## UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION



## MEMORANDUM

Date: 6 / 29 / 2015

SUBJECT : P ho smet: Data Ev aluation Records (DERs) for EDSP Tier 1 

## Assays

PC Code: 059201



## Decision No.: 459049

, 463273


## Petition No. : NA 

## DP Barcode: D397165

, D400672 

## Registration No.: NA 

## Regulatory Action: NA



## R i sk Assessme nt Type: NA

TXR 

## No.: 0056199

MRID 

## No.: See Table 

## Case No.: NA



## CAS No .: 732-11-6

40 

## CFR: NA



## FROM: Greg Akerman

, Ph.D. 

# Do- ff

-- - -

lmmediate Office

Health Effects Divi sio n (7509 P )



## THROUGH: J ess R owland

# ~-**~** Deputy Director

Health Effects Division



## TO: Jolene Trujillo

B iolo g i st/C h em ical Review Manager

Risk Management and Implementation Branch V

Pesticide Re-evaluatio n Division (7505P)



## I. 

## ACTION REQ UESTE D Ver.Apr. 20 1 0



## The Pesticide Re-evaluation Division (PRD) of OPP h as r equested that the Health Effects

Division (HED) review t h e Endocrine Disruptor Screening Program (E DSP ) T i er 1 assays submitte d 

## in response to the agency's Test Order for phosmet: T est Order # EDSP-059201-54.

Pagel of2

### Page 2 of 2 

## II. RESPONSE

Attached are the EDSP Tier 1 assay DERs for phosmet.

III

. MRID Table

Chemical: Phosmet PC Code: 059201

Guideline Assay MRID

890.1100 Amphibian Metamorphosis Assay (Frog) 48673001

890.1150 Androgen Receptor Binding (Rat Prostate) 48618703

890.1200 Aromatase Assay (Human Recombinant) 48618702

890.1250 Estrogen Receptor Binding 48618704

890.1300 Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa

- 9903) 48618705

890.1350 Fish Short

- Term Reproduction 48673002

890.1400 Hershberger (Rat) 48618706

890.1450 Female Pubertal (Rat) 48673003

890.1500 Male Pubertal (Rat) 48673003

890.1550 Steroidogenesis (Human Cell Line

– H295R) 48618701

890.1600 Uterotrophic (Rat) 48618707

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԡԹՌԹԯԽՉՍՁՊԽՅԽՆՌ    ԢԭԞԡԭԟԹՊԻ ՇԼԽ  

ԬԢԠԡԡԹՌԹԭՇՁՆՌ  

ԢԭԞԪԯԦԡ   

ԢԭԞԤՍՁԼԽՄՁՆԽ   

      ԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊ ՈՀՇՋՁՋԞՋՋԹՑ
ԣՊՇԿ 

ԱԽՋՌԪԹՌԽՊՁԹՄ ԭՀՇՋՅԽՌ          ԭՍՊՁՌՑ
     

ԠՇՅՅՇՆԫԹՅԽԭՀՇՋՅԽՌ

ԠՀԽՅՁԻԹՄԫԹՅԽ  ԦԲԭԞԠ   ԫՇՌԯԽՈՇՊՌԽԼ

 ԠԞ԰ԫԹՅԽ  ԫՇՌԯԽՈՇՊՌԽԼ

ԠԞ԰ԫՇ  

԰ՑՆՇՆՑՅՋ  ԦՅՁԼԹՆնԱԽԻՀՆՁԻԹՄ

ԢԭԞԭԠԠՇԼԽ 

ԭՊՁՅԹՊՑԯԽՎՁԽՏԽՊ ԧՇՀՆԪԹՊՌՇՆ  ԰ՁԿՆԹՌՍՊԽ 

԰ՌԹԾԾ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ ԡԹՌԽ 

԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ ԱԽՊՁ԰ԪՑԽՊՋ  ԰ՁԿՆԹՌՍՊԽ  

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ ԡԹՌԽ   ԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ ԠԹՌՀԽՊՁՆԽԞՍԺԽԽ  ԡԹՌԽ 

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԲ԰ԢԭԞԬԭԭԢԣԢԡԢԯԟԦԳ ԰ՁԿՆԹՌՍՊԽ

ԡԹՌԽԢՎԹՄՍԹՌՁՇՆԠՇՅՈՄԽՌԽԼ #ԼԼՅՅՅՑՑՑՑ%

ԠԦԱԞԱԦԬԫ ԩԽԽԪԯԭՀՇՋՅԽՌԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑՏՁՌՀԞԾ ՊՁԻԹՆԠՄԹՏԽԼԣՊՇԿ ԵԽՆՇՈՍՋ

ՄԹԽՎՁՋ ԣՇՄՄՇՏՁՆԿԬԭԭԱ԰ԱԽՋՌԤՍՁԼԽՄՁՆԽԹՆԼԬԢԠԡԱԽՋՌԤՍՁԼԽՄՁՆԽԫՇԲՆՈՍԺՄՁՋՀԽԼՋՌՍԼՑ

ՈԽՊԾՇՊՅԽԼԺՑ԰ՅՁՌՀԽՊՋԳՁՋԻՁԽՆՌԴԹՊԽՀԹՅԪԹՋՋԹԻՀՍՋԽՌՌՋԩ ԹԺՇՊԹՌՇՊՑՊԽՈՇՊՌՆՍՅԺԽՊ

԰ՌՍԼՑՋՈՇՆՋՇՊԽԼԺՑԤՇՏԹՆԠՇՅՈԹՆՑԶՍՅԹԞՊՁՒՇՆԹ԰ՌՍԼՑԻՇ ՅՈՄԽՌԽԼԣԽԺՊՍԹՊՑ

ԡՁՋԻՄԹՁՅԽՊ ԱՀԽԿՍՁԼԽՄՁՆԽՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋՁՆՌՀՁՋԡԢԯՌԽՅՈՄԹՌԽԹՊԽՇԾԾԽՊԽԼ ԹՋԹԿԽՆԽՊԹՄՊԽԾԽՊԽՆԻԽՌՇԹՁԼ ՁՆՈՊԽՈԹՊԹՌՁՇՆՇԾՌՀԽԡԢԯԱՀԽՈՍՊՈՇՋԽՇԾՌՀԽՋԽՊԽԻՇՅՅԽՆԼԹՌՁՇՆ ՋՁՋՆՇՌՌՇՋԽՊՎԽԹՋՋՍԺՋՌՁՌՍՌԽԾՇՊՌՀԽԱԽՋՌ ԤՍՁԼԽՄՁՆԽՋՆՇՊՌՇՈՊՇՎՁԼԽԹՆՑԿՍՁԼԹՆԻԽՇՆՀՇՏՌՀԽՋՌՍԼՑՋՀՇՍՄԼ ԺԽԻՇՆԼՍԻՌԽԼ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  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

ԱՀԽԼԹՑԹՋՋԹՑՇԾՈՀՇՋՅԽՌՇՆԹՅՈՀՁԺՁԹՆՅԽՌԹՅՇՊՈՀՇՋՁՋՇԾԞԾՊՁԻ ԹՆԠՄԹՏԽԼԣՊՇԿ ԵԽՆՇՈՍՋՄԹԽՎՁՋ ՏԹՋ

ԻՇՆԼՍԻՌԽԼ ՍՆԼԽՊԾՄՇՏՌՀՊՇՍԿՀԻՇՆԼՁՌՁՇՆՋԞՅՈՀՁԺՁԹՆՄԹՊՎԹԽ 
ՌԹԼՈՇՄԽՋՌՊԽԹՌՅԽՆՌ ԿՊՇՍՈՊԽՈՄՁԻԹՌԽԹՌ

ԫՁԽՍՏՃՇՇՈԣԹԺԽՊ 
ԫԣՋՌԹԿԽՏԽՊԽ ԽՐՈՇՋԽԼՌՇ ՈՀՇՋՅԽՌ 
 ՈՍ ՊՁՌՑ ԹՌ ՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ՇԾ

ՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩԪԽԹՆՅԽԹՋՍՊ ԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽ
ԩԬԮ

ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩԱՀԽՌԽՋՌՋՑՋՌԽՅՏԹՋ ՅԹՁՆՌԹՁՆԽԼԹՌՌՇոԠԹՆԼԹՈԥՇԾ

ՌՇ

ԭՀՇՋՅԽՌՋՁԿՆՁԾՁԻԹՆՌՄՑԼԽԻՊԽԹՋԽԼՆՇՊՅԹՄՁՒԽԼՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩ ԩՁՆՆՇՆՄԹՌԽՋՌԹԿԽՌԹԼՈՇՄԽՋ
ԫԣՋՌԹԿԽ 

ԹՌՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՇՆԡԹՑՋԹՆԼԪԽԼՁԹՆԫՁԽՍՏՃՇՇՈԣԹԺԽՊ

ԫԣՋՌԹԿԽՏԹՋՍՆԹԾԾԽԻՌԽԼՇՆԡԹՑՌՀՇՍԿՀԹՋՁԿՆՁԾՁԻԹՆՌԼԽՄԹՑՏԹՋՇԺՋԽՊՎԽԼԹՌՇՆԡԹՑԹՌՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼ

ԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԫՇԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄ ՇՈՅԽՆՌՏԹՋՇԺՋԽՊՎԽԼԪՁՄԼՌՀՑՊՇՁԼԿՄԹՆԼ

ՀՑՈԽՊՌՊՇՈՀՑԾՇՄՄՁԻՍՄԹՊ ԻԽՄՄ ՀՑՈԽՊՈՄԹՋՁԹ ԹՆԼԾՇՄՄՁԻՍՄԹՊ ԻԽՄՄ Հ ՑՈԽՊՌՊՇՈՀՑՏԽՊԽ ՇԺՋԽՊՎԽԼ ԹՌ ԹՄՄ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ

ՁՆԻՄՍԼՁՆԿԻՇՆՌՊՇՄՋՌՀԽՊԽՏԹՋՆՇԹՈՈԹՊԽՆՌՌՊԽԹՌՅԽՆՌՊԽՄԹՌԽԼՈԹՌՌԽՊՆՁՆՀՁՋՌՇՈԹՌՀՇՄՇԿՁԻԹՄԾՁՆԼՁՆԿՋԱԹԼՈՇՄԽՋՏՁՌՀ

ՋՈՁՆԹՄԻՍՊՎԹՌՍՊԽՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՇՇԾՌԹԼՈՇՄԽՋՁՆՌՀԽ ԻՇՆՌՊՇՄԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽ

ՊԽՈՇՊՌԽԼԹՄՄԹՆԹՄՑՋԽՋԹՊԽԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ ԣԢԱԞԵԻՇՆՌՊՇՄԹՆԼԹՆԹՄՑՋԽՋՇԾ԰ԳԩՆՇՊՅԹՄՁՒԽԼ

ԥԩԩԹՆԼԺՇԼՑՏԽՁԿՀՌՏԽՊԽՈԽՊԾՇՊՅԽԼԽՐԻՄՍԼՁՆԿՄԹՌԽՋՌԹԿԽ
ԫԣՋՌ ԹԿԽ ՌԹԼՈՇՄԽՋ

ԪՁՆՇՊԼԽՎՁԹՌՁՇՆՋԾՊՇՅՌՀԽԿՍՁԼԽՄՁՆԽՏԽՊԽՆՇՌԽԼԺՍՌՌՀԽՑԼՁԼՆՇՌ ՋՍԺՋՌԹՆՌՁՎԽՄՑԹԾԾԽԻՌՌՀԽՊԽՋՍՄՌՋՇՊՁՆՌԽՊՈՊԽՌԹՌՁՇՆ

ՇԾՌՀԽՋՌՍԼՑԱՀԽԹՋՋԹՑ ՋԹՌՁՋԾՁԽՋ ՌՀԽԢԡ԰ԭԱՁԽՊԱԽՋՌԬՊԼԽՊՊԽՉՍՁՊԽՅԽՆՌԾՇՊԹՆԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇ ՊՈՀՇՋՁՋԹՋՋԹՑ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ

ԯԽՋՍՄՌՋ԰ՑՆՇՈՋՁՋ

ԱԽՋՌՇՊԿԹՆՁՋՅԫԣՋՌԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ

ԱԽՋՌՇՊԿԹՆՁՋՅՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՇՈՌՁՇՆԹՄԫՇՌԯ ԽՈՇՊՌԽԼ

ԱԽՋՌՌՑՈԽԾՄՇՏՌՀՊՇՍԿՀ

ԱԹԺՄԽ  ԰ՍՅՅԹՊՑ ՇԾ ԡԽՎԽՄՇՈՅԽՆՌԹՄ ԹՆԼ ԱՀՑՊՇՁԼ ԭԹՌՀՇՄՇԿՑԥՁՋՌՇՈԹ ՌՀՇՄՇԿՑ ԢԾԾԽԻՌՋ  

###  ՁՆ ՌՀԽ ԞՅՈՀՁԺՁԹՆ

ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ
ԞԪԞՏՁՌՀԭՀՇՋՅԽՌ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԫԣԡԽՎԽՄՇՈՅԽՆՌԹՄ

԰ՌԹԿԽ ԥՁՆԼԩՁՅԺ

ԩԽՆԿՌՀ  

### ԞՋՑՆԻՀՊՇՆՇՍՋ

ԡԽՎԽՄՇՈՅԽՆՌ ԱՀՑՊՇՁԼԤՊՇՋՋ

ԹՆԼ

ԥՁՋՌՇՈԹՌՀՇՄՇԿՑ

ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

 ԫՇ ԫՇ ԫՇ ԫՇ ԫԞ ԫԞ ԫՇ

 ԫՇ ԶԽՋ ԶԽՋ ԶԽՋ ԫԞ ԫԞ ԫՇ

 ԫՇ ԶԽՋ ԶԽՋ ԶԽՋ ԫԞ ԫԞ ԫՇ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ 

### ԡՁԾԾԽՊԽՆԻԽ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

###  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 ԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼԾՇՄՄՇՏՁՆԿԿՍՁԼԽՄՁՆԽՋՇՍՌՄՁՆԽԼՁՆՌՀԽ Բ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄ

ԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ0ՋԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅԱԽՋՌԤՍՁԼԽՄՁՆԽՋ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋ
ԣՊՇԿԹՆԼԬԢԠԡԤՍՁԼԽՄՁՆԽԾՇ ՊԱԽՋՌՁՆԿ

ՇԾԠՀԽՅՁԻԹՄՋԫՇԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑԱՀԽԾՇՄՄՇՏ ՁՆԿ

ԼԽՎՁԹՌՁՇՆՋՏԽՊԽՆՇՌԽԼ

 ԦՌՏԹՋՆՇՌՋՈԽԻՁԾՁԽԼՇՆՏՀՁԻՀԼԹՑՋԽՅԺՊՑՇՋՏԽՊԽԻՀԽԻՃԽԼԾՇՊՎՁԹ ԺՁՄՁՌՑ

 ԱՀԽԾՄՇՏՊԹՌԽՊԽՋՍՄՌԽԼՁՆԹՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌԽՎԽՊՑՀՇՍՊՋԤՍՁԼԹՆԻԽՊԽԻՇՅՅԽՆԼՋԻՇՅՈՄԽՌԽ

ՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌԹՈՈՊՇՐՁՅԹՌԽՄՑԽՎԽՊՑՀՇՍՊՋ

 ԯԽՋՍՄՌՋԾՊՇՅՌՀԽՈԽՊՁՇԼՁԻՋԻՊԽԽՆՁՆԿԹՆԹՄՑՋՁՋՇԾՌՀԽԼՁՄՍՌՁՇՆՏԹ ՌԽՊՏԽՊԽՆՇՌՈՊՇՎՁԼԽԼԥՇՏԽՎԽՊՌՀԽ

ՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌՀԹՌՆՇՈԽՋՌՁԻՁԼԽՋԭԠԟՋՇՊՌՇՐՁԻՅԽՌԹՄՋ ՏԽՊԽԼԽՌԽԻՌԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋ

ԻՇՆՋՁԼԽՊԽԼՌՇՐՁԻԹԻԻՇՊԼՁՆԿՌՇԞ԰ԱԪՋՌԹՆԼԹՊԼՋ

 ԱՀԽՄՁԿՀՌՁՆՌԽՆՋՁՌՑ
ԨՄՍՐՏԹՋՄՇՏԽՊՌՀԹՆՊԽԻՇՅՅԽՆԼ ԽԼ
ԨՄՍՐ

 ԴԹՌԽՊՀԹՊԼՆԽՋՋ
ՅԿԩԹՋԠԹԠԬ  

### ԽՐԻԽԽԼԽԼՌՀԽՊԽԻՇՅՅԽՆԼԽԼՀԹՊԼՆԽՋՋ
ՅԿԩ

ԹՋԠԹԠԬ  

### 

 ԱՀԽՌԽՅՈԽՊԹՌՍՊԽ
ոԠԾԽՄՄՇՍՌՋՁԼԽՇԾՌՀԽՊԽԻՇՅՅԽՆԼԽԼՊԹՆԿԽ 
չոԠ

ԱՀԽՋԽԼԽՎՁԹՌՁՇՆՋԼՇՆՇՌՋՍԺՋՌԹՆՌՁՎԽՄՑՁՅՈԹԻՌՌՀԽՊԽՋՍՄՌՋՇՊՁՆՌ ԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀԽՋՌՍԼՑ

 ԠՇՅՈՄՁԹՆԻԽ   ԰ՁԿՆԽԼԹՆԼԼԹՌԽԼԫՇԡԹՌԹԠՇՆԾՁԼԽՆՌՁԹՄՁՌՑԤԩԭԹՆԼԮՍԹՄՁՌՑԞՋՋՍՊԹՆԻԽՋՌԹՌԽՅԽՆՌՋ

ՏԽՊԽՈՊՇՎՁԼԽԼԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼՁՆԻՇՅՈՄՁԹՆԻԽՏՁՌՀԹՄՄ ՈԽՊՌՁՆԽՆՌԬԢԠԡ

ԬԢԠԡԹՆԼԲ԰ԢԭԞ
ԠԣԯԭԹՊՌԹՆԼԠԣԯԭԹՊՌ ԤՇՇԼ

ԩԹԺՇՊԹՌՇՊՑԭՊԹԻՌՁԻԽՊԽԿՍՄԹՌՁՇՆՋՏՁՌՀՌՀԽԾՇՄՄՇՏՁՆԿԽՐԻԽՈՌՁՇՆՊ ՇՍՌՁՆԽԾՇՇԼԹՆԼ

ՏԹՌԽՊԻՇՆՌԹՅՁՆԹՆՌՋԻՊԽԽՆՁՆԿԹՆԹՄՑՋԽՋՏԽՊԽԻՇՆԼՍԻՌԽԼՍՋՁՆԿՋՌԹՆԼ ԹՊԼԲ԰

ԢԭԞՈՊՇԻԽԼՍՊԽՋԺՑԤԽՇԩԹԺՋԦՆԻԟՊԹՁՆՌՊԽԽԪԹՋՋԹԻՀՍՋԽՌՌԽՋ

ԞԱԽՋՌԪԹՌԽՊՁԹՄ    ԭՀՇՋՅԽՌ

ԡԽՋԻՊՁՈՌՁՇՆ   ԰ՇՄՁԼ

ԬԢԠԡՊԽԻՇՅՅԽՆԼՋԼԽՋԻՊՁԺՁՆԿՏԹՌԽՊՋՇՄՍԺՁՄՁՌՑՅԽՄՌՁՆԿԺՇՁՄՁՆԿՈՇ ՁՆՌՋՌԹԺՁՄՁՌՑՁՆՏԹՌԽՊԹՆԼՄՁԿՀՌՈԨԹԭՇՏՇՊԨՇՏ

ՎԹՈՇՊՈՊԽՋՋՍՊԽՇԾՌԽՋՌԻՇՅՈՇՍՆԼԽՐՈՁՊԹՌՁՇՆԼԹՌԽ



### ԩՇՌԫՇԟԹՌԻՀԫՇ  ԤԮԥ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԭՍՊՁՌՑ     

ԦՅՈՍՊՁՌՁԽՋ    ԫ ՇՆԽԯԽՈՇՊՌԽԼ

԰ՌԹԺՁՄՁՌՑՇԾԠՇՅՈՇՍՆԼ ԱՀԽԼԹՑՅԽԹՆՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇՆՄՑՑՁԽՄԼԽԼՊԽԻՇՎԽՊՁԽՋ ՇԾ

ՇԾՆՇՅՁՆԹՄԥՇՏԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽՊԽՄԹՌՁՎԽՄՑՋՌԹԺՄԽՏՁՌՀ ԠԳՋՊԹՆԿՁՆԿ

ԾՊՇՅՌՇ

԰ՌՇՊԹԿԽԠՇՆԼՁՌՁՇՆՋՇԾ

ԱԽՋՌԠՀԽՅՁԻԹՄՋ   ԰ՌՇՊԽԼԹՌՊՇՇՅՌԽՅՈԽՊԹՌՍՊԽՁՆՌՀԽՇՊՁԿՁՆԹՄԻՇՆՌԹՁՆԽՊՁՆԹԼԹՊՃՎԽՆՌՁՄԹՌԽԼ

ԻԹԺՁՆԽՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԟԱԽՋՌԬՊԿԹՆՁՋՅԱԹԺՄԽԤԽՆԽՊԹՄԦՆԾՇՊՅԹՌՁՇՆԞԺՇՍՌՌՀԽԱԽՋՌ԰ՈԽԻՁԽՋԹՆԼԭԹՊԽՆՌԹՄԠԹՊԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԽԻՁԽՋԻՇՅՅՇՆՆԹՅԽ ԞԾՊՁԻԹՆԠՄԹՏԽԼԣՊՇԿ ԢԭԞՊԽԻՇՅՅԽՆԼՋԞԾՊՁԻԹՆԻՄԹՏԽԼԾՊՇԿ ԵԽՆՇՈՍՋՄԹԽՎՁՋԴԽՋՌԽՊՆ#ԞԾՊՁԻԹ%ԻՄԹՏԽԼ ԾՊՇԿ԰ՁՄՍՊԹՆԹ
ԵԽՆՇՈՍՋՌՊՇՈՁԻԹՄՁՋՅԹՑԺԽ ՍՋԽԼԹՋԹՆԹՄՌԽՊՆԹՌԽՋՈԽԻՁԽՋ ՀՇՏԽՎԽՊԹՄՁՋՌ ՇԾԹՄՄՇԾՌՀԽՆԽԻԽՋՋԹՊՑՈՊՇՌՇԻՇՄԼԽՎՁԹՌՁՇՆՋՌՇ ԹԻԻՇՅՅՇԼԹՌԽՌՀՁՋՋՈԽԻՁԽՋՁՋՊԽԻՇՅՅԽՆԼԽԼ ԾՇՊՁՆԻՄՍՋՁՇՆՁՆՌՀԽՋՌՍԼՑՊԽՈՇՊՌԱՀԽԿՍՁԼԽՄՁՆԽ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹ ՍՋԽԼՌՇՋՍՈՈՇՊՌՌՀԽՊԽՄՁԹԺՁՄՁՌՑՇԾՌՀԽՌԽՋՌԺԽ

ՁԼԽՆՌՁԾՁԽԼ԰ՈԽԻՁԽՋՋԻՁԽՆՌՁԾՁԻՆԹՅԽ ԵԽՆՇՈՍՋՄԹԽՎՁՋ԰ՈԽԻՁԽՋՋՌՊԹՁՆ
ՁԾՋՌԹՌԽԼ ԫՇՌԯԽՈՇՊՌԽԼԲ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ
ԢԭԞ
ԠՇՊՊԽԻՌՁՇՆՋԹՆԼԠՄԹՊՁԾՁԻԹՌՁՇՆՋՇՆԱԽԻՀՆՁԻԹՄԞՋՈԽԻՌՋՇԾՌՀԽԱԽՋՌԤՍՁԼԽՄՁՆԽՋԾՇՊՌՀԽԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅԱՁԽՊԞՋՋԹՑՋ
ԬԠ԰ԭԭԱԽՋՌԤՍՁԼԽՄՁՆԽ԰ԽՊՁԽՋԪԹՊԻՀԬԾԾՁԻԽՇԾԠՀԽՅՁԻԹՄ԰ԹԾԽՌՑԹՆԼԭՇՄՄՍՌՁՇՆԭՊԽՎԽՆՌՁՇՆ
ԬԠ԰ԭԭԴԹՋՀՁՆԿՌՇՆԡԠՀՌՌՈՏՏՏԽՈԹԿՇՎԽՆԼՇՈՍԺՋԹՋՋԹՑՎԹՄՁԼԹՌՁՇՆԻՄԹՊՁԾՁԻԹՌՁՇՆԼՇԻՈԼԾԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԽՊԽՈԹՊԽՆՌՋՅԹՁՆՌԹՁՆԽԼԹՋՁՆՀՇՍՋԽՋՌՇԻՃ!ԶԽՋ ԦՆՀՇՍՋԽԻՍՄՌՍՊԽՏԹՋՇՊՁԿՁՆԹՄՄՑՇԺՌԹՁՆԽԼԾՊՇՅԫԹՋԻՇԣՇՊՌԞՌՃՁՆՋՇՆԴՁՋԻՇՆՋՁՆԹՆԼՏԹՋՅԹՁՆՌԹՁՆԽԼԹՋԺՊԽԽԼԽՊՋԾՇՊԹՈՈՊՇՐՁՅԹՌԽՄՑՇՆԽՑԽԹՊՈՊՁՇՊՌՇՍՋԽԾՇՊԿԽՆԽՊԹՌՁՆԿՌԹԼՈՇՄԽՋՍՋԽԼՁՆՌՀՁՋԽՐՈՇՋՍՊԽ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՄԹՊՎԹԽ ՍՋԽԼ ՁՆ ՌՀԽ ԹՋՋԹՑԺԽԼԽՊՁՎԽԼԾՊՇՅՁՆՀՇՍՋԽԹԼՍՄՌՋԴԽՊԽՈԹՊԽՆՌԹՄԹԻԻՄՁՅԹՌՁՇՆԻՇՆԼՁՌՁՇՆՋՋԹՅԽԹՋԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԶԽՋԞԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԾՇՊՈԹՊԽՆՌԹՄԾՊՇԿՋ
ՁԾԹՈՈՄՁԻԹԺՄԽԠՇՆՌՁՆՍՇՍՋԡԽՌԹՁՄՋՇՆՈԹՊԽՆՌԹՄԾԽԽԼՁՆԿ ԡՍՊՁՆԿՌՀԽՈՊԽԽՐՈՇՋՍՊԽՈԽՊՁՇԼՌԹԼՈՇՄԽՋՏԽՊԽԾԽԼՌՏՁԻԽՈԽՊԼԹՑՏՁՌՀՅԿՌԹԼՈՇՄԽՏՁՌՀՁՆԻՊԽԹՋՁՆԿՊԹՌԽՋՌՀՊՇՍԿՀՇՍՌՌՀԽԽՐՈՇՋՍՊԽԱԹԼՈՇՄԽՋՏԽՊԽԾԽԼԵԽՆՇՈՍՋԢՐՈՊԽՋՋԱԹԼՈՇՄԽԣՇՇԼ
ԵԽՆՇՈՍՋԢՐՈՊԽՋՋԟՊՇՇՃՋՎՁՄՄԽԣՄՇՊՁԼԹԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՈԹՊԽՆՌԹՄՀԽԹՄՌՀ ԱՀԽԺՊՇՇԼՋՌՇԻՃԼՁԼՆՇՌՋՀՇՏԹՆՑՋՁԿՆՇԾՋՁԻՃՆԽՋՋԼՁՋԽԹՋԽՁՆՂՍՊՁԽՋՇՊԹԺՆՇՊՅԹՄՁՌՁԽՋԾՊՇՅՌՀԽԼԹՑՇԾՊԽԻԽՁՈՌՌՇՌՀԽԼԹՑՇԾՈՊԽԽՐՈՇՋՍՊԽՁՆՁՌՁԹՌՁՇՆԱԹԺՄԽԩԹՊՎԹՄ԰ԽՄԽԻՌՁՇՆԹՆԼԠԹՊԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԟԽՋՌՋՁՆԿՄԽՋՈԹՏՆ!ԶԽՋ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՌՀԽԺԽՋՌ- ՁՆԼՁՎՁԼՍԹՄՋՈԹՏՆՋՏՁՌՀԹՅՁՆՁՅՍՅՇԾ ՄԹՊՎԹԽՋՈԹՏՆԺԽԽՎԹՄՍԹՌԽԼՌՇՁԼԽՆՌՁԾՑՌՀԽ ԺԽՋՌՋՁՆԿՄԽՋՈԹՏՆԹՆԼՌՀԹՌՌՀԽՄԹՊՎԹԽՋԽՄԽԻՌԽԼ ԾՇՊՌԽՋՌՁՆԿՇՊՁԿՁՆԹՌԽԾՊՇՅՌՀԽԺԽՋՌՋՁՆԿՄԽՋՈԹՏՆ

ՁԽ ՌՀԽՋՈԹՏՆՋԹՊԽՆՇՌԻՇՅՁՐԽԼԫՍՅԺԽՊՇԾՋՈԹՏՆՋԽՎԹՄՍԹՌԽԼ
ՁԾԹՈՈՄՁԻԹԺՄԽԫՍՅԺԽՊՇԾԽԿԿՋՋԹՅՈՄԽԼՈԽՊՋՈԹՏՆԞՌՄԽԹՋՌ ԦՌՏԹՋՆՇՌՋՈԽԻՁԾՁԽԼՇՆՏՀՁԻՀԼԹՑՋԽՅԺՊՑՇՋՏԽՊԽԻՀԽԻՃԽԼԾՇՊՎՁԹԺՁՄՁՌՑԫԣՋՌԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ԫԣ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԼԽԾՁՆՁՌՁՎԽՋՌՍԼՑԺԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԼԹՑՋՈՇՋՌԾԽՊՌՁՄՁՒԹՌՁՇՆԼՈԾ ՁՆՁՌՁԹՌԽԼՏՁՌՀՄԹՊՎԹԽԹՌԫՁԽՍՏՃՇՇՈ-ԣԹԺԽՊ ԫԣԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽ ԼԹՑՋ ՈՇՋՌԾԽՊՌՁՄՁՒԹՌՁՇՆԪԽԹՆՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆՁԾՊԽՈՇՊՌԽԼԫՇՌՅԽԹՋՍՊԽԼԯԹՆԿԽՇԾՌՇՌԹՄՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾՊԽՈՇՊՌԽԼԫՇՌՅԽԹՋՍՊԽԼԴԹՋՌՀԽՇՈՌՁՇՆԹՄՋՁՒԽՋԽՄԽԻՌՁՇՆՅԽՌՀՇԼՍՋԽԼ!ԫՇ ԡԽՌԹՁՄՋՇՆՄԹՊՎԹՄՋԽՄԽԻՌՁՇՆ ԫՁՆԽՀՍՆԼՊԽԼՌԹԼՈՇՄԽՋԾՊՇՅՌՀԽՀՁԿՀԽՋՌՉՍԹՄՁՌՑՋՈԹՏՆՏԽՊԽՌՊԹՆՋԾԽՊՊԽԼՌՇՊԽԹՊՁՆԿՎԽՋՋԽՄՋ
ՌԹԼՈՇՄԽՋԩԬՆԻԽՌԹԼՈՇՄԽՋՊԽԹԻՀԽԼԫԣՋՌԹԿԽՀԽԹՄՌՀՑՌԹԼՈՇՄԽՋՏԽՊԽՊԹՆԼՇՅՄՑՋԽՄԽԻՌԽԼԾՇՊՍՋԽՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽԽՐՈՇՋՍՊԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԩՇԹԼՁՆԿՊԹՌԽ
ՊԽԹՊՁՆԿԼԽՆՋՁՌՑ +ՄԹՊՎԹԽԩ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՊԽԹՊՁՆԿ ԼԽՆՋՁՌՑ ՄՇԹԼՁՆԿ ՊԹՌԽ ՆՇՌ ԽՐԻԽԽԼ ԹՈՈՊՇՐՁՅԹՌԽՄՑ  ՄԹՊՎԹԽԩ ԻՍՄՌՍՊՁՆԿ ՋՑՋՌԽՅ ԾՇՊ ԾՄՇՏՌՀՊՇՍԿՀ ՋՑՋՌԽՅՋ ՇՊ  ՌԹԼՈՇՄԽՋԩ ՁՆ ՋՌԹՌՁԻՊԽՆԽՏԹՄ ԽՐՈՇՋՍՊԽՋՑՋՌԽՅՋԱՑՈԽՇԾԾՇՇԼԵԽՆՇՈՍՋԢՐՈՊԽՋՋԱԹԼՈՇՄԽԣՇՇԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋ԰ԽՊԹԪՁԻՊՇՆ ն ՌՀՊՇՍԿՀՇՍՌ ՈՊԽԽՐՈՇՋՍՊԽ
ԹԾՌԽՊԫԣՋՌԹԿԽԹՆԼ ԼՍՊՁՆԿՌՀԽԽՆՌՁՊԽԼԼԽԾՁՆՁՌՁՎԽՋՌՍԼՑԦԾ ԹՆՇՌՀԽՊԼՁԽՌՁՋՍՋԽԼՌՀԽՋՌՍԼՑՊԽՈՇՊՌՋՀՇՍՄԼ ՈՊՇՎՁԼԽԹՆԹՄՑՋՁՋՇԾՁՇԼՁԼԽԻՇՆՌԽՆՌԹՆԼՈՇՌԽՆՌՁԹՄ ԻՇՆՌԹՅՁՆԹՆՌՋԹՆԼՌՀԽԼՁԽՌՋՀՇՍՄԼ ԼԽՅՇՆՋՌՊԹՌԽԽՉՍԹՄՈԽՊԾՇՊՅԹՆԻԽՌՇ԰ԽՊԹ

ԪՁԻՊՇՆ ն ԰ՇՍՊԻԽՇԾԾՇՇԼԵԽՆՇՈՍՋԢՐՈՊԽՋՋԟՊՇՇՃՋՎՁՄՄԽԣԩԦՇԼՁԼԽԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆԼՁԽՌ
ՁԾՃՆՇՏՆԫՇՌՊԽՈՇՊՌԽԼ ԣՊԽՉՍԽՆԻՑՇԾԾԽԽԼՁՆԿՌՁՅԽՋԼԹՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾԽԽԼՁՆԿՇԻԻՍՊԹՌՄԽԹՋՌ

ՌՏՁԻԽՈԽՊԼԹՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆԾԽԽԼՁՆԿՊԽԿՁՅԽ ԣԽԽԼՁՆԿՊԽԿՁՅԽԾՇՄՄՇՏԽԼԿՍՁԼԽՄՁՆԽՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋ ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌԾՇՇԼՊԹՌՁՇՆՋԼՍՊՁՆԿՌՀԽ ՈՊԽԽՐՈՇՋՍՊԽՈԽՊՁՇԼԺԽՁՆԻՊԽԹՋԽԼԹՄՇՆԿՏՁՌՀ ՄԹՊՎԹՄԿՊՇՏՌՀՌՇԹՈՈՊՇՐՁՅԹՌԽՄՑ ՅԿՄԹՊՎԹԼԹՑԺՑՌԽՋՌՁՆՁՌՁԹՌՁՇՆԢԭԞԹՆԼ ԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌԾՇՇԼՊԹՌՁՇՆՋՁՆԻՊԽԹՋԽ ԾՊՇՅՅԿՄԹՊՎԹԼԹՑԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
԰ՌՍԼՑ ԡԹՑՌՇՅԿՄԹՊՎԹԼԹՑՁՆՌՀԽՄԹՋՌՏԽԽՃ ՇԾՌՀԽՌԽՋՌ
԰ՌՍԼՑԡԹՑԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԠԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԦՆԾՇՊՅԹՌՁՇՆՇՆՌՀԽԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԹՆԼԱԽՋՌԳԽՋՋԽՄԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱՑՈԽՇԾԽՐՈՇՋՍՊԽԣՄՇՏՌՀՊՇՍԿՀ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԾՄՇՏՌՀՊՇՍԿՀ

ՋՑՋՌԽՅԱՑՈԽՇԾԾՄՇՏՌՀՊՇՍԿՀԼՁՄՍՌՁՇՆՋՑՋՌԽՅ
ՁԾԹՈՈՄՁԻԹԺՄԽԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋ ԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋՇՊ ԻՇՆՌՁՆՍՇՍՋԾՄՇՏՋԽՊՁԹՄԼՁՄՍՌԽՊՋԹՊԽ ՊԽԻՇՅՅԽՆԼԽԼ ԣՄՇՏՌՀՊՇՍԿՀՊԹՌԽ
ՁԾԹՈՈՄՁԻԹԺՄԽ+ՅԩՅՁՆ ԠԹՄԻՍՄԹՌԽԼԺԹՋԽԼՇՆԩԾՁՄՄՎՇՄՍՅԽԹՆԼՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌՋԽՎԽՊՑՀՇՍՊՋԱՀՁՋՊԽՋՍՄՌԽԼՁՆԹՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌԽՎԽՊՑՀՇՍՊՋ ԯԽԻՇՅՅԽՆԼԽԼԾՄՇՏՌՀՊՇՍԿՀՊԹՌԽՁՋ ՅԩՅՁՆ
ԻՇՅՈՄԽՌԽՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌԻԹ

ԽՎԽՊՑՀՊՋԞԼԼՁՌՁՇՆԹՄԿՍՁԼԹՆԻԽԾՇՊԹՉՍԹՌՁԻՌԽՋՌԼԽՋՁԿՆՁՋՄՇԻԹՌԽԼՁՆԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ԰ՈԽԻՁԹՄԠՇՆՋՁԼԽՊԹՌՁՇՆՋԾՇՊԠՇՆԼՍԻՌՁՆԿԞՉՍԹՌՁԻԩԹԺՇՊԹՌՇՊՑ԰ՌՍԼՁԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋ
ՁԾԹՈՈՄՁԻԹԺՄԽ԰ՌՇԻՃՋՇՄՍՌՁՇՆՋԾՁՄՄԽԼԻՀԽՅՁԻԹՄԼՁՄՍՌԽՊԻԽՄՄՋՏՀՁԻՀՌՀԽՆՌՊԹՆՋԾԽՊՊԽԼՌՀԽԼՁՄՍՌԽԼՋՌՇԻՃՋՇՄՍՌՁՇՆՋՌՇՌՀԽԹՈՈՊՇՈՊՁԹՌԽՌԽՋՌԻՀԹՅԺԽՊ ԯԽԻՇՅՅԽՆԼԽԼՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊ ԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋԪՁՐՁՆԿԻՀԹՅԺԽՊՁՋ ՊԽԻՇՅՅԽՆԼԽԼԺՍՌՆՇՌՊԽՉՍՁՊԽԼԞԽՊԹՌՁՇՆ ՁՋՆՇՌՊԽԻՇՅՅԽՆԼԽԼԾՇՊՅՁՐՁՆԿԞ ԼԽՅՇՆՋՌՊԹՌՁՇՆՌՀԹՌՌՀԽՌԽՋՌՋՇՄՍՌՁՇՆՁՋ ԻՇՅՈՄԽՌԽՄՑՅՁՐԽԼԺԽԾՇՊԽՁՆՌՊՇԼՍԻԽԼՁՆՌՇՌՀԽ ՌԽՋՌՋՑՋՌԽՅՁՋՊԽԻՇՅՅԽՆԼԽԼԱՀԽ ՊԽԻՇՅՅԽՆԼԽԼԾՄՇՏՋՈՄՁՌՌՁՆԿԹԻԻՍՊԹԻՑՁՋ

ՏՁՌՀՁՆԯԽՆԽՏԹՄՈԽՊՁՇԼԾՇՊՋՌԹՌՁԻՊԽՆԽՏԹՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԦԾՋՌԹՌՁԻՊԽՆԽՏԹՄՁՋՍՋԽԼԢԭԞՊԽԻՇՅՅԽՆԼՋ ՀՊՊԽՆԽՏԹՄՊԽՆԽՏԹՄՈԽՊՁՇԼՁՋ ՊԽԻՇՅՅԽՆԼԽԼՆՇՌՌՇԽՐԻԽԽԼՀՇՍՊՋԞԽՊԹՌՁՇՆ!ԫՇ ԢԭԞՊԽԻՇՅՅԽՆԼՋՅԹՁՆՌԹՁՆՁՆԿԼՁՋՋՇՄՎԽԼ ՇՐՑԿԽՆԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԹՁՊՋԹՌՍՊԹՌՁՇՆ

ՅԿԩ ԞԽՊԹՌՁՇՆՅԹՑԺԽՅԹՁՆՌԹՁՆԽԼ ՌՀՊՇՍԿՀԺՍԺԺՄԽՊՋԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՇՋԽՌ ԺՍԺԺՄԽՊՋԹՌՄԽՎԽՄՋՌՀԹՌԼՇՆՇՌԻԹՍՋԽՋՌՊԽՋՋ

ՇՆՌՀԽՌԹԼՈՇՄԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՇՍՊԻԽՇԾԼՁՄՍՌՁՇՆՏԹՌԽՊ ԩԹԺՇՊԹՌՇՊՑՏԽՄՄՏԹՌԽՊՇԺՌԹՁՆԽԼԾՊՇՅԹՆՇՆՋՁՌԽՅԽՌԽՊԺԽԼՊՇԻՃՏԽՄՄՏԹՋԾՇՊՌՁԾՁԽԼՏՁՌՀԣԢԱԞԵՋՇՄՍՌՁՇՆԹԻԻՇՊԼՁՆԿՌՇԞ԰ԱԪԿՍՁԼԽՄՁՆԽՋԱՀԽՏԹՌԽՊՏԹՋՈՍՅՈԽԼՌՇԹԻՇՆԻՊԽՌԽՊԽՋԽՊՎՇՁՊՏՀԽՊԽՁՌՏԹՋՋՍՈՈՄԽՅԽՆՌԽԼՇՆԼԽՅԹՆԼՏՁՌՀԼԽԻՀՄՇՊՁՆԹՌԽԼԱՇՏՆՇԾԴԹՊԽՀԹՅՏԽՄՄՏԹՌԽՊԴԹՌԽՊՏԹՋԹԽՊԹՌԽԼՈՊՁՇՊՌՇՍՋԽՌՇԽՆՋՍՊԽՈՊՇՈԽՊԽՉՍՁՄՁԺՊԹՌՁՇՆՇԾԼՁՋՋՇՄՎԽԼԿԹՋԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՆԹՌՍՊԹՄՇՊՊԽԻՇՆՋՌՁՌՍՌԽԼ ՏԹՌԽՊՁՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՆԹՌՍՊԹՄՏԹՌԽՊ ԺԽՋՌԽՊՁՄՁՒԽԼՏՁՌՀԲԳԹՆԼՌԽՋՌԽԼԾՇՊ ՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊ ՈՇՋՋՁԺՄԽԻՇՆՌԹՅՁՆԹՆՌՋՁՆԻՄՍԼՁՆԿՃՆՇՏՆ ՋՍԺՋՌՊԹՌԽՋՇԾՌՀԽՁՇԼՁՆԽՌՊԹՆՋՈՇՊՌԽՊՇԾՌՀԽ ՌՀՑՊՇՁԼԿՄԹՆԼ
ԽԿ ԾՄՍՇՊՁԼԽԻՀՄՇՊԹՌԽ ՈԽՊԻՀՄՇՊԹՌԽԬԢԠԡԹԻԻԽՈՌՋԹՆՑՏԹՌԽՊՁՆ ՏՀՁԻՀՌՀԽՌԽՋՌՋՈԽԻՁԽՋՋՀՇՏԻՇՆՌՊՇՄՋՍՊՎՁՎԹՄ ԹՌՄԽԹՋՌԹՋԿՇՇԼԹՋՁՆԼՁԻԹՌԽԼՁՆՌՀԽՌԽՋՌ

ԿՍՁԼԽՄՁՆԽԴԹՋԼՁՄՍՌՁՇՆՏԹՌԽՊԹՆԹՄՑՒԽԼԾՇՊՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊԻՇՆՌԹՅՁՆԹՆՌՋ!ԶԽՋԫՇՈԽՋՌՁԻՁԼԽՋԭԠԟՋՇՊՌՇՐՁԻՅԽՌԹՄՋՏԽՊԽԼԽՌԽԻՌԽԼԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԻՇՆՋՁԼԽՊԽԼՌՇՐՁԻՁՆԹՆՑՇԾՌՀԽՏԹՌԽՊՋԹՅՈՄԽՋԹՆԹՄՑՒԽԼՁՆԹԿՊԽԽՅԽՆՌՏՁՌՀԞ԰ԱԪՋՌԹՆԼԹՊԼՈՊԹԻՌՁԻԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԦՇԼՁԼԽՋՍՈՈՄԽՅԽՆՌԹՌՁՇՆՁՆՏԹՌԽՊ!ԫՇ ԱՀԽՅՇՋՌՊԽԻԽՆՌԹՆԹՄՑՋՁՋՇԾՌՀԽՏԽՄՄՏԹՌԽՊԾՇՍՆԼՁՇԼՁԼԽԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾ+սԿԩ 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 ԾՊԹՅԽՋԹՊԽԹԻԻԽՈՌԹԺՄԽԽՐԹՅՈՄԽՋԱԽՋՌՎԽՋՋԽՄՋՁՒԽՐՐԻՅԣՁՄՄՎՇՄՍՅԽ+ԩԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋՇՆԽՐՈՇՋՍՊԽՋՑՋՌԽՅԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԴԹՌԽՊԮՍԹՄՁՌՑԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋՁՆՌՀԽԱԽՋՌ԰ՑՋՌԽՅԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԥԹՊԼՆԽՋՋ
ՅԿԩԹՋԠԹԠԬ ԫԞՇՆՄՑՊԹՆԿԽՋՈՊՇՎՁԼԽԼԪԽԹՋՍՊԽԼԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԹՆԼՏԽԽՃՄՑՌՀԽՊԽԹԾՌԽՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՀԹՊԼՆԽՋՋՌՇ ՅԿԩԹՋԠԹԠԬ ՈԥԪԽԹՋՍՊԽԼՁՆԹՄՄՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋՇՆԡԹՑԹՆԼՁՆԹՄՌԽՊՆԹՌՁՆԿՊԽՈՄՁԻԹՌԽՋԼԹՁՄՑՌՀԽՊԽԹԾՌԽՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈԥչ ՁՆՌԽՊՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌ ԼՁԾԾԽՊԽՆՌՁԹՄՋՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼԡՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ՅԿԩ 
 
 ԪԽԹՋՍՊԽԼՁՆԹՄՄՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋՇՆԡԹՑԹՆԼՁՆԹՄՌԽՊՆԹՌՁՆԿՊԽՈՄՁԻԹՌԽՋԼԹՁՄՑՌՀԽՊԽԹԾՌԽՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ԡԬ ՅԿԩ
 ԹՁՊՋԹՌՍՊԹՌՁՇՆԬԢԠԡ ՊԽԻՇՅՅԽՆԼՋԡԬԻՇՆԻԽՆՌՊԹՌՁՇՆ ՅԿԩ ԹՁՊՋԹՌՍՊԹՌՁՇՆԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՅՈԽՊԹՌՍՊԽ
ոԠԪԽԹՋՍՊԽԼՁՆԹՄՄՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋՇՆԡԹՑԹՆԼՁՆԹՄՌԽՊՆԹՌՁՆԿՊԽՈՄՁԻԹՌԽՋԼԹՁՄՑՌՀԽՊԽԹԾՌԽՊԞՄՋՇՅԽԹՋՍՊԽԼԻՇՆՌՁՆՍՇՍՋՄՑՁՆԯԽՈՄՁԻԹՌԽԞՇԾՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌԽՅՈԽՊԹՌՍՊԽչ Շ Ԡ ՁՆՌԽՊՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌ ԼՁԾԾԽՊԽՆՌՁԹՄՋՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼ Շ ԠԦՇԼՁԼԽ
սԿԩԫԞԫԞԟԹՋԽԼՇՆՅՇՋՌՊԽԻԽՆՌԹՆԹՄՑՋՁՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՉՍԹՌՁԻՁՇԼՁԼԽՊԹՆԿԽ -սԿԩ
ՋՍՈՈՄԽՅԽՆՌԹՄՁՇԼՁԼԽՋՀՇՍՄԼՆՇՌ
ԽՐԻԽԽԼսԿԩԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞՅՅՇՆՁԹԫՇՌԯԽՈՇՊՌԽԼ ԤԽՆԽՊԹՄՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋԾՇՊԾՊԽՉՍԽՆԻՑՇԾ ՅԽԹՋՍՊԽՅԽՆՌՋԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ՏԹՌԽՊՉՍԹՄՁՌՑՈԹՊԹՅԽՌԽՊՋԺԽՅԽԹՋՍՊԽԼՁՆԹ ԻՇՆՌՊՇՄԹՆԼԹՌՇՆԽՌԽՋՌՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆ ԹՌՄԽԹՋՌՏԽԽՃՄՑԦՆՋՌԹՌՁԻՊԽՆԽՏԹՄՋՑՋՌԽՅՋ ՏԹՌԽՊՉՍԹՄՁՌՑՈԹՊԹՅԽՌԽՊՋՁՆԻՄՍԼՁՆԿ ԹՅՅՇՆՁԹՋՀՇՍՄԼԺԽՅԽԹՋՍՊԽԼՂՍՋՌՈՊՁՇՊՌՇ ՊԽՆԽՏԹՄԦՆԹԼԼՁՌՁՇՆԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԡԬԺԽՅԽԹՋՍՊԽԼԹՌԽԹԻՀԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌ ՄԽԹՋՌՏԽԽՃՄՑԹՆԼՌՀԹՌՌԽՅՈԽՊԹՌՍՊԽԺԽ ՅԽԹՋՍՊԽԼԻՇՆՌՁՆՍՇՍՋՄՑԬԢԠԡ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԡԬԹՆԼՌԽՅՈԽՊԹՌՍՊԽԺԽ ՅԽԹՋՍՊԽԼԹՌՄԽԹՋՌՏԽԽՃՄՑԹՆԼՌՀԹՌՈԥԹՆԼ ՀԹՊԼՆԽՋՋԺԽՅԽԹՋՍՊԽԼԹՌՄԽԹՋՌԹՌՌՀԽ ԺԽԿՁՆՆՁՆԿԹՆԼԽՆԼՇԾՌՀԽՌԽՋՌԣՄՍՇՊՁԼԽԫՇՌԯԽՈՇՊՌԽԼԭԽՊԻՀՄՇՊԹՌԽԫՇՌԯԽՈՇՊՌԽԼԠՀՄՇՊԹՌԽԫՇՌԯԽՈՇՊՌԽԼԞՄՃԹՄՁՆՁՌՑ
ՅԿԩԹՋԠԹԠԬԠՇՆԼՍԻՌՁՎՁՌՑ
սՅՀՇՋԻՅԫԞՇՆՄՑՊԹՆԿԽՋՈՊՇՎՁԼԽԼԪԽԹՋՍՊԽԼԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԹՆԼՏԽԽՃՄՑՌՀԽՊԽԹԾՌԽՊ ԡ԰ՌՍԼՑԡԽՋՁԿՆԹՆԼԞԼԼՁՌՁՇՆԹՄԢՐՈԽՊՁՅԽՆՌԹՄԠՇՆԼՁՌՁՇՆՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԯԹՆԿԽԣՁՆԼՁՆԿ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋ
ՁԾԞՈՈՄՁԻԹԺՄԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԹՊԹՆԿԽԾՁՆԼԽՊԻՇՆԼՍԻՌԽԼ!ԶԽՋԦԾՑԽՋՏՀԹՌՏԹՋՌՀԽՅԽՌՀՇԼԾՇՊԼԽՌԽՊՅՁՆՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽՊԹՆԿԽԾՁՆԼԽՊ!԰ՇՄՍԺՁՄՁՌՑՌՊՁԹՄՋՈՊՁՇՊՌՇՌՀԽՊԹՆԿԽԾՁՆԼԽՊՊԽՎԽԹՄԽԼՌՀԹՌՈՀՇՋՅԽՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋՏԽՊԽՊԽՄԹՌՁՎԽՋՌԹԺՄԽՇՎԽՊՀՇՍՊՋՍՋՁՆԿԹԺՍԾԾԽՊԽԼԹՉՍԽՇՍՋՋՇՄՍՌՁՇՆՇԾՈԥԞՆՁՆՁՌՁԹՄՊԹՆԿԽԾՁՆԼՁՆԿՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼՏՁՌՀՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՍՈՌՇՅԿԩԺՍՌՆՇՌՇՐՁԻՊԽՋՈՇՆՋԽՏԹՋՇԺՋԽՊՎԽԼԞՋԽԻՇՆԼՌՊՁԹՄՏԹՋԻՇՆԼՍԻՌԽԼՏՁՌՀՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՍՈՌՇՅԿԩԱՀԽՋԽԻՇՆԼՊԹՆԿԽԾՁՆԼՁՆԿՋՌՍԼՑՑՁԽՄԼԽԼԹՆԩԠՇԾՅԿԹՁԩԱՀԽՀՁԿՀԽՋՌՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌՏԹՋՋԽՌԹՌԹՈՈՊՇՐՁՅԹՌԽՄՑՇԾՌՀԽԢԠԹՆԼՏՁՌՀԹԼՁՄՍՌՁՇՆԾԹԻՌՇՊՇԾ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽ ՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊԼԽՅՇՆՋՌՊԹՌԽՋ ԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ
ԽԿ  ՅՇՊՌԹՄՁՌՑՏՀՁԻՀԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌ԰ՈԽԻՁԽՋ ԵԽՆՇՈՍՋՄԹԽՎՁՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԩՁԾԽՋՌԹԿԽԫԣԱԽՋՌԼՍՊԹՌՁՇՆՀՇՍՊՋԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԱՀԽՁՆՁՌՁԹՄՊԹՆԿԽԾՁՆԼԽՊՏԹՋԻՇՆԼՍԻՌԽԼՍՆԼԽՊԾՄՇՏՌՀՊՇՍԿՀԻՇՆԼՁՌՁՇՆՋՏՁՌՀՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾԹՆԼՅԿԹՁԩԱՀԽՋԽԻՇՆԼՏԹՋԻՇՆԼՍԻՌԽԼՍՆԼԽՊԾՄՇՏՌՀՊՇՍԿՀԻՇՆԼՁՌՁՇՆՋՏՁՌՀՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾԹՆԼՅԿԹՁԩԱՀԽՀՁԿՀԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽՋԽԻՇՆԼՊԹՆԿԽԾՁՆԼԽՊՏԹՋՌՀԽՀՁԿՀԽՋՌԹՌՌԹՁՆԹԺՄԽԻՇՆԻԽՆՌՊԹՌՁՇՆՏՁՌՀՌՀԽՍՋԽՇԾԹԺՍԾԾԽՊԽԼԹՉՍԽՇՍՋՋՇՄՍՌՁՇՆՏՁՌՀՈԥԱԹԺՄԽԡԽԾՁՆՁՌՁՎԽ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՋՌԼՍՊԹՌՁՇՆԼԹՑՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌՀԽ ԼՍՊԹՌՁՇՆ ՇԾ ՌՀԽ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԼԹՑՋԪԽՌՀՇԼԾՇՊՋԽՄԽԻՌՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԯԹՆԿԽԾՁՆԼԽՊՇԾՌՀԽԢԠՏՁՌՀԹԼՁՄՍՌՁՇՆԾԹԻՌՇՊՇԾԾՇՊՌՀԽՌՏՇՄՇՏԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾՌՀԽ ՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊԼԽՅՇՆՋՌՊԹՌԽՋ ԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ
ԽԿ  ՅՇՊՌԹՄՁՌՑՏՀՁԻՀԽՎԽՊԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌԯԽԾԽՊԽՆԻԽՋՌՍԼՑԻՁՌԹՌՁՇՆ
ՁԾԹՈՈՄՁԻԹԺՄԽԫՇՌԹՈՈՄՁԻԹԺՄԽ԰ԽՈԹՊԹՌՁՇՆՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌՀԽ ՅԹՐՁՅՍՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՋԽՈԹՊԹՌՁՇՆ ԺԽ  ԹՆԼ ՌՀԽ ՅՁՆՁՅՍՅԺԽԫՍՅԺԽՊՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹՆԼԹԻՇՆՌՊՇՄՈՄՍՋՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄՁԾԹՈՈՊՇՈՊՁԹՌԽԞՊԽՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹԼՂՍՋՌԽԼԾՇՊՈՍՊՁՌՑ!ԶԽՋ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԦՆԼՁԻԹՌԽՌՀԽՌՑՈԽՇԾՎԹՄՍԽՋՈՊԽՋԽՆՌԽԼԾՇՊՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋԪԽԹՆՅԽԹՋՍՊԽԼ ԩՁՅՁՌՇԾՉՍԹՆՌՁԾՁԻԹՌՁՇՆ
ԩԬԮ ՅԿԹՁԩ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՇՊԻՀԽՅՁԻԹՄՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՄՇՏՌՀԽԩԬԮԹՆԹՄՑՋԽՋԺԽ ԻՇՆԼՍԻՌԽԼՇՆՌՀԽՋՌՇԻՃՋՇՄՍՌՁՇՆՋԩԽՎԽՄՇԾԼԽՌԽԻՌՁՇՆ
ԩԬԡ ԫՇՌԯԽՈՇՊՌԽԼԣՊԽՉՍԽՆԻՑՇԾՅԽԹՋՍՊԽՅԽՆՌ ԡԹՑՋԹՆԼ ԱՀԽՊԽՋՍՄՌՋԾՊՇՅՌՀԽԡԹՑՋԹՅՈՄՁՆԿԼԽՅՇՆՋՌՊԹՌԽԼՈՇՇՊԮԠՊԽԻՇՎԽՊՁԽՋՊԹՆԿՁՆԿԾՊՇՅՌՇՇԾՆՇՅՁՆԹՄԾՇՊՌՁԾՁԽԼՄԽՎԽՄՋԡՍԽՌՇՌՀԽՈՇՇՊՊԽԻՇՎԽՊՁԽՋՌՀԽՈՊԽԻՁՋՁՇՆԹՆԼՉՍԹՄՁՌՑԻՇՆՌՊՇՄԾՇՊՌՀՁՋԹՆԹՄՑՋՁՋՏԽՊԽԼԽԽՅԽԼՉՍԽՋՌՁՇՆԹԺՄԽԱՀԽՊԽԾՇՊԽՌՀԽԽՐՈՇՋՍՊԽՋՑՋՌԽՅՏԹՋՊԽՋԹՅՈՄԽԼՇՆԡԹՑԱՀԽՋԽՊԽԻՇՎԽՊՁԽՋՏԽՊԽՏՁՌՀՁՆԽՐՈԽԻՌԹՌՁՇՆՋԹՆԼՏԽՊԽՍՋԽԼԾՇՊԻԹՄԻՍՄԹՌՁՇՆՇԾՅԽԹՆՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋ
ԡԹՑՎԹՄՍԽՋՏԽՊԽԽՐԻՄՍԼԽԼ ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌԽՋՌՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆ ԺԽՅԽԹՋՍՊԽԼՁՆՇՆԽՌԹՆՃԹՌԽԹԻՀՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԹՆԼԽՎԽՊՑՏԽԽՃ

ՌՀԽՊԽԹԾՌԽՊԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆԻՇՆՌՊՇՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ  ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԽՍՋԽՇԾԹ ԻՇՆԻՍՊՊԽՆՌՋՇՄՎԽՆՌԻՇՆՌՊՇՄՏՀԽՆԹՋՇՄՍԺՁՄՁՒՁՆԿ ԹԿԽՆՌՁՋՍՋԽԼԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՈԽՊՌԽՋՌՁՌԽՅՌՊԽԹՌՅԽՆՌՄԽՎԽՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՄԹՊՎԹԽՈԽՊՌՊԽԹՌՅԽՆՌԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ ԴԹՋԹՋՇՄՎԽՆՌՍՋԽԼ!ԫՇ԰ՇՄՎԽՆՌՌՑՈԽ
ՁԾԹՈՈՄՁԻԹԺՄԽ ԫԞԪԹՐՁՅՍՅՋՇՄՎԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՋՇՄՎԽՆՌՆՇՌԽՐԻԽԽԼ

ՅՄԩ ԬԢԠԡՊԽԻՇՅՅԽՆԼՋՌՀԹՌՋՇՄՎԽՆՌ ՀԹՎԽՆՇԽԾԾԽԻՌՇՆՋՍՊՎՁՎԹՄՆՇՊՈՊՇԼՍԻԽԹՆՑ ՇՌՀԽՊԹԼՎԽՊՋԽԽԾԾԽԻՌՋԹՆԼՌՀԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆ ՆՇՌԺԽԿՊԽԹՌԽՊՌՀԹՆՅՄԩ ԥՍՌԻՀՁՆՋՇՆԱԥ԰ՀՁՄՄԹԺԽԽՊԫԴՁՆՌԽՊԪԧԭՁԻՃԾՇՊԼԡԟ
ԞԻՍՌԽԹՆԼԻՀՊՇՆՁԻԽԾԾԽԻՌՋՇԾԻԹՊՊՁԽՊՋՇՄՎԽՆՌՋՁՆԹՉՍԹՌՁԻՇՊԿԹՆՁՋՅՋԞԻՊՁՌՁԻԹՄՊԽՎՁԽՏԯԽՎՁԽՏԞՉՍԹՌՁԻԱՇՐՁԻՇՄՇԿՑՈՈ-ԬԢԠԡ
ԤՍՁԼԹՆԻԽԡՇԻՍՅԽՆՌՇՆԞՉՍԹՌՁԻԱՇՐՁԻՁՌՑԱԽՋՌՁՆԿՇԾԡՁԾԾՁԻՍՄՌ԰ՍԺՋՌԹՆԻԽՋԹՆԼԪՁՐՌՍՊԽՋԢՆՎՁՊՇՆՅԽՆՌԹՄԥԽԹՄՌՀԹՆԼ԰ԹԾԽՌՑԭՍԺՄՁԻԹՌՁՇՆՋ԰ԽՊՁԽՋՇՆԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ          ԢԭԞԪԯԦԡԫՍՅԺԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋՋԽԼ! ԫՇԹԺՄԽ ԫԞԹՌՁՇՆ
Ջ ԫԞՀՊՋՄՁԿՀՌՀՊՋԼԹՊՃԞՅՁՆՍՌԽՄՇՏՄՁԿՀՌՌՊԹՆՋՁՌՁՇՆՈԽՊՁՇԼՏԹՋՍՋԽԼԺԽՌՏԽԽՆՌՀԽՄՁԿՀՌԹՆԼԼԹՊՃՈՀԹՋԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈՀՇՌՇՈԽՊՁՇԼ

ՄՁԿՀՌԼԹՊՃՋՍՊԾԹԻԽ ԨՄՍՐ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՄՁԿՀՌՁՆՌԽՆՋՁՌՑ-ԨՄՍՐ ԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽԱՀԽՋՌՇԻՃՋՇՄՍՌՁՇՆՋՏԽՊԽՊԽՈՇՊՌԽԼԹՋԻՄԽԹՊԹՆԼԻՇՄՇՊՄԽՋՋԭԹՊՁՋԣՊԹՆԻԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԱՊԽԹՌՅԽՆՌԠՇՆԻԽՆՌՊԹՌՁՇՆՋՁՆՌՀԽԞՅՈՀՁԺՁԹՆԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԱՊԽԹՌՅԽՆՌԦԡԫՇՅՁՆԹՄԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՋՍՊԽԼԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՆԠԳ
ԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ ԩԬԮԫԞ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՌԽՋՌՁՌԽՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՅԹՁՆՌԹՁՆԽԼԹՌԹԻՇԽԾԾՁԻՁԽՆՌՇԾ

ՎԹՊՁԹՌՁՇՆ
ԠԳ ԱՊԽԹՌՅԽՆՌԱՊԽԹՌՅԽՆՌԱՊԽԹՌՅԽՆՌԞԺԺՊԽՎՁԹՌՁՇՆՋԠԳԠՇԽԾԾՁԻՁԽՆՌՇԾՎԹՊՁԹՌՁՇՆ       ԢԬԺՋԽՊՎԹՌՁՇՆՋԟՁՇՄՇԿՁԻԹՄԢՆԼՈՇՁՆՌՋԡԹՑԫԣՋՌԹԿԽՏԽՌՏԽՁԿՀՌՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩԩՆՇՊՅԹՄՁՒԽԼԥԩԩ        ԡԹՑԫԣՋՌԹԿԽՏԽՌՏԽՁԿՀՌՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԥԩԩՆՇՊՅԹՄՁՒԽԼԥԩԩՌՀՑՊՇՁԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑ        ԡԹՁՄՑՅՇՊՌԹՄՁՌՑՋՍԺՄԽՌՀԹՄԽԾԾԽԻՌՋԴԽՊԽՊԹՏ
ՁՆԼՁՎՁԼՍԹՄԼԹՌԹՈՊՇՎՁԼԽԼ!ԶԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋՇԾՅՇՊՌԹՄՁՌՑԹՆԼԻՄՁՆՁԻԹՄՋՁԿՆՋՇԻԻՍՊԼԹՁՄՑԹՌԹՅՁՆՁՅՍՅՇՌՀԽՊՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽՊԽԻՇՅՅԽՆԼԽԼ ԹՋԾՇՄՄՇՏՋԫԣ ԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽ
ԼԹՑՋԹՆԼԹՆՑԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄՇՈՅԽ ՆՌՁՆԼՁԻԹՌԽԼԺՑՌԹԼՈՇՄԽՋՌՀԹՌԻԹՆՆՇՌԺԽԹՋՋՁԿՆԽԼԹՆԫԣՋՌԹԿԽ
ԼԹՑՋԹՆԼ ՀՁՆԼՄՁՅԺՄԽՆԿՌՀ
ԼԹՑՋԹՆԼՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
ԼԹՑՋԹՆԼ ԺՇԼՑՏԽՁԿՀՌ
ՌԽՋՌՁՆՁՌՁԹՌՁՇՆԾՇՊՇՈՌՁՇՆԹՄՋՁՒԽԺԹՋԽԼՄԹՊՎԹՄՋԽՄԽԻՌՁՇՆԹՆԼՌՀՑՊՇՁԼ
ԿՄԹՆԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑ
ԼԹՑԫՇՌԽՌՀԽՀՁ ՋՌՇՈԹՌՀՇՄՇԿՑՋԽԻՌՁՇՆՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽԹՄՋՇՁՆԻՄՍԼԽՋՌՀՑՊՇՁ ԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑՇԺՋԽՊՎԹՌՁՇՆՋ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԦԦ ԯԢ԰ԲԩԱ԰ԞԫԡԡԦ԰ԠԲ԰԰ԦԬԫ

Ԟ ԯԽՋՍՄՌՋ

ԡԹՁՄՑՄԹՊՎԹՄՋՍՊՎՁՎԹՄՏԹՋՆՇՌՈՊՇՎՁԼԽԼԯԹՌՀԽՊՌՇՌԹՄՋՍՊՎՁՎԹՄ ՇՎԽՊՌՀԽԼԹՑԽՐՈՇՋՍՊԽՈԽՊՁՇԼՏԹՋՊԽՈՇՊՌԽԼ

ԟՑՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆՋՍՊՎՁՎԹՄԹՎԽՊԹԿԽԼՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌ ՊՇՄԹՆԼԹՆԼ
ՄՇՋՋՇԾ

