ATTACHMENl 111

vn]ozolin OEHH SpL~mb~r woo

HE~ DOC NC ~24 2H

C~NCZR AssESSMENT DoctMENT

VINCLOZOLIN ~FOURTH REVIEW)

P c Cgtitgt UJ20

fDill REOilT

20-JUNE-2000

CA~CER ASSESS1YlEN r RbVIEW COYLviTITEE HEALTII EfocCfS Dl VISION

ltlFFICE O PESTICIDE P KOGRA1S

OAT PRFSElTATI0-1 David Anderson Toxiltologigtt

DOCUMElJ RFPARATlON s~qjivmi Diwm Ixecurive Sc~nllaquo)

COMOITEE MEMBt-RS N ATTENDAKCFmiddot (Signature indicates concurrence ~th tltc a~scssm~nl unless otheNise ~tatcd)

Villiam n llnlBm

Kerry Dearfield

Vuginia Dobozy

Yiru~naltis Ioannou

Nancy McCR rmll

Timothy McMahon

Joyc~lyn Slewan

Clark Swentzel

Linda Taylor

NQN-COMMITTEEMEMBERS IN 1m 6N)AICF

Joh11 Pwtcher Pathology

(SigMillrc illllicatz ccncurtence with j1e

pathology report and statistical an~ lysis ofdftta n~-peclively)

Lori lnmsman

lit lEST )N AUE-fDINCf

jj

~uul kcpor1

CO-TEltTS

FXECliTIVE SUvl1-RY

1 1--IT RODI JCTI01 bullbull

11 BACKGROL--D OOORMATION I

lif VALLATI01 OF TlE PATlfOLOltiY WORKING GROLf RI~PORT 2

IV EvALUATIOt OF ANTIAKDROGEI1C rrFFCTS TO imtSSfSS T-IE PONT OF ~

bullbull LDEPARTUamp

Y RECOKSID2RAT10N OF THE POIIT OF DEPARl URE FOR NOK-LlIE-R APPJIOCH FOR CANCER lUSKASSESS~vLENT ~

VI ASSESSlvfENT Or CHILDRENS SUSCEPTliIIIITY ~

VII CARCS COtCLUSION 9

VUL BIBLIOGRAPHY -- 10

iii

Vinclo2Xllin IPC CocJmiddot 11 3201) Wlt$ previously ~v~luated for carcinogenicity by h~ Carcer Peer RtviewCommitee (CPRC) urAugu-r 30 1995 Apn l 17 J996endJmua-y 15 1997 Allhc conclUSon ofllu at nxting the CPRC Wltssiiied bullindozdin as ltjroup C-possible human carcinngcu (CPRC 1997j CPRC recommenderl an ~xlrlt~polation approach (1Jtrltin ofExposure or MOE) hllgtltlti on a 1-0AI-1 Jirr hormone-related effects Tiris decision wa~ hacd on thtl Registrants submission of preliminAry results of a re-evaluation orpathology slides from the ovary and prostate of the rat The Cor1mittee puvisiooally acceted these data R~gted on these data the only rumnr lype with a statistically ~igcifiant increa~ w~s Lytlig cell tumors in male ral3 Aloo ooue members felt tl~t the uuc=s in proState tumor were eqnivoasl hut could cot he Ci~miscol

On Aprul9 2000 the Cancer Assessme~l RemiddotiewComrnitteeCARC)mcr to discuss possible childrens susceptihilityto villcloLolin-indlJCedLeydigcell turnurs Tee discussionofdu mccriog wascemeredu-ound ihe following issncs 1) The acceptJbility of the Paiholugy Working Groups (PWG) ooutonatiol of the lac of any compournl-nhtloo ovaran and prostate tumvtli in he rat chronic toxi=zytcarcinOCIiciry stillies 2) Selection of ll point of departure (POLl) ba~cd on antiand--ogenic effects een in tht prltrata1postr~ltttal studie~ peri nflt~J study 2-~~nerationreproductinn slldyand other special studies in ral~ (measuring Clllng~ iiLH and testn~lertnc ~-penn ccunt and change in r--pnxluctive organ weightS and hitopadwlogy) as -w-ell as chonic oxicitycarciuogclliiy srudies in mts one dogs lltld 3) Dcternrination ofwhether tlJe PO 0 is wllicitlly prorective ofOful~ and childrc fon vn~ozolin-iJalcerl rcsticular Leydig cell tumors

l11e CARC aecepttcl the PWGs repmt on rh rc-cvaluationofthe ovarian~nd prostateadenomas Based on the reVltCW of~tbullaJable data the CiRC ooncluticd that infanS chicren and adult Wltgtuld be protected

fromVncomlin-iooulXgtl testicular Leyltiig cell tumo~(Tf CT) tlrnngha non-Iii= a~scs~mc~1 with a POD of 3 trgltkgiday and 11 MOE appwach (The FQP factor Bod consequently the MOE nece~ary to proteot infurJs and childrcll will he ltletermined by the FQPA SlfCiy F~ctor Committee) Tne CARC deiennimd that me node of action for vinclowlin related antiandrogemc effectS iu infunts children and adultbull i~ mcdi~lid via iclDbicon of a1drogen rcccpLors In adriition the Committee CCK1clud~ltl that() lthough dle detgtilcd =hanismis unknow1 it hpound bcc11 ~huwn that 6e alCancrogecictyaxi pltJgtOltibly b inrltltsed levels of LH are comnoulig factors to the deveoprncnl uf Leydig eel hypeP asia (TLCH)tumors (2) It is wllLltely that thur will be a carcbogenic bmoard nr risk concern for infants or ~hi ld1 0 11 xpo~~tl to vinclozoEngiventhatrh~ ikclihood ofleydig cell tmor tcumatiun in these individucll is small Howt~v~r the potential ftr incregtYltI inlticc-ucc oftbullgticttlar Leydig cell rumnrs ilaquo ltlaquolults nulting fioo bful1t lnd 6 iirihUOll cxpone to vilcOznlin can101 b ruled out (3) TherefOre the weight of1hc

middot evidence imEcates mat it ~ lrolultjcclly pausible that the nttigt111dttgcnic eifecls ofvinclozolin lead to tx tltmnation of the Leydig cell hyp-_0a~iltl1umors anlti Llllt protecting ~C itJ~Illntiandrogen effeciS Vould

HE~ DOC NC ~24 2H

C~NCZR AssESSMENT DoctMENT

VINCLOZOLIN ~FOURTH REVIEW)

P c Cgtitgt UJ20

fDill REOilT

20-JUNE-2000

CA~CER ASSESS1YlEN r RbVIEW COYLviTITEE HEALTII EfocCfS Dl VISION

ltlFFICE O PESTICIDE P KOGRA1S

OAT PRFSElTATI0-1 David Anderson Toxiltologigtt

DOCUMElJ RFPARATlON s~qjivmi Diwm Ixecurive Sc~nllaquo)

COMOITEE MEMBt-RS N ATTENDAKCFmiddot (Signature indicates concurrence ~th tltc a~scssm~nl unless otheNise ~tatcd)

Villiam n llnlBm

Kerry Dearfield

Vuginia Dobozy

Yiru~naltis Ioannou

Nancy McCR rmll

Timothy McMahon

Joyc~lyn Slewan

Clark Swentzel

Linda Taylor

NQN-COMMITTEEMEMBERS IN 1m 6N)AICF

Joh11 Pwtcher Pathology

(SigMillrc illllicatz ccncurtence with j1e

pathology report and statistical an~ lysis ofdftta n~-peclively)

Lori lnmsman

lit lEST )N AUE-fDINCf

jj

~uul kcpor1

CO-TEltTS

FXECliTIVE SUvl1-RY

1 1--IT RODI JCTI01 bullbull

11 BACKGROL--D OOORMATION I

lif VALLATI01 OF TlE PATlfOLOltiY WORKING GROLf RI~PORT 2

IV EvALUATIOt OF ANTIAKDROGEI1C rrFFCTS TO imtSSfSS T-IE PONT OF ~

bullbull LDEPARTUamp

Y RECOKSID2RAT10N OF THE POIIT OF DEPARl URE FOR NOK-LlIE-R APPJIOCH FOR CANCER lUSKASSESS~vLENT ~

VI ASSESSlvfENT Or CHILDRENS SUSCEPTliIIIITY ~

VII CARCS COtCLUSION 9

VUL BIBLIOGRAPHY -- 10

iii

Vinclo2Xllin IPC CocJmiddot 11 3201) Wlt$ previously ~v~luated for carcinogenicity by h~ Carcer Peer RtviewCommitee (CPRC) urAugu-r 30 1995 Apn l 17 J996endJmua-y 15 1997 Allhc conclUSon ofllu at nxting the CPRC Wltssiiied bullindozdin as ltjroup C-possible human carcinngcu (CPRC 1997j CPRC recommenderl an ~xlrlt~polation approach (1Jtrltin ofExposure or MOE) hllgtltlti on a 1-0AI-1 Jirr hormone-related effects Tiris decision wa~ hacd on thtl Registrants submission of preliminAry results of a re-evaluation orpathology slides from the ovary and prostate of the rat The Cor1mittee puvisiooally acceted these data R~gted on these data the only rumnr lype with a statistically ~igcifiant increa~ w~s Lytlig cell tumors in male ral3 Aloo ooue members felt tl~t the uuc=s in proState tumor were eqnivoasl hut could cot he Ci~miscol

