011) / Page 5 of 9

PRO N AMIDE / 101701 O CS PP 8 9 0. 1600/ OECD 440



## weight gains were observed at the ≥ 500 mg/kg/day dose groups, and terminal body weights

were decreased in the ≥ 600 mg/kg/day dose groups. The absolute and relative liver weights

were increased in the ≥ 100 mg/kg/day dose groups. Relative kidney and adrenal weights were increased at 1000 mg/kg/day. Based on these results, the dose levels selected for this study were ≤ 4 00 mg/kg/day

.

5. Dose Preparation : Dose formulations were prepared by mixing appropriate amounts of

test substance with 0.5% methylcellulose , such that a dose volume of 4 mL/kg BW yielded the target dose . Pronamide dosing solutions were prepared once at the beginning of the study in acco rdance with established stability limits. Dose volumes were adjusted daily based on individual body weight measurements. Prior to dose administration, samples of pronamide dose formulations from all three dose levels were analyzed for achieved

concentrat ion and samples from the low and high dose formulations were tested for homogeneity. Samples were taken from the top, middle, and bottom of the container after stirring overnight. In a previous study, 1 

## pronamide was determined to be stable in 0.5%

aqueou s methylcellulose for up to 12 days at concentrations ranging 0.250-250 mg/mL (temperature not specified).

Results of D ose Analysis

Homogeneity (%RSD): 0.6-0.9%

Stability: Stable in 0.5% methylcellulose for up to 12 days; temperature of stability determination not reported (Dow Chemical Company, 2005)

Concentration (% of nominal): 86.3-101.0%

The analytical data indicated that the mixing procedure was adequate and that the variation between nominal and actual dosage to the animals was acceptable.

6. Dosage A dministration : Animals were administered the pronamide formulations , positive control (EE) or vehicle control daily via gavage for three consecutive days in a dose volume

of 4 mL/kg body weight. Dose volumes were adjusted daily based on the concurrent body weight measurement.

7. S tatistics : Body weights and body weight gains were analyzed by a forced parametric test. The blotted and wet uterine weights were first analyzed by Bartlett’s test for homogeneity of

variance. A log transformation was performed when data variance was not homogeneous. Analysis of covariance (ANCOVA) was performed with terminal body weight as the covariate. If the ANCOVA was significant (p ≤ 0.05), either one-sided least square means

with Dunnett’s correction was performed. Significance was denoted at p ≤ 0.05. The

as sumptions of parametric testing (homogeneity of variance and normal distribution) should be confirmed prior to using parametric testing, and non- parametric testing is performed when these assumptions are not met.

1 

### Dryzga, M.D. and Yano, B.L. (2005). PronamideTechnical: 28

- Day dermal toxicity study in F344/DuCrl rats. Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.In Vivo Uterotrophic Assay ( 2011) / Page 6 of 9

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## C. METHODS

1. Clinical Examinations : Cage -side checks for mortality, moribundity and clinical signs of toxicity were conducted at least twice daily.

On PND 22 prior to necropsy, all animals were examined for vaginal patency.

2. Body W eight : Animals were weighed at randomization, daily throughout the dosing period

and at termination.

3. Food Consumption (Optional) : Food consumption was not determined.

4. Necropsy and Measurement of Uterine Weight : On PND 22 (approximately 24 hours after final administration of the test substance), all surviving animals were anesthetized by

CO 2 

## , euthanized by cervical dislocation , and subjected to a gross necropsy. Dissection of the uterus was performed according to the U.S. EPA Guideline. Briefly, the vagina was removed just below the cervix in order to retain the luminal fluid in the uterus. The “wet” uterus (i.e., containing the luminal fluid) was weighed. Subsequently, the uterine horns

were nicked three times and gently blotted with moist filter paper to remove the luminal

fluid , and the blotted uterus was weighed. Uterine desiccation was avoided. After weighing, the uteri were fixed in 10% neutral phosphate- buffered formalin for potential

future examination.

5. Microscopic Examination (Optional) : Microscopic examinations were not conduc ted.

II. RESULTS

A. OBSERVATIONS

1. Mortality : All animals survived until scheduled termination.

2. Clinical S igns of Toxicity : No clinical signs of toxicity were observed in animals for any dose groups.

No precocious vaginal opening was observed in the pronamide treated groups or vehicle control. One animal exhibited precocious vaginal opening in the positive control group (EE).