ՌԹԼՈՇՄԽՇՎԽՊԼՍՊԹՌՁՇՆՇԾՌԽՋՌՌՁՅԽՈՇՁՆՌՍՆՃՆՇՏՆՁՆՌՀԽՅԽԹՆ ՅԽԹՋՍՊԽԼԹՆԼՅԿ

ԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽ

ԱԹԺՄԽԩԹՊՎԹՄԪՇՊՌԹՄՁՌՑՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ 
ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԩԹՊՎԹՄԪՇՊՌԹՄՁՌՑ

ԡԹՑ  

### ԡԹՑ

Ն ԪՇՊՌԹՄՁՌՑ ԪՇՊՌԹՄՁՌՑ Ն ԪՇՊՌԹՄՁՌՑ ԪՇՊՌԹՄՁՌՑ

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ  ԫԯ ԫԯ ԫԯ ԫԯ 

  ԫԯ ԫԯ ԫԯ ԫԯ 

  ԫԯ ԫԯ ԫԯ ԫԯ 

  ԫԯ ԫԯ ԫԯ ԫԯ 

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

### ԰ԹՅՈՄԽՋՁՒԽԹՆԼԻՍՅՍՄԹՌՁՎԽՅՇՊՌԹՄՁՌՑՎԹՄՍԽՋԹՌԡԹՑՈՊՁՇՊՌՇ ՁՆՌԽՊՁՅՋԹԻՊՁԾՁԻԽ

ԪԽԼՁԹՆԫԣԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽՏԹՋՇՆԡԹՑՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ
ԱԹԺՄԽ

ԟՑՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆՅԽԼՁԹՆԫԣԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽՏԹՋՁՆՌՀ ԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՅԽԹՆՅԽԹՋՍՊԽԼ

ՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹՆԼՁՆՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼ ԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌ

ԿՊՇՍՈՋ
ԱԹԺՄԽԱՀԽ ՌՀ 

### ԹՆԼ ՌՀ 

### ՈԽՊԻԽՆՌՁՄԽՋՇՆԡԹՑԼՁԼՆՇՌԼՁԾԾԽՊԺՑՅՇՊԽՌՀԹՆՋՌԹԿԽՋԫՇ

ԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄՇՈՅԽՆՌՏԹՋՊԽՈՇՊՌԽԼ

ԱԹԺՄԽԩԹՊՎԹՄԡԽՎԽՄՇՈՅԽՆՌՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ -ԡԽՎԽՄՇՈՅԽՆՌԹՄ԰ՌԹԿԽԹՆԼԞՋՑՆԻՀՊՇՆՇՍՋԡԽՎԽՄՇՈՅԽՆՌ

ԱՊԽԹՌՅԽՆՌ 
ՅԿԹՁԩ ԡԽՎԽՄՇՈՅԽՆՌԹՄ԰ՌԹԿԽ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  #ՅԽԹՆՅԽԹՋՍՊԽԼ% ԡԹՑ ԡԹՑ

Ն ԪԽԼՁԹՆ

԰ՌԹԿԽ ԞՋՑՆԻՀՊՇՆՇՍՋ Ն ԪԽԼՁԹՆ

԰ՌԹԿԽ ԞՋՑՆԻՀՊՇՆՇՍՋ

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ      

      

      

      

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

ԪԽԹՆՆՇՊՅԹՄՁՒԽԼԥԩԩՊԹՆԿԽԼԾՊՇՅՌՇՇՆԡԹՑԹՆԼԾՊՇ ՅՌՇՇՆԡԹՑ
ԱԹԺՄԽ



ԱԹԺՄԽԩԹՊՎԹՄԡԽՎԽՄՇՈՅԽՆՌՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ -ԥՁՆԼԩՁՅԺԩԽՆԿՌՀ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԥՁՆԼԩՁՅԺԩԽՆԿՌՀ
ԥԩԩ

ԡԹՑ ԡԹՑ

Ն ԪԽԹՆ

ՅՅ չ԰ԡ ԥԩԩ

԰Գԩ  Ն ԪԽԹՆ

ՅՅ չ԰ԡ ԥԩԩ

԰Գԩ 



### ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ        

        

        

        

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԰ԡ 

### ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

 

###  ԰ՍՅՅԹՊՑՊԽՋՍՄՌՋԾՇՊՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰ԳԩԹՊԽՈՊԽՋԽՆՌԽԼՁՆՌ ՀԽՆԽՐՌՌԹԺՄԽ ԱԹԺՄԽ 

ԴՀՇՄԽԺՇԼՑՏԽՌՏԽՁԿՀՌՇՆԡԹՑԹՎԽՊԹԿԽԼԿՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼՊԹՆԿԽԼԾՊՇՅՌՇ

ԿՁՆՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ
ԱԹԺՄԽԬՆԡԹՑԺՇԼՑՏԽՁԿՀՌ ԹՎԽՊԹԿԽԼԿՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԹՆԼՊԹՆԿԽԼԾՊՇՅՌՇԿՁՆՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ

ԱԹԺՄԽԩԹՊՎԹՄԤՊՇՏՌՀՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

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             

            

            

            



### ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԫԡ 

### ԫՇՌԼԽՌԽՊՅՁՆԽԼ ԰ԡ 

### ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

 

### ԞՄՋՇՊԽԾԽՊՊԽԼՌՇԹՋ՟ՏԽՌՏԽՁԿՀՌՠՁՆՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽ

ԱՀՑՊՇՁԼԿՄԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑՊԽՎԽԹՄԽԼՌՀՑՊՇՁԼԿՄԹՆԼՀՑՈԽՊՌՊՇՈՀՑԾՇՄՄՁԻՍՄԹՊԻԽՄՄՀՑՈԽՊՈՄԹՋՁԹԹՆԼԾՇՄՄՁԻՍՄԹՊ

ԻԽՄՄՀՑՈԽՊՌՊՇՈՀՑԥՇՏԽՎԽՊՌՀԽՋԽԾՁՆԼՁՆԿՋՏԽՊԽԻՇՆՋՁԼԽՊԽԼՍՆՊԽՄԹՌԽԼՌՇՌՊԽԹՌՅԽՆՌԺԽԻԹՍՋԽՌՀԽՑՏԽՊԽ

ՇՆՄՑՇԾՅՁՄԼՋԽՎԽՊՁՌՑԹՆԼՇԻԻՍՊՊԽԼՁՆԹՄՄՌՊԽԹՌԽԼԿՊՇՍՈՋԹՆԼԻՇ ՆՌՊՇՄՋՁՆԹՅԹՆՆԽՊՍՆՊԽՄԹՌԽԼՌՇԻՇՆԻԽՆՌՊԹՌՁՇՆ

ԱԹԺՄԽՋԹՆԼ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽԤՊՇՋՋԭԹՌՀՇՄՇԿՑԹՆԼԥՁՋՌՇՈԹՌՀՇՄՇԿՑՇԾՌՀԽԱՀՑՊՇՁԼԤՄԹ ՆԼՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ 

### ԱՀՑՊՇՁԼԤՄԹՆԼ

ԥՑՈԽՊՌՊՇՈՀՑ ԱՀՑՊՇՁԼԤՄԹՆԼ

ԞՌՊՇՈՀՑ ԣՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՌՊՇՈՀՑ ԣՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ



### ԫԽԿԹՌՁՎԽ

ԠՇՆՌՊՇՄ  

###         

        

        

        

         

        

        

        

         

        

        

        

         

        

        

        

  ԱՀՑՊՇՁԼԿՄԹՆԼԿՊՇՋՋՈԹՌՀՇՄՇԿՑԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑԹՊԽԿՊԹԼԽԼ -ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՄԼ

ԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԬԢԠԡԫՇԾՇՊՊԽԾԽՊԽՆԻԽ

  ԪՁՋՋՁՆԿՌՁՋՋՍԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԞԼԼՁՌՁՇՆԹՄԱՀՑՊՇՁԼԤՄԹՆԼԥՁՋՌՇՈԹՌՀՇՄՇԿՑԬԺՋԽՊՎԹՌՁՇՆՋՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԮՍԹՄՁՌԹՌՁՎԽԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԣՇՄՄՁԻՍՄԹՊԩՍՅԽՆԞՊԽԹ
ԦՆԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԩՍՅԽՆԞՊԽԹ
ԡԽԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄԥԽՁԿՀՌ
ԦՆԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄԥԽՁԿՀՌԡԽԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄ԰ՀԹՈԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ      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 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԮՍԹՄՁՌԹՌՁՎԽԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԣՇՄՄՁԻՍՄԹՊԩՍՅԽՆԞՊԽԹ
ԦՆԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԩՍՅԽՆԞՊԽԹ
ԡԽԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄԥԽՁԿՀՌ
ԦՆԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄԥԽՁԿՀՌԡԽԻՊԽԹՋԽԣՇՄՄՁԻՍՄԹՊԠԽՄՄ԰ՀԹՈԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ     ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԱՀՑՊՇՁԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑՁՋԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԬԢԠԡԫՇԾՇՊՊԽԾԽՊԽՆԻԽ ԱՀԽՊԽՏԹՋՅՁՋՋՁՆԿՌՁՋՋՍԽԾՊՇՅՇՆԽՌԹԼՈՇՄԽԟԽԿՁՆՆՁՆԿՇՆԡԹՑԹՆԼԻՇՆՌՁՆՍՁՆԿՌՀՊՇՍԿՀՇՍՌՌՀԽԼՍՊԹՌՁՇՆՇԾՌՀԽԽՐՈՇՋՍՊԽՈԽՊՁՇԼՋՈՁՆԹՄԻՍՊՎԹՌՍՊԽՏԹՋՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԟՑՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆՁՆԻՁԼԽՆԻԽՇԾՋՈՁՆԹՄԻՍՊՎԹՌՍՊԽԹՎԽՊԹԿԽԼՁՆՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԹՆԼԹՆԼՁՆՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ                  ԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԠՄՁՆՁԻԹՄ԰ՁԿՆՋՁՆ ԵԽՆՇՈՍՋՄԹԽՎՁՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԠՄՁՆՁԻԹՄ԰ՁԿՆՋԱՑՈԽՆԦՆԻՁԼԽՆԻԽԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ԰ՈՁՆԹՄԻՍՊՎԹՌՍՊԽ  ԰ՈՁՆԹՄԻՍՊՎԹՌՍՊԽ  ԰ՈՁՆԹՄԻՍՊՎԹՌՍՊԽ  ԰ՈՁՆԹՄԻՍՊՎԹՌՍՊԽ  

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԟ ԰ՌՍԼՑԞՍՌՀՇՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

ԞՆԹՄՑՒԽԼԽՆԼՈՇՁՆՌՋՁՆԻՄՍԼԽԼԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽ԰ԳԩԥԩԩԹՆԼ ՏԽՌՏԽՁԿՀՌԞՄՄՋՌԹՌՁՋՌՁԻԹՄԻՇՆԻՄՍՋՁՇՆՋ

ՏԽՊԽՅԹԼԽԹՌՌՀԽՄԽՎԽՄՇԾԻԽՊՌԹՁՆՌՑԽՐԻԽՈՌՁՆՌՀԽԻԹՋԽՇԾՌՀԽԺԹՋՁԻԹՋՋՍՅՈՌՁՇՆՌԽՋՌՋ
԰ՀԹՈՁՊՇԴՁՄՃՋ0

ԱԽՋՌԹՆԼԟԹՊՌՄԽՌՌ0ՋԱԽՋՌՁՆՏՀՁԻՀՌՀԽՄԽՎԽՄՇԾԻԽՊՌԹՁՆՌՑ ՏԹՋԹՈՈՄՁԽԼ

ԪՇՊՌԹՄՁՌՑՏԹՋԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽԣՁՋՀԽՊ0ՋԢՐԹԻՌԱԽՋՌՏՁՌՀԟՇՆԾԽ ՊՊՇՆՁԥՇՄՅԹԼՂՍՋՌՅԽՆՌԡԽՎԽՄՇՈՅԽՆՌԹՄ

ՋՌԹԿԽՏԹՋԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՋՌԽՈԼՇՏՆՌԽՋՌ ԥԩԩ԰ԳԩԹՆԼՏԽՌՏԽՁԿՀՌՏԽՊԽ

ԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌՏՀԽՆԹՅՇՆՇՌՇՆՁԻՌՊ ԽՆԼՏԹՋՈՊԽՋԽՆՌԴՀԽՆԹՅՇՆՇՌՇՆՁԻ

ՌՊԽՆԼՏԹՋՆՇՌԹՈՈԹՊԽՆՌՌՀԽՋԽԽՆԼՈՇՁ ՆՌՋՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽ ԡՍՆՆԽՌՌ0ՋԪՍՄՌՁՈՄԽԠՇՅՈԹՊՁՋՇՆՌԽՋՌ

ՏՀԽՆՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՈԹՊԹՅԽՌՊՁԻՋՌԹՌՁՋՌՁԻՋՏԽՊԽՅԽՌՇՊՌՀԽ ԪԹՆՆԴՀՁՌՆԽՑՌԽՋՌՏՁՌՀԟՇՆԾԽՊՊՇՆՁԥՇՄՅ

ԹԼՂՍՋՌՅԽՆՌ ՏՀԽՆ ՌՀԽ ԼԹՌԹ ԼՁԼ ՆՇՌ ՅԽԽՌ ՌՀԽ ԹՋՋՍՅՈՌՁՇՆՋ ՇԾ ՆՇՊՅԹՄՁՌՑ ԹՆԼ ՀՇՅՇՋՃԽԼԹՋՌՁԻՁՌՑ

ԠԢԱԦ԰ԠՇՅՈՊԽՀԽՆՋՁՎԽԢՆՎՁՊՇՆՅԽՆՌԹՄԱՇՐՁԻՁՌՑԦՆԾՇՊՅԹՌՁՇՆ԰ՑՋՌԽՅ ԱԪ 

### ԳԽՊՋՁՇՆՋՇԾՌՏԹՊԽՏԹՋՍՋԽԼ

ՌՇՈԽՊԾՇՊՅԹՄՄՋՌԹՌՁՋՌՁԻԹՄԻՇՅՈՍՌԹՌՁՇՆՋ

ԟՑՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆՆՇԼՁԾԾԽՊԽՆԻԽՋՏԽՊԽԾՇՍՆԼՁՆՄԹՊՎԹՄՋՍՊՎՁՎԹՄԺԽՌՏԽԽՆՌՀԽԻՇՆՌՊՇՄԹՆԼՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ

ԬՆԡԹՑՆՇՋՁԿՆՁԾՁԻԹՆՌՁՆՀՁԺՁՌՁՇՆՋՇՊՈՊՇՅՇՌՁՇՆՋՏԽՊԽՇԺՋԽՊՎԽ ԼԾՇՊԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽՇՊՏԽՌՏԽՁԿՀՌ

ԹՌԹՆՑՌՊԽԹՌՅԽՆՌԿՊՇՍՈ԰ԳԩՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌՌՀԽՀՁ ԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՏՀԽՊԽԹՋԺՇՌՀԥԩԩ

ԹՆԼՆՇՊՅԹՄՁՒԽԼԥԩԩՏԽՊԽՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌՌՀԽՅՁԼԼՄԽԹՆԼ ՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԬՆԡԹՑ

ԼԽՎԽՄՇՈՅԽՆՌԹՄՋՌԹԿԽԥԩԩԹՆԼՆՇՊՅԹՄՁՒԽԼԥԩԩՏԽՊԽԹՄՄՋՁԿՆՁԾՁԻԹ ՆՌՄՑՊԽԼՍԻԽԼՁՆՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԽՋՌ

ՌՊԽԹՌՅԽՆՌ ԿՊՇՍՈՋ ՊԽՄԹՌՁՎԽՌՇՌՀԽ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄԥՇՏԽՎԽՊ ՇՆ ԡԹՑ ՏԽՌՏԽՁԿՀՌ ԹՆԼ԰ԳԩՏԽՊԽ

ՍՆԹԾԾԽԻՌԽԼԹՌԹՄՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋԱՀԽՊԽՏԽՊԽՆՇԹՈՈԹՊԽՆՌՌՊԽԹ ՌՅԽՆՌՊԽՄԹՌԽԼՌՊԽՆԼՋՁՆՌՀՑՊՇՁԼԿՄԹՆԼ

ՀՁՋՌՇՈԹՌՀՇՄՇԿՁԻԹՄՇԺՋԽՊՎԹՌՁՇՆՋ

ԦՆՊԽԿԹՊԼՋՌՇՋՈՁՆԹՄԻՍՊՎԹՌՍՊԽՌՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌՀԹՌ ՌՀԽՁՆԻՁԼԽՆԻԽՇԾՋՈՁՆԹՄԼԽԾՇՊՅՁՌՁԽՋՁՆՌՀԽ

ԻՍՊՊԽՆՌԹՋՋԹՑՏԽՊԽՍՆՊԽՄԹՌԽԼՌՇՌՊԽԹՌՅԽՆՌՏՁՌՀՈՀՇՋՅԽՌԣՍՊՌՀԽՊՁՌՏԹՋՊԽՈՇՊՌԽԼՌՀԹՌԺԹՋԽԼՇՆՀՁՋՌՇՊՁԻԹՄ

ԻՇՆՌՊՇՄԼԹՌԹԻՇՄՄԽԻՌԽԼԹՌ԰ՅՁՌՀԽՊՋԳՁՋԻՁԽՆՌՌՀԽՋԽԼԽԾՇՊՅՁՌՁԽՋԼՁԼՆՇՌՀԹՎԽԹՆԽԿԹՌՁՎԽՁՅՈԹԻՌՇՆՌՀԽ

ՁՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀՁՋՋՌՍԼՑԱՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌՀԹՌԾՇ ՊՌՀԽՈՊԽՎՁՇՍՋՄՑԻՇՆԼՍԻՌԽԼՋՌՍԼՁԽՋՌՀԽՊԽՏԹՋ

ՆՇԻՇՊՊԽՄԹՌՁՇՆԺԽՌՏԽԽՆՌՀԽՈՊԽՋԽՆԻԽՇԾՋՈՁՆԹՄԼԽԾՇՊՅՁՌՁԽՋԹՆԼՌ ՀԽՁՆԻՊԽԹՋԽՁՆԠԳԾՇՊՈՇՌԽՆՌՁԹՄՄՑԹԾԾԽԻՌԽԼ

ԽՆԼՈՇՁՆՌՋ
ԽԿ԰ԳԩԥԩԩՏԽՌԺՇԼՑՏԽՁԿՀՌ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ   ԠԯԽՎՁԽՏԽՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

԰ՌԹՌՁՋՌՁԻԹՄԪԽՌՀՇԼՋ ԰ՍՊՎՁՎԹՄՊԹՆԿԽԼԾՊՇՅՌՇԱՀԽՊԽԾՇՊԽՌՀԽՊԽՎՁԽՏԽՊՎՁՋՍԹ ՄՄՑԼԽՌԽՊՅՁՆԽԼՌՀԹՌ

ՌՀԽՌԽՋՌՅԹՌԽՊՁԹՄՀԹԼՆՇԽԾԾԽԻՌՇՆՄԹՊՎԹՄՅՇՊՌԹՄՁՌՑԡԹՑԹՆԼ ԡԹՑԿՊՇՏՌՀՈԹՊԹՅԽՌԽՊՋ
԰ԳԩԹՆԼԺՇԼՑ

ՏԽՁԿՀՌԼՁԼՆՇՌԽՐՀՁԺՁՌՅՇՆՇՌՇՆՁԻՌՊԽՆԼՋԺՍՌՅԽՌՌՀԽԹՋՋՍՅՈՌՁՇՆ ՋՇԾՈԹՊԹՅԽՌՊՁԻՋՌԹՌՁՋՌՁԻՋԹՆԼՏԽՊԽ

ՌՀԽՊԽԾՇՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽՌՏՇՋՁԼԽԼԡՍՆՆԽՌՌ0ՋՌԽՋՌԡԹՑԹՆԼԡԹՑԼԽՎԽՄՇՈՅԽՆՌԹՄՈԹՊԹՅԽՌԽՊՋ

ԫԣՋՌԹԿԽԹՆԼՆՇՊՅԹՄՁՒԽԼԥԩԩԼՁԼՆՇՌԽՐՀՁԺՁՌՋՍԺՋՌԹՆՌՁՎԽԼԽՈԹՊՌՍՊԽՋԾՊՇՅՅՇՆՇՌՇՆՁԻՁՌՑՌՀԽՊԽԾՇՊԽ

ԻՇՆՋՁՋՌԽՆՌՏՁՌՀՌՀԽԬԠ԰ԭԭԿՍՁԼԽՄՁՆԽՌՀԽՋԽԽՆԼՈՇՁՆՌՋՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽՇՆԽՋՁԼԽԼ

ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՋՌԽՈԼՇՏՆՌՊԽՆԼՌԽՋՌԞՄՄԹՆԹՄՑՋԽՋՏԽՊԽԻՇՆԼՍԻՌԽԼԺՑԻՇՅՈԹՊՁՆԿՌՊԽԹՌՅԽՆՌԼԹՌԹՌՇ

ՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄՍՋՁՆԿԹՆ Į ՇԾՍՆՄԽՋՋՋՈԽԻՁԾՁԽԼՇՌՀԽՊՏՁՋԽԯԽՋՍՄՌՋԾՊՇՅՇՆԽՋՁԼԽԼՌՊ ԽՆԼՌԽՋՌՋ

ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՏԽՊԽԻՇՅՈԹՊԽԼՌՇԹՋԽԻՇՆԼԹՊՑ Į ՌՇՁՄՄՍՋՌՊԹՌԽՏՀԽՌՀԽՊՌՀԽԽԾԾԽԻՌՏՇՍՄԼՋՌՁՄՄ

ԺԽԻՇՆՋՁԼԽՊԽԼՋՁԿՆՁԾՁԻԹՆՌՁԾԹՌՏՇՋՁԼԽԼ
ՎԽՊՋՍՋՇՆԽՋՁԼԽԼՌՊԽ ՆԼՌԽՋՌՏԽՊԽՍՋԽԼ

ԫՇԹՋՑՆԻՀՊՇՆՇՍՋԼԽՎԽՄՇՈՅԽՆՌՏԹՋՊԽՈՇՊՌԽԼ

 ԠՇՆԻՄՍՋՁՇՆՋ

ԱՀԽՊԽՎՁԽՏԽՊԾՇՍՆԼՆՇՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋՁՆԡԹՑՏԽՌՏԽՁԿ ՀՌՇՊՅԽԼՁԹՆԫԣՋՌԹԿԽ
ԡՍՆՆԽՌՌ0ՋՌԽՋՌ

Ո

 ԡԹՑ԰ԳԩՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌՌՀԽՀՁԿՀԽՋՌՌՊ ԽԹՌՅԽՆՌԿՊՇՍՈ
ՊԽԼՍԻՌՁՇՆԡՍՆՆԽՌՌ0Ջ

Ո

ԣՍՊՌՀԽՊԡԹՑԥԩԩՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼ
 ՁՆՀՁԺՁՌՁՇՆՋԹՌԹՄՄՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋ

ԧՇՆԻՃՀԽԽՊԽ Ո = ՏՀԽՊԽԹՋՆՇՊՅԹՄՁՒԽԼԥԩԩՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼ
 ԹՌՌՀԽՅՁԼԼՄԽԹՆԼ

ՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋ
ԧՇՆԻՃՀԽԽՊԽ Ո  

ԡԹՑԼԽՎԽՄՇՈՅԽՆՌԹՄՈԹՊԹՅԽՌԽՊՋ
ՁԽԫԣՋՌԹԿԽՆՇՊՅԹՄՁՒԽԼԥԩԩ ՏԽՊԽԺՇՌՀՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼԹՌ

ՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԽՄԹՌՁՎԽՌՇՌՀԽՆԽԿԹՌՁՎ ԽԻՇՆՌՊՇՄ
ԧՇՆԻՃՀԽԽՊԽ Ո = ԬԾՌՀԽ

ՌՀՊԽԽԿՊՇՏՌՀՈԹՊԹՅԽՌԽՊՋՇՆԡԹՑ
ՁԽ԰ԳԩԥԩԩԹՆԼՏԽՌՏԽՁԿ ՀՌՇՆՄՑԥԩԩՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼ

ԹՌՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈ
ՊԽԼՍԻՌՁՇՆԧՇՆԻՃՀԽԽՊԽ Ո  ԡԹՑ԰ԳԩԹՆԼ

ՏԽՌՏԽՁԿՀՌՏԽՊԽՍՆԹԾԾԽԻՌԽԼ
ԡՍՆՆԽՌՌ0Ջ Ո  

ԞՄՄԽԾԾԽԻՌՋՁԼԽՆՌՁԾՁԽԼԹՋՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌՍՋՁՆԿՌՀԽԧ ՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌՊԽՅԹՁՆՋՁԿՆՁԾՁԻԹՆՌՏՀԽՆ

ԻՇՅՈԹՊԽԼՌՇՌՀԽԹԼՂՍՋՌԽԼ Į ՏՀՁԻՀԹԻԻՇՍՆՌՋԾՇՊՌՀԽԻՇՆՋԽՊՎԹՌՁՋՅՇԾՌՀԽՇՆԽՋՁԼԽԼՌՊ ԽՆԼՌԽՋՌ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽ  ԡԽՎԽՄՇՈՅԽՆՌԹՄ ԹՆԼ ԱՀՑՊՇՁԼ ԤՊՇՋՋ ԭԹՌՀՇՄՇԿՑԥՁՋՌՇՈԹՌՀՇՄ ՇԿՑ ԢՆԼՈՇՁՆՌՋ  

###  ՁՆ ՌՀԽ ԞԪԞ ՏՁՌՀ

ԭՀՇՋՅԽՌ

ԱՊԽԹՌՅԽՆՌ

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### ԱՀՑՊՇՁԼԤՊՇՋՋ

ԹՆԼԥՁՋՌՇ

ՈԹՌՀՇՄՇԿՑ

ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

ԪԽԼՁԹՆ Ո ԪԽԼՁԹՆ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո ԱՊԽԹՌՅԽՆՌ

ԯԽՄԹՌԽԼ

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ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ  ԫԞ  ԫԞ  ԫԞ  ԫԞ ԫՇ

         ԫՇ

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         ԫՇ

԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹ ԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹ ԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹ ԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹ ԫԞ



### ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ 

### ԡՁԾԾԽՊԽՆԻԽ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

###  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄԠՇՆԻՄՍՋՁՇՆՋ

ՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌ ՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ

 

###  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄ ՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌ Ո  

 

###  ԥՁՆԼՄՁՅԺՄԽՆԿՌՀՁՋՆՇՊՅԹՄՁՒԽԼՌՇՋՆՇՍՌՎԽՆՌՄԽՆԿՌՀ
԰Գԩ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԱԹԺՄԽԤՊՇՏՌՀԢՆԼՈՇՁՆՌՋ  

### ՁՆՌՀԽԞԪԞՏՁՌՀԭՀՇՋՅԽՌ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԰ՆՇՍՌԳԽՆՌԩԽՆԿՌՀ ԟՇԼՑԴԽՁԿՀՌ

ԡԹՑ ԡԹՑ ԡԹՑ ԡԹՑ

ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո

ԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ ԫԞ ԫԞ  ԫԞ  ԫԞ  ԫԞ

        

        

        

԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ 

### ԡՁԾԾԽՊԽՆԻԽ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

### ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼԽԾԾԽԻՌՋԹՊԽՊԽՈՇՊՌԽԼԺԹՋԽԼՇՆԻՇՅ ՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄ

 

### ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹ ՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌ Ո  

Ԣ԰ՌՍԼՑԡԽԾՁԻՁԽՆԻՁԽՋ

ԱՀԽՌԽՅՈԽՊԹՌՍՊԽՎԹՊՁԹՆԻԽ
ոԠՏԹՋՋՄՁԿՀՌՄՑՇՍՌՋՁԼԽՌՀԽՊԹՆ ԿԽՊԽԻՇՅՅԽՆԼԽԼՁՆՌՀԽՈԽՊԾՇՊՅԹՆԻԽ

ԻՊՁՌԽՊՁԹ
չոԠԞՄՌՀՇՍԿՀՌՀԽՊԽՏԽՊԽՇՌՀԽՊԼԽՎՁԹՌՁՇՆՋԾՊՇՅՌՀԽԿՍՁԼԽՄՁՆԽՁՆԻՄՍԼՁՆԿՏԹՌԽՊՀԹՊԼՆԽՋՋՌՀԹՌ

ՏԹՋՀՁԿՀԽՊՌՀԹՆՊԽԻՇՅՅԽՆԼԽԼՌՀԽՋՌՍԼՑՅԽՌԹՄՄՊԽՅԹՁՆՁՆԿՎԹՄՁԼՁ ՌՑԹՆԼՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹ

ԣԯԽՎՁԽՏԽՊ0ՋԠՇՅՅԽՆՌՋ

ԱՀԽՊԽՎՁԽՏԽՊ0ՋՊԽՋՍՄՌՋՏԽՊԽԻՇՅՈԹՊԹԺՄԽՌՇՌՀՇՋԽՇԾՌՀԽՋՌՍԼՑԹՍ ՌՀՇՊՏՁՌՀՌՀԽԽՐԻԽՈՌՁՇՆՌՀԹՌՌՀԽՊԽՎՁԽՏԽՊ

ԾՇՍՆԼՋՁԿՆՁԾՁԻԹՆՌՊԽԼՍԻՌՁՇՆՋՁՆԡԹՑՆՇՊՅԹՄՁՒԽԼԥԩԩԹՌԹՄՄՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՏՀԽՊԽԹՋՌՀԽՋՌՍԼՑԹՍՌՀՇՊ

ՇՆՄՑԾՇՍՆԼՊԽԼՍԻՌՁՇՆՋՁՆՌՀԽՅՁԼԼՄԽԹՆԼՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈԱՀԽՋՌՍԼՑԹՍՌՀՇՊԹՄՋՇՅՁՋՁԼԽՆՌՁԾՁԽԼ

ՇՆԽՌԹԼՈՇՄԽՁՆՌՀԽՀՁԿՀԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄ
ԱԹԼՈՇՄԽԦԡԡԫԣՋՌԹԿԽԹՋԺԽՁՆԿՄԹՌԽՋՌԹԿԽ
ԫԣՋՌԹԿԽ

ՀՇՏԽՎԽՊԺԹՋԽԼՇՆՌՀԽԼԽՋԻՊՁՈՌՁՎԽՋՌԹՌՁՋՌՁԻՋՁՆՌՀԽՊԽՈՇ ՊՌՁՌԼՁԼՆՇՌԹՈՈԽԹՊՌՇԺԽԽՐԻՄՍԼԽԼԾՊՇՅ

ԹՆԹՄՑՋՁՋ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԦԦԦ ԯԢԣԢԯԢԫԠԢ԰

ԦՎԽՋԪՁԻՀԹԽՄԠԢԱԦ԰ԠՇՅՈՊԽՀԽՆՋՁՎԽԢՆՎՁՊՇՆՅԽՆՌԹՄԱՇՐՁԻՁ ՌՑԦՆԾՇՊՅԹՌՁՇՆ԰ՑՋՌԽՅ ԱԪ 

### ԲՋԽՊ0ՋԤՍՁԼԽ

ԱՁԼԽՈՇՇՄ԰ԻՁԽՆՌՁԾՁԻ԰ՇԾՌՏԹՊԽԪԻԨՁՆՄԽՑՎՁՄՄԽԠԹՄՁԾՇՊՆՁԹ

ԩՇՈԽՒԞԥՑԼՊՇՄՑՋՁՋՇԾ#  

### Ԡ%ԭՀՇՋՅԽՌԹՌԳԹՊՁՇՍՋՈԥԩԽՎԽՄՋԹՆԼԱԽՅՈԽՊԹՌՍՊԽՋԭԱԯԩԯԽՈՇՊՌԫ ՍՅԺԽՊ

Դ԰ՈՇՆՋՇՊԽԼԹՆԼՋՍԺՅՁՌՌԽԼԺՑԤՇՏԹՆԠՇՅՈԹՆՑՈՈԪԯԦԡ

ԪՇՍՆՌԡԦ ԹՆԼԴԞԟՊՍՆԿՋ ԞՋՁՅՈՄՁԾՁԽԼ ԼՇՋՁՆԿ ԹՈՈԹՊԹՌՍ ՋԾՇՊԾՁՋՀՌՇՐՁԻՇՄՇԿՁԻԹՄ ՋՌՍԼՁԽՋԴԹՌԽՊ

ԯԽՋԽԹՊԻՀ

ԫՁԽՍՏՃՇՇՈԭԡԹՆԼԣԹԺԽՊԧԫՇՊՅԹՄԱԹԺՄԽՇԾԵԽՆՇՈՍՋՄԹ ԽՎՁՋԤԹՊՄԹՆԼԭՍԺՄՁՋՀՁՆԿԫԽՏԶՇՊՃ

԰ՈՊԹԿՍԽԧԟԪԽԹՋՍՊԽՅԽՆՌՇԾՈՇՄՄՍՌԹՆՌՌՇՐՁԻՁՌՑՌՇԾՁՋՀ ԟՁՇԹՋՋԹՑՅԽՌՀՇԼՋԾՇՊԹԻՍՌԽՌՇՐՁԻՁՌՑԴԹՌԽՊ

ԯԽՋԽԹՊԻՀ

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  ԞԭԭԢԫԡԦԵԦԬԲԱԭԲԱԬԣԯԢԳԦԢԴԢԯ0԰԰ԱԞԱԦ԰ԱԦԠԞԩԳԢԯԦԣԦԠԞԱԦԬԫ

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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 0.142 1.571 0.248 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.51 0.04 0.02 7.47 0.45, 0.57
Dose1 4 0.45 0.02 0.01 3.54 0.42, 0.47
Dose2 4 0.48 0.05 0.03 10.86 0.40, 0.56
Dose3 4 0.44 0.07 0.04 16.03 0.33, 0.56

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

Ctrl 0.52 0.46 0.54 . .

Dose1 0.44 0.43 0.47 87.96 12.04

Dose2 0.46 0.44 0.56 94.50 5.50

Dose3 0.42 0.39 0.55 87.13 12.87

******************************************************************************** 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 1.60 0.241

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 0.51 . 0.51 . . . . . .

Dose1 0.45 0.228 0.46 0.130 . . . . .

Dose2 0.48 0.758 0.46 0.138 0.771 . . . .

Dose3 0.44 0.188 0.44 0.051 0.999 0.702 . . .

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.768 0.001 1.000 0.426 USE NON-PARAMETRIC TESTS

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

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 53.50 0.58 0.29 1.08 52.58, 54.42
Dose1 4 53.50 0.58 0.29 1.08 52.58, 54.42
Dose2 4 53.75 0.50 0.25 0.93 52.95, 54.55
Dose3 4 53.50 0.58 0.29 1.08 52.58, 54.42

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

Ctrl 53.50 53.00 54.00 . .

Dose1 53.50 53.00 54.00 100.00 0.00

Dose2 54.00 53.00 54.00 100.47 -0.47

Dose3 53.50 53.00 54.00 100.00 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

3 0.71 0.870

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 53.50 . .

Dose1 53.50 1.000 0.500

Dose2 54.00 0.624 0.754

Dose3 53.50 1.000 0.586

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

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.960 0.653 1.293 0.322 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 20.25 0.67 0.33 3.29 19.19, 21.31
Dose1 4 19.38 0.28 0.14 1.42 18.94, 19.81
Dose2 4 19.73 0.65 0.32 3.30 18.69, 20.76
Dose3 4 18.90 1.02 0.51 5.41 17.27, 20.53

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

Ctrl 20.45 19.30 20.80 . .

Dose1 19.35 19.10 19.70 95.68 4.32

Dose2 19.60 19.10 20.60 97.41 2.59

Dose3 18.50 18.20 20.40 93.33 6.67

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

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  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 2.61 0.100

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 20.25 . 20.25 . . . . . .

Dose1 19.38 0.237 19.55 0.110 . . . . .

Dose2 19.73 0.603 19.55 0.117 0.894 . . . .

Dose3 18.90 0.048 18.90 0.012 0.778 0.387 . . .

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

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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 0.859 2.971 0.074 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 2.48 0.16 0.08 6.45 2.22, 2.73
Dose1 4 2.26 0.07 0.04 3.13 2.14, 2.37
Dose2 4 2.13 0.09 0.05 4.32 1.98, 2.28
Dose3 4 2.10 0.23 0.11 10.90 1.73, 2.46

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

Ctrl 2.45 2.31 2.69 . .

Dose1 2.23 2.21 2.36 91.11 8.89

Dose2 2.14 2.02 2.22 86.06 13.94

Dose3 2.07 1.87 2.37 84.65 15.35

******************************************************************************** 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 5.19 0.016

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 2.48 . 2.48 . . . . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  Dose1 2.26 0.146 2.26 0.036 . . . . .

Dose2 2.13 0.019 2.13 0.004 0.655 . . . .

Dose3 2.10 0.010 2.10 0.002 0.467 0.987 . . .

******************************************************************************** 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 9.09 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 2.45 . .

Dose1 2.23 0.103 0.022

Dose2 2.14 0.067 <.001

Dose3 2.07 0.103 <.001

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose1

Jonckheere Dose1

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.953 0.540 3.268 0.059 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.12 0.01 0.00 6.75 0.11, 0.14
Dose1 4 0.12 0.00 0.00 3.85 0.11, 0.12
Dose2 4 0.11 0.00 0.00 3.05 0.10, 0.11
Dose3 4 0.11 0.01 0.00 7.20 0.10, 0.12

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

Ctrl 0.12 0.11 0.13 . .

Dose1 0.12 0.11 0.12 95.31 4.69

Dose2 0.11 0.11 0.11 88.37 11.63

Dose3 0.11 0.10 0.12 90.41 9.59

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

3 12 4.00 0.035

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

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

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

Ctrl 0.12 . 0.12 . . . . . .

Dose1 0.12 0.467 0.12 0.135 . . . . .

Dose2 0.11 0.021 0.11 0.008 0.285 . . . .

Dose3 0.11 0.058 0.11 0.008 0.563 0.944 . . .

******************************************************************************** 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 7.19 0.066

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 0.12 . .

Dose1 0.12 0.413 0.155

Dose2 0.11 0.080 0.003

Dose3 0.11 0.156 0.007

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.936 0.305 1.220 0.345 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 59.13 0.85 0.43 1.44 57.77, 60.48
Dose1 4 59.13 0.63 0.31 1.06 58.12, 60.13
Dose2 4 58.13 0.25 0.13 0.43 57.73, 58.52
Dose3 4 57.75 0.50 0.25 0.87 56.95, 58.55

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

Ctrl 59.25 58.00 60.00 . .

Dose1 59.00 58.50 60.00 100.00 0.00

Dose2 58.00 58.00 58.50 98.31 1.69

Dose3 58.00 57.00 58.00 97.67 2.33

******************************************************************************** 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 9.65 0.022

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  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 59.25 . .

Dose1 59.00 1.000 0.441

Dose2 58.00 0.168 0.021

Dose3 58.00 0.107 <.001

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.961 0.682 3.150 0.065 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.66 0.03 0.02 1.89 1.61, 1.71
Dose1 4 1.72 0.09 0.04 5.24 1.57, 1.86
Dose2 4 1.71 0.04 0.02 2.06 1.65, 1.76
Dose3 4 1.61 0.12 0.06 7.39 1.42, 1.80

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

Ctrl 1.67 1.61 1.68 . .

Dose1 1.71 1.63 1.81 103.56 -3.56

Dose2 1.70 1.67 1.75 103.11 -3.11

Dose3 1.58 1.50 1.78 97.45 2.55

******************************************************************************** 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 1.47 0.273

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 1.66 . 1.69 . . . . . .

Dose1 1.72 0.596 1.69 0.822 . . . . .

Dose2 1.71 0.684 1.69 0.851 0.999 . . . .

Dose3 1.61 0.789 1.61 0.305 0.308 0.369 . . .

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.961 0.689 0.816 0.510 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 29.18 0.50 0.25 1.71 28.38, 29.97
Dose1 4 29.90 0.63 0.32 2.12 28.89, 30.91
Dose2 4 29.93 0.26 0.13 0.88 29.51, 30.34
Dose3 4 29.65 0.58 0.29 1.96 28.73, 30.57

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

Ctrl 29.30 28.50 29.60 . .

Dose1 30.00 29.10 30.50 102.49 -2.49

Dose2 29.90 29.70 30.20 102.57 -2.57

Dose3 29.60 29.00 30.40 101.63 -1.63

******************************************************************************** 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 1.84 0.194

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 29.18 . 29.67 . . . . . .

Dose1 29.90 0.162 29.67 0.947 . . . . .

Dose2 29.93 0.145 29.67 0.961 1.000 . . . .

Dose3 29.65 0.447 29.65 0.964 0.900 0.872 . . .

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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

0.950 0.482 5.729 0.011 USE NON-PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

ԭԹԿԽ  ՇԾ  Ctrl 4 15.93 1.23 0.61 7.70 13.97, 17.88
Dose1 4 15.43 0.95 0.48 6.18 13.91, 16.94
Dose2 4 13.98 0.39 0.20 2.82 13.35, 14.60
Dose3 4 11.95 2.16 1.08 18.11 8.51, 15.39

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

Ctrl 16.35 14.20 16.80 . .

Dose1 15.85 14.00 16.00 96.86 3.14

Dose2 14.05 13.50 14.30 87.76 12.24

Dose3 11.80 9.80 14.40 75.04 24.96

******************************************************************************** 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 7.01 0.006

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 15.93 . 15.93 . . . . . .

Dose1 15.43 0.913 15.43 0.363 . . . . .

Dose2 13.98 0.149 13.98 0.039 0.455 . . . .

Dose3 11.95 0.003 11.95 <.001 0.015 0.200 . . .

******************************************************************************** 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 8.31 0.040

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 16.35 . .

Dose1 15.85 0.410 0.153

Dose2 14.05 0.152 0.011

Dose3 11.80 0.101 <.001

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

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

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS Shapiro-Wilks test for Normality of Residuals N/A alpha-level=0.01 Levenes test for homogeneity of variance(absolute residuals) N/A 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 0.231 3.947 0.036 USE NON-PARAMETRIC TESTS

### ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԱՇ ՐՁԻՁՌՑՇԾԭՀՇՋՅԽՌՌՇԞՅՈՀՁԺՁԹՆՋ ԪԽՌԹՅՇՊՈՀՇՋՁՋԞՋՋԹՑ

                  ԢԭԞԪԯԦԡԫՍՅԺԽՊ 

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 0.55 0.05 0.02 8.53 0.48, 0.62
Dose1 4 0.53 0.04 0.02 7.21 0.46, 0.59
Dose2 4 0.47 0.02 0.01 3.21 0.44, 0.49
Dose3 4 0.40 0.07 0.03 17.26 0.29, 0.51

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

Ctrl 0.57 0.48 0.58 . .

Dose1 0.54 0.47 0.55 95.45 4.55

Dose2 0.47 0.45 0.48 85.00 15.00

Dose3 0.40 0.33 0.48 73.18 26.82

******************************************************************************** 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 7.94 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 0.55 . 0.55 . . . . . .

Dose1 0.53 0.791 0.53 0.276 . . . . .

Dose2 0.47 0.069 0.47 0.017 0.344 . . . .

Dose3 0.40 0.002 0.40 <.001 0.014 0.251 . . .

******************************************************************************** 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 9.98 0.019

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 0.57 . .

Dose1 0.54 0.230 0.072

Dose2 0.47 0.094 0.004

Dose3 0.40 0.080 <.001

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CS PP 890.1150, Androgen Receptor Binding (Rat Prostate Cytosol)

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618703)

Prepared for

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

Arlington, VA 22202

Prepared by Dynamac Corporation

1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature:
David A. McEwen, B.S. Date: 11 / 30 /2011

Secondary Reviewer Signature: Michelle J. Sharpe

- Kass, M.S

. Date: 1 2 / 01 /2011

Program Manager: Signature: Jack D. Early, M.S. Date: 1 2 / 0 5 /2011

Quality Assurance: Signature: Jack D. Early, M.S. Date: 1 2 / 0 5 / 2011

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

### PHOSMET/059201 Androgen Receptor Binding (Rat Prostate Cy to sol) (20 11 ) I 

### Page I of 14

OCSPP 890.1150/ OECD None



## Primary Reviewer: Jessica Ryman. Ph

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### /,~ Template ve r sion 0812011



## DATA EVALUATI ON RECORD

STUDY 

## TYPE: Androgen Receptor Bindin g (Rat Pro state Cytoso l ); OCSPP 890.1150



## PC CODE: 059201 

## DP BARCODE: D397 I 65



## TXR#: 0056199 

## CAS No.: 732-11-6



## TEST MATERIAL (PURITY): Phosm et ( 96.8% a.i.)



## SYNONYMS: 2-( dimethoxyphosphinothioylsulfanylmethyl)isoindol e- 1,3-dione ; Imidan

technical



## CITATION : Willoughby

, J

. A (2011). Phosmet: Androgen Receptor Binding (Rat Prostate Cytosol)

. CeeTox, Kalamazoo

, Ml. Laboratory Study #: 9142V

- l 00348ARB

, November 2

, 20 11. MRID 48618703. U npublished

.



## SPONSOR: Gowan

, 370 Main Street

, Yuma

, AZ 85364



## TEST ORDER#: E DSP-059201-54



## EXECUT IVE SUMMARY: In an androgen receptor (AR) binding assay ( MRIO 4861870 3),

ventral prostate cytosol from Sprague Dawt ey rats was u se d as the so urce of the AR. The

saturation bindin g experiment was conducted to demonstrate that the AR in the rat prostate cytosol was pre sen t in reasonable number s and was functioning with appropriate affinity for the

radiolabeled reference androgen (RI 881).

Saturation binding data were not origina ll y provided in the study report; however

, summarized

saturation bindin g data (MRID 48843501 ) from the perform in g laboratory were s ubmitted

fo ll owing a request by the Agency. The mean dissociation constant (K-0) for [3H]-R l 881 was
1.080±0.690 nM, and the estimated Bm a.x 

## was l.071±0.167 fmol/100 μg protein for the single

batch of prostate cytosol that was used in the assay

. Only one of the three Kd values was within

the range report e d in the EPA validation program (0.685 to 1.57 nM)

, and all Bm ax 

## values were
below the recommended ran ge (7 to 1 6 fmo l / I 00 μg protein). Although the goodness of fit for

indi vid ual runs was acceptable (R 2



### = 

## 0.880

- 0.986), confidence in th ese numbers i s lo w based on
the lar ge variat ion in 

## l<d estimates among runs.

The competitive binding experiment was conducted to measure the binding of a single

concentration of [3 H]-Rl 881 (10 nM) 

## in the presence of incr easing concentrat i ons of phosm e t (96.8% purity; logarithmic increase from 10

· 1 0 

## to 10· 3 

## M). Dimethyl s ulfoxide ( DMSO) was
used as a vehicle at a final as say concentration of approximately 3.2%. The assay included

dexamethasone as a weak positive control

, and RI 881 as the ligand reference standard

. ThreeAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 2 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## independent runs were conducted with 3 replicates per concentration per run. T he estimated log

IC 50 

## s for R1881 and the weak positive control (dexamethasone) were in the ranges of -9.0 to -9.9 M and -4.3 to -4.6 M, respectively. Phosmet displaced more than 50% of the radiolabeled R1181 from the AR in all three competitive binding runs. Th e estimated log IC 50 

## was -5.0 M in each run and averaged -5.0 M; therefore, phosmet is classified as an AR “binder”. The mean relative binding affinity (RBA) for the positive control dexamethasone was 0.0013 %. The RBA for phosmet was calculated to be 0.0050%, indicating a stronger affinity for the AR than the weak positive control. Confidence in these numbers is high due to the small variation. The solvent control responses indicated no drift in the study assay. All performance criteria were met, with the exception of the bottom (% binding) of dexamethasone in Assay #1, and the bottom plateau level could not be accurately calculated because of a deviation where the concentration range for dexamethasone was prepared slightly different than that specified in the guideline. This was considered a minor deviation.

Based on the results of the three competitive binding ru ns, phosmet is classified as a Binder in the Androgen Receptor Binding Assay.

The assay satisfies the EDSP Tier 1 Test Order requirement s for an Androgen Receptor Binding

a ssay (OCSPP 890.1150).

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

Assurance statements were provided.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 3 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test f acility : CeeTox, Inc.

Location: 4717 Campus Drive, Kalamazoo, MI 49008 Study Director: J.A. Willoughby, Sr.

Other Personnel: D. Blakeman, C. Haines, and S. McColley Study Period: September 10 , 2011 to September 1 7 , 2011



## 2

. Test substance : Phosmet

Description: White crystalline solid

Source: Gowan Company

Batch #: GQH9118000 Purity: 9 6. 8 % Solubility : Not reported Volatility : Not reported Stability: Not reported Storage conditions: Ambient

CAS #: 732

- 11

- 6 Molecular weight: 317.32

Structure: O

O S P S

OCH 3 OCH 3 N



## 3

. Non

- labeled ligand : R1881

Supplier : Sigma Aldrich, St. Louis, MO Catalog # : R0908

Batch #: 060M4638 Purity: 9 8 %

CAS #: 965

- 93

- 5



## 4

. Radioactive ligand : [ 3 

## H]

- R1881

Supplier : Perkin

- Elmer , Boston, MA Catalog and Batch #: NET590; Lot # 6 53698 Date of production: February 24, 2011

Date of use: September 10, 2011 to September 18, 2011 Radiochemical purity: >97 % Specific activity : 85.1 Ci/mmol *

*The SA adjusted was 82.6 Ci/mol (10

- Sept

- 2011), 82.5 Ci/mol (13

- Sept

- 2011), and 92.5 Ci/mol (17

- Sept

- 2011).

Concentration in stock : 1.0 nM



## 5

. Positive control : Dexamethasone

Supplier : Sigma Aldrich , St. Louis, MO Catalog # : D1756

Lot #: 077K1050 Purity: 99%

CAS # : 50

- 02

- 2



## 6

. Solvent/vehicle control : DMSO

Justification for choice of solvent : Not provided

Final c oncentration : 3.2 %Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 4 of 14

PHOSMET /0 59201 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 (location not reported ). M ale Sprague Dawley

rats (number not reported) were castrated at 90 days of age and were euthanized the following day. The ventral prostate 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 (10 mM Tris, 1 mM sodium molybdate, 1.5 mM EDTA, 10% glycerol and 1 mM DTT, 0.5% protease inhibitor) at pH 7.4 to the ventral prostate tissues at 10 mL/g of tissue. The tissues were minced, homogenized at 4°C, and centrifuged for 30 min at 30,000 × g at 4 °C. The s upernatant was aliquoted (2 -4 mL) in tubes and stored at -80°C until used. Protein concentration of the cytosol prepared for this study was determined to be 6.2 mg/mL using the Bradford method ( Bio

- Rad ).

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 (MRID 48843501). 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 ventral prostate cytosol
Concentration of radioligand (as serial dilutions) 0.25 to 10 nM

Concentration of non

- labeled ligand (100X [radioligand]) 2 to 1000 nM
Optimization of receptor concentration Sufficient to bind 25 to 35 % of radioligand at 0.25 nM
Temperature 4o C

Incubation time 16 to 20 hours
Composition of assay buffer (TEDG) Tris 10 mM (pH 7.4)

EDTA 1.5 mM
Glycerol 10%
Phenylmethylsulfonyl fluoride (PMSF) 1 mM

DTT 1 mM
Sodium Molybdate 1 mM

a Data were obtained from page 2 of the study report (MRID 48843501).



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

## H] -R1881 (originally 85.1 Ci/mmol as manufactured on February 24, 2011) was adjusted for decay over time (adjusted specific activities were not reported), and serial dilutions in low- salt TEDG+PMSF buffer were prepared to achieve t he final concentrations in cytosol of 0.25,0.50, 0.70, 1.0, 1.5, 2.5, 5.0, and 10 nM to determine total binding. To determine nonspecific binding, solutions of non-labeled R1881 were prepared 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 in 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.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 5 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## For each batch of cytosol, the optimal protein concentration was determined by calculating specific binding to differing amounts of protein per tube with 0.25 nM radiolabeled R1881. The optimal protein concentration was determined to be 1.86 mg protein/assay tube, which resulted in the binding of approximately 25-35% of the total radioactivity added. 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 saturation binding ex periment consisted of three noncurrent runs (conducted on September 9, 11, and 16, 2011, respectively), and each run contained three replicates at each concentration, resulting in the 72 samples depicted in

Table 2.

TABLE 2

. Saturation Binding Experime nt 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) [ 3 

### H]

- R1881 (μL)

0.25 0.25 25 10 7.5

0.50 0.50 50 10 15

0.70 0.70 70 10 21

1.0 1.0 100 10 30

1.5 1.5 150 10 45

2.5 2.5 250 100 7.5

5.0 5.0 500 100 15

10 10 1000 100 30

a Data were obtained from page 3 of the study report (MRID 48843501).

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]

- R18 81 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 in a rotor for 20 hou rs at approximately 4°C. Samples were maintained at temperatures of approximately 4°C except during whole rack vortexing. To separate bound from free R1881, hydroxyapatite (HAP) slurry was added to each tube and vortexed 5 times with 4- minute intervals ov er 20 minutes. The samples were then centrifuged, and the supernatant was aspirated and discarded. The samples were washed 4 times in 2 mL of ice cold TEDG+PMSF buffer, followed by vortexing and centrifugation for 3 minutes at 700 x g. Following the last wash and decanting of the Tris buffer pellets were then extracted by additional of 2 mL of ethanol. The samples were vortexed and centrifuged for 10 minutes at 1000 x g. Samples were maintained on ice at all times between vortexing. After the final ce ntrifugation, the ethanol supernatants were decanted into scintillation vials that each contained 14 -mL portions of scintillation cocktail, and the radiation was quantified by liquid scintillation counting. A total of three runs were performed.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 6 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## 3. Compet itive Binding Experiment : A summary of the assay conditions for the competitive binding experiment is presented in Table 3.

TABLE 3 . Summary of Conditions for Competitive Binding Experiment a


### Source of receptor Rat prostate cytosol

Concentration of radioligand 1 nM
Optimization of receptor c oncentration Sufficient to bind 10

- 15 % of radioligand b



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

- 10 

### to 10

- 3 

### M

Incubation Temperature 4 ±2 ° C

Incubation time 16

- 20 hours
Composition of assay buffer Tris 10 m M (pH 7.4 )

EDTA 1.5 mM
Glycerol 10 % (v/v)

Protease inhibitor 0.5% (v/v)

DTT 1 mM
Sodium Molybdate 1 mM

a Data were obtained from page 15 of the study report.

b Obtained in Study Report on page 15.



## The competitive binding experiment was performed according to the protocol provided in

the EPA Test Guidelines OCSPP 890.1150. The competitive binding experiment measures the binding of a single concentration of [ 3 

## H] -R1881 (adjusted specific activity of 85.1

Ci/mmol ) to the AR in the presence of increasing concentrations of a test substance.

DMSO was used as the vehicle, and the solubility of the test material at the top

concentration s of 10 -3 

## and 10

- 4 

## M in 100% DMSO was determined by visual observation. Additionally, all test material solutions were examined for precipitation following the overnight incubation period. Due to precipitation being observed at 10 -3 

## M, the suitable top concentration of Phosmet for use in all independent runs was 10 -4 

## M.

Dilutions of the test substance, reference standard (R1881 ), weak positive control ( dexamethasone ), and solvent control ( DMSO ) were prepared to achieve the concentrations

shown in Table 4. E ach assay consisted of three independent runs on three different days, and each run contained three replicates at each concentration, resulting in a total of 81 samples per run

.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 7 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



### TABLE 4. Competitor Final Molar (M) Concentrations in Competitive Binding Assay a b



### Solvent Control Reference standard c 

### Weak positive control d 

### Test Chemical e 

### None DMSO R1881 Dexamethasone Phosmet

Tubes 7

- 12 Tubes 13

- 18 and 19

- 33 f 

### Tubes 37

- 60 Tubes 61

- 84 Tubes 1

- 6

1×10

- 7.48 

### 1×10

- 6 

### 1×10

- 3 

### 1×10

- 4 

### 1×10

- 3 

### 1×10

- 4



### 1×10

- 8.48 

### 1×10

- 7 

### 1×10

- 4 

### 1×10

- 5 

### 1×10

- 4 

### 1×10

- 5



### 1×10

- 9.48 

### 1×10

- 8 

### 1×10

- 5 

### 1×10

- 6 

### 1×10

- 5 

### 1×10

- 6



### 1×10

- 10.48 

### 1×10

- 9 

### 1×10

- 6 

### 1×10

- 7 

### 1×10

- 6 

### 1×10

- 7



### 1×10

- 11.48 

### 1×10

- 10 

### 1×10

- 7 

### 1×10

- 8 

### 1×10

- 7 

### 1×10

- 8



### 1×10

- 12.48 

### 1×10

- 11 

### 1×10

- 8 

### 1×10

- 9 

### 1×10

- 8 

### 1×10

- 9



### -- 1×10

- 9 

### 1×10

- 10 

### 1×10

- 9 

### 1×10

- 10



### -- 1×10

- 10 

### 1×10

- 11 

### 1×10

- 10 

### 1×10

- 11



### a Data were obtained from pages 53

- 58 of the study report.

b Each concentration of each chemical was run in triplicate for a total of 81 tubes per run. Tubes 7

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

### H]

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

were added. Tubes 7

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

- radiolabeled R

1881), weak positive control, or test substance, with the exception of Tubes 13

- 18 that contained 30 μL of non

radiolabeled R1881 (used to evaluate non

- specific binding). Tubes 1

- 6 contained only 30 μl of [ 3 

### H]

- R1881.

c The concentrations of R1881 used in the 1 st 

### competitive binding assay ranged from 1x10 -7.48 

### to 1x10 -12.48 

### , while

the standard concentrations of 1x 10 -6 

### to 1x10 -11 

### were used in the 2 nd 

### and 3 rd 

### assays. d The concentrations of dexamethasone used in the 1 st 

### competitive binding assay ranged from 1x10 -3 

### to 1x10 -10



### , while the standard concentrations of 1x10 -4 

### to 1x10 -11 

### were used in the 2 nd 

### and 3 rd 

### assays.

e The concentrations of p hosmet used in the 1 st 

### competitive binding assay ranged from 1x10 -3 

### to 1x10 -10 

### , while

concentrations of 1x10 -4 

### to 1x10 -11 

### were used in the 2 nd 

### and 3 rd 

### assays. f Tubes 13

- 18 were used to evaluate non

- specific binding by adding 100X of cold (non

- radiolabeled) R1881



## 4. Data Analysis : The maximal binding capacity (B
max 

## ), dissociation constant (K d 

## ), the top and bottom of the curve, Hill slope, inhibition concentration (IC 50 

## ), and standard deviations

w ere assessed using GraphPad PRISM (GraphPad Software, Inc., San Diego, CA).

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 ( i.e. a Log IC 50 

## was obtained).

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.

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).

b. Descriptors for receptor binding

B max 

## : maximal binding capacity

K d 

## : dissociation constantsAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 8 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## 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

A. SATURATION BINDING EXPERIMENT : Saturation binding e xperiment parameters are presented in Table 5. The mean K d 

## for [ 3 

## H] -R1881 was 1.080±0.690 nM, and the

estimated B
max 

## was 1.071±0.167 fmol/100 μg protein for the single batch of prostate cytosol that was used in the assay. Only one of the three individual K d 

## values was within the range reported in the EPA validation program (0.685 to 1.57 nM ); the mean value was above the acceptable range. Although the goodness of fit (R 2 

## = 0.880-0.986) was acceptable, confidence in these numbers is low based on the large variation in Kd estimates among runs.

TABLE 5 . Saturation Binding Experiment of [ 3 

### H]

- R1881 with Androgen Recepto r from Rat Prostate Cytosol a



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



### R 2 

### (unweighted) 0.880 0.986 0.893 0.880

- 0.986

B
max 

### (nM) 0.010 0.008 0.011 0.010 ± 0.002

B
max 

### (fmol/100 μg protein) 1.087 0.896 1.229 1.071 ± 0.167

K d 

### (nM) 0.855 0.531 1.855 1.080 ± 0.690

a Data were obtained from supplemental information provided by the laboratory (MRID 48843501 ).

b The range of R 2 

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

R 2 

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



## Figure 1 illustrates the non -specific, specific, and total binding curves for [ 3 

## H] -R1881 to the androgen receptor for the three independent runs. The specific binding reached a plateau in each run, and non-specific binding was less than 20% of total binding. Figu re 2 contains the Scatchard plots that illustrate the binding of [ 3 

## H] -R1881 to the androgen receptor.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 9 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## FIGURE 1. Binding of [ 3 

## H] -R1881 to the Androgen Receptor during the Saturation Binding Experiment.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 10 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## FIGURE 2. Scatchard Plots of the Binding of [ 3 

## H]

- R1881 to the Androgen Receptor.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 11 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## B. COMPETITIVE BINDING EXPERIMENT : The results from the three c ompetitive binding e xperiment s are summarized in Table 6 and shown graphically in Figures 3 – 5.

Non -specific binding values were 8.9%, 10.3%, and 14.0%. Phosmet reduced the radiolabeled R1881 binding to the AR by more than 50% in each of the three runs. The estimated log IC 50 

## s for R -1881 and the weak positive control (dexamethasone) were in the

ran ges of -9.0 to -9.9 M and -4.3 to -4.6 M, respectively. The estimated log IC 50 

## for phosmet was -5.0 M in each run which resulted in the mean l og IC 50 

## of -5.0 M for the test

material . The mean RBA for the positive control was 0.0013%. P hosmet was classified as a “binder” in all three runs, as the RBA was calculated to be 0.0050%, indicating a stronger affinity for the androgen receptor than the positive control, dexamethasone

. Confidence in these numbers is high due to the small variation. The solvent control responses indicated no drift in the study assay

.

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



### Parameter Assay 1 Assay 2 Assay 3 Mean

r 2 

### (unweighted) R1881 NR NR NR NR

Dexamethasone NR NR NR NR

Phosmet NR NR NR NR Log IC 50 

### (M) R1881

- 9.9

- 9.0

- 9.0

- 9.3 b



### Dexamethasone

- 4. 3

- 4.4

- 4. 6

- 4. 4 b



### Phosmet

- 5.0

- 5.0

- 5.0

- 5.0

IC 50 

### (M) b 

### R1881 1.3 x 10

- 10 

### 10

- 9 

### 10

- 9 

### 1.1 x 10

- 10



### Dexamethasone 5.0 x 10

- 5 

### 4.0 x 10

- 5 

### 2.5 x 10

- 5 

### 4.0 x 10

- 5



### Phosmet 10

- 5 

### 10

- 5 

### 10

- 5 

### 10

- 5



### RBA ( as % IC 50 

### ) c 

### R1881

Dexamethasone 100

0.0003 100

0.0025 100

0.0040 100

0.0013

Phosmet 0.0013 0.0100 0.0100 0.0050

a Data were obtained from page 20 of the study report.

b Calculated by reviewer

c Calculated by reviewer: [ IC 50 

### (in M) Dexamethasone or Phosmet / IC 50 

### (in M) R1881] x 100%

NA N ot applicable

NR Not reported RBA (%) relative binding affinity



## FIGURE 3. Binding of Phosmet, R1881 and Dexamethasone in Assay 1.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 12 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## FIGURE 4. Binding of Phosmet, R1881 and Dexamethasone in Assay 2.

FIGURE 5. Binding of Phosmet, R1881 and Dexamethasone in Assay 3.

C. PERFORMANCE CRITERIA : To ensure that the competitive binding assay was functioning properly, each run was evaluated using the following criteria in 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 (% binding) ≤15 10.5 to 12.6 X

Test chemical Top (% binding) 80 to 115 10 2.3 to 10 7.5 X

R1881 fitted curve parameters
Top (% binding) 82 to 114 96 to 10 3 X Bottom (% binding)

- 2.0 to 2.0 0 X Hill Slope

- 1.2 to

- 0.8

- 1.0 X Weak positive control (dexam e thasone ) fitted curve parameters
Top (% binding) 87 to 106 101 to 10 5 X Bottom (% binding)

- 12 to 1 2

- 1 to 7 X Hill Slope

- 1. 4 to

- 0. 6

- 1.0 to

- 0.6 X
Saturation Binding Experiment K d 

### (nM) 0.685 to 1.57 nM 0.531 to 1.855 d 

### X d



### Non

- specific binding (%) c 

### 8.1

- 10.0 <20% X

a Data were obtained from page s 23

- 28 of the study report.

b These values represent ran ges from the validation study.

c MRID 48843501

d One value was below the limit, one value was within the limit, and one value was above the limit.



## 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, asAndrogen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 13 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## indicated by a Hill slope of -1.0 to -0.6. Examination across the runs indicated consistency of the Hill slope, placement along the X-axis, and top and bottom plateaus.

The percentage of the total specific binding in the solvent controls was approximately 10%.

This was within the less than the ≤ 20% recommended in the guideline. Ligand depletion was also minimal. Sufficient optimization of the number of specific binding sites is supported by curves for controls of acceptable steepness, low non-specific binding, and low variability.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : All three assays achieved the binder criterion described in the guidel ine (<50 % radioligand binding ). There were no apparent alterations in radiolabeled R1881 binding at any of the lower concentrations tested. Phosmet was classified as binding based on the average of the three valid assays with a mean value of

“2 ”. The mean RBA (calculated by dividing the l og IC 50 

## of the control /test material by the log IC 50 

## of the positive control R1881) was 0.5 for both dexamethasone and phosmet.

B. AGENCY COMMENTS : In the saturation binding experiment, t he mean K d for [ 3 H]

- R1881 was 1.080 nM, and the mean estimated B
max 

## was 1.071 fmol/100 μg protein for the single batch of prostate cytosol that was used in the assay. Only one of the three individual

K d 

## values was within the range reported in the EPA validation program (0.685 to 1.57 nM); the mean value was above the acceptable range.

In the competitive binding experiment, t he estimated log IC 50 

## s for R -1881 and the weak positive control (dexamethasone) were in the ranges of -9.0 to -9.9 M and -4.3 to -4.6 M, respectively. The estimated log IC 50 

## for p hosmet was -5.0 M in each run, and the mean l og IC 50 

## for ph o smet was -5.0 M, classifying it as an AR binder. The mean RBA for the positive control was 0.0013%, and the mean RBA for phosmet was 0.0050%, indicating a stronger affinity for the androgen receptor compared to dexamethasone . Confidence in these numbers is high due to the small variation. The solvent control responses indicated no drift in the study assay. All performance criteria were met, with the exception of the bottom (% binding) of dexamethasone in Assay #1, the bottom plateau level could not b e accurately calculated because of a deviation where the concentration range for dexamethasone was prepared slightly different than that specified in the guideline. As this was a minor deviation, t he reviewers conc luded that the performance criteria were met

. Phosmet is

classified as a binder in the androgen receptor 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 required r 2 

## value for the competitive binding assay w as not reported

.