On Aprul9 2000 the Cancer Assessme~l RemiddotiewComrnitteeCARC)mcr to discuss possible childrens susceptihilityto villcloLolin-indlJCedLeydigcell turnurs Tee discussionofdu mccriog wascemeredu-ound ihe following issncs 1) The acceptJbility of the Paiholugy Working Groups (PWG) ooutonatiol of the lac of any compournl-nhtloo ovaran and prostate tumvtli in he rat chronic toxi=zytcarcinOCIiciry stillies 2) Selection of ll point of departure (POLl) ba~cd on antiand--ogenic effects een in tht prltrata1postr~ltttal studie~ peri nflt~J study 2-~~nerationreproductinn slldyand other special studies in ral~ (measuring Clllng~ iiLH and testn~lertnc ~-penn ccunt and change in r--pnxluctive organ weightS and hitopadwlogy) as -w-ell as chonic oxicitycarciuogclliiy srudies in mts one dogs lltld 3) Dcternrination ofwhether tlJe PO 0 is wllicitlly prorective ofOful~ and childrc fon vn~ozolin-iJalcerl rcsticular Leydig cell tumors

l11e CARC aecepttcl the PWGs repmt on rh rc-cvaluationofthe ovarian~nd prostateadenomas Based on the reVltCW of~tbullaJable data the CiRC ooncluticd that infanS chicren and adult Wltgtuld be protected

fromVncomlin-iooulXgtl testicular Leyltiig cell tumo~(Tf CT) tlrnngha non-Iii= a~scs~mc~1 with a POD of 3 trgltkgiday and 11 MOE appwach (The FQP factor Bod consequently the MOE nece~ary to proteot infurJs and childrcll will he ltletermined by the FQPA SlfCiy F~ctor Committee) Tne CARC deiennimd that me node of action for vinclowlin related antiandrogemc effectS iu infunts children and adultbull i~ mcdi~lid via iclDbicon of a1drogen rcccpLors In adriition the Committee CCK1clud~ltl that() lthough dle detgtilcd =hanismis unknow1 it hpound bcc11 ~huwn that 6e alCancrogecictyaxi pltJgtOltibly b inrltltsed levels of LH are comnoulig factors to the deveoprncnl uf Leydig eel hypeP asia (TLCH)tumors (2) It is wllLltely that thur will be a carcbogenic bmoard nr risk concern for infants or ~hi ld1 0 11 xpo~~tl to vinclozoEngiventhatrh~ ikclihood ofleydig cell tmor tcumatiun in these individucll is small Howt~v~r the potential ftr incregtYltI inlticc-ucc oftbullgticttlar Leydig cell rumnrs ilaquo ltlaquolults nulting fioo bful1t lnd 6 iirihUOll cxpone to vilcOznlin can101 b ruled out (3) TherefOre the weight of1hc

middot evidence imEcates mat it ~ lrolultjcclly pausible that the nttigt111dttgcnic eifecls ofvinclozolin lead to tx tltmnation of the Leydig cell hyp-_0a~iltl1umors anlti Llllt protecting ~C itJ~Illntiandrogen effeciS Vould

OAT PRFSElTATI0-1 David Anderson Toxiltologigtt

DOCUMElJ RFPARATlON s~qjivmi Diwm Ixecurive Sc~nllaquo)

COMOITEE MEMBt-RS N ATTENDAKCFmiddot (Signature indicates concurrence ~th tltc a~scssm~nl unless otheNise ~tatcd)

Villiam n llnlBm

Kerry Dearfield

Vuginia Dobozy

Yiru~naltis Ioannou

Nancy McCR rmll

Timothy McMahon

Joyc~lyn Slewan

Clark Swentzel

Linda Taylor

NQN-COMMITTEEMEMBERS IN 1m 6N)AICF

Joh11 Pwtcher Pathology

(SigMillrc illllicatz ccncurtence with j1e

pathology report and statistical an~ lysis ofdftta n~-peclively)

Lori lnmsman

lit lEST )N AUE-fDINCf

jj

~uul kcpor1

CO-TEltTS

FXECliTIVE SUvl1-RY

1 1--IT RODI JCTI01 bullbull

11 BACKGROL--D OOORMATION I

lif VALLATI01 OF TlE PATlfOLOltiY WORKING GROLf RI~PORT 2

IV EvALUATIOt OF ANTIAKDROGEI1C rrFFCTS TO imtSSfSS T-IE PONT OF ~

bullbull LDEPARTUamp

Y RECOKSID2RAT10N OF THE POIIT OF DEPARl URE FOR NOK-LlIE-R APPJIOCH FOR CANCER lUSKASSESS~vLENT ~

VI ASSESSlvfENT Or CHILDRENS SUSCEPTliIIIITY ~

VII CARCS COtCLUSION 9

VUL BIBLIOGRAPHY -- 10

iii

Vinclo2Xllin IPC CocJmiddot 11 3201) Wlt$ previously ~v~luated for carcinogenicity by h~ Carcer Peer RtviewCommitee (CPRC) urAugu-r 30 1995 Apn l 17 J996endJmua-y 15 1997 Allhc conclUSon ofllu at nxting the CPRC Wltssiiied bullindozdin as ltjroup C-possible human carcinngcu (CPRC 1997j CPRC recommenderl an ~xlrlt~polation approach (1Jtrltin ofExposure or MOE) hllgtltlti on a 1-0AI-1 Jirr hormone-related effects Tiris decision wa~ hacd on thtl Registrants submission of preliminAry results of a re-evaluation orpathology slides from the ovary and prostate of the rat The Cor1mittee puvisiooally acceted these data R~gted on these data the only rumnr lype with a statistically ~igcifiant increa~ w~s Lytlig cell tumors in male ral3 Aloo ooue members felt tl~t the uuc=s in proState tumor were eqnivoasl hut could cot he Ci~miscol

On Aprul9 2000 the Cancer Assessme~l RemiddotiewComrnitteeCARC)mcr to discuss possible childrens susceptihilityto villcloLolin-indlJCedLeydigcell turnurs Tee discussionofdu mccriog wascemeredu-ound ihe following issncs 1) The acceptJbility of the Paiholugy Working Groups (PWG) ooutonatiol of the lac of any compournl-nhtloo ovaran and prostate tumvtli in he rat chronic toxi=zytcarcinOCIiciry stillies 2) Selection of ll point of departure (POLl) ba~cd on antiand--ogenic effects een in tht prltrata1postr~ltttal studie~ peri nflt~J study 2-~~nerationreproductinn slldyand other special studies in ral~ (measuring Clllng~ iiLH and testn~lertnc ~-penn ccunt and change in r--pnxluctive organ weightS and hitopadwlogy) as -w-ell as chonic oxicitycarciuogclliiy srudies in mts one dogs lltld 3) Dcternrination ofwhether tlJe PO 0 is wllicitlly prorective ofOful~ and childrc fon vn~ozolin-iJalcerl rcsticular Leydig cell tumors

l11e CARC aecepttcl the PWGs repmt on rh rc-cvaluationofthe ovarian~nd prostateadenomas Based on the reVltCW of~tbullaJable data the CiRC ooncluticd that infanS chicren and adult Wltgtuld be protected

fromVncomlin-iooulXgtl testicular Leyltiig cell tumo~(Tf CT) tlrnngha non-Iii= a~scs~mc~1 with a POD of 3 trgltkgiday and 11 MOE appwach (The FQP factor Bod consequently the MOE nece~ary to proteot infurJs and childrcll will he ltletermined by the FQPA SlfCiy F~ctor Committee) Tne CARC deiennimd that me node of action for vinclowlin related antiandrogemc effectS iu infunts children and adultbull i~ mcdi~lid via iclDbicon of a1drogen rcccpLors In adriition the Committee CCK1clud~ltl that() lthough dle detgtilcd =hanismis unknow1 it hpound bcc11 ~huwn that 6e alCancrogecictyaxi pltJgtOltibly b inrltltsed levels of LH are comnoulig factors to the deveoprncnl uf Leydig eel hypeP asia (TLCH)tumors (2) It is wllLltely that thur will be a carcbogenic bmoard nr risk concern for infants or ~hi ld1 0 11 xpo~~tl to vinclozoEngiventhatrh~ ikclihood ofleydig cell tmor tcumatiun in these individucll is small Howt~v~r the potential ftr incregtYltI inlticc-ucc oftbullgticttlar Leydig cell rumnrs ilaquo ltlaquolults nulting fioo bful1t lnd 6 iirihUOll cxpone to vilcOznlin can101 b ruled out (3) TherefOre the weight of1hc

middot evidence imEcates mat it ~ lrolultjcclly pausible that the nttigt111dttgcnic eifecls ofvinclozolin lead to tx tltmnation of the Leydig cell hyp-_0a~iltl1umors anlti Llllt protecting ~C itJ~Illntiandrogen effeciS Vould

~uul kcpor1

CO-TEltTS

FXECliTIVE SUvl1-RY

1 1--IT RODI JCTI01 bullbull

11 BACKGROL--D OOORMATION I

lif VALLATI01 OF TlE PATlfOLOltiY WORKING GROLf RI~PORT 2

IV EvALUATIOt OF ANTIAKDROGEI1C rrFFCTS TO imtSSfSS T-IE PONT OF ~

bullbull LDEPARTUamp

Y RECOKSID2RAT10N OF THE POIIT OF DEPARl URE FOR NOK-LlIE-R APPJIOCH FOR CANCER lUSKASSESS~vLENT ~

VI ASSESSlvfENT Or CHILDRENS SUSCEPTliIIIITY ~

VII CARCS COtCLUSION 9

VUL BIBLIOGRAPHY -- 10

iii

Vinclo2Xllin IPC CocJmiddot 11 3201) Wlt$ previously ~v~luated for carcinogenicity by h~ Carcer Peer RtviewCommitee (CPRC) urAugu-r 30 1995 Apn l 17 J996endJmua-y 15 1997 Allhc conclUSon ofllu at nxting the CPRC Wltssiiied bullindozdin as ltjroup C-possible human carcinngcu (CPRC 1997j CPRC recommenderl an ~xlrlt~polation approach (1Jtrltin ofExposure or MOE) hllgtltlti on a 1-0AI-1 Jirr hormone-related effects Tiris decision wa~ hacd on thtl Registrants submission of preliminAry results of a re-evaluation orpathology slides from the ovary and prostate of the rat The Cor1mittee puvisiooally acceted these data R~gted on these data the only rumnr lype with a statistically ~igcifiant increa~ w~s Lytlig cell tumors in male ral3 Aloo ooue members felt tl~t the uuc=s in proState tumor were eqnivoasl hut could cot he Ci~miscol

