# 4 L££2£ — # Si

——~ " Apri l 02 , 198 7

FINA L REPOR T T K 1244 3 TERATOLOG YSTUD YI NRAT S G UPROJEC TNO
. 84086 2 TTNUVCi 4 ^3 V

SEN TT O CORPORAT E TOX : YE S BN O D 

### DATE : V^A ?
. P & APRODUC TSAFET Y

200202/GF , WE , F R 

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### Z F G U G U

### 1. 1 QS E GUhLIT YASSURANC E STATEHEH T For « 30 1 C

STUD YTITL E ; T K 1244 3 TE:RATOLOG YSTUD YI N RAT S
Sponso r; Tes tNo , : 84086 2 Stud y directo r

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1 26,07,8 5 3 29,08,8 5 5 07,03.8 6 4 0 9,10,8 5 6 16,12' , 8 6

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Sfjdi j directo r0 G U 1, 1 Fil eTERATOLOG YSTUD YI NRAT S Page- I G UProjec t No . 84086 2 Tes t Article : T K 1244 3
TABL E O F CONTENT S 1 Introductio n1 2 Suminar yan dconclusio n3 3 Personne l 7 4 Tim e schedul e 8 5 Material s andMethod s 9 5 . 1 Tes t materia l 9 5 . 2 Experimenta l animal s 1 0 5.2. 1 Species , stock, sourc e 1 0 5.2. 2 Husbandr y' 1 0 5.2. 3 Die t 1 1 5.2. 4 Wate r 1 1 5 . 3 Procedur e 1 1 5.3. 1 Matin g an dacclimatio n1 1 5.3. 2 Identification , randomisatio nan dhousin g o f

dam s 1 2 5.3. 3 Dose-level s 1 2 5.3. 4 Preparatio no f tes t article , administration.. . 1 2 5.3. 5 Conten t analysi s 1 3 5.3. 6 Grou p identificatio n1 3 5.3. 7 Observation s o ndam s durin g lif e phas e 1 3 5.3. 8 Euthanasi a 1 4 5.3. 9 Observation s o ndam s a t sacrific e 1 4 5.3.1 0 Observatio no nfetuse s 1 5 5.3.10. 1 Gros s examinatio n1 5 5.3.10. 2 Viscera l examinatio n1 6 5.3.10. 3 Skeleta l examinatio n1 7 5.3.1 1 Classificatio no f feta l finding s 1 8 5. 4 Statistica l analysi s 1 9 5 . 5 Deviation s fro mth e protoco l 2 0 6 Reference s 2 1 7 Archive s 2 2 8 Result s • - . . . 2 3 8 . 1 Observation s i ndam s 2 3 8.1. 1 Materna l clinica l examinatio n2 3 8.1.1. 1 Table : Summarize dmaterna l clinica l

observation s 2 4 8.1. 2 Mortalit y2 5 8.1. 3 Materna lbody-weigh t gai n2 6 8.1.3. 1 TABLE : Mea nbod yvzeight s o f dam s (i n g ) 2 7 8.1.3. 2 FIGURE : Mea nbodyweight s o f dam s (i n

g ) • 2 8 8.1. 4 Materna l body-weigh t change s 2 9 8.1.4. 1 TABL E : Mea nmaterna l body-weigh t

change s durin g gestatio n3 0TERATOLOG YSTUD YINRAT S Page-I I G UProjec t No . 84086 2 Tes t Article : T K 1244 3

TABL E O F CONTENT S (cont'd ) 8.1. 5 "Corrected " bod yweight s a t necrops ynea r ter m3 1 8.1.5. 1 TABLE : Mea n"corrected " bod yweigh t o f

dam s 3 2 8.1. 6 Foo dconsumptio n3 3 8.1.6. 1 TABL E : Foo dconsumptio ndurin g

gestatio n(i n g ) 3 4 8.1.6. 2 FIGUR E : Grou p mea nfoo dconsumptio n

durin g gestatio n(i n g ) 3 5 8.1. 7 Materna l postmorte mexaminatio n3 6 8.1.7. 1 TABLE : Summar yo f materna l postmorte m

examinatio n3 7 8.1. 8 Examinatio no f ovaries , uteru s an d uterin e

content s 3 8
• 8.1.8. 1 TABLE : Summar yo f cesarea nsection ,

pregnanc ydat a 4 0 8.1.8. 2 TABLE : Summar yo f cesarea nsection ,

uterin e data(1 ) 4 1 8.1.8. 3 TABLE : Summar yo f cesarea nsection ,

uterin e data(2 ) 4 3 8.1.8. 4 TABLE : Summar yo f ceasarea nsection ,

feta l dat a . 4 4 8 . 2 Observation s i n fetuse s 4 5 8.2. 1 Externa l examinatio no f th e fetuse s 4 5 8.2.1. 1 TABLE : Summar yo f feta l externa l