• Non -specific binding exceeded the tolerance limits for Assays 2 and 3. This was not considered to have a negative impact on the study b ecause there was still enough of a dynamic range in which to detect changes in binding with concentration for control and

test chemicals.Androgen Receptor Binding (Rat Prostate Cytosol) ( 2011 ) / Page 14 of 14

PHOSMET /0 59201 O CSPP 89 0.1150 / OECD None



## APPENDIX 1 (from page 49 of the Study Report)

# DATA EVALUATION RECORD

PHOSMET

Study Type: OCSPP 890.1200; Aromatase Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48616302)

Prepared for

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

Arlington, VA 22202

Prepared by 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: 12/ 1 5/2011

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 12/15 /2011

Program Manager: Signature: Jack D. Early, M.S. Date: 12/15 /2011

Quality Assurance: Signature: Jack D. Early, M.S. Date: 12/15 /2011

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

### PHOSMET I 

### 059201



## Primary Reviewer: Vincent Chen, M.S



## Health Effects Division

Secon da ry Reviewer: Greg Akerman, Ph.D

. 

## Health Effects Division Aromatase ( Hum an Recombinant) Assay (2011) I 

### Page I of 13

OCSPP 890.1200 I OECD None



### /--**Signature:~** 

### c-- 

## Date : 

## z_y -s v Al W ...LS 

## Signature: 

# , 4**~** 

## Date: Gb.:r /1 )

Template version 08/2011



## DATA EV ALU A TI ON RECORD

STUDY TYPE: Aromata s e (Human Recombinant); OCSPP 890

. 1200



## PC CODE: 059201 

## DP BARCODE: D397165

TXR: 

## 0056199 

## CAS: 732-11-6



## TEST MATERIAL (PURITY): Phosmet (96.8% a.i.)



## SYNONYMS:

IUPAC: 0,0-dimethy l S-phthalimidomethyl phosphorodith i oate


## CAS: S-[(l ,3-dihydro-l ,3-dioxo-2H-isoindol

- 2

- y l)m ethyl] 0

, 0-dimethyl phosphorodithioate



## CITATION: Wilga

, P

. C

. (2011)

. Pho s met: Human Recombinant Aromatase A s say. CeeTox

, Inc (4717 Campus Drive, Kalamazoo

, MI 49009

, US]. Laboratory Study

Number: 9142V-100348AROM. 03 November 2011. MRID 48618702. Unpublished.



## SPONSOR: Gowan Co.

, 370 Main Street

, Yuma

, AZ 85364

, U S



## TEST ORDER: EDSP-059201-54



## EXECUTIVE SUMMARY: In an 

## in vitro aromatase (CYP 19) assay (MRJD 48618702)

, phosmet (96

. 8% a.i., batch # GQH9 11 8000) in dimethyl sulfoxide (DMSO) was incubated with

human rec o mbinant aromat ase and tritiated androstenedione ([ 1P- 3 

## H(N)]-andro s t-4-ene-3,17

- dione ; [3 H]-ASDN ) at concentrations of 0

, 10

- 3

, 

## 10- 3



## . s
, 10

- 4

, 

## 10

- s, 10- 6

, 

## 10- 1

, 

## 10

- 8

, 

## 10 -9, or
10- 1 0 M for 15 minutes at 37 ° C to assess the effect on aromata s e activity. Due to s li ght precipitation that was obse r ved at the high concentration in the first two runs
, the high

concentrat i on was decreased to l 

## 0· 3



## . s M for the third run.

Aromat as e acti v ity wa s d e t e rmined by mea s urin g the amount of trit i ated water produced at the

end of a 15-minute incubation p e riod for ea c h concentration of chemical. Tritiated water was quantifi e d u s i ng liquid scintillation counting (LSC). Three independent runs were conducted

, and each run included a full act i vity control

, a background activ i ty control, a positive contro l

series (10

- 1 0 to 10- 5 

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

, and

the test chemical series (10

- 1 0 to 10- 3 ) 

## with 3 r e plicates per concentration.

Aromata se activity in the full a c tivit y contr o l s ranged from 0.150 to 0.376 nmol

· mgprotein

- 1

· min

- 1 for the 3 te s t run s, with a mean and standard deviation of0.268 ± 0.081 nmol

· mgprotein

- 1·min

- 1. Activity in the background contro l s ranged from 0.37% to 0.97% and averaged

0.56% of th e full control activ it y. The response of the full activity controls and backgroundAromatase (Human Recombinant) Assay ( 2011 ) / Page 2 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## controls were acceptable for each run. However, e ach full activity control was not generally within 10% of the average for the full activity controls, as recommended by the EPA. Run 1 had roughly half the activity of the other runs and the 0.5 mL count for total activity was roughly half that of the other runs. This discrepancy was not explained in the methods of the study report, and applies to both the controls and phosmet in run 1 compared to runs 2 and 3.

For the positive control substance (4- OH ASDN ), aromatase activity averaged 0.257±0.078 nmol∙mg -protein −1 

## ∙min −1 

## at the lowest tested concentration (10 −10 

## M) and 0.002±0.001 nmol∙mg

protein −1 

## ∙min −1 

## at the highest tested concentration (10 −5 

## M). The 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.

For phosmet, aromatase activity averaged 0.231±0.059 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest

tested concentration of 10

- 10 

## M and 0.033±0.002 nmol

∙ mg -protein -1



## ∙ min

− 1 

## at the highest tested

concentration of 10

− 3 

## M. The lowest portion of the response curve across runs for phosmet was less than 50% activity, indicating that phosmet is an inhibitor of aromatase activity at the highest

soluble concentration. Phosmet decreased aromatase activity to 34% at 10 −4 

## M.

The estimated l og IC 50 

## ranged from -4.37 to -4.89 M for phosmet and averaged -4.54 M compared to 4OH- ASDN , which averaged -7.21 M. The average slope of the concentration

response curve was -1.20 for phosmet and -0.97 for 4OH- ASDN . Confidence in the mean log

IC 50 

## for both chem icals and the H ill slope for the positive control is high due to the small variation, but the variation was moderate (22.5% CV) for the slope value of phosmet. At 10

- 10 

## M in Run 2, aromatase activity was only 69-73% of control, as compared to 95-101% of control in the other runs; no explanation was provided.

Based on the data from the average response curve, phosmet is classified as an Inhibitor of aromatase activity in this assay

The assay satisfi es the EDSP Tier 1 Test Order requirement s for an Aromatase a ssay (OCSPP

890.120 0).

COMPLIANCE : Signed and dated GLP Compliance and Quality Assurance statements were provided.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 3 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS :

1. Test S ubstance : Phosmet Description: Off

- white crystals

Source: Gowan

Batch # (Expiration D ate) : GQH9118000 ( January 31, 2013 ) Purity: 96.8 % a.i.

V apor P ressure at 25°C : 0.065 mPa Storage C onditions: Room temperature Stability: Not reported

Solvent : DMSO Solubility (in Test S olvent): Approximately 10

− 3 .5 M Highest C oncentration T ested: 10

− 3 M

Stock S olution P reparation M ethodology: Not provided; serial dilutions assumed

Molecular W eight: 317 .3

CAS #: 732

- 11

- 6

Structure:



## 2. Non

- L abeled S ubstrate : Androstenedione (ASDN)

CAS # : 63

- 05

- 8

Source: Steraloids, Inc. (Cat. # L1712)

Batch # ( E xpiration D ate) : L1712 (April 2016) Purity: 99.8%



## 3

. Radiolabeled S ubstrate : [ 1 β

- 3 H(N)]

- Androst

- 4

- ene

- 3,17

- dione ; ( [ 3 H]

- ASDN)

Source: Perkin Elmer (Cat. # NET

- 926)

Batch # ( E xpiration D ate) : 619344 ( 10 January 2012)

Radiochemical P urity ( S upplier): 97% Specific A ctivity: 26.3 Ci/mmol

Radiochemical P urity ( I n

- L ab D etermination): Not provided



## 4. Positive C ontrol : 4

- hydroxyandrostenedione (4

- OH ASDN)

CAS # 566

- 48

- 3

Source: Sigma

- Aldrich (Cat. # F2552)

Batch # (Expiration D ate) : 081K2133 (March 2015) Purity: 99.6%



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

Source: Sigma

- Aldrich (Cat. # D2650)

Lot # (Expiration D ate) : RNBB7617 (February 2013)

Justification for Choice of S olvent : Acceptable vehicle by OCSPP guideline 890.1200

Concentration (% of Total Volume in A ssays) : 1%



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

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

Lot # (Expiration D ate) : 03897 (February 2014)

Protein C oncentration : 7.4 mg/mL
Cytochrome C Reductase A ctivity: 290 nmol/min/mg

Aromatase A ctivity: 6 .0 pmol/min/pmol P450Aromatase (Human Recombinant) Assay ( 2011 ) / Page 4 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## B. METHODS

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

## H]

- ASDN was prepared such that the final concentration of ASDN in the assay was approximately 100 nM ASDN , and the amount of tritium added to each incubation tube was approximately 0.1 μCi

.

Test chemical stock solutions were prepared such that the total volume of each test chemical formulation used per assay was 1 % (20 μL in 2 mL) of the total assay volume to minimize the potential for the solvent to inhibit the enzyme. Selection of the solvent, DMSO

, was based on the following reasons: i) DMSO was listed as an acceptable vehicle in the OCSPP 890.1200 Guidelines; ii) DMSO was less volatile than ethanol; and iii) DMSO was more accurate to pipette because of its density and viscosity

.

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

. Fresh dilutions of the stock solution w ere prepared in the same solvent on the day of use.

Dilutions wer e prepared such that the target concent rations of the positive control substance (0.1–10,000 nM; Table 4) wer e achieved by the addition of 20 μ L of the dilution for a final assay volume of 2 mL.

Human recombinant microsomes were purchased from BD Gentest TM 

## , and stored at

−80±10 oC for no longer than 7 months. Microsomes were portioned into individual vials based on the protein concentration of the batch ( approximately 0.004 mg/ml microsomal protein/tube) and stored at −80±10 o C until used to minimize freeze -thaw cycles to no more

than one.

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

TABLE 1. Assay Components and Conditions
Assay Factor Values

S odium phosphate buffer (pH 7.4) 0.1M Microsomal p rotein 0.004 mg/mL

NADPH 0.3 mM
[ 3 H]ASDN 100 nM Propylene g lycol 5% Temperature 37 ±2 °C

Incubation t ime 15 min



## 2. Suitability Ass es s ments : The protein concentration of the microsomes was supplied by the vendor as 7.4 mg/mL. Aromatase activity of the microsomes was also provided by the vendor as 6.0 pmol/min/pmole P450. The minimum mean aromatase activity in the full activity control samples was determined to be 0.150 nmol/mg

- protein/min , which wa s greater than the minimum recommended aromatase activity of 0.1 nmol/mg

- protein/min.

3. Aromatase A ssay : Each assay run contained 4 tubes for the full enzyme activity and 4 tubes for 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 concentration curve in duplicate for the positive control, and a full concentration curve in triplicate for theAromatase (Human Recombinant) Assay ( 2011 ) / Page 5 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## test substance were established

. The aromatase assay was generally conducted according to

the procedures described in O CSPP 890.1200 (Section h, pp. 9-10).

The amount of 3 

## H 2 

## O in the aqueous fraction was quantified for each assay tube by LS C, and

aromatase a ctivity was reported in units of nmol

∙ mg

- protein -1



## ∙ min -1



## .

4. Demonstration of P roficiency : It was stated that prior to conducting this assay, a full

- scale assay consisting of three independent runs was conducted using the positive control (4- OH ASDN) and the four proficiency chemicals (econazole, fenarimol, nitrofen, and atrazine) listed in the OCSPP 890.1200 guideline. Proficiency was demonstrated when the positive control met the performance criteria stated in the guideline and by the correct classification of the proficiency chemicals. It was stated that the data were generated and maintained at the Performing Laboratory; however, chemical proficiency dat a were not provided.

a. Positive Control :

Initial Demonstration of Laboratory Proficiency : Prior to conducting the aromatase activity assay, positive control assays were conducted with three independent runs. These data were not provided. However, positive controls were run concurrently with the test compound in the aromatase activity assay. The se positive control data met the following criteria:

• M ean 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%.

• Performance criteria (Table 2) were met , and served as guidance in identifying runs that provided parameters in the preferred ranges.

Demonstration of Proficiency of New Technician for Conducting Assay (when applicable) : The positive control data met the criteria as listed in section (i) of O CSPP 890.1200.

TABLE 2. Perfo rmance Criteria for the Positive Control

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

- 1.2

- 0.8

- 1.02

- 0.94 Top (%) 90 110 85.58 100.53 Bottom (%)

- 5 +6

- 0.28 0.69 Log IC 50 (M)

- 7.3

- 7.0

- 7.35

- 7.09



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

TABLE 3. Proficiency Chemicals
Compound CAS# Class Concentrations

Econazole 24169

- 02

- 6 Inhibitor

--- Fenarimol 60168

- 88

- 9 Inhibitor

--- Nitrofen 1836

- 75

- 5 Inhibitor

--- Atrazine 1912

- 24

- 9 Non

- inhibitor

---



## 5. Determination of Aromatase A ctivity with T est C hemical : T he response of aromatase activity to the presence of eight concentrations of the t est chemical per run, in triplicate , was tested during three independent runs. After complet ion of the first run, the data we reAromatase (Human Recombinant) Assay ( 2011 ) / Page 6 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## reviewed and solubility was visually assessed (presence of cloudiness or a precipitate)

. No data adjustments were necessary. The full enzymatic activity was obtained at the two lowest

concentrations of the test chemica l in two runs but not the third, defining the top of the

concentration

- response curve.

TABLE 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

Phosmet Conc 1 a b 3 All test components plus phosmet 1×10

- 3

Phosmet Conc 1b c 3 All test components plus phosmet 1×10

- 3.5

Phosmet Conc 2 3 All test components plus phosmet 1×10

- 4

Phosmet Conc 3 3 All test components plus phosmet 1×10

- 5

Phosmet Conc 4 3 All test components plus phosmet 1×10

- 6

Phosmet Conc 5 3 All test components plus phosmet 1×10

- 7

Phosmet Conc 6 3 All test components plus phosmet 1×10

- 8

Phosmet Conc 7 3 All test components plus phosmet 1×10

- 9

Phosmet Conc 8 3 All test components plus phosmet 1×10

- 10

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

. b Th e high dose for runs 1 and 2. Slight p recipitation was observed at this dose.

c The high dose for run 3. No precipitation was observed at this dose.



## 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 test chemical . The following raw data and calculated endpoints for each run were included in the report (Table 5).

TABLE 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

XLfit , v5.2.0.0 (IDBS, Guildford, UK). Basic statistical analyses were performed on the data, which included means of replicates, standard deviation of the mean, standard error of the mean, and coefficient of variation.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 7 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## The response curve was fitted by weighted least squares nonlinear regres sion analysis with weights equal to 1/Y. Model fits were carried out using a 4

- parameter regression model (XLfit ; IDBS; v5.2.0.0; Fit Model 208,) and Tukey’s Bi- Weight statistical analysis for outlier analysis . For each run, the individu al percent of control values were plotted versus

the logarithm (base 10) of the test chemical concentration. The fitted concentration

response curve was superimposed on the plot, with individual plots prepared for each run. The average percent of control values versus the logarithm of test chemical concentration

for the individual runs were included on the same graph with their respective fitted response

curves. In addition, the average percent of control values for each run versus the logarithm of test chemical concentration were plotted on a separate graph along with t he avera ge concentration response curve across runs were superimposed on the same plot.

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% 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 Non

- inhibitor

Data do not fit model

---



## II

. RESULTS

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

0.150 to 0.376 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## for the 3 test runs, with a mean and standard

deviation of 0.268±0.081 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## . Activity in the background controls ranged from 0.37% to 0.97% and averaged 0.56% of the full control activity. The res ponse of the full activity controls and background controls were acceptable within each run. However, Run 1 had roughly half the activity of the other runs, and the 0.5 mL count for total activity was roughly half that of the other runs. This discrepancy was not explained in the methods of the study report, and applies to both the controls and phosmet in run 1 compared to runs 2 and 3.

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

- OH ASDN ), a romatase activity averaged 0.257±0.078 nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration (10

− 10 

## M) and 0.002±0.001 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 3 runs is presented in Table 7, along with

the o verall standard deviation and % CV. The inhibition response curves for the positive

control are shown in Figure 1. These results were generally within the recommended ranges for the top of the curve, bottom curve, H ill slope, l og IC 50 

## , and coefficient of variation for replicates of each concentration.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 8 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None

TABLE 7 . Effect of Phosmet on Aromatase Activity (as Percent of Control ) from Independent Runs a

Chemical Conc. Log M # Runs Overall Mean Overall SD Overall SEM Overall %CV

4

- OH ASDN (positive control) - 5 3 0.82 0.12 0.05 14.14

- 6 3 6.44 1.07 0.43 16.54

- 6.5 3 16.66 2.81 1.15 16.89

- 7 3 36.05 3.52 1.44 9.76

- 7.5 3 63. 50 4. 18 1.7 1 6. 5 9

- 8 3 79.85 6.57 2.68 8.23

- 9 3 92.27 10.27 4.19 11.13

- 10 3 96.78 8.58 3.50 8.87

Phosmet

- 3 3 14. 79 5.23 2.14 35.3 6

- 3.5 3 29.49 1.22 0.50 4.14

- 4 3 34.08 5.16 2.11 15.13

- 5 3 72.43 10.38 4.24 14.33

- 6 3 89.94 9.27 3.79 10.31

- 7 3 91.36 9.99 4.08 10.93

- 8 3 90.40 9.16 3.74 10.13

- 9 3 90.63 11.04 4.51 12.18

- 10 3 88.53 12.70 5.18 14.34

a Calculated by the reviewers using the information presented on pages 29

- 31 of the study report

. SD Standard Deviation

SEM Standard Error of the Mean

CV Coefficient of VarianceAromatase (Human Recombinant) Assay ( 2011 ) / Page 9 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



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

- OH ASDN

.

C. TEST SUBSTANCE : For phosmet , aromatase activity averaged 0.231±0.059

nmol

∙ mg -protein

− 1



## ∙ min

− 1 

## at the lowest tested concentration of 10

- 10 

## M and 0.033±0.002

nmol

∙ mg -protein -1



## ∙ min

− 1 

## at the highest tested concentration of 10

− 3 

## M . The mean aromataseAromatase (Human Recombinant) Assay ( 2011 ) / Page 10 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## activity of phosmet (expressed as % full control activity) for each concentration tested

across all 3 runs is presented in Table 7, along with the overall standard deviation and %CV. Inhibition response curves for phosmet from each run are shown in Figure 2, and the average inhibition response curve across all runs is shown in Figure 3.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 11 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## FIGURE 2. Inhibition R esponse C urves for Phosmet

.

A slight amount of the compound was observed in the miniscus, near the surface for the highest concentration.

A slight amount of the compound was observed in the miniscus, near the surface for the highest concentration.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 12 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## FIGURE 3. Mean I nhibition R esponse C urve for Phosmet

A slight amount of the compound was observed in the

meniscus , near the surface for the highest concentration.



## The effect of phosmet on inhibition of aromatase activity is presented in Table 8. The

estimated l og IC 50 

## ranged from -4.37 to -4.89 M for phosmet and averaged -4.54 M compared to 4OH- ASDN , which averaged -7.21 M. The average slope of the concentration

response curve was -1.20 for phosmet and -0.97 for 4OH

- ASDN . Confidence in the mean log IC 50 

## for both chemicals and the Hill slope for the positive control is high due to the

small variation, but the variation was moderate (22.5% CV) for the slope value of phosmet.

TABLE 8 . Effect of Phosmet and 4OH

- ASDN 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)

Phosmet

- 4.37

- 4.37

- 4.89

- 4.54 0.30 6.62

4

- OH ASDN

- 7.19

- 7.09

- 7.35

- 7.21 0.13 1.82 Slope

Phosmet

- 1.16

- 0.95

- 1.48

- 1.20 0.27 22.48

4

- OH ASDN

- 0.94

- 1.02

- 0.95

- 0.97 0.04 4.49

a Data for individual control runs were obtained from page 27 of the study report . IC 50 and slope values for phosmet were calculated by the reviewers using Graphpad Prism based on data provided on pages 44, 49 and 54. Mean, SD, and %CV for phosmet and control were calculated by the reviewers.

SD Standard Deviation

CV Coefficient of Variance

NA Not applicable



## At 10

- 10 

## M in Run 2, aromatase activity was only 69-73% of control, as compared to 95-101% of control in the other runs. No explanation was provided in the study report concerning this observation. Based on the data from the average response curve and the

criteria listed above in Table 6 , the results support the conclusion that phosmet inhibits

aromatase

.Aromatase (Human Recombinant) Assay ( 2011 ) / Page 13 of 13

PHOSMET / 059201 OCSPP 890.1200 / OECD None



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS CONCLUSIONS : A decrease in aromatase activity was identified at the very highest concentration of phosmet tested (e.g., 10

− 3 

## M), but solubility issues were observed. Phosmet reduced aromatase to 34.1% of control activity at 10

− 4 

## M and thus was classified as an inhibitor, per OPPTS 890.1200 guideline, under the conditions of this assay.

Phosmet at lower exposures of 10

– 10 

## M to 10 –5 

## M showed essentially no effect (e.g., non-inhibitor).

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

0.150 to 0.376 nmol∙mg -protein −1 

## ∙min −1 

## for the 3 test runs, with a mean and standard deviation of 0.268±0.081 nmol∙mg -protein −1 

## ∙min −1 

## . Activity in the background controls ranged from 0.37% to 0.97% and averaged 0.56% of the full control activity. The response

of the fu ll activity controls and background controls were acceptable for each run. However, each full activity control was not generally within 10% of the average for the full activity controls as recommended by the EPA. Run 1 had roughly half the activity of th e other runs and the 0.5 mL count for total activity was roughly half that of the other runs. This discrepancy was not explained in the methods of the study report, and applies to both the controls and phosmet in run 1 compared to runs 2 and 3. For the p ositive control substance (4

- OH ASDN ), aromatase activity averaged 0.257±0.078 nmol∙mg

protein −1 

## ∙min −1 

## at the lowest tested concentration (10 −10 

## M) and 0.002±0.001 nmol∙mg

protein −1 

## ∙min −1 

## at the highest tested concentration (10 −5 

## M). The estimated l og IC 50 

## ranged

from -4.37 to -4.89 M for phosmet and averaged -4.54 M compared to 4OH- ASDN , which averaged −7.21 M. The average slope of the concentration response curve was -1.20 for phosmet and -0.97 for 4OH- ASDN . Confidence in the mean log IC 50 

## for both chemicals and the Hill slope for the positive control is high due to the small variation, but the variation was moderate (22.5% CV) for the slope value of phosmet. At 10

- 10 

## M in Run 2, aromatase activity was only 69-73% of control, as compared to 95-101% of control in the other runs ; an explanation was not provided.

The lowest portion of the response curve across runs for phosmet was less than 50% activity,

indicating that phosmet is an inhibitor of aromatase activity at the highest soluble

co ncentration (p hosmet decreased aromatase activity to 34% at 10

− 4 

## M ). Based on the data from the average response curve, the results indicate the phosmet is an inhibitor of aromatase activity in this 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:

• Proficiency chemical data were not provided.

• Different counts for total activity in 0.5 mL and full activity control s (nmol/mg/min) were observed in Run 1 compared to Runs 2 and 3, but no explanation was provided.

• At 10

- 10 

## M in Run 2, aromatase activity was only 69-73% of control, as compared to 95- 101% of control in the other runs. No explanation was provided in the s tudy report concerning this observation.

• Information on the stability o f the stock solution was not reported.

# DATA EVALUATION RECORD

PHOSMET

Study Type: OCSPP 890.1250, Estrogen Receptor Binding Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618704)

Prepared for

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

Arlington, VA 22202

Prepared by Dynamac Corporations

1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Michelle J. Sharpe

- Kass, M.S. Date: 12/12 /201 1

Secondary Reviewer Signature:
David A. McEwen, B.S. Date: 12/19 /201 1

Program Manager: Signature: Jack D. Early, M.S. Date: 12 / 23 /201 1

Quality Assurance: Signature: Jack D. Early, M.S. Date: 12 / 23 /201 1

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

### of 13

OCSPP 890.1150/ OECD None



## Primary Reviewer: 

## Patience Browne, Ph.D.

Health Effects Division,

. Office of Pesticide Progra

. ms Secondary Reviewer: 

## Greg Akerman, Ph.D

. . Health Effects Division; Office of Pesticide Programs

# Signatu~ e__

l>ate:

# ~~ Signature:**~**



## · Date: 

# \:20of

2

Temp l ate version 08/2011



## DATA EVALUATION RECORD

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

OCSPP 890.1250

PC CODE: 059201 DP BARCODE: D397 l 65

TXR#: 0056199 CAS No.: 732-11-6

TEST MATERIAL CPURIT\'): Phosmet (96.8%)

SYNONYMS: Imidan Technical; 2-( dimethoxyphosphinothioylsulfanylmethyl)isoindole-1

, 3-

dione

CITATION: Willoughby, J.A. Sr. (2011). Phosmet: Estrogen Receptor Binding (Rat Uterine Cytosol). CeeTox, Kalamazoo, MI. 9142V-100348ERB, November 2, 2011.

MRID 48618704 Unpublished.

SPONSOR: Gowan Company, 370 Main Street, Yuma, AZ 85364

TEST ORDER#: EDSP-059201-54

EXECUTIVE SUMMARY: 

## In 

## an estrogen receptor (ER) binding assay (MRID 

## 48618704),

uterine cytosol from Sprague-Dawley rats was used as the source of ER to conduct saturation

and competitive binding experiments. 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. The competitive binding experiment was conducted to measure the binding of a single concentration of [3H]-17P-estradiol (1 nM) 

## in the

presence of increasing concentrations of phosmet (96.8% purity; logarithmic increase from I 0- 10



## to 10- 3 

## M). 

## DMSO was used as a vehicle at a final concentration of <4%

. The assay included

19-norethindrone as a weak positive control, octyltriethoxysilane as a negative control, and l 7Pestradiol as the natural ligand reference material.

Saturation binding data were not provided in the study report; however, summarized saturation binding data (MRID 48843501) from the perfor,ming laboratory were submitted following a request by the Agency.

For the Competitive Binding Experiment, a log ICso could not be calculated for phosmet. The

mean log 

## ICso for l 7P-estradiol was -9.0 Mand the average log ICso for 19-norethindrone was

- 5.5 M. The mean RBA was 0.03% for 19-norethindrone compared to the positive control (I

nM 

## I 7P-estradiol), but a RBA could not be calculated for phosmet.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 2 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## Based on the top % binding for 19-norethindrone at 49%, Run 2 should not be considered for evaluation of phosmet for binding to the ER. The Hill slope for 17β

- es tradiol in Run 3 (

− 1.7 ) was outside of parameter limits . Precipitation was observed at 10 -4 

## M (but not 10 -3 

## M) in Run 1

and at the 10 -3 

## M in Runs 2 and 3. In these instances, data for those concentrations were disregarded by the study author despite indications of potential interaction with the estrogen receptor. The investigators failed to follow assay guidelines that recommend testing solubility of test substances in increasing solvent concentrations (up to 10% DMSO) and including half log concentrations at the limit of solubility . Because of insufficient attempts to resolve issues with solubility of the test substance at concentrations that suggested an ER interaction, there is lack of

confidence in the results of the three runs; therefore the assay is considered to be technically inadequate.

The assay does not satisfy does not satisfy the EDSP Tier 1 Test Order requirement s for an Estrogen Receptor Binding assay (OCSPP 890.1250). This assay is not satisfied due to issues with

test chemical solubility. However a repeat of this assay is not required since negative results were seen in the Tier 1 ERTA and OSRI which evaluated potential interaction of phosmet with the ER. For additional information see the EDSP Tier 1 Weight of Evidence Analysis for Phosmet (TXR 0057145).

COMPLIANCE : Signed and dated GLP and Quality Assurance statements were provided.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 3 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : CeeTox

Location: Kalamazoo, MI Study Director: Jamin A. Willoughby, Ph.D.

Other Personnel: Karen Rutherford, Director of Laboratory Operations David Blakeman, Senior Scientiet/Endocrine Group Leader
Cameron Haines, Scientist Steven McColley, Scientist
Biranna Wallace, Lead Cell Culture Scientist
Colleen Toole, Ph.D., Dire ctor of Project Management Study Period: May 25

- Nov 2, 2011



## 2

. Test substance : Phosmet

Description: White crystalline solid

Source: Gowan Company (Yuma, AZ)

Lot/Batch #: GQH9118000, Exp Jan 31, 2013 Purity: 96.8 % a.i. Solubility : N ot reported Volatility : N ot reported Stability: N ot reported Storage conditions: Ambient

CAS #: 732

- 11

- 6 Molecular weight: 317.32 g/mol

Structure: O

O S P S

OCH 3 OCH 3 N



## 3

. Non

- labeled ligand : 17 β

- estradiol

Supplier : Sigma

- Aldrich (St Louis, MO) Catalog # E8875

Batch #: 1 1 0M0138V Purity: 100 % a.i.

CAS #: 50

- 28

- 2



## 4

. Radioactive ligand : [ 3 

## H]

- 17 β

- estradiol

Supplier : Perkin

- Elmer (Boston, MA) Catalog #: NET517

Batch#: 650702 Radiochemical p urity: N ot reported Specific activity : 

### 130.2 Ci/mol

Concentration of stock : 1 nM



## 5

. Positive control : 19

- n orethindrone

Supplier: Sigma

- Aldrich (St Louis, MO) Catalog # N4128

Batch #: 030 M 1359V Purity: 99% a.i.

CAS # : 66

- 22

- 4



## 6

. Negative control : OctyltriethoxysilaneEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 4 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None

Supplier: Sigma

- Aldrich (St Louis, MO) Catalog # 440213

Batch #: 2499KK Purity: 99.34% a.i.

CAS # : 2943

- 75

- 1



## 7

. Solvent/vehicle control : DMSO

Justification for choice of solvent : None reported

Final Concentration 4 % v/v



## B. METHODS

1. Preparation of R at U terine Cytosol (RUC) : Rat uteri from female Sprague

- Dawley rats (number not reported) aged 12-13 weeks were obtained from Harlan Laboratories. Rats were ovariectomized 7 days prior to being euthanized. Upon receipt, the uterine tissue was inspected for signs of residual ovarian tissue after ovariectomy, and compromised tissue was

discarde d. The uteri were weighed, placed in ice

- cold TEDG (Tris, EDTA, DTT, glycerol) + Protease inhibitor (PI) buffer and used immediately. Uteri were homogenized in buffer, centrifuged for 10 min at 2500 × g at 4oC. Supernatant was transferred and centrifuge d for 60 minutes at 105,000 × g , discarding the resulting pellets. Protein concentration of th e cytosol was determined to be 3.22 mg/mL using a BioRad Protein Assay Kit (compatible

with DTT in the TEDG buffer ). Cytosol was divided into aliquots (1-6 mL) for either immediate use or storage at -80oC until use.

2. Saturation (radioligand) B inding E xperiment : It was stated that proficiency records for this assay are archived and maintained at CeeTox, Inc. Saturation binding data were not provided in the study report; however, summarized saturation binding data (MRID 48843501) from the performing laboratory were submitted following a request by the Agency (Tables 1 and 2)

.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 5 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## 3. Competitive B inding E xperiment : A summary of the experiment conditions for the Competitive Bind ing Experiment is included in Table 3.

TABLE 3 . Summary of Conditions for Competitive Binding Experiment a



### Source of receptor Rat U terine C ytosol

Concentration of radioligand 1 nM
Concentration of receptor Sufficient to bind 11

- 12% of radioligand b



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

- 10 

### to 10

- 3 

### mM

Temperature 4 ± 2 ° C

Incubation time 16

- 20 hours
Composition of assay buffer Tris 10 mM (pH 7.4)

EDTA 1.5 mM

Glycerol 10% v/v

Protease Inhibitor 0.5% v/v

DTT 1 mM

a Data were obtained from page 15 of the study report.

b Calculated by reviewer. Data obtained from pages 35, 40 and 45 of the study report

.



## A solubility test was performed to determine the appropriate solvent ( DMSO ) using visual observation (it was not stated if magnification was used). On the day of the assay, the specific activity of the stock solution [ 3 

## H] -17 β

- estradiol was adjusted for decay over time,

and diluted in TEDG + PI buffer to achieve a final concentration of 1 nM. No details were provided on the determination of the optimal protein concentration, but the amount used was

sufficient to bin d 11-12% of the radioligand, based on the data provided for total binding and total activity. The amount of protein used in each tube was 80.0 μg protein per tube. Serial dilutions of the phosmet , positive control (19 -norethindrone), negative control ( octyltriethoxysilane ), and reference material ( non- labeled 17β

- estrad iol ) were prepared to

ach ieve the concentrations shown in Table 4 . E ach assay co nsisted of three runs, and eachEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 6 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## run contained three replicates at each co ncentration, plus six tubes to determine total activity (master mix) resulting in a total of 102 tubes/assay run.

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



### Phosmet Positive control Negative control Reference Chemical

19

- Norethindrone Octyltriethoxysilane Non

- labeled 17β

- estradiol

Tubes 79

- 102 c 

### Tubes 31

- 54 c 

### Tubes 55

- 78 c 

### Tubes 7

- 30 c



### 10

- 10 

### 10

- 8.5 

### 10

- 10 

### Solvent control 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 35

- 49 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 + PI 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 was run in triplicate, for a total of 9 3 tubes per run plus 9 tubes to determine total activity and total binding

. d Solvent is DMSO (4%) in Tubes 7

- 9.



## Tubes were incubated with gentle vortexing for 16-20 hours at 4 ° C. To separate bound from free estradiol, hydroxyapatite (HAP) slurry was added to each tube and vortexed for approximately 10 seconds at 5 minute intervals for a total of 15 minutes. 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 ex tract the [ 3 

## H] -17 β

- estradiol

, followed by vortexing, and centrifugation for 10 min at 1000 x g . An aliquot of supernatant was radioassayed by scintillation counting. The temperature was maintained at 4oC throughout the assay prior to extraction with ethanol.

C. D ATA ANALYSIS : For the saturation binding e xperiment (data not reported), total binding

and non- specific binding data were modeled via non- linear regression using Graph Pad Prism (version not reported; GraphPad Software, Inc., La Jolla, CA) or XLfit , no method was reported for outlier exclusion. It was not reported if r eceptor binding data plots were corrected for ligand depletion. For the c ompetitive binding a ssay, similar methods of nonlinear regression were used to fit a curve (for 17β -estradiol, the positive control, and the test substance) to the Hill equation formula which incorporated log IC 50 

## as a parameter to be

estimated.

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:Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 7 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## Interactive = lowest point on the fitted curve within the range of the data is less than 50% (i.e., >50% of the radiolabel ed estradiol has been displaced from the ER).

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 above75% (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 not 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 :

B max 

## : 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 Bindin g Affinity ( RBA % ): IC 50 

## of 17 β

- estradiol ÷ IC 50 

## of test substance × 100)Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 8 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## II. RESULTS

A. SATURATION BINDING EXPERIMENT : Saturation binding data were not provided in the study report; however, summarized saturation binding data (MRID 48843501) from the performing laboratory were submitted following a request by the Agency

. Saturation binding

e xperiment parameters are presented in Table 5. Figures 1 -6 show the specific, no n-specific, and total binding curve s for [ 3 

## H]- 17β -e st ra diol to the estr og en re ce ptor for saturation binding and the Scatchard plots for runs 1-3.Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 9 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD NoneEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 10 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD NoneEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 11 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD NoneEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 12 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## B. COMPETITIVE BINDING EXPERIMENT : The results from the three C ompetitive Binding Assays are summarized in Table 6 and shown graphically in Figures 7, 8 and 9 . The

estimated mean log IC 50 

## was not calculated for phosmet, as the percent binding did not cross the 50% mark. The estimated mean log IC 50 

## s for 17β

- estradiol and the positive control were

− 9.0 M and

− 5.5 M, respectively . T he mean RBA was 0.03% for the positive control.

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



### Parameter Run 1 b 

### Run 2 b 

### Run 3 b 

### Mean ± SE

r 2 

### (unweighted), 17 β

- estradiol NR NR NR NA

19

- norethindrone NR NR NR NA

Phosmet NR NR NR NA Log IC 50 

### (M), 17 β

- estradiol

- 9

- 9.1

- 9

- 9.0

19

- norethindrone

- 5.6

- 5.4

- 5.5

- 5.5

Phosmet NA NA NA NA

IC 50 

### (M), 17 β

- estradiol 1.00 x 10

- 9 

### 7.94 x 10

- 10 

### 1.00 x 10

- 9 

### 9.26 x 10

- 10



### 19

- norethindrone 2.51 x 10

- 6 

### 3.98 x 10

- 6 

### 3.16 x 10

- 6 

### 3.16 x 10

- 6



### Phosmet NA NA NA NA Log RBA (%), 19

- norethindrone

- 3.40

- 3.70

- 3.50

- 3.53

Phosmet NA NA NA NA RBA (%), 19

- norethindrone 0.04 0.02 0.03 0.03

Phosmet NA NA NA NA

a Data were obtained from page s 21

- 22 of the study report.

b The mean and standard deviation are reported for the concurrent replicates within each run.

r 2 

### Goodness of fit RBA (%) R elative binding affinity

NA Not applicable

NR Not reportedEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 13 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## F IGURE 71. Percentage E2 Bound to the Estrogen Receptor in the Presence of Phosmet

, Unlabeled EW, 19- norethindrone or Octyltriethoxysilane

. Run 1Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 14 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## F IGURE 8. Percentage E2 Bound to the Estrogen Receptor in the Presence of Phosmet, Unlabeled EW, 19- norethindrone or Octyltriethoxysilane. Run 2Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 15 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## F IGURE 9. Percentage E2 Bound to the Estrogen Receptor in the Presence of Phosmet, Unlabeled EW, 19- norethindrone or Octyltriethoxysilane. Run 3Estrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 16 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## The classification of the test material is based on the average of three runs. Each run was individually classified as shown in Table 7.

TABLE 7. Binding Classification of Phosmet with Estrogen Receptor a



### Run 1 2 3 Mean Binding Classification c 

### Classification category value b 

### NA NA NA NA NA

a Technical deficiencies noted in all three runs.

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



## C. PERFORMAN CE CRITERIA : To ensure that the competitive binding assay function ed properly, each run was evaluated using the following criteria:

T ABLE 8. Criterion a 

### Tolerance Limit(s) Value Yes No

17 β

- estradiol fitted curve parameters Log
e 

### residual SD ≤2.35 1.20 to 1.95 X Top (% binding) b 

### 94 to 111 95 to 109 X Bottom (% binding)

- 4 to 1

- 1 to 5 X Hill Slope (log 10 

### (M)

- 1 

### )

- 1.1 to

- 0.7

- 1.7 to

- 1 X

Weak Positive control ( 19

- noreth indrone ) fitted curve parameters Log
e 

### residual SD` NA 0.91 to 1.59 Top (% binding) b 

### NA 49 to 100 Bottom (% binding) NA

- 9 to 0

Hill Slope (log 10 

### (M)

- 1 

### )

- 1.1 to

- 0.7

- 2.5 to

- 0.9

Solvent concentration

DMSO ≤10% 4% 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% <11% X

a Data were obtained from page s 25, 27 and 29 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 applicable



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

- estradiol displaced [ 3 

## H]

- 17β -estradiol in a manner consistent with one- site binding, as indicated by a Hill slope of -1.0 for the first run. The second and third runs showed Hill slopes of

− 1.4 and

− 1.7.

The w eak positive control, 19-norethindrone had a Hill Slope of -1.4 in the third assay, and the second assay showed a top plateau level of 49% binding, a bottom plateau level of

− 9% and a hill slope of

− 2.5. Th ese d ata are consistent with a weak posi tive control and therefore,

invalidate the run.

Phosmet was tested over a concentration range that fully defined the top of the curve. Th e maximum percent binding 105.7% was within 25 percentage points of the value for theEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 17 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## lowest concentration of the estrad iol standard 95.1%. Examination across the runs indicated consistency of placement along the X- axis, and a top plateau for phosmet.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : In all three independent runs, the mean specific binding was >80% for the negative control octyltriethoxysilane. The data for 17 β

- estradiol and 17-norethyndrone were within the acceptable ranges, with deviations which were minor and not considered to reflect true deviation from the suggested ranges outlined in the OPPTS guideline. The data for 19-norethindrone were outs ide the acceptance criteria in Run 1. However, the positive and negative controls both were within acceptance criteria. This suggests that the problem with the 19-norethindrone data in the second run was most likely in the preparation of the compound.

The mean RBA (calculated by dividing the l og IC 50 

## of the test material by the l og IC 50 

## of

17 β -estradiol) [sic] was 0.6 for 19-norethindrone. There was no RBA to be calculated for pho smet.

Phosmet solubilized in DMSO was classified as "non- interacting" in all three independent runs and thus had a final classification of "non-interacting" under the conditions of this study.

B. AGENCY COMMENTS : The saturation binding e xperiment demonstrated that the ER isolated from rat uterine cytosol was present in reasonable numbers and was functioning with appropriate affinity for the radio- labeled reference estrogen prior to routinely conducting ER Competitive Binding Experiments. The mean K d 

## for [ 3 

## H]

- 17β

- estradiol was

0.331 ± 0.061 nM and the mean B
max 

## was 0.549 ± 0.100 nM (74.55 ± 3.03 fmol/100μg) protein for the prepared rat uterine cytosol Precipitation was observed at 10 -4 

## M (but not

10 -3 

## M) in Run 1 and 10 -3 

## M concentrations in Runs 2 and 3. In these instances, data for those concentrations were disregarded by the study author despite indications of potential interaction with the estrogen receptor. The investigators failed to follow assay guidelines that recommend testing solubility of test substances in increasing solvent concentrations (up to 10% DMSO) and including half log concentrations at the limit of solubility . Because of

in sufficient attempts to resolve solubility of test substance at concentrations where there were indications of potential ER interactions, there is lack of in all the 3 runs; therefore the assay is considered to be technically inadequate. In addition, the intra assay weak positive control (19-norethindrone) did not show an acceptable response for run 2 , and t he Hill slope

for 17 β

- estradiol in the third run (

− 1.7 ) did not fall within parameter limits specified in the guidelines.

C. STUDY DEFICIENCIES : The following deficiencies were noted that are considered to have had an adverse impact on the results, interpretation or conclusions of this study:

• Hill slopes for 17 β

- estradiol outside guideline criteria. The weak positive control, 19- norethindrone showed a top plateau level of 49% binding in the second run, a bottom plateau level of

− 9% and a hill slope of

− 2.5. The Investigator noted that the weak positive control data were well outside the guidelines for acceptance, however, in theEstrogen Receptor Binding (Rat Uterine Cytosol) ( 2011 ) / Page 18 of 18

PHOSMET / 059201 O CSPP 89 0.1250 / OECD None



## same run the positive and negative controls were within the acceptable criteria. They suggest that the problem was not due to the system but the preparation of the compound.

• Higher concentrations (<10%) of DMSO were not tested to resolve solubility issues, nor was EtOH tried as an alternative solvent (as instructed by guidel ines).

• No logical physicochemical rationale for precipitate at 10 -4 

## M and not at 10 -3 

## M ; either precipitate was overlooked or technical differences in treatment of assay tubes at different

concentrations. Insufficient attempts to resolve issues with solubility of the test substance at concentrations that suggested an ER interaction

.

# DATA EVALUATION RECORD

PHOSMET

Study Type: OCSPP 890.1300, Estrogen Receptor Transcriptional Activation

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618705)

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 J. Sharpe

- Kass, M.S. Date: 12/05 /201 1

Secondary Reviewer Signature: Rebecca Bryan, B.S. Date: 12/07 /201 1

Program Manager: Signature: Jack D. Early, M.S. Date: 12/15 /201 1

Quality Assurance: Signature:

Jack D. Early, M.S. Date: 12/15 /201 1

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).

### PHOSMET / 059201 Estrogen Receptor Tran sc riptional Activ a t ion (2011) I 

### Page 1 of2

O CS PP 890.1300 / OE C D 455



## Primary Reviewer: Sheila Healy. Ph

. D

. 

## Health Effec ts Division Secondary Reviewer: M in erva Mercado, Ph.D., DABT



## Health Effects Division

# Signa{~**. ~_........""""......q..**  __ _ D ate:

## -c~~**-7': ~-:::?-** 

Template version 08 /2 011



## DATA EV ALU A TI ON RECORD

STUDY TYPE: Estrogen Receptor Transcriptional Activation (Human ce ll L in e
, HeLa-9903) ;
OCSPP 890.1300; OECD 455.



## PC CODE: 0 592 01 

## DP BARCODE: 039716 5

TXR#: 0056 19 9 

## CAS No.: 732 -11-6



## TEST MATERIAL (PURITY): Pho smet (96.8% a.i.)



## SYNONYMS: 2-( dimethoxyphosphinothioyl s ulfanylmeth y l )iso indole-1 ,3 -dion e; Imidan

technical



## CITATION: Willoug h by

, J.A. Sr. (2011). Phosmet: E strogen Receptor Transcriptional

Act i vatio n (Human cell L in e
, H e L a-9 90 3). CeeTox

, Kalam azoo
, Ml. Labor atory Study#: 9142V-l 00348 ERT A, November 2, 2 011. MRID 48618705.

U npubli s h ed.



## SPONSOR: Gowan

, 370 Ma in Street

, Yuma

, 

## AZ 85364



## TEST ORDER#: EDSP-059201-5 4



## EXECUT IVE SUMMARY: In an estrogen r ece ptor tran scr iptional activation assay (ERTA;

MRID 48618705) conducted by CeeTox

, hERa.-HeLa-9903 cells cu ltured 

## in v it ro were exposed

to phosmet (96.8% a.i.

, lot# GQ H 9 l 800) at conce ntra t ion s increasing logarithmically fro m I 0- 11

to 10-4 M mg/mL in DMSO (0. 1 %) for approxima t ely 24 hours. The assay was performed tw i ce

u si n g 96-we ll plates and each p h os m e t concentration was tested in 6 wells / plate in eac h as · say.
Cells were ex po sed to the phosmet for 24 ± 

## 2 hour s to indu ce r eporte r (luciferase) gene products

. Lucif erase expression in r es pon se to activation of th e estrogen receptor by phosmet was

mea sured u s in g a proprietary CeeTox Standard Ope ratin g Protocol (S OP ), which was no t

included in the report.

Phosmet was tested up t o the limit of cytotoxicity

, 1 0-4 M. The mean RPCMax for phosmet was 1.6- 3.9%

, t h e P CMax was 10

· 7 

## Mand the PC1 0 could not b e calc ul ate d a s the RPCMax was l ess
than 10 %. Cy totoxicity of 20.1 % was observed in the high es t co ncentration i n the first run . A

s imil ar trend of cyto toxi city was observed in th e second run
, w ith the highest co n ce ntrati o n
h aving ce ll v iabili ty of o nl y 8 1. 7%.

In the main assays, the responsive ne ss of the cells to the very weak pos i tive contro l 17a.-

meth y lt es t os t ero ne was low e r than t he expected va lue s, indi ca ting a decrea sed sens itivity of the

assay to very weak agonists. The PC1 0 for 17a.-m e thylte s to sterone s hould have be e n reached b yEstrogen Receptor Transcriptional Activation ( 2011 ) / Page 2 of 2

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## 10 -6 

## M but its maximum RPC was 8.8%, at that concentration. A higher concentration (10 -5 

## M) reached 47% RPC but in the presence of cytotoxicity. C ytotoxicity was also observed at the highest concent rations of 17α -estradiol and corticosterone. Although the conditions of this assay were not optimal to detect very weak activity, phosmet responses were similar to those of the negative control corticosterone and not comparable to the responses of 17α

- met hyltestosterone,

which was able to reach a maximum of 6.8-8.8 % PC. Phosmet was only able to reach a

maximum of 1.6-3.9% PC when tested up to the highest concentration possible based on cytotoxicity. Because the RPC Max 

## < PC 10 

## in both assay runs, phosmet w as considered negative for estrogen receptor transcriptional activation in this test system.

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

COMPLIANCE : Signed and d ated GLP

, Quality Assurance and Data Confidentiality

statements were provided.Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 3 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Substance : Phosmet

Description: Technical, white crystalline solid, MW 317.32 g/mol

Source: Gowan Company (no catalog#)

Lot/Batch #: GQH91800; E x p 1/31/2013 Purity: 96.8 % Solubility : Not reported ( NR ) Volatility : NR Stability: NR Storage conditions: Ambient Vapor pressure : NR

CAS #: 732

- 11

- 6

Structure :



## 2. Reference substances 17β

- estradiol (strong estrogen; positive control)

Supplier: NR Catalogue and Batch #: NR Purity: NR

CAS # : 50

- 28

- 2



## 17α

- estradiol (weak estrogen)

Supplier: NR Catalogue and Batch #: NR Purity: NR

CAS # : 57

- 91

- 0



## Corticosterone (negative compound)

Supplier: NR Catalogue and Batch #: NR Purity: NR

CAS # : 50

- 22

- 6



## 17α

- methyltestosterone (very weak agonist)

Supplier: NR Catalogue and Batch #: NR Purity: NR

CAS # : 58

- 18

- 4



## 3. Vehicle(s)

Solvent: DMSO. Supplier, lot and purity not reported

Solvent control (final concentration): 0.1%Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 4 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## B. METHODS

1. C ell C ulture : Stably

- transfected hERα

- HeLa

- 9903 cells were obtained from the Japanese

Colle ction of Research Bioresources Cell Bank and were verified to be free of mycoplasma infection using DNA Fluorochrome analysis by Bionique Testing Laboratories. Cells were

maintained in E agles Minimum Essential Medium without phenol red, supplemented with 60 mg/L kanamycin and 10% dextran

- coated charcoal

- treated fetal bovine serum ( source not reported), in an incubator under 5% CO 2 

## at 37oC. Cells used in the range -finding study (7/5/2011) were from P assage 21. For the main study new cells were brought up from

cryo preservation and were P assages 19 and 20 for the experimental runs (8/23/2011 and 8/25/2011). Upon reaching 75- 90% confluence , c ells we re subcultured into test plates.

2. Transcriptional Activation Assay s : For each run , cells were plated in 96

- well culture plates at a d ensity of 1× 10 4 

## cells/100 μL medium/well and allowed to attach for at least 3 hours. The g rowth media was replaced with media containing serial log dilutions of phosmet

in DMSO. Cells were incubated for 24 ± 2 hours at 37 ± 1°C. All concentrations were tested in replicates of 6/plate. Additionally, for each concentration 2 replicates/plate were prepared

with hERα antagonist ICI 182,780 co

- treatment , to allow for the identification of nonspecific induction of the luciferase gene. The total final concentration of DMSO was 0.1%. Transcriptional activation of the estrogen receptor was determined using a proprietary

CeeTox SOP, which was not provided. A list of reagents was provided, but ingredients of

the luciferase assay reagent were identified as proprietary information.

a. P reliminary T est : A preliminary test evaluating concentrations ranging from10

- 6.5 

## to 10 -3 

## M was conducted to determine the appropriate concentration range and to determine concentrations resulting in insolubility and/or cytotoxicity. Cytotoxicity was determined by a

two -read propidium iodide (PI) uptake assay. Cells were seeded into black- walled 96

- well plate and exposed to phosmet at logarithmic concentrations of 10

- 6.5 

## to 10 -3 

## M; digitonin was

als o used as a positive control for cytotoxicity. Following exposure, growth medium was removed and cells were exposed to PI. Background- corrected fluorescence was calculated for each well. Limit of solubility was determined by visual inspection of the test materials and controls after preparation of the final 1X dosing solutions in culture media. A sample of the 1x dosing solution was placed into wells of a clear 96- well plate and an endoscope was used to assess precipitation.

b. Proficiency Chemicals : Prior to testing unknown chemicals, each laboratory must confirm the responsiveness of the test system, at least once for each newly prepared batch of cell stocks taken from the frozen stock by independent testing of the 10 proficiency chemicals

listed below. Proficiency records were not provided in the study report; however, proficiency data for the performing laboratory was submitted following a request by the Agency (MRID 48843501). The responsiveness of the test system was evaluated on March 5, 2010 and April 12 and April 28, 2011. Cells used for the proficiency tests were at passage 15, 25 and 28, respectively. It is not clear if the cells used in the proficiency tests are from the same frozen stock as cells used in the current assay.Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 5 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455

Compound CAS No. Concentration Range (M) Expected Response a Notes

Diethylstilbestrol (DES) 56

- 53

- 1 10

− 14 to 10 −8 Positive

---

17 α

- 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 100 μM. PC max approx. 50%

PC. Binds hER α 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 M ax 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 selected to challenge solubility and cytotoxicity

d DBP is negative for ER α mediated transcriptional activation, but may not be negative for non

- ER β mediated transcriptional activation. A positive result would indicate that the system is detecting activity other than that due to pure ER α, and is therefore unacceptable.



## c. Refer ence 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 transcriptional activity relative to 1 nM E2 positive control (PC) , luminescence signals from the concurre nt plate were analyzed by subtracting the mean vehicle control value from each well value to normalize the data . Normalized values were then divid ed by the mean normalized PC value and multiplied by 100 to express relative transcriptional activity as a percentage of the PC (RPC) ( software used to calculate RPC Max 

## not reported). The test material was defined as negati ve for inducing estrogen receptor transcriptional activation if the RPC Max 

## < PC 10 

## in 2 of 2 (or 2 of 3) runs. Log EC 50 

## and Hill slop 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 between 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 plateEstrogen Receptor Transcriptional Activation ( 2011 ) / Page 6 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## PC 50 

## = concentration of a test chemical at which the response is 50% of the res ponse 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 : Percent cell viability is reported in Table 1. Cytotoxicity was observed with phosmet at 10 -3 

## M in the rangefinder (7/5/2011). Based on these results, logarithmic concentrations of phosmet from 10

- 11 

## to 10 -4 

## M were selected for the assay. However, cytotoxicity was observed at 10 -4 

## M in the first run (8/23/2011) only.

T ABLE 1

. Preliminary T est for Solubility , C ytotoxicity , and Concentration

- Selection for Phosmet a

Concentration (M) % Viability Comments

10

- 6.5 104

10

- 6 101

10

- 5.5 100

10

- 5 96

10

- 4.5 98

10

- 4 86

10

- 3.5 80

10

- 3 15 Cytotoxicity of >20% was observed

E2 1nM NR

VC NR

a Data were obtained from page 19 of the study report.

VC = Vehicle control



## B. Positive and Negative Reference Chemicals

1. Proficiency Chemicals : R esponsiveness of cells to proficiency chemicals was tested in duplicate on different days. Results are reported in Table 2. In general, the responses

demonstrate proficiency; however some deviations from validated ranges were noted. Mean activity of the PC (1 nM 17β

- estradiol) was > 4 -fold VC activity on each plate, for all runs. The reference compounds 17β

- estradiol, 17α

- estradiol and 17α

- methyltestosterone were within the acceptable ranges with a few exceptions in runs 1 and 3, as noted in Appendix 1.

TABLE 2. Proficiency Chemicals a

Compound Expected Response Lab Response
Diethylstilbestrol 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 Negative

Atrazine Negative Negative

Corticosterone Negative NegativeEstrogen Receptor Transcriptional Activation ( 2011 ) / Page 7 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## 2. Reference Chemicals : Values derived from the concentration response curve ( e.g ., log

PC 50, 

## log PC 10, 

## log EC 50, 

## Hill slope) for the four concurrently run reference materials are included in Table 3. The transcriptional responsiveness of 17α

- estradiol and 17β

- estradiol were within the acceptable range. The l og PC 50 

## and l og PC 10 

## for the very weak agonist 17α

methyltestosterone were not reported. The study author indicated that the PC 10 

## was not reached due to cytotoxicit y at the highest concentration. I nspection of the raw data by the

reviewer indicated that 17α

- methyltestosterone did not attain transcriptional activation equal to 10% of the positive control; therefore a PC 10 

## or PC 50 

## could not be calculated. A doserespon sive trend was observed starting at approximately at 10 -8 

## M. M aximum RPC of 17α

methyltestosterone was 8.8% at 10 -6 

## M, and cytotoxicity occurred at the next higher concentration tested (10 -5 

## M testosterone) in both experimental runs.

T ABLE 3. Pe rformance Criteria for Reference Chemicals a

Reference Chemical

Parameter Acceptable Range Values Acceptable

Run 1 Run 2 Yes No
17β

- estradiol Log PC 50

- 11.4 to

- 10.1

- 10.3

- 10.4 X Log PC 10 <

- 11

- 11.5

- 11.3 X Log EC 50

- 11.3 to

- 10.1

- 10.3

- 10.3 X Hill Slope 0.7 to 1.5 0.9 1.2 X Test range 10

- 14 to 10

- 8 M 10

- 15 to 10

- 8 M 10

- 15 to 10

- 8 M X

17α

- estradiol Log PC 50

- 9.6 to

- 8.1

- 8.5

- 8.6 X Log PC 10

- 10.7 to

- 9.3

- 9.6

- 9.6 X Log EC 50

- 9.6 to

- 8.4

- 8.5

- 8.6 X Hill Slope 0.9 to 2.0 1.2 1.4 X Test range 10

- 12 to 10

- 6 M 10

- 13 to 10

- 6 M 10

- 13 to 10

- 6 M X

Corticosterone Test range 10

- 10 to 10

- 4 M 10

- 11 to 10

- 4 M 10

- 11 to 10

- 4 M X

17α

- methyltestosterone Log PC 50

- 6.0 to

- 5.1 NC NC X Log PC 10

- 8.0 to

- 6.2 NC NC X

Test range 10

- 11 to 10

- 5 M 10

- 12 to 10

- 5 M 10

- 12 to 10

- 5 M X

a Data were obtained from page s 11 and 22 of the study report

. NC = not calculated



## C. DEFINITIVE ASSAY

1. Vehicle and Positive Controls : Data for the vehicle and positive controls are included in

Table 4. The overall mean response value s (Light units) for the vehicle control w ere 10892 for the first run and 9933 for the second run. The mean normalized value for the positive

control was 253542 for the first run and 167033 for the second run. Light units corresponding to t he PC 50 

## (50% of the maximum response) for E2 in this assay is 132217 for the first run and 88483 for the second run; the PC 10 

## (10% of the maximum response) is

35157 for the first run and 25643 for the second run.Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 8 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



### T ABLE 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 10892 2749 253542 142342 23

2 9933 1246 167033 34868 17

a Data were obtained from page s 30 and 31 of the study report. Values were calculated by the reviewer.

b Positive control was 17β

- estradiol (E2) at 1 nM.

c Fold

- induction = (mean TA of PC)/(mean TA of VC)



## 2. Test Material : Relative (to the PC) transcriptional activation at each concentration of phosmet during the two assay runs is presented in Table 5. The concentration -response curves depicting fold induction of relative transcriptional activation is presented in Figure 1

below. The mean RPC M ax 

## for phosmet was 1.6% for the first run and 3.9% for the second

run , and the associated PC M ax 

## was 10 -7 

## M. Cytotoxicity of 20.1% was observed in the highest concentration in the first run, and a similar trend of cytotoxicity (18.3%) was observed in the second run at the highest concentration.

Due to the failed responsiveness of these cells to the very weak agonist 17α

methyltestosterone, the possibility that phosmet is a very weak estrogen agonist could not be

evaluated

T ABLE 5. Relative Transcriptional Activation (RTA) of Phosmet a



### Parameter RTA (mean ± SD); % of Positive Control (PC)

Run 1 Run 2
Conc. (M) Mean SD Mean SD

10

- 4



### -- b



### -- b 

### 2.6 0.9

10

- 5 

### 0.5 0.8 2.5 1.2

10

- 6 

### 1.6 0.8 3.0 1.2

10

- 7 

### 1.6 0.8 3.9 0.8

10

- 8



### - 0.1 0.8 1.7 1.0

10

- 9 

### 0.8 1.0 1.4 1.3

10

- 10



### - 0.1 0.7 0.9 1.2

10

- 11 

### 0.0 1.8 0.8 1.1

Log EC 50 

### NA NA
Hill Slope NA NA

RPC M ax 

### 1.6% 3.9%

PC M ax 

### 10

- 6



### - 10

- 7 

### 10

- 7



### PC 50 

### NA NA

PC 10 

### NA NA

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

b Not reported due to cytotoxicity 

### >20% NA= Not ApplicableEstrogen Receptor Transcriptional Activation ( 2011 ) / Page 9 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



### F IGURE 1. Fold Induction of Relative Transcription Activation (RTA) of phosmet compared to the

Positive Control.

VC= Vehicle Control PC= Positive Control (1 nM E2)



## 3. Performance C riteria : Proficiency chemicals were tested in duplicate on different days, with appropriate responses (Table 2). The transcriptional responsiveness of 17α

- estradiol

and 17β

- estradiol were within the acceptable range. However, 17α

- methyltestosterone did

not ind uce transcriptional activation equal to 50% or 10% of the positive control; therefore a

PC 10 

## and PC 50 

## could not be calculated for this very weak agonist . Based on calculations conducted by the reviewer on the raw data provided, the fold-induction corresponding to

PC 10 

## of concurrent PC was greater than 1+2 standard deviations of the fold-induction value

of the concurrent VC as expected . The CV of the lum inescence data was not reported

.Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 10 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS ’ CONCLUSIONS : The suitable top concentration of phosmet for use in the transcriptional activation assays was 10 -4 

## M. Cytotoxicity was observed in the highest concentration tested (10

- 3 

## M) in the range finding test and at 10 -4 

## M in the fir st valid run.

C ytotoxicity was <20% at all of the exposure concentrations tested in the second valid run.

Phosmet did not result in in an increase in luciferase activity at any of the viable concentrations tested in either run; phosmet is not an agonist of hERα in the HeLa -9903

model system

.

B. AGENCY COMMENTS : Phosmet was tested up to the limit of cytotoxicity, 10

- 4 

## M. Cytotoxicity of 20.1% was observed in the highest concentration in the first run. A similar trend of cytotoxicity was observed in the second run, with the highest concentration having cell viability of only 81.7%.

The mean RPC M ax 

## for phosmet was 1.6-3.9%, the PC M ax 

## was 10 -7 

## M and the PC 10 

## could not

be calculate d as the RPC M ax 

## was less than 10%.

Although the conditions of this assay were not optimal to detect very weak activity, phosmet responses were similar to those of the negative control corticosterone and not comparable to the responses of 17α -methyltestosterone, which was able to reach a maximum of 6.8-8.8% PC. Phosmet was only able to reach a maximum of 1.6-3.9% PC when tested up to the highest concentration possible based on cytotoxicity. Because the RPC Max 

## < PC 10 

## in both assay runs, phosmet was considered negative for estrogen receptor transcriptional activation in this test system.

C. STUDY DEFICIENCIES : The following deficiencies were noted:

• 17α

- methyltestosterone did not induced transcriptional activation equal to 50% or 10% of the positive control; therefore a PC 10 

## and PC 50 

## could not be calculated.

• Cytotoxicity observed at the highest concentrations of 17α

- estradiol , 17α

methyltestosterone and corticosterone.