On Aprul9 2000 the Cancer Assessme~l RemiddotiewComrnitteeCARC)mcr to discuss possible childrens susceptihilityto villcloLolin-indlJCedLeydigcell turnurs Tee discussionofdu mccriog wascemeredu-ound ihe following issncs 1) The acceptJbility of the Paiholugy Working Groups (PWG) ooutonatiol of the lac of any compournl-nhtloo ovaran and prostate tumvtli in he rat chronic toxi=zytcarcinOCIiciry stillies 2) Selection of ll point of departure (POLl) ba~cd on antiand--ogenic effects een in tht prltrata1postr~ltttal studie~ peri nflt~J study 2-~~nerationreproductinn slldyand other special studies in ral~ (measuring Clllng~ iiLH and testn~lertnc ~-penn ccunt and change in r--pnxluctive organ weightS and hitopadwlogy) as -w-ell as chonic oxicitycarciuogclliiy srudies in mts one dogs lltld 3) Dcternrination ofwhether tlJe PO 0 is wllicitlly prorective ofOful~ and childrc fon vn~ozolin-iJalcerl rcsticular Leydig cell tumors

l11e CARC aecepttcl the PWGs repmt on rh rc-cvaluationofthe ovarian~nd prostateadenomas Based on the reVltCW of~tbullaJable data the CiRC ooncluticd that infanS chicren and adult Wltgtuld be protected

fromVncomlin-iooulXgtl testicular Leyltiig cell tumo~(Tf CT) tlrnngha non-Iii= a~scs~mc~1 with a POD of 3 trgltkgiday and 11 MOE appwach (The FQP factor Bod consequently the MOE nece~ary to proteot infurJs and childrcll will he ltletermined by the FQPA SlfCiy F~ctor Committee) Tne CARC deiennimd that me node of action for vinclowlin related antiandrogemc effectS iu infunts children and adultbull i~ mcdi~lid via iclDbicon of a1drogen rcccpLors In adriition the Committee CCK1clud~ltl that() lthough dle detgtilcd =hanismis unknow1 it hpound bcc11 ~huwn that 6e alCancrogecictyaxi pltJgtOltibly b inrltltsed levels of LH are comnoulig factors to the deveoprncnl uf Leydig eel hypeP asia (TLCH)tumors (2) It is wllLltely that thur will be a carcbogenic bmoard nr risk concern for infants or ~hi ld1 0 11 xpo~~tl to vinclozoEngiventhatrh~ ikclihood ofleydig cell tmor tcumatiun in these individucll is small Howt~v~r the potential ftr incregtYltI inlticc-ucc oftbullgticttlar Leydig cell rumnrs ilaquo ltlaquolults nulting fioo bful1t lnd 6 iirihUOll cxpone to vilcOznlin can101 b ruled out (3) TherefOre the weight of1hc

middot evidence imEcates mat it ~ lrolultjcclly pausible that the nttigt111dttgcnic eifecls ofvinclozolin lead to tx tltmnation of the Leydig cell hyp-_0a~iltl1umors anlti Llllt protecting ~C itJ~Illntiandrogen effeciS Vould

Vinclo2Xllin IPC CocJmiddot 11 3201) Wlt$ previously ~v~luated for carcinogenicity by h~ Carcer Peer RtviewCommitee (CPRC) urAugu-r 30 1995 Apn l 17 J996endJmua-y 15 1997 Allhc conclUSon ofllu at nxting the CPRC Wltssiiied bullindozdin as ltjroup C-possible human carcinngcu (CPRC 1997j CPRC recommenderl an ~xlrlt~polation approach (1Jtrltin ofExposure or MOE) hllgtltlti on a 1-0AI-1 Jirr hormone-related effects Tiris decision wa~ hacd on thtl Registrants submission of preliminAry results of a re-evaluation orpathology slides from the ovary and prostate of the rat The Cor1mittee puvisiooally acceted these data R~gted on these data the only rumnr lype with a statistically ~igcifiant increa~ w~s Lytlig cell tumors in male ral3 Aloo ooue members felt tl~t the uuc=s in proState tumor were eqnivoasl hut could cot he Ci~miscol

On Aprul9 2000 the Cancer Assessme~l RemiddotiewComrnitteeCARC)mcr to discuss possible childrens susceptihilityto villcloLolin-indlJCedLeydigcell turnurs Tee discussionofdu mccriog wascemeredu-ound ihe following issncs 1) The acceptJbility of the Paiholugy Working Groups (PWG) ooutonatiol of the lac of any compournl-nhtloo ovaran and prostate tumvtli in he rat chronic toxi=zytcarcinOCIiciry stillies 2) Selection of ll point of departure (POLl) ba~cd on antiand--ogenic effects een in tht prltrata1postr~ltttal studie~ peri nflt~J study 2-~~nerationreproductinn slldyand other special studies in ral~ (measuring Clllng~ iiLH and testn~lertnc ~-penn ccunt and change in r--pnxluctive organ weightS and hitopadwlogy) as -w-ell as chonic oxicitycarciuogclliiy srudies in mts one dogs lltld 3) Dcternrination ofwhether tlJe PO 0 is wllicitlly prorective ofOful~ and childrc fon vn~ozolin-iJalcerl rcsticular Leydig cell tumors

l11e CARC aecepttcl the PWGs repmt on rh rc-cvaluationofthe ovarian~nd prostateadenomas Based on the reVltCW of~tbullaJable data the CiRC ooncluticd that infanS chicren and adult Wltgtuld be protected

fromVncomlin-iooulXgtl testicular Leyltiig cell tumo~(Tf CT) tlrnngha non-Iii= a~scs~mc~1 with a POD of 3 trgltkgiday and 11 MOE appwach (The FQP factor Bod consequently the MOE nece~ary to proteot infurJs and childrcll will he ltletermined by the FQPA SlfCiy F~ctor Committee) Tne CARC deiennimd that me node of action for vinclowlin related antiandrogemc effectS iu infunts children and adultbull i~ mcdi~lid via iclDbicon of a1drogen rcccpLors In adriition the Committee CCK1clud~ltl that() lthough dle detgtilcd =hanismis unknow1 it hpound bcc11 ~huwn that 6e alCancrogecictyaxi pltJgtOltibly b inrltltsed levels of LH are comnoulig factors to the deveoprncnl uf Leydig eel hypeP asia (TLCH)tumors (2) It is wllLltely that thur will be a carcbogenic bmoard nr risk concern for infants or ~hi ld1 0 11 xpo~~tl to vinclozoEngiventhatrh~ ikclihood ofleydig cell tmor tcumatiun in these individucll is small Howt~v~r the potential ftr incregtYltI inlticc-ucc oftbullgticttlar Leydig cell rumnrs ilaquo ltlaquolults nulting fioo bful1t lnd 6 iirihUOll cxpone to vilcOznlin can101 b ruled out (3) TherefOre the weight of1hc

middot evidence imEcates mat it ~ lrolultjcclly pausible that the nttigt111dttgcnic eifecls ofvinclozolin lead to tx tltmnation of the Leydig cell hyp-_0a~iltl1umors anlti Llllt protecting ~C itJ~Illntiandrogen effeciS Vould

Fira Hmiddotpor

protect agnin~t Lcydir w ll hyperplasiaadeioma~ (lt1) A NOAEL of 3 I11fl-lltg(ay for the lowest icysiolo)iiccl antianltirogen -SQme seen in peirutal dvlopmntal toxicty studies wittmiddot a LOAE- of 6 mgkiwy VJlid be proetl oTLCH a-~c 1LCT Howel-ebulllJc is manageB should ac aware c the fibull~bull 11ult1 the LOAEL is vey cr~~ IltJ t~ ~OAE (5) At dose lev I~ lowe- thm a LOAF nf) mgk)rl~y poitntiaJ effects could not t ~trlisticaJly distinguished f1 oJu the normal variorim1 in i1ldroge1i7atinn ofrr11tk illd female mt off~pring bullvgtl uu~um uabullmiddoto Therefbc givrn the commonclily in the node of action a POD based anc-androgettc eftci shuud be prot~cive oflgtotb ltltUlC~r and nonshycalce- effects

v

VmcJozolin (41h Review)

I INTRODO(TION

VinclcwJn has b~enevalUpoundted by the Cancer Peer Review Comnittee (CtRC) pPviousiyonugust 30 1))5 bullqril 17 1996 and Jamllty 1 S 1997 At lbronclu~ionofihe lastCtHC nJettinamp it was classified ns a Clrrmgt C-pusible human carcinogenoasee gtn ~1e in~reas~tl incidence of testiculllrLyilig cell (ie inurmitial iegttinulttr cells) turners in tIS supported by the incre~setllllcidence of testiwl11r Leydig c-ell hyperplaltia ill nuw (CPRC 1997) middotnlc CPRC cocluded that the Cl4Tently avai 1ablc dala appear IC demonstrate an Wlli -1ncirtwenic activtyby vir~lozcEnas the node ofaConfor teltgticular Leydig celllumoc limnation TI)e CPRC noomllended that tor the puPoses of dose-response assessnent aucl d Jarlttcterization a non-linear appwach using a M DE basedon a NOEL too Autillndrogelic effects sboulct be usltxl for quantitalionofpotentiAhurnancaocer r~k In audition the CPRC recommended the toxicity endpoint gtlt~ccud by the Tcxicily ndpoinl Seleeton Committee (HIARC 1999) be nilmd Titis loxdty odpoint wa- iltbullcd ona decrease inepidicymal weiWrt at 30 mg1kgdaj gten n a 2-genention ~ampf The dose selected for ri~k assssmcn was 49 mgkgday ~NOltB)