B. BODY WEIGHT AND WEIGHT GAIN : B ody weight and body weight gain data are presented in Table 2. The body weights and overall body weight gain were decreased in all pronamide treated groups. Body weights were decreased (p<0.05) at 25 mg/kg/day (↓11%, Day 4), 100 mg/kg/day (↓7

- 8%, Days 3- 4), and 400 mg/kg/day (↓10

- 25%, Days 2-4). Overall body weight gains were decreased (p<0.05) for the 25, 100 and 400 mg/kg/day by 58, 38, and 112%, respectively.

In the positive control group (EE), body weights on Day 4 were decreased (p<0.05) by 14%, and overall body weight gains decreased (p<0.05) for Days 1

- 4 (↓ 58 %).In Vivo Uterotrophic Assay ( 2011) / Page 7 of 9

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### T ABLE 2. Group Body Weights and Cumulative Body Weight Gains (g) in the Estrogen Agonist Assay a

Study Day

# Dose Group (mg/kg/day)

Vehicle Control Pronamide ( 2 5 ) Pronamide ( 100 ) Pronamide ( 4 00 ) Estrogen, EE ( 10 μ g/kg/day )

N Mean S D N Mean S D N Mean S D N Mean S D N Mean S D

1 6 44.1 2.2 6 45.1 2.3 6 44.3 2.1 6 44.4 1.7 6 43.8 2.0

2 6 48.3 2.4 6 47.6 2.2 6 45.6 2.4 6 43.5* ( ↓ 10 ) 1.7 6 46.1 2.2

3 6 53.3 2.7 6 52.5 2.3 6 49.4* ( ↓7) 2.0 6 41.5* ( ↓ 22 ) 2.0 6 50.3 2.7

4 6 57.0 2.9 6 50.5* ( ↓ 11 ) 2.5 6 52.3* ( ↓ 8 ) 2.1 6 42.9* ( ↓ 25 ) 4.2 6 49.2* ( ↓ 14 ) 2.1

BWG Days 1

- 4 6 12.9 1.2 6 5.4* ( ↓ 58 ) 0.8 6 8.0* ( ↓ 38 ) 1.0 6 - 1.6* ( ↓ 112 ) 5.2 6 5.4* ( ↓ 58 ) 0.8

a Data were obtained from Table 3 on page 29 of t he study report.

N No. of animals in the group

SD Standard Deviation

* Significantly different from vehicle control at p < 0.05.



## C. FOOD CONSUMPTION (OPTIONAL) : Food consumption was not determined.

D. PATHOLOGY

1. Uterine W eights : U terine weight data are presented in Table 3. Uterine weights in the pronamide treated groups were comparable to the controls.

Absolute wet and blotted uterus weights for the positive EE group were increased (p<0.0 5 ) by 797 % and 423 %, respectively. The se wet and blotted uterine weights inc reased as expected.

Imbibed and blotted weights in the vehicle group were within the range of historic control values 0.0234 – 0.0318 g (0.0259± 0.0032 g) and 0.0209-0.0308 g (0.0240±0.0037 g), respectively, in the corn oil vehicle-control animals in six studies. Mean imbibed and blotted uterine weights in untreated control animals in four other studies (historical control data) were (0.0254±0.0032 g and 0.0235±0.0022 g) similar to the weights seen in the current methylcellulose vehicle controls. It was concluded that there was no estrogenic potential from the vehicle used in this study.In Vivo Uterotrophic Assay ( 2011) / Page 8 of 9

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### T ABLE 3. Uterine Weights ( g) from Estrogen Agonist Assay in SD Rats a

Parameter Dose Group (mg/kg/day)

Vehicle Control Pronamide (25) Pronamide ( 100 ) Pronamide (4 00 ) Estrogen, EE (10 μ g/kg/day)

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD
Terminal BW (g) 6 57.0 2.9 6 50.5* ( ↓11) 2.5 6 52.3* ( ↓8) 2.1 6 42.9* ( ↓25) 4.2 6 49.2* ( ↓14) 2.1