• The source for the fetal bovine serum was not provided.Estrogen Receptor Transcriptional Activation ( 2011 ) / Page 11 of 9

PHOSMET / 059201 O CSPP 89 0.1300 / OECD 455



# A PPENDIX 1. Performance Criteria for Reference Chemicals in Proficiency Test (MRID 48843501)

Reference Chemical

Parameter Acceptable Range Values Acceptable

Run 1 Run 2 Run 3 Yes No

PC Fold Induction 21.1

- 24.6 75.1

- 84.7 17.9

- 20.2

17β

- estradiol
Log PC 50 −11.4 to −10.1

- 9.6

- 11.3

- 10.6 Run 1
Log PC 10 <−11

- 11.5

- 12.5

- 12.1 Run 1
Log EC 50 −11.3 to −10.1

- 9.0

- 11.3

- 10.6 Run 1 Hill Slope 0.7 to 1.5 1.2 0.9 0.8 X
Test range 10 −14 to 10 −8 M 10

- 13 to 10

- 7 10

- 15 to 10

- 7 M 10

- 15 to 10

- 7 M Run 1

17α

- estradiol
Log PC 50 −9.6 to −8.1

- 8.3

- 9.4

- 8.7 X
Log PC 10 −10.7 to −9.3

- 9.3

- 10.5

- 9.9 X
Log EC 50 −9.6 to −8.4

- 8.2

- 9.3

- 8.9 Run 1 Hill Slope 0.9 to 2.0 0.9 0.9 2.9 Run 3
Test range 10 −12 to 10 −6 M 10

- 15 to 10

- 7 M 10

- 13 to 10

- 5 M 10

- 13 to 10

- 5 M Run 1

17α

- methyltestosterone
Log PC 50 −6.0 to −5.1

- 6.2 NR

- 5.2 Run 1,2
Log PC 10 −8.0 to −6.2

- 8.1

- 6.3

- 7.7 Run 1
Log EC 50 NA

- 6.2 NR

- 5.1 NA
Hill Slope NA 0.7 0.3 0.4 NA
Test range 10 −11 to 10 −5 M 10

- 12 to 10

- 4 M 10

- 12 to 10

- 4 M 10

- 12 to 10

- 4 M X
NA = not applicable NR = not reported

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԡԹՌԹԯԽՉՍՁՊԽՅԽՆՌ    ԢԭԞԡԭԟԹՊԻ ՇԼԽ 

ԢԭԞԪԯԦԡ   

ԢԭԞԤՍՁԼԽՄՁՆԽ  ԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ

ԱԽՋՌՅԹՌԽՊՁԹՄ  ԭՀՇՋՅԽՌ   ԭՍՊՁՌՑ  

ԠՇՅՅՇՆՆԹՅԽ

ԠՀԽՅՁԻԹՄՆԹՅԽԦԲԭԞԠ

 ԠԞ԰ՆԹՅԽ

 ԠԞ԰ԫՇ

 ԰ՑՆՇՆՑՅՋԦՅՁԼԹՆ ®



###  ԢԭԞԭԠԠՇԼԽ

ԭՊՁՅԹՊՑԯԽՎՁԽՏԽՊ ԧՇԹՆԤԹՁԼՇՋ ԰ՁԿՆԹՌՍՊԽ

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ    ԡԹՌԽ 

԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ ԱԽՊՁ԰ԪՑԽՊՋ      ԰ՁԿՆԹՌՍՊԽ

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԠԹՅԺՊՁԼԿԽԢՆՎՁՊՇՆՅԽՆՌԹՄԦՆԻ    ԡԹՌԽ 

ԭՊՁՅԹՊՑԯԽՎՁԽՏԽՊ ԠԹՌՀԽՊՁՆԽԞՍԺԽԽ ԰ՁԿՆԹՌՍՊԽ

ԟՁՇՄՇԿՁՋՌԲ԰ԢԭԞԢԣԢԡԢԯԟԦԳ        ԡԹՌԽ 

԰ԽԻՇՆԼԹՊՑԯԽՎՁԽՏԽՊ
Ջ ԞՅՑԟՄԹՆՃՁՆՋՀՁՈ     ԰ՁԿՆԹՌՍՊԽ

԰ԽՆՁՇՊ԰ԻՁԽՆՌՁՋՌԲ԰ԢԭԞԢԣԢԡԢԯԟԳԦ      ԡԹՌԽ

ԡԹՌԽԢՎԹՄՍԹՌՁՇՆԠՇՅՈՄԽՌԽԼ#ԼԼՅՅՑՑՑՑ% 

ԠԦԱԞԱԦԬԫ   ԶՇՊՃ ԡԬ  ԭՀՇՋՅԽՌ  ԰ՀՇՊՌՌԽՊՅ ԯԽՈՊՇԼՍԻՌՁՇՆ ԞՋՋԹՑ ՏՁՌՀ ՌՀԽ ԣԹՌՀԽԹԼ ԪՁՆՆՇՏ

ԭՁՅԽՈՀԹՄԽՋ ՈՊՇՅԽՄԹՋ  ԣՇՄՄՇՏՁՆԿ ԬԭԭԱ԰  ԹՆԼ ԬԢԠԡ  ԤՍՁԼԽՄՁՆԽՋ ԲՆՈՍԺՄՁՋՀԽԼ ՋՌՍԼՑ

ՈԽՊԾՇՊՅԽԼԺՑ԰ՅՁՌՀԽՊՋԳՁՋԻՁԽՆՌ ԴԹՊԽՀԹՅԪԹՋՋԹԻՀՍՋԽՌՌՋԩԹԺ԰ՌՍ ԼՑԫՇ԰ՌՍԼՑՋՈՇՆՋՇՊԽԼ

ԺՑԤՇՏԹՆԠՇՅՈԹՆՑԶՍՅԹԞՊՁՒՇՆԹ԰ՌՍԼՑԻՇՅՈՄԽՌԽԼԣԽԺՊՍԹՊՑ 

### AMY

BLANKINSHIP Digitally signed by AMY BLANKINSHIP
DN: c=US, o=U.S. Government, ou=USEPA, ou=Staff, cn=AMY
BLANKINSHIP,
dnQualifier=0000040917

Date: 2015.06.15 05:23:09 -04'00'

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ 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 ՈՀՇՋՅԽՌ ՏՁՌՀ ԾԹՌՀԽԹ Լ ՅՁՆՆՇՏՋ ԭՁՅԽՈՀԹՄԽՋ ՈՊՇՅԽՄԹՋ  ՏԹՋ

ԻՇՆԼՍԻՌԽԼ ՍՆԼԽՊԾՄՇՏՌՀՊՇՍԿՀ ԻՇՆԼՁՌՁՇՆՋ԰ՁՐՌԽԽՆ ԿՊՇՍՈՋ ՇԾ ՅՇ ՆՌՀ ՇՄԼԾՁՋՀ 
ՅԹՄԽՋ ԹՆԼ ԾԽՅԹՄԽՋ ՈԽՊ

ԿՊՇՍՈ  ԿՊՇՍՈՋ ՈԽՊ ՌՊԽԹՌՅԽՆՌ ՏԽՊԽ ԽՐՈՇՋԽԼ ՌՇ ՈՀՇՋՅԽՌ 
 Ո ՍՊՁՌՑ ԹՌ ՆՇՅՁՆԹՄ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ՇԾ 

ԻՇՆՌՊՇՄ   ԹՆԼ  ՅԿ ԹՁԩ ՅԽԹՆՅԽԹՋՍՊԽԼ ԻՇ ՆԻԽՆՌՊԹՌՁՇՆՋ ՏԽՊԽ ԩԬԮ 


ԹՆԼՅԿԹՁԩԱՀԽՌԽՋՌՋՑՋՌԽՅՏԹՋՅԹՁՆՌԹՁ ՆԽԼԹՌՌՇ Շ 

### ԠԹՆԼԹՈԥՇԾՌՇ



԰ՍՊՎՁՎԹՄՏԹՋ ՄՇՏ ԹՌՌՀԽ ՀՁԿՀՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
ՏՁՌՀ ՇՆՄՑ ՇՆԽՅԹՄԽ ԹՆԼ ՇՆԽԾԽՅԹՄԽ ՋՍՊՎՁՎՁՆԿՌՇ ՋՌՍԼՑ

ՌԽՊՅՁՆԹՌՁՇՆԽՆԼՈՇՁՆՌՋԹՌՌՀՁՋՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԽՊԽՆՇՌՋՌԹՌՁՋՌ ՁԻԹՄՄՑԹՆԹՄՑՒԽԼՇՊՁՆԻՄՍԼԽԼՁՆՌՀԽՊԽՋՍՄՌՋԞՌՌՀԽ

ՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆՌՀԽՊԽՏԹՋԹԼԽԻՊԽԹՋԽՁՆՋՍՊՎՁՎԹ ՄԻՇՅՈԹՊԽԼՌՇԻՇՆՌՊՇՄԹՆԼԿԽՆԽՊԹՄՁՒԽԼՇՎԽՊՌ

ՋՁԿՆՋՇԾՌՇՐՁԻՁՌՑՁՆԺՇՌՀՅԹՄԽՋԹՆԼԾԽՅԹՄԽՋՁՆԻՄՍԼՁՆԿՄԽՌՀԹՊԿՑ ՁՆԹՄՄՋՍՊՎՁՎՁՆԿԾՁՋՀԹՆԼՄՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅՁՆ

ԾԽՅԹՄԽՋԞՌՌՀԽՄՇՏԻՇՆԻԽՆՌՊԹՌՁՇՆՋՍՊՎՁՎԹՄՏԹՋՊԽԼՍԻԽԼԺՑ ԻՇՅՈԹՊԽԼՌՇԻՇՆՌՊՇՄԟՇԼՑՏԽՁԿՀՌԹՆԼՄԽՆԿՌՀ

ՏԽՊԽՆՇՌՋՁԿՆՁԾՁԻԹՆՌՄՑԼՁԾԾԽՊԽՆՌՁՆՅԹՄԽՇՊԾԽՅԹՄԽԾՁՋՀԹՌԹՆՑ ՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԦՆՌՀԽԻՇՆՌՊՇՄԿՊՇՍՈՋՈԹՏՆՁՆԿՇԻԻՍՊՊԽԼԹՌՄԽԹՋՌԽՎԽՊՑԼԹՑՋՁ ՆՌՏՇՇԾՌՀԽԾՇՍՊՊԽՈՄՁԻԹՌԽՋԹՆԼԾԽԻՍՆԼՁՌՑՏԹՋ

 ԽԿԿՋԾԽՅԹՄԽԼԹՑՊԽՈՄՁԻԹՌԽ ԾԽԻՍՆԼՁՌՑ ՏԹՋ   ԽԿԿՋԾԽՅԹՄԽԼԹՑ ԾՇՊ ՌՀՊԽԽ ՊԽՈՄՁԻԹՌԽՋ ԹՆԼ 

ԽԿԿՋԾԽՅԹՄԽԼԹՑ ԾՇՊ ՇՆԽ ՊԽՈՄՁԻԹՌԽ ԣԽՊՌՁՄՁՒԹՌՁՇՆ ՋՍԻԻԽՋՋ ՁՆ ՌՀԽ  ԻՇՆՌՊՇՄ ԿՊՇՍՈ ԹՎԽՊԹԿԽԼ  ԞՌ ՌՀԽ

ՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆՈՀՇՋՅԽՌՋՁԿՆՁԾՁԻԹՆՌՄՑ ՊԽԼՍԻԽԼԾԽՊՌՁ ՄՁՌՑ
ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՈԺՑԹՆԼ

ԾԽԻՍՆԼՁՌՑ
ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՈԺՑԻՇՅՈԹՊԽԼՌՇՌՀԽ ԻՇՆՌՊՇՄ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԣԽՅԹՄԽ ԿՇՆԹԼՇՋՇՅԹՌՁԻ ՁՆԼԽՐ 
Ԥ԰Ԧ ՏԹՋ ՋՁԿՆՁԾՁԻԹՆՌՄՑ ՊԽԼՍԻԽԼ ԺՑ  ԹՌ ՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆ

ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ Ո ՊԽՄԹՌՁՎԽ ՌՇ ԻՇՆՌՊՇՄ ՅԹՄԽ Ԥ԰Ԧ ՏԹՋ  ՍՆԹԾԾԽԻՌԽԼ ԺՑ ՈՀՇՋՅԽՌ ՌՊԽԹՌՅԽՆՌ

Ո ԴՀՁՄԽ ՆՇՌ ՋՌԹՌՁՋՌՁԻԹՄՄՑ ՋՁԿՆՁԾՁԻԹՆՌ 
ԪԹՆՆԴՀՁՌՆԽՑ Ո  ՅԽԼՁԹՆ ՅԹՄԽ ՆՍՈՌՁԹՄ ՌՍԺԽՊԻՄԽ ՋԻՇՊԽՋ

ՏԽՊԽՊԽԼՍԻԽԼԺՑԹՌՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆԻՇՅՈԹՊԽԼՌՇՌՀԽԻՇՆՌՊՇՄՆՇՌՍԺԽՊԻՄԽՋՏԽՊԽՇԺՋԽՊՎԽԼ

ԾՇՊ ԾԽՅԹՄԽՋ ԪԹՄԽ ԹՆԼ ԾԽՅԹՄԽ ՎՁՌԽՄՄՇԿԽՆՁՆ 
ԳԱԤ ՄԽՎԽՄՋ ՏԽՊԽ ՆՇՌ  ՋՁԿՆՁԾՁԻԹՆՌՄՑ ԼՁԾԾԽՊԽՆՌ ԾՊՇՅ ՌՀԽ ԻՇՆՌՊՇՄ

ԹՄՌՀՇՍԿՀՌՀԽՊԽՏԹՋԹՆԹՈՈԹՊԽՆՌՁՆԻՊԽԹՋԽՁՆՅԹՄԽԳԱԤԹՌՌՀ ԽՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆԼՍԽՋՇՄԽՄՑՌՇ

ՀՁԿՀՄԽՎԽՄՋՁՆՌՏՇՅԹՄԽՋՁՆՌՀՁՋԿՊՇՍՈԭՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋՏԽՊ ԽՆՇՌՅԽԹՋՍՊԽԼ

ԤՇՆԹԼԹՄՋՌԹԿՁՆԿԽԾԾԽԻՌՋՏԽՊԽՁՆԼՁԻԹՌԽԼԾՇՊԾԽՅԹՄԽԾՁՋՀԹՌՌՀԽՄ ՇՏՌՊԽԹՌՅԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆԹՆԼԾՇՊՅԹՄԽՋԹՆԼ

ԾԽՅԹՄԽՋ ԹՌ ՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ԢԾԾԽԻՌՋ ՇՆ ԿՇՆԹԼԹՄ ՀՁՋՌՇՈԹՌՀՇՄՇԿՑ ՁՆ ՅԹՄԽ ԾՁՋՀ ՁՆԻՄՍԼԽԼ ԹՆ

ՁՆԻՊԽԹՋԽԼՈԽՊԻԽՆՌԹԿԽՇԾՋՈԽՊՅԹՌՇԿՇՆՁԹ
ԹՆԼՅՁՄԼԼՁԾԾՍՋԽՌՀՁԻՃԽՆՁՆԿՇԾՌՀԽԿԽՊՅՁՆԹՄ ԽՈՁՌՀԽՄՁՍՅՄՁՆՁՆԿԺՑ

ՋՈԽՊՅԹՌՇԿՇՆՁԹԹՌՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆԾԽՅԹՄԽԾՁՋՀՁՆԻՁԼԽՆԻԽՋՇԾԼԽԻՊԽԹՋԽԼՑՇՄՃՋՑՆՌՀԽՋՁՋՏԽՊԽ

ՇԺՋԽՊՎԽԼ ԹՌ ԺՇՌՀ ՄՇՏ 
 ԹՆԼ ՁՆՌԽՊՅԽԼՁԹՌԽ 
 ԻՇՆԻԽՆՌՊԹՌՁ ՇՆՋ ՊԽՄԹՌՁՎԽ ՌՇ ՌՀԽ ԻՇՆՌՊՇՄՋ 


ԬԻԻԹՋՁՇՆԹՄ ԼՁՋՊՍՈՌՁՇՆՋ ՇԾ ԳԱԤ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՏԽՊԽ ՆՇՌԽԼ ՁՆ ՌՀԽ Ծ ՇՄՄՁԻՄԽՋ ՇԾ ՋՇՅԽ ԾԽՅԹՄԽՋ ԹՆԼ ՅՁՆՁՅԹՄ

ՁՆՌԽՊՋՌՁՌՁԹՄԾՁԺՊՇՋՁՋՏԹՋՇԺՋԽՊՎԽԼԹՌՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊ ԹՌՁՇՆԦՆԹԼԼՁՌՁՇՆՁՆԻՁԼԽՆԻԽՋՇԾՁՆԻՊԽԹՋԽԼՇՇԻՑՌԽ

ԹՌՊԽՋՁԹՏԽՊԽՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՏՁՌՀ ԹՆԼՇԾՌՀԽԾՁՋՀԽՐՀՁԺՁՌՁՆԿ

ՌՀՁՋԾՁՆԼՁՆԿՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼՄՇՏԹՆԼՅՁԼՌՊԽԹՌՅԽՆՌՋ ՊԽՋՈԽԻՌ ՁՎԽՄՑԦՆՇԾՌՀԽՋԽԻԹՋԽՋԿՊԹՆՍՄՇՅԹՌՇՍՋ

ՁՆԾՄԹՅՅԹՌՁՇՆՏԹՋՇԺՋԽՊՎԽԼԽՎՁԼԽՆԻԽՇԾՅՁԻՊՇՋՈՇՊՁԼՁԹՁՆԾԽԻՌՁՇՆ ՏԹՋԹՄՋՇՇԺՋԽՊՎԽԼ

ԦՆՋՍՅՅԹՊՑԹՌՌՀԽՅՁԼԻՇՆԻԽՆՌՊԹՌՁՇՆԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՒԹՌՁՇՆԹՆԼԾԽՅԹՄԽՏԽՊԽԤ԰ԦՏԽՊԽԼԽԻՊԽԹՋԽԼԻՇՅՈԹՊԽԼ

ՌՇԻՇՆՌՊՇՄՋԤՇՆԹԼԹՄՀՁՋՌՇՈԹՌՀՇՄՇԿՑՏԹՋԹԾԾԽԻՌԽԼԹՋՋՀՇՏՆԺՑԼԽԻՊԽԹՋԽԼՑՇՄՃՋՑՆՌՀԽՋՁՋՁՆՌՀԽՄՇՏԹՆԼՅՁԼ

ԻՇՆԻԽՆՌՊԹՌՁՇՆ ԾԽՅԹՄԽՋ ԹՆԼ ՇԻԻԹՋՁՇՆԹՄ ԼՁՋՊՍՈՌՁՇՆՋ ՇԾ ԾՇՄՄՁԻՍՄԹՊ  ԳԱԤ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ԱՀԽ ՈՊՇՈՇՊՌՁՇՆ ՇԾ

ՋՈԽՊՅԹՌՇԿՇՆՁԹ ՁՆ ՌՀԽ ՌԽՋՌԽՋ ՏԹՋ ՁՆԻՊԽԹՋԽԼ ԹՌ ՌՀԽ ՀՁԿՀ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ԥՁԿՀ ՅՇՊՌԹՄՁՌՑ ԹՆԼ ԻՄՁՆՁԻԹՄ ՋՁԿՆՋ ՇԾ

ՌՇՐՁԻՁՌՑՁՆՌՀՁՋՋՌՍԼՑՅԹՑԻՇՆԾՇՍՆԼՌՀԽՁՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՌՀԽՋԽ ՈԹՊԹՅԽՌԽՊՋ

ԞՄՄ ՌՀԽ ՈԽՊԾՇՊՅԹՆԻԽ ԹՆԼ ՎԹՄՁԼՁՌՑ ԻՊՁՌԽՊՁԹ ՏԽՊԽ ՅԽՌ ԾՇՊ ՌՀՁՋ ՋՌՍ ԼՑ ԽՐԻԽՈՌ ԾՇՊ ՇՆԽ ԣՇՊ ՇՆԽ ՊԽՈՄՁԻԹՌԽ ՁՆ ՌՀԽ

ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ ՌՀԽ ԾԽԻՍՆԼՁՌՑ ՏԹՋ  ԽԿԿՋԾԽՅԹՄԽԼԹՑ ԹՆԼ ՁՌ ԼՁԼ ՆՇՌ ՋՈԹՏՆ ԹՌ ՄԽԹՋՌ ԽՎԽՊՑ  ԼԹՑՋ

ՅԽԽՌՁՆԿ ՇՆԽ ՇԾ ՌՀԽՋԽ ԻՊՁՌԽՊՁԹ ՁՋ ՍՋԽԼ ՌՇ ԼԽՅՇՆՋՌՊԹՌԽ ԹԻՌՁՎԽ ՋՈԹ ՏՆՁՆԿ ԞՄՌՀՇՍԿՀ ՆՇՌ Թ ՎԹՄՁԼՁՌՑ ԻՊՁՌԽՊՁԹ ՌՀԽ

ԽՆԼՈՇՁՆՌՋ ԹՌ ՌՀԽ ՀՁԿՀ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
 ՅԿ ԹՁԩ ՏԽՊԽ ՆՇ Ռ ՋՌԹՌՁՋՌՁԻԹՄՄՑ ԹՆԹՄՑՒԽԼ ԼՍԽ ՌՇ ՅՇՊՌԹՄՁՌՑ

ԱՀԽՊԽԾՇՊԽՇՆՄՑՌԽՋՌՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՏԽՊԽԹՆԹՄՑՒԽԼՁՆ ՌՀՁՋՋՌՍԼՑԞԼԼՁՌՁՇՆԹՄՄՑՌՀԽՋՍՊՎՁՎԹՄ ՊԹՌԽՁՆ

ՌՀԽ ՄՇՏԽՋՌ ՌՊԽԹՌՅԽՆՌ ԿՊՇՍՈ ՏԹՋ  ԹՆԼ ՁՆ ՇՆԽ ՊԽՈՄՁԻԹՌԽ ՌՀՊԽԽ ՇԾ ՌՀԽ ԾՇՍՊ ԹՎԹՁՄԹԺՄԽ ԾԽՅԹՄԽՋ ԼՁԽԼ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԽՋՋԽՆՌՁԹՄՄՑՄԽԹՎՁՆԿՇՆՄՑՌՀՊԽԽՎՁԹԺՄԽՊԽՈՄՁԻԹՌԽՋՁՆՌՀԽՄՇՏԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆԹՎԹՁՄԹԺՄԽԾՇՊԹՆԹՄՑՋՁՋՁՆՌԽՊՈՊԽՌԹՌՁՇՆ

ԞՄՌՀՇՍԿՀ ՁՆԼՁՎՁԼՍԹՄՋ ԼՁՋՈՄԹՑՁՆԿ ԻՄՁՆՁԻԹՄ ՋՁԿՆՋ ՇԾ ՌՇՐՁԻՁՌՑ ՏԽՊԽ  ՆՇՌ ԽՐԻՄՍԼԽԼ ԾՊՇՅ ՋՌԹՌՁՋՌՁԻԹՄ ԹՆԹՄՑՋԽՋ ՌՀԽ

ՈՊԽՋԽՆԻԽՇԾՌՀԽՋԽԻՄՁՆՁԻԹՄՋՁԿՆՋԹՄՇՆԿՏՁՌՀՌՀԽՀՁԿՀՊԹՌԽՇԾՁՆԻՊԽԹՋԽԼՇՇԻՑՌԽԹՌՊԽՋՁԹՁՆՌՀԽԻՇՆՌՊՇՄՋՅԹՃԽՋՁՌ

ՅՇՊԽԼՁԾԾՁԻՍՄՌՌՇՁՆՌԽՊՈՊԽՌՌՀԽՊԽՋՍՄՌՋՇԾՌՀԽՋՌՍԼՑ

ԞՄՌՀՇՍԿՀՌՀԽՅՇՊՌԹՄՁՌՑՁՆՌՀԽՀՁԿՀՌՊԽԹՌՅԽՆՌՄԽՎԽՄԻՄՁՆՁԻԹՄՋՁ ԿՆՋՇԾՌՇՐՁԻՁՌՑՁՆՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԹՆԼ ՆՇՌԽՏՇՊՌՀՑ ՊԹՌԽ ՇԾ ՇՇԻՑՌԽ ԹՌՊԽՋՁԹ ՁՆ ԻՇՆՌՊՇՄ ԾԽՅԹՄԽՋ ՅԹՃԽ Ռ ՀԽ ՊԽՋՍՄՌՋ ԼՁԾԾՁԻՍՄՌ ՌՇ ՁՆՌԽՊՈՊԽՌ ՏՀԽՆ

ԻՇՆՋՁԼԽՊԽԼՁՆԻՇՆՌԽՐՌՇԾՇՌՀԽՊԹՎԹՁՄԹԺՄԽԱՁԽՊԢԡ԰ԭԼԹՌԹԾՇՊՈՀՇՋՅԽՌՌՀՁՋՋՌՍԼՑՋԹՌՁՋԾՁԽՋՌՀԽԢԡ԰ԭԱՁԽՊ

ԱԽՋՌԬՊԼԽՊՊԽՉՍՁՊԽՅԽՆՌԾՇՊԹԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ
ԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԯԽՋՍՄՌՋ԰ՑՆՇՈՋՁՋ

ԱԽՋՌԬՊԿԹՆՁՋՅԹԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆՅՇՆՌՀՋ

ԪԽԹՆԺՇԼՑՏԽՁԿՀՌԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾՅԽԹՋՍՊԽԼԪԹՄԽԿ ԾԽՅԹՄԽԿ

ԪԽԹՆՄԽՆԿՌՀԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾՅԽԹՋՍՊԽԼԫՇՌՊԽՈՇՊՌԽԼ ԱԽՋՌԱՑՈԽ
ԣՄՇՏՌՀՊՇՍԿՀ԰ՌԹՌՁԻ԰ՌԹՌՁԻԯԽՆԽՏԹՄԣՄՇՏՌՀՊՇՍԿՀ

ԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢԾԾԽԻՌՋ  

### ՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ

ԣ԰ԱԯԞՏՁՌՀԭՀՇՋՅԽՌ

ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԣԽԻՍՆԼՁՌՑ ԣԽՊՌ

԰ՍԻԻԽՋՋ ԱՍԺԽՊԻՄԽ԰ԻՇՊԽ Ԥ԰Ԧ ԤՇՆԹԼԹՄԥՁՋՌՇ ԭՄԹՋՅԹԳԱԤ

Ԫ ԣ Ԫ ԣ Ԫ ԣ Ԫ ԣ



###  ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԫՇ ԶԽՋ ԫՇ ԫՇ

 ԶԽՋ ԶԽՋ ԫՇ ԫՇ ԫՇ ԶԽՋ ԶԽՋ ԶԽՋ ԫՇ ԫՇ

  

### ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԠՇՆԻ 

### ԠՇՆԻԽՆՌՊԹՌՁՇՆ ԡՁԾԾ 

### ԡՁԾԾԽՊԽՆԻԽ Ԣ 

###  ȕ ԽՋՌՊԹԼՁՇՄ ԣ 

### ԣԽՅԹՄԽ ԣԽՊՌ 

### ԣԽՊՌՁՄՁՒԹՌՁՇՆ Ԥ԰Ԧ 

### ԤՇՆԹԼՇ

԰ՇՅԹՌՁԻԦՆԼԽՐ ԥՁՋՌՇ 

### ԥՁՋՌՇՈԹՌՀՇՄՇԿՑ

Ԫ 

### ԪԹՄԽ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ Ա 

### ԱԽՋՌՇՋՌԽՊՇՆԽ ԳԱԤ 

### ԳՁՌԽՄՄՇԿԽՆՁՆ

 

###  Ԟ՟ՑԽՋՠՁՆԼՁԻԹՌԽՋԹՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆ ՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊԻՇՆՌՊՇՄՍՆՄԽՋՋ

ՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼ

 

###  ԱՀԽԻՊՁՌԽՊՁԹԾՇՊՋՁԿՆՁԾՁԻԹՆԻԽԹՊԽԼԽՋԻՊՁԺԽԼՁՆՌՀԽԯԽՎՁԽՏԽՊ0Ջ ԞՆԹՄՑՋՁՋԹՆԼ԰ՌԹՌՁՋՌՁԻԹՄԳԽՊՁԾՁԻԹՌՁՇՆՋԽԻՌՁՇՆՋՇԾ

ՌՀԽԡԢԯԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽ ՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼ

ԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ

 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՀՁԿՀՅՇՊՌԹՄՁՌՑ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԦԪԞԱԢԯԦԞԩ԰ԞԫԡԪԢԱԥԬԡ԰

ԤԲԦԡԢԩԦԫԢԣԬԩԩԬԴԢԡ   ԱՀՁՋՋՌՍԼՑՏԹՋԻՇՆԼՍԻՌԽԼԹԻԻՇՊԼՁՆԿՌՇՌՀԽԲ԰ԢԭԞԬԠ԰ԭԭ

՟ԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՎԽԞՋՋԹՑՠԹՆԼԬԢԠԡ

ԱՀԽԾՇՄՄՇՏՁՆԿԼԽՎՁԹՌՁՇՆՋՏԽՊԽՆՇՌԽԼ

 ԱՀԽ ԾԽԻՍՆԼՁՌՑ ՁՆ ՇՆԽ ՊԽՈՄՁԻԹՌԽ ՇԾ ՌՀԽ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ ՏԹՋ 

ԽԿԿՋԾԽՅԹՄԽԼԹՑ ՆՇՊ ԼՁԼՌՀԽ ՊԽՈՄՁԻԹՌԽ ՋՈԹՏՆ ԹՌ ՄԽԹՋՌ ԽՎԽՊՑ  ԼԹ ՑՋ ԪԽԽՌՁՆԿ

ՇՆԽՇԾՌՀԽՋԽԻՊՁՌԽՊՁԹՁՋՆԽԽԼԽԼՌՇԼԽՅՇՆՋՌՊԹՌԽԹԻՌՁՎԽՋՈԹՏՆՁՆԿ

 ԱՀԽ ԽՆԼՈՇՁՆՌՋ ԹՌ ՌՀԽ ՀՁԿՀ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
 ՅԿ ԹՁԩ ՏԽՊ Խ ՆՇՌ

ՋՌԹՌՁՋՌՁԻԹՄՄՑ ԹՆԹՄՑՒԽԼ ԼՍԽՌՇՅՇՊՌԹՄՁՌՑ ՇՆՄՑ ՇՆԽՅԹՄԽ ԹՆԼ ՇՆԽ ԾԽՅԹՄԽՋՍՊՎՁՎԽԼ

ԹՌ ՋՌՍԼՑ ՌԽՊՅՁՆԹՌՁՇՆ ԞՄՋՇ ԻՄՁՆՁԻԹՄ ՋՁԿՆՋ ՇԾ ՌՇՐՁԻՁՌՑ ԹՌ ՌՀԽ   ՅԿ ԹՁԩ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՅԹՃԽՊԽՋՍՄՌՋԹՌՌՀՁՋՌՊԽԹՌՅԽՆՌՄԽՎԽՄԼՁԾԾՁԻՍՄՌՌՇ ՁՆՌԽՊՈՊԽՌ

 

### ԱՀԽՈՀՑՋՁԻՇԻՀԽՅՁԻԹՄՈՊՇՈԽՊՌՁԽՋՇԾՌՀԽՌԽՋՌՅԹՌԽՊՁԹՄՏԽՊԽՆՇՌՊ ԽՈՇՊՌԽԼ

 

### ԱՀԽ ՍՆՁՇՆՁՒԽԼ ԹՅՅՇՆՁԹ ԹՆԼ ՊԽՋՁԼՍԹՄ ԻՀՄՇՊՁՆԽ ՁՆ ՌՀԽ ՌԽՋՌ ՏԹՌԽՊ Տ ԽՊԽ ՆՇՌ

ՊԽՈՇՊՌԽԼԱՀԽԬԠ԰ԭԭՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹԽՋՌԹԺՄՁՋՀՅԹՐ ՁՅՍՅՄԽՎԽՄՋ

ԾՇՊ ՌՀԽՋԽ ՎԹՄՍԽՋ ԹՆԼ ՁՌ ՁՋ ՍՆԻՄԽԹՊ ՁԾ ՌՀԽ ՅԹՐՁՅՍՅ ՊԽԻՇՅՅԽՆԼԹՌՁՇ ՆՋ ՏԽՊԽ

ԽՐԻԽԽԼԽԼ

ԱՀԽՀՁԿՀՁՆԻՁԼԽՆԻԽՇԾՅՇՊՌԹՄՁՌՑԹՆԼԻՄՁՆՁԻԹՄՋՁԿՆՋՅԹՃԽՌՀԽՊԽՋ ՍՄՌՋՇԾՌՀՁՋՋՌՍԼՑԼՁԾԾՁԻՍՄՌՌՇՁՆՌԽՊՈՊԽՌ

ԥՇՏԽՎԽՊԾԽՏԽԾԾԽԻՌՋՏԽՊԽՋԽԽՆՁՆՌՀԽԹԺՋԽՆԻԽՇԾՇՎԽՊՌՌՇՐՁԻՁՌՑ ՁՆՌՀԽԹՎԹՁՄԹԺՄԽՊԽՈՄՁԻԹՌԽՋՇԾՌՀԽՄՇՏ

ՌՊԽԹՌՅԽՆՌՄԽՎԽՄԹՆԼՁՌՁՋԻՇՆՋՁԼԽՊԽԼՍՆՄՁՃԽՄՑՌՀԹՌՊԽՈԽՌՁՌՁՇՆ ՇԾՌՀԽՋՌՍԼՑԹՌՄՇՏԽՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՏՇՍՄԼՑՁԽՄԼ

ՋՌՊՇՆԿԽՊՊԽՋՍՄՌՋ

 ԠԬԪԭԩԦԞԫԠԢ    ԰ՁԿՆԽԼ ԹՆԼ ԼԹՌԽԼ Ԥԩԭ ԮՍԹՄՁՌՑ ԞՋՋՍՊԹՆԻԽ ԹՆԼ ԡԹՌԹ ԠՇՆԾՁԼԽՆՌՁ ԹՄՁՌՑ ԻՄԹՁՅՋ

ՋՌԹՌԽՅԽՆՌՋՏԽՊԽ ՈՊՇՎՁԼԽԼ ԱՀՁՋ ՋՌՍԼՑՏԹՋ ԻՇՆԼՍԻՌԽԼ ՁՆ ԹԻԻՇՊԼԹՆԻ ԽՏՁՌՀԤԩԭ

԰ՌԹՆԼԹՊԼՋ ԹՋ ՈՍԺՄՁՋՀԽԼ ԺՑ ՌՀԽ Բ԰ ԢԭԞ 
 Ԡԣԯ ԭԹՊՌՋ  ԹՆԼ ԬԢԠԡ

ԭՊՁՆԻՁՈՄԽՋՇԾԤԩԭ#ԢԫԳԪԠԠԥԢԪ
%

ԞԱԢ԰ԱԪԞԱԢԯԦԞԩ  ԭՀՇՋՅԽՌԠԞ԰ԫՇ

ԡԽՋԻՊՁՈՌՁՇՆ    ԫՇՆԽՊԽՈՇՊՌԽԼԢՐՈՁՊԹՌՁՇՆԼԹՌԽԧԹՆՍԹՊՑ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԬԢԠԡ ՊԽԻՇՅՅԽՆԼՋ ԼԽՋԻՊՁԺՁՆԿՏԹՌԽՊ ՋՇՄՍԺՁՄՁՌՑ ՅԽՄՌՁՆԿԺՇՁՄՁՆԿ ՈՇ ՁՆՌ ՋՌԹԺՁՄՁՌՑ ՁՆՏԹՌԽՊ ԹՆԼ ՄՁԿՀՌ ՈԨԹԭՇՏ ՇՊ

ԨՇՏՎԹՈՇՊՈՊԽՋՋՍՊԽՇԾՌԽՋՌԻՇՅՈՇՍՆԼԽՐՈՁՊԹՌՁՇՆԼԹՌԽ



### ԩՇՌԫՇԟԹՌԻՀԫՇ  ԤԮԥ

ԭՍՊՁՌՑ      

ԦՅՈՍՊՁՌՁԽՋ     ԫՇՆԽՊԽՈՇՊՌԽԼ

԰ՌԹԺՁՄՁՌՑ ՇԾ ԠՇՅՈՇՍՆԼ  ԞՆԹՄՑՌՁԻԹՄ ՎԽՊՁԾՁԻԹՌՁՇՆ ՇԾ ՌՀԽ ՌԽՋՌ ՅԹՌԽՊՁԹՄ ԾՊՇՅ ՌՁՅԽ   ԹՆ Լ  ԼԹՑՋ

ՑՁԽՄԼԽԼՊԽԻՇՎԽՊՁԽՋՇԾՌՇՇԾՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԱԽՋՌՋՇՄՍՌՁՇՆԾՇՊՌՁԾՁԽԼՏՁՌՀՈՀՇՋՅԽՌ

ԹՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋՇԾԹՆԼՅԿԹՁԩՑՁԽՄԼ ԽԼՊԽԻՇՎԽՊՁԽՋՇԾՌՇՏՁՌՀ

ՇՆԽ ՇՍՌՄՁԽՊ ՊԽԻՇՎԽՊՑ ՇԾ ՈՇՋՋՁԺՄՑ ԼՍԽՌՇՋՈՁՃՁՆԿ ՀԹՆԼՄՁՆԿ  ՇՊ ՁՆՋՌՊՍՅԽՆՌ ԽՊՊՇՊՋԱՀԽԠԳ0ՋԾՇՊ

ՌՀԽՁՆԼՁՎՁԼՍԹՄՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՊԹՆԿԽԼԾՊՇՅԾՇՊՌՀԽԽՐ ՈՇՋՍՊԽՈԽՊՁՇԼԱՀԽՋԽԼԹՌԹՁՆԼՁԻԹՌԽ

ՌՀԽՌԽՋՌՅԹՌԽՊՁԹՄՏԹՋՋՌԹԺՄԽՍՆԼԽՊՌՀԽՌԽՋՌԻՇՆԼՁՌՁՇՆՋ

԰ՌՇՊԹԿԽԠՇՆԼՁՌՁՇՆՋՇԾ

ԱԽՋՌԠՀԽՅՁԻԹՄՋ    ԱՀԽՌԽՋՌՋՍԺՋՌԹՆԻԽՏԹՋՋՌՇՊԽԼԹՌՊՇՇՅՌԽՅՈԽՊԹՌՍՊԽՁՆԼԹՊՃՎԽՆՌՁՄԹՌԽԼ

ԻԹԺՁՆԽՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԟԱԽՋՌՇՊԿԹՆՁՋՅԱԹԺՄԽԤԽՆԽՊԹՄԦՆԾՇՊՅԹՌՁՇՆԞԺՇՍՌՌՀԽԱԽՋՌ԰ՈԽԻՁԽՋԹՆԼԞԻԻՄՁՅԹՌՁՇՆԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԽԻՁԽՋԻՇՅՅՇՆՆԹՅԽ ԣԹՌՀԽԹԼԪՁՆՆՇՏ ԢԭԞՊԽԻՇՅՅԽՆԼՋԾԹՌՀԽԹԼՅՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ԰ՈԽԻՁԽՋՋԻՁԽՆՌՁԾՁԻՆԹՅԽ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ԰ՈԽԻՁԽՋՋՌՊԹՁՆ
ՁԾՋՌԹՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼԴԽՊԽԾՁՋՀՇԺՌԹՁՆԽԼԾՊՇՅԹՋՁՆԿՄԽՄԹԺՇՊԹՌՇՊՑՋՌՇԻՃ!ԶԽՋ ԰ՇՍՊԻԽՆՇՌՊԽՈՇՊՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԾՊՇՅԹՋՁՆԿՄԽ

ՄԹԺՇՊԹՌՇՊՑՋՌՇԻՃԴԽՊԽԹԻԻՄՁՅԹՌՁՇՆԻՇՆԼՁՌՁՇՆՋՋԹՅԽԹՋԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԶԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԹԻԻՄՁՅԹՌԽԼ ՍՆԼԽՊՏԹՌԽՊՉՍԹՄՁՌՑԹՆԼՁՄՄՍՅՁՆԹՌՁՇՆ ԻՇՆԼՁՌՁՇՆՋՌՀԹՌԹՊԽՋՁՅՁՄԹՊՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽ

ՌԽՋՌԞԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԼԹՑՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՌՏՇՏԽԽՃ ԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԫՇՌԽՌՀԹՌՌՀԽԹԻԻՄՁՅԹՌՁՇՆ ՈԽՊՁՇԼՁՋԼՁԾԾԽՊԽՆՌԾՊՇՅՌՀԽՋՍԺՋԽՉՍԽՆՌՁՆ ՋՁՌՍՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՀԽԹՄՌՀԪՇՊՌԹՄՁՌՁԽՋԼՍՊՁՆԿԼԹՑՋՈՊՁՇՊՌՇՈՊԽԽՐՈՇՋՍՊԽՈԽՊՁՇԼՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼԣՁՋՀԼՁԼՆՇՌՊԽԻԽՁՎԽԹՆՑՌՊԽԹՌՅԽՆՌԾՇՊԼՁՋԽԹՋԽԼՍՊՁՆԿԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼԟԽՀԹՎՁՇՊԹՄԹԺՆՇՊՅԹՄՁՌՁԽՋՇՊԻՄՁՆՁԻԹՄՋՁԿՆՋՏԽՊԽՆՇՌՊԽՈՇՊՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՅՇՊՌԹՄՁՌՑԼՍՊՁՆԿՌՀԽ ԼԹՑՋՈՊՁՇՊՌՇՌՀԽՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽԺԽ ՄԽՋՋՌՀԹՆՇԾՌՀԽԻՍՄՌՍՊԽՈՇՈՍՄԹՌՁՇՆԦԾ ՅՇՊՌԹՄՁՌՑԼՍՊՁՆԿՌՀԽՋԽԼԹՑՋՁՋԿՊԽԹՌԽՊՌՀԹՆ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԾՁՋՀԺԽ ՊԽՂԽԻՌԽԼԦԾՅՇՊՌԹՄՁՌՑՁՋԺԽՌՏԽԽՆԢԭԞ ՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽՀԽՄԼԹՆՇՌՀԽՊ ԼԹՑՋԦԾՅՇՊՌԹՄՁՌՁԽՋԿՊԽԹՌԽՊՌՀԹՆՇԻԻՍՊ ԼՍՊՁՆԿՌՀՁՋԽՐՌԽՆԼԽԼԹԻԻՄՁՅԹՌՁՇՆՈԽՊՁՇԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽԾՁՋՀՆՇՌԺԽՍՋԽԼԱՑՈԽՇԾԾՇՇԼԩՁՎԽԺՊՁՆԽՋՀՊՁՅՈՆԹՍՈՄՁՁ ԞՊՌԽՅՁԹ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՁՋՀԺԽԾԽԼԾՊՇՒԽՆ ԺՊՁՆԽՋՀՊՁՅՈՌՏՁԻԽՈԽՊԼԹՑՌՇՈՊՇՅՇՌԽ ԹԻՌՁՎԽՊԽՈՊՇԼՍԻՌՁՇՆԹՆԼՅԹՁՆՌԹՁՆԺՇԼՑ

ԻՇՆԼՁՌՁՇՆ԰ՇՍՊԻԽՇԾԾՇՇԼԫՇՌՊԽՈՇՊՌԽԼԣՊԽՉՍԽՆԻՑՇԾԾԽԽԼՁՆԿՌՁՅԽՋԼԹՑԡԽՌԹՁՄՋՇՆԾԽԽԼՁՆԿԫՇՆԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԣՁՋՀ԰ԽՄԽԻՌՁՇՆԹՆԼԭՊԽԢՐՈՇՋՍՊԽԭԽՊԾՇՊՅԹՆԻԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞԿԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆՅՇՆՌՀՋ ԯԽՈՇՊՌԽԼԹՋՏԽԽՃՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՊՇԼՍԻՌՁՎԽՄՑՅԹՌՍՊԽ ՋԽՐՍԹՄՄՑԼՁՅՇՊՈՀՁԻԾՁՋՀՅՇՆՌՀՋ

ՇՄԼԪԽԹՆՏԽՁԿՀՌՇԾՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԿ ԟԹՋԽԼՇՆՅԹՄԽՋՍՋԽԼՌՇՋՌՇԻՃԹՉՍԹՊՁԹԾՇՊՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ԹՋՍԺՋԹՅՈՄԽ ՇԾԾՁՋՀԺԽՏԽՁԿՀԽԼԺԽԾՇՊԽՌՀԽՌԽՋՌՌՇ ԽՋՌՁՅԹՌԽՌՀԽՅԽԹՆՏԽՁԿՀՌԾՇՊԽԹԻՀՋԽՐԦՌՁՋ ՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌՀԽՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՇԾ ԽԹԻՀԾՁՋՀՋԽՄԽԻՌԽԼԾՇՊՌՀԽՌԽՋՌԺԽՏՁՌՀՁՆ չՇԾՌՀԽԽՋՌՁՅԹՌԽԼՅԽԹՆԾՇՊԽԹԻՀՋԽՐԯԹՆԿԽՇԾՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼՌՇԿ ԦՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋՏՁՌՀՁՆչՇԾՌՀԽԽՋՌՁՅԹՌԽԼՅԽԹՆԪԽԹՆՏԽՁԿՀՌՇԾԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԿ ԟԹՋԽԼՇՆԾԽՅԹՄԽՋՍՋԽԼՌՇՋՌՇԻՃԹՉՍԹՊՁԹԾՇՊՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽԯԹՆԿԽՇԾՁՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼՌՇԿ ԦՆԼՁՎՁԼՍԹՄՏԽՁԿՀՌՋՏՁՌՀՁՆչՇԾՌՀԽԽՋՌՁՅԹՌԽԼՅԽԹՆԪԽԹՆՄԽՆԿՌՀՇԾՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԫՇՌՊԽՈՇՊՌԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԪԽԹՆՄԽՆԿՌՀՇԾԾԽՅԹՄԽՋԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ
ՁԾԼԽՌԽՊՅՁՆԽԼԫՇՌՊԽՈՇՊՌԽԼԡՍՊԹՌՁՇՆՇԾՈՊԽԽՐՈՇՋՍՊԽՈՀԹՋԽ ԼԹՑՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾԼԹՑՋԴԽՊԽՈՊԽԽՐՈՇՋՍՊԽԻՇՆԼՁՌՁՇՆՋՁԼԽՆՌՁԻԹՄՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌ!ԶԽՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՈՊԽԽՐՈՇՋՍՊԽ ԻՇՆԼՁՌՁՇՆՋՁՆԻՄՍԼՁՆԿՌԽՅՈԽՊԹՌՍՊԽ ՈՀՇՌՇՈԽՊՁՇԼԾԽԽԼՁՆԿԽՌԻԺԽՁԼԽՆՌՁԻԹՄՌՇ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԻՇՆԼՁՌՁՇՆՋԫՍՅԺԽՊՇԾՈՊԽԽՐՈՇՋՍՊԽՌԹՆՃՋԢՐՌՊԹՊԽՈՄՁԻԹՌԽՋՏԽՊԽԽՋՌԹԺՄՁՋՀԽԼՌՇԹԻԻՇՍՆՌԾՇՊԹՈՇՌԽՆՌՁԹՄՄԹԻՃՇԾՋՈԹՏՆՁՆԿՁՆՋՇՅԽԻՀԹՅԺԽՊՋԹՆԼՇՊՅՇՊՌԹՄՁՌՑԼՍՊՁՆԿՌՀՁՋՈՀԹՋԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԹԼԼՁՌՁՇՆԹՄՌԹՆՃՋՋԽՌ ՍՈԹՌՌՀԽԺԽԿՁՆՆՁՆԿՇԾՈՊԽԽՐՈՇՋՍՊԽՏՁՄՄ ԽՆՋՍՊԽՌՀԹՌՋՍԾԾՁԻՁԽՆՌՊԽՈՄՁԻԹՌԽՋՏՁՌՀՌՀԽ ԻՇՊՊԽԻՌՋԽՐՊԹՌՁՇԹՊԽԹՎԹՁՄԹԺՄԽԾՇՊՌՀԽ

ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԫՍՅԺԽՊՇԾՅԹՄԽՋՈԽՊՌԹՆՃԫՍՅԺԽՊՇԾԾԽՅԹՄԽՋՈԽՊՌԹՆՃԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԭՊԽԽՐՈՇՋՍՊԽԾԽԻՍՆԼՁՌՑԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՊԽՈՄՁԻԹՌԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՈՊԽԽՐՈՇՋՍՊԽ ԾԽԻՍՆԼՁՌՑՁՆԽԹԻՀՊԽՈՄՁԻԹՌԽ
ՌԹՆՃՋԽՄԽԻՌԽԼ ԾՇՊՍՋԽՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԹՌՄԽԹՋՌ ԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՊԽՈՄՁԻԹՌԽ ԼՍՊՁՆԿՌՀԽԼԹՑՋՈՊՁՇՊՌՇՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԫՍՅԺԽՊՇԾՋՈԹՏՆՋԼՍՊՁՆԿՈՊԽԽՐՈՇՋՍՊԽՌՏՇՌՁՅԽՋՁՆԼԹՑՋ ԰ՈԹՏՆՁՆԿՇԻԻՍՊՊԽԼԹՌՄԽԹՋՌԽՎԽՊՑԼԹՑՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՋՈԹՏՆՁՆԿՇԻԻՍՊԹՌ ՄԽԹՋՌՌՏՁԻԽՁՆՌՀԽԼԹՑՋՈՊՁՇՊՌՇՌՀԽ

ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԡԽՌԹՁՄՋՇՆՈՊԽԽՐՈՇՋՍՊԽ ԫՇՆԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԠԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԦՆԾՇՊՅԹՌՁՇՆՇՆՌՀԽԢՐՈՇՋՍՊԽ԰ՑՋՌԽՅԹՆԼԱԽՋՌԳԽՋՋԽՄԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱՑՈԽՇԾԽՐՈՇՋՍՊԽԣՄՇՏՌՀՊՇՍԿՀ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԾՄՇՏ ՌՀՊՇՍԿՀՋՑՋՌԽՅԞՋՆՇՌԽԼՁՆՌՀԽ ԠՇՊՊԽԻՌՁՇՆՋԹՆԼԠՄԹՊՁԾՁԻԹՌՁՇՆՋԼՇԻՍՅԽՆՌ   ՌՀԽՍՋԽՇԾԹՋՌԹՌՁԻՊԽՆԽՏԹՄՋՑՋՌԽՅՁՋՆՇՌ ՊԽԻՇՅՅԽՆԼԽԼԾՇՊՌՀՁՋԹՋՋԹՑԱՑՈԽՇԾԾՄՇՏՌՀՊՇՍԿՀԼՁՄՍՌՁՇՆՋՑՋՌԽՅԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊ ԦՆՌԽՊՅՁՌՌԽՆՌԾՄՇՏՈՊՇՈՇՊՌՁՇՆԹՄԼՁՄՍՌԽՊՋՇՊ ԻՇՆՌՁՆՍՇՍՋԾՄՇՏՋԽՊՁԹՄԼՁՄՍՌԽՊՋԹՊԽ ՊԽԻՇՅՅԽՆԼԽԼ ԣՄՇՏՌՀՊՇՍԿՀՊԹՌԽԠԹԩՀՊԽՉՍՁՎԹՄԽՆՌՌՇՎՇՄՍՅԽՊԽՈՄԹԻԽՅԽՆՌՋԼԹՑԠԹՄԻՍՄԹՌԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊԺԹՋԽԼՇՆԩԻՑԻՄԽԹՌԹՊԹՌԽՇԾԻՑԻՄԽՋՀՊՋ ԯԽԻՇՅՅԽՆԼԽԼԾՄՇՏՌՀՊՇՍԿՀՊԹՌԽՁՋ ՅԩՅՁՆ
ԩՀՊՇՊԹՌՄԽԹՋՌՌՇՌԹՄ ՎՇՄՍՅԽԽՐԻՀԹՆԿԽՋՈԽՊԼԹՑԲ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑ
ԢԭԞ
ԠՇՊՊԽԻՌՁՇՆՋԹՆԼԠՄԹՊՁԾՁԻԹՌՁՇՆՋՇՆԱԽԻՀՆՁԻԹՄԞՋՈԽԻՌՋՇԾՌՀԽԱԽՋՌԤՍՁԼԽՄՁՆԽՋԾՇՊՌՀԽԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌՇՊ԰ԻՊԽԽՆՁՆԿԭՊՇԿՊԹՅԱՁԽՊԞՋՋԹՑՋ
ԬԠ԰ԭԭԱԽՋՌԤՍՁԼԽՄՁՆԽ԰ԽՊՁԽՋԪԹՊԻՀԬԾԾՁԻԽՇԾԠՀԽՅՁԻԹՄ԰ԹԾԽՌՑԹՆԼԭՇՄՄՍՌՁՇՆԭՊԽՎԽՆՌՁՇՆ
ԬԠ԰ԭԭԴԹՋՀՁՆԿՌՇՆԡԠՀՌՌՈՏՏՏԽՈԹԿՇՎԽՆԼՇՈՍԺՋԹՋՋԹՑՎԹՄՁԼԹՌՁՇՆԻՄԹՊՁԾՁԻԹՌՁՇՆԼՇԻՈԼԾԞԼԼՁՌՁՇՆԹՄԿՍՁԼԹՆԻԽԾՇՊԹՉՍԹՌՁԻՌԽՋՌԼԽՋՁԿՆՁՋՄՇԻԹՌԽԼՁՆԬԠ԰ԭԭԤՍՁԼԽՄՁՆԽ԰ՈԽԻՁԹՄԠՇՆՋՁԼԽՊԹՌՁՇՆՋԾՇՊԠՇՆԼՍԻՌՁՆԿԞՉՍԹՌՁԻԩԹԺՇՊԹՌՇՊՑ԰ՌՍԼՁԽՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԡԽՌԹՁՄՋՇՆՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏՌՀՊՇՍԿՀՋՑՋՌԽՅՋԣՄՇՏՋՈՄՁՌՌՁՆԿԻՀԹՅԺԽՊՋՏԽՊԽՍՋԽԼԺԽՌՏԽԽՆԼՁՄՍՌԽՊԻԽՄՄՋԹՆԼՌՀԽՊԽՈՄՁԻԹՌԽՌԽՋՌՎԽՋՋԽՄՋԱՊԽԹՌՅԽՆՌՊԽԻՇՎԽՊՁԽՋՏԽՊԽՆՇՌՅԽԹՋՍՊԽԼՈՊՁՇՊՌՇՌԽՋՌՁՆՁՌՁԹՌՁՇՆՌՇՁՆԼՁԻԹՌԽՁԾԼՁՄՍՌԽՊՀԹԼՊԽԹԻՀԽԼԽՉՍՁՄՁԺՊՁՍՅԣՄՇՏՋՈՄՁՌՌՁՆԿԹԻԻՍՊԹԻՑՏԹՋՆՇՌՊԽՈՇՊՌԽԼ ԯԽԻՇՅՅԽՆԼԽԼՌՇՐՁԻԹՆՌՅՁՐՁՆԿԾՇՊԾՄՇՏ ՌՀՊՇՍԿՀՋՑՋՌԽՅՋԪՁՐՁՆԿԻՀԹՅԺԽՊՁՋ ՊԽԻՇՅՅԽՆԼԽԼԺՍՌՆՇՌՊԽՉՍՁՊԽԼ ԞԽՊԹՌՁՇՆՁՋՆՇՌՊԽԻՇՅՅԽՆԼԽԼԾՇՊՅՁՐՁՆԿ ԞԼԽՅՇՆՋՌՊԹՌՁՇՆՌՀԹՌՌՀԽՌԽՋՌՋՇՄՍՌՁՇՆ ՁՋԻՇՅՈՄԽՌԽՄՑՅՁՐԽԼԺԽԾՇՊԽՁՆՌՊՇԼՍԻԽԼ ՁՆՌՇՌՀԽՌԽՋՌՋՑՋՌԽՅՁՋՊԽԻՇՅՅԽՆԼԽԼ ԱՀԽՊԽԻՇՅՅԽՆԼԽԼԾՄՇՏՋՈՄՁՌՌՁՆԿԹԻԻՍՊԹԻՑ

ՁՋՏՁՌՀՁՆԞԽՊԹՌՁՇՆ!ԫՇ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹԽՊԹՌՁՇՆՁԾԼՁՋՋՇՄՎԽԼ ՇՐՑԿԽՆՊԽԹԻՀԽՋ ՅԿԩ
 

ՋԹՌՍՊԹՌՁՇՆ԰ՇՍՊԻԽՇԾԼՁՄՍՌՁՇՆՏԹՌԽՊ ԴԽՄՄՏԹՌԽՊԡՁՄՍՌՁՇՆՏԹՌԽՊՏԹՋԹԽՊԹՌԽԼՈՊՁՇՊՌՇՍՋԽ ԢԭԞՊԽԻՇՅՅԽՆԼՋՆԹՌՍՊԹՄՇՊՊԽԻՇՆՋՌՁՌՍՌԽԼ ՏԹՌԽՊՁՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՆԹՌՍՊԹՄ ՏԹՌԽՊԺԽՋՌԽՊՁՄՁՒԽԼՏՁՌՀԲԳԹՆԼՌԽՋՌԽԼԾՇՊ ՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊ ՈՇՋՋՁԺՄԽԻՇՆՌԹՅՁՆԹՆՌՋԬԢԠԡԹԻԻԽՈՌՋ ԹՆՑՏԹՌԽՊՁՆՏՀՁԻՀՌՀԽՌԽՋՌՋՈԽԻՁԽՋՋՀՇՏ ԻՇՆՌՊՇՄՋՍՊՎՁՎԹՄԹՌՄԽԹՋՌԹՋԿՇՇԼԹՋ ՁՆԼՁԻԹՌԽԼՁՆՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԼՁՄՍՌՁՇՆՏԹՌԽՊԹՆԹՄՑՒԽԼԾՇՊՈԽՋՌՁԻՁԼԽՋՀԽԹՎՑՅԽՌԹՄՋԹՆԼՇՌՀԽՊԻՇՆՌԹՅՁՆԹՆՌՋ!ԶԽՋ ԱԽՋՌՎԽՋՋԽՄՌՑՈԽՅԹՌԽՊՁԹՄՋ ԤՄԹՋՋԹՉՍԹՊՁԹՏՁՌՀՋՁՄՁԻՇՆԽՋԽԹՄԹՆՌԹՆԼՆՑՄՇՆ ԢԭԞԹՆԼԬԢԠԡՊԽԻՇՅՅԽՆԼՌՀԹՌՏԹՌԽՊ ԻՇՆՌԹԻՌՈՇՊՌՁՇՆՋՇԾՌՀԽՋՑՋՌԽՅՆՇՌ ԻՇՅՈՊՇՅՁՋԽՌՀԽՋՌՍԼՑ
ԽԿ ԹՄՄԿՄԹՋՋ ՎԽՋՋԽՄՋՇՊԿՄԹՋՋՎԽՋՋԽՄՋՏՁՌՀՋՌԹՁՆՄԽՋՋ ՋՌԽԽՄԾՊԹՅԽՋԹՊԽԹԻԻԽՈՌԹԺՄԽԽՐԹՅՈՄԽՋԱԽՋՌՎԽՋՋԽՄՋՁՒԽԻՅՏՁԼԽՐԻՅՄՇՆԿՐԻՅՀՁԿՀՋՇՄՍՌՁՇՆԼԽՈՌՀԻՅ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԩՌԽՋՌ ԻՀԹՅԺԽՊՋ
ԽԿՐՐԻՅԣՁՄՄՎՇՄՍՅԽԩ ԢԭԞՊԽԻՇՅՅԽՆԼՋԩՋՇՄՍՌՁՇՆՈԽՊՌԹՆՃ԰ՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՅԹՌԽՊՁԹՄ ՁՆԻՀԼՁԹՅԽՌԽՊԹԿԽԼԭԳԠԻՍՌՁՆՀԹՄԾ
ԹՊԻՀԽՋԹՆԼՁՆՌՇԻՅՋԽԻՌՁՇՆՋԹՆԼՈՇՋՁՌՁՇՆԽԼՁՆԹՋԻՊԽԽՆԽԼԿՄԹՋՋԻՇՄՄԽԻՌՁՇՆՌՊԹՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԽԹԻՀՌԹՆՃԻՇՆՌԹՁՆ ՌՀՊԽԽՋԽՅՁԻՁՊԻՍՄԹՊՋՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՋ ԽԿԹԿԽԼԭԳԠՈՁՈԽԻՅՁՆ ՄԽՆԿՌՀՋՈՄՁՌՄԽՆԿՌՀՏՁՋԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋ԰ՈԹՏՆՁՆԿՋՍԺՋՌՊԹՌԽՋՁՒԽԭԳԠԻՍՌՁՆՀԹՄԾ
ԹՊԻՀԽՋԹՆԼՁՆՌՇԻՅՋԽԻՌՁՇՆՋԢԹԻՀՋՍԺՋՌՊԹՌԽՈՄԹԻԽԼՇՆՋԻՊԽԽՆԽԼԿՄԹՋՋԻՇՄՄԽԻՌՁՇՆՌՊԹՑ
ՐՐԻՅԩՐԴՐԥԻՇՎԽՊԽԼՏՁՌՀԻՅՋՌԹՁՆՄԽՋՋՋՌԽԽՄՅԽՋՀԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋՇՆԽՐՈՇՋՍՊԽՋՑՋՌԽՅ ԫՇՆԽԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԴԹՌԽՊԮՍԹՄՁՌՑԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋՁՆՌՀԽԱԽՋՌ԰ՑՋՌԽՅԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՅՈԽՊԹՌՍՊԽ
ոԠ ԠՇՆՌՁՆՍՇՍՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌԽՅՈԽՊԹՌՍՊԽչ Շ Ԡ ՁՆՌԽՊՊԽՈՄՁԻԹՌԽԹՆԼՁՆՌԽՊՌՊԽԹՌՅԽՆՌ ԼՁԾԾԽՊԽՆՌՁԹՄՋՋՀՇՍՄԼՆՇՌԽՐԻԽԽԼ Շ ԠՈԥ ԡԹՁՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈԥՌՇԡՁՋՋՇՄՎԽԼՇՐՑԿԽՆ
ՅԿԩ 
 
 
 ԡԹՁՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ

ԡԬ ՅԿԩ
 ԹՁՊՋԹՌՍՊԹՌՁՇՆԱՇՌԹՄԹՄՃԹՄՁՆՁՌՑ
ՅԿԩԹՋԠԹԠԬ  ԴԽԽՃՄՑ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՇՌԹՄԹՄՃԹՄՁՆՁՌՑ  ՅԿԩԹՋԠԹԠԬ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԪՁՆՁՅՍՅԪԹՐՁՅՍՅԪԽԹՆԪԽԹՋՍՊԽՅԽՆՌԦՆՌԽՊՎԹՄԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԥԹՊԼՆԽՋՋ
ՅԿԩԹՋԠԹԠԬ ԴԽԽՃՄՑԱՇՌԹՄՇՊԿԹՆՁԻԻԹՊԺՇՆ
ՅԿԩ  ԫԞ ԫՇՎԡԽԻ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՇՌԹՄՇՊԿԹՆՁԻ ԻԹՊԺՇՆՁՆԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ ՅԿԩԲՆՁՇՆՁՒԽԼԹՅՅՇՆՁԹμԿԩ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՍՆՁՇՆՁՒԽԼ ԹՅՅՇՆՁԹՁՆՌՀԽԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ 

μ ԿԩԯԽՋՁԼՍԹՄԻՀՄՇՊՁՆԽμԿԩ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԫՇՌՊԽՈՇՊՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՊԽՋՁԼՍԹՄԻՀՄՇՊՁՆԽ ՁՆԼՁՄՍՌՁՇՆՏԹՌԽՊԺԽ μ ԿԩԠՇՆԼՍԻՌՁՎՁՌՑμՅՀՇՋԻՅ  ԴԽԽՃՄՑ ԤԽՆԽՊԹՄՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋԾՇՊԾՊԽՉՍԽՆԻՑ ՇԾՅԽԹՋՍՊԽՅԽՆՌՋԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌ ՌԽՅՈԽՊԹՌՍՊԽՈԥԹՆԼԼՁՋՋՇՄՎԽԼՇՐՑԿԽՆ ԺԽՅԽԹՋՍՊԽԼՁՆԹՄՄՌԽՋՌՌԹՆՃՋԹՌՄԽԹՋՌ ՏԽԽՃՄՑԹՆԼՌՀԹՌՀԹՊԼՆԽՋՋԹՆԼԹՄՃԹՄՁՆՁՌՑ ԺԽՅԽԹՋՍՊԽԼՁՆԻՇՆՌՊՇՄՋԹՆԼՁՆՇՆԽՌԹՆՃ ԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆԹՌՄԽԹՋՌ ՏԽԽՃՄՑԦՆԹԼԼՁՌՁՇՆԻՇՆՌՁՆՍՇՍՋ ՌԽՅՈԽՊԹՌՍՊԽՅՇՆՁՌՇՊՁՆԿՇԾԹՌՄԽԹՋՌՇՆԽ ՌԹՆՃՁՋԽՆԻՇՍՊԹԿԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԞԺԺՊԽՎՁԹՌՁՇՆՋԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԪԽԹՆՋՏԽՊԽԻԹՄԻՍՄԹՌԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊԹՋՌՀԽԹՎԽՊԹԿԽՇԾՌՀԽՅՁՆՁՅԹԹՆԼՅԹՐՁՅԹԾՇՊՌՀԽՊԹՆԿԽՋՈՊՇՎՁԼԽԼԹԻՊՇՋՋԻՇՆՌՊՇՄԹՆԼՌՊԽԹՌԽԼՄԽՎԽՄՋԡ԰ՌՍԼՑԡԽՋՁԿՆԹՆԼԞԼԼՁՌՁՇՆԹՄԢՐՈԽՊՁՅԽՆՌԹՄԠՇՆԼՁՌՁՇՆՋԱԹԺՄԽԯԹՆԿԽԣՁՆԼՁՆԿ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋ
ՁԾԞՈՈՄՁԻԹԺՄԽԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԹՊԹՆԿԽԾՁՆԼԽՊԻՇՆԼՍԻՌԽԼ!ԶԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԻՇՆԼՍԻՌՁՆԿԹՊԹՆԿԽԾՁՆԼԽՊ

ՁԾՀՇՍՊԩԠ  ԼԹՌԹԾՇՊՌՀԽԾԹՌՀԽԹԼՅՁՆՆՇՏ

ԹՊԽՍՆԹՎԹՁՄԹԺՄԽԦԾՑԽՋՏՀԹՌՏԹՋՌՀԽՅԽՌՀՇԼԾՇՊԼԽՌԽՊՅՁՆՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽՊԹՆԿԽԾՁՆԼԽՊ!ԟԹՋԽԼՇՆՌՀԽՊԽՋՍՄՌՋՇԾՀՊՊԹՆԿԽԾՁՆԼՁՆԿՌԽՋՌԹՆԼՁՆԻՇՆՋՍՄՌԹՌՁՇՆՏՁՌՀՌՀԽՋՌՍԼՑՋՈՇՆՋՇՊ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆԺԽՋԽՄԽԻՌԽԼԺԹՋԽԼՇՆՌՇՐՁԻՁՌՑ ԼԹՌԹԾՇՊՇՌՀԽՊԾՁՋՀՋՌՍԼՁԽՋՇՊՋՈԽԻՁԽՋՁԾ ԹՎԹՁՄԹԺՄԽԬՌՀԽՊՏՁՋԽԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑ ՄՁՅՁՌՇԾՌՀԽՌԽՋՌԻՇՅՈՇՍՆԼՇՊՅԿԩ ՏՀՁԻՀԽՎԽՊՁՋՄՇՏԽՊՁՋԹՈՈՊՇՈՊՁԹՌԽ԰ՈԽԻՁԽՋԣԹՌՀԽԹԼԪՁՆՆՇՏ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԩՁԾԽՋՌԹԿԽԫՇՌՊԽՈՇՊՌԽԼ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՊԹՆԿԽԾՁՆԼՁՆԿՌԽՋՌՋ ԺԽՈԽՊԾՇՊՅԽԼՏՁՌՀԾՁՋՀՇԾՋՁՅՁՄԹՊԹԿԽԹՆԼ ՋՁՒԽՌՇՌՀՇՋԽՌՀԹՌՏՇՍՄԼԺԽՍՌՁՄՁՒԽԼՁՆՌՀԽ

ՌԽՋՌԱԽՋՌԼՍՊԹՌՁՇՆՀՊՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՀՇՍՊԽՐՈՇՋՍՊԽԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋԻՇՆԼՍԻՌՁՆԿԹՊԹՆԿԽԾՁՆԼԽՊ ՏՁՌՀԾՁՎԽՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋՈՄՍՋԹԻՇՆՌՊՇՄ ՋՁՐՌՇՌԹՄՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՏՁՌՀԾՇՍՊ ԾԽՅԹՄԽՋԹՆԼՌՏՇՅԹՄԽՋՈԽՊԽՐՈՇՋՍՊԽՌԹՆՃ ԾՁՋՀՌՇՌԹՄԱՀԽՆՍՅԺԽՊՇԾՅՇՊՌԹՄՁՌՁԽՋ ՌՀԹՌՇԻԻՍՊՅԹՑԺԽՍՋԽԼՌՇԼԽՎԽՄՇՈԹ ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽԻՍՊՎԽ ԟԹՋԽԼՍՈՇՆՌՀԽՊԽՋՍՄՌՋՌՀԽՀՁԿՀԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՌՀԹՌԼՇԽՋՆՇՌՊԽՋՍՄՌՁՆ ՁՆԻՊԽԹՋԽԼՅՇՊՌԹՄՁՌՑՇՊՋՁԿՆՋՇԾՇՎԽՊՌ ՅՇՊԺՁԼՁՌՑԻՇՅՈԹՊԽԼՌՇԻՇՆՌՊՇՄՋՇՊՌՀԽ
ԼԽՊՁՎԽԼՀՊԩԠ  ՅԹՑԺԽՋԽՄԽԻՌԽԼԹՋՌՀԽ ՀՁԿՀԽՋՌԽՐՈՇՋՍՊԽԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽ

ԼԹՑՌԽՋՌԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԡԽԾՁՆՁՌՁՎԽ԰ՌՍԼՑԠՇՆԼՁՌՁՇՆՋԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԱԽՋՌԼՍՊԹՌՁՇՆԼԹՑՋ ԢԭԞ ՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌ ՌՀԽ ԼՍՊԹՌՁՇՆ ՇԾ ՌՀԽ ԼԽԾՁՆՁՌՁՎԽՌԽՋՌԺԽԼԹՑՋԪԽՌՀՇԼԾՇՊՋԽՄԽԻՌՁՆԿՌՀԽՀՁԿՀԽՋՌՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁՆՌՀԽԼԽԾՁՆՁՌՁՎԽՌԽՋՌԱՀԽԹԻՍՌԽՌՇՐՁԻՁՌՑՀՇՍՊԩԠԾՇՊՈՀՇՋՅԽՌՏՁՌՀԾԹՌՀԽԹԼՅՁՆՆՇՏՁՋՅԿԩ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՀՁԿՀԽՋՌՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋԽՁՌՀԽՊՌՀԽՋՇՄՍԺՁՄՁՌՑՄՁՅՁՌՇԾ ՌՀԽՌԽՋՌԻՇՅՈՇՍՆԼՅԿԩՇՊ ԼԽՅՇՆՋՌՊԹՌԽՋԹԼԽՉՍԹՌԽԽՎՁԼԽՆԻԽՇԾՌՇՐՁԻՁՌՑ ԽԿՌՀԽՀՇՍՊԩԠ  ՏՀՁԻՀԽՎԽՊ ԻՇՆԻԽՆՌՊԹՌՁՇՆՁՋՄՇՏԽՋՌԯԽԾԽՊԽՆԻԽՋՌՍԼՑԻՁՌԹՌՁՇՆ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ԰ԽՈԹՊԹՌՁՇՆՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋԱԽՆԾՇՄԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩ ԢԭԞՋՍԿԿԽՋՌՋՌՀԹՌԹԻՇՆԻԽՆՌՊԹՌՁՇՆ ՋԽՈԹՊԹՌՁՇՆՇԾԺԽՌՏԽԽՆ
ՇՊՌՀՊԽԽԾՇՄԼ ԹՆԼ
ՇՊՌԽՆԾՇՄԼՁՋՋԻՁԽՆՌՁԾՁԻԹՄՄՑ