Vmclnznlin is umnJly being evalumed fnr rcrltgislration eligiliJitj As a JRl(l o this evaluation H FD was asked to de~enn im tk pxential cancer risk to int~rtts aJlti C~crcn exposed lCgt this pestdde An d Hoc =ring liS hd among the ltenlistgt inHIID on Marclt 17 2000 to Ciscuo~ tlts issue The participarts wcr David ltndenon Karl Baetckc Viclci Dellarco Willia11 Had] EEzabethlvlendez Mich~clMclzger

and Vlug Phans The discussirowns tocuswd on the issue ofvinclowlils anti-androgemc effe~t aml it~ re1atilt11~hip middot- iUrlhJ inducticnoftesricular l eylig tcll tulnors in rats a~ -Cll ~s its irnplicatioos for potential risk to mfan~s anc c1l1clrc A key question tn addrcs w~ wneue ths mode ofactial woUa result in lc~ticular Leydg cell rumors ill ciilltlrn It IWJS ~reed lllal the possibility ofdevciopmclt of rescicular l ydig cell tumors later in lif~ resulting fro-n cbildhooc cxpo~ure could not be rlismi$Sltd although folllliUiul of these tumors n1 chUdngtn was unlikely It was n~o agrotd thrt if the toXlcity cndpoi111Jor

ltUtiandm1cac dTclu Tmiddotecursors to ttl1cgtf llllll yperplaso fomatio11 were used for cacer risk assessment ct Wlt1nkl be prolCClive for tumo fonuetion which occurred at hi~hcr ck-se evels than the antishyandrogelic efl~c~ The lJeelin Jarticipmts also o-ccvcd thai in a p~rinallll middotat lti~vdopmental toxiciiy study(Gray et al 1999 ) n dL~ltr-bullscinprosrateweightgtlt-as s~~n in mts wiich received vinclo~lgtlin ~t doses OlS low as bull 6 rng-ks The l0EL for this cJlict was J rng19 After eltuosidlring all the dam the meenng particpatL~COtlllutld 31 it aJpeagt to be more nlsomble to ba~ 1e toxicity ecipoint orcance- risk assessmen~ on tJC cfcct obgterve~ in the Gny er ftl study (decrease in pm~tarc middotmiddot(igbt at bull 6 mgbullkg) and roc dose for point nl nPpmnumiddote (POD) tt J nlgkg ne Akll-ioc meeting oho Clt)ndud u llutl this issue ~hnuld be considered by tlie CAR C

On pni l ltJ 20CO 6e Cancer tssessmet Ri-vicw Colllitree (CAR) oue lo discuss le potential

VmcJozolin (41h Review)

I INTRODO(TION

VinclcwJn has b~enevalUpoundted by the Cancer Peer Review Comnittee (CtRC) pPviousiyonugust 30 1))5 bullqril 17 1996 and Jamllty 1 S 1997 At lbronclu~ionofihe lastCtHC nJettinamp it was classified ns a Clrrmgt C-pusible human carcinogenoasee gtn ~1e in~reas~tl incidence of testiculllrLyilig cell (ie inurmitial iegttinulttr cells) turners in tIS supported by the incre~setllllcidence of testiwl11r Leydig c-ell hyperplaltia ill nuw (CPRC 1997) middotnlc CPRC cocluded that the Cl4Tently avai 1ablc dala appear IC demonstrate an Wlli -1ncirtwenic activtyby vir~lozcEnas the node ofaConfor teltgticular Leydig celllumoc limnation TI)e CPRC noomllended that tor the puPoses of dose-response assessnent aucl d Jarlttcterization a non-linear appwach using a M DE basedon a NOEL too Autillndrogelic effects sboulct be usltxl for quantitalionofpotentiAhurnancaocer r~k In audition the CPRC recommended the toxicity endpoint gtlt~ccud by the Tcxicily ndpoinl Seleeton Committee (HIARC 1999) be nilmd Titis loxdty odpoint wa- iltbullcd ona decrease inepidicymal weiWrt at 30 mg1kgdaj gten n a 2-genention ~ampf The dose selected for ri~k assssmcn was 49 mgkgday ~NOltB)

Vmclnznlin is umnJly being evalumed fnr rcrltgislration eligiliJitj As a JRl(l o this evaluation H FD was asked to de~enn im tk pxential cancer risk to int~rtts aJlti C~crcn exposed lCgt this pestdde An d Hoc =ring liS hd among the ltenlistgt inHIID on Marclt 17 2000 to Ciscuo~ tlts issue The participarts wcr David ltndenon Karl Baetckc Viclci Dellarco Willia11 Had] EEzabethlvlendez Mich~clMclzger

and Vlug Phans The discussirowns tocuswd on the issue ofvinclowlils anti-androgemc effe~t aml it~ re1atilt11~hip middot- iUrlhJ inducticnoftesricular l eylig tcll tulnors in rats a~ -Cll ~s its irnplicatioos for potential risk to mfan~s anc c1l1clrc A key question tn addrcs w~ wneue ths mode ofactial woUa result in lc~ticular Leydg cell rumors ill ciilltlrn It IWJS ~reed lllal the possibility ofdevciopmclt of rescicular l ydig cell tumors later in lif~ resulting fro-n cbildhooc cxpo~ure could not be rlismi$Sltd although folllliUiul of these tumors n1 chUdngtn was unlikely It was n~o agrotd thrt if the toXlcity cndpoi111Jor

ltUtiandm1cac dTclu Tmiddotecursors to ttl1cgtf llllll yperplaso fomatio11 were used for cacer risk assessment ct Wlt1nkl be prolCClive for tumo fonuetion which occurred at hi~hcr ck-se evels than the antishyandrogelic efl~c~ The lJeelin Jarticipmts also o-ccvcd thai in a p~rinallll middotat lti~vdopmental toxiciiy study(Gray et al 1999 ) n dL~ltr-bullscinprosrateweightgtlt-as s~~n in mts wiich received vinclo~lgtlin ~t doses OlS low as bull 6 rng-ks The l0EL for this cJlict was J rng19 After eltuosidlring all the dam the meenng particpatL~COtlllutld 31 it aJpeagt to be more nlsomble to ba~ 1e toxicity ecipoint orcance- risk assessmen~ on tJC cfcct obgterve~ in the Gny er ftl study (decrease in pm~tarc middotmiddot(igbt at bull 6 mgbullkg) and roc dose for point nl nPpmnumiddote (POD) tt J nlgkg ne Akll-ioc meeting oho Clt)ndud u llutl this issue ~hnuld be considered by tlie CAR C

On pni l ltJ 20CO 6e Cancer tssessmet Ri-vicw Colllitree (CAR) oue lo discuss le potential

talce-risk to infrtgtana ch1ldren iOat ltXltOsure to bullindo2Xllin Dr Ih viti lfttlerson presentee infimiddotnnM illt wd tblt issullgt which were the foc11~ omiddot tho rncclog (CARC 2000a) The JSltIIllgt ~tlrlressed il the meew1e w~n~ (1) Evalu~tion of the PWG rep~P ill liglu oJ tlv~ loiimltiol o d1e oonlusionraquo of the J CPJC meeting on~llciNoliulhat there were no si~ ovru iau ltr prostate tumors from expnsmcw -ixOzolir (CJRC 2000h) () Rl~Sltsment cf~ OD a- non-lielr ridc asgtessmnoi testJIIa- lcytlig ceU adenomus fron posua 10 viDJozolin and (3) Jhe dlaquonnin~lon of whether ilie selected point of ieparmre s sbulllllidertly pmtccnvc oJ infunts and children fi-cm viEcomli~-illiuced testicular Leycig cell twnors

Ill RVoLCATION OF TIIE PAUJOLO(y WOJU(ING GROUP REJgtOKT poundPWG)

The PWG (99) ellhllkd UJ~ ov~ricsandp~ostatcs from two 24-mnmibull studi~ irWistar rats doed widbull

inclozolin Tile 1-WCT cnnclurleltl llli1i cmale mtS doselti for 24 monthgt vith viuduzulin deveioped ovuiun stromalhypexplasi~ only Ovariun so-omal hypcqgtiasiltt U ~ommon agc-~socated le~irm howtvcr there wa~ a tllnniJJ~l dose-related increase in severity of the hypltmiddotrpl~sia No statistic2lly significant incr-cgtit2 ircidence ofovlll inn d-ncmas ur ote- OYarian neoplasm~ w~gt gtled

Toe PVG =eluded thatin male Ill closed over 2LmorJhs there middotmiddotas an incn~W bcic=of arypicL hyplt~lasia of the glandular epitheli-arn of t~e prostlt~te Ilowever there were nn ~tmisticgtilly signi5cmt icc~gtcs in be incidences of prostatic adenomas or oilKr prostate neoplasJDS

The data in tht~ middotepnrt sl1ow similltr lesions io previous repmtlt hut show ewe ova--ian adenomas (Inc p-roiate adenomas than n the origirllll report nvie--ed forlb gtbullltcPRC report (middotIFO One 014143) ln lild wl= 6e criteria ofBoshland (1996) were usccl thn was xgt dose response reiarioruhip ccn in eithec 11lt ov~rian ad=mas or the prostate adennnalt n bullc CARC altcepted t~ PWGs evclllation

IV EVALJJATION Oflt ANT ANDROGEJIIC EFFECTS T O DETEKM ltF T HE POINT OF D~PARTlJRE

At Antiadroanjc Efiects

Titltmiddot-prbcipal toxic cffeclgt induced by v indomliu are rdatel to iis antirudrogenic nCrvity aad its aoilily lC act-~ ~ wrnpclitibull antagonigti at the aldrogen receptor 11bullrc i~ tvidence tblt1t vi-cozolin bind~ frurly weakly to the Andmgt~C rCltXptu~ lui lhatwc inclozolic metllbo1ite~ o~qnriug il11ll-I111liliplwrs and soi l aie re~gtOmible for much of the autillltlrogenic activity attrihu-ahc to vindu~lin Some of tlle rrore