Wet, absolute (g) 6 0.0250 0.0033 5 0.0239 0.0031 6 0.0205 0.0028 6 0.0181 0.0025 5 0.2243* (↑ 797 ) 0.0377

Wet, relative (%) c 6 0.044 0.006 6 0.047 0.004 6 0.039 0.006 6 0.042 0.004 6 0.455 0.079

Blotted, absolute (g) 6 0.0231 0.0040 6 0.0189 0.0057 6 0.0198 0.0015 6 0.0162 0.0036 6 0.1208* (↑ 423 ) 0.0157

Blotted, relative (%) c 6 0.040 0.006 6 0.037 0.011 6 0.038 0.004 6 0.038 0.009 6 0.246 0.031

a Data were obtained from Table 4 on page 30 of the study report. Percent difference from controls (calculated by reviewer) is presented in parentheses.

b T wo wet uterine weights were excluded from analysis

, one from 25 mg/kg/day (0.0228 g) and one from EE group (0.1428 g)

.

c Relative wet and blotted uterine weights were calculated by the reviewer from the individual data ( Appendix Table 2 , page s 35

- 36 ).

BW B ody weight

N No. of animals in the group

SD Standard Deviation

* Significantly different from vehicle control at p < 0.0 5.



## 2. Microscopic Examination (Optional) : No microscopic examinations were conducted.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : There was no animal mortality or treatment

related clinical signs observed in this study. All pronamide -dosed animals had significantlydecreased body weight gains throughout the study period. At study termination, pronamidetreated animals at dose levels of 25, 100, and 400 mg/kg bw/day exhibited 11.4%, 8.3%, and 24.7% decreases in body weight gains, respectively, compared to the vehicle -control

animals. Significant body weight decreases were observed in the 400 mg/kg bw/day pronamide group (TD 2-4) and in the 100 mg/kg bw/day pronamide group (TD 3-4). However, there were no treatment

- related increases in mean uterine weights (wet or blotted)

in immature rats treated with ≤ 400 mg/kg bw/day pronamide. Neither the vehicle control animals nor the pronamide- treated anim als had precocious vaginal opening. The EE positive-control group had a 13.7% decrease in terminal body weight compared to the

vehicle -control group. In contrast to the body weight decrease, the positive- control group

animals had 797.2% and 422.9% increa ses in imbibed and blotted uterine weights, respectively. One rat in the EE positive-control group exhibited precocious vaginal opening. Uterine weights of the vehicle

- control animals met the performance criteria outlined in the applicable test guideline s, indicating acceptable assay sensitivity.

Overall, under the conditions of this study, there was no indication of estrogenicity in

immature female rats at doses ≤ 400 mg/kg bw/day pronamide, the highest dose level tested

in female immature rats.In Vivo Uterotrophic Assay ( 2011) / Page 9 of 9

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## B. AGENCY COMMENTS : All animals survived until scheduled termination. No clinical signs of toxicity were observed in animals for any pronamide treated groups, and no precocious vaginal opening was observed in the treated females . The body weights and overall body weight gain were decreased in all pronamide treated groups. Body weights were decreased (p<0.05) for 25 mg/kg/day (↓11%, D ay 4), 100 mg/kg/day (↓7

- 8%, D ays 3- 4), and 400 mg/kg/day (↓10 -25%, D ays 2

- 4). Overall body weight gains were decreased (p<0 .05) for the 25, 100 and 400 mg/kg/day by 58, 38, and 112%, respectively. Uterine weights in the pronamide treated groups were comparable to the controls. Absolute wet and blotted uterus weights for the positive EE group were increased (p<0.05) by 797% and 423%, respectively, as expected

.

Dosing for the assay (high dose of 400 mg/kg/day) was adequate based on decreased body weight observed at all doses.

No statistically significant changes were seen in uterine weight in this assay. Pronamide is negative in the uterotrophic assay.

C. STUDY DEFICIENCIES : The following deficiencies were noted that are not considered to have had an adverse impact on the results, interpretation or conclusions of this study:

• The temperature at which the test substa nce was found to be stable in 0.5% methylcellulose was not reported.

• Six immature females were housed per cage; three/cage is recommended.