ԹԻԻԽՈՌԹԺՄԽ  ԫՍՅԺԽՊՇԾՌԽՋՌԻՇՆԻԽՆՌՊԹՌՁՇՆՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋԹՅՁՆՁՅՍՅՇԾ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹՆԼԹԻՇՆՌՊՇՄՈՄՍՋՋՇՄՎԽՆՌ ԻՇՆՌՊՇՄՁԾԹՈՈՊՇՈՊՁԹՌԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԞՊԽՆՇՅՁՆԹՄԻՇՆԻԽՆՌՊԹՌՁՇՆՋԹԼՂՍՋՌԽԼԾՇՊՈՍՊՁՌՑ!ԶԽՋ ԦՆԼՁԻԹՌԽՌՀԽՌՑՈԽՇԾՎԹՄՍԽՋՈՊԽՋԽՆՌԽԼԾՇՊՅԽԹՋՍՊԽԼԻՇՆԻԽՆՌՊԹՌՁՇՆՋԪԽԹՆՅԽԹՋՍՊԽԼ ԩՁՅՁՌՇԾՉՍԹՆՌՁԾՁԻԹՌՁՇՆ
ԩԬԮ ՅԿԹՁԩ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԾՇՊԻՀԽՅՁԻԹՄՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽՄՇՏՌՀԽԩԬԮԹՆԹՄՑՋԽՋԺԽ ԻՇՆԼՍԻՌԽԼՇՆՌՀԽՋՌՇԻՃՋՇՄՍՌՁՇՆՋԩԽՎԽՄՇԾԼԽՌԽԻՌՁՇՆ
ԩԬԡԫՇՌՊԽՈՇՊՌԽԼ ԣՊԽՉՍԽՆԻՑՇԾՅԽԹՋՍՊԽՅԽՆՌ ԹՆԼԼԹՑՋ  ԦՌՁՋՊԽԻՇՅՅԽՆԼԽԼՌՀԹՌՌԽՋՌՁՌԽՅ ԻՇՆԻԽՆՌՊԹՌՁՇՆԺԽՅԽԹՋՍՊԽԼՈՊՁՇՊՌՇՌՀԽ ԹԼԼՁՌՁՇՆՇԾԾՁՋՀՁՆԹՄՄՌԹՆՃՋԹՆԼԹՌՄԽԹՋՌ ՏԽԽՃՄՑՌՀԽՊԽԹԾՌԽՊՁՆՌՏՇՊԽՈՄՁԻԹՌԽՋՈԽՊ
ՌՊԽԹՌՅԽՆՌՄԽՎԽՄԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋՌՀԽՊԹՆԼՇՅՁՒԽԼԻՇՅՈՄԽՌԽԺՄՇԻՃԼԽՋՁԿՆՍՋԽԼ!ԶԽՋ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌԹՄՄԾՁՋՀԺԽՊԹՆԼՇՅՄՑ ԹՋՋՁԿՆԽԼՌՇՌԹՆՃՋԼՍՊՁՆԿՈՊԽԽՐՈՇՋՍՊԽ ԱԹՆՃՋԹՊԽՌՀԽՆՊԹՆՃԽԼԹԻԻՇՊԼՁՆԿՌՇՈՊԽ ԽՐՈՇՋՍՊԽԾԽԻՍՆԼՁՌՑԹՆԼՌՀԽՌԹՆՃՋՏՁՌՀՌՀԽ ՀՁԿՀԽՋՌԾԽԻՍՆԼՁՌՑԹՊԽՊԹՆԼՇՅՄՑԹՋՋՁԿՆԽԼՌՇ ԹԼԽԾՁՆՁՌՁՎԽՌԽՋՌՌՊԽԹՌՅԽՆՌԹՆԼԺՄՇԻՃԾՁՊՋՌ ԢԹԻՀԺՄՇԻՃԻՇՆՌԹՁՆՋՇՆԽՊԽՈՄՁԻԹՌԽՇԾԽԹԻՀ ՌՊԽԹՌՅԽՆՌՁՆԻՄՍԼՁՆԿԻՇՆՌՊՇՄՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆԻՇՆՌՊՇՄ ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՁՆՋՇՄՎԽՆՌԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԽՍՋԽՇԾԹԻՇՆԻՍՊՊԽՆՌ ՋՇՄՎԽՆՌԻՇՆՌՊՇՄՏՀԽՆԹՋՇՄՍԺՁՄՁՒՁՆԿԹԿԽՆՌՁՋ ՍՋԽԼԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՊԽՈՄՁԻԹՌԽՋՈԽՊՌԽՋՌՁՌԽՅՌՊԽԹՌՅԽՆՌՄԽՎԽՄ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՊԽՈՄՁԻԹՌԽՋԫՍՅԺԽՊՇԾՅԹՄԽԾՁՋՀՈԽՊՊԽՈՄՁԻԹՌԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՅԹՄԽՋՈԽՊՊԽՈՄՁԻԹՌԽ ԫՍՅԺԽՊՇԾԾԽՅԹՄԽԾՁՋՀՈԽՊՊԽՈՄՁԻԹՌԽԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆ  ԢԭԞՊԽԻՇՅՅԽՆԼՋԾԽՅԹՄԽՋՈԽՊՊԽՈՄՁԻԹՌԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԴԹՋԹՋՇՄՎԽՆՌՍՋԽԼ!ԫՇ԰ՇՄՎԽՆՌՌՑՈԽ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞԪԹՐՁՅՍՅՋՇՄՎԽՆՌԻՇՆԻԽՆՌՊԹՌՁՇՆՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌՀԽՋՇՄՎԽՆՌՆՇՌ ԽՐԻԽԽԼՅՄԩ ԬԢԠԡՊԽԻՇՅՅԽՆԼՋ ՌՀԹՌՋՇՄՎԽՆՌՀԹՎԽՆՇԽԾԾԽԻՌՇՆՋՍՊՎՁՎԹՄՆՇՊ ՈՊՇԼՍԻԽԹՆՑՇՌՀԽՊԹԼՎԽՊՋԽԽԾԾԽԻՌՋԹՆԼՌՀԹՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆՆՇՌԺԽԿՊԽԹՌԽՊՌՀԹՆՅՄԩ ԴԹՋԹՈՇՋՁՌՁՎԽԻՇՆՌՊՇՄՍՋԽԼ!ԫՇԭՇՋՁՌՁՎԽԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞԭՇՋՁՌՁՎԽԻՇՆՌՊՇՄԻՇՆԻԽՆՌՊԹՌՁՇՆ
ՋՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԭՀՇՌՇՈԽՊՁՇԼՀՊՋՄՁԿՀՌՀՊՋԼԹՊՃ ԢԭԞՊԽԻՇՅՅԽՆԼՋՈՀՇՌՇՈԽՊՁՇԼ

ՄՁԿՀՌԼԹՊՃԥՍՌԻՀՁՆՋՇՆԱԥ԰ՀՁՄՄԹԺԽԽՊԫԴՁՆՌԽՊԪԧԭՁԻՃԾՇՊԼԡԟ
ԞԻՍՌԽԹՆԼԻՀՊՇՆՁԻԽԾԾԽԻՌՋՇԾԻԹՊՊՁԽՊՋՇՄՎԽՆՌՋՁՆԹՉՍԹՌՁԻՇՊԿԹՆՁՋՅՋԞԻՊՁՌՁԻԹՄՊԽՎՁԽՏԯԽՎՁԽՏԞՉՍԹՌՁԻԱՇՐՁԻՇՄՇԿՑՈՈ-ԬԢԠԡ
ԤՍՁԼԹՆԻԽԡՇԻՍՅԽՆՌՇՆԞՉՍԹՌՁԻԱՇՐՁԻՁՌՑԱԽՋՌՁՆԿՇԾԡՁԾԾՁԻՍՄՌ԰ՍԺՋՌԹՆԻԽՋԹՆԼԪՁՐՌՍՊԽՋԢՆՎՁՊՇՆՅԽՆՌԹՄԥԽԹՄՌՀԹՆԼ԰ԹԾԽՌՑԭՍԺՄՁԻԹՌՁՇՆՋ԰ԽՊՁԽՋՇՆԱԽՋՌՁՆԿԹՆԼԞՋՋԽՋՋՅԽՆՌԫՇԭԹՊՁՋԣՊԹՆԻԽԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԭԹՊԹՅԽՌԽՊԳԹՄՍԽ
ՋԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԩՁԿՀՌՁՆՌԽՆՋՁՌՑԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽՄՍՐ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՄՁԿՀՌՁՆՌԽՆՋՁՌՑ- ՄՍՐ
ԹՌՏԹՌԽՊ0ՋՋՍՊԾԹԻԽԞԼԼՁՌՁՇՆԹՄԼԽՌԹՁՄՋԱԽՋՌՋՇՄՍՌՁՇՆՋՏԽՊԽՊԽՈՇՊՌԽԼՌՇԺԽԻՄԽԹՊԹՆԼԻՇՄՇՊՄԽՋՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽ԰ՍՅՅԹՊՑՇԾԱՊԽԹՌՅԽՆՌԠՇՆԻԽՆՌՊԹՌՁՇՆՋՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԱՊԽԹՌՅԽՆՌԦԡԫՇՅՁՆԹՄԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՆԪԽԹՋՍՊԽԼԠՇՆԻԽՆՌՊԹՌՁՇՆՅԿԹՁԩԪԽԹՆԠԳ
ԡԽՌԹՁՄՋՇՊԯԽՅԹՊՃՋԤՍՁԼԽՄՁՆԽԯԽԻՇՅՅԽՆԼԹՌՁՇՆՋԠՇՆՌՊՇՄ
ԼՁՄՍՌՁՇՆՏԹՌԽՊՇՆՄՑ ԩԬԮ ԫԞ  ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՌԽՋՌ ՁՌԽՅԻՇՆԻԽՆՌՊԹՌՁՇՆՋԺԽ ՅԹՁՆՌԹՁՆԽԼԹՌԹԻՇԽԾԾՁԻՁԽՆՌՇԾ ՎԹՊՁԹՌՁՇՆ
ԠԳ  ԰ՇՄՎԽՆՌԻՇՆՌՊՇՄ
ՁԾԹՈՈՄՁԻԹԺՄԽԫԞ ԫԞ ԫԞ ԱՊԽԹՌՅԽՆՌ ԯԽՎՁԽՏԽՊԻԹՄԻՍՄԹՌԽԼչԠԳԱՊԽԹՌՅԽՆՌԯԽՎՁԽՏԽՊԻԹՄԻՍՄԹՌԽԼչԠԳԱՊԽԹՌՅԽՆՌԯԽՎՁԽՏԽՊԻԹՄԻՍՄԹՌԽԼչԠԳԡՁՄՍՌԽՊ԰ՌՇԻՃԫԞԫԞԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԠԳԠՇԽԾԾՁԻՁԽՆՌՇԾՎԹՊՁԹՌՁՇՆ ԩԬԮՅԿԹՁԩԢԬԺՋԽՊՎԹՌՁՇՆՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԟՁՇՄՇԿՁԻԹՄԢՆԼՈՇՁՆՌՋ ԰ՍՊՎՁՎԹՄԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋԹՆԼԻՄՁՆՁԻԹՄՋՁԿՆՋՏԽՊԽՇԺՋԽՊՎԽԼԼԹՁՄՑԞՌՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆ
ԡԹՑՋԽԻՇՆԼԹՊՑՋԽՐ ԻՀԹՊԹԻՌԽՊՁՒԹՌՁՇՆ 
ԺՇԼՑ ԻՇՄՇՊ ՈԹՌՌԽՊՆ ԺՇԼՑ ՋՀԹՈԽ ԺՇԼՑ ՏԽՁԿՀՌ ՄԽՆԿՌՀ ՌՍԺԽՊԻՄԽ ՋԻՇՊԽ ԿՇՆԹԼԹՄ ՋՌԹԿՁՆԿ ԹՆԼՀՁՋՌՇՈԹՌՀՇՄՇԿՑԹՆԼՈՄԹՋՅԹՎՁՌԽՄՄՇԿԽՆՁՆՏԽՊԽԽՎԹՄՍԹՌԽԼԭՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋՏԽՊԽՆՇՌՅԽԹՋՍՊԽԼԴԽՊԽՊԹՏ
ՁՆԼՁՎՁԼՍԹՄԼԹՌԹՈՊՇՎՁԼԽԼ!ԶԽՋ ԢԭԞՊԽԻՇՅՅԽՆԼՋՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋՇԾՋՍՊՎՁՎԹՄԾԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋՋԽԻՇՆԼԹՊՑՋԽՐԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼՇՌՀԽՊԻՄՁՆՁ ԻԹՄՋՁԿՆՋՇԻԻՍՊԹՌՄԽԹՋՌԼԹՁՄՑԞՌ ՌԽՋՌ ՌԽՊՅՁՆԹՌՁՇՆ 
ԼԹՑ  ԹԼԼՁՌՁՇՆԹՄ ՇԺՋԽՊՎԹՌՁՇՆՋ ՁՆԻՄՍԼԽ ԺՇԼՑ  ՏԽՁԿՀՌ ԹՆԼ ՄԽՆԿՌՀ ՆՍՈՌՁԹՄ ՌՍԺԽՊԻՄԽ ՋԻՇՊԽ ԿՇՆԹԼԹՄ ՋՌԹԿՁՆԿ ԹՆԼ  ՀՁՋՌՇՈԹՌՀՇՄՇԿՑ ՈՄԹՋՅԹ

ՎՁՌԽՄՄՇԿԽՆՁՆԹՆԼՈՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋ
ՌԽՋՌՇՋՌԽՊՇՆԽԹՆԼȕ ԽՋՌՊԹԼՁՇՄՁԾՅԽԹՋՍՊԽԼԤՇՆԹԼՇՋՇՅԹՌՁԻՁՆԼԽՐ
Ԥ԰ԦՁՋԻԹՄԻՍՄԹ ՌԽԼՍՋՁՆԿԹՊԹՌՁՇՇԾԿՇՆԹԼՏԽՁԿՀՌ ՌՇԺՇԼՑՏԽՁԿՀՌ
ԿՇՆԹԼՏԽՁԿՀՌՌՇՌՀԽՆԽԹՊԽՋՌՅԿԺՇԼՑՏԽՁԿՀ ՌՁՆՅԿՐԹՌՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆ ԠՄՁՆՁԻԹՄՋՁԿՆՋՇԾՇՎԽՊՌՌՇՐՁԻՁՌՑՅԹՑՁՆԻՄՍԼԽ
ԺՍՌԹՊԽՆՇՌՄՁՅՁՌ ԽԼՌՇՀԽՅՇՊՊՀԹԿԽԻԽՋՋԹՌՁՇՆՇԾԾԽԽԼՁՆԿԹՆԼՇՌՀԽՊԹԺՆՇՊՅԹՄԺԽՀԹՎՁՇՊԦԦԯԢ԰ԲԩԱ԰ԞԫԡԡԦ԰ԠԲ԰԰ԦԬԫԣՇՊ ԹՄՄ ՋՌՍԼՑ ԹՍՌՀՇՊ ՊԽՋՍՄՌՋ ՌՀԽ ԽՆԼՈՇՁՆՌՋ ԹՌ ՌՀԽ ՀՁԿՀ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
 ՅԿ ԹՁԩ ՏԽՊԽ ՆՇՌ ՋՌԹՌՁՋՌՁԻԹՄՄՑ ԹՆԹՄՑՒԽԼ ԼՍԽՌՇ ՅՇՊՌԹՄՁՌՑԞԼԼՁՌՁՇՆԹՄՄՑՌՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊՌԽԼՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋԹՌՌՀԽՅԿԹՁԩԻՇՆԻԽՆՌՊԹՌՁՇՆՅԽՌՌՀԽԿՍՁԼԽՄՁՆԽԼԽԾՁՆՁՌՁՇՆՇԾՇՎԽՊՌՅՇՊԺՁԼՁՌՑԥՇՏԽՎԽՊՁՆԼՁՎՁԼՍԹՄՋԾՊՇՅՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԽՊԽՆՇՌԽՐԻՄՍԼԽԼԾՊՇՅՌՀԽՋՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋՁՋԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԞԯԽՋՍՄՌՋԱՀԽՊԽՏԹՋՋՍՊՎՁՎԹՄՁՆՌՀԽԻՇՆՌՊՇՄԿՊՇՍՈԞՌՌՀԽՄՇՏԻՇՆԻԽՆՌՊԹՌՁՇՆԾՇՍՊԾԽՅԹՄԽՋԼՁԽԼԹՆԼՌՀՊԽԽՇԾՌՀԽՋԽԾԽՅԹՄԽՋՏԽՊԽԾՊՇՅՇՆԽՊԽՈՄՁԻԹՌԽԞՌՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՌՏՇ ՅԹՄԽՋ ԹՆԼ ԾՇՍՊԾԽՅԹՄԽՋ ԼՁԽԼ ԼՍՊՁՆԿ ՌՀԽ ՋՌՍԼՑ ԞՄՄ ԺՍՌ ՇՆԽ ՅԹՄԽ ԹՆԼ ԾԽՅԹՄԽ ԼՁԽԼ ԹՌ ՌՀԽ ՀՁԿՀ ԻՇՆԻԽՆՌՊԹՌՁՇՆԬՎԽՊԹՄՄՅԽԹՆՋՍՊՎՁՎԹՄՎԹՄՍԽՋՏԽՊԽԹՆԼՁՆՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑԱԹԺՄԽԞԼՍՄՌԣՁՋՀ԰ՍՊՎՁՎԹՄՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԪԹՄԽՋԣԽՅԹՄԽՋՆ԰ՍՊՎՁՎՁՆԿ԰ՍՊՎՁՎԹՄՆ԰ՍՊՎՁՎՁՆԿ԰ՍՊՎՁՎԹՄԠՇՆՌՊՇՄ
ԩԬԮ     ԞԺԺՊԽՎՁԹՌՁՇՆՋԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽ ԦՆՌՀՁՋՌԹԺՄԽ՟ՆՠՊԽԾԽՊՋՌՇՌՀԽՌՇՌԹՄՆՍՅԺԽՊՇԾԾՁՋՀՈԽՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄԹՌՌԽՋՌՁՆՁՌՁԹՌՁՇՆԩԬԮՅԿԹՁԩԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԪԽԹՆՅԹՄԽԺՇԼՑՏԽՁԿՀՌՎԹՄՍԽՋՏԽՊԽԹՆԼԿԹՆԼԾԽՅԹՄԽԺՇԼՑՏԽՁԿՀՌՎԹՄՍԽՋՏԽՊԽԹՆԼԿՁՆՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽԱԹԺՄԽ԰ՁՒԽԹՌԱԽՋՌԱԽՊՅՁՆԹՌՁՇՆՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԟՇԼՑԴԽՁԿՀՌԩԽՆԿՌՀԪԹՄԽՋԣԽՅԹՄԽՋԪԹՄԽՋԣԽՅԹՄԽՋՆԪԽԹՆԿչ԰ԡՆԪԽԹՆԿչ԰ԡՆԪԽԹՆՅՅչ԰ԡՆԪԽԹՆՅՅչ԰ԡԠՇՆՌՊՇՄ
ԩԬԮ                                  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԞԺԺՊԽՎՁԹՌՁՇՆՋԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԫԡԫՇՌԼԽՌԽՊՅՁՆԽԼ԰ԡ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ ԦՆՌՀՁՋՌԹԺՄԽ՟ՆՠՊԽԾԽՊՋՌՇՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹՌԽՋ
ՌԹՆՃՋՈԽՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՀՁԿՀՅՇՊՌԹՄՁՌՑԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԪԽԹՆԾԽԻՍՆԼՁՌՑՎԹՄՍԽՋՏԽՊԽԹՆԼԹՆԼԾԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻ ԻԽՋՋՏԹՋԹՆԼՁՆՌՀԽՅԽԹՆ

ՅԽԹՋՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎ ԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽ

ԱԹԺՄԽԣԽԻՍՆԼՁՌՑԹՆԼԣԽՊՌՁՄՁՒԹՌՁՇՆ԰ՍԻԻԽՋՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ  ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԣԽԻՍՆԼՁՌՑ  

### ԣԽՊՌՁՄՁՒԹՌՁՇՆ԰ՍԻԻԽՋՋ
 



### ԪԽԹՆ չ԰ԡ ԪԽԹՆ չ԰ԡ

ԠՇՆՌՊՇՄ
ԩԬԮ    

    

    

  

### ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԫԡ 

### ԫՇՌԼԽՌԽՊՅՁՆԽԼ

 

### ԣԽԻՍՆԼՁՌՑՁՋԻԹՄԻՍՄԹՌԽԼԹՋՌՀԽՆՍՅԺԽՊՇԾԽԿԿՋՈԽՊՋՍՊՎՁՎՁՆԿԾԽՅԹՄԽՈԽՊՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑՈԽՊՊԽՈՄՁԻԹՌԽ

 

###  ԣԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋ
ՁՋԻԹՄԻՍՄԹՌԽԼԹՋՌՀԽՆՍՅԺԽՊՇԾԽՅԺՊՑ ՇՋԼՁՎՁԼԽԼԺՑՌՀԽՆՍՅԺԽՊՇԾԽԿԿՋՅՍՄՌՁՈՄՁԽԼ

ԺՑ

 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩ



### ԪԽԼՁԹՆՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՋՏԽՊԽԹՆԼՁՆՌՀԽՅԽԹՆՅԽԹՋ ՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼ

ՅԿ ԹՁԩ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ ՊԽՋՈԽԻՌՁՎԽՄՑ 
ԱԹԺՄԽ ԫՇՆԽ ՇԾ ՌՀԽ ՋՍՊՎՁՎՁՆԿ ԾԽՅԹՄԽՋՏԽՊԽ ԾՇՍՆԼ ՌՇ ՀԹՎԽ

ՌՍԺԽՊԻՄԽՋ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԫՍՈՌՁԹՄԱՍԺԽՊԻՄԽ԰ԻՇՊԽՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն  

### ԪԽԼՁԹՆ

ԱՍԺԽՊԻՄԽ԰ԻՇՊԽ Ն  

### ԪԽԼՁԹՆ

ԱՍԺԽՊԻՄԽ԰ԻՇՊԽ

ԠՇՆՌՊՇՄ
ԩԬԮ    

    

    

  

### ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԫԡ ԫՇՌԼԽՌԽՊՅՁՆԽԼ ԰ԡ ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

  ԦՆՌՀՁՋՌԹԺՄԽ՟ՆՠՊԽԾԽՊՋՌՇՌՀԽՆՍՅԺԽՊՇԾՁՆԼԽՈԽՆԼԽՆՌՊԽՈՄՁԻԹ ՌԽՋ
ՌԹՆՃՋՈԽՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ ԩԬԮՅԿԹՁԩ



### ԪԽԹՆ ՅԹՄԽ Ԥ԰Ԧ ՏԹՋ   ԹՆԼ  ԹՆԼ ՅԽԹՆ ԾԽՅԹՄԽ Ԥ԰Ԧ ՏԹՋ    ԹՆԼ  ՁՆ ՌՀԽ ՅԽԹՆ

ՅԽԹՋՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎ ԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐ
Ԥ԰ԦՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԹՆԤ԰Ԧ 



###  չ԰ԡ Ն ԪԽԹՆԤ԰Ԧ 



###  չ԰ԡ

ԠՇՆՌՊՇՄ
ԩԬԮ      

      

      

  

### ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ 

### ԫՇՌԹՈՈՄՁԻԹԺՄԽ

 

### ԤՇՆԹԼՇՋՇՅԹՌՁԻՁՆԼԽՐ
ՁՋԻԹՄԻՍՄԹՌԽԼԹՋԿՇՆԹԼՏԽՁԿՀՌ
ՌՇՌՀԽՆԽԹՊԽՋՌՅԿԺՇԼՑՏԽՁԿՀՌ
ՅԿՐ



 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩ



### ԪԽԼՁԹՆ ՅԹՄԽ ԿՇՆԹԼԹՄ ՋՌԹԿԽՏԹՋ   ԹՆԼ  ԹՆԼ ՅԽԼՁԹՆ ԾԽՅԹՄԽ ԿՇՆԹԼԹՄ ՋՌԹԿԽՏԹՋ   ԹՆԼ  ՁՆ ՌՀԽ

ՅԽԹՆՅԽԹՋՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն  ԪԽԼՁԹՆ԰ՌԹԿԽ  Ն  ԪԽԼՁԹՆ԰ՌԹԿԽ 



### ԠՇՆՌՊՇՄ
ԩԬԮ   

###  



###    

###  



###    

###  



###   ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԧ ԧՍՎԽՆՁՄԽ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԫԡ ԫՇՌԼԽՌԽՊՅՁՆԽԼ ԲԱ԰ ԲՆԹԺՄԽՌՇՋՌԹԿԽ

 ԦՆՌՀՁՋՌԹԺՄԽ՟ՆՠՊԽԾԽՊՋՌՇՌՀԽՌՇՌԹՄՆՍՅԺԽՊՇԾՁՆԼՁՎՁԼՍԹՄՋՈԽ ՊՌՊԽԹՌՅԽՆՌՄԽՎԽՄՍՈՇՆՏՀՁԻՀՇԺՋԽՊՎԹՌՁՇՆՋՏԽՊԽՅԹԼԽԹՌ

ՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆ

  ԱՀԽԿՍՁԼԽՄՁՆԽՊԽԻՇՅՅԽՆԼՋՌՀԽԾՇՄՄՇՏՁՆԿԿՇՆԹԼԹՄՋՌԹԿՁՆԿՋԻԹՄԽԾ ՇՊՅԹՄԽԾԹՌՀԽԹԼՅՁՆՆՇՏՍՆԼԽՎԽՄՇՈԽԼԽԹՊՄՑ

ՋՈԽՊՅԹՌՇԿԽՆՁԻՅՁԼՋՈԽՊՅԹՌՇԿԽՆՁԻՄԹՌԽՋՈԽՊՅԹՌՇԿԽՆՁԻՋՈԽ ՆՌ

  ԱՀԽԿՍՁԼԽՄՁՆԽՊԽԻՇՅՅԽՆԼՋՌՀԽԾՇՄՄՇՏՁՆԿԿՇՆԹԼԹՄՋՌԹԿՁՆԿՋԻԹՄԽԾՇՊԾԽՅԹՄԽԾԹՌՀԽԹԼՅՁՆՆՇՏՍՆԼԽՎԽՄՇՈԽԼԽԹՊՄՑ

ԼԽՎԽՄՇՈՅԽՆՌՅՁԼԼԽՎԽՄՇՈՅԽՆՌՄԹՌԽԼԽՎԽՄՇՈՅԽՆՌՄԹՌԽԼԽՎԽՄՇՈՅԽՆՌՀՑԼՊԹՌԽԼՈՇՋՌՇՎՍՄԹՌՇՊՑ

  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩ



### ԞԻԻՇՊԼՁՆԿՌՇՌՀԽՋՌՍԼՑՊԽՈՇՊՌՁՆՅԹՄԽԾՁՋՀՌՀԽՊԽՏԽՊԽԹՆՁՆԻՊ ԽԹՋԽԼՈԽՊԻԽՆՌԹԿԽՇԾՋՈԽՊՅԹՌՇԿՇՆՁԹ
ԱԹԺՄԽ

ՁՆՌՀԽՅԿ ԹՁԩ ԿՊՇՍՈՏՁՌՀԾՇՍՊՅՁՆՁՅԹՄՌՇՅՁՄԼ ՁՆԻՁԼԽ ՆԻԽՋ ՇՍՌ ՇԾ ՁՆԼՁՎՁԼՍԹՄՋԱՏՇՅԹՄԽՋ ԹՄՋՇ

ՀԹԼՅՁՄԼԼՁԾԾՍՋԽՌՀՁԻՃԽՆՁՆԿՇԾՌՀԽԿԽՊՅՁՆԹՄԽՈՁՌՀԽՄՁՍՅՄՁՆՁՆԿԺ ՑՋՈԽՊՅԹՌՇԿՇՆՁԹԱՀԽՊԽՏԽՊԽՌՏՇՁՆԻՁԼԽՆԻԽՋՇԾ

ՅՁՆՁՅԹՄՁՆԻՊԽԹՋԽԼՌԽՋՌՁԻՍՄԹՊԼԽԿԽՆԽՊԹՌՁՇՆՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼՌՀ ԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՋՏՁՌՀԻՇՆԻՍՊՊԽՆՌ

ՅՁՆՁՅԹՄՁՆՌԽՊՋՌՁՌՁԹՄԻԽՄՄՀՑՈԽՊՈՄ ԹՋՁԹՁՆՌՀԽԻՇՆՌՊՇՄՅԹՄԽԹՆԼՅ ՁՆՁՅԹՄՄՑՁՆԻՊԽԹՋԽԼՈՊՇՈՇՊՌՁՇՆՇԾՋՈԽՊՅԹՌՇԿՇՆՁԹՁՆ

ՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԱՀԽՊԽՏԽՊԽՌՀՊԽԽՁՆԻՁԼԽՆԻԽՋՇԾՅ ՁՆՁՅԹՄՁՆՌԽՊՋՌՁՌՁԹՄԻԽՄՄՀՑՈԽՊՈՄԹՋՁԹՇՆԽՁՆՌՀԽ

ԻՇՆՌՊՇՄԹՆԼՌՏՇՁՆՌՀԽՅԿԹ ՁԩՌՊԽԹՌՅԽՆՌԱՀԽՊԽՏԽՊԽԹՄ ՋՇՇՆԽԻՇՆՌՊՇՄԹՆԼՇՆԽՅԹՄԽԾՊՇՅՌՀԽ

ՅԿԹՁԩՌՊԽԹՌՅԽՆՌՏՁՌՀՅՁՆՁՅԹՄԹՋՑՆԻՀՊՇՆՇՍՋԿՇՆԹԼԼԽՎԽՄՇՈՅԽՆՌ 
ԱԹԺՄԽ

ԞՄՋՇԹԻԻՇՊԼՁՆԿՌՇՌՀԽՋՌՍԼՑՊԽՈՇՊՌՁՆԾԽՅԹՄԽՋՌՀԽՊԽՏԽՊԽՅՁ ՄԼԹՆԼՋԽՎԽՊԽՁՆԻՁԼԽՆԻԽՋՇԾԼԽԻՊԽԹՋԽԼՑՇՄՃ

ՋՑՆՌՀԽՋՁՋՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈԹՆԼՅՁՆՁՅԹՄ ՅՁՄԼՅՇԼԽՊԹՌԽԹՆԼՋԽՎԽՊԽՁՆԻՁԼԽՆԻԽ

ՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈ
ԱԹԺՄԽԱՀԽՇՆԽԾԽՅ ԹՄԽՅՇԼԽՊԹՌԽՄՑԹԾԾԽԻՌԽԼԹՄՋՇՀԹԼԹԺՍՆԼԹՆՌ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԳԱԤՁՆՇՆՄՑԹԾԽՏԾՇՄՄՁԻՄԽՋՏՁՌՀՌՏՇԾԽՅԹՄԽՋՋԽՎԽՊԽՄՑԹԾԾԽԻՌԽԼ ՇՆԽԽԹԻՀՁՆՌՀԽԹՆԼՅԿԹՁԩ

ԿՊՇՍՈՋ ՏՁՌՀ ՄՁՌՌՄԽ ԳԱԤ ԾՇՊՅԹՌՁՇՆ ԱՀԽ ԾԽՅԹՄԽ ՏՁՌՀ ՌՀԽ ՋԽՎԽՊԽ Լ ԽԻՊԽԹՋԽԼ ՑՇՄՃ ՋՑՆՌՀԽՋՁՋ ՁՆ ՌՀԽ  ՅԿ

ԹՁԩ ԿՊՇՍՈ ԹՄՋՇ ՀԹԼ ՋԽՎԽՊԽ ԿՊԹՆՍՄՇՅԹՌՇՍՋ ՁՆԾՄԹՅՅԹՌՁՇՆ ՏՁՌՀՁՆ ՌՀԽ ՇՎԹՊՑ 
ԱԹԺՄԽ  ԤՊԹՆՍՄՇՅԹՌՇՍՋ

ՁՆԾՄԹՅՅԹՌՁՇՆ ՏԹՋ ՆՇՌ ՈՊԽՋԽՆՌ ՁՆ ՌՀԽ ՋԽՎԽՊԽՄՑ ԹԾԾԽԻՌԽԼ ԾԽՅԹՄԽ ԾՊ ՇՅ ՌՀԽ  ՅԿ ԹՁԩ ԿՊՇՍՈ ԺՍՌ ՏԹՋ

ԻՇՅՅՇՆՏՁՌՀՋԽՎԽՆԾԽՅԹՄԽՋՁՆՌՀԽԻՇՆՌՊՇՄՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌԹՆԼՁՆՌՀԽՅԿ

ԹՁԩ 
ՅՁՆՁՅԹՄ ՌՇ ՅՁՄԼ ԹՆԼ ԹՋՋՇԻՁԹՌԽԼ ՏՁՌՀ ՁՆԻՊԽԹՋԽԼ ՇՇԻՑՌԽ Թ ՌՊԽՋՁԹ ԽՁԿՀՌ ԻԹՋԽՋ ՀԹԼ ՈՊՇՌՇՒՇԹՄ ՋՈՇՊԽՋ

ՏՁՌՀՁՆԿՊԹՆՍՄՇՅԹՋԞՆՁՆԻՊԽԹՋԽՁՆՇՇԻՑՌԽԹՌՊԽՋՁԹՏԹՋՇԺՋԽՊՎԽԼՁՆՌՀԽԻՇՆՌՊՇՄԹՆԼՌՊԽԹՌՅԽՆՌԿՊՇՍՈՋՏՁՌՀ

ԹՆԼՇԾՌՀԽԾՁՋՀԽՐՀՁԺՁՌՁՆԿՌՀՁՋԾՁՆԼՁՆԿՁՆՌՀԽԻՇՆՌՊՇՄ ԹՆԼՄՇՏԹՆԼՅՁԼՌՊԽԹՌՅԽՆՌՋՊԽՋՈԽԻՌՁՎԽՄՑԱՀԽՊԽ

ՏԹՋ ՇՆԽ ՁՆԻՁԼԽՆԻԽ ՇԾ ՄՑՅՈՀՇԻՑՌՁԻ ՁՆԾՁՄՌՊԹՌԽՋՏՁՌՀՁՆՌՀԽ ՇՎՁԼՍԻՌ  ՁՆ ՌՀԽ ՅԿ ԹՁԩ ԿՊՇՍՈ ԹՆԼ  ՁՆՌՀԽ

 ՅԿ ԹՁԩ ԱՀԽՊԽ ՏԹՋ ՅՁՆՁՅԹՄ ՁՆՌԽՊՋՌՁՌՁԹՄ ԾՁԺՊՇՋՁՋ ՁՆ ՌՀ Խ  ՅԿ ԹՁԩ ԿՊՇՍՈ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑՁՆԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 

԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼ

ԭՊՇՈՇՊՌՁՇՆՇԾ

԰ՈԽՊՅԹՌՇԿՇՆՁԹ ԭՊԽՋԽՆԻԽՇԾ

ԱԽՋՌՁՋԬՎԹ ԦՆԻՊԽԹՋԽԼ

ԱԽՋՌՁԻՍՄԹՊ

ԡԽԿԽՆԽՊԹՌՁՇՆ ԦՆՌԽՊՋՌՁՌՁԹՄԠԽՄՄ

ԩԽՑԼՁԿ

ՀՑՈԽՊՌՊՇՈՀՑ

ՀՑՈԽՊՈՄԹՋՁԹ ԤԽՊՅՁՆԹՄ

ԢՈՁՌՀԽՄՁՍՅ

ԞՌՊՇՈՀՑ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԠՇՆՌՊՇՄ

ԩԬԮ          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 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԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄ ՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԞԼԼՁՌՁՇՆԹՄԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑԬԺՋԽՊՎԹՌՁՇՆՋՁՆԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԡԽԻՊԽԹՋԽԼԭՊՇՈՇՊՌՁՇՆՇԾ԰ՈԽՊՅԹՌՇԿՇՆՁԹԦՆԻՊԽԹՋԽԼԳԹՋԻՍՄԹՊՇՊԦՆՌԽՊՋՌՁՌՁԹՄԭՊՇՌԽՁՆԹԻԽՇՍՋԣՄՍՁԼԞՋՑՆԻՀՊՇՆՇՍՋԤՇՆԹԼԡԽՎԽՄՇՈՅԽՆՌԞՄՌԽՊԽԼԭՊՇՈՇՊՌՁՇՆՋՇԾ԰ՈԽՊՅԹՌՇԻՑՌԽՋՇՊ԰ՈԽՊՅԹՌՁԼՋԤՊԹՆՍՄՇՅԹՌՇՍՋԦՆԾՄԹՅՅԹՌՁՇՆՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽԠՇՆՌՊՇՄ
ԩԬԮ ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ԰ԽՎԽՊՁՌՑԡԽԻՊԽԹՋԽԼԭՊՇՈՇՊՌՁՇՆՇԾ԰ՈԽՊՅԹՌՇԿՇՆՁԹԦՆԻՊԽԹՋԽԼԳԹՋԻՍՄԹՊՇՊԦՆՌԽՊՋՌՁՌՁԹՄԭՊՇՌԽՁՆԹԻԽՇՍՋԣՄՍՁԼԞՋՑՆԻՀՊՇՆՇՍՋԤՇՆԹԼԡԽՎԽՄՇՈՅԽՆՌԞՄՌԽՊԽԼԭՊՇՈՇՊՌՁՇՆՋՇԾ԰ՈԽՊՅԹՌՇԻՑՌԽՋՇՊ԰ՈԽՊՅԹՌՁԼՋԤՊԹՆՍՄՇՅԹՌՇՍՋԦՆԾՄԹՅՅԹՌՁՇՆՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽՆԦՆԻՁԼԽՆԻԽԫԞԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞ ԤՇՆԹԼԹՄՀՁՋՌՇՈԹՌՀՇՄՇԿՑԼՁԹԿՆՇՋՌՁԻՇԺՋԽՊՎԹՌՁՇՆՋԹՊԽԿՊԹԼԽԼ-ԺԹՋԽԼՇՆՋԽՎԽՊՁՌՑԫՇՌՊԽՅԹՊՃԹԺՄԽԪՁՆՁՅԹՄԪՁՄԼԪՇԼԽՊԹՌԽ԰ԽՎԽՊԽ԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԤՇՆԹԼԹՄԥՁՋՌՇՈԹՌՀՇՄՇԿՑՁՆԣԽՅԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 



### ԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼԬՇԻՑՌԽ

ԞՌՊԽՋՁԹ ԭԽՊՁԾՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

ԥՑՈԽՊՌՊՇՈՀՑ ԡԽԻՊԽԹՋԽԼԶՇՄՃ

ԣՇՊՅԹՌՁՇՆ ԦՆԾԽԻՌՁՇՆ

ԪՁԻՊՇՋՈՇՊՁԼՁԹ

Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ Ն ԦՆԻՁԼԽՆԻԽ

ԠՇՆՌՊՇՄ
ԩԬԮ        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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆ

ՅԽԹՋՍՊԽԼ% ԞԼԼՁՌՁՇՆԹՄԡՁԹԿՆՇՋՌՁԻԬԺՋԽՊՎԹՌՁՇՆՋ 



### ԰ԽՎԽՊՁՌՑ ԦՆԻՊԽԹՋԽԼԬՇԻՑՌԽ

ԞՌՊԽՋՁԹ ԭԽՊՁԾՇՄՄՁԻՍՄԹՊԠԽՄՄ

ԥՑՈԽՊՈՄԹՋՁԹ

ԥՑՈԽՊՌՊՇՈՀՑ ԡԽԻՊԽԹՋԽԼԶՇՄՃ

ԣՇՊՅԹՌՁՇՆ ԦՆԾԽԻՌՁՇՆ

ԪՁԻՊՇՋՈՇՊՁԼՁԹ

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԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄ ՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ


ԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ 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         

        

        

        

        

         

        

        

        

        

         

        

        

        

        

   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԰ԽԽԞՈՈԽՆԼՁՐԢՇԾՌՀԽՌԽՋՌԿՍՁԼԽՄ ՁՆԽԾՇՊՊԽԾԽՊԽՆԻԽ

  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԪԽԹՆՅԹՄԽԳԱԤՏԹՋՐ  

### Ր  

### ԹՆԼՐ  

### ԹՆԼԾԽՅԹՄԽԳԱԤՏԹՋՐ  

### Ր  

### ԹՆԼՐ 



### ՁՆՌՀԽՅԽԹՆՅԽԹՋՍՊԽԼ
ԻՇՆՌՊՇՄԹՆԼՅԿԹՁՅԩ ՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑ
ԱԹԺՄԽ



ԱԹԺՄԽԭՄԹՋՅԹԳՁՌԽՄՄՇԿԽՆՁՆՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԭՄԹՋՅԹԳՁՌԽՄՄՇԿԽՆՁՆ
ԳԱԤ

ԪԹՄԽՋ ԣԽՅԹՄԽՋ

Ն ԪԽԹՆ

ՆԿՅԩՈՄԹՋՅԹ չ԰ԡ  

### Ն ԪԽԹՆ

ՆԿՅԩՈՄԹՋՅԹ չ԰ԡ 



### ԠՇՆՌՊՇՄ
ԩԬԮ  Ր   

### Ր  

###  Ր   

### Ր 



###   Ր   

### Ր  

###  Ր   

### Ր 



###   Ր   

### Ր  

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###   

###  ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ ԫԡ ԫՇՌԼԽՌԽՊՅՁՆԽԼ ԰ԡ ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆ

  ԰ՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆՋԻԹՄԻՍՄԹՌԽԼԺՑՌՀԽՊԽՎՁԽՏԽՊ

 

###  ԫՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑ

ԩԬԮՅԿԹՁԩ



### ԱԹԺՄԽԭՄԹՋՅԹ԰ԽՐ԰ՌԽՊՇՁԼՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋ ԫՇՌՅԽԹՋՍՊԽԼ

ԱՀՁՋՌԹԺՄԽՁՋՇՅՁՌՌԽԼԺԽԻԹՍՋԽՋԽՐՋՌԽՊՇՁԼՋՏԽՊԽՆՇՌՅԽԹՋՍՊԽԼԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱՀԽՊԽՏԽՊԽՆՇՆՇՌԹԺՄԽՇԺՋԽՊՎԹՌՁՇՆՋՏՁՌՀՊԽԿԹՊԼՋՌՇԻՇՄՇՊԹՌՁՇՆԺԹՆԼՁՆԿԻՀԹՆԿԽՋՁՆՇՎՁՈՇՋՁՌՇՊԹՈՈԽԹՊԹՆԻԽՇՊՋՁՒԽՇԾԼՇՊՋԹՄՆԹՈԽՈԹԼԱՀԽՈՊԽՋԽՆԻԽՇԾԻՇՄՇՊԽԼԺԹՊՋ
ԺԹՆԼՁՆԿՁՆՅԹՄԽԾՁՋՀԺՍՌՆՇՌԾԽՅԹՄԽԾՁՋՀ
ԱԹԺՄԽՁՋԻՇՆՋՁԼԽՊԽԼՆՇՊՅԹՄՋԽՐՍԹՄԼՁՅՇՊՈՀՁՋՅԾՇՊՌՀՁՋՋՈԽԻՁԽՋԥՇՏԽՎԽՊՋՁԿՆՋՇԾՅՇՊԺՁԼՁՌՑՁՆԻՄՍԼՁՆԿՄԽՌՀԹՊԿՑԹՆԼՄՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅՏԽՊԽՇԺՋԽՊՎԽԼՁՆԾՁՋՀԹՌՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄ
ԱԹԺՄԽԱԹԺՄԽ԰ԽԻՇՆԼԹՊՑ԰ԽՐԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼԠՄՁՆՁԻԹՄ԰ՁԿՆՋՁՆԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋԹՌԱԽՋՌԱԽՊՅՁՆԹՌՁՇՆԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%԰ԽԻՇՆԼԹՊՑ԰ԽՐԠՀԹՊԹԻՌԽՊՁՋՌՁԻՋԹՆԼԠՄՁՆՁԻԹՄ԰ՁԿՆՋԪԹՄԽՋԣԽՅԹՄԽՋԱՑՈԽՆԦՆԻՁԼԽՆԻԽԱՑՈԽՆԦՆԻՁԼԽՆԻԽԠՇՆՌՊՇՄ
ԩԬԮԠՇՄՇՊԺԹՊՋ   ԫՇՆԽ  ԠՇՄՇՊԺԹՊՋ ԫՇՆԽ ԡԽԾՇՊՅԽԼՄԽՌՀԹՊԿՁԻ ԩԽՌՀԹՊԿՁԻՄՇՋՋՇԾԽՉՍՁՄՁԺՊՁՍՅ  ԫԞԫԞ ԫԞԫԞԫԞ ԫԞ ԫՇՌԽՌՀԹՌՆՍՈՌՁԹՄՌՍԺԽՊԻՄԽՋԻՇՊԽՁՋՊԽՈՇՊՌԽԼՈՊԽՎՁՇՍՋՄՑՁՆԱԹԺՄԽԦՆՌՀՁՋՌԹԺՄԽ՟ՆՠՊԽԾԽՊՋՌՇՌՀԽՆՍՅԺԽՊՇԾՁՆԼՁՎՁԼՍԹՄՋՍՈՇՆՏՀՁԻՀՇԺՋԽՊՎԹՌՁՇՆՋՏԽՊԽՅԹԼԽԹՌՌԽՋՌՌԽՊՅՁՆԹՌՁՇՆԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԟ ԰ՌՍԼՑԞՍՌՀՇՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

ԱՀԽՋՌՍԼՑԹՍՌՀՇՊԹՆԹՄՑՒԽԼՋՍՊՎՁՎԹՄՏԽՁԿՀՌՄԽՆԿՌՀՌՍԺԽՊԻՄԽՋԻՇՊԽԤ԰ԦԾԽՊՌՁՄՁՌՑԾԽԻՍՆԼՁՌՑԹՆԼԳԱԤ

ԡԹՌԹՏԽՊԽԿԽՆԼԽՊՋՈԽԻՁԾՁԻԹՆԼԹՆԹՄՑՒԽԼՁՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿ ԹՌՁՎԽԻՇՆՌՊՇՄՋ

ԡԽՋԻՊՁՈՌՁՎԽՋՌԹՌՁՋՌՁԻՋ
ՅԽԹՆՋՌԹՆԼԹՊԼԼԽՎՁԹՌՁՇՆԽՌԻՏԽՊԽԼԽ ՌԽՊՅՁՆԽԼԾՇՊԽԹԻՀԽՆԼՈՇՁՆՌ԰ՁԿՆՁԾՁԻԹՆՌ

ԽԾԾԽԻՌՋՏԽՊԽ ԼԽՌԽԻՌԽԼ ԾՇՊ ՈՏՁՌՀ ՌՀԽ ԽՐԻԽՈՌՁՇՆ ՇԾ ԰ՀԹՈՁՊՇ ԴՁՄՃ0Ջ ԹՆԼ ԟԹՊՌՄԽՌՌ0Ջ ԱԽՋՌՋՏՀՁԻՀ

ՏԽՊԽԺԹՋԽԼՇՆՈ
ԠԢԱԦ԰ԳԽՊՋՁՇՆ԰ՍՊՎՁՎԹՄԼԹՌԹՏԽՊԽ ԹՆԹՄՑՒԽԼՍՋՁՆԿԹԣՁՋՀԽՊ0ՋԽՐԹԻՌ

ՌԽՋՌ
ՏՁՌՀԟՇՆԾԽՊՊՇՆՁԥՇՄՅԹԼՂՍՋՌՅԽՆՌԪԹՄԽԤ԰ԦԾԽԻՍՆԼՁՌՑԹՆ ԼԳԱԤՏԽՊԽԹՆԹՄՑՒԽԼՍՋՁՆԿԞԫԬԳԞ

ԹՆԼ Թ ՇՆԽՌԹՁՄԽԼ ԡՍՆՆԽՌՌ0Ջ ՌԽՋՌ ԣԽՊՌՁՄՁՌՑ ՅԹՄԽ ՌՍԺԽՊԻՄԽ ՋԻՇՊԽ  ՅԹՄԽ ՏԽՁԿՀՌ ԹՆԼ ԾԽՅԹՄԽ Ԥ԰Ԧ ԼԹՌԹ

ՏԽՊԽԹՆԹՄՑՒԽԼԺՑԞԫԬԳԞԹՆԼԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԭՊՁՇՊՌՇԡ ՍՆՆԽՌՌ0ՋԼԹՌԹՏԽՊԽԹՆԹՄՑՒԽԼԺՑ

԰ՀԹՈՁՊՇԴՁՄՃ0ՋՌԽՋՌԹՆԼԩԽՎԽՆԽ0ՋՌՇՌԽՋՌԾՇՊՆՇՊՅԹՄՁՌՑԹՆԼՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽՋՊԽՋՈԽԻՌՁՎԽՄՑԦԾ

ՆՇՊՅԹՄՁՌՑ ԹՆԼ ՀՇՅՇԿԽՆԽՁՌՑ ՌԽՋՌՋ ՏԽՊԽ ՈԹՋՋԽԼ 
Ո  Թ ՈԹՊԹՅԽՌՊՁԻ ԹՆԹՄՑՋՁՋ ՏԹՋ ՈԽՊԾՇՊՅԽԼ ԦԾ

ՆՇՆՆՇՊՅԹՄՁՌՑ ՇՊ ՍՆԽՉՍԹՄ ՎԹՊՁԹՆԻԽ ՏԽՊԽ ՁՆԼՁԻԹՌԽԼ 
Ո Թ ՆՇ ՆՈԹՊԹՅԽՌՊՁԻ ԹՆԹՄՑՋՁՋ ՏԹՋ

ՈԽՊԾՇՊՅԽԼ ՇՆ ՌՀԽ ՊԹՆՃՋ ՇԾ ՌՀԽ ԼԹՌԹ ԱՀԽՋԽ ՅԽՌՀՇԼՋ ԹՈՈԽԹՊ ՌՇ ԺԽ ԻՇՆՋՁՋՌԽՆՌ ՏՁՌՀ ՌՀԽ ՅԽՌՀՇԼՋ

ՊԽԻՇՅՅԽՆԼԽԼՁՆՌՀԽԿՍՁԼԽՄՁՆԽ

ԣՇՊ ԹՄՄ ՋՌՍԼՑ ԹՍՌՀՇՊ ՊԽՋՍՄՌՋՌՀԽ ԽՆԼՈՇՁՆՌՋ ԹՌՌՀԽՀՁԿՀՌՊԽԹՌՅԽ ՆՌ ՄԽՎԽՄ 
ՅԿ ԹՁԩՏԽՊԽ ՆՇՌ

ՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼԼՍԽՌՇՅՇՊՌԹՄՁՌՑԱՀԽՋՌՍԼՑԹՍՌՀՇՊՊԽՈՇՊ ՌԽԼՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋԹՌՌՀԽՅԿ

ԹՁԩԻՇՆԻԽՆՌՊԹՌՁՇՆՅԽՌՌՀԽԿՍՁԼԽՄՁՆԽԼԽԾՁՆՁՌՁՇՆՇԾՇՎԽՊՌՅՇՊԺ ՁԼՁՌՑՌՀԽՊԽԾՇՊԽՊԽԼՍԻՌՁՇՆՋԾՇՊԽՆԼՈՇՁՆՌՋ

ԹՌՌՀՁՋԻՇՆԻԽՆՌՊԹՌՁՇՆԻԹՆԺԽ՟ԹՌՌՊՁԺՍՌԽԼՌՇԿԽՆԽՊԹՄՌՇՐՁԻՁՌՑԹՋՇՈՈՇՋԽԼՌՇԽԾԾԽԻՌՋՊԽՄԹՌԽԼՌՇԽՆԼՇԻՊՁՆԽ

ԹԻՌՁՎՁՌՑՠ ԞԼՍՄՌ ՋՍՊՎՁՎԹՄ 
ԻՇՅԺՁՆԽԼ ՋԽՐԽՋ ԹՌ ՌՀԽ  ՅԿ ԹՁ ԩ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
 ՏԹՋ

ՋՁԿՆՁԾՁԻԹՆՌՄՑ ԼՁԾԾԽՊԽՆՌ ԻՇՅՈԹՊԽԼՌՇՌՀԽԻՇՆՌՊՇՄՋ 
 Ո ԣՁՋՀԽՊԢՐԹԻՌԟՇՆԾԽՊՊՇՆՁԥՇՄՅՌԽՋՌ

ԱԹԺՄԽԱՀԽՊԽՏԹՋԹՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԼԽԻՊԽԹՋԽՁՆԾԽՊ ՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋԹՌՅԿԹՁԩ

ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ ԻՇՅՈԹՊԽԼ ՌՇ ՌՀԽ ԻՇՆՌՊՇՄ 
Ո ԧՇՆԻՃՀԽԽՊԽԱԽ ՊՈՋՌՊԹ ՌԽՋՌ ԱԹԺՄԽ ԴՀՁՄԽ ՆՇՌ

ՋՌԹՌՁՋՌՁԻԹՄՄՑԼՁԾԾԽՊԽՆՌԾՊՇՅՌՀԽԻՇՆՌՊՇՄՌՀԽՋՍՈՈՊԽՋՋՁՇՆՇԾԾԽ ԻՍՆԼՁՌՑՁՆՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌ

ՏԹՋԻՇՆՋՁԼԽՊԽԼԺՁՇՄՇԿՁԻԹՄՄՑՊԽՄԽՎԹՆՌ
Ո ԡՍՆՆԽՌՌ0ՋԣՇՊՅ ԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽԹՆԼԺՇԼՑՏԽՁԿՀՌ

ՌՀԽՋՌՍԼՑԹՍՌՀՇՊՆՇՌԽԼ ՊԽԼՍԻՌՁՇՆՋՁՆԽՆԼՈՇՁՆՌՋՇԺՋԽՊՎԽԼԹՌՌՀԽ ՅԿԹՁԩՌՊԽԹՌՅԽՆՌԿՊՇՍՈ

ՌՀԹՌՅԽՌԿՍՁԼԽՄՁՆԽԼԽԾՁՆՁՌՁՇՆՇԾՇՎԽՊՌՅՇՊԺՁԼՁՌՑՌՀԽՊԽԾՇՊԽՌՀ ԽՋԽՊԽԼՍԻՌՁՇՆՋՏԽՊԽԹՌՌՊՁԺՍՌԽԼՌՇԿԽՆԽՊԹՄ

ՌՇՐՁԻՁՌՑ ԹՋ ՇՈՈՇՋԽԼ ՌՇ ԽԾԾԽԻՌՋ ՊԽՄԹՌԽԼ ՌՇ ԽՆԼՇԻՊՁՆԽ ԹԻՌՁՎՁՌՑ 
Ա ԹԺՄԽՋ  ԹՆԼ  ԱՀԽՊԽ ՏԹՋ Թ

ՋՌԹՌՁՋՌՁԻԹՄՄՑ ՋՁԿՆՁԾՁԻԹՆՌ ԼԽԻՊԽԹՋԽ ՁՆ ՅԽԼՁԹՆ ԾԽՅԹՄԽ Ԥ԰Ԧ ՁՆ ՌՀԽ  ՅԿ ԹՁԩ ՌՊԽԹՌՅԽՆՌ ԿՊՇՍՈ

ԻՇՅՈԹՊԽԼՌՇՌՀԽԻՇՆՌՊՇՄ
ՈԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԱԹԺՄ Խ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԞՄՌՀՇՍԿՀՆՇՌԹՆԹՄՑՒԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՌՀԽՊԽՏԽՊԽԿԽՆԽՊԹՄՁՒԽԼՇՎԽ ՊՌՋՁԿՆՋՇԾՌՇՐՁԻՁՌՑՁՆԺՇՌՀՅԹՄԽՋԹՆԼ

ԾԽՅԹՄԽՋՁՆԻՄՍԼՁՆԿԹՄՄՋՍՊՎՁՎՁՆԿԾՁՋՀԹՌՌՀԽՅԿ ԹՁԩՌՊԽԹՌՅԽՆՌՏՀՁԻՀՏԽՊԽՇԺՋԽՊՎԽԼՌՇԺԽ

ՄԽՌՀԹՊԿՁԻ
ԱԹԺՄԽԦՆՅԹՄԽԾՁՋՀՌՀԽՊԽՏԹՋԹՄՋՇԹՆՁՆԻՊԽԹՋԽԼ ՈԽՊԻԽՆՌԹԿԽՇԾՋՈԽՊՅԹՌՇԿՇՆՁԹՁՆՌՀԽ

ՅԿԹՁԩԿՊՇՍՈԹՆԼՁՆԾԽՅԹՄԽԾՁՋՀԼԽԻՊԽԹՋԽԼՑՇՄՃՋՑՆՌՀԽ ՋՁՋՁՆԺՇՌՀՌՀԽԹՆԼ

ՅԿԹՁԩՌՊԽԹՌՅԽՆՌՋՊԽՄԹՌՁՎԽՌՇՌՀԽԻՇՆՌՊՇՄՋ
ԱԹԺՄԽՋԹՆԼ 

ԠԯԽՎՁԽՏԽՊ0ՋԞՆԹՄՑՋՁՋԹՆԼԠՇՆԻՄՍՋՁՇՆՋ

԰ՌԹՌՁՋՌՁԻԹՄ ԪԽՌՀՇԼՋ   ԱՀԽ ՊԽՎՁԽՏԽՊ ԹՆԹՄՑՒԽԼ ՋՍՊՎՁՎԹՄ 
ՅՇՊՌԹՄՁՌՑ ԼԹՌԹ ԾՇՊ ՅԹՄԽ ԹՆԼ ԾԽՅԹՄԽ ԾՁՋՀ

ԻՇՅԺՁՆԽԼՍՋՁՆԿԣՁՋՀԽՊ0ՋԢՐԹԻՌՌԽՋՌՎՁԹԱՇՐՋՌԹՌԣԽՅԹՄԽԺՇԼ ՑՏԽՁԿՀՌԹՆԼՄԽՆԿՌՀՅԹՄԽՄԽՆԿՌՀ

ՅԹՄԽ ԿՇՆԹԼՇՋՇՅԹՌՁԻ ՁՆԼԽՐ 
Ԥ԰Ԧ ԹՆԼ ԾԽՅԹՄԽ ՎՁՌԽՄՄՇԿԽՆՁՆ 
ԳԱԤ ՏԽՊԽ ՆՇՌ ԻՇՆՋՁՋՌԽՆՌ ՏՁՌՀ Թ

ՅՇՆՇՌՇՆՁԻ ԻՇՆԻԽՆՌՊԹՌՁՇՆՊԽՋՈՇՆՋԽ ԞՄՄ ԼԹՌԹՏԽՊԽ ՌԽՋՌԽԼ ԾՇՊ ՆՇՊՅ ԹՄՁՌՑ ՍՋՁՆԿ ԰ՀԹՈՁՊՇԴՁՄՃՋ ՌԽՋՌ ԹՆԼ

ԾՇՊՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽՍՋՁՆԿԩԽՎԽՆԽ0ՋՌԽՋՌԱՀԽՋԽԼԹՌԹՅԽՌ ՌՀԽԹՋՋՍՅՈՌՁՇՆՋՇԾՆՇՊՅԹՄՁՌՑԹՆԼ

ՀՇՅՇԿԽՆԽՁՌՑՇԾՎԹՊՁԹՆԻԽԹՆԼՏԽՊԽՌՀԽՆԹՆԹՄՑՒԽԼՍՋՁՆԿՌՀԽՈԹՊԹՅԽ ՌՊՁԻՌՏՇՋՁԼԽԼԡՍՆՆԽՌՌ0ՋՌԽՋՌ

ԪԹՄԽՅԽԼՁԹՆՌՍԺԽՊԻՄԽՋԻՇՊԽԼՁԼՆՇՌԽՐՀՁԺՁՌԹԻՄԽԹՊՅՇՆՇՌՇՆՁԻՊԽՋՈՇՆՋԽԹՆԼՌՀԽՊԽԾՇՊԽՏԹՋԹՆԹՄՑՒԽԼ

ՍՋՁՆԿՌՀԽՌՏՇՋՁԼԽԪԹՆՆԴՀՁՌՆԽՑՌԽՋՌ

ԣԽԻՍՆԼՁՌՑԾԽՊՌՁՄՁՒԹՌՁՇՆՋՍԻԻԽՋՋ ՅԹՄԽՈՄԹՋՅԹԳԱԤԹՆԼՅԹՄԽԺՇԼ ՑՏԽՁԿՀՌԽԹԻՀԽՐՀՁԺՁՌԽԼԹՆԹՈՈԹՊԽՆՌ

ՅՇՆՇՌՇՆՁԻԹՄՄՑ ԼԽԻՊԽԹՋՁՆԿ ՌՊԽՆԼ ՏՀԽՆ ԻՇՅՈԹՊԽԼ ՌՇ ՌՀԽ ՆԽԿԹՌՁՎԽ Ի ՇՆՌՊՇՄ ՌՀԽՋԽ ԽՆԼՈՇՁՆՌՋ ՏԽՊԽ

ԹՆԹՄՑՒԽԼԾՇՊՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԼՁԾԾԽՊԽՆԻԽՋՍՋՁՆԿՌՀԽԧՇ ՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՋՌԽՈԼՇՏՆՌԽՋՌ

ԲՆՄԽՋՋ ՇՌՀԽՊՏՁՋԽ ՁՆԼՁԻԹՌԽԼ ԽԾԾԽԻՌՋ ՏԽՊԽ ԻՇՆՋՁԼԽՊԽԼ ՋՌԹՌՁՋՌՁԻԹՄՄՑ ՋՁԿՆՁԾՁԻԹՆՌ ԹՌ Ո ԴՁՌՀ ՌՀԽ

ԽՐԻԽՈՌՁՇՆ ՇԾ ԣՁՋՀԽՊ0Ջ ԢՐԹԻՌ ԱԽՋՌ ԹՄՄ ԹՆԹՄՑՋԽՋՏԽՊԽ ԻՇՆԼՍԻՌԽԼ Ս ՋՁՆԿ ՌՀԽ ԣԦ԰ԥ ՈՊՇԻԽԼՍՊԽ ՁՆ ԰Ԟ԰ ն



### ԰Ԟ԰ԦՆՋՌՁՌՍՌԽԠԹՊՑԫԠՎԽՊՋՁՇՆ

ԫՇՆԽՇԾՌՀԽՋՍՊՎՁՎՁՆԿԾԽՅԹՄԽՋՏԽՊԽԾՇՍՆԼՌՇՀԹՎԽՌՍԺԽՊԻՄԽՋԱՀԽ ՊԽԾՇՊԽԾԽՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՏԹՋ

ՆՇՌ ՋՌԹՌՁՋՌՁԻԹՄՄՑ ԹՆԹՄՑՒԽԼ ԥՁՋՌՇՈԹՌՀՇՄՇԿՑ ՇԺՋԽՊՎԹՌՁՇՆՋ ՏԽՊԽ ԽՎ ԹՄՍԹՌԽԼ ՁՆ ԻՇՆՂՍՆԻՌՁՇՆ ՏՁՌՀ ՌՀԽ

ՈԹՌՀՇՄՇԿՁՋՌ0ՋՊԽՈՇՊՌԺՍՌՋԽՎԽՊՁՌՑԹՆԼՁՆԻՁԼԽՆԻԽԼԹՌԹՏԽՊԽՆՇՌ ՋՍԺՂԽԻՌԽԼՌՇԾՇՊՅԹՄՋՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋԽՋ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ  ԠՇՆԻՄՍՋՁՇՆՋ

԰ՍՊՎՁՎԹՄՏԹՋՋՁԿՆՁԾՁԻԹՆՌՄՑՊԽԼՍԻԽԼ
ՈՌՇՇԾՌՀԽԻՇՆՌՊ ՇՄԹՌՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԱԹԺՄԽ  ԹՆԼ ԾՍՊՌՀԽՊ ՊԽԼՍԻԽԼ ՌՇ  
ՌՀՇՍԿՀ ՆՇՌ ՋՌԹՌՁՋՌՁԻԹՄՄՑ Թ ՆԹՄՑՒԽԼ ԹՌ ՌՀԽ ՀՁԿՀԽՋՌ ՌՊԽԹՌՅԽՆՌ

ՄԽՎԽՄՅԿԹՁԩՏՀՁԻՀՏԹՋԽՐԻՄՍԼԽԼԾՊՇՅԹՆԹՄՑՋԽՋԣՁՋՀ ՁՆՌՀԽՁՆՌԽՊՅԽԼՁԹՌԽՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԼՁՋՈՄԹՑԽԼ ՋՁԿՆՋ ՇԾ ՅՇՊԺՁԼՁՌՑ ՁՆԻՄՍԼՁՆԿ ՄԽՌՀԹՊԿՑ ԹՆԼ ՄՇՋՋ ՇԾ ԽՉՍՁՄՁԺՊՁՍՅ ԞՄՌՀՇՍԿՀ ՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ

ՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԹՋՆՇՌԽՐԻՄՍԼԽԼԾՊՇՅՋՌԹՌՁՋՌՁԻԹՄԹՆԹՄՑՋԽՋՌՀԽՈՊԽՋԽՆԻԽՇԾԻՄՁՆՁԻԹՄՋՁԿՆՋՇԾՌՇՐՁԻՁՌՑԹՌ

ՌՀՁՋ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ ՋՀՇՍՄԼ ԺԽ ԻՇՆՋՁԼԽՊԽԼ ՏՀԽՆ ՁՆՌԽՊՈՊԽՌՁՆԿ ՌՀԽ  ՊԽՋՍՄՌՋ ԞԼԼՁՌՁՇՆԹՄՄՑ ՌՀԽ ՇՎԽՊԹՄՄ

ՋՍՊՎՁՎԹՄՁՆՌՀԽՄՇՏԽՋՌՌՊԽԹՌՅԽՆՌԿՊՇՍՈ
ՅԿԹՁԩՏԹՋ ՏՁՌՀՌՀՊԽԽՇԾՌՀԽԾՇՍՊԾԽՅԹՄԽՋՁՆ

ՇՆԽ ՊԽՈՄՁԻԹՌԽ ԼԽԹԼ ԹԿԹՁՆ ՌՀՁՋ ՊԽՈՄՁԻԹՌԽ ՏԹՋ ՆՇՌ ԽՐԻՄՍԼԽԼ ԾՊՇՅ  ՌՀԽ ԹՆԹՄՑՋԽՋ ԺՍՌ ՋՀՇՍՄԼ ԺԽ

ԻՇՆՋՁԼԽՊԽԼՏՀԽՆՁՆՌԽՊՈՊԽՌՁՆԿՌՀԽՊԽՋՍՄՌՋ

ԣԽԻՍՆԼՁՌՑ 
Ո ԹՆԼ ԾԽՊՌՁՄՁՌՑ 
Ո ԹՌ ՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ Ի ՇՆԻԽՆՌՊԹՌՁՇՆ ՏԽՊԽ ՋՁԿՆՁԾՁԻԹՆՌՄՑ