2

Fin1 Repnrr

reievant iulullTllltion related to antiouclrugcnic activity o ~nch)Ctlin is sumwarized beow Fo~ a more thorougb di~c11ssiou ofthese effectlt rercr to the foilowing sources Grdy et al ( 1999) Hellwig ( 1989) 2nd repor of the Ifazrd Identificntiou _osessment Remiddotiebullv Couunillec (IIIARC 999) ltlnd Developmntal and Rr-1Jroduccive Toxicity A=ment R~ew Com1it1ltcb report on Vnclozoin (DRA~C 199K)

Pre-Nawl Develcpm(mal Swditmiddott

In a -at ckvclopmentalstudy(Grayct aL l999) a vuietyofanliud--ugnir effects were reported inducing deCTase iu pro~tateweiglt (L01-1- 6 mgltkglday) rud increased nippl development azd decreaed mo-genifal distance 0 male ofsprirg (LOA~T = 12 mgfgtlthy)2bull Otlu nlatcd efects seen in male o~g inclutOO decreased seminal ve~icle Cighis an increased inidence ofvaginal pouches zcreased numbers onipple~ ancl hypmgtadias decreased ejacuiRtcd sp~nn counts decreased fertility rl~ltnlttscd caudal epididymal wegtghl ~nd an increased incidence ofcclrlrgtil lesre_ Table l sumnwizes the result~ nr this study

Tle resulll of tits study =used o estnhiish cwlpoinl$ for acute diemry ancl short-fintCIIIIzdiate-telll dermal rislt ass~~rmu~ It is also the srudy fiOm which the gtoposed new POD for can= risk llSgttssmem wa~ choocn ()lOAEL =3 mgkgday decreased vtnt-il prostate weght seen at LO~ Fr- 6 rngkgday)

Sml~ry antilllldrogenic effects were ~~cu in WistaTand Lmg-Evans ratlt itt ~ srully conducted by DiSF (Hellwig 1997a amp ) Developmentnl effect~ lt1~-vetl in these studies ncuded signiflcaotiKrases in areolastipple anlagen in bolh strdios (OA2L = 12 mglkg6ty) and decreased mo-geniml ditnncc (LOAEL =200 mglkglday) A related ciT= obsetvelti in other smnics w11s ambigJOU3 genitliia in nales

n pos-Jatal stuCy using Long F~~w looed rns (Gry et AI 1999 HIARC 1999) a delay ilpubeny Cage ar reputia cparation) was founn I(gtbe s~isticaly~t (plt1Hi5j iu uaC offi-pring at doses of 15 ngfglda- wlrw oornpared to controls l11is finding was sugtported by sigmficant dccrca~cs in cami

It should he noted tbtt tbce is a nomal variation irt th~ tl~gree ofandrogenimtion of inrlivictlal iluses luring gesctinn ie the llllUrogen dep~nd~ruo-geni~l digttanre in a mae fetus appears to be dept1dmt among OL~e- iilctnrs on whether it is positiored hcO(u 2 nal~ fetuses l mae olti I lem~k lttus or bellmiddoteo 2 remae ~l~C-gt dmi11g gestation in wmea7ed ltts aod mice

This high LOAEL wagt due to dose spacing nrc slaristical evclUltlrion t)f a smdy by Gtfly sup_potec a r(JA 1- L lor Jccrea~ed ano -genitll dist~ncc tJ I l2 mg-kgday in pe-inmal studies

Fin1 Repnrr

reievant iulullTllltion related to antiouclrugcnic activity o ~nch)Ctlin is sumwarized beow Fo~ a more thorougb di~c11ssiou ofthese effectlt rercr to the foilowing sources Grdy et al ( 1999) Hellwig ( 1989) 2nd repor of the Ifazrd Identificntiou _osessment Remiddotiebullv Couunillec (IIIARC 999) ltlnd Developmntal and Rr-1Jroduccive Toxicity A=ment R~ew Com1it1ltcb report on Vnclozoin (DRA~C 199K)

Pre-Nawl Develcpm(mal Swditmiddott

In a -at ckvclopmentalstudy(Grayct aL l999) a vuietyofanliud--ugnir effects were reported inducing deCTase iu pro~tateweiglt (L01-1- 6 mgltkglday) rud increased nippl development azd decreaed mo-genifal distance 0 male ofsprirg (LOA~T = 12 mgfgtlthy)2bull Otlu nlatcd efects seen in male o~g inclutOO decreased seminal ve~icle Cighis an increased inidence ofvaginal pouches zcreased numbers onipple~ ancl hypmgtadias decreased ejacuiRtcd sp~nn counts decreased fertility rl~ltnlttscd caudal epididymal wegtghl ~nd an increased incidence ofcclrlrgtil lesre_ Table l sumnwizes the result~ nr this study

Tle resulll of tits study =used o estnhiish cwlpoinl$ for acute diemry ancl short-fintCIIIIzdiate-telll dermal rislt ass~~rmu~ It is also the srudy fiOm which the gtoposed new POD for can= risk llSgttssmem wa~ choocn ()lOAEL =3 mgkgday decreased vtnt-il prostate weght seen at LO~ Fr- 6 rngkgday)

Sml~ry antilllldrogenic effects were ~~cu in WistaTand Lmg-Evans ratlt itt ~ srully conducted by DiSF (Hellwig 1997a amp ) Developmentnl effect~ lt1~-vetl in these studies ncuded signiflcaotiKrases in areolastipple anlagen in bolh strdios (OA2L = 12 mglkg6ty) and decreased mo-geniml ditnncc (LOAEL =200 mglkglday) A related ciT= obsetvelti in other smnics w11s ambigJOU3 genitliia in nales

n pos-Jatal stuCy using Long F~~w looed rns (Gry et AI 1999 HIARC 1999) a delay ilpubeny Cage ar reputia cparation) was founn I(gtbe s~isticaly~t (plt1Hi5j iu uaC offi-pring at doses of 15 ngfglda- wlrw oornpared to controls l11is finding was sugtported by sigmficant dccrca~cs in cami

It should he noted tbtt tbce is a nomal variation irt th~ tl~gree ofandrogenimtion of inrlivictlal iluses luring gesctinn ie the llllUrogen dep~nd~ruo-geni~l digttanre in a mae fetus appears to be dept1dmt among OL~e- iilctnrs on whether it is positiored hcO(u 2 nal~ fetuses l mae olti I lem~k lttus or bellmiddoteo 2 remae ~l~C-gt dmi11g gestation in wmea7ed ltts aod mice

This high LOAEL wagt due to dose spacing nrc slaristical evclUltlrion t)f a smdy by Gtfly sup_potec a r(JA 1- L lor Jccrea~ed ano -genitll dist~ncc tJ I l2 mg-kgday in pe-inmal studies

fnai Reprm

atd paired epididyml2 wdghts at doses amvc l5 mgkgampy The sl ight ly delltyed pube1ty gtnbly resulced from androgen ckprivatiun from weaning lfl ~bout d2y 40 dning crowth and developmem ~foreif~ middotioclowEnmay result i adehyinSltltUlL =tion in childrcL This endpoilt uas

nstU n lhe hon md ntermediate teo risk a-sessmenS fur mfilns anrl t-Lcrenmiddot~ subpogtpul~to (lOPpoundL - 5 mgktdC)

Tajle I Summay ofcJTccls ofbullinozolin (art11 nigttcrtd GO 14 to PNU ) on luJy md or)Zm weight5 and other parameterlt mcaHml il LE rr21e at offspnng boul 12 months of a~c lnfomaticn ald eata are exu-cted from Gmy et aI (1999)

4

fina Report

fable I s middotof A Eff~ of

~

oody tizlar~ss -~b 6R120 691gt1 726=6 ~ss JJX)(i ~44~32

tolin~~ iYJJO) i (Sbulll9) fJi46) (41) (3-b) (22)

Srrur111v~icJ~ yen-1 imrJ 1945plusmn 4 Jampl$3plusmn141 111711)~ tsoooo 1744plusmn134 lt59~1 l6 6~rplusmnVl2

~Jittcnifrmalcs) (2) (36) (R37) (7i45) (418) (JSi (22)

Vennmiddot pr ostate wt (mU) 564~7 49950 bull45gt00 4391 i8t27 bullJOSb33 ~~69plusmn4i-

(1 irtlt-sfbullm nJ~1) (9127) (736) (8i37) (145) (41~) (315) (l2

Ttegt Wt (2_) 3 i (lQ()IJ 1iJcent06G 3SS~I 1 36~15 3tt2014 15~plusmn0 1 gt4Hltll4 (ltlttstflmtv) ~1il~) (7119i (8i2)) (118) (4 3) Ottti (J2

AdrcnaJ wt (mg) pound6shy 1 ll=lt lt9J1 43 5 43+C2 45=3 60-~ =J

(5i11) (312j lllJ (410) (2Gl (36i (22

CaulJltt pidiUyrllut~ (r1i) )(69 JI~lo JO~~ 3237 10111 6 18i2 1 bullbullJ3plusmn4 ~lirtJmiddotstttnd~~) (9lt24) 719 (amp23) 719) (4ll) (6) C2)

C uamp pitftf-ml syettu (x 10) 1~9 1~13 1316 ISl=Hgt ISJ20 I~K=25 bull61~7

c l (Sill) (3~2) (IZ) (2ii0) 2JoJ tJiJ) ( 22)

middot-ems spcnntid~ l 101) l c8~tl Zl3=4 2064 19plusmn 223+21 lil~li 17575

(jflitltrlmulcs) (SI) (]il2) t3ip) 21 0) l0) (316) (12)

fow ejactl~eC S~tlUI CUUClt (--~6) 014 nwmiddot J13 010 (bullt6 36 33

Ej-ulalcd sem- (bull lo) 12lt-()1 l~iiJli J R2Ml1 2~~plusmnJI 193~amp1 --vuo l6 middotmiddoto (il)) ( 312 (l1l2) ( 210) (116) (36) (313)

fcHility 100 oo~ 9middot~middot )ory nrl Cf()laquoltM middotmiddot~ P~m~mgc wth i1yrllp~dia 0 0 0 0 0 45~ 6 100

ltff lirrer~ e-t~minrrVn-CS (9ti1) 1696 191117) (J2S4) (1 156) (3[ i) (27)

cx1rrend)

ll4rccnmge ltltb ntppleltt 0 104-ID ~6Lt4 360 54)0 91oo 100

(I)Jiltrrt uamine-dmalu tHnl) (1096) (lll l ) (111114) (11156 (31) (27

txaruim=d)

( rmrt with Jliplhi)F(tlpups examinPrl)~ Ol2uoJoo d li96 1 t1 3184 3iS6 67 l7 lmlnlmum litttgt1lt tffbull~rrl) bull [bull)] jlJ Jlor 31 f or J l fl or3] JJ] 21

tCJlfr e~tCJslenmc (n~ml) l8SlO-~~ 13)1- 10~~7 9-l=middotJZ lS90JJ5 LI~Jol5~ J 5)041

(litttr$ exauU~ptp) cumincd) (SilJj (1bullL1) a l 2tiQ) (26 t36) Oi

lcrcna~ edltlpic middotCSI~t 0 (bull 0 ~ 0 w (t~1tcrs cxamineft~upA rtlnnet (19n j J6) Oitl i ) (PJ~bull) i5E) 3111) (20)

- bullbull middot p middot ObullJ5 ormiddot UOJ middot fh middot~- ~1 rbullJJOIylt~l u~I S itt m~ars b bull ~tfnu~al v~-icl and pmltHe wnitw were 1101 m~USUJ(cl ibullt 1ltost rn~i es

hft gro~ irnammancr aldor di~ellTMirl rf th~ ~x ~s~u middotins~ wcr~ inflemed hut includeO fr

5

A 2-gcncration reproductim1 tly in ratS wa~ suhniuoo by BSr (Hcllvig 1997 aamp hJ F~ a ltietaiicd discussion of li1is stutly refer to the npot of til DRA RC (1998) ResuI L lniucnt to lhis diS(us~i L-c ~-urnrnlrized 1 middot1 ahlu 2 beiow

0 17 24 (u

() v 0

0 0

0 c n

0 (l 10 off~ring

0 0 f)

0 ro oUsprn

n oltspnra

Toc high dese F mal hgtd o signinc~ntly ir=azcltl (jl lt OUI) ttCittl for testicular Leydf c1ii a(knolas Hovvur no sigrnicad in~nase wa1 noted n pllir-v~se con1parson oflhu bigh-iiose group witJ11h( control Te~cll~r Leydig cell hyp~pl ia was seen at doses cgti 30 m_ggtcay and al-w t The incide1ce of Leydig Cmiddot~U

6

fina Report

fable I s middotof A Eff~ of

~

oody tizlar~ss -~b 6R120 691gt1 726=6 ~ss JJX)(i ~44~32

tolin~~ iYJJO) i (Sbulll9) fJi46) (41) (3-b) (22)

Srrur111v~icJ~ yen-1 imrJ 1945plusmn 4 Jampl$3plusmn141 111711)~ tsoooo 1744plusmn134 lt59~1 l6 6~rplusmnVl2

~Jittcnifrmalcs) (2) (36) (R37) (7i45) (418) (JSi (22)

Vennmiddot pr ostate wt (mU) 564~7 49950 bull45gt00 4391 i8t27 bullJOSb33 ~~69plusmn4i-

(1 irtlt-sfbullm nJ~1) (9127) (736) (8i37) (145) (41~) (315) (l2

Ttegt Wt (2_) 3 i (lQ()IJ 1iJcent06G 3SS~I 1 36~15 3tt2014 15~plusmn0 1 gt4Hltll4 (ltlttstflmtv) ~1il~) (7119i (8i2)) (118) (4 3) Ottti (J2

AdrcnaJ wt (mg) pound6shy 1 ll=lt lt9J1 43 5 43+C2 45=3 60-~ =J

(5i11) (312j lllJ (410) (2Gl (36i (22

CaulJltt pidiUyrllut~ (r1i) )(69 JI~lo JO~~ 3237 10111 6 18i2 1 bullbullJ3plusmn4 ~lirtJmiddotstttnd~~) (9lt24) 719 (amp23) 719) (4ll) (6) C2)

C uamp pitftf-ml syettu (x 10) 1~9 1~13 1316 ISl=Hgt ISJ20 I~K=25 bull61~7

c l (Sill) (3~2) (IZ) (2ii0) 2JoJ tJiJ) ( 22)

middot-ems spcnntid~ l 101) l c8~tl Zl3=4 2064 19plusmn 223+21 lil~li 17575

(jflitltrlmulcs) (SI) (]il2) t3ip) 21 0) l0) (316) (12)

fow ejactl~eC S~tlUI CUUClt (--~6) 014 nwmiddot J13 010 (bullt6 36 33

Ej-ulalcd sem- (bull lo) 12lt-()1 l~iiJli J R2Ml1 2~~plusmnJI 193~amp1 --vuo l6 middotmiddoto (il)) ( 312 (l1l2) ( 210) (116) (36) (313)

fcHility 100 oo~ 9middot~middot )ory nrl Cf()laquoltM middotmiddot~ P~m~mgc wth i1yrllp~dia 0 0 0 0 0 45~ 6 100

ltff lirrer~ e-t~minrrVn-CS (9ti1) 1696 191117) (J2S4) (1 156) (3[ i) (27)

cx1rrend)

ll4rccnmge ltltb ntppleltt 0 104-ID ~6Lt4 360 54)0 91oo 100

(I)Jiltrrt uamine-dmalu tHnl) (1096) (lll l ) (111114) (11156 (31) (27

txaruim=d)

( rmrt with Jliplhi)F(tlpups examinPrl)~ Ol2uoJoo d li96 1 t1 3184 3iS6 67 l7 lmlnlmum litttgt1lt tffbull~rrl) bull [bull)] jlJ Jlor 31 f or J l fl or3] JJ] 21

tCJlfr e~tCJslenmc (n~ml) l8SlO-~~ 13)1- 10~~7 9-l=middotJZ lS90JJ5 LI~Jol5~ J 5)041

(litttr$ exauU~ptp) cumincd) (SilJj (1bullL1) a l 2tiQ) (26 t36) Oi

lcrcna~ edltlpic middotCSI~t 0 (bull 0 ~ 0 w (t~1tcrs cxamineft~upA rtlnnet (19n j J6) Oitl i ) (PJ~bull) i5E) 3111) (20)

- bullbull middot p middot ObullJ5 ormiddot UOJ middot fh middot~- ~1 rbullJJOIylt~l u~I S itt m~ars b bull ~tfnu~al v~-icl and pmltHe wnitw were 1101 m~USUJ(cl ibullt 1ltost rn~i es

hft gro~ irnammancr aldor di~ellTMirl rf th~ ~x ~s~u middotins~ wcr~ inflemed hut includeO fr

5

A 2-gcncration reproductim1 tly in ratS wa~ suhniuoo by BSr (Hcllvig 1997 aamp hJ F~ a ltietaiicd discussion of li1is stutly refer to the npot of til DRA RC (1998) ResuI L lniucnt to lhis diS(us~i L-c ~-urnrnlrized 1 middot1 ahlu 2 beiow

0 17 24 (u

() v 0

0 0

0 c n

0 (l 10 off~ring

0 0 f)

0 ro oUsprn

n oltspnra

Toc high dese F mal hgtd o signinc~ntly ir=azcltl (jl lt OUI) ttCittl for testicular Leydf c1ii a(knolas Hovvur no sigrnicad in~nase wa1 noted n pllir-v~se con1parson oflhu bigh-iiose group witJ11h( control Te~cll~r Leydig cell hyp~pl ia was seen at doses cgti 30 m_ggtcay and al-w t The incide1ce of Leydig Cmiddot~U

6

A 2-gcncration reproductim1 tly in ratS wa~ suhniuoo by BSr (Hcllvig 1997 aamp hJ F~ a ltietaiicd discussion of li1is stutly refer to the npot of til DRA RC (1998) ResuI L lniucnt to lhis diS(us~i L-c ~-urnrnlrized 1 middot1 ahlu 2 beiow

0 17 24 (u

() v 0

0 0

0 c n

0 (l 10 off~ring

0 0 f)

0 ro oUsprn

n oltspnra

Toc high dese F mal hgtd o signinc~ntly ir=azcltl (jl lt OUI) ttCittl for testicular Leydf c1ii a(knolas Hovvur no sigrnicad in~nase wa1 noted n pllir-v~se con1parson oflhu bigh-iiose group witJ11h( control Te~cll~r Leydig cell hyp~pl ia was seen at doses cgti 30 m_ggtcay and al-w t The incide1ce of Leydig Cmiddot~U

6

lta1cct Aneurttnt D~~nt

lypcrplagtia ms in=reased in the F 1 genera-jon reative to he parental SJjmaJs Tcis innalgted incidex~ vas poasiigtly du ro 11tc incna~x tiurampiot odOgting oft1e F1 geneaCon relauve to the P 0 gcncraunn lht F1 miirnh heingdoedu to 28-34 wck iulttltli-r2 in utero llrosure and dosing prior to s~-ual natnizy It Dsigniiicant finding ll1at an increl in the ill~rle-gtcc of lhc SlitrJ type oflesion w-as ser from dosing rolS in urero through sexual mntuity in(o adutimiddotood and from dos(n[ ylt1UIJ etdult -1 for 22-28 weeks (P parental generation) Tris suggeSiS that Leydig cell hype1pjasia is a common ctfc -witlJ vindozolin reulling from dosing the animals both