ԼԽԻՊԽԹՋԽԼ ՏՀԽՆ ԻՇՅՈԹՊԽԼ ՌՇ ՌՀԽ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄ ԢԾԾԽԻՌՋ ՇՆ ԾԽՅԹՄԽ ԿՇՆԹԼԹՄ ՀՁՋՌՇՈԹՌՀՇՄՇԿՑ

ՁՆԻՄՍԼՁՆԿ ԼԽԻՊԽԹՋԽԼ ՑՇՄՃ ՋՑՆՌՀԽՋՁՋ ՏԽՊԽ ՇԺՋԽՊՎԽԼ ԹՌ ՌՀԽ ՄՇՏ ԹՆ Լ ՁՆՌԽՊՅԽԼՁԹՌԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆՋ

ԣԽՅԹՄԽ Ԥ԰Ԧ 
Ո ՏԹՋ ՋՁԿՆՁԾՁԻԹՆՌՄՑ ԼԽԻՊԽԹՋԽԼ ԹՌ ՁՆՌԽՊՅԽԼՁԹՌԽ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ԴՀՁՄԽ ՆՇՌ

ՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌՅԹՄԽՌՍԺԽՊԻՄԽՋԻՇՊԽՏԽՊԽ ՊԽԼՍԻԽԼԺՑ ԹՌՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽԻՇՆԻԽՆՌՊԹՌՁՇՆ

ԪԹՆՆԴՀՁՌՆԽՑՈԦՆՅԹՄԽԾՁՋՀՌՀԽՊԽՏԹՋԹՄՋՇԹՆՁՆԻՊԽԹՋ ԽԼՈԽՊԻԽՆՌԹԿԽՇԾՋՈԽՊՅԹՌՇԿՇՆՁԹԹՌ

ՌՀՁՋՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԴՀՁՄԽ ՆՇՌ ՋՁԿՆՁԾՁԻԹՆՌՄՑ ԼՁԾԾԽՊԽՆՌ ՌՀԽՊԽ ՏԹՋ Թ  ՁՆԻՊԽԹՋԽ Ձ Ն ՅԹՄԽ ԳԱԤ ԹՌ ՌՀԽ ՁՆՌԽՊՅԽԼՁԹՌԽ

ԻՇՆԻԽՆՌՊԹՌՁՇՆԿՊՇՍՈԻՇՅՈԹՊԽԼՌՇՌՀԽԻՇՆՌՊՇՄՌՀՁՋԼՁԾԾԽՊԽՆԻԽՁՋ ԼՍԽՌՇՌՏՇՅԹՄԽՋՁՆՌՀՁՋԿՊՇՍՈՏՁՌՀ

ՀՁԿՀԽՊԳԱԤՄԽՎԽՄՋԻՇՅՈԹՊԽԼՌՇՌՀԽԻՇՆՌՊՇՄ

ԟՇԼՑՏԽՁԿՀՌԹՆԼՄԽՆԿՌՀՏԽՊԽՆՇՌՋՁԿՆՁԾՁԻԹՆՌՄՑԼՁԾԾԽՊԽՆՌՁՆՅԹՄԽՇՊԾԽՅԹՄԽԾՁՋՀԹՌԹՆՑՌՊԽԹՌՅԽՆՌՄԽՎԽՄԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢՆԼՈՇՁՆՌՋԾՇՊԪԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋՁՆՌՀԽԣ԰ԱԯԞՏՁՌՀԭՀՇՋՅԽՌԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԱՍԺԽՊԻՄԽ԰ԻՇՊԽԤ԰ԦԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿԹՆԼԥՁՋՌՇԭՄԹՋՅԹԳԱԤԪԽԼՁԹՆՈԡՁԾԾՈԢԾԾԽԻՌ!
ԶԽՋԫՇԡՁԾԾԭԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄ
ԩԬԮ ԫԞ  ԫԞ ԫՇ  ԫԞ  ԫՇ   ԶԽՋ ԫԞԫԞԫԞԫԞԫԞԫԞԫԞ԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌԪԹՆՆԴՀՁՌՆԽՑԡՍՆՆԽՌՌ0Ջ ԫԞ ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹԞԺԺՊԽՎՁԹՌՁՇՆՋԠՇՆԻԠՇՆԻԽՆՌՊԹՌՁՇՆԡՁԾԾԡՁԾԾԽՊԽՆԻԽԢԽՋՌՊԹԼՁՇՄԤ԰ԦԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐԥՁՋՌՇԥՁՋՌՇՈԹՌՀՇՄՇԿՑԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԱԱԽՋՌՇՋՌԽՊՇՆԽԳԱԤԳՁՌԽՄՄՇԿԽՆՁՆ ԲՆՄԽՋՋ ՇՌՀԽՊՏՁՋԽ ՁՆԼՁԻԹՌԽԼ ԽԾԾԽԻՌՋ ԹՆԼ ՈԽՊԻԽՆՌ 
 ԼՁԾԾԽՊԽՆԻԽՋ ԹՊԽ ՊԽՈՇՊՌԽԼ ԺԹՋԽԼ ՇՆ ԻՇՅՈԹՊՁՋՇՆ ՌՇ ՌՀԽ ՆԽԿԹՌՁՎԽ 
ԻՄԽԹՆ ՏԹՌԽՊ ԻՇՆՌՊՇՄ ԠՇՆԻՄՍՋՁՇՆՋ ՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈԱՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՋՌԽՈԼՇՏՆՌԽՋՌՏԹՋՍՋԽԼՌՇԹՆԹՄՑՒԽՅԹՄԽՎՁՌԽՄՄՇԿԽՆՁՆ
ԳԱԤՊԽՋՈՇՆՋԽԼԹՌԹԺԽԻԹՍՋԽՌՀԽՊԽՎՁԽՏԽՊՎՁՋՍԹՄՄՑԼԽՌԽՊՅՁՆԽԼԹՅՇՆՇՌՇՆՁԻԹՄՄՑԼԽԻՊԽԹՋՁՆԿՌՊԽՆԼՁՆՌՀԽՌՊԽԹՌՅԽՆՌՅԽԼՁԹՆՎԹՄՍԽՋ
 ԹՆԼ ՆԿՅԩ ՈՄԹՋՅԹ ԹՌՌՀԽ ԹՆԼՅԿԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋ ՊԽՋՈԽԻՌՁՎԽՄՑՏՀԽՆԻՇՅՈԹՊԽԼՌՇՌՀԽ ՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄ
ՆԿՅԩՈՄԹՋՅԹԥՇՏԽՎԽՊՌՀԽՇՎԽՊԹՄՄՅԽԹՆԾՇՊՌՀՁՋՌՊԽԹՌՅԽՆՌՏԹՋԿՊԽԹՌԽՊՌՀԹՆՌՀԽԻՇՆՌՊՇՄԹՆԼՌՀՁՋՏԹՋԼՍԽՌՇՌՏՇՅԹՄԽԾՁՋՀՁՆՌՀՁՋՌՊԽԹՌՅԽՆՌՏՁՌՀՊԽՈՇՊՌԽԼԳԱԤՄԽՎԽՄՋՌՀԹՌՏԽՊԽՋՍԺՋՌԹՆՌՁԹՄՄՑԿՊԽԹՌԽՊՌՀԹՆՌՀԽԻՇՆՌՊՇՄՋԭՄԹՋՅԹՋԽՐՋՌԽՊՇՁԼՋՏԽՊԽՆՇՌՅԽԹՋՍՊԽԼԩԬԮՅԿԹՁԩԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌԢԭԞԪԯԦԡԫՍՅԺԽՊԭԹԿԽՇԾԱԹԺՄԽԯԽՈՊՇԼՍԻՌՁՎԽԹՆԼԥԭԤԢՆԼՈՇՁՆՌՋԾՇՊԣԽՅԹՄԽԣԹՌՀԽԹԼԪՁՆՆՇՏ ԭՁՅԽՈՀԹՄԽՋՈՊՇՅԽՄԹՋՁՆՌՀԽԣ԰ԱԯԞՏՁՌՀԭՀՇՋՅԽՌԱՊԽԹՌՅԽՆՌՅԿԹՁԩ#ՅԽԹՆՅԽԹՋՍՊԽԼ%ԣԽԻՍՆԼՁՌՑԣԽՊՌ԰ՍԻԻԽՋՋԱՍԺԽՊԻՄԽ԰ԻՇՊԽԤ԰ԦԤՇՆԹԼԹՄ԰ՌԹԿՁՆԿԹՆԼԥՁՋՌՇԭՄԹՋՅԹԳԱԤԡՁԾԾՈԡՁԾԾԭԪԽԼՁԹՆՈԡՁԾԾՈԢԾԾԽԻՌ!ԶԽՋԫՇԡՁԾԾՈԫԽԿԹՌՁՎԽԠՇՆՌՊՇՄԩԬԮԩԬԮ ԫԞ  ԫԞ  ԫԞ  ԫԞԫՇ ԫԞ     ԫԞ  ԶԽՋ     ԫԞ  ԶԽՋ ԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞԫԞ԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ ԫԞ ԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹ ԫԞ ԡՍՆՆԽՌՌ0ՋԞԺԺՊԽՎՁԹՌՁՇՆՋԠՇՆԻԠՇՆԻԽՆՌՊԹՌՁՇՆԡՁԾԾԡՁԾԾԽՊԽՆԻԽԢԽՋՌՊԹԼՁՇՄԣԽՊՌԣԽՊՌՁՄՁՒԹՌՁՇՆԤ԰ԦԤՇՆԹԼՇ԰ՇՅԹՌՁԻԦՆԼԽՐԥՁՋՌՇԥՁՋՌՇՈԹՌՀՇՄՇԿՑԫԞԫՇՌԹՈՈՄՁԻԹԺՄԽԱԱԽՋՌՇՋՌԽՊՇՆԽԳԱԤԳՁՌԽՄՄՇԿԽՆՁՆ ԲՆՄԽՋՋ ՇՌՀԽՊՏՁՋԽ ՁՆԼՁԻԹՌԽԼ ԽԾԾԽԻՌՋ ԹՆԼ ՈԽՊԻԽՆՌ 
 ԼՁԾԾԽՊԽՆԻԽՋ ԹՊԽ ՊԽՈՇՊՌԽԼ ԺԹՋԽԼ ՇՆ ԻՇՅՈԹՊՁՋՇՆ ՌՇ ՌՀԽ ՆԽԿԹՌՁՎԽ 
ԻՄԽԹՆ ՏԹՌԽՊ ԻՇՆՌՊՇՄ ԠՇՆԻՄՍՋՁՇՆՋ ՊԽԿԹՊԼՁՆԿՀՁՋՌՇՈԹՌՀՇՄՇԿՑՅԹՑԺԽՀԽԹՎՁՄՑՏԽՁԿՀՌԽԼԺՑՌՀԽԽՐՈԽՊՌՇՈՁՆՁՇՆՇԾԹԺՇԹՊԼԻԽՊՌՁԾՁԽԼՈԹՌՀՇՄՇԿՁՋՌ ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈԱՀԽԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՋՌԽՈԼՇՏՆՌԽՋՌՏԹՋՍՋԽԼՌՇԹՆԹՄՑՒԽԾԽԻՍՆԼՁՌՑ ՊԽՋՈՇՆՋԽԼԹՌԹԺԽԻԹՍՋԽՌՀԽ ՊԽՎՁԽՏԽՊՎՁՋՍԹՄՄՑԼԽՌԽՊՅՁՆԽԼԹՅՇՆՇՌՇՆՁԻԹՄՄՑԼԽԻՊԽԹՋՁՆԿՌՊԽՆԼՁՆՌՀԽՌՊԽԹՌՅԽՆՌՅԽԼՁԹՆՎԹՄՍԽՋ
ԹՆԼԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑԹՌՌՀԽԹՆԼՅԿԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՋՊԽՋՈԽԻՌՁՎԽՄՑՏՀԽՆԻՇՅՈԹՊԽԼՌՇՌՀԽՆԽԿԹՌՁՎԽԻՇՆՌՊՇՄԽԿԿՋԾԽՅԹՄԽՊԽՈՊՇԼՍԻՌՁՎԽԼԹՑԩԬԮՅԿԹՁԩ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱԹԺՄԽԤՊՇՏՌՀԢՆԼՈՇՁՆՌՋ  

### ՁՆՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑ
ԣ԰ԱԯԞՏՁՌՀԭՀՇՋՅԽՌ



ԱՊԽԹՌՅԽՆՌ

ՅԿԹՁԩ

#ՅԽԹՆՅԽԹՋՍՊԽԼ% ԟՇԼՑԴԽՁԿՀՌ ԩԽՆԿՌՀ

ԪԹՄԽՋ ԣԽՅԹՄԽՋ ԪԹՄԽՋ ԣԽՅԹՄԽՋ

ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո ԡՁԾԾ Ո

ԠՇՆՌՊՇՄ
ԩԬԮ  ԫԞ  ԫԞ  ԫԞ  ԫԞ

        

        

 ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ ԫԞ

԰ՌԹՌՁՋՌՁԻԹՄԱԽՋՌ ԧՇՆԻՃՀԽԽՊԽ

ԱԽՊՈՋՌՊԹ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ ԡՍՆՆԽՌՌ0Ջ

ԞԺԺՊԽՎՁԹՌՁՇՆՋ ԡՁԾԾ ԡՁԾԾԽՊԽՆԻԽ ԫԞ ԫՇՌԹՈՈՄՁԻԹԺՄԽ

  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՁՆԼՁԻԹՌԽԼՈԽՊԻԽՆՌ
ԼՁԾԾԽՊԽՆԻԽՋԹՊԽ ՊԽՈՇՊՌ ԽԼԺԹՋԽԼՇՆԻՇՅՈԹՊՁՋՇՆՌՇՌՀԽՆԽԿԹՌՁՎԽ
ԻՄԽԹՆՏԹՌԽՊ

ԻՇՆՌՊՇՄ

  ԲՆՄԽՋՋՇՌՀԽՊՏՁՋԽՋՈԽԻՁԾՁԽԼԽԾԾԽԻՌՋԹՊԽԻՇՆՋՁԼԽՊԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌԹՌՈ

ԩԬԮՅԿԹՁԩ



### Ԣ԰ՌՍԼՑԡԽԾՁԻՁԽՆԻՁԽՋ

ԱՀԽՊԽՏԽՊԽՅՁՆՇՊԼԽՎՁԹՌՁՇՆՋԼԽՋԻՊՁԺԽԼՁՆ԰ԽԻՌՁՇՆԦԪԹՌԽՊՁԹՄՋԹ ՆԼԪԽՌՀՇԼՋՇԾՌՀՁՋԡԢԯՊԽԿԹՊԼՁՆԿԾԹՁՄՍՊԽՌՇ

ՊԽՈՇՊՌ ԻԽՊՌԹՁՆ ՏԹՌԽՊ ԻՀԹՊԹԻՌԽՊՁՋՌՁԻՋ ԪՇՊԽ ՁՅՈՇՊՌԹՆՌՄՑ ՌՀԽ ՋՌՍ ԼՑ ԼՁԼ ՆՇՌ ՅԽԽՌ ՌՀԽ ՅՁՆՁՅՍՅ ՇԾ  ՌԽՋՌ

ԻՇՆԻԽՆՌՊԹՌՁՇՆՋՌՀԹՌԼՁԼՆՇՌԽՐՀՁԺՁՌՌՇՐՁԻՁՌՑԹՋՊԽԻՇՅՅԽՆԼԽԼԺՑ ՌՀԽԬԠ԰ԭԭԿՍՁԼԽՄՁՆԽ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ  ԱՀԽԾԽԻՍՆԼՁՌՑ ՁՆ ՇՆԽ ՊԽՈՄՁԻԹՌԽ ՇԾՌՀԽ ՆԽԿԹՌՁՎԽ ԻՇՆՌՊՇՄՏԹՋ ԽԿԿՋԾԽՅԹՄԽԼԹՑ ՆՇՊ ԼՁԼ

ՌՀԽ ՊԽՈՄՁԻԹՌԽ ՋՈԹՏՆ ԹՌ ՄԽԹՋՌ ԽՎԽՊՑ  ԼԹՑՋ ԪԽԽՌՁՆԿ ՇՆԽ ՇԾ ՌՀԽՋԽ ԻՊՁՌԽՊՁԹ ՁՆ ՆԽԽԼԽԼ ՌՇ

ԼԽՅՇՆՋՌՊԹՌԽԹԻՌՁՎԽՋՈԹՏՆՁՆԿ

 ԱՀԽԽՆԼՈՇՁՆՌՋԹՌՌՀԽՀՁԿՀՌՊԽԹՌՅԽՆՌՄԽՎԽՄ
ՅԿԹՁԩՏԽՊ ԽՆՇՌՋՌԹՌՁՋՌՁԻԹՄՄՑԹՆԹՄՑՒԽԼ

ԼՍԽ ՌՇ ՅՇՊՌԹՄՁՌՑ ՇՆՄՑ ՇՆԽ ՅԹՄԽ ԹՆԼ ՇՆԽ ԾԽՅԹՄԽ ՋՍՊՎՁՎԽԼ ԹՌ ՋՌՍԼՑ ՌԽՊՅՁՆԹՌՁՇՆ ԱՀԽՊԽԾՇՊԽ

ՇՆՄՑ  ՌԽՋՌ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄՋ ՏԽՊԽ ԹՆԹՄՑՒԽԼ ՁՆ ՌՀՁՋ ՋՌՍԼՑ ԬԠ԰ԭԭ  ԤՍՁԼԽՄՁՆԽ 

ՊԽԻՇՅՅԽՆԼՋ Թ ՅՁՆՁՅՍՅ ՇԾ  ՌԽՋՌ ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՈՄՍՋ Թ ՆԽԿԹՌՁՎԽ ԻՇ ՆՌՊՇՄ ԞՄՋՇ ՌՀԽ ՋՌՍԼՑ

ԹՍՌՀՇՊ ՊԽՈՇՊՌԽԼՌՀԹՌՇԺՋԽՊՎԹՌՁՇՆՋԹՌՌՀԽՅԿԹՁԩԻՇՆԻԽ ՆՌՊԹՌՁՇՆՅԽՌՌՀԽԿՍՁԼԽՄՁՆԽ

ԼԽԾՁՆՁՌՁՇՆՇԾՇՎԽՊՌՅՇՊԺՁԼՁՌՑՅԹՃՁՆԿՊԽՋՍՄՌՋԾՇՊՌՀՁՋՌՊԽԹՌՅԽՆ ՌՄԽՎԽՄԼՁԾԾՁԻՍՄՌՌՇՁՆՌԽՊՈՊԽՌ

 ԱՀԽՌՇՌԹՄ ՇՊԿԹՆՁԻ ԻԹՊԺՇՆ ՍՆՁՇՆՁՒԽԼ ԹՅՅՇՆՁԹ ԹՆԼ ՊԽՋՁԼՍԹՄ ԻՀՄՇՊՁ ՆԽ ՁՆՌՀԽ ՌԽՋՌՏԹՌԽՊՏԽՊԽ

ՆՇՌ ՊԽՈՇՊՌԽԼ ԱՀԽ ԬԠ԰ԭԭ  ՈԽՊԾՇՊՅԹՆԻԽ ԻՊՁՌԽՊՁԹ ԽՋՌԹԺՄՁՋՀ ՅԹՐՁՅՍՅ ՄԽՎԽՄՋ ԾՇՊ

ՌՀԽՋԽՎԹՄՍԽՋԹՆԼՁՌՁՋՍՆԻՄԽԹՊՁԾՌՀԽՅԹՐՁՅՍՅՊԽԻՇՅՅԽՆԼԹՌՁՇՆՋ ՏԽՊԽԽՐԻԽԽԼԽԼ

   ԱՀԽՊԽՅԹՁՆՁՆԿՎԹՄՁԼՁՌՑ ԹՆԼՈԽՊԾՇՊՅԹՆԻԽԻՊՁՌԽՊՁԹԾՇՊԬԠ԰ԭԭՏԽՊԽՅԽՌ

ԣԯԽՎՁԽՏԽՊ0ՋԠՇՅՅԽՆՌՋ

ԱՀԽ ՊԽՎՁԽՏԽՊ0Ջ ԹՆԼ ՌՀԽ ՋՌՍԼՑ ԹՍՌՀՇՊՋ0 ՊԽՋՍՄՌՋ ՏԽՊԽ ՁՆ ԹԿՊԽԽՅԽՆՌ ՊԽԿԹՊԼՁՆԿ ԽԾԾԽԻՌՋ ՇՆ ՋՍՊՎՁՎԹՄ

ԾԽՊՌՁՄՁՒԹՌՁՇՆԹՆԼԾԽՅԹՄԽԤ԰ԦԠՇՆԻՄՍՋՁՇՆՋՊԽԿԹՊԼՁՆԿԾԽԻՍՆԼՁՌՑՏ ԽՊԽԹՄՋՇՋՁՅՁՄԹՊՁՆՌՀԹՌՌՀԽՋՍՈՈՊԽՋՋՁՇՆԹՌ

ՌՀԽՅԿԹՁԩՌՊԽԹՌՅԽՆՌՄԽՎԽՄՏԹՋԻՇՆՋՁԼԽՊԽԼԺՁՇՄՇԿՁԻԹՄՄ ՑՊԽՄԽՎԹՆՌԟՇՌՀՌՀԽՋՌՍԼՑԹՍՌՀՇՊ0ՋԹՆԼ

ՊԽՎՁԽՏԽՊ0ՋԹՆԹՄՑՋՁՋԼԽՌԽԻՌԽԼՋՌԹՌՁՋՌՁԻԹՄՄՑՋՁԿՆՁԾՁԻԹՆՌՊԽԼՍԻՌՁՇ ՆՋ
ՈՁՆԾԽՊՌՁՄՁՌՑԹՆԼԾԽՅԹՄԽԤ԰ԦԹՌՌՀԽ

 ՅԿ ԹՁԩ ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ ԻՇՆՋՁՋՌԽՆՌ ՏՁՌՀ ՌՀԽ ԻՇՆԻՄՍՋՁՇ ՆՋ ԾՇՄՄՇՏՁՆԿ ՌՀԽ ԬԠ԰ԭԭ 

ՅԽՌՀՇԼՇՄՇԿՑ
ՍՋՁՆԿՌՀԽՊԽՋՍՄՌՋՇԾԧՇՆԻՃՀԽԽՊԽԱԽՊՈՋՌՊԹՌԽՋՌԦԾ ՌՀԽՊԽՎՁԽՏԽՊԾՇՄՄՇՏՋՌՀԽՋՍԿԿԽՋՌՁՇՆՇԾՌՀԽ

ՌՊԹԼՁՌՁՇՆԹՄ ԢԣԢԡ ՅԽՌՀՇԼՇՄՇԿՑ ՏՀՁԻՀ ՊԽԻՇՅՅԽՆԼՋ ԴՁՄՄՁԹՅ0Ջ ՌԽՋՌ Ծ ՇՊ ԻՇՆԻԽՆՌՊԹՌՁՇՆԼԽՈԽՆԼԽՆՌ ՈԹՌՌԽՊՆՋ

ՋԹՌՁՋԾՑՁՆԿ ՈԹՊԹՅԽՌՊՁԻ ԹՋՋՍՅՈՌՁՇՆՋ ՋՁԿՆՁԾՁԻԹՆՌ ՊԽԼՍԻՌՁՇՆՋ ՏԽՊԽ ԹՄՋՇ ԼԽՌԽԻՌԽԼ ԹՌ ՌՀԽ  ՅԿ ԹՁԩ

ՌՊԽԹՌՅԽՆՌ ՄԽՎԽՄ 
Ո ԱՀԽ ՇԺՋԽՊՎԹՌՁՇՆՋ ՇԾ ԻՄՁՆՁԻԹՄ ՋՁԿՆՋ ԹՌ   ՅԿ ԹՁԩ ՅԽՌ ՌՀԽ ԿՍՁԼԽՄՁՆԽ

ԼԽԾՁՆՁՌՁՇՆՇԾՇՎԽՊՌՅՇՊԺՁԼՁՌՑՏՀՁԻՀՄԽՆԼՋՍՆԻԽՊՌԹՁՆՌՑՌՇՌՀԽՁ ՆՌԽՊՈՊԽՌԹՌՁՇՆՇԾՊԽՋՍՄՌՋԹՌՌՀՁՋՌՊԽԹՌՅԽՆՌՄԽՎԽՄ

ԱՀԽ ՊԽՎՁԽՏԽՊ0Ջ ԻՇՆԻՄՍՋՁՇՆՋ ԺԹՋԽԼ ՇՆ ՌՀԽ ԬԠ԰ԭԭ  ԾՄՇՏԻՀԹՊ Ռ ԹՊԽ ՈՊԽՋԽՆՌԽԼ ՁՆ ՌՀԽ ԢՐԽԻՍՌՁՎԽ

԰ՍՅՅԹՊՑԹՆԼԠՇՆԻՄՍՋՁՇՆՋՋԽԻՌՁՇՆՋՇԾՌՀՁՋԡԢԯ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԱՀԽՋՌՍԼՑԹՍՌՀՇՊՋՊԽՈՇՊՌԽԼՅԽԹՆՅԽԹՋՍՊԽԼՊԽԻՇՎԽՊՁԽՋՇԾՈՀՇՋՅԽՌ ԹՋՅԿԹՁԩԺԹՋԽԼՇՆՆՇՅՁՆԹՄ

ԻՇՆԻԽՆՌՊԹՌՁՇՆ ՇԾ  ՅԿ ԹՁԩ ՏԹՋ ՁՆԻՇՊՊԽԻՌ ՌՀԽ ՊԽՎՁԽՏԽՊ ՅԽ ԹՆ ՅԽԹՋՍՊԽԼ ՏԹՋ  ՅԿ ԹՁԩ

ԺԹՋԽԼՇՆՌՀԽԼԹՌԹՈՊՇՎՁԼԽԼԱՀԽՅԽՌՀՇԼ ՊԽԻՇՎԽՊՁԽՋՇԾՈՀՇՋՅԽՌՁՆԣՊՇԿԢՅԺՊՑՇԱԽՊԹՌՇԿԽՆԽՋՁՋԞՋՋԹՑ

ԵԽՆՇՈՍՋ
ԣԢԱԞԵՋՇՄՍՌՁՇՆԾՇՊՌՁԾՁԽԼԹՌԹՆԼ ՅԿԹՁԩՏԽՊԽչ
Ն

ՍՋՁՆԿԹՆԞԿՁՄԽՆՌ԰ԩԻՇՄՍՅՆՀՇՏԽՎԽՊԣԢԱԞԵՋՇՄՍՌՁՇՆՏԹՋՆՇ ՌՍՋԽԼԹՋՌՀԽԼՁՄՍՌՁՇՆՏԹՌԽՊՋՇՍՊԻԽ

ՁՆՌՀՁՋԹՋՋԹՑ

ԦԦ ԯԢԣԢԯԢԫԠԢ԰

ԞՆՃՄԽՑԤԱԧԽՆՋԽՆԨԪԨԹՀՄ ԪԡԨՇՊՌԽԧԧԹՆԼԪԹՃՑՆԽ ՆԢԞԡԽՋԻՊՁՈՌՁՇՆԹՆԼԽՎԹՄՍԹՌՁՇՆ

ՇԾԹՋՀՇՊՌՌԽՊՅՊԽՈՊՇԼՍԻՌՁՇՆՌԽՋՌՏՁՌՀՌՀԽԾԹՌՀԽԹԼՅՁՆՆՇՏ
ԭՁՅԽ ՈՀԹՄԽՋՈՊՇՅԽՄԹՋԢՆՎՁՊՇՆԱՇՐՁԻՇՄԠՀԽՅ



ԞԭԥԞ ԞԴԴԞ ԴԭԠԣ  ԰ՌԹՆԼԹՊԼ ԪԽՌՀՇԼՋ ԾՇՊ ՌՀԽ ԢՐԹՅՁՆԹՌՁՇՆ ՇԾ  ԴԹՌԽՊ ԹՆԼ ԴԹՋՌԽՏԹՌԽՊ ՌՀ

ԢԼՁՌՁՇՆԴԹՋՀՁՆԿՌՇՆԡԠ

Ԟ԰ԱԪ  ԠՇՅՅՁՌՌԽԽ Ԣ ՇՆ ԟՁՇՄՇԿՁԻԹՄ ԢԾԾԽԻՌՋ ԹՆԼ ԢՆՎՁՊՇՆՅԽՆ ՌԹՄ ԣԹՌԽ ԰ՌԹՆԼԹՊԼ ԤՍՁԼԽ ԾՇՊ

ԠՇՆԼՍԻՌՁՆԿԢԹՊՄՑԩՁԾԽ԰ՌԹԿԽԱՇՐՁԻՁՌՑԱԽՋՌՋՏՁՌՀԣՁՋՀԽՋԞ԰ԱԪԡԽՋՁԿՆԹՌՁՇՆԢԞՅԽՊՁԻԹՆ԰ՇԻՁԽՌՑ

ԾՇՊԱԽՋՌՁՆԿԹՆԼԪԹՌԽՊՁԹՄՋԟԹՊՊԥԹՊԺՇՊԡՊՁՎԽԭԬԟՇՐԠԴԽՋՌԠՇՆՋՀՇՀՇԻՃԽՆԭԽՆՆՋՑՄՎԹՆՁԹ

ԦՎԽՋԪՁԻՀԹԽՄԠԢԱԦ԰ԠՇՅՈՊԽՀԽՆՋՁՎԽԢՆՎՁՊՇՆՅԽՆՌԹՄԱՇՐՁԻՁՌ ՑԦՆԾՇՊՅԹՌՁՇՆ԰ՑՋՌԽՅգԲՋԽՊ	ՋԤՍՁԼԽ

ԱՁԼԽՈՇՇՄ԰ԻՁԽՆՌՁԾՁԻ԰ՇԾՌՏԹՊԽԪԻԨՁՆՄԽՑՎՁՄՄԽԠԹՄՁԾՇՊՆՁԹԪՇՍՆՌ ԡԦԹՆԼԴԞԟՊՍՆԿՋԞՋՁՅՈՄՁԾՁԽԼ

ԼՇՋՁՆԿԹՈՈԹՊԹՌՍՋԾՇՊԾՁՋՀՌՇՐՁԻՇՄՇԿՑՋՌՍԼՁԽՋԴԹՌԽՊԯԽՋԽԹՊԻՀ 

԰ՈՊԹԿՍԽ ԧԟ  ԪԽԹՋՍՊԽՅԽՆՌ ՇԾ ՈՇՄՄՍՌԹՆՌ ՌՇՐՁԻՁՌՑ ՌՇ ԾՁՋՀ   ԟՁՇԹՋՋԹՑ ՅԽՌՀՇԼՋ ԾՇՊ ԹԻՍՌԽ ՌՇՐՁԻՁՌՑ

ԴԹՌԽՊԯԽՋ

ԬԢԠԡ 
ԣՁՋՀ԰ՀՇՊՌ ԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑԬԢԠԡԤՍՁԼԽՄՁՆԽ ԾՇՊՌՀԽՌԽՋՌՁՆԿԠՀԽՅՁԻԹՄՋԱԽՋՌ

ԫՇԭԹՊՁՋԣՊԹՆԻԽՈՈ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ Բ԰ ԢԭԞ   Ԡԣԯ ԭԹՊՌ  ԣԽԼԽՊԹՄ ԦՆՋԽԻՌՁԻՁԼԽ ԣՍՆԿՁԻՁԼ Խ ԹՆԼ ԯՇԼԽՆՌՁԻՁԼԽ ԞԻՌ ԤՇՇԼ

ԩԹԺՇՊԹՌՇՊՑ ԭՊԹԻՌՁԻԽՋ ԰ՌԹՆԼԹՊԼՋ ԣՁՆԹՄ ԯՍՄԽ ԬԾԾՁԻԽ ՇԾ ՌՀԽ ԣԽԼԽՊ ԹՄ ԯԽԿՁՋՌԽՊ ԫԹՌՁՇՆԹՄ ԞՊԻՀՁՎԽՋ ԹՆԼ

ԯԽԻՇՊԼՋԞԼՅՁՆՁՋՌՊԹՌՁՇՆԲ԰ԤՇՎԽՊՆՅԽՆՌԭՊՁՆՌՁՆԿԬԾԾՁԻԽԴԹՋՀՁՆ ԿՌՇՆԡԠ

Բ԰ԢԭԞ԰ՀՇՊՌՌԽՊՅՅԽՌՀՇԼՋԾՇՊԽՋՌՁՅԹՌՁՆԿՌՀԽԻՀՊՇՆՁԻՌ ՇՐՁԻՁՌՑՇԾԽԾԾՄՍԽՆՌՋԹՆԼՊԽԻԽՁՎՁՆԿՏԹՌԽՊՋ

ՌՇ ՅԹՊՁՆԽ ԹՆԼ ԽՋՌՍԹՊՁՆԽ ՇՊԿԹՆՁՋՅՋ ԱՀՁՊԼ ԽԼՁՌՁՇՆ ԬԾԾՁԻԽ ՇԾ ԴԹՌ ԽՊ Բ ԰ ԢՆՎՁՊՇՆՅԽՆՌԹՄ ԭՊՇՌԽԻՌՁՇՆ

ԞԿԽՆԻՑԴԹՋՀՁՆԿՌՇՆԡԠԢԭԞԯ

Բ԰ԢԭԞԬԾԾՁԻԽՇԾԭՊԽՎԽՆՌՁՇՆԭԽՋՌՁԻՁԼԽՋԹՆԼԱՇՐՁԻ԰ՍԺՋ ՌԹՆԻԽՋԢՆԼՇԻՊՁՆԽԡՁՋՊՍՈՌԽՊ԰ԻՊԽԽՆՁՆԿ

ԭՊՇԿՊԹՅԱԽՋՌԤՍՁԼԽՄՁՆԽԬԠ԰ԭԭԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍ ԻՌՁՇՆԞՋՋԹՑԢԭԞԠ

ԬԻՌՇԺԽՊԲ԰ԢՆՎՁՊՇՆՅԽՆՌԹՄԭՊՇՌԽԻՌՁՇՆԞԿԽՆԻՑԴԹՋՀՁՆԿՌՇՆ ԡԠ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ ԞԭԭԢԫԡԦԵԦԬԲԱԭԲԱԬԣԯԢԳԦԢԴԢԯ0԰԰ԱԞԱԦ԰ԱԦԠԞԩԳԢԯԦԣԦԠԞԱԦԬԫ

Fisher's Exact Test

============================================================================
NUMBER OF

----------------------------------------

IDENTIFICATION ALIVE DEAD TOTAL ANIMALS

-------------------------- ----- ----- ---------------

CONTROL 24 0 24

0.001 20 4 24

----------------------------------------------------------------------------

TOTAL 44 4 48

============================================================================

Critical Fisher's value (24,24,24) (alpha=0.05) is 19.0. b value is 20. Since b is greater than 19.0 there is no significant difference

between CONTROL and TREATMENT at the 0.05 level.

Fisher's Exact Test

============================================================================
NUMBER OF

----------------------------------------

IDENTIFICATION ALIVE DEAD TOTAL ANIMALS

-------------------------- ----- ----- ---------------

CONTROL 24 0 24

0.0093 18 6 24

----------------------------------------------------------------------------

TOTAL 42 6 48

============================================================================

Critical Fisher's value (24,24,24) (alpha=0.05) is 19.0. b value is 18. Since b is less than or equal to 19.0 there is a significant difference

between CONTROL and TREATMENT at the 0.05 level.

Summary of Fisher's Exact Tests

---------------------------------------------------------------------------- NUMBER NUMBER SIG

GROUP IDENTIFICATION EXPOSED DEAD 0.05

----- ------------------------- ----------- ----------- ----- CONTROL 24 0

1 0.001 24 4

2 0.0093 24 6 *

----------------------------------------------------------------------------

Test for fish screen study - Phosmet ANALYSIS RESULTS FOR VARIABLE VAR01 ( F body weight (g) )

TESTS OF ASSUMPTIONS FOR PARAMETRIC ANALYSIS

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ 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

0.934 0.421 0.388 0.689 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.51 0.11 0.06 7.43 1.33, 1.69
Dose1 4 1.55 0.16 0.08 10.44 1.29, 1.81
Dose2 4 1.33 0.19 0.10 14.35 1.03, 1.63

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

Ctrl 1.52 1.40 1.61 . .

Dose1 1.54 1.39 1.75 102.58 -2.58

Dose2 1.29 1.15 1.59 87.85 12.15

******************************************************************************** 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 2.26 0.160

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 1.51 . 1.53 . . . . . .

Dose1 1.55 0.916 1.53 0.654 . . . . .

Dose2 1.33 0.226 1.33 0.084 0.170 . . . .

******************************************************************************** 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 4.19 0.123

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 1.52 . .

Dose1 1.54 0.889 0.614

Dose2 1.29 0.156 0.054

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet 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

0.897 0.146 1.040 0.392 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 3.18 0.59 0.30 18.62 2.23, 4.12
Dose1 4 3.11 0.71 0.36 22.94 1.97, 4.24
Dose2 4 2.69 0.27 0.13 10.03 2.26, 3.12

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

Ctrl 2.94 2.77 4.05 . .

Dose1 2.96 2.41 4.10 97.80 2.20

Dose2 2.77 2.31 2.90 84.61 15.39

******************************************************************************** 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 0.90 0.440

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 3.18 . 3.18 . . . . . .

Dose1 3.11 0.977 3.11 0.508 . . . . .

Dose2 2.69 0.393 2.69 0.156 0.559 . . . .

******************************************************************************** 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 2.92 0.232

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 2.94 . .

Dose1 2.96 0.889 0.614

Dose2 2.77 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)

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

0.958 0.749 0.033 0.968 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 51.25 1.26 0.63 2.46 49.25, 53.25
Dose1 4 52.00 1.41 0.71 2.72 49.75, 54.25
Dose2 4 51.00 1.41 0.71 2.77 48.75, 53.25

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

Ctrl 51.00 50.00 53.00 . .

Dose1 51.50 51.00 54.00 101.46 -1.46

Dose2 51.50 49.00 52.00 99.51 0.49

******************************************************************************** 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 0.58 0.578

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 51.25 . 51.63 . . . . . .

Dose1 52.00 0.666 51.63 0.734 . . . . .

Dose2 51.00 0.952 51.00 0.504 0.574 . . . .

******************************************************************************** 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 0.80 0.671

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 51.00 . .

Dose1 51.50 0.467 0.822

Dose2 51.50 1.000 0.561

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

0.905 0.184 1.641 0.247 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 62.25 2.22 1.11 3.56 58.72, 65.78
Dose1 4 62.75 5.12 2.56 8.16 54.60, 70.90
Dose2 4 62.25 1.89 0.95 3.04 59.24, 65.26

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

Ctrl 62.00 60.00 65.00 . .

Dose1 61.50 58.00 70.00 100.80 -0.80

Dose2 61.50 61.00 65.00 100.00 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

2 9 0.03 0.972

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 62.25 . 62.50 . . . . . .

Dose1 62.75 0.969 62.50 0.626 . . . . .

Dose2 62.25 1.000 62.25 0.618 0.977 . . . .

******************************************************************************** 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 0.04 0.980

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 62.00 . .

Dose1 61.50 1.000 0.442

Dose2 61.50 1.000 0.530

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet 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

0.869 0.063 2.862 0.109 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1440000 518716.4 259358.2 36.02 614606.5, 2265393
Dose1 4 950000.0 574224.1 287112.1 60.44 36281.29, 1863719
Dose2 4 1430000 1600458 800229.1 111.92 -1116686, 3976686

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

Ctrl 1350000 960000.0 2100000 . .

Dose1 1070000 160000.0 1500000 65.97 34.03

Dose2 740000.0 440000.0 3800000 99.31 0.69

******************************************************************************** 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 0.30 0.749

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 1440000 . 1440000 . . . . . .

Dose1950000.0 0.732 1190000 0.438 . . . . .

Dose2 1430000 1.000 1190000 0.467 0.791 . . . .

******************************************************************************** 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 1.42 0.491

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 1350000 . .

Dose1 1070000 0.346 0.124

Dose2 740000.0 0.494 0.153

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet 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

0.672 <.001 8.295 0.009 USE NON-PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 27478.00 44186.91 22093.45 160.81 -42833.2,97789.23
Dose1 4 8064.75 9220.67 4610.33 114.33 -6607.39,22736.89
Dose2 4 350353.0 699764.8 349882.4 199.73 -763129, 1463835

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

Ctrl 8450.00 12.00 93000.00 . .

Dose1 8046.50 66.00 16100.00 29.35 70.65

Dose2 665.00 82.00 1400000 1275.03 -1175.03

******************************************************************************** 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 0.90 0.439

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 27478.00 . 128631.9 . . . . . .

Dose1 8064.75 0.997 128631.9 0.722 . . . . .

Dose2350353.0 0.453 128631.9 0.756 0.485 . . . .

******************************************************************************** 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 0.04 0.981

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 8450.00 . .

Dose1 8046.50 1.000 0.500

Dose2 665.00 0.889 0.500

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

0.943 0.538 0.989 0.409 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 12.50 1.91 0.96 15.32 9.45, 15.55
Dose1 4 11.30 3.22 1.61 28.48 6.18, 16.42
Dose2 4 8.23 3.26 1.63 39.66 3.03, 13.42

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

Ctrl 12.00 11.00 15.00 . .

Dose1 11.50 7.20 15.00 90.40 9.60

Dose2 8.60 4.70 11.00 65.80 34.20

******************************************************************************** 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 2.36 0.149

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 12.50 . 12.50 . . . . . .

Dose1 11.30 0.784 11.30 0.339 . . . . .

Dose2 8.23 0.112 8.23 0.039 0.329 . . . .

******************************************************************************** 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 3.93 0.140

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 12.00 . .

Dose1 11.50 0.775 0.328

Dose2 8.60 0.135 0.028

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

0.874 0.074 0.161 0.854 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 1.33 0.32 0.16 24.16 0.82, 1.83
Dose1 4 1.45 0.38 0.19 26.11 0.85, 2.05
Dose2 4 1.29 0.26 0.13 20.27 0.87, 1.71

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

Ctrl 1.20 1.10 1.80 . .

Dose1 1.30 1.20 2.00 109.43 -9.43

Dose2 1.35 0.96 1.50 97.36 2.64

******************************************************************************** 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 0.27 0.769

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 1.33 . 1.39 . . . . . .

Dose1 1.45 0.811 1.39 0.692 . . . . .

Dose2 1.29 0.983 1.29 0.551 0.770 . . . .

******************************************************************************** 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 0.54 0.764

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 -1.20 . .

Dose1 -1.30 0.467 0.178

Dose2 -1.35 1.000 0.380

INCREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. GREATER THAN CONTROL Williams >highest dose (no sign. differences) Jonckheere >highest dose (no sign. differences)

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

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

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet
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

0.953 0.686 1.098 0.374 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 26.00 2.94 1.47 11.32 21.32, 30.68
Dose1 4 29.50 5.00 2.50 16.95 21.54, 37.46
Dose2 4 12.50 6.45 3.23 51.64 2.23, 22.77

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

Ctrl 25.50 23.00 30.00 . .

Dose1 27.00 27.00 37.00 113.46 -13.46

Dose2 15.00 3.00 17.00 48.08 51.92

******************************************************************************** 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 12.84 0.002

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 26.00 . 27.75 . . . . . .

Dose1 29.50 0.534 27.75 0.769 . . . . .

Dose2 12.50 0.008 12.50 0.002 0.003 . . . .

******************************************************************************** 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 8.46 0.015

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 25.50 . .

Dose1 27.00 0.225 0.930

Dose2 15.00 0.067 0.052

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2 Jonckheere >highest dose (no sign. differences)

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet 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

0.904 0.180 2.959 0.103 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 15.85 6.95 3.48 43.87 4.78, 26.92
Dose1 4 19.00 12.91 6.45 67.95 -1.54, 39.54
Dose2 4 3.01 2.35 1.17 78.05 -0.73, 6.74

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

Ctrl 17.50 6.40 22.00 . .

Dose1 14.00 10.00 38.00 119.87 -19.87

Dose2 2.55 0.83 6.10 18.97 81.03

******************************************************************************** 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 3.91 0.060

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 15.85 . 17.43 . . . . . .

Dose1 19.00 0.827 17.43 0.687 . . . . .

Dose2 3.01 0.110 3.01 0.039 0.064 . . . .

******************************************************************************** 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 7.38 0.025

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 17.50 . .

Dose1 14.00 1.000 0.500

Dose2 2.55 0.067 0.010

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ test for fish screen study - Phosmet 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

0.987 0.998 3.109 0.094 USE PARAMETRIC TESTS

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

BASIC SUMMARY STATISTICS

Level N Mean StdDev StdErr Coef of Var 95% Conf.Interval
Ctrl 4 97.00 2.16 1.08 2.23 93.56, 100.44
Dose1 4 95.75 1.89 0.95 1.98 92.74, 98.76
Dose2 4 90.25 4.79 2.39 5.30 82.63, 97.87

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

Ctrl 96.50 95.00 100.00 . .

Dose1 96.50 93.00 97.00 98.71 1.29

Dose2 90.00 85.00 96.00 93.04 6.96

******************************************************************************** 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 4.97 0.035

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 97.00 . 97.00 . . . . . .

Dose1 95.75 0.810 95.75 0.356 . . . . .

Dose2 90.25 0.029 90.25 0.009 0.090 . . . .

******************************************************************************** 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 5.10 0.078

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 96.50 . .

Dose1 96.50 0.775 0.328

Dose2 90.00 0.125 0.016

DECREASING TREND TEST SUMMARY LOWEST CONCENTRATION SIGNIF. LESS THAN CONTROL

Williams Dose2

Jonckheere Dose2

Male tubercle score (exact Mann-Whitney)



### Obs conc endpoint

1 

## 0 23

2 

## 0 30

3 

## 0 26

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ

ԭԹԿԽՇԾ 

### Obs conc endpoint

4 

## 0 25

5 

## 1 37

6 

## 1 27

7 

## 1 27

8 

## 1 27

9 

## 2 17

10 

## 2 16

11 

## 2 14

12 

## 2 3

13 

## 3

.

14 

## 3

.

15 

## 3

.

16 

## 3

.

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ 

### Wilcoxon Scores (Rank Sums) for Variable end point Classified by Variable conc

conc N Sum
of

Scor

es Expected
Under H0 Std Dev
Under H0 Mean

Score

0 

## 4 29.0 26.0 5.846522 7.250

1 

## 4 39.0 26.0 5.846522 9.750

2 

## 4 10.0 26.0 5.846522 2.500

Average scores were used for ties.

Kruskal-Wallis Test

Chi-Square 

## 8.4645

DF 

## 2

Asymptotic Pr > Chi-Square 

## 0.0145

Exact Pr >= Chi-Square 

## 0.0017

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ 

### Wilcoxon Scores (Rank Sums) for Variable endpoint Classified by Variable conc

conc N Sum of

Scores Expected
Under H0 Std Dev
Under H0 Mean

Score

0 

## 4 13.0 18.0 3.380617 3.250

1 

## 4 23.0 18.0 3.380617 5.750

Average scores were used for ties.

Kruskal-Wallis Test

Chi-Square 

## 2.1875

DF 

## 1

Pr > Chi-Square 

## 0.1391

Wilcoxon Two-Sample Test

Statistic (S) 

## 13.0000

Normal Approximation

Z 

## -1.3311

One-Sided Pr < Z 

## 0.0916

Two-Sided Pr > |Z| 

## 0.1832

t Approximation

One-Sided Pr < Z 

## 0.1124

Two-Sided Pr > |Z| 

## 0.2249

Exact Test

One-Sided Pr <= S 

## 0.1000

Two-Sided Pr >= |S - Mean| 

## 0.2000

Z includes a continuity correction of 0.5.

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ 

### Wilcoxon Scores (Rank Sums) for Variable endpoin

t Classified by Variable conc

conc N Sum of

Scores Expected
Under H0 Std Dev
Under H0 Mean

Score

0 

## 4 26.0 18.0 3.464102 6.50

2 

## 4 10.0 18.0 3.464102 2.50

Wilcoxon Two-Sample Test

Statistic (S) 

## 26.0000

Normal Approximation

Z 

## 2.1651

One-Sided Pr > Z 

## 0.0152

Two-Sided Pr > |Z| 

## 0.0304

t Approximation

One-Sided Pr > Z 

## 0.0336

Two-Sided Pr > |Z| 

## 0.0671

Exact Test

One-Sided Pr >= S 

## 0.0143

Two-Sided Pr >= |S - Mean| 

## 0.0286

Z includes a continuity correction of 0.5.

Kruskal-Wallis Test

Chi-Square 

## 5.3333

DF 

## 1

Pr > Chi-Square 

## 0.0209

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ

## ԡԹՌԹԢՎԹՄՍԹՌՁՇՆԯԽԻՇՊԼՇՆ ՌՀԽԣՁՋՀ԰ՀՇՊՌԱԽՊՅԯԽՈՊՇԼՍԻՌՁՇՆԞՋՋԹՑՏՁՌՀԭՀՇՋՅԽՌ

ԢԭԞԪԯԦԡԫՍՅԺԽՊ



## The NPAR1WAY

Procedure

ԭԹԿԽՇԾ

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CSPP 890.1400, In vivo Hershberger Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618706)

Prepared for

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

Arlington, VA 22202

Prepared by Dynamac Corporation

1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Rebecca Bryan, B.S

. Date: 12 / 20 /2011

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 1/03/2012

Program Manager: Signature: Jack D. Early, M.S. Date: 1/04/2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 1/04/2012

This Data Evaluation Record may have been altered by the Health Effects Division subsequent to signing by 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 streng ths 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 bu t 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).

### PHOSMET/059201



## Primary Reviewer: Greg Akerman, Ph.D.



## Health Effects Division Secondary Reviewer: John 

## Liccione. Ph .D.



## Health Effects Division /11 

### vivo Hershberger Assay (20 11) / Page I of 13

OCSPP 890.1400/ OECD 441



## Signature: _e,;.......,..1£.9,,........:::.L...---



## Da**te: ,,.--....;~""-~~!...,.._­**  

## Signature:**::::zS~~==~z:=** 

## Date:**=-~'64~..+--!'-.;2---**



## DATA EVALUATION RECORD

STUDY TYPE: In Vivo 

## Hershberger Assay (Rat) ; OCSPP 890.1400; OECD 441



## PC CODE: 059201 

## DP BARCODE: D397165



## TXR#: 0056199 

## CAS#: 732-11-6



## TEST MATERIAL (PURITY): Phosm et (96.8% a.i.)



## SYNONYMS: 

## 0

, 0-dimethy l S-phthalimidomethylphosphorodithioate



## CITATION: Zorrilla, L. (2011 ). The Hershber ge r assay with phosmet in castrated CRL:CD(SD) IGS Rats. Integrated Laboratory Systems

, Inc.

, Durham, NC. Laboratory Project Study ID: C 194-200, October 26

, 2011. MRID 48618706. Unpub lished

.



## SPONSOR: Gowan Company, P.O. Box 5569, Yuma

, AZ



## TEST ORDER#: EDSP -059 201 -54



## EXECUTIVE SUMMARY: The Hershberger Assay consists of androgenic and antiandrogenic components. To screen for potential androgenic activity

, phosmet (96.8% a.i., Batch

# 6QH9118000) in 0.5% aqueous carboxymethyl cellulose was administered daily via oral

gavage to 59- to 60-day old

, castrated male Sprague Dawley rats (8/dose group) at dose levels of

0 (vehi cle)

, 5 or 25 mg/kg/day. An 

## androgenic positive control g roup cons i sted of 10 castrated

rats dosed by su bcutaneous injection with 0.4 mg/kg/day testosterone propionate (TP) prepared

in com oil.

To sc reen for potential anti-androgenic activity ph os met (96.8% a.i., Batch# 6QH91l8000) in

0.5% aqueous carboxymethyl cellulose was administered daily via oral gavage to 59 to 60-day
old, castrated male Sprague Dawley rats (8/dose group) at dose l evels ofO (vehicle)

, 5, 15

, or 25 mg/kg / day in conjunction with a daily dose of reference androgen TP at 0.4 mg/k g/day by

s ubcutan eous injection. An 

## anti-androgenic positi ve control group consisted of 10 castrated rats exposed to 0.4 mg/kg / day TP and 3.0 mg/k g/ day flutamide (FT). Flutamide and TP were prepared in com oil.

For both components of the assay
, the animals were dosed for 10 consecutive day s and necropsied approximately 24 hours after the final dose administration to determine weights of

the five androgen-dependent ti ssues.In vivo Hershberger Assay (2011 ) / Page 2 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## All animals survived until scheduled termination. Cholinergic signs (tremors) and a 12% decrease in terminal bodyweight was seen at 25 mg/kg/day suggesting that the high dose may

have been excessive.

In the androgen agonist assay, clinical signs in the 25 mg/kg/day group included tremors,
uncoordinated movements and porphyrin staining around the eyes. No clinical signs were observed in the 5 mg/kg/day group. Body weights in the 5 and 25 mg/kg/day groups were comparable to controls throughout the duration of the assay. At 25 mg/kg/day, mean overall (Days 1 -11) body weights gains were decreased (p≤0.05) by 69%. Animals dosed with 0.4 mg/kg/day TP had increased (p≤0.05) mean body weights of 12% on Day 11, and increased

mean overall body weight gains (p≤0.05) of 105% . There were no significant increases in the

access ory sex organ weights in animals dosed with the test compound. Animals in the 0.4 mg/kg/day TP group had accessory sex organ weight increases (p≤0.05) as follows: 1926% in seminal vesicles; 1264% in ventral prostate; 251% in levator ani -bulbocavernosus ( LABC) ; 794% in Cowper’s gland; and 72% in glans penis. All tissue weight CVs were below the maximum values recommended by the test guideline. The performance criteria indicated that this assay was performing as expected

.

In the anti-androgen assay, clinical signs in the 25 mg/kg/day group included tremors, and

uncoordinated movement s. No clinical signs were observed in the 5 or 15 mg/kg/day group s. At

25 mg/kg/day, mean body weights were decreased (p≤0.05) by 12% on Day 11, and overall body weight gains were decreased (p≤0.05) by 60%. There were no effects on body weights or body weight gains in the 5 and 15 mg/kg/day group, or the positive control group. At 15 mg/kg/day, the weights of seminal vesicles were de creased 25% (p≤0.05 ). At 25 mg/kg/da y, accessory sex organ weight decreases (p≤0.05) were noted as follows: 50% in seminal vesicles; 40% in ventral prostate; 27% in LABC; 34% in Cowper’s gland; and 10% in glans penis. Animals dosed with 0.4 mg/kg/day TP + 3 mg/kg/day FT had decreased (p≤0.05) accessory sex organ weights as follows: 85% in seminal vesicles; 76% in ventral prostate; 50% in LABC; 66% in Cowper’s gland; and 21% in glans penis. All tissue weight CVs were below the maximum values recommended by the test guideline. The per formance criteria indicated that this assay was performing as expected.

Phosmet was negative for androgenic activity as n o statistically significant increases in organ weights were seen in two or more of the five androgen sensitive tissues in the androg en agonist

assay. However, phosmet was positive for anti- androgenicity in the Hershberger assay as

s tatistically significant decreases in organ weights were seen in all five androgen sensitive tissues in the androgen antagonist assay. However, the decreases in androgen

- sensitive tissue weights were seen at a dose (25 mg/kg/day) that resulted in overt toxicity (12% decrease in body weight and clinical signs), which confounds the interpretation of the results. .

Th e assay satisfies the EDSP Tier 1 Test Or der requirement s for a Hershberger a ssay (OCSPP 890.1400).

COMPLIANCE : Signed and dated GLP Compliance and Quality Assurance statements were provided.In vivo Hershberger Assay (2011 ) / Page 3 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Integrated Laboratory Systems, Inc.

Location: Durham, NC Study Director: L. Zorrilla

Other Personnel: Not provided Study Period: April 28, 2011

- May 9, 2011



## 2. Test Substance : Phosmet

Description: Off white solid

Source: Gowan Company (commercial technical product)

Batch #: 6QH9118000, expires January 31

, 201 2 Purity: 96.8 % Stability: Stable in the vehicle for up to 11 days at 2

- 8 ° C.

CAS #: 732

- 11

- 6

Structure:



## 3

. Reference Androgen : Testosterone propionate (TP)

Supplier : Sigma

- Aldrich Company (St

. Louis, MO)

Lot #: 048K1328 Purity: 100.2 % , expires March 17, 2012

CAS # : 57

- 85

- 2



## 4

. Reference Anti

- androgen : Flutamide ( FT )

Supplier : Sigma

- Aldrich Company (St. Louis, MO)

Lot #: 107K1293 Purity: >99 %

CAS # : 13311

- 84

- 7



## 5

. Solvent/Vehicle Control (Phosmet) : Carboxymethyl cellulose (in sodium phosphate buffer )

Supplier : Sigma

- Aldrich Company (St. Louis, MO)

Lot #: 100M0113
Rationale (if other than water) : CMC (0.5%) was the vehicle used in several sponsor studies where th

test substance was administered by gavage.

Final concentration : 0.5%



## 6. Solvent/Vehicle Control ( Testosterone propionate and Flutamide) : Corn Oil

Supplier : MP Biomedicals, LLC (Solon, OH)

Lot/Batch #: 7862K
Rationale (if other than water) : Not provided

. Final concentration : Not app licableIn vivo Hershberger Assay (2011 ) / Page 4 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## 7

. Test Animals :
Species: Rat (castrated males)

Strain: Sprague Dawley (Crl:CD[SD]) Age/weight at dose initiation: Post

- natal day (PND ) 59

- 60; 240.0

- 313.5 g
Source : Charles River Laboratories International , Inc.

, Raleigh, NC Housing: 2 /cage in polycarbonate cages with absorbent heat

- treated hardwood bedding (Northeastern P ro ducts Corp., Warrensburg, NY)

Diet: Tekla d Global 16% Protein Rodent Diet ( Teklad Diets, Madison, WI)

, ad libitum ; low phytoestrogen wi th total geinstein equivalents

= 6.2 μg/g diet

. Water: Reverse osmosis treated t ap water, ad libitum

Environmental conditions: Temperature: Humidity: Air changes: Photoperiod: 22

- 26 oC

33

- 48 % Not provided

12 hrs light/ 12 hrs dark Acclimation period: 10 days at test facility



## B. STUDY DESIGN

1. In life dates : Start: 4/28/11 End: 5/9/11

2. Study Design : The present Hershberger Assay was conducted to screen for both potential

anti

- androgenic and androgenic activity . T he test substance was administered daily via oral

gavage to groups of castrated male rats both without TP (androgenic activity) and with a daily dose of TP (0.4 mg/kg/day) by s ubcutaneous injection (anti

- androgenic activity)

. 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 TP-only control group. Positive androgenic activity is defined as a significant increase in two or

more organ weights compared to the vehicle control. 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 : Following a 10- day ac climation period at the test facility , castrated male rats (surgical manipulation performed by Supplier at PND 42) were administered the test

substance from PND 59-60 to PND 68-69. Rats were euthanized on PND 69-70, approximately 24 hours after the last dose and necropsied for organ weight measurements.

4. Animal Assignment : Animals were randomly 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.In vivo Hershberger Assay (2011 ) / Page 5 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441

Table 1. Study design a
Test group Dose (mg/kg/day) # of Males
Androgen Agonist Assay
Vehicle control ( 0.5% CMC ) 0 8

Low 5 8 High 25 8
Positive control (0.5% CMC) +TP b 0.4 8

Anti

- Androgen Assay
Vehicle control (0.5% CMC) +TP b 0 8
Low (+TP) 5 8
Mid (+TP) 15 8 High (+TP) 25 8 Flutamide (oral gavage) + TP (s.c.), positive control 3 8

a Data were obtained from Tables 1 and 2 on page 17 of the study report.

b Same animals dosed for both androgen agonist (serves as positive control) and anti

- androgen (served as vehicle control)

assays



### . This did not affect the outcome or conclusions of this study.



## 5. Dose Selection Rationale : The pho smet dose levels were selected based on the results from an acute oral gavage study (MRID 46593101), repeated -dose studies (MRIDs 44811801, 41520001, and 41916401), and a non- GLP six week range -finding study (no MRID or study number). Mortality was observed in ≥ 75 mg/kg treatment groups for the acute study. No mortality was observed in the repeated -dose dietary studies conducted at doses of up to 98.3 mg/kg/day. C holinergic clinical signs were observed in 36 mg/kg males

in the acut e oral gavage study; however , no effects were observed at 22.5 mg/kg. In the range finding study, no cholinergic effects were observed for dietary doses up to 49.2 mg/kg/day and body weights were reduced 11.2% at 22.5 mg/kg/day. Based on these results, doses of 0, 5 and 25 mg/kg/day were used for both the androgen agonist and antiandrogen assays

.

6. (a) Dose Preparation : Dose formulations were prepared once prior to initiation of

treatment and twice during treatment by initially suspending the appropriate amounts of test

su bstance in 0.5% aqueous carboxymethyl cellulose

. Flutamide and TP were prepared daily

as solutions in corn oil. Homogeneity and concentration analyses were performed on all

dose formulations . Stability analyses were perform ed on 1.00, 3.00, and 5.00 mg a.i. /mL formulations prior to administration following storage at 2-8°C for up to 8 days.

In a previous storage stability study 1 

## , phosmet (lot number not reported) was determined to

be stable in the 0.5% aqueous carboxymethyl cellulose for up to 11 days (temperature not reported).

1 

### Reibach, R . 2011

. Storage Stability of Phosmet in 0.5% Aqueous Carboxymethylcellulose. Unpublished study report prepared by Smithers Viscient Inc., Study No. 12791

- 6139.In vivo Hershberger Assay (2011 ) / Page 6 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## ( b ) Dose Analysis

Results

Homogeneity (%CV): 2.45-5.45%

Stability (% of Day 0): 98-104% following storage for up 8 days at 2-8° C.

Concentration (% of nominal): 87-105%

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 administration : Test formulations were administered to the animals daily via oral gavage (5 mL/kg bw) for 10 days. TP was given via s.c. injection at 0.5 mL/kg bw, and FT was administered via oral gavage at 5 mL/kg bw. Dose volumes were adjusted daily based on the concurrent body weight measurement.

8. Statistics : Body weights, body weight gains and accessory sex organ weights were analyzed using studentized residual plots for outliers and Levene’s test for homogeneity of variance. Heterogeneous data (glans penis weights) were transformed and re

- analyzed using

Krus kal -Wallis and Dunn’s test. Body weights, body weight gains, and accessory sex organ weights were analyzed using one

- way ANOVA followed by Dunnett’s t

- test s. The positive controls were compared to the vehicle controls using the t- test. Significance was denoted at

p ≤ 0.05. The statistical analyses were considered adequate.

C. METHODS

1. Clinical Examinations : Animals were checked for mortality or moribundity twice daily on weekdays and once daily on weekends. Rats were also checked for clinical signs of toxicity prior to dose administration and at termination

. If adverse clinical signs were seen,

additional observations were noted.

2. Body Weight : Animals were weighed at randomization, daily prior to dosing throughout the dosing period, and at termination.

3. Food Consumption (Optional) : Food consumption was not determined.

4. Serum Hormone Measurements (Optional) : Serum hormone measurements were not

conducted.

5. Dissection and Measurement of Tissue and Organ Weights : On PND 69-70 (approximately 24 hours after the final administration of the test substance) , all rats were weighed, anesthetized by CO 2 

## inhalation followed by cervical dislocation and subjected to a gross necropsy. The five mandatory androgen-dependent organs (ventral prostate, seminal vesicles with coagulating glands and fluid, 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 Guidelin e (O CSPP 890.1400).In vivo Hershberger Assay (2011 ) / Page 7 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## II. RESULTS

A. OBSERVATIONS

1. Mortality : All animals survived until scheduled termination.

2. Clinical signs of toxicity : In the androgen agonist assay , clinical signs at 1 -4 hours after dosing included one 25 mg/kg/day rat with tremors on Days 3-9 and the same animal

showed uncoordinated movement on Days 4 and 5. Six other 25 mg/kg/day rats also

exhibited tremors 1-4 hours post-dose on Days 3-9 (7 total rats). At 24 hours after dosing, one 25 mg/kg/day rat exhibited porphyrin staining around the eyes on Day 9. No clinical signs were observed in the 5 mg/kg/day group.

Table 2. Incidence of Clinical Observations in the Androgen Agonist Assay a ,b



### Observation Dose (mg/kg/day)

Vehicle Control Positive Control

Vehicle + TP (0.4) b 5 25

#

Obs. #

Exam #

Obs. #

Exam #

Obs. #

Exam #

Obs. #

Exam 

### Porphyrin

staining around eyes 0 8 0 8 0 8 1 8

a Data were obtained from page 83 of the study report.

b The observations of tremors were reported on page 21 of the study report but were not included in the clinical observation tables in the appendices.

# Obs. = number of observed incidences.

# Exam = number of animals examined.



## In the anti- androgen assay, clinical signs at 1 -4 hours after dosing included one

25 mg/kg/day rat wit h tremors on Day s 3 and 7 and uncoordinated movement on Day 3. Another 25 mg/kg rat exhibited tremors on days 3-9 and uncoordinated movement on day 5. Six other 25 mg/kg/day rats also exhibited tremors between Days 4 and 8. At 24 hours after dosing, no clinical signs were observed in any dose group. No clinical signs were observed

in the 5 or 15 mg/kg/day group s.

Table 3. Incidence of Clinical Observations in the Anti

- Androgen Assay a



### Observation Dose (mg/kg/day)

Vehicle

Control

+ TP (0.4) b TP + FT

Positive

Control 5 15 25

#

Obs. #

Exam #

Obs. #

Exam #

Obs. #

Exam #

Obs. #

Exam #

Obs. # Exam



### None

a Data were obtained from page 84 of the study report.

b The observations of tremors were reported on page 22 of the study report but were not included in the clinical observation tables in the appendices.

# Obs. = number of observed incidences.

# Exam = number of animals examined.In vivo Hershberger Assay (2011 ) / Page 8 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## B. BODY WEIGHT AND WEIGHT GAIN : Selected body weight and body weight gain data are presented in Table 4 for the agonist assay. Body weights in the 5 and 25 mg/kg/day groups were comparable to controls throughout the duration of the assay. At 25 mg/kg/day, mean overall (Days 1

- 11) body weights gains were decreased (p≤0.05) by 69%. Animals dosed with 0.4 mg/kg/day TP had a mean body weight increase (p≤0.05) of 12% on Day 11,

and increased (p≤0.05) mean overall body weight g ains of 105%.

Table 4 . Selected Group Mean (±S E ) 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 ) b Phosmet 5 Phosmet 25

N Mean S D N Mean S D N Mean S D N Mean S D

1 8 274.0 19.2 8 276.6 17.2 8 276.7 19.0 8 275.4 19.5

4 8 282.2 21.5 8 298.8 18.3 8 284.9 22.0 8 278.8 21.6

7 8 290.3 23.0 8 314.9 23.5 8 29 5 .9 23.5 8 280.3 19.8

11 8 305.1 28.0 8 340.5 * (↑12) 28.5 8 311.5 27.6 8 285.1 19.7

BWG (days 1

- 11) 8 31.1 12.3 8 63.9 * (↑105) 11.9 8 34.8 11.3 8 9.7 * (↓69) 10.7

a D ata were obtained from Table s 6 on page 23 and Appendix V on page s 92

- 93 of the study report . Percent differences from

controls were calculated by the reviewers and included in parentheses.

b The positive control group for the androgen agonist assay is same as the vehicle control group for the anti

- androgen assay.

This did not affect the outcome or conclusions of this study.

N = Number of animals in the group

SE= Standard Deviation

* Significantly different from vehicle controls at p<0.05

.



## Body weight and body weight gain data for the anti-androge n assay are presented in Table

5. At 25 mg/kg/day, mean body weights were decreased (p≤0.05) by 12% on Day 11, and

mean overall body weight gains were decreased (p≤0.05) by 60 %. There were no effects from phosmet on body weights or body weight gains in the 5 and 15 mg/kg/day group, or in the positive control group.In vivo Hershberger Assay (2011 ) / Page 9 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



### Table 5. Selected Group Mean (±SD) 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) b TP + FT

Positive Control Phosmet 5 Phosmet 15 Phosmet 25

N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD

1 8 276.6 17.2 8 275.5 15.6 8 277.4 18. 5 8 279.8 12.8 8 275.4 14.2

4 8 298.8 18.3 8 292.7 18.7 8 295.8 19.1 8 296.8 15.7 8 282.4 14.7

7 8 314.9 23.5 8 306.2 23.2 8 313. 8 20.1 8 313.8 15.8 8 290.3 12.9

11 8 340.5 28.5 8 329.8 25.2 8 337.4 21.4 8 339.3 17.4 8 301.0 * (↓ 12 ) 17.1

BWG (days 1

- 11) 8 63.9 11.9 8 54.3 26.2 8 60.0 8.8 8 59.5 10.8 8 25.6 * (↓ 60 ) 15.4

a D ata were obtained from Table 7 on pages 24 and Appendix V on pages 93

- 94 of the study report. Percent differences from

controls were calculated by the reviewers and included in parentheses.

b The vehicle control group for the anti

- androgen assay is same as the positive control group for the androgen agonist assay. This did not affect the outcome or conclusions of this study.

N = N umber of animals in the group

SD= Standard Deviation

* Significantly different from vehicle controls at p<0.05

.



## C. FOOD CONSUMPTION (OPTIONAL) : Food consumption was not determined (optional).

D. SERUM HORMONE CONCENTRATIONS (OPTIONAL) : Serum hormone

concentrations were not determined

.

E. ORGAN WEIGHTS : Accessory sex organ weights for the androgen agonist assay are presented in Table 6 for the agonist assay. There were no treatment

- related effects in any of the accessory sex organs of animals dosed with the phosmet. Animals in the 0.4 mg/kg/d ay TP group had accessory sex organ weight increases (p≤0.05) as follows: 1926 % in seminal vesicles; 1264 % in ventral prostate; 251 % in LABC; 794% in Cowper’s gland; and 72 % in glans penis. The CVs for all treatment groups were compared to the performanc e criteria

values as stated in the Guidelines. All %CV values were less than the maximum

recommended values.In vivo Hershberger Assay (2011 ) / Page 10 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



### Table 6 . Accessory Sex Organ Weights (mg) from Androgen Agonist Assay in Sprague

- Dawley Rats a

Organ Dose (mg/kg/day)

Vehicle Control Phosmet 5 Phosmet 25 Positive Control

Vehicle + TP (0.4) b

N Mean SD CV N Mean SD CV N Mean SD CV N Mean SD CV

Seminal

vesicles 8 33.7 3.6 11 8 39.1 9.2 24 8 30.4 3.8 12 8 682.9* (↑ 1926 ) 135.7 20

Ventral

prostate 8 15.5 3.1 20 8 16.1 2.7 17 8 13.2 2.0 15 8 211.4* (↑1264 ) 37.6 18

LABC 8 143.8 14.1 10 8 158.3 21.1 13 8 120.5 19.1 16 8 505.4* (↑251 ) 41.9 8

Cowper’s glands 8 5.1 1.1 21 8 5.6 1.5 27 8 4.8 1.0 22 8 45.6* (↑794 ) 9.6 21

Glans penis 8 47.3 3.6 8 8 49.2 3.6 7 8 44.9 4.4 10 8 81.2* (↑72 ) 8.5 11

a Data were obtained from Table 8 on page 26 of the study report. Percent differences from controls were calculated by the reviewers and included in parentheses.

b The positive control group for the androgen agonist assay is same as the vehicle control group for the anti

- androgen assay.

This did not affect the outcome or conclusions of this study.

N = N umber of animals in the group

SD= Standard Deviation

CV= Coefficient of Variation

* Significantly different from vehicle controls at p<0.05

.



## Accessory sex organ weights for the anti -androge n assay are presented in Table 7

. At 15 mg/kg/day, the weights of seminal vesicles were de creased by 25% (p≤0.05). At 25 mg/kg/day, accessory sex organ weight decreases (p≤0.05) were noted as follows: 50 % in seminal vesicles; 40% in ventral prostate; 27% in LABC; 34% in Cowper’s gland; and 10% in glans penis. Animals dosed with 0.4 mg/kg/day TP + 3 mg/kg/day FT had decreas ed (p≤0.05) accessory sex organ weights as follows: 85 % in seminal vesicles; 76% in ventral prostate; 5 0 % in LABC; 6 6% in Cowper’s gland; and 21% in glans penis. The CVs for all

treatment groups were compared to the performance criteria values as stated in the

Guidelines. All %CV values were less than the maximum recommended values.In vivo Hershberger Assay (2011)/ Page 11 of 13

PHOSMET/059201 OCSPP 890.1400/ OECD 441



### Table 7 . Accessory Sex Organ Weights (mg) from Anti

- Androgen Agonist Assay in Sprague

- Dawley Rats a

Organ Dose (mg/kg/day)

Vehicle Control

+TP (0.4) b Phosmet 5 Phosmet 15 Phosmet 25 TP + FT

Positive Control

N Mean SD CV N Mean SD CV N Mean SD CV N Mean SD CV N Mean SD CV

Seminal

vesicles 8 682.9 135.7 20 8 612.7 123.6 20 8 510.5* (↓25 ) 55.1 11 8 339.4* (↓ 50 ) 60.8 18 8 103.3* (↓85 ) 26.8 26

Ventral

prostate 8 211.4 37.6 18 8 184.8 28.8 16 8 181.9 23.4 13 8 127.6 * (↓ 40 ) 16.0 13 8 50.2 * (↓ 76 ) 10.9 22

LABC 8 505.4 41.9 8 8 515.3 65.0 13 8 465.5 60.9 13 8 367.6 * (↓ 27 ) 39.5 11 8 250.8 * (↓ 50 ) 45.0 18

Cowper’s glands 8 45.6 9.6 21 8 41.5 9.2 22 8 40.0 5.8 15 8 30.2 * (↓ 34 ) 7.1 24 8 15.6 * (↓ 66 ) 1.5 10

Glans penis 8 81.2 8.5 11 8 79.9 3.3 4 8 78.0 5.5 7 8 73.0 * (↓ 10 ) 3.8 5 8 64.5 * (↓ 21 ) 7.4 12

a Data were obtained from Tables 9 on page 27 of the study report. Percent differences from controls were calculated by the reviewers and included in parentheses.

b The vehicle control group for the anti

- androgen assay is same as the positive control group for the androgen agonist assay. This did not affect the outcom e or conclusions of this study.

N = N umber of animals in the group

SD = Standard Deviation

CV= Coefficient of Variation

* Significantly different from vehicle controls at p<0.05.In vivo Hershberger Assay (2011 ) / Page 12 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## F. MACROSCOPIC PATHOLOGY : No gross observations were made at necropsy.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR’S CONCLUSIONS : In the agonist assay, final body weights of animals administered phosmet were not statistically different compared to the vehicle control (0.5% carboxymethylcellulose) animals. Mean body weight gain was significantly

de creased in animals administered 25 mg/kg/day phosmet compared to veh icle control rats.

In addition, cholinergic clinical signs (e.g. tremor s) were observed following dose administration of 25 mg/kg/day phosmet on 7 of 10 days of the study. Phosmet

adminis tered at dose levels of 5 and 25 mg/kg/day to castrated SD male rats did not increase androgen dependent tissue weights.

In the androgen antagonist assay, final animal body weights and mean body weight gain were significantly decreased in rats co

- administered 25 mg/kg/day phosmet and TP compared to control rats. Cholinergic clinical signs were observed following coadministration of 25 mg/kg/day phosmet and TP on 7 of 10 days of the study. Phosmet (25 mg/kg) co

- administered with TP was associated with significant decreases in LABC, glans penis, ventral prostate, Cowper's glands, and seminal ves icle weights, and a decrease in

seminal vesicle w eight with 15 mg/kg/day phosmet and TP compared to the control group (0.5% carboxymethylcellulose and TP). Using the castrated rat model Hershberger Assay,

oral administr ation of phosmet up to 25 mg/kg/day resulted in cholinergic clinical signs and body weight effects, but did not show any androgen agonist ac tivity. Co

- administration of

25 mg/kg/day phosmet a nd TP was also associated with c holinergic clinical signs, body weight effects, and a reduction in androgen -depende nt tissue weights.

B. AGENCY COMMENTS : All animals survived until scheduled termination.

In the androgen agonist assay, clinical signs in the 25 mg/kg/day group included tremors,
uncoordinated movements and porphyrin staining around the eyes. No clinical signs were observed in the 5 mg/kg/day group. Body weights in the 5 and 25 mg/kg/day groups were comparable to controls throughout the duration of the assay. At 25 mg/kg/day, mean overall (Days 1 -11) body weights gains were decreased (p≤0.05) by 69%. Animals dosed with 0.4 mg/kg/day TP had increased (p≤0.05) mean body weights of 12% on Day 11, and increased (p≤0.05) mean overall (Days 1-11) body weight gains of 105%. There were no significant increases in the weights of the five target accessory sex organs of animals dosed with the test compound. Animals in the 0.4 mg/kg/day TP group had accessory sex organ weight increases (p≤0.05) as follows: 1926% in seminal vesicles; 1264% in ventral prostate; 251% in LABC; 794% in Cowper’s gland; and 72% in glans penis. The performance criteria indicated that this assay was performing as expected.

In the anti-androgen assay, clinical signs in the 25 mg/kg/day group included tremors, and

uncoordinated movement s. No clinical signs were observed in the 5 or 15 mg/kg/day

groups. At 25 mg/kg/day, mean body weights were decreased (p≤0.05) by 12% on Day 11,

and decreased (p≤0.05) overall body weigh t gains of 60%. There were no effects on body weights or body weight gains in the 5 and 15 mg/kg/day group, or the positive control

group. At 15 mg/kg/day, the weights of seminal vesicles were de creased 25% (p≤0.05). At 25 mg/kg/day, accessory sex organ weight decreases (p≤0.05) were noted as follows: 50%In vivo Hershberger Assay (2011 ) / Page 13 of 13

PHOSMET/059201 O CS PP 8 9 0. 1400/ OECD 441



## in seminal vesicles; 40% in ventral prostate; 27% in LABC; 34% in Cowper’s gland; and 10% in glans penis. Animals dosed with 0.4 mg/kg/day TP + 3 mg/kg/day FT had

d ecreased (p≤0.05) accessory sex organ weights as follows: 85% in seminal vesicles; 76% in ventral prostate; 50% in LABC; 66% in Cowper’s gland; and 21% in glans penis. The performance criteria indicated that this assay was performing as expected. All ti ssue weight

CVs were below the maximum recommended values indicated in the test guideline

.

Administration of phosmet up to 25 mg/kg/day did not result in an increase in any of the five target organ weights indicating that the test substance is negative fo r androgenic activity. At 25 mg/kg/day, significant de creases were seen in all five of the target organ weights indicating that phosmet is positive for potential anti -androgenic activity in this bioassay. Cholinergic signs (tremors) and a 12% decrease in terminal bodyweight was seen at 25 mg/kg/day suggesting that the high dose may have been excessive (overt toxicity)

.

No statistically significant increases in organ weights were seen in two or more of the five androgen responsive tissues in the androgen agonist assay. Phosmet was negative for androgenic activity. Statistically significant decreases in organ weights were seen in all five androgen responsive tissues only at the high dose in the androgen antagonist assay. Phosmet was positive for potential anti -androgenic activity in this Hershberger assay. However, the decreases in androgen

- sensitive tissue weights were seen at a dose (25 mg/kg/day) that resulted in overt toxicity (12% decrease in body weight and clinical signs), which confounds the interpr etation of the results.

C. STUDY DEFICIENCIES : None

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CSPP 890.1450, Fem ale Pubertal Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-61-2012 (MRID 48673003)

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: 5/7 /2012

Secondary Reviewer : Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 5 / 18 /2012

Program Manager: Signature: Jack D. Early, M.S. Date: 5 / 21 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 5/21/2012

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).

### PHOSMET I 

### 059201



## Primary Reviewer : Linda Taylor. Ph.D

. 

## Hea lth Effects Division

Secon dary Reviewer: Elizabeth Mendez, Ph .D

. 

## Health Effects Division

DATA EVALUATION RECORD

STUDY TYPE: Fema le Pubertal Assay ; OCSPP 890.1450 ; OECD None.



## PC CO D E: 059201 

## DP BARCODE: D400672



## TXR#: 0056199 

## CAS No.: 732-11-6

TEST MATERIAL (PURIT Y): Pho smet (96.8%)



## SYNONYMS: S-[( 1 ,3

- dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl] 

## 0

, 0-dimethyl phosphorodi thioate



## C I TATI ON : Zor illa

, L. 

## (2012). Pub ertal developmenta l and thyroid function with phosmet

in juvenile / peripuberta l CRL: CD (SD) IGS female and male rats. Integrated Laboratory Sys tem s, Inc.

, Durham

, NC, Laboratory Study No.: Cl 94-300, February 24, 2012. MRID 48673003. Unpu bli shed.



## SPONSOR: Gowan Company, P

. O. Box 5569, Y uma
, AZ



## TEST ORD ER#: E DSP-0 59201-54



## EXECUTIVE SUMMARY: In a female pub erta l assay (MRID 

## 48673003), 1 6 SpragueDaw l ey (Crl:CD ® (S D) IGS ) rats/dose group were treated daily by oral gavage with phosmet ( 96.8% a.i.

, Batch #: GQH9118000) in aqueous 0.5% carboxy m ethylcelJu lo se (CMC) at doses of
0, 1 0

, or 20 mg/k g/ day (5 mL/kg dosing volume) from post-natal day (PND) 22 to 42 or 43. The

animals were examined for vaginal opening (VO) daily beginning on PND 22

, and age and body weight at day of atta i nment was recorded. After sacrifice on PND 42/43, serum thyroxine (T 

## 4)

and thyroid s timulatin g hormone (TSH) concentrations were analyzed using radioimmunoassays.

Various clinical chemistry parameters were measured in the serum. Liver

, kidney

, pituitary

, adrenals

, thyroid

, ovaries, and uterus were weighed and exami ned macroscopically ; microscopic

examination was also conducted on the thyroid, ovaries

, uterus, and kidneys.

No treatme nt-r elated effects were observed on mortality

, organ weights

, serum TSH
concentrations, clinical chemi s try

, or gross patho lo gy. Changes (NS) in ovary
, uterus

, thyroid,

and pituitary weights were noted in the lo w- and high-dose animals. There were no treatmentre l ated hi stopat h o l ogica l findings noted in the ovaries

, uterus

, thyroid

, or kidney s. In addition

,

no treatment -r e l ate d effects were noted on cy cle status, mean age at first estrus

, mean cycle

l ength, percent cycling, or percent regularl y cycling.Female Pubertal Assay ( 2012 ) / Page 2 of 17

PHOSMET / 059201 OCSPP 890.1450/ OECD None



## One 10-mg/kg/day rat exhibited localized head tremors on a single day, and tremors were observed at various times post-dose in up to 10/16 10-mg/kg/day rats on 10 days and up to sixteen 20-mg/kg/day rats at 18 days. No other treatment- related clinical signs were observed in animals from either dose group. Decreased body weights (p<0.05; ↓9% to 10%) were observed at 20-mg/kg/day during PND 26 to 36. No significant change in mean final body weight or body weight gain was observed in either treatment group compared to the vehicle control group.

The day of VO was comparable among the groups. Unadjusted and adjusted body weights at VO

were decreased (p<0.05) by 9% each in the 20 mg/kg/day group compared to control. No

treatment

- related effect was noted on cycle status

, mean age at first estrus, mean cycle length, percent cycling, or percent regularly cycling. At 20 mg/kg/day , the number of ovarian antral

follicles was increased ( ↑ 93%) , and the number of atretic follicles was decreased ( ↓ 29%) . All

other values in the treated groups were similar to control.

Serum T 4 

## concentrations were increased ( ↑ 24 to 38%) in the treated groups. A marginal decrease in the thyroid colloid area and increase in the follicular cell height was observed in animals administered phosmet (10 and 20 mg/kg) compared to control.

There were no effects on liver, kidney, pituitary, adrenal, uterus, or thyroid organ weights at either dose level compared to the control.

Thyroid effects (increased serum T4 levels and thyroid histopathology) were s een at both doses. However, the se doses (10 and 20 mg/kg/day) were determined to be excessive based on persistent tremors seen at both doses and severe body weight loss at the high dose. Additionally, data from the existing toxicity database show that low er doses should have been tested in this

assay. Following the agency’s determination, the registrant submitted additional information (MRID 49610501) in response to the agency’s review of this assay. The submitted data show

that tremors were seen in 10/16 rats at the 10 mg/kg/day dose level (during 10 days) and all animals at the 20 mg/kg/day dose (during 18 days). The severity of the tremors ranged from “not

characterized to moderate.” Upon review of these data, the agency reaffirms its previous

con clusion that both do ses tested in this assay were excessive.

Th e assay does NOT satisfy the EDSP Tier 1 Test Order requirement s for a Fem ale Pubertal Assay (OCSPP 890.1450) since overt toxicity was seen at both doses tested . However, a new assay is not required at this time since the results from a repeat assay would have no impact on the

risk assessment. The point of departure (PoD) for the phosmet risk assessment is based on

cholinesterase inhibition at substantially lower doses than the ones tested in this assay. For additional information see the EDSP Tier 1 Weight of Evidence Analysis for Phosmet ( TXR

0057145 ).

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

Assur ance statements were provided.Female Pubertal Assay ( 2012 ) / Page 3 of 17

PHOSMET / 059201 OCSPP 890.1450/ OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Integrated Laboratories Systems , Inc.

Location: Durham, NC Study Director s : L. Zorilla.

Other Personnel: S. Borghoff, s tudy toxicologist M. Boyle, study pathologist Study Period: Ma y 25 , 2011 through February 24, 201 2



## 2

. Test S ubstance : Phosmet

Description: Off white solid

Source: Gowan Company

Batch #: 6 QH9118000 ( expires January 31, 2013 ) Purity : 9 6 .8 % a.i. Stability: Report stated that the compound is stable in the vehicle at 1

– 10°C for up to 15 days

CAS #: 732

- 11

- 6

Structure: O

O S P S

OCH 3 OCH 3 N



## 3

. Vehicle : 0.5% C arboxymethylcellulose in sodium phosphate buffer

4

. Test A nimals : Species: Rat ( fe males)

Strain: Sprague

- Dawley ( Crl:CD ® (SD ) IGS ) Age/ Mean W eight

at S tudy I nitiation: PND 22 / 45.9

– 67.8 g

Source: Charles River Laboratories International, Inc. (Raleigh, NC) Housing: P arental dams were individually housed in polycarbonate cages with micro

- isolator tops and absorbent, heat

- treated, hardwood bedding; each dam was housed with her litter until weaning on PND 21. After weaning, up to 2 fe males were housed per cage.
Diet: Teklad Global 1 6 % Protein Rodent Diet (T e klad Diets , Madison, WI), ad libitum . It was

stated that the total genistein equivalents of genistein plus daidzein was determined to be 8.0 μg/g of feed.

Water: Reverse osmosis

- purified tap water

, ad libitum

Environmental

C onditions: Temperature: Humidity: Air changes: Photoperiod : 19

– 2 4 °C

43

– 78 % Not reported

14 h light / 10 h dark



## B. ST UDY DESIGN

1. In -L ife D ates : Start: July 1 , 2011 End: December 12 , 2011

2. Mating : Time

- mated pregnant nulliparous dams (age not reported ) were received from the supplier on gestation day ( GD ) 8 and were allowed to deliver naturally and rear their pups to

PND 21. Between postnatal days (PND) 3 and 5, litters with the same date of birth were standardized to 8 pups with equal numbers of males and females.Female Pubertal Assay ( 2012 ) / Page 4 of 17

PHOSMET / 059201 OCSPP 890.1450/ OECD None



## 3. Animal A ssignment : Following weaning on PND 21, animals were assigned to study using a procedure that stratifies animals across groups by body weight such that mean body weight of each group was not statistically different from any other group using analysis of

variance. Care was taken to av oid placing littermates in the same dose group. The test

groups a re provided in Table 1.

TABLE 1. Study Design a

Test group Dose (mg/kg/day) # of Fem ales

Control 0 16

Low 10 16

High 20 16

a Data were obtained from Table 1 on page 16 of the study report.



## 4. Dose S election Rationale : The doses were selected based on the results of several previous

studies. A 7 -day relative sensitivity study (MRID 44839301) compared the toxic responses of PND 11 rat pups versus adult rats following repeated gavage administration of phosmet.

No treatment

- related effects on body weight or cholinergic clinical signs were seen in either pups or adults at the highest tested dose (HTD) of 5 mg/kg/day, however significant cholinesterase inhibition was evident (e.g. responses were 57-62% of controls in adult RBC and 81-86% of controls in adult brain at the HTD). The U.S. EPA (ToxSAC memorandum, May 6, 2009) calculated a BMD10 L 

## of 0.60 mg/kg/day for adult rat RBC cholinesterase

inhibition and a BMD10 L 

## of 2.84 mg/kg/day for brain cholinesterase inhibition from the study data.

Body weight effects were observed in a rat teratology study (MRID 41962902) that treated pregnant dams with 10 consecutive gavage doses of phosmet from GD 7–16. At the end of dosing, a statistically significant reduction in body weight gain was observed at 15 mg/kg/day (the HTD). This was associated with a 7% reduction in body weight, compared

to controls. Probable treatment- related cholinergic clinical effects (shaking and/or stains around mouth) were seen in a few animals (4/24) after 6 days of dosing through the end ofdosing in the 15 mg/kg/day group. There was no unambiguous evidence of treatmentrelated cholinergic clinical signs or body weight effects at 5 or 10 mg/kg/day.

In a recent Uterotrophic assay (MRID 48618707) , there were n o body weight effects after 3 consecutive days of gavage dosing at 5 or 20 mg/kg/day. However, r educed activity was noted in a few of the 20 mg/kg/day animals on the third dosing day, within several hours of dosing.

In a recent Hershberger assay ( MRID 48618706) , there were treatment

- related cholinergic clinical signs in the agonist and antagonist cohorts at 25 mg/kg/day after ≥ 3 consecutive dosing days. These effects were typically noted within a few hours of dose administration but did not persist to the pre-dosing examination on the following treatment day.

Treatment

- related cholinergic cl inical signs were not seen at ≤ 15 mg/kg/day. Statistically significant reductions in body weight gain were found for both agonist and antagonistFemale Pubertal Assay ( 2012 ) / Page 5 of 17

PHOSMET / 059201 OCSPP 890.1450/ OECD None



## cohorts at the 25 mg/kg/day dose. Additionally, mean final body weight was significantly reduced at the 25 mg/kg/day treatment level as compared to controls in the antagonist portion of the study. No body weig ht effe cts were noted at ≤ 25 mg/kg/day in the agonist

cohort.

The highest doses tested in the relative sensitivity and Hershberger studies appear to bracket the appropriate range for the highest dose for the phosmet pubertal assays (>5 and <25 mg/kg/day), based on the target of achieving significant body weight effects while avoiding severe clinical signs. Considering the longer exposure intervals employed in the pubertal assays, compared to those used in the other gavage studies, the availa ble data suggest that 20 mg/kg/day will elicit measurable body weight effects in the pubertal assays. It should be noted that it may not be possible to avoid the occurrence of some cholinergic clinical signs with an organophosphate such as phosmet, given the target to elicit body weight effects. However, such effects, if present, should be transient and would not be anticipated to be severe and persist, based on the 25 mg/kg/day data from the Hershberger assay. A robust existing database shows that substantial cholinesterase inhibition will occur at 10 and 20 mg/kg/day. Both selected doses significantly exceed the regulatory benchmark of 0.6 mg/kg/day, which is the EPA

- calculated BMD 10 L 

## , for RBC cholinesterase inhibition in the repeated

- dose relative sen sitivity study. Both doses also exceed the EPA- calculated BMD10 for brain cholinesterase inhibition (3.86 mg/kg/day) following repeated exposures. Accordingly, the selected doses ensure that an appropriately conservative experimental challenge is employe d in the phosmet pubertal screening assays.

5. Dose P reparation and Analysis : Phosmet dose formulations were prepared at ILS in 0.5% aqueous carboxymethylcellulose five times during the study at concentrations of 2 and 4 mg/mL. Formulations were dispensed into vials to be used daily during the study. Dose concentrations were adjusted to correct for purity of phosmet. Samples of dose formulations prepared on June 28, 2011 and July 6, 13, 19, and 26, 2011 were collected from the top, middle, and bottom o f the formulation and sent to Smithers Viscient (Wareham, MA) for analysis. Smithers Viscient analyzed, in duplicate, samples received for concentration and homogeneity. The report stated that dose formulations of phosmet in 0.5% aqueous carboxymethylcel lulose held from 1 to 10°C for up to 15 days were considered stable ( Dix

, 2012 1 

## ); however, no data were submitted to allow independent verification.

Results

Stability (% of time zero): R eported in Study No. 12791.6159.

Concentration (% of nominal): 96–106%

Homo geneity (% CV ): 2.3–11.8%

The analytical data indicated that the mixing procedure was adequate and the variation between nominal and actual dosage to the animals was acceptable. Homogeneity as %CV only exceeded 10% for the 2 mg/mL formulation on July 13, 2011.

1 

### Dix, M. (2012). Storage Stability of Phosmet in Aqueous, Buffered Carboxymethylcellulose. Unpublished study

report prepared by Smithers Viscient Inc. Study No. 12791.6159.Female Pubertal Assay ( 2012 ) / Page 6 of 17

PHOSMET / 059201 OCSPP 890.1450/ OECD None



## 6. Dosage A dministration : Dose formulations were administered by oral gavage at a dose volume of 5 mL/kg body weight. The dose formulations were administered for 21 or 22 consecutive days on PND 22–42/43. Dosing occurred 24- hours (±2 hours) from the previous dose. Dose volume was adjusted daily based on individual animal body weight. The dosing sequence was stratified across all dose groups; one animal from each group and then repeated until all animals were dosed.

7. Statistics : Descriptive statistics (mean, standard deviation, coefficient of variance, and sample size) were calculated using Microsoft Excel 2003/2007 (Redmond, WA). Data sets listed below were analyzed using Statistical Analysis System version 9.2 (SAS Institute, Cary, NC). Studentized residual plots were used to detect possible outliers in the data and Levene’s test was used to assess homogeneity of variance. Heterogeneous data were transformed (logarithm, square root, and multiplicative inverse), and if still he terogeneous

, analyzed using the non- parametric Kruskal

- Wallis and Dunn’s test. If data sets were not homogenous, ANCOVA analyses were not performed. Trend tests were performed on body weight and tissue weight data sets and reported when significant (p<0.05) for endpoints that did not show any significant pairwise comparisons.

Classification Procedure

Initial body weights
Final body weight (use last day all body weights collected)
Final body weight gain (use last day all body weights collected)
Age and body weight at VO
Age at first estrus
Cycle length
Ovarian counts (follicles, cysts, corpora lutea) Homogeneous data sets:

One

- way analysis of variance (ANOVA) followed by pair

wise comparisons performed using Dunnett’s two

- tailed

t- tests

Tissue weights
Relative tissue weights (liver, kidneys, pituitary

, and adrenals)

Hormone levels
Clinical chemistry levels Two

- way ANOVA with treatment and necropsy day (if >1 day) as main effects.

Pair

- wise comparisons were performed using Dunnett’s

two

- tailed t

- tests.

Initial body weights
Final body weight (use last day all body weights collected)
Final body weight gain (use last day all body weights collected)
Age and body weight at VO
Tissue weights Two

- way analysis of covariance (ANCOVA) with PND 21 body weight (weight on day of allocation ) as the covariable.

Pair

- wise comparisons were performed using Dunnett’s

two

- tailed t

- tests.

In the instances where VO had not occurred prior to necropsy, the last day of examination plus 1 was used as the

age at VO and terminal body weight was used for body weight at VO . In instances when at least 1 animal in any
group exhibited incomplete VO , including partial threads for > 3 days, the day partial separation was first recorded was used in the analyses.

Cycling status Percent of animals cycling regularly Chi- square analysis

Thyroid scoring (colloid area and follicular cell height) Fisher’s Exact testFemale Pubertal Assay ( 2012 ) / Page 7 of 17

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## Significance was reported as exact p -values. T he statistical analyses were considered appropriate.

C. METHODS

1. Mortality and C linical Examinations : Animals were observed twice daily for mortality and moribundity on weekdays and once daily on weekends and holidays. Rats were observed prior to allocation of animals to study groups, daily prior to dose administration, and prior to euthanasia.

2. Body W eight : Body weights were collected weekly following birth, prior to allocation of animals to study groups, daily prior to dose administration, and prior to euthanasia.

3. Food Consumption : Food consumption was not measured.

4. Vaginal Opening : Beginning on PND 22, all animals were examined daily for onset of VO. VO was recorded as: VO not initiated, appearance of a pin hole, vaginal thread, or complete VO. Age and weight on the day of completion of VO were recorded.

5. Estrous Cyclicity : Beginning on the day of complete VO through euthanasia, vaginal smears were prepared daily, evaluated and classified as diestrus, proestrus, or estrus; metestrus was classified as diestrus. The overall cycling pattern for each female was

characterized as regular, irregular, or not cycling. Regular cycling was defined as having recurring 4 to 5 day cycles, while irregular cycling was defined as having cycles with diestrus for a period >3 days or estrus ≥3 days. Animals were not considered to be cycling

if there was ≥3 consecutive days of estrus or ≥5 consecutive days of diestrus. Mean cycle length was defined as the number of days from one diestrus to the next diestrus. Incomplete cycles were not used in calculating mean cycle length.

In instances where the time between VO and humane euthanasia did not allow observation of more than 1 complete cycle, classification was based on data available and the assumption that animals were cycling regularly if the partial data fit the definition, and cycling irregu larly if the study ends without being able to distinguish between irregular and not cycling.

6. Sacrifice and Pathology : At least 2 hours after the final dose administration, animals were humanely euthanized by decapitation, in the same order as they were dosed. After euthanasia and prior to tissue collection, trunk blood was collected, and serum was obtained. All serum samples were stored at or below

− 70°C. Serum samples w ere shippe d on dry ice to AniLytics Inc. ( Gaithersburg, MD) for analysis.

a. Hormone Analysis : T 4 

## and TSH were measured in serum using radioimmunoassays (RIAs). Samples were assayed in duplicate and in conjunction with multiple quality control samples.Female Pubertal Assay ( 2012 ) / Page 8 of 17

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## 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 Total cholesterol

X Potassium Globulins

X Sodium Glucose

ENZYMES X Total bilirubin

X Alkali ne phosphatase (ALP ) X Total protein

Cholinesterase (ChE) Triglycerides

Creatine phosphokinase Albumin/globulin ratio (calculated)

Lactic acid dehydrogenase (LDH) Bile acids

X Alanine aminotransferase (ALT/also SGPT)

X Aspartate aminotransferase (AST/also SGOT)

X Sorbitol dehydrogenase

X Gamma glutamyl transferase (GGT)

Glutamate dehydrogenase

* Recommended for the pubertal assay in fe male rats based on guideline 890.1 45 0.



## c. Organ W eights and Histopathology : The following CHECKED (X) tissues were collected and weighed and grossly observed from all study animals

.

UROGENITAL OTHER

X Ovaries (paired, without oviducts)*+ X Thyroid a *+

X Uterus*+ X Liver*

X Kidneys (paired)*+ X Adrenals (paired)*

X Pituitary*

a Thyroid was weighed post

- fixation.

* Weights required based on guideline 890.1 45 0.

+ Histopathological examination required based on guideline 890.1 45 0.



## Uterus (without fluid), left ovary, left kidney, and thyroid were fixed in 10% neutral

buffered formalin for at least 24 -hours. After fixation, tissues were transferred to 70% histology grade alcohol, histologically processed, embedded, sectioned, and stained with hematoxylin and eosin . Histologically

- processed tissues (thyroid, kidneys, uterus, and

ovary ) from all animals were microscopically evaluated. Five random sections of the ovary were examined for follicular development (including presence/absence of tertiary/antral follicles, presence/absence of corpora lutea, changes in corpus luteum development, and changes in number of both primary and atretic follicles) in addition to any abnormalities/lesions, such as ovarian atrophy. Two sections of each of the 2 lobes of the thyroid were examined and ev aluated for follicular cell height and colloid area. A 5 -pointFemale Pubertal Assay ( 2012 ) / Page 9 of 17

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## grading scale (1 = shortest/smallest; 5 = tallest/largest) was used , and the thyroids were evaluated relative to photomicrographs supplied by the U.S. EPA.

II. RESULTS

A. Mortality : All animals survived.

B. Clinical Signs of Toxicity : No treatment

- related clinical signs were observed in animals

f rom any dose group 24 hours post-dose ; i.e. , at the subsequent time of dosing. One 10 mg/kg/day rat exhibited localized head tremors on one day, and tremors were observed at
various times post-dose in up to ten 10 mg/kg/day rat s on 10 days and up to sixteen 20 mg/kg/day rats on 18 days.

C. General Growth and Vaginal Opening : Body weights, body weight gains, age of

attainment of VO

, weight at VO , and proportion/incidence of unopened vagina are presented

in Tables 2 and 3 below.

Unadjusted and adjusted body weight at VO were decreased (p<0.05) by 9% each in the 20 mg/kg/day group compared to controls. No significant change in mean final body weight or body weight gain was observed in females administered 10 or 20 mg/kg/day phosmet compared to the vehicle control group. The treated groups displayed body weight gain deficits that diminished with time on test; e.g., at 20 mg/kg/day, body weight gain was ↓ 30% during Days 22- 23; ↓20% during Days 26

- 29; and ↓6% during Days 29-36 (Table 2).

At 20 mg/kg/day, body weights were decreased (p≤0.05) by 8– 10% from PND 26 –36. A water bottle malfunction is thought to have led to a body weight loss (compared to the previous day) in half the control group on PND 36 –37. The report stated that it wa s likely that the terminal body weights of the 20 mg/kg/day phosmet group would have been ~90% of vehicle control body weights had the water bottle malfunction in the control not occurred. It is to be noted that all of the control females had attained VO by PND 36 so the

malfunction had no impact on this parameter for this group. All but one of the 10 mg/kg/day females and all but two of the 20 mg/kg/day females ha d attained VO by PND 36

also.

TABLE 2. Body Weight and Body Weight Gain (grams) a

Days Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

PND 22 57.0±4.9 56.8±4.2 56.6±5.0

PND 27 82.8±7.0 80.9±6.7 75.9±6.5 ↓8% *

PND 29 95.8±8.2 92.5±7.3 86.3±7.7 ↓10% *

PND 36 140.9±11.9 134.3±9.9 128.5±13.4 ↓9% *

PND 37 139.6±12.1 139.7±9.4 131.6±14.9 ↓6%

PND 42 169.1±15.1 165.1±11.2 163.7±17.5 ↓4%

PND 22

- 23 4.0 3.4 ↓15% 2.8 ↓30%

PND 2 3- 26 1 7 .0 1 5

. 6 ↓ 8 % 1 2

. 5 ↓2 6 %

PND 26

- 29 17.8 16.7 ↓6% 14.4 ↓20%

PND 29

- 36 45.1 41.8 ↓8% 42.2 ↓6%Female Pubertal Assay ( 2012 ) / Page 10 of 17

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### TABLE 2. Body Weight and Body Weight Gain (grams) a

PND 26

- 36 62.9 58.5 ↓7% 56.6 ↓10%

PND 36

- 37

- 1.3 5.4 3.1

PND 38

- 42 21.6 19.8 25.5 ↑18%

PND 22

- 36 83.9 77.5 ↓8% 71.9 ↓14%

PND 22

- 42 112.1 108.3 ↓4% 107.1 ↓4%

a Data were obtained from Appendix IV, page s 101

- 103 of the study report. * p<0.05; body weight gains calculated by

reviewer.



## All performance criteria were met ; however, weaning weight (PND 21) was not reported.

TABLE 3 . General Growth and Vaginal Opening (VO) a

Parameter Evaluated Vehicle Control 10 mg/kg/day Phosmet 2 0 mg/kg/day Phosmet

N Mean SD CV (%) N Mean SD CV

(%) N Mean SD CV

(%)

Initial body weight (PND 22; g) U 16 57.0 4.9 8.5 16 56.8 4.2 7.4 16 56.6 5.0 8.8

A 16 57.0

--- --- 16 56.9

--- --- 16 56.5

--- ---

Body weight at vaginal opening (g) U 16 122.1 11.3 9.2 16 115.6 13.7 11.9 15 111.5* (↓9) 9.8 8.8

A 16 122.1

--- --- 16 115.6

--- --- 15 111.6* (↓9) --- ---

Final body weight (g) U 16 169.1 15.1 8.9 16 165.1 11.2 6.8 16 163.7 17.5 10.7

A 16 169.1

--- --- 16 165.3

--- --- 16 163.4

--- ---

Final body weight (% of control) U 16

--- --- --- 16 97.6

--- --- 16 96.8

--- ---

A 16

--- --- --- 16 97.8

--- --- 16 96.6

--- ---

Body weight gain (final

– initial; g) U 16 112.1 12.1 10.8 16 108.3 8.7 8.0 16 107.1 14.8 13.8

A 16 112.1

--- --- 16 108.4

--- --- 16 106.9

--- ---

Age at vaginal opening (PND) U 16 33.2 1.2 3.7 16 32.9 2.0 6.0 15 33.4 1.5 4.5

A 16 33.2

--- --- 16 32.9

--- --- 15 33.4

--- ---
Proportion unopened (#/N) 0/16 0/16 1/16

a Data were obtained from Table 7 on page 27 of the study report. Percent difference from controls (calculated by reviewers) is presented parenthetically.

U Unadjusted for body weight on PND 21

A Adjusted for body weight on PND 2 1

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05.



## D. Organ Weights : Organ weights at necropsy are presented in Table 4 below. No significant differences were observed in liver, kidney, adrenal, pituitary, thyroid, uterus (wet or blotted), or ovar y weights of the treated groups compared to controls, but t here was a dose

related significant trend (p≤0.05) in relative liver weights (↑3

- 5%) . Although adrenalFemale Pubertal Assay ( 2012 ) / Page 11 of 17

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## weights in both groups were comparable to/ slightly lower than (↓2 -3%) the control, the adrenal weight of the control was below the acceptable range of the performance criteria. Compared to the low range value, the adrenal weight s were ↓16 -18%. Thyroid weight was slightly increased (↑6%) at 10 mg/kg/day and slightly decreased (↓8%) at 20 mg/kg/day. Pituitary weights were slightly lower than control (↓6% and ↓8%) at 10 mg/kg/day and 20 mg/kg/day, respectively.

The following performance cri teria were not met: mean adrenal weight of 32.9 m g (acceptable range : 38.34–48.84); and %CV= 11.4 for kidneys (top acceptable range: 10.76).

TABLE 4

. Organ Weights at Necropsy a

Organ Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N Mean SD CV (%) N Mean SD CV (%) N Mean SD CV (%)

Liver (g) U 16 7.52 0.67 9 .0 16 7.6 0 0.66 8.7 16 7.74 1.15 14.8

A 16

--- --- --- 16

--- --- --- 16

--- --- ---

R* 16 4.45 0.2 4.6 16 4.57 (↑3) 0.25 5.5 16 4.66 (↑5) 0.36 7.6

Kidneys (g) U 16 1.33 0.15 11.4 16 1.33 0.07 5.1 16 1.32 0.14 10.8

A 16

--- --- --- 16

--- --- --- 16

--- --- --- R 16 0.78 0.06 7.3 16 0.8 0.05 6.4 16 0.8 0.04 5.6

Pituitary (mg) U 16 9.9 1.3 13.3 16 9.4 1.2 12.6 16 9.2 1.6 17 .0

A 16 9.9

--- --- 16 9.4 (↓6) --- --- 16 9.2 (↓8) --- ---

R 16 5.8 0.7 11.8 16 5.7 0.7 13.1 16 5.6 1 16.9

Adrenals (mg) U 16 32.9 4.9 14.9 16 32.1 6.5 20.4 16 31.8 5.5 17.2

A 16 32.9

--- --- 16 32.1

--- --- 16 31.8 (↓4) --- ---

R 16 19.7 3.7 18.9 16 19.4 4.3 22.3 16 19.5 4.3 22.2

Ovaries (mg) U 16 59.8 11.9 19.9 16 55 .0 (↓8) 6.6 12 16 56.7 (↓6) 10 17.7

A 16 59.8

--- --- 16 55.1

--- --- 16 56.6

--- ---

Uterus, wet (mg) U 16 418.6 206 49.2 16 383.4 (↓8) 194.8 50.8 16 373.5 (↓ 11) 153.3 41.1

A 16 418.6

--- --- 16 384.4

--- --- 16 372.4 (↓12) --- ---

Uterus, blotted (mg) U 16 330.3 74.9 22.7 16 301.1 (↓9) 90.8 30.1 16 321.3 (↓3) 65.8 20.5

A 16 330.3

--- --- 16 301.8

--- --- 16 320.5

--- ---

Thyroid, fixed (mg) U 16 20.6 3.1 15.1 16 22 .0 (↑6) 4.4 19.9 16 19.1 (↓8) 3.7 19.5

A 16 20.6

--- --- 16 22

--- --- 16 19.1

--- ---

a Data were obtained from Table 8 on page 29 of the study report. No statistical differences were noted in pair

- wise comparisons of treated groups with control.

U Unad justed for body weight on PND 21

A Ad justed for body weight on PND 21

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

R Organ

- to

- body weight ratio (relative to body weight)

* Significant trend ( p<0.05 )Female Pubertal Assay ( 2012 ) / Page 12 of 17

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## E. Estrus Cyclicity : Estrus cycle data are provided in Table 5. No treatment

- related effect

was noted on cycle status at necropsy, mean age at first estrus, mean cycle length, percent cycling, or percent regularly cycling.Female Pubertal Assay ( 2012 ) / Page 13 of 17

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### TABLE 5

. Estrous Cyclicity a

Treatment Groups N Mean Age at

First Estrus (PND) Mean Cycle Length (days) Cycling (%) Regularly Cycling

(%) Cycle Status at Necropsy (# Females)

Diestrus Proestrus Estrus Not Cycling

Vehicle 16 35.1±2.2 4.1±1.4 93.75 87.5 5 2 9 1

1 0 mg/kg/day

Phosmet 16 35.6±3.2 3.5±0.9 100 87.5 10 3 3 0

2 0 mg/kg/day

Phosmet 16 35.4±2.7 3.9±0.9 93.3 86.7 6 1 8 1

a Data were obtained from Table s 8 and 9 on page s 29

- 30 of the study report. No statistical differences were noted in pair

wise comparisons of treated groups with control.

N Number of animals

* Significantly different from controls at p<0.05.



## F. Clinical Chemistry and Hormone Levels : Clinical chemistry and h ormone levels are presented in Table 6 below.

Serum T 4 

## levels were increased (p<0.05 ) by 24–38% in the treated groups. The CV (28.7) was slightly greater than the performance criteria mean (21.38) but was less than the top of the acceptable range (29.39). Serum TSH levels in the treated groups were slightly greater than ( ↑ 2% -6%) the control.

The following clinical chemistry parameters differed from control in one or both treatment groups, although statistical significance was not always attained (NS) : (i) minor increases in sodium of 4–6% at 10 mg/kg/day and 20 mg/kg/day (p<0.05 ); (ii) increases in alanine

aminotransferase o f 11 –17% (NS at 20 mg/kg/day) ; (i ii ) increases of alkaline phosphatase (↑ 14-24%, NS at 10 mg/kg/day ); (iv ) increases in bilirubin at 10 mg/kg/day and 20 mg/kg/day ( ↑ 23- 38%; NS); (v ) increases in blood urea nitrogen (↑ 8-23%, NS at 10 mg/kg/day ); and (v i) i ncreases in sorbitol dehydrogenase (↑ 13-33%, NS at 10 mg/kg/day ).

It is to be noted that several of the control values are outside the normal range. For example,

the control ALP value is 246 U/L and the range provided in Table 12 of the study report is 17-183 U/L; control ALT value is 94 U/L, whereas the range is 20-56 U/L. It is to be noted that Table 12 of the study report is labeled as female data, but the same hormone and clinical chemistry ranges are listed in Table 25 of the study report as male ranges.

TABLE 6 . Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

Hormones

Serum T 4 , Total (μg/dL) 16 3.09 0.89 28.7 16 3.84* (↑24) 1.12 29.1 16 4.27* (↑38) 1.06 24.9

Serum TSH (ng/mL) 16 1.47 0.72 50.0 16 1.50
(↑2) 0.70 46.4 16 1.57
(↑6) 1.02 65.0Female Pubertal Assay ( 2012 ) / Page 14 of 17

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### TABLE 6 . Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

Clinical Chemistry

Sodium (mE q /L) 16 141 4 3 16 147* (↑4) 2 2 16 150* (↑6) 2 2

Potassium (mEq/L) 16 8.2 0.7 8.4 16 8.4 1 11.9 16 8.6 0.7 7.8

Chloride (mEq/L) 16 104 2 2 16 110 (↑6) 2 2 16 114 (↑14) 2 2

Calcium (mg/dL) 16 10.3 0.4 4.3 16 10.8* (↑5) 0.4 3.5 16 10.5 0.7 6.4

Phosphorus

(mg/dL) 16 9.7 0.5 5.4 16 10.0 1.0 9.7 16 10.0 1.0 9.9

AST (U/L) 16 281 48 17 16 284 87 31 16 294 74 25

ALT (U/L) 16 94 10 11 16 104* (↑11) 21 20 16 110 (↑17) 21 19

GGT (U/L) 16 0.1 0.5 400 16 0.2 0.5 290 16 0 0

ALP (U/L) 16 246 48 19 16 280 (↑14) 49 18 16 305* (↑24) 63 21

BUN (mg/dL) 16 13 2 16 16 14 (↑8) 2 14 16 16* (↑23) 2 15

Creatinine (mg/dL) 16 0.40 0.05 12.9 16 0.41 0.06 14.1 16 0.38 0.05 14.3

Total Bilirubin (mg/dL) 16 0.13 0.11 86.7 16 0.16 (↑23) 0.11 66.9 16 0.18 (↑38) 0.18 97.1

SDH (U/L) 16 15 5 35 16 17 (↑13) 5 29 16 20* (↑33) 5 27

Total Protein (g/dL) 16 5.5 0.3 5.4 16 5.7 0.4 6.6 16 5.5 0.4 7.4

Albumin (g/dL) 16 4.3 0.3 6.3 16 4.5 0.3 6.9 16 4.3 0.4 8.7

a Data were obtained from Table 10 on page 30 and Table 11 on page 32 of the study report. Percent difference from controls (calculated by reviewers) is presented parenthetically.

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05.



## F. Gross pathology : There was a focus on the median liver lobe proximal to the hilus observed in one animal administered 20 mg/kg/day phosmet. No other gross observations were noted in female rats surviving to the scheduled termination.

G. Histopathology : The incidences of histopathological findings of the thyroid gland are presented below in Table 7 ; follicular cell shape was not reported . A marginal decrease in

the colloid area and increase in the follicular cell height was observed in animals administered phosmet (10 and 20 mg/kg) compared to controls. The number of rats with the largest follicular colloid area (G rades 4 or 5) included 14/16 in the control, 10/16 at 10 mg/kg/day and 8 /1 6 at 20 mg/kg/day. Likewise, the number of rats with the shortest

follicular cell height (G rades 1 or 2) in cluded 14 /16 in the control, 10/16 at 10 mg/kg/day and 8/16 at 20 mg/kg/day.Female Pubertal Assay ( 2012 ) / Page 15 of 17

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TABLE 7 . 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 1 16

2 0 16 2 13 16

3 2 16 3 2 16

4 13 16 4 0 16

5 1 16 5 0 16

10 mg/kg/day

Phosmet 1 0 16 1 0 16

2 0 16 2 10 16

3 6 16 3 6 16

4 10 16 4 0 16

5 0 16 5 0 16

20 mg/kg/day

Phosmet 1 0 16 1 1 16

2 1 16 2 7 16

3 7 16 3 7 16

4 7 16 4 1 16

5 1 16 5 0 16

a Data were obtained from Table 14 on page 35 of the study report.

b A 5

- point grading scale (1 = shortest/smallest; 5 = tallest/largest) was used

. O No. Observed

E No. Examined



## The incidence of histopathological findings of the ovary, uterus, thyroid, and kidneys are presented in Table 8. In the ovary, the number of a ntral follicles was increased by 57% at 10 mg/kg/day (NS) and by 93% (<0.05) at 20 mg/kg/day. T he number of a tretic follicles

was decreased by 24% (NS) at 10 mg/kg/day and 29% (<0.05) at 20 mg/kg/day. All other

ovarian values in the treated groups were similar to the control. There were no treatment

related histopathological findings noted in the uterus, thyroid (except as noted in Table 6)

, or kidneys at any dose.Female Pubertal Assay ( 2012 ) / Page 16 of 17

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### TABLE 8 . Incidence of Histopathological Lesions of the Ovary , Thyroid, Uterus, and Kidney a

Findings Dose Level (mg/kg bw/day)

Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

#

Observed #

Examined #

Observed #

Examined #

Observed #

Examined
Ovary [ Mean ± SD ( CV )]

Small follicles 27.7 ± 9.6 (34.7) b 16 30.6 ± 7.1 (23.2) 16 26.1 ± 10.1 (38.7) 16

Medium follicles 13.7 ± 4.0 (30.8) 16 14.4 ± 3.1 (21.5) 16 14.6 ± 5.0 (34.2) 16

Antral follicles

1.4 ± 1.0 (69.9) b 16 2.2 ± 0.7 (31.8)

[ ↑ 57] 16 2.7 ± 2.2* (81.5)
[ ↑ 93] 16

Atretic follicles 7.9 ± 2.5 (31.6) b 16 6.0 ± 2.7 (45.0)
[ ↓ 24%] 16 5.6 ± 1.5* (26.8)
[ ↓ 29] 16

Follicular cysts 0.013 ± 0.05 (384.6) b 16 0.025 ± 0.1 (400.0) b

[ ↑ 92] 16 0.0 ± 0.0 16

Corpora lutea 6.8 ± 1.9 (27.9) b 16 7.5 ± 1.7 (22.7) 16 6.6 ± 2.2 (33.3) 16 Thyroid

Minimal C

- cell hyperplasia 0 16 0 16 1 16

Uterus

Minimal dilatation 7 16 5 16 2 16 Minimal eosinophilic

material 1 16 0 16 1 16

Minimal inflammatory

cells/debris 3 16 0 16 6 16

Mild inflammatory

cells/debris 0 16 0 16 1 16

Minimal endometrial folding 6 16 7 16 7 16

Minimal inflammatory

cells in the endometrium 1 16 0 16 3 16

Kidneys
Minimal nephropathy 8 16 8 16 6 16

Minimal tubular dilatation 1 16 5 16 2 16

Minimal cysts 1 16 0 16 0 16

Minimal mineralization 0 16 1 16 0 16

a Data were obtained from Appendi x X on page s 148, 150 and 152 of the study report

. b (CV)

* Significantly different from controls at p<0.05.



## III

. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR’S CONCLUSIONS : Administration of phosmet to intact juvenile/peripubertal female rats at a dose that met, but did not exceed the MTD, did not cause any changes in the evaluated endpoints to suggest a disruption in pubertal development or thyroid function.

B. AGENCY COMMENTS : No treatment

- related effects were observed on mortality, organ weights, serum TSH concentrations, clinical chemistry, or gross pathology. Changes (NS) in ovary, uterus, thyroid, and pituitary weights were noted in the low- and high-dose animals.

There were no treatment -related histopathological findings noted in the ovaries, uterus, thyroid, or kidneys. In addition, no treatment- related effects were noted on cycle status, mean age at first estrus, mean cycle length, percen t cycling, or percent regularly cyclingFemale Pubertal Assay ( 2012 ) / Page 17 of 17

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## One 10-mg/kg/day rat exhibited localized head tremors on a single day, and tremors were observed at various times post-dose in up to 10/16 10-mg/kg/day rats on 10 days and up to sixteen 20-mg/kg/day rats at 18 days. No other treatment- related clinical signs were observed in animals from either dose group. Decreased body weights (p<0.05; ↓9% to 10%)

were observed at 20 -mg/kg/day during PND 26 to 36. No significant change in mean final body weight or body weight gain was observed in either treatment group compared to the vehicle control group.

The day of VO was comparable among the groups. Unadjusted and adjusted body weights at
VO were decreased by 9% each in the 20 mg/kg/day group compared to controls. No

treatment

- related effect was noted on cycle status, mean age at first estrus, mean cycle length, percent cycling, or percent regularly cycling. At 20 mg/kg/day, the number of ovarian antral follicles was increased ( ↑ 93%) , and the number of atretic follicles was decreased ( ↓ 29%) . All other values in the treated groups were similar to control.

Serum T 4 

## concentrations were increased by 24 –38% in the treated groups compared to the control, and TSH was slightly increased (6%) at 20 mg/kg/day

. A marginal decrease in the thyroid colloid area and increase in the follicular cell height was observed in animals administered phosmet (10 and 20 mg/kg) compared to control.

There were no effects on liver, kidney, pituitary, adrenal, uterus, or thyroid or gan weights at either dose compared to control

The high dose tested (20 mg/kg/day) was determined to be an excessive dose due to the occurrence of tremors in up to 16 of 20 rats at 20 mg/kg/day rats on 18 days. In addition,

tremors were observed at vari ous times post-dose in up to 10/16 10 mg/kg/day rats on 10 days . Also, d ecreased body weights ( ↓ 9%–10%) were observed at 20 mg/kg/day during

PND 26 –36.

Following the agency’s determination, the registrant submitted additional information (MRID 49610501) in response to the agency’s review of this assay. The submitted data show that tremors were seen in 10/16 rats at the 10 mg/kg/day dose level (during 10 d ays) and all animals at the 20 mg/kg/day dose (during 18 days). The severity of the tremors ranged from “not characterized to moderate.” Upon review of these data, the agency reaffirms its previous conclusion that both doses tested in this assay were excessive.

C. STUDY DEFICIENCIES : Dose levels tested were excessive.

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CSPP 890.1500, M ale Pubertal Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-61-2012 (MRID 48673003)

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: 5/7 /2012

Secondary Reviewer : Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 5/17/2012

Program Manager: Signature: Jack D. Early, M.S. Date: 5 / 21 /2012

Quality Assurance: Signature: Jack D. Early, M.S. Date: 5 / 21 / 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).PHOSMET I 059201



## Primary Reviewer: Linda Tavlor. Ph.D.



## Health Effects Division Secondary Reviewer: John Liccione, Ph.D.



## Health Effects Division Male Pubertal Assay (2012) I Page I of 15

OCSPP 890.1500/ OECD None



## DATA EVALUATION RECORD

STUDY TYPE: Male Pubertal Assay; O CS PP 890.1500 ; OECD None.



## PC CODE: 059201 

## DP BARCODE: D400672



## TXR# : 0056199 

## CAS No.: 732-11-6



## TEST MATERIAL (PURITY) : Phosmet (96.8% a.i.)



## SYNONYMS: S-[(1,3-dihydro -l

, 3-dioxo-2H -i soindol-2-yl)methyl] 

## 0, 0-dim e thyl phosphorodithioate



## CITATION: Z orilla

, L. (2012). Pub e rtal developmental and thyroid function with phosmet injuvenile / peripubertal CRL :CD(SD) IGS female and male rats. Integrated Laboratory Systems, Inc.

, Durham

, NC

, Laboratory Study No.: Cl94-300, February 24

, 2012. MRID 48673003. Unpublished.



## SPONSOR: Gowan Company, P.O. Box 5569

, Yuma, AZ



## TEST ORDER#: EDSP-059201-54



## EXECUTIVE SUMMARY: Jn a male pubertal assay (MRID 48673003)

, 16 Sprague-Dawley (Crl : CD ® (SD) IGS) rats/dose group were treated daily via 

## oral gavage with phosmet (96.8% a.i

., Batch #: 6QH9118000) in aqueous 0.5% carboxymethylce llulo se (5 mL/kg) at doses ofO

, 10

, or
20 mg/kg/day from post -n atal day (PND) 23 to 53 or 54. The animal s were examined for preputial separation (PPS) daily beginning on PND 30, and age and body weight at day of

attainment was recorded. Fo ll owing sacrifice on PND 

## 53154, total serum testosterone, thyro xine
(T4)

, and thyroid stimulating hormone (TSH) levels were analyzed by radioimmunoassay.

Various clinical chemistry parameters we r e measured in the serum. Liver, kidney

, pituitary

, adrenals

, se minal ves icles with coagulating glands

, and ventral and dorsolateral prostate were weighed and examined macroscopically ; in addition, microscopic examinations were conducted

on the epididyrnides, testis

, thyroid, and kidneys.

All rat s survived until study termination. Tremors were observed periodically in 

## the majority of

the rats at 20 mg/kg / day. No other clinical signs of toxicity were observed in the stu dy at either

dose.

The decreases in bod y weight g ains and final body weights were minimal (<10%) and not

biolo g i cally significant. The s mall v ariations in clinical chemistry parameters observed at 20 mg/kg/day were not considered to be indicative of toxic effects on the kidney or liver.Male Pubertal Assay (2012) / Page 2 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## There was no treatment

- related effect on preputial separation at either dose level.

The adjusted ventral prostate weights showed a linear trend of decreased weight with increasing dose; however, no statistically significant effect was detected between the treated groups and control. Both means were lower than historical control mean ventral weight for Sprague- Dawley male rats but were within the acceptable range. There were no effects on liver, kidney, pituitary, adrenal, testis, or other sex organ weights at either dose level compared to the control.

Testosteron e levels were lower in both dose groups compared to the control, but statistical significance was not attained and the means were within the expected range for Sprague

- Dawley

rats. It is to be noted that the standard deviation for testosterone in the 20 mg/kg/day dose group (1.62) was similar to the mean value (1.80).

Serum T 4 

## levels were increased in both treatment groups compared to the concurrent control and the mean value for Sprague- Dawley male rats, but they were within the acceptable range in the

p erformance criteria. Additionally, these increases were within the range of control values observed at the analytical laboratory (3

- 7 μg/dL) . TSH levels were slightly higher at both dose levels compared to the control, but the control value was below the acceptable range and the Guideline criteria for this parameter were not met.

During the agency’s initial review, t he doses (10 and 20 mg/kg/day) used in this study were considered excessive, based on the dose- selection rationale and the periodic occurrence of tremors in the majority of the males at 20 mg/kg/day. Subsequently, the registrant submi tted additional data (MRID 4961502) in response to the agency’s review of this assay. The submitted

data show at the 10 mg/kg/day dose level, mild tremors were seen during one day only in 6/16

animals . In contrast, the severity of tremors at the 20 mg/kg/day dose level ranged from mild to moderate and were seen on multiple days in 11/16 animals. Based on this additional

information

, the l ow dose was determined to be adequate with only the high dose showing evidence of overt toxicity.

Th e assay satisf ies the EDSP Ti e r 1 Test Order requirement s for a M ale Pubertal Assay (OCSPP 890.1500).

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

Assurance statements were provided.Male Pubertal Assay (2012) / Page 3 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Integrated Laboratories Systems , Inc.

Location: Durham, NC Study Director s : L. Zorilla.

Other Personnel: S. Borghoff, s tudy toxicologist M. Boyle, study pathologist Study Period: Ma y 25 , 2011 through February 24, 201 2



## 2

. Test S ubstance : Phosmet

Description: Off white solid

Source: Gowan Company

Batch #: 6 QH9118000 ( expires January 31, 2013 ) Purity : 9 6 .8 % a.i. Stability: Report stated that the compound is stable in the vehicle at 1

– 10°C for up to 15 days

CAS #: 732

- 11

- 6

Structure: O

O S P S

OCH 3 OCH 3 N



## 3

. Vehicle : 0.5% C arboxymethylcellulose in sodium phosphate buffer

4

. Test A nimals : Species: Rat (males)

Strain: Sprague

- Dawley ( Crl:CD ® (SD ) IGS ) Age/ Mean W eight

at S tudy I nitiation: PND 23 / 51.5 –7 2.1 g

Source: Charles River Laboratories International, Inc. (Raleigh, NC) Housing: P arental dams were individually housed in polycarbonate cages with micro

- isolator tops and absorbent, heat

- treated, hardwood bedding; each dam was housed with her litter until weaning on PND 21. After weaning, up to 2 males were housed per cage.
Diet: Teklad Global 1 6 % Protein Rodent Diet (T e klad Diets , Madison, WI), ad libitum . It was

stated that the total genistein equivalents of genistein plus daidzein was determined to be 8.0 μg/g of feed.

Water: Reverse osmosis

- purified tap water

, ad libitum

Environmental

C onditions: Temperature: Humidity: Air changes: Photoperiod : 19

– 2 4 °C

43

– 78 % Not reported

14 h light / 10 h dark



## B. ST UDY DESIGN

1. In -L ife D ates : Start: July 1 , 2011 End: Approximately August 2 , 2011

2. Mating : Time

- mated pregnant nulliparous dams (age not reported ) were received from the supplier on gestation day ( GD ) 8 and were allowed to deliver naturally and rear their pups to

PND 21. Between postnatal days (PND) 3 and 5, litters with the same date of birth were standardized to 8 pups with equal numbers of males and females.Male Pubertal Assay (2012) / Page 4 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## 3. Animal A ssignment : Following weaning on PND 21, animals were assigned to study using a procedure that stratifies animals across groups by body weight such that mean body weight of each group was not statistically different from any other group using analysis of

variance. Care was taken to avoid placing littermates in the same dose group. The test

groups a re provided in Table 1.

TABLE 1. Study Design a

Test group Dose (mg/kg/day) # of Males

Control 0 16

Low 10 16

High 20 16

a Data were obtained from Table 2 on page 16 of the study report.



## 4. Dose S election Rationale : The doses were selected based on the results of several previous

studies. A 7 -day relative sensitivity study (MRID 44839301) compared the toxic responses

of PND 11 rat pups versus adult rats following repeated gavage administration of phosmet.

No treatment

- related effects on body weight or cholinergic clinical signs were seen in either pups or adults at the highest tested dose (HTD) of 5 mg/kg/day, however si gnificant cholinesterase inhibition was evident (e.g. responses were 57-62% of controls in adult RBC and 81-86% of controls in adult brain at the HTD). The U.S. EPA (ToxSAC memorandum, May 6, 2009) calculated a BMD10 L 

## of 0.60 mg/kg/day for adult rat RBC c holinesterase

inhibition and a BMD10 L 

## of 2.84 mg/kg/day for brain cholinesterase inhibition from the study data.

Body weight effects were observed in a rat teratology study (MRID 41962902) that treated pregnant dams with 10 consecutive gavage doses of pho smet from GD 7 –16. At the end of dosing, a statistically significant reduction in body weight gain was observed at 15 mg/kg/day (the HTD). This was associated with a 7% reduction in body weight, compared

to controls. Probable treatment- related cholinerg ic clinical effects (shaking and/or stains around mouth) were seen in a few animals (4/24) after 6 days of dosing through the end ofdosing in the 15 mg/kg/day group. There was no unambiguous evidence of treatmentrelated cholinergic clinical signs or body weight effects at 5 or 10 mg/kg/day.

In a recent Uterotrophic assay (MRID 48618707), there were no body weight effects after 3 consecutive days of gavage dosing at 5 or 20 mg/kg/day. However, r educed activity was noted in a few of the 20 mg/kg/day animals on the third dosing day, within several hours of dosing.

In a recent Hershberger assay (MRID 48618706), there were t reatment

- related cholinergic clinical signs in the agonist and antagonist cohorts at 25 mg/kg/day after ≥ 3 consecutive dosing days. These effects were typically noted within a few hours of dose administration but did not persist to the pre-dosing examination on the following treatment day.

Treatment

- related cholinergic cl inical signs were not seen at ≤ 15 mg/kg/day. Statistically sign ificant reductions in body weight gain were found for both agonist and antagonist cohorts at the 25 mg/kg/day dose. Additionally, mean final body weight was significantlyMale Pubertal Assay (2012) / Page 5 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## reduced at the 25 mg/kg/day treatment level as compared to controls in the antagonis t portion of the study. No body weig ht effects were noted at ≤ 25 mg/kg/day in the agonist

cohort.

The highest doses tested in the relative sensitivity and Hershberger studies appear to bracket the appropriate range for the highest dose for the phosmet pu bertal assays (> 5 and < 25 mg/kg/day), based on the target of achieving significant body weight effects while avoiding severe clinical signs. Considering the longer exposure intervals employed in the pubertal assays, compared to those used in the other g avage studies, the available data clearly suggest that 20 mg/kg/day will elicit measurable body weight effects in the pubertal assays. It should be noted that it may not be possible to avoid the occurrence of some cholinergic clinical signs with an organophosphate such as phosmet, given the target to elicit body weight effects. However, such effects, if present, should be transient and would not be anticipated to be severe and persist, based on the 25 mg/kg/day data from the Hershberger assay. A robust e xisting database shows that substantial cholinesterase inhibition will occur at 10 and 20 mg/kg/day. Both selected doses significantly exceed the regulatory benchmark of 0.6 mg/kg/day, which is the EPA- calculated BMD 10 L 

## , for RBC cholinesterase inhibition in the repeated -dose relative sensitivity study. Both doses also exceed the EPA- calculated BMD10 for brain cholinesterase inhibition (3.86 mg/kg/day) following repeated exposures. Accordingly, the selected doses ensure that an appropriately conservative experimental challenge is employed in the phosmet pubertal screening assays.

5. Dose P reparation and Analysis : Phosmet dose formulations were prepared at ILS in 0.5% aqueous carboxymethylcellulose five times during the study at concentrations of 2 and 4 mg/mL. Formulations were dispensed into vials to be used daily during the study. Dose concentrations were adjusted to correct for purity of phosmet. Samples of dose formulations prepared on June 28, 2011 and July 6, 13, 19, and 26, 2011 were collected from the top, middle, and bottom of the formulation and sent to Smithers Viscient (Wareham, MA) for analysis. Smithers Viscient analyzed, in duplicate, samples received for concentration and homogeneity. The report stat ed that dose formulations of phosmet in 0.5% aqueous carboxymethylcellulose held from 1 to 10°C for up to 15 days were considered stable ( Dix

, 2012 1 

## ); however, no data were submitted to allow independent verification.

Results

Stability (% of time zero): Not reported

Concentration (% of nominal): 96–106%

Homo geneity (% CV ): 2.3–11.8%

The analytical data indicated that the mixing procedure was adequate and the variation between nominal and actual dosage to the animals was acceptable. Homogeneity as %CV only exceeded 10% for the 2 mg/mL formulation on July 13, 2011. Stability data should be

submitted for review.