1as adult-s anti from dosing th~ amrrals prior to sexllll marurity

ChroiC Dog Study

b a -year chrodc rlog sturly_ ioc(cascd tcllotivc tctts weights and prcsate atrophy were observed at the LOAIL bull 48 mg)kgeay (NOAEL = 24 mgkJday)

Tniie 3 ~umonllries fl oe ~ulitmdrogerlic dfccts ofvincluzulin sen in riOUS studies (HIARC 1999 DRA~C

lltJIR CfRC 199)

Tabln 1 Fnfin oln tA Mnoiilenbullr1 rurin~ d~olib~r-~rions o r fht CARC The lnhlc irulutlcs rcJeYani data from the avallablt srudle~

stu-cr tOIKI ~NOAEL Fi~ings

(u~lk~ily (u bull(Vkamp11fl))

1elt)raquoUaatt11 DGte-~d pll~ial Wllfhl 6 6 l l ~criul disUncc d~c- middot11ud JS ulatbullliJII IC$ ~~~ lpiCtCym middotvei~ d~uc t~ti~IN LoU cell iJ)erfltu4f 30

10 STIbal v-iek w~ismiddotn demiddottc~

C~Irti-= elltoC~Otll~ u frcYJ$11 middot~middot~ tl$ht11-middot bull Vl-~11cd ~taJ OttlW OtbO 1Wys IS

s u Ul=o JO r~~iK~spcode~ IIgtC T~ston~ oetU-

~

bull11-1 TllJII~ middotlt~t iocreiOs prcatc air)J)lrJ~tmk4oa

~ (~-gt0 ppmj I ( IS(() PIIIIJ lh11ht~~ r rnJae $1~ (tU pusnccrpJy) CVOnit l1ot FoatlXI ~~1$111lt ltni~ltJw ~~obull n~middotJIUil 11 nw ~ m1 tnt ll11ttal

celllpireg~is io fnuk halt~OO ~a MRlfJIIJ middot1J~Sgtf)U3

12 ~1S pm) 24 (SO ppm)

(bullce~ 1Hn bull ~l(l)cent ppM) i esdeclc L~disccl td~nolia111all$e middot 1 (5C rpmmiddotmiddot

The Scoorul C~~rinolt~laquoo-nicity Peer Revew for Vinclozolin (CPRC 1996) corudltl that the anishyaldmgenic mode )faction for tJ k-li~ulttr uytlig cell ttnnors ir rodeltS ~pcas to have Y---en

7

fjnu_ Rcpon

denm~StaC(i For ltieaiis see th~ gt amp 3ro CPKC ~I) arui 1997)

In general it wagt condurkxl hat vbclozolin and ~orne of itS metabol itts competitively bmd to anclroge1 1~plors thus recbcinganrl-ogltnbindirg Tis ~uhs in lte ilc--Sed relelt~gte o~ utini2ing homlt (LE) which tinulales tesiostemne fJrWttetion in lstixla lc-1 U oeUs and Leydig xU hypetplasia )y Rn

UJ11cmiddotnwn nuclmw_ Allhough th rle~Jiled mecha11im is unknown it hns lgtgt1 silowJ that 1he umshyandrogeJicityand possibly the increa~cltllcvels ofLII are contribming facto-s to the debulld nprnltnl oruydig cell h11epla~bulllltwnUs Theore tllc wcight ofthe evilence illliaus that it is biobgi~ly plltuiole tlat the mti-andltlgcJi~ clll-ct~ ovinctozolin ed to the oll3tion ~ftllc Leydig cell hperpla-tiawmon ard llmt protecting Qgainst a1t -~mlrogen effect woulrl pwttgt against ~ydig cll hyperplasaladenomA~

y RRCONSIDERTIQN O F THE lOD FOR NON-lNEAR CA~CER RlSK ASSESSMENT

b order to assue adcqultttc rotectiro of all suscltptible adult su~gtopulnliuns considering potemial ltpusures throughout ~1cir lifetimes cRC recnmmcnlkd that lle cancer middotik ~_sment should be performed uliiangfue most sensitive cudpoinuelated ttninclooxrlins lt111tiandrogenic effe=L- Tills udpoint is identical t1 that used for the short and ilermediate tern nnncao= isk assesment (ie decreased votrd prosla~ weights) Thi eifec- gtll~ seen lttl 6 mg~dly reviOHlily a l0UL of49 ngbulllcfidlt~r

w~s used as a POV for threshold carcinogemc dosc-nsprmse assessmenL Till endpoint was based o1 dxrca~ed epididymal weight sc~n at 30 tngkgdlly rn 2-g~ncrdtion rat repmducliuu study Vcile tllis endpoint ul1) be protective for Sllle auull populations and e~gtOgture curarions ba5edon the nsulS ofthe 2-geueration rproduction StUdy there is cumem that it =Y not x prutlcrive ofall subpopulatinn8 and longer expo~ure drugtlttioru because ontiandbullngrlic effectS were seen At lower ltiose ievels in the l~vclopmental rat studi~~ The CARC theref(gt~c rcloommended Umt a POO ol lt19 mgkglday be tellacC(I -jth che 3 mgks-dey givo that this )101loL is (llllloclive fur all mtimdnampe1ie ct-~~ which could lead tltt I ~yiligce1lmmorfunnacnn and is therefore proteCtive uf~UpupulationJnd orall expusurG durations

YlASSESSME~T Ot CHILORENS SCSCEPTlBllJIY

The ioxicity JlOlilc Ior bullincOzolin cleamiddotiy indicates that 1he toxic dlc-~~ of nost concern m ilfunl~ ami chilltlreare tIC reprcxbCih-c aID oevelopzrentaleflecarclated to me ch~ic31~ antiurlrogenic ropenies 1vc o[ thse effccis decmiddotea~d pro~tate weigjll and dmiddotHy~rl pulgterty llle sele~crl ~middot endpoints for lOn~anccrmiddot luanan health rik a~e~irrK~uls

Tbe cmce- elll point oflOncen related to vmclowlin exposure 1~ the fomllltio of testiculcr Leycig ~il tlmlurgt rs ciescrJe~ ~middotgtobull it asbeen connrhl lhal plusmntis oiologically pl~nsiuk thatLeydig cell tumnrs result fiurn the pesticides aHuxr~iruge~c Ogtltrties Hcltaugte he ogttinal honno1sl1nilieu o forrllltioJ

Vindmolin (4th Rrev) Cmcec Ass~amnl DtgtlWTnt final ltccn

of these tummc occu rs prx1onumllltly in ~dull ~Junllib folioing chronic treatment with vinclozolin rt tgt unlikely that there will he serious conecm tor Jbonatiou of these ttunors durinr childhood Although fmration ofthese tmno in children is unlikely the young adults males du tkvclop testicuht= cltmcer An increased incidence of testicular Leydig cell hypergta-ia in adult animals may rS1lll liorn dusipg of th animlls prior to sexuai maturity (includh-g in utero exposures) a~ ~uggested hy 61e results of the) 2shygelerttion reproduction study discussed above It is a significant finding that the ~me types nflesions are iormed in cdult males funr dcsing ofbothadult anlti irrJlature ani-nals

flat on human caneltr indicate lhlltLyilig Ullltllloro are Wlcommon in adult t1121es Approxirrmtdy 1 of all cancers m men are oftcsticdar mig in and only 1 ofrbatarc Leydig cell tumorgt (ie 001 ofall cancer in men) (Cortran et al 994 Gilliland and Key 1 )95j Approxitllaidy 10-15 ofl cyltiig O~U tunors bmencan be malignant (Grem et ~L l986) Leydig cell tumors are extremely rare in children and when they do occur they are eltclusiveiy benign (Kaplan et a 1 986) According to a 1994 paper by trrtpin gtt al (1994) the ircidence ofte~~ular tumors b child111 is approxi-nately I in 100000 male children Furthermore a 1996 paper by JiIr= cl al (1996) states that in patients under 14 yca~ the incidence oftesticular orpamtesticulartumors is 05 - 21OO(XlO with Leydig cell tumors acounting tor approxi-nately 7 ofthoe tumors ThlL~ the occurrence ofLeydig cell tumors in the US population does not indicate an increased susceptibility ofchildren tgt development of this tumor type Nevertheless the posgtibilityofmcreasedincidence oftesticular Leydig cell tumors in adults resultingfromchildhc-odexposure to vinduwlin cmmot be ruled out

vTI CARCS CONCLUSIONS

1 The IWGs evaluation ofovaran and prostate tumors in a 24-month study with Wismr rats was acceptab le

2) TI1 NOASL on mgtkgciay shotlti rplacc lh -OAEL uf49 mgkgiJ~yas the POD to be us~d fcgtr a nnn-linc3r (MOE ) approach tor caneer risk ass=ment

J) The MOE approach using a POD of3 rngkgldayfor lhe most sensitimiddote antiandrogenic effe---t should be protective of all population subgroups and durations of exposure including exposures to inf211ts and ~hildrcn fur elttnw r eonccn1S

4) It is unlikely ampat ther-~ middotill be a carciI10genic hazard mmiddot ri~k concern for ii1fants or children exposelti to inclozoilil given that the likelihood of Leydig ~ll ilJnor fonmtion in ihese ndividuals is small However 1r potential for increase-J incidence of testicuiar Leydig cell mmors in adults re~-ulting Om infant and children ltxposure lO VlllClOZOJin CltUlflOl re n 1led out

C)