1 

### Dix, M. (2012). Storage Stability of Phosmet in Aqueous, Buffered Carboxymethylcellulose. Unpublished study

report prepared by Smithers Viscient Inc. Study No. 12791.6159.Male Pubertal Assay (2012) / Page 6 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## 6. Dosage A dministration : Dose formulations were administered by oral gavage at a dose volume of 5 mL/kg body weight. The dose formulations were administered for 31 or 32 consecutive days on PND 23–53/54. Dosing occurred 24-hours (±2 hours) from the previous dose. Dose volume was adjusted daily based on individual animal body weight. The dosing sequence was stratified acro ss all dose groups; one animal from each group and then repeated until all animals were dosed.

7. Statistics : Descriptive statistics (mean, standard deviation, coefficient of variance, and sample size) were calculated using Microsoft Excel 2003/2007 (Redmond, WA). Data sets listed below were analyzed using Statistical Analysis System version 9.2 (SAS Institute, Cary, NC). Studentized residual plots were used to detect possible outliers in the data and Levene’s test was used to assess homogeneity of variance. Heterogeneous data were transformed (logarithm, square root, and multiplicative inverse) and if still het erogeneous analyzed using the non- parametric Kruskal

- Wallis and Dunn’s test. If data sets were not homogenous, ANCOVA analyses were not performed. Trend tests were performed on body weight and tissue weight data sets and reported when significant (p<0.05) for endpoints that did not show any significant pairwise comparisons.

Classification Procedure

Initial body weights
Final body weight (use last day all body weights collected)
Final body weight gain (use last day all body weights collected)
Age and body weight at PPS Homogeneous data sets:

One

- way analysis of variance (ANOVA) followed by pair

wise comparisons performed using Dunnett’s two

- tailed

t- tests

Tissue weights
Relative tissue weights (liver, kidneys, pituitary

, and adrenals)

Hormone levels
Clinical chemistry levels Two

- way ANOVA with treatment and necropsy day (if >1 day) as main effects.

Pair

- wise comparisons were performed using Dunnett’s

two

- tailed t

- tests.

Initial body weights
Final body weight (use last day all body weights collected)
Final body weight gain (use last day all body weights collected)
Age and body weight at PPS
Tissue weights Two

- way analysis of covariance (ANCOVA) with PND 21 body weight (weight on day of allocation ) as the covariable.

Pair

- wise comparisons were perform ed using Dunnett’s

two

- tailed t

- tests.

In the instances where PPS had not occurred prior to necropsy, the last day of examination plus 1 was used as the age at PPS and terminal body weight was used for body weight at PPS. In instances when at least 1 animal in any group exhibited incomplete PPS, including partial threads for >3 days, the day partial separation was first recorded was used in the analyses.

Thyroid scoring (colloid area and follicular cell height) Fisher’s Exact test



## Significance was reported as exact p -values, except no p-value was reported for Dunn's Test (p<0.05) . The statistical analyses were considered appropriate.

C. METHODS

1. Mortality and C linical Examinations : Animals were observed twice daily for mortalityMale Pubertal Assay (2012) / Page 7 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## and moribundity on weekdays and once daily on weekends and holidays. Rats were observed prior to allocation of animals to study groups, daily prior to dose administration, and prior to euthanasia.

2. Body W eight : Body weights were collected weekly following birth, prior to allocation of animals to study groups, daily prior to dose administration, and prior to euthanasia.

3. Food Consumption : Food consumption was not measured.

4. Preputial Separation (PPS) : Beginning on PND 30, males were examined daily following dosing, and PPS was noted as: progression not initiated, partial separation, a persistent thread of tissue between the glans and prepuce, or complete PPS

.

5. Sacrifice and Pathology : At least 2 hours after the final dose administration, animals were humanely euthanized by decapitation, in the same order as they were dosed. After euthanasia and prior to tissue collection, trunk blood was collected, and serum was obtained. All serum samples were stored at or below

− 70°C. Serum samples were shippe d on dry ice to AniLytics Inc. ( Gaithersburg, MD) for analysis.

a. Hormone Analysis : Testosterone, T 4 

## , and TSH were measured in serum using radioimmunoassays (RIAs). Samples were assayed in duplicate and in conjunction with multiple quality c ontrol samples.

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 Total cholesterol

X Potassium Globulins

X Sodium Glucose

ENZYMES X Total bilirubin

X Alkali ne phosphatase (ALP ) X Total protein

Cholinesterase (ChE) Triglycerides

Creatine phosphokinase Albumin/globulin ratio (calculated)

Lactic acid dehydrogenase (LDH) Bile acids

X Alanine aminotransferase (ALT/also SGPT)

X Aspartate aminotransferase (AST/also SGOT)

X Sorbitol dehydrogenase

X Gamma glutamyl transferase (GGT)

Glutamate dehydrogenase

* Recommended for the pubertal assay in male rats based on guideline 890.1 500.



## c. Organ W eights and Histopathology : The following CHECKED (X) tissues were collected and weighed and grossly observed from all study animals

.Male Pubertal Assay (2012) / Page 8 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None

UROGENITAL OTHER

X Testes (left and right separately) * + X Thyroid a * +

X 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*

X Kidneys (paired)* +

Gross lesions and masses

a Thyroid was weighed post

- fixation.

* Weights required based on guideline 890.1 50 0.

+ Histopathological examination required based on guideline 890.1 50 0.



## Left kidney and thyroid were fixed in 10% neutral buffered formalin for at least 24 -hours. Left testis and left epididymis were each placed in Bouin’s fixative for 18- to 24-hours and then washed in 70% histology grade alcohol. After fixation, tissues were transferred to 70% histology grade alcohol, histologically proce ssed, embedded, sectioned, and stained with hematoxylin and eosin . Histologically

- processed tissues (thyroid, kidneys, epididymis, and testis) from all animals were microscopically evaluated. Two sections of each of the 2 lobes of the thyroid were examined and evaluated for follicular cell height and colloid area. A 5-point grading scale (1 = shortest/smallest; 5 = tallest/largest) was used , and the thyroids were evaluated relative to photomicrographs supplied by the U.S. EPA.

II. RESULTS

A. Mortality : All animals survived.

B. Clinical Signs of Toxicity : No treatment

- related clinical signs were observed in animals

f rom any dose group 24 hours post-dose. However, it was noted in the report that t remors were observed in 6/16 animals receiving 10 mg/kg/day (during one day only ) and in eleven 20 mg/kg/day rats (on 16 days).

C. General Growth and Preputial Separation : Body weights, body weight gains, age of

attainment of preputial separation ( PPS ), weight at PPS , and proportion/incide nce of unseparated preputia are presented in Table 2 below.

Body weight gains (adjusted and unadjusted) were decreased (p≤0.05) by 6 -7% in the treated groups. Final body weights (adjusted and unadjusted) were decreased by 6% (p≤0.05) at 10 mg/kg/day and by 4% (NS) at 20 mg/kg/day.

There was no treatment

- related effect on PPS at either dose level . Although a djusted age at

PPS showed a statistically significant increase at 10 mg/kg/day (PND 45.4 treated vs. PND 43.7 controls; 1.7 days), this difference is considered to be within biological variation. Body weight at PPS, age at partial PPS, and initial body weight were similar in the treated

groups compared to the control.Male Pubertal Assay (2012) / Page 9 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## The following performance criteria were outside of the specified values : %CV= 11.7% for body weight at PPS ( top o f acceptable range: 7.57%); and %CV= 7.7% for final body weight (top of acceptable range: 7.47%). Additionally, weaning weight (PND 21) was not reported.

TABLE 2 . General Growth and Preputial Separation (PPS) a

Parameter Evaluated Vehicle Control 1 0 mg/kg/day Phosmet 2 0 mg/kg/day Phosmet

N Mean SD CV (%) N Mean SD CV

(%) N Mean SD CV

(%)

Age at PPS (PND) U 15 43.6 2.1 4.8 16 45.3 2.4 5.3 15 44.7 1.5 3.3

A 15 43.7

--- --- 16 45.4*

--- --- 15 44.6

--- ---
Body weight at PPS (g) U 15 226.1 26.5 11.7 16 225.4 17.6 7.8 15 228.5 17.0 7.5

A 15 227.0

--- --- 16 226.4

--- --- 15 227.6

--- ---

Age at partial PPS (PND) U 12 41.7 0.9 2.1 14 41.1 1.4 3.4 9 41.4 1.1 2.7

A 12 41.7

--- --- 14 41.1

--- --- 9 41.4

--- ---

Initial body weight
(PND 23; g) U 16 62.2 4.1 6.6 16 61.9 5.0 8.1 16 63.8 4.1 6.4

A 16 62.2

--- --- 16 62.1

--- --- 16 63.5

--- ---

Final body weight (g) U 16 313.2 24.0 7.7 16 294.5* (↓6) 17.8 6.1 16 300.3 (↓4) 18.6 6.2

A 16 313.3

--- --- 16 295.0* (↓6) --- --- 16 299.8 (↓4) --- ---

Final body weight

(% of control) U 16

--- --- --- 16 94.0

--- --- 16 95.9

--- ---

A 16

--- --- --- 16 94.2

--- --- 16 95.7

--- ---

Body weight gain

(final

– initial; g) U 16 256.3 21.6 8.4 16 237.5* (↓7) 18.1 7.6 16 239.9* (↓6) 19.0 7.9

A 16 256.3

--- --- 16 237.8* (↓7) --- --- 16 239.6 * (↓7) --- ---

Proportion unseparated (#/N) 1/16 0/16 1/16

a Data were obtained from Table 21 on page 45 of the study report

. Percent difference from controls (calculated by reviewers) is presented parenthetically.

U Unadjusted for body weight on PND 23

A Adjusted for body weight on PND 23

N Number of animals examined

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05.



## D. Organ Weights : Organ weights at necropsy are presented in Table 3 below. The adjusted ventral prostate weights showed a linear trend of decreased (p≤0.05) weight with increasing

dose (↓9 -15%); however, no statistically significant effect was detected between the treated groups and control using Dunnett’s test. It is noted that some of the criteria values CV(%)

w ere greater than the specified range. No other trend or statistically significant effect was detected for the sex tissues or any other organ weighed.

The following performance criteria were outside of the specified ranges : (i) mean kidney weight of 2.07 g (acceptable range : 2.242–3.050 g ); (ii) %CV=2 9.9% for seminal vesicles with coagulating gland and fluid (top acceptable range: 21.06% ); (iii) %CV=2 3.3% forMale Pubertal Assay (2012) / Page 10 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## ventral prostate (top acceptable range: 22.32%); (iv) %CV=27.4% for left epididymis (top acceptable range: 16.39% ; right epididymis was within acceptable range); and (v) mean thyroid weight of 27.0 m g (acceptable range: 14 –26 mg ).

TABLE 3 . Organ Weights at Necropsy a

Organ Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

Liver
(g) U 16 14.39 1.59 11 16 13.84 1.43 10.4 16 13.79 1.36 9.9

A 16 14.39

- - 16 13.87

- - 16 13.76

- -

R 16 4.51 0.25 5.5 16 4.62 0.31 6.8 16 4.54 0.26 5.7

Kidneys
(g) U 16 2.07 0.17 8.1 16 2 0.18 9.1 16 2.06 0.21 10.4

A 16 2.07

- - 16 2

- - 16 2.06

- -

R 16 0.65 0.03 4.2 16 0.67 0.04 5.7 16 0.68 0.05 7.4

Pituitary
(mg) U 16 10 1.5 14.9 16 9.2 1.7 18.5 16 9.8 1.2 12.5

A 16 10

- - 16 9.2

- - 16 9.8

- -

R 16 3.1 0.5 16 16 3.1 0.6 18 16 3.2 0.4 13.4

Adrenals
(mg) U 16 49.8 10.5 21 16 44.7 8.6 19.3 16 45.1 5.9 13

A 16 49.9

- - 16 44.9

- - 16 45

- -

R 16 15.6 2.7 17.1 16 14.9 2.6 17.4 16 14.9 1.9 12.9

Seminal vesicle + coagulating gland, with fluid (mg) U 16 558 167 29.9 16 497.9 112.7 22.6 16 476.5 96.8 20.3

A 16 558

- - 16 498.2

- - 16 476.2

- -

Seminal vesicle + coagulating gland, without fluid (mg) U 16 354.7 83.8 23.6 16 316 54.1 17.1 16 320.5 57.3 17.9

A 16 354.7

- - 16 316.1

- - 16 320.3

- -

Ventral prostate (mg) U 16 238.8 55.7 23.3 16 216.6 43.9 20.3 16 205.3 36.8 17.9

A c 16 238.9

- - 16 217.7 (↓9) - - 16 204.1 (↓15) - -

Dorsolateral prostate (mg) U 16 148.8 27.6 18.5 16 140.3 31.5 22.5 16 146.8 33.9 23.1

A 16 148.8

- - 16 140.1

- - 16 146.9

- -

LABC
(mg) U 16 529.8 62.9 11.9 16 513.4 66.8 13 16 549.6 61.4 11.2

A 16 529.8

- - 16 513.5

- - 16 549.6

- -
Epididymis, left (mg) U 15 b 191.8 52.6 27.4 16 209.5 22 10.5 16 205.4 18.4 9

A 15 b 204.3

- - 16 209.9

- - 16 205.2

- - Epididymis, right (mg) U 16 212.9 14.6 6.9 16 211.9 25.2 11.9 16 208 16.2 7.8

A 16
- - - 16
- - - 16
- - -
Testis, left (mg) U 15 b 1343.3 372.6 27.7 16 1406.1 111.1 7.9 16 1367.1 93.3 6.8

A 15 b 1432.6

- - 16 1406.8

- - 16 1366.6

- - Testis, right (mg) U 16 1481.1 154.9 10.5 16 1403.4 106 7.6 16 1396.2 107 7.7

A 16 1481.2

- - 16 1403.8

- - 16 1395.8

- -Male Pubertal Assay (2012) / Page 11 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



### TABLE 3 . Organ Weights at Necropsy a

Organ Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

Thyroid, fixed
(mg) U 16 27 8.9 33.1 16 23.8 3.7 15.4 16 25.3 4 15.8

A 16 25

- - 16 23.8

- - 16 25.3

- -

a Data were obtained from Table 22 on page s 47–48 of the study report. No differences (p≤0.05) were noted between treated groups and controls.

b One animal removed due to potential recording error.

c Significant trend (p<0.05)

U Unadjusted for body weight on PND 23

A Adjusted for body weight on PND 23

R Organ

- to

- body weight ratio (relative to body weight)

SD Standard Deviation

CV Coefficient of Variation



## E. Clinical Chemistry and Hormone Levels : Clinical chemistry and h ormone levels are presented in Table 4 below.

Serum T 4 

## levels were increased (p<0.0001) at both dose levels ( ↑ 48% at 10 mg/kg/day and ↑ 43 % at 20 mg/kg/day) compared to the control. Serum TSH was slightly increased ( ↑ 7%- 8%) to a similar extent at both dose levels compared to the control, although the control value was low (3.63 ng/mL) compared to the acceptable range (4.212-24.112 ng/mL) and

the performance criteria were not met . T estosterone levels in the treated groups were lower than the control ( ↓ 18% at 10 mg/kg/day and ↓ 12% at 20 mg/kg/day), but statistical significance was not attained , and the means were within the background levels.

The following performance criteria were outside of the specified ranges : mean serum TSH level of 3.63 ng/m L (acceptable range: 4. 212–24.112 ng/mL ); and %CV=61.2% for serum TSH (top acceptable range: 58.29% ).

The following clinical chemistry parameters differed (p<0.05) in the 20 mg/kg/day group compared to controls: (i) sodium (↓ 2%); (ii) potassium (↓8%); (iii) phosphorus (↓9 %); (iv) aspartate transferase (↓14 %); and (v) creatinine (↓12 %) . The values for sodium and aspartate transferase were within the range of control values; all values for potassium and phosphorus were slightly above the range of control values; and all values for creatinine were slightly below the range of control values. These small variatio ns were not considered to be indicative of toxic effects on the kidney or liver. All measured clinical chemistry parameters in the 10 mg/kg/day group were similar to controls.

TABLE 4 . Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N b Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

Hormones

Serum T 4 , Total 15 4.13 0.72 17.3 16 6.10* (↑48) 0.81 13.3 16 5.91* (↑43) 0.99 16.7Male Pubertal Assay (2012) / Page 12 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



### TABLE 4 . Hormone Levels and Clinical Chemistry a

Parameter

Evaluated Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

N b Mean SD CV

(%) N Mean SD CV

(%) N Mean SD CV

(%)

(μg/dL)

Serum TSH (ng/mL) 15 3.63 2.22 61.2 16 3.92 2.24 57.0 16 3.89 2.53 65.0

Serum

testosterone (ng/ m L) 15 2.04 0.92 45.1 16 1.67 0.99 59.0 16 1.80 1.62 90.1

Clinical Chemistry

Sodium (mEq/L) 15 153 2 1 16 151 4 2 16 150 * (↓2) 3 2

Potassium (mEq/L) 15 9.1 0.6 6.8 16 8.7 0.6 7 16 8.4 * (↓8) 0.8 9.2

Chloride (mEq/L) 15 114 2 2 16 112 2 2 16 113 2 2

Calcium (mg/dL) 15 10.9 0.3 2.6 16 10.8 0.5 4.8 16 10.8 0.3 3.1

Phosphorus (mg/dL) 15 10.7 0.9 8.8 16 10.4 0.9 8.3 16 9.7 * (↓9) 0.8 8

AST (U/L) 15 217 42 19 16 213 43 20 16 186 * (↓14) 26 14

ALT (U/L) 15 93 15 16 16 97 14 14 16 90 11 12

GGT (U/L) 15 0

--- --- 16 0.2 0.5 290 16 0.2 0.8 400

ALP (U/L) 15 318 72 23 16 325 62 19 16 320 58 18

BUN (mg/dL) 15 14 2 13 16 15 3 19 16 15 2 15

Creatinine (mg/dL) 15 0.43 0.06 14.2 16 0.39 (↓10) 0.07 17.3 16 0.38 * (↓12) 0.06 15.4

Total

Bilirubin (mg/dL) 15 0.1 0.15 146 16 0.08 0.1 133 16 0.18 0.16 92.1

SDH (U/L) 15 20 3 17 16 22 3 16 16 20 4 18

Total

Protein (g/dL) 15 5.8 0.3 5.3 16 5.7 0.3 5 16 5.6 0.3 5.1

Albumin (g/dL) 15 4.2 0.3 6.3 16 4.2 0.3 6 16 4.1 0.3 6.7

a Data were obtained from Table 23 on page 50 and Table 24 on page 51 of the study report. Percent difference from controls (calculated by reviewers) is presented parenthetically.

SD Standard Deviation

CV Coefficient of Variation

* Significantly different from controls at p<0.05.

* Significantly different from controls at p<0.01.

* Significantly different from controls at p<0.001.



## F. Gross pathology : There were no effects of treatment observed at necropsy. In one control rat, th e right testis was noted as enlarged, the left testis and epididymis were noted as markedly small, and the seminal vesicle was also noted as being small . No other gross observations were noted in male rats surviving to the scheduled termination.Male Pubertal Assay (2012) / Page 13 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## G. Histop athology : The incidences of histopathological findings of the thyroid gland are presented below in Table 5 ; follicular cell shape was not reported . A marginal increase in

the colloid area and decrease in the follicular cell height was observed in animals administered phosmet (10 and 20 mg/kg) compared to controls. The number of rats with

G rade 3 follicular colloid area decreased in a dose

- related manner from 10/16 in the control (62%) , to 6 /1 6 at 10 mg/kg/day (38%), and 3 /1 6 at 20 mg/kg/day (18%)

. Similarly, the

number of animals having G rade 4 increased in a dose-related manner from 6/16 in the

control (38%) , to 10/16 at 10 mg/kg/day (62%), and 12/16 at 20 mg/kg/day (75%)

. There

was a dose

- related increase in the number of rats with Grade 2 follicular cell height (6/16 in

the control (38%) , 10/16 at 10 mg/kg/day (62%) , and 12 /1 6 at 20 mg/kg/day (75% ), and a

dose- related decrease in the number of the animals with G rade 3 follicular cell height (10/16 in the control (38%), 6/16 at 10 mg/kg/day (62%), and 3/16 at 20 mg/kg/day (18%).

TABLE 5 . Incidence of Histopathological Lesions of the Thyroid Gland a

Treatment Groups Parameter Evaluated

Colloid Area Follicular Cell Height

Grade b Incidence Grade b Incidence

O E O E

Vehicle Control 1 0 16 1 0 16

2 0 16 2 6 16

3 10 16 3 10 16

4 6 16 4 0 16

5 0 16 5 0 16

10 mg/kg/day

Phosmet 1 0 16 1 0 16

2 0 16 2 10 16

3 6 16 3 6 16

4 10 16 4 0 16

5 0 16 5 0 16

20 mg/kg/day

Phosmet 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

a Data were obtained from Table 26 on page 53 of the study report.

b A 5

- point grading scale (1 = smallest / shortest ; 5 = largest /tallest ) was used.

O No. Observed

E No. Examined



## The incidence of histopathological findings of the testes, epididymides, liver, thyroid, and kidneys are presented in Table 6. There were no treatment -related histopathological findings noted in the testes, epididymides, or kidneys at any dose.Male Pubertal Assay (2012) / Page 14 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



### TABLE 6 . Incidence of Histopathological Lesions of the Epididymides , T estis

, and Kidney a

Findings Dose Level

Vehicle Control 10 mg/kg/day Phosmet 20 mg/kg/day Phosmet

#

Observed #

Examined #

Observed #

Examined #

Observed #

Examined

Epididymides

Minimal interstitium inflammation 5 16 6 16 4 16

Minimal aberrant cells in tubule

lumen 15 16 15 16 13 16

Mild aberrant cells in tubule lumen 0 16 0 16 1 16

Marked atrophy 1 16 0 16 0 16

Testis

Minimal cellular debris in the

seminiferous tubules 0 16 4 16 2 16

Minimal atrophy/hypoplasia 2 16 1 16 0 16

Marked atrophy/hypoplasia 1 16 0 16 0 16

Kidneys

Minimal nephropathy 13 16 8 16 8 16

Minimal tubular dilatation 4 16 4 16 2 16

Minimal cysts 0 16 0 16 1 16

a Data were obtained from Appendi x X on page s 160 , 162, and 164 of the study report.



## III

. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR’S CONCLUSIONS : Administration of phosmet to intact juvenile/peripubertal male rats at a dose that met, but did not exceed the MTD, did not cause changes in any endpoints evaluated to suggest a disruption in pubertal development or thyroid function.

B. AGENCY COMMENTS : No treatment

- related related effect s w ere observed on survival,

b ody weight at PPS, age at partial PPS, organ weights, serum TSH and testosterone levels, clinical chemistry, necropsy, or histology at dose up to 20 mg/kg/day.

No clinical signs of toxicity wer e observed at either dose level at the time of dosing throughout the study. However, tremors were observed periodically in the majority of the rats at 20 mg/kg/day.

The decreases in body weight gains and final body weights were minimal and not biologically significant

. The small variations in clinical chemistry parameters observed at 20 mg/kg/day were not considered to be indicative of toxic effects on the kidney or liver.

There was no treatment

- related effect on PPS at either dose level.Male Pubertal Assay (2012) / Page 15 of 15

PHOSMET / 059201 OCSPP 890.1500/ OECD None



## The adjusted ventral prostate weights showed a linear trend of decreased weight with increasing dose; however, no statistically significant effect was detected between the treated groups and control using Dunnett’s test. Both means were lower than histori cal control mean ventral weight for Sprague

- Dawley male rats but were within the acceptable range.

Serum T 4 

## levels were increased in both treatment groups compared to the concurrent control

and mean value s for Sprague

- Dawley male rats , but they were within the acceptable range in the performance criteria

. Additionally , these increases were within the range of control values provided by the analytical laboratory (3- 7 μg/dL ).

A marginal decrease in the follicular cell height and an increase in the colloid area were observed in animals administered phosmet at both dose levels compared to controls. There

were no treatment -related histopathological findings in the testes, epididymides, or kidneys

at either dose level.

During the agency’s initial rev iew, t he doses (10 and 20 mg/kg/day) used in this study were considered excessive, based on the dose- selection rationale and the periodic occurrence of tremors in the majority of the males at 20 mg/kg/day. Subsequently, the registrant submitted additional data (MRID 4961502) in response to the agency’s review of this assay. The submitted data show at the 10 mg/kg/day dose level, mild tremors were seen during one day only in 6/16 animals. In contrast, the severity of tremors at the 20 mg/kg/day dose level ranged from mild to moderate and were seen on multiple days in 11/16 animals. Based on this additional information, the low dose was determined to be adequate with only the high dose showing evidence of overt toxicity.

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:

• CV=11.7% for body weight at PPS (top of acceptable range: 7.57%)

• CV=7.7% for final body weight (top of acceptable range: 7.47%)

• weaning weight (PND 21) was not reported

• mean kidney weight of 2.07 g (acceptable range: 2.242–3.050 g)

• CV=29.9% for seminal vesicles with coagulating gland and fluid (top acceptable range: 21.06%)

• CV=23.3% for ventral prostate (top acceptable range: 22.32%)

• CV=27.4% for left epididymis (top acceptable range: 16.39 %; right epididymis was within acceptable range)

• mean thyroid weight of 27.0 m g (acceptable range: 14 –26 mg )

• mean serum TSH level of 3.63 ng/mL (acceptable range: 4.212 –24.112 ng/mL )

• CV=61.2% for serum TS H (top acceptable range: 58.29%)

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CSPP 890.1550, Steroidogenesis Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618701)

Prepared for

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

Arlington, VA 22202

Prepared by 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: 12/19/2011

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 12/19/2011

Program Manager: Signature: Jack D. Early, M.S. Date: 12/ 27 /2011

Quality Assurance: Signature: Jack D. Early, M.S. Date: 12/ 27 /2011

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

### PHOSMET I 

### 059201



## Primary Reviewer: Gregory Akerman



## Health Effects Division Secondary Reviewer: John Liccione, Ph.D.



## Health Effects Division Steroidogenesis Assay (2011) I 

### Pag e 1 of 14

OCSPP 890.1550/ OECD None



## Signature:

# ~,.If--:.**Date~**

Signature:

Date.

- - Template version 0812011



## DATA EVALUATION RECORD

STUDY TYPE : Steroidogenesis Assay (H295R Cells); OCSPP 890.1550



## PC CODE: 059201 

## DP BARCODE: 0397165

TXR#: 0056199 

## CAS No.: 732-11-6



## TEST MATERIAL (PURITY): Phosmet (96.8% a.i.)



## SYNONYMS: S-[( l

, 3-dihydro-l

, 3-dioxo-2H-isoindol-2-yl)methyl] 0

, 0-dimethy l phosphorodithioate



## CITATION: Wagner

, H. (2011). Phosmet: H295R Steroidogenesis Assay. CeeTox, Inc.,

Kalamazoo

, Ml. Laboratory Study No. 9142V-100348STER, November 3,

201 I. MRID 48618701. Unpublished.



## SPONSOR: Gowan

, 370 Main Street

, Yuma

, AZ 85364



## TEST ORDER#: EDSP-059201 -54



## EXECUTIVE SUMMARY: In a steroidoge n esis assay (MRID 48618701)

, H295R cells

culture d in vitro in 24-well plates we re incubat ed w ith phosmet (96.8% purity, Batch# GQH9118000) at concentrations of 100

, IO

, 1

, 0

. 1

, 0.01, 0.001, and 0 .000 1 μM for 48 hours in triplicate for four independent experiments. Run 1 was not analyzed because one of the forskolin

concentrat ions o n the quality contro l plate was different than the proposed conce ntration outlined

in the test guideline (3.33 μM was used in stead of l μM). Dimethyl sulfoxide (DMSO) was used

as a vehicle, at a final co n centration of 0.05% v / v.

Testosterone and estradio l levels were measured using HPLC-MS/MS. A Quality Control (QC) plate was run concurrently with each independent run of a test chemical plate to demonstrate that

the assay responded properly to positive control agents at two concentration le ve l s. Positive

contro l s included the known inhibitor (prochloraz) and inducer (forskolin) of estrad iol and

testosterone production.

All guide lin e acceptability recommendations and requirements were met

, including l ack of cytotoxicity, adequate production of testosterone and estradio l, acceptable reproducibi lity (low

% CV)

, and appropriate indu ction and inhibi tion with positive controls.

Neither testosterone nor estradio l concentrations were affected by phosmet. Decreases (p<0.05)

of I 

## 0-11 % in estradiol concentration were observed at 0.0001, 0.001, and 0.0 I μM of phosmet in

Run 2, but not at hi gher co n ce ntration s nor at any concentration in the other runs. An 

## increaseSteroidogenesis Assay ( 2011 ) / Page 2 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## (p≤0.05) of 10% in estradiol concentration was observed at 100 μM of phosmet in only one of

the three runs.

Based on hormone responses in each of three independent runs, phosmet treatment did not result in statistically significant and reproducible alteration s in testosterone or estradiol production.

Th e assay satisfies / the EDSP Tier 1 Test Order requirement s for a Steroidogenesis a ssay (OCSPP 890.1550).

COMPLIANCE : Signed and dated GLP Compliance and Quality Assurance statements were provided.Steroidogenesis Assay ( 2011 ) / Page 3 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : CeeTox

Location: Kalamazoo, MI Study Director: Hilary Wagner, M.S.

Other Personnel: Colleen Tool e , Ph.D., Director of Project Management Karen Rutherford, B.S., Director of Laboratory Operations David Blakeman, B.S., Senior Scientist/Endocrine Group Leader
Briana Wallace, B.S., Lead Cell Culture Scientist Steven McColley, M.S., Scientist
Cameron Haines, B.S., Scientist Francisca Wong, M.S., Scientist Joey Burgam, B.S., Associate Scientist
Lisa Blakeman, B.S., Associate Scientist Study Period: July 1 5, 2011 through November 2, 2011



## 2

. Test S ubstance : Phosmet

Description: Off

- white crystals Batch # (expiration date): GQH9118000 (January 31, 2013) Purity: 96.8% a.i. Solubility (in solvent): Approximately 10

− 3.5 M Vapor pressure at 25°C: 0.065 mPa Stability: Not reported Storage conditions: Room temperature

CAS #: 732

- 11

- 6 Molecular weight: 317.3

Structure:



## 3

. Positive C ontrol : Forskolin

Description (molecular weight) : White powder (410.50)

Source: Sigma Aldrich (St. Louis, MO)

Lot # ( expiration d ate) : 109K50571V (July 2016) Purity: 98% Solubility (in s olvent): DMSO Storage conditions: Room temperature

CAS #: 66575

- 29

- 9



## 4. Negative C ontrol : Prochloraz

Description (molecular weight): White powder (376.67)

Source: Sigma Aldrich (St. Louis, MO) Lot # (expiration date): SZE6220X ( August 8, 2012 ) Purity: 99.1 % Solubility (in solvent): DMSO Storage conditions: Room temperature

CAS #: 6 7747

- 09

- 5Steroidogenesis Assay ( 2011 ) / Page 4 of 14

PHOSMET / 059201 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): RNBB7617 ( Not provided ) Purity: Not provided Storage conditions: Sigma

- Aldrich (Cat. # D2650)

CAS #: 67

- 68

- 5

Justification for choice of

solvent: Not provided

Final concentration in assay : 0.05 % v/v



## 6. Other Materials : 22R

- Hydroxycholesterol

Description (molecular weight) : White powder (402.65)

Source: Sigma

- Aldrich (St. Louis, MO) Lot # (expiration date): 089K4132, 060M4098 (not provided) Purity: 99.0% Storage conditions: Room temperature

Solvent used: Ethanol, final concentration in assay, 0.025% v/v

CAS #: 17954

- 98

- 2



## 7. Stock Medium : Dulbecco’s modified Eagle’s medium/nutrient mixture F12

Ham

Source: Sigma

- Aldrich (St. Louis, MO) Lot # (expiration date): 021M8304 ( not provided )

HEPES: 15 mM; Sigma

- Aldrich (St. Louis, MO); Lot # 021M8304

Sodium bicarbonate : Sigma

- Aldrich (St. Louis, MO); Lot # 068K0105 ; purity not reported

Nu

- Serum : 2.5%; Becton

- Dickinson (Franklin Lakes, NJ ) ; Catalog # 355500 ; Lot # 81515 ) ; tested for background hormone concentrations by performing laboratory

ITS+ premix: Becton

- Dickinson (Franklin Lakes, NJ ) ; Catalog # 354352; Lot # 05245, 09233)



## 8

. Test C ells : H295R human adrenocortical carcinoma cells (ATCC CLR

- 2128; l ot # 7635054). Cells were used in the assay at passage 7.5 – 8.5 and were incubated in the stock medium supplemented with 10 μM 22R- hydroxycholesterol in ethanol at the time of platin g, dosing, and harvest. Incubation conditions were at 5% CO 2 

## and 37±2°C for approximately 24 hours prior to exposure.

The following performance criteria were met (indicated by an “x”) :

x Cell passage identifier . Cell Passage # : 7.5

– 8.5

X Cells frozen down at passage 5

x Frozen cells cultured for at least 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 hormone assay interference test was not performed.

b. Hormone Extraction : See Section on “Hormone Measurement Section.”

c. Laboratory Proficiency Test : The laboratory proficiency test data were not provided.Steroidogenesis Assay ( 2011 ) / Page 5 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## 2. Test Solutions : Phosmet was dissolved in DMSO to make a 200 mM stock solution and then serially diluted in DMSO. 22R-Hydroxycholesterol was dissolved in ethanol to make a 40 mM stock and then diluted in supplemented medium to a final concentration of 10 μM.

Phosmet was then diluted in supplemented medium containing 10 μ M 22Rhydroxycholesterol to prepare mastermix solutions. Forskolin and prochloraz were dissolved in DMSO to make 100 mM solutions and then serially diluted in DMSO. Forskolin and prochloraz were then diluted in supplemented medium containing 10 μ M

22R- hydr oxycholesterol. 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 μM for prochloraz and 0.0001, 0.001, 0.01, 0.1, 1, 10, and 100 μM for phosmet, with the final concentration o f DMSO in the medium being held constant at 0.05% (v/v). The final ethanol concentration in the supplemented medium was 0.025% (v/v). No precipitation was visible.

3. Cell Plating and P reincubation : Cells were maintained in the Stock Medium described above. It was reported that hormone concentrations in undiluted Nu-Serum were 3754 pg/mL testosterone and 3846 pg/mL estradiol. H295R cells were grown for five passages, frozen in liquid nitrogen, then thawed and cultured for seven or eight additional passagesprior to use in the assay. The culture medium was supplemented with 10 uM 22Rhydroxycholesterol at the time of plating, dosing, and harvest. The concentration of 22Rhydroxycholesterol was chosen based on laboratory proficiency experiments previously conducted at the Performing Laboratory. The cells were plated into wells of a 24

- well cell culture plate at a density of approximately 300,000 cells/mL. The cells were then placed

into a 5% CO 2 

## incubator at 37±2°C for approximately 24 hours prior to chemical exposure. Prior to dosing, the cells were checked microscopically for attachment and proper morphology.

4. Exposure : The medium was removed from the cells and replaced with 1 mL of medium

co ntaining 10 μ M 22R- hydroxycholesterol and concentrations of test chemical in triplicate, according to the schematic presented in Table 1.

TABLE 1

. Dosing S chematic for the E xposure of H295R C ells to Phosmet ( F inal C oncentrations in μM). a

1 2 3 4 5 6

A DMSO DMSO DMSO 0.1 0.1 0.1

B 100 100 100 0.01 0.01 0.01

C 10 10 10 0.001 0.001 0.001

D 1 1 1 0.0001 0.0001 0.0001

a Data were obtained from page 13 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 14

PHOSMET / 059201 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 Background c Background Background

B DMSO DMSO DMSO DMSO + MeOH d DMSO + MeOH DMSO + MeOH

C Forskolin 1μM Forskolin 1μM Forskolin 1μM Prochloraz 0.1μM Prochloraz 0.1μM Prochloraz 0.1μM

D Forskolin 10μM Forskolin 10μM Forskolin 10μM Prochloraz 1μM Prochloraz 1μM Prochloraz 1μM

a Data were obtained from page 13 of the study report.

b Blank wells received medium containing 22R

- hydroxycholesterol

.

c Background wells received medium only.

d MeOH = methanol was added to these wells for 30 minutes at room temperature following medium removal.



## Following dosing, the plates were incubated for 48±2 hours under the conditions previously described. After the 48±2 hour exposure, each well was examined under the m icroscope and images were taken of the vehicle control wells as well as the two greatest non

- cytotoxic concentrations (based on observation under the microscope). The media was collected from all wells in two equal aliquots and stored at -80±10°C until shipment to the analytical laboratory for hormone measurement.

5. Cell V iability/ Cytotoxicity A ssay : After media removal, cell viability was measured by MTT assay. On the QC plates, wells designated to receive methanol (control wells for cell death measurements) were rinsed twice with phosphate buffered saline (PBS), then incubated in methanol for 30 minutes at room temperature. After the methanol incubation,

the methanol- treated wells were rinsed again with PBS three times. Following media removal and/or methanol treatment, 0.5 mL of 0.5 mg/mL MTT (Sigma, Cat#M5655, Lot#

MKBG161 1V) solution in supplemented medium containing 10 μM 22Rhydroxycholesterol was added to each well of the test chemical and QC plates. The plates

were incubated at 37±2°C in a 5% CO 2 

## incubator for 3 hours. Following the 3 hour incubation, the MTT solution was removed and 0.5 mL of isopropanol was added to each

well. Plates were incubated at room temperature for 20 minutes with shaking. Following this incubation, absorbance at 570 nm and 650 nm were measured on a Packard Fusion plate

reader. The absorbance at 650 nm was subtracted from the absorbance at 570 nm to calculate the MTT value for each well. The change in cell viability was determined by comparing treated wells to the solvent control (SC) wells. A greater than 20% reduction in cell viability was considered evidence of cytotoxicity.

6. Hormone M easurement S ystem : Testosterone and estradiol levels were measured at OpAns, LLC (Durham, NC). Testosterone and estradiol were extracted from H295R supplemented medium by liquid- liquid extraction using methyl tert

- butyl ether (MTBE) after the addition of [ 2 

## H 5 

## ]-testosterone and [ 2 

## H 5 

## ]- estradiol as internal standards. Extracts were analyzed by HPLC

- MS/MS using positive ion multiple reaction monitoring. This method was validated over the range 100 to 100,000 pg/mL for testosterone and 10 to 10,000 pg/mL for estradiol (OpAns Document Number OPR- OPP -0006). The lower limit of quantification (LLQ) was 100 pg/mL for testosterone and 10 pg/mL for estradiol using a 300 μL aliquot of H295R supplemented medium. Freshly prepared calibration standards (n = 7) were prepared in supplemen ted medium for each run. QC samples spiked in supplemented medium at three concentrations (2 replicates per concentration), were included with each run. No study samples were re-analyzed during this study.Steroidogenesis Assay ( 2011 ) / Page 7 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## The following performance criteria were met (i ndicated 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

- reactivity (antibody

- based assays only; ≤30% of basal production of the respective hormone)

NR Solvent control within 75% range below maximum response on standard curve

X Test compound tested for interference with measurement system



## C. DATA ANALYSIS : Mean values (pg/mL) and standard deviations for testosterone and estradiol were calculated for each concentration of the test chemical, reference chemicals, and the solvent controls. Relative changes in testosterone and estradiol production were calculated using the equation below:

Relative Change = [Hormone] in each well ÷ [Hormone] of mean solvent (vehicle) control

For forskolin induction of testosterone, relative change was calculated both with and without subtracting the background hormone production from the forskolin- treated wells and blank and solvent control wells. This was done because of the high background production of testosterone and the small dynamic range for forskolin induction. Background hormoneproduction was calculated from three wells with cells on the QC plate that received no 22Rhydroxycholesterol at the time of exposure.

Normality of the d ata was evaluated using Shapiro

- Wilk's test. Homogeneity of the variances between the treatment groups was evaluated using Levene's test. If the p

- values were greater than 0.05 in both tests, statistical significance between each treatment group and the control group was evaluated using Dunnett's test. If the p

- values were less than or equal to 0.05 in either the normality or the homogeneity test, a log transformation was performed on the data to attempt to approximate a normal distribution. If, following the transformation, p-values were greater than 0.05 in both the normality and homogeneity tests, Dunnett's test was performed on the transformed data to evaluate statistical significance between the each treatment group and the control group. If follow ing the log transformation, p-values were less than or equal to 0.05 in either the normality or the homogeneity test, the non- transformed data set was analyzed using the nonparametric

Kruskal- Wallis test followed by Dunn's test to evaluate statistical sign ificance between each treatment group and the control group. Data analysis was conducted in Microsoft Excel. Statistics were calculated using Unistat 6.0 Light for Excel. Graphs were generated using

Microsoft Excel.

II. RESULTS

A. TEST COMPOUND : Comp ared to the minimum detection level (MDL), b asal hormone production in the SC wells was 18 to 30- fold MDL for testosterone and 17 to 23- fold MDL

for estrogen. The between plate %CV for the SC based on absolute hormone concentrations

was 26% for testosterone and 14% for estradiol. The %CVs for the absolute concentration within replicate wells of a plate were 4.87-6.68% for testosterone and 2.25-5.32% for

estradiol . These values were below the maximum guideline recommended level of 30%.

The Sponsor stated: “Four independent runs of the steroidogenesis assay were conducted. Run 1 was not analyzed because one of the forskolin concentrations on the quality controlSteroidogenesis Assay ( 2011 ) / Page 8 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## plate was different than the proposed concentration outlined in the test guideline (3.33 uM was used instead of 1 uM). Data from Run 1 will not be presented in this report as the media was not analyzed for testosterone and estradiol.” The concentrations of estradiol and testosterone observed in the other three assay runs are summ arized in Table 3 and graphically depicted in Figures 1 and 2.

Neither testosterone or estradiol concentration was affected by phosmet. Decreases (p<0.05) of 10-11% in estradiol concentration were observed at 0.0001, 0.001, and 0.01 μM phosmet, but not at higher concentrations nor at any concentration in the other runs. An increase (p≤0.05) of 10% in estradiol concentration was observed at 100 μM phosmet in only 1 of the three runs.

TABLE 3

. Mean (±SD) Hormone Concentrations Following Treatment with Phosmet f or 48 Hours. a

Nominal

Concentration (μM) Run 2 Run 3 Run 4 Run 2 Run 3 Run 4 Mean b ± SD b Statistical Significance

Testosterone (pg/mL) Fold Difference

DMSO 3044±203 1801±93 2292±112 NA NA NA NA

--
0.0001 2778±108 1803±49 2351±19 0.91 1.00 1.03 0.98 0.06

—
0.001 2833±176 1858±75 2248±91 0.9 3 1.03 0.98 0.98 0.05

—
0.01 2781±40 1814±56 2303±134 0.91 1.01 1.00 0.97 0.06

—
0.1 2883±91 1904±56 2205±144 0.95 1.06 0.96 0.99 0.06

—
1 2981±113 1793±93 2422±14 0.98 1.00 1.06 1.01 0.04

—
10 2899±106 1892±108 2359±60 0.95 1.05 1.03 1.01 0.05

—
100 2813±84 1647±10 2223±41 0.92 0.91 0.97 0.93 0.03

— Estradiol (pg/mL) Fold Difference

DMSO 227±12 171±4 206±8 NA NA NA NA

--
0.0001 202±4 166±4 217±2 0.89* 0.97 1.06 0.97 0.09 Run 2

0.001 203±4 167±3 208±3 0.90* 0.97 1.01 0.96 0.06 Run 2

0.01 202±3 164±5 214±8 0.89* 0.96 1.04 0.96 0.08 Run 2

0.1 212±9 175±3 203±11 0.93 1.03 0.99 0.98 0.05

—
1 222±9 161±4 218±1 0.98 0.94 1.06 0.99 0.06

—
10 222±6 175±7 226±3 0.98 1.03 1.10 1.04 0.06

—
100 239±4 170±2 226±5 1.06 0.99 1.10* 1.05 0.06 Run 4

a Data were obtained from page s 25

- 26 and 32

- 34 of the study report. The lower limit of quantification (LLQ) was 100 pg/mL for testosterone and 10 pg/mL for estradiol.

b Calculated by the revi ewers.Steroidogenesis Assay ( 2011 ) / Page 9 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## FIGURE 1. Change in Testosterone P roduction Relative to Phosmet C oncentration.Steroidogenesis Assay ( 2011 ) / Page 10 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## FIGURE 2. Change in Estradiol Production Relative to Phosmet Concentration.

B. CYTOTOXICITY : It was stated that cytotoxicity was not assessed in Run 3 because the plate was dropped by the plate reader prior to data acquisition. Less than 5% cytotoxicitySteroidogenesis Assay ( 2011 ) / Page 11 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## was noted, except in the positive control (92-95% cytotoxicity ). Data are summarized in

Table 4 and depicted graphically in Figure 3.

T ABLE 4 . Mean (±SD) MTT Cell Viability Results after Treatment with F orskolin, Prochloraz, or

Phosmet for 48 Hours. a



### Compound Concen. ( μ M) Cell Viability

– Run 2 Cell Viability

– Run 3 Cell Viability

– Run 4

Mean SD Mean SD Mean SD

Blank N A 99.4 10.54 100.1 4.93 103 .0 1.84 

### Background NA 102.5 5.95 98.7 0.69 104 .0 1.76



### SC + Methanol NA 4.9 0.99 5.7 0.64 8.3 1.79



### Forskolin 1 103.9 3.88 97.2 2.2 107.3 0.91



### Forskolin 10 105.1 4.9 97.5 2.67 106.7 4.11



### Prochloraz 0.1 100.7 1.89 97.8 1.79 101.7 2.17



### Prochloraz 1 101.1 2.01 96.1 2.79 105 .0 4.29



### Phosmet 0.0001 95.4 2.8 0 ND ND 95.6 2.97



### Phosmet 0.001 98.3 1.6 0 ND ND 98 .0 1.12



### Phosmet 0.01 99.1 3.07 ND ND 97.7 0.92



### Phosmet 0.1 97.8 2.59 ND ND 99.2 0.37



### Phosmet 1 97.3 3.12 ND ND 101.6 3.54



### Phosmet 10 97.6 3.51 ND ND 99.4 1.58



### Phosmet 100 99.1 3.59 ND ND 99.4 4.51

a Data were obtained from pages 19

- 20 of the study report.

NA Not applicable

ND Not determined due to dropped plateSteroidogenesis Assay ( 2011 ) / Page 12 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## FIGURE 3. MTT cell viability results for phosmet- treated cells.

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 meanSteroidogenesis Assay ( 2011 ) / Page 13 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## ± 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. O CSPP 890.1550 guideline requirements for basal hormone production in SC wells, induction by 10 μM forskolin, and inhibition by 1 μM prochloraz were met for

testosterone and estradiol. Basal hormone production in SC wells was ≥ 5 -fold MDL for
testosterone and ≥ 2.5 -fold MDL for estrogen . Compared to SC, 10 μM forskolin on

ave rage induced testosterone 1.74- fold (instead of 2 -fold as per the guideline) and estradiol by 9.55-fold. However, when the background is subtracted, 10 μM forskolin induced testosterone an average of 2.74 -fold. Compared to SC, 1 μM prochloraz inhibited t he synthesis of testosterone to 0.48- fold and estradiol to 0.35-fold. Thus, the guideline requirements were met indicating that the assay was sensitive to induction and inhibition of

testosterone and estradiol.

The variability (%CV) between the runs (calculated by the reviewer) based on the absolute

hormone concentrations in the SC were 19 % for testosterone and 14 % for estradiol , which meets the guideline criteria of ≤30% for the assay. The %CVs within each run for the QC plates were 2.19 to 2.64% for testosterone and 1.89 to 4.01 % for estradiol.

TABLE 5 . Mean (±SD) Hormone Concentrations Following Treatment with Forskolin or Prochloraz for 48 Hours. a

Concentration (μM) Trial 1 Trial 2 Trial 3 Trial 1 Trial 2 Trial 3 Mean b ± SD b

Testosterone (pg/mL) Fold Difference (Relative to DMSO)
Background 1493 1035 1359 0.57 0.58 0.59 0.58 0.01

Blank 2921 1799 2338 1.12 1.01 1.01 1.05 0.06

DMSO 2612 1782 2319 1.00 1.00 1.00 1.00 0.00

1 μM Forskolin 4325 2403 3108 1.66 c 1.35 c 1.34 c 1.45 c 0.18

10 μM Forskolin 5604 2561 3765 2.15 d 1.44 d 1.62 d 1.74 d 0.37

0.1 μM Prochloraz 2145 1505 1843 0.82 0.84 0.79 0.82 0.03

1 μM Prochloraz 1351 740 1168 0.52 0.42 0.5 0 0.48 0.05

Estradiol (pg/mL) Fold Difference (Relative to DMSO)

Background 66 57 76 0.29 0.33 0.34 0.32 0.03

Blank 244 179 242 1.07 1.02 1.08 1.06 0.03

DMSO 229 175 223 1.00 1.00 1.00 1.00 0.00

1 μM Forskolin 1550 1014 1559 6.76 5.79 6.99 6.51 0.64

10 μM Forskolin 2396 1363 2321 10.46 7.78 10.41 9.55 1.53

0.1 μM Prochloraz 168 151 176 0.73 0.86 0.79 0.79 0.07

1 μM Prochloraz 77 62 78 0.34 0.36 0.35 0.35 0.01

a Data were obtained from page s 21

- 22 of the study report. The lower limit of quantification (LLQ) was 100 pg/mL for testosterone and 10 pg/mL for estradiol.

b Calculated by the reviewers.

c When the background is subtracted, t he values are 2.53

- , 1.83

- , and 1.82

- fold difference for Runs 2, 3, and 4, respectively,

with a mean of 2.06

- fold change.

d When the background is subtracted, the values are 3.67

- , 2.04

- , and 2.51

- fold difference for Runs 2, 3, and 4, respectively

, with a mean of 2.74

- fold change.



## III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : Phosmet did not induce or inhibit testosterone at any of the concentrations tested in the three independent runs of the assay. Based on theSteroidogenesis Assay ( 2011 ) / Page 14 of 14

PHOSMET / 059201 O CSPP 89 0. 1550/ OECD None



## results of the three independent assays using H295R cells, phosmet was not considered to be an inducer or inhibitor of estradiol or testosterone in this steroidogenesis assay.

B. AGENCY COMMENTS : All performance criteria were met, including lack of cytotoxicity, adequate production of testosterone and estradiol, acceptable reproducibility (low %CV), and appropriate induction and inhibition with positive controls.

Neither testosterone nor estradiol concentrations w ere affected by phosmet. Decreases (p<0.05) of 10-11% in estradiol concentration were observed at 0.0001, 0.001, and 0.01 μM phosmet, but not at higher concentrations nor at any concentration in the other runs. An increase (p≤0.05) of 10% in estradiol concentration was observed at 100 μM phosmet in only 1 of the three runs.

Based on hormone responses in each of three independent runs, phosmet treatment did not result in a statistically significant reproducible alteration in testosterone or estradiol production.

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 number of cell passages was 12-13, exceeding 10.

• The laboratory proficiency test data were not provided.

• Mean±SD and %CV for the fold

- differences were not reported.

# DATA EVALUATION RECORD

PHOSMET

Study Type: O CSPP 890.1600, In vivo Uterotrophic Assay

EPA Contract No. EP10H001452 Task Assignment No. 2-4-2012 (MRID 48618707)

Prepared for

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

Arlington, VA 22202

Prepared by Dynamac Corporation

1910 Sedwick Road, Building 100, Suite B

Durham, NC 27713

Primary Reviewer Signature: Rebecca Bryan, B.S

. Date: 12/05/11

Secondary Reviewer Signature:
Michael E. Viana, Ph.D., D.A.B.T. Date: 12/07/11

Program Manager: Signature: Jack D. Early, M.S. Date: 12 / 15 /2011

Quality Assurance: Signature: Jack D. Early, M.S. Date: 12 / 15 /2011

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

### PHO SME T / 059201



## Prim a ry Reviewer: S h e il a Healy. Ph.D. In 

### vivo Uterotrophic Assay (2011) I 

### Pa ge I of 7

OCSPP 890.1600 / OECD 440



## Health Effects Division Date:**--=-J.6..1....~::...L-_,.,__** 

## Secondary Reviewer : _""'"" Je=s= s""""

R =o;...;.w'"" l=an=d =--------- Signature: 

# d;?**~** 

# -**~** Health Effects Division Date: 

## <9.LSi t 

# r

Template version 0912011



## DATA EVALUATION RECORD

STUDY TYPE: Uterotrophic Assay (Rat); OCSPP 890.1600; OECD 440

PC CODE: 05920 1 DP BARCODE: D397165

TXR# : 0056199 CAS#: 732-11-6

TEST MATERIAL (PURITY): Pho smet (96.8% a.i.)

SYNONYMS: S -[ ( 1 ,3 -dihydro- 1

, 3 -di oxo-2H-isoindol-2

- y l )methyl] 

## 0

, 0-dimethy l phosphorodithioate; Imidan technical

CITATION : Zorrilla

, L., and Codrea

, E. (20 11 ). The Uterotrop hi c Assay with Phosmet in

O variecto mized CRL:CD(SD) I GS R ats. Integrated Laboratory Systems

, Inc.,

Durh a m
, NC. Laboratory Project Study ID: C194-100

, Octo b e r 1 9, 2011.

MRID 48618707. Unpublished.

SPONSOR: Gowan Company, P .O. Box 5569

, Yuma

, AZ

TEST ORDER# : EDSP-05920 1- 54

EXECUTIVE SUMMARY: In an uterotrophic assay (MRI D 48618707) con du cted to screen
fo r pot e ntial estrogenic act i vity

, phosm e t (96.8% a.i., Batch# 6QH9118000) in 0.5 % carboxymethyl ce llulo se was a dmini stered daily v i a oral gavage to gro up s of eight

ovariectomized female Sprague-Dawley rats at dose le ve l s ofO (vehicle)

, 5

, or 20 mg/kg/day on post-natal da ys (PND) 63-65. A posi t ive contro l gro up was treated with 17a-ethynyl estradiol
(EE) by daily ora l gavage at a dose le ve l of O.l mg/kg/day. All animals were terminated and necropsied on PN D 66 ap pr oximate l y 2 4 hour s after the final dose to determine wet and blotted

ut erine weights.

All ani m als s urvived until sched ul ed terminat i on. Two 20 mg/k g/ da y rats had decreased

movements at 1- 4 h post-dosing on D ays 1 and 2. Body weig h ts in the do se gr o ups were

co mp arab le to the controls throughout the duration of th e assay. Uterine we i g ht s in the dose

groups we r e comparable to the controls. Absol ut e wet and blotted uterus we ights for the 0

. 1 mg/kg/day EE group were increased (p < 0.05) b y 407% and 23 1 %, respectively.

The dose level s se lected for this study are adequate based on previously conducted stud i es which

showed no mortality at doses up to 27 mg/kg/day an d significant c h olinesterase inhibition at 10

m g/kg/day.

N o statistica ll y s ignificant changes were see n in u terine weig h t in this assay. Pho smet was negative in the ut erotrop hic assay.In vivo Uterotrophic Assay (2011) / Page 2 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



## Th e assay satisf ies the EDSP Tier 1 Test Order requirements for a uterotrophic assay (OCSPP 890.1600).

COMPLIANCE : Signed and dated GLP Compliance and Quality Assurance statements were provided.In vivo Uterotrophic Assay (2011) / Page 3 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



## I. MATERIALS AND METHODS

A. MATERIALS

1. Test Facility : Integrated Laboratory Systems, Inc.

Location: Durham, NC Study Director: L. Zorrilla

Other Personnel: Study Period: May 3

- 6 , 2011



## 2

. Test S ubstance : Phosmet

Description: Off white solid

Source: Gowan Company (commercial technical product)

Batch #: 6QH9118000, expires January 13, 2012 Purity: 96.8 % a.i. Stability: Stable in the vehicle for up to 8 days at 1

- 10 ° C (Smithers Viscient Inc., Study No. 12791

- 6159)

CAS #: 732

- 11

- 6

Structure:



## 3

. Reference E strogen : 17α

- ethynyl estradiol (EE)

Supplier Sigma Aldrich, St. Louis, MO

Lot/ Batch #: 090M1241V, expires February 2012 Purity: ≥ 98 %

CAS # : 57

- 63

- 6



## 4

. Solvent/ V ehicle C ontrol (Phosmet) : Carboxymethyl cellulose

Supplier Spectrum Chemical Mfg. Corp.

Lot/Batch #: ZE0383, expires August 1, 2011 Rationale (if other than water) Not provided

Final concentration 0.5%



## 5

. Solvent/ Vehicle C ontrol (EE) : Corn Oil

Supplier MP Biomedicals, LLC, Solon, OH

Lot #: 7862K, expires August 1, 2011 Rationale (if other than water) Not P rovided

Final concentration Not Applicable



## 6

. Test A nimals : Species : Rat (ovariectomized females)

Strain: Sprague

- Da w ley (Crl :CD[SD] IGS ) Age/weight at dose initiation : PND 63 days old / 236.6

- 298.7 g fe males

Source: Charles River Laboratories International , Inc. , Raleigh, NC

Housin g: 2 /cage in polycarbonate cages with absorbent heat

- treated hardwood bedding (Northeastern Pr o ducts Corp., Warrensburg, NY)

Diet : Tekla d Global 16% Protein Rodent Diet ( Teklad Diets, Madison,

WI ), ad libitum ; low phytoestrogen wi th total gen i stein equivalents = 6.2 μg/g diet

. Water: Reverse osmosis

- treated t ap water, ad libitum

Environmental conditions: Temperature: Humidity: Air changes: Photoperiod: 22

- 26 oC

33

- 48 % Not provided

12 hrs light/ 12 hrs dark Acclimation period: 8 daysIn vivo Uterotrophic Assay (2011) / Page 4 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



## B. METHODS

1. In L ife D ates : Start: May 3, 2011 End: May 6, 2011

2. Study Design : Following an 8-day acclimation period, ovariectomized female rats (surgery performed by Supplier) were administered the test substance from PND 63-65 . 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. Statistical analysis indicated that there were no significant

differences between group mean weights at study initiation.

Table 1. Study Design of Estrogen Agonist Assay a



### Test G roup Dose (mg/kg/day) # of Females

Vehicle C ontrol 0 8

Low 5 8 High 20 8

17 α

- ethynyl estradiol (EE), R eference E strogen 0.1 8

a Data were obtained from Table 1 on page 16 o f the study report.



## 4. Dose S election Rationale : T he phosmet dose levels were selected based on the results

from an acute oral gavage study (MRID 46593101) and repeated-dose stud ies (MRID s 44811801, 41962902, 41520001, 41916401, and 44839301). Mortality was observed in ≥ 75 mg/kg treatment groups for the acute oral study. No mortality was observed in the repeateddose dietary studies conducted at doses of up to 27 mg/kg/day, or in repeated

- dose gavage studies with doses up to 15 mg/kg/day. An acute relative sensitivity study ( MRID 47087401) compared the toxic responses of PND 11 rat pups versus adult rats following single -dose gavage administration of phosmet. No cholinergic clinical signs were found in either pups or adults at 10 mg/kg; however, significant cholinesterase inhibition was observed at this dose, espe cially in RBC. The adult rat RBC cholinesterase response was 62

- 63% of controls at 10 mg/kg. EPA has calculated a BMD 10 L 

## of 5.122 mg/kg for brain

cholinesterase inhibition from the data. In the 7

- day relative sensitivity study (MRID 44839301), no cholinergic clinical signs were observed for the 5 mg/kg/day dose group.

Based on the se results , doses selected for the main study were 0, 5 and 20 mg/kg/day.

5. Dose P reparation and Analysis : Dose formulations were prepared once prior to initiation

of treatment by initially dissolving the a ppropriate amounts of test su bstance in 0.5% carboxymethyl cellulose

. T he reference estrogen, EE, was mixed with corn oil for dosing. Doses were adjusted daily based on individual body weight measurements. Homogeneity and concentration analyses w ere measured prior to administration in the 5 and 20 mg/kg/day formulations. In a previous storage stability study 1 

## , phosmet (lot number not reported) was

1 

### Reibach, R. (2011) Storage Stability of Phosmet in Aqueous, Buffered Carboxymethylcellulose. Unpublished study report prepared by Smithers Viscient Inc., Study No. 12791

- 6159.In vivo Uterotrophic Assay (2011) / Page 5 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



## determined to be s table in the 0.5% aqueous carboxymethyl cellulose for up to 8 days at 1-

10°C.

Results of D ose Analysis

Homogeneity (% CV ): 2.45-14.1%

Stability: Stable for up to 8 days following storage at 1-10°C ( Smithers Viscient Inc., Study No. 12791-6159).

Concentration (% of nomin al): 81-109% (the 5 mg/kg dose measured at 4.06 mg/kg was only used on study day 1, and for days 2-3 the 5 mg/kg dose was 87% of nominal).

The analytical data indicated that the mixing procedure was marginally adequate and that the variation between nominal and actual dosage to the animals was marginally acceptable.

6. Dosage A dministration : Animals were administered the test formulations and/or EE or vehicle daily via oral gavage for three consecutive days in a dose volume of 5 mL/kg body weight . Dose volumes were adjusted daily based on the concurrent body weight

measurement.

7. S tatistics : Body weights, body weight gains, and uterine weights were analyzed using studentized residual plots for outliers and Levene’s test for homogeneity of variance. Body weights and body weight gains were analyzed using one- way ANOVA followed by

Dunnett’s two tailed t

- test. The wet and blotted uterine weights were analyzed by Kruskal

Wallis and Dunn’s test. Significance was denoted at p ≤ 0.05. The statistical analyses we re considered adequate.

C. METHODS

1. Clinical Examinations : Animals were checked for mortality or moribundity twice daily on weekdays and once daily on weekends. Rats were also checked for clinical signs of toxicity prior to dose administration and three h ( ±30 min) post-dosing.

2. Body W eight : Animals were weighed at randomization, daily prior to dosing throughout the dosing period, and at termination.

3. Food Consumption (Optional) : Food consumption was not measured

.

4. Necropsy and Measurement of Uterine Weight : On PND 66 (approximately 24 hours after final administration of the test substance) , all surviving animals were euthanized by

CO 2 

## inhalation followed 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 cut longitudinally and gently blotted with moist filter paper to remove the luminal fluid while preventing desiccation and the blotted uterus was weighed.In vivo Uterotrophic Assay (2011) / Page 6 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



## 5. Microscopic Examination (Optional) : Microscopic examinations were n ot conducted.

II. RESULTS

A. OBSERVATIONS

1. Mortality : All animals survived until scheduled termination.

2. Clinical S igns of Toxicity : Two 20 mg/kg/day rats had d ecreased movements at 1 -4 h postdosing on D ays 1 and 2. No clinical signs of toxicity were observed in the 5 mg/kg/day

animals.

B. BODY WEIGHT AND WEIGHT GAIN : Selected body weight and body weight gain data are presented in Table 2. Body weights in the 5 and 20 mg/kg/day dose groups were comparable to controls throughout the duration of the assay.

Table 2

. Selected Group Body Weights and Cumulative Body Weight Gains (g) In the Estrogen Agonist Assay a



### Study Day

# Dose (mg/kg/day)

Vehicle Control 5 20 EE ( 0.1 )

N Mean SD N Mean SD N Mean SD N Mean SD

1 8 264.3 18.4 8 265.3 19.8 8 262.1 12.2 8 265.7 16.4

2 8 266.5 19.9 8 268.2 19.4 8 266.2 17.1 8 266.8 21.0

3 8 268.7 19.6 8 270.3 21.6 8 266.5 16.1 8 264.1 19.8

4 8 270.6 20.4 8 271.2 20.4 8 265.3 17.0 8 258.7 20.8 Body Weight Gain (1

- 4 ) 8 6.4 3.0 8 5.9 5.8 8 3.2 5.9 8

- 7.0 5.8

a Data were obtained from Table 3 on page 20 and Appendix V on page 66 of the study report. N= No. of animals in the group

SD = Standard Deviation

* Significantly different from controls at p <0.05

.



## C. FOOD CONSUMPTION (Optional) : Food consumption was not measured.

D. PATHOLOGY

1. Uterine W eights : Selected uterine weight data are presented in Table 3. Uterine weights in the dose groups were comparable to the controls. Due to an outlier (666 mg wet; 601 mg blotted), the uterine weight means for the 20 mg/kg/day dose group we re based on 7

animals. The mean blotted vehicle control uterine weight was <0.04% of the mean vehicle control terminal body weight, which meets the guideline requirement.

Absolute wet and blotted uterus weights for the 0.1 mg/kg/day EE group were increased (p<0.05) by 407 % and 231 %, respectively. These increased uterine weights were in the expected range.In vivo Uterotrophic Assay (2011) / Page 7 of 7

PHOSMET/ 059201 OCSPP 890.1600/ OECD 440



### Table 3 . Uterine Weights from Estrogen Agonist Assay in SD Rats a



### Parameter Dose (mg/kg/day)

Vehicle Control 5 20 Reference Estrogen

EE ( 0.1 )

N Mean SD N Mean SD N Mean SD N Mean SD

Terminal BW (g) 8 270.6 20.4 8 271.2 20.4 8 265.3 17.0 8 258.7 20.8 Wet, absolute (mg) 8 70.9 12.0 8 74.1 6.5 7 C 

### 68.2 6.8 8 359.6 * (↑407) 94.8

Wet, relative (%) b 

### 8 0.026 0.004 8 0.027 0.001 8 0.026 0.004 8 0.140 0.039 Blotted, absolute (mg) 8 63.9 10.1 8 66.5 4.8 8 61.0 5.3 8 211.3* (↑231) 29.7

Blotted, relative (%) b 

### 8 0.024 0.003 8 0.025 0.002 8 0.023 0.003 8 0.082 0.011

a Data were obtained from Table 4 on page 21 and Appendix VI on page 68 of the study report.

b Relative wet and blotted uterine weights were calculated by the reviewer from the individual data. BW= body weight

C Outlier removed N= No. of animals in the group

SD = Standard Deviation

* Significantly different from vehicle control at p < 0.05

.



## 2. Microscopic Examination (Optional) : M icroscopic examinations were not conducted.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATOR ’ S CONCLUSIONS : Phosmet administered at dose levels of 5 and 20 mg/kg/day to ovariectomized Sprague-Dawley rats did not induce a change in body weight, body weight gain or uterine weight, wet or blotted, as compared to the vehicle control. Using the ovariectomized rat model, Ute rotrophic Assay (OPPTS 890.1600), oral administration of phosmet at dose levels up to 20 mg/kg/day is not estrogenic unde r these experimental conditions.

B. AGENCY COMMENTS : All animals survived until scheduled termination. Two 20 mg/kg/day rats had dec reased movements at 1 -4 h post-dosing on D ays 1 and 2. No clinical signs of toxicity were observed in the 5 mg/kg/day animals. Body weights in the dose groups were comparable to the controls throughout the duration of the assay. Uterine weights in the treatment groups were comparable to the controls. The mean blotted vehicle control uterine weight was <0.04% of the mean vehicle control terminal body weight, which meets the guideline requirement. Absolute wet and blotted uterus weights for the 0.1 mg/k g/day EE group were increased (p<0.05) by 407% and 231%, respectively. These increased uterine weights were in the expected range. No statistically significant changes were seen in uterine weight in this study. Phosmet was negative in the uterotrophic as say.

C. STUDY DEFICIENCIES : None