5) he iornmliltJn ufother t)-pe5 oftllnur n lnfants ad citildrm froo iJcn7olimiddot ltxposw-e igt unliKe) Although other ry~ n lunors wre repmtctl in lhe a-aiable cance SWe5 (ie ovaJftn ~C prostae lITors) the Ci1( concludoc Lbat the rcreascs il tlu occliC1ce oftk~( rnors we-e bullot liulogcally sgDillcant and

Sj h ~lxnLC be emphasized tiat ~~i~uhr Leyog ce tlul()rignesis is he cane Cut oiconcec 1 dt~ iUlirnnl hicasSlt~ys lowever the relfgtcl tKtimiddote colSeq~eJc~ tht rray also result fi11111 vindpzolirs mtiandmge~middotn~ mod~ ofaciion are ofequal cuncern Therefore e ivcn the corrmClnality iu the noee of action a POD ba~cd on aJtiadrogenic etlxt ltilwtud be protective ofbuthcmcer and noncancr health wnseque1cc~ Ho-ever t h~ risk managers ~h1r1ci be ware of he cirncmiddotIC$ of tbe N01EL and IX I OAEL for amudmsenic dfJXUgt ofinclozolin i) anulllls

J(j

Vlll RiRI JOGRAPHY

nderscm D G ( WOO) fincozolirt pathology Working Group (PWG) report on ovarian and prostate tumors ir a chronic toxicitJ and oncogenicity study in mts Memota11dum by David G- A11derson ReregistrationmiddotBranch2 Health Effects Dimiddotision to Susan Le-winDeanna Scher Reregistn1tion Brru1ch1 SRRD dated April lS 2000 HED Doc 014143

CARC (1996) Carciuogenicry Peer Review of Vindozolin (lnd) A memornndum from David Anderson Tnxicoogy Hrancb I and E~ther Rinde Science Analysis Branch Heclth Effects Division (7509C) to Connie Welch Registration Division (7505C) and Bruce Sidwell Special Review and Reregi-stration Division truough Stephanie Irene Ilealth Effects Division (7509C) Offiee-of Pcstitidc ProgrJtDS

CARC (1997) Cerci nogeniciiy Peer Review of VinclozoUn (3rd) A memonnd= from Edwin R Budd and Esther (inde Healtl Effects Division to Connie Welch Regi_-talion Division (7505C) ~nd Bmce Sidwell Special Rview nnci ReregiSiationDivisionthroughStephanie Irene HealthElix1s Di visiun (7509C) Office ofPesticide ProgrdTs dited Apri13 1997 HED Doc 012639

CRC (2000a) Vindazolin Cancer Assessment ReviewCommitree (CAR C) Supplememal vieeting Pwpogtlt~d Cbaoges in the Endpoint for Cancer Risk ssessment Jncluding the Issues of Jfalts and Chihinn A memomndwn fimiddotom vichael S Metzger RRBI adDavid Anderson RolU32 Heall11 3ITor~ts Di-~sinn to Nillirun Bumall SiB HealtlJ Effects Oiviion Office ofiesucidc Pwgrams datOO April 4 woo

CARC (2000b) Vinclmolin As~essment of new Enfonnat~on relevaJt to carcinogenic polcntiaL A memorandum limn Jolm M Pletcher ConUlting Pathologist SAlC to Sanjivali Diw~n Rxecbullllive Secetary Cancer Assessment Review Committee Health EITects Divigtion (7 Olt)C) Office of festicide Programs dated 13 AprJ 2000

Conlran Pv3 Kumar V Rnnhns SL and Schoen FJ (1994) Male genitalS)Stem inRo~bins Pathologic tla~is nfDseae 5d1 Edition Contran RS KJLlar V aod Robbins SL SDs wB Saunders Philadelphia l015- 022

DRgtRC ( 1998) Reproductive and Develmiddot~pmental Toxicitf Peer Review ofVidowlin A mcmogtandum fimiddotmn Kit Fanvell RRBl to Clark Swentzel Chairnan IJJARC through David A ndcmiddoton Chainnan DKARC Heath Effects Division(7509C) Office of Pesticice ProgniIT1gt ltlatcd ltprmiddotil 7 l YiR -HLJ Doc 0 12562

Gilli land FD md Key CR (1995) Male geniial cancers CmG 75 (uppl 1) 25-3 15

11

Vlll RiRI JOGRAPHY

nderscm D G ( WOO) fincozolirt pathology Working Group (PWG) report on ovarian and prostate tumors ir a chronic toxicitJ and oncogenicity study in mts Memota11dum by David G- A11derson ReregistrationmiddotBranch2 Health Effects Dimiddotision to Susan Le-winDeanna Scher Reregistn1tion Brru1ch1 SRRD dated April lS 2000 HED Doc 014143

CARC (1996) Carciuogenicry Peer Review of Vindozolin (lnd) A memornndum from David Anderson Tnxicoogy Hrancb I and E~ther Rinde Science Analysis Branch Heclth Effects Division (7509C) to Connie Welch Registration Division (7505C) and Bruce Sidwell Special Review and Reregi-stration Division truough Stephanie Irene Ilealth Effects Division (7509C) Offiee-of Pcstitidc ProgrJtDS

CARC (1997) Cerci nogeniciiy Peer Review of VinclozoUn (3rd) A memonnd= from Edwin R Budd and Esther (inde Healtl Effects Division to Connie Welch Regi_-talion Division (7505C) ~nd Bmce Sidwell Special Rview nnci ReregiSiationDivisionthroughStephanie Irene HealthElix1s Di visiun (7509C) Office ofPesticide ProgrdTs dited Apri13 1997 HED Doc 012639

CRC (2000a) Vindazolin Cancer Assessment ReviewCommitree (CAR C) Supplememal vieeting Pwpogtlt~d Cbaoges in the Endpoint for Cancer Risk ssessment Jncluding the Issues of Jfalts and Chihinn A memomndwn fimiddotom vichael S Metzger RRBI adDavid Anderson RolU32 Heall11 3ITor~ts Di-~sinn to Nillirun Bumall SiB HealtlJ Effects Oiviion Office ofiesucidc Pwgrams datOO April 4 woo

CARC (2000b) Vinclmolin As~essment of new Enfonnat~on relevaJt to carcinogenic polcntiaL A memorandum limn Jolm M Pletcher ConUlting Pathologist SAlC to Sanjivali Diw~n Rxecbullllive Secetary Cancer Assessment Review Committee Health EITects Divigtion (7 Olt)C) Office of festicide Programs dated 13 AprJ 2000

Conlran Pv3 Kumar V Rnnhns SL and Schoen FJ (1994) Male genitalS)Stem inRo~bins Pathologic tla~is nfDseae 5d1 Edition Contran RS KJLlar V aod Robbins SL SDs wB Saunders Philadelphia l015- 022

DRgtRC ( 1998) Reproductive and Develmiddot~pmental Toxicitf Peer Review ofVidowlin A mcmogtandum fimiddotmn Kit Fanvell RRBl to Clark Swentzel Chairnan IJJARC through David A ndcmiddoton Chainnan DKARC Heath Effects Division(7509C) Office of Pesticice ProgniIT1gt ltlatcd ltprmiddotil 7 l YiR -HLJ Doc 0 12562

Gilli land FD md Key CR (1995) Male geniial cancers CmG 75 (uppl 1) 25-3 15

11

Gay LE Jr Ostby J Mono~sonE and Keke VR (1999) GnvJonmeotamtiandrog= low doses nfth~ fimiddotJnecicJe vincn7rinalter~extml di7i~nutiatiuuofthe IIltk (I ~S Tox_cology md Jrdustrial Ee~tJth 1~

4~-64 (pc11tions o7the data mec bullvere Isltgt f(HH IlK 1996 SAP JHtgtenfgt)t inlt)

Orem JL Ronin Hl Wilon KS Gilchrst K and Thlrp DL ( i9S6) 1e~IJtk Leydig cell tlllno oftile testis Repon of6ree cases and review ofthe literature Cancer Res 55216-2119

Grarln C Royer C ~nr Rmcmiddot M (_191J4) TurllgtI of the Teks in Chi lch~ - J Urol 100(12) S-16

HIRC (1999) To)ljc~logy 3ndpoint Selection Document 2lod Report ofHazard Identification Kevew Comtlirtce cated December 8 1999 HED Doc ti 0 13919

1e~lmiddotvig J ( 1997a) Pre-~)ostnata ~oxi)ity study ln -istar ntts aftcx orU aclrninistrltion (gavage) Reg lo 83-258 Dcpl of Toxicoiogy B-SF Akicngeslilid NbullIl FRG 9i 97 llibullpubli$cJ~d MRJn

4439gt70 i

Helhvg J (1997b ) Premiddotfpostnatll toxicity stgtJltiy in Long Evans rars after o-i adminislm tion (gavag~) Reg No 83-258 Dept of Toxicolo-y BASF Akiengeseil~chail FRG 9197 llnpubligtbcd MruD 44395702

Jimenez Ilv1 Gonez FA Aransay BA et ~- (1996) Testicukr tu-nors in clrilcilood Revie-_v ofcaselt in the cott-seof lJ yearsmiddot Cir Pzdiatr 9 (1) JJ-16

Kaplan OW Cmmie Wl Kelalis PP Silber I and Tltmk BS 19ii6 Gonadal trorral tounors A report of thqrepubertal testiculartumor regisny J Urol 136300-02

Pad1oiogj Working Group Report (1997) Vinclowlin Rlg ~middot 83 25J 24-Montl Chronic Toxicttj (B ASF Projxl No 7 JS03758~021gt)ad Carcinogcnicity(ProjeC No 71 S375881 05) Studies inWistar R~t~ RpM prcpar~ri by PathComiddotlnc August 28 1997 372 pages pbs l ~ amp l b DASf Reg Doc

Pilll )4 (MRID 44430301) Case 819455 Rereg cltSeli 2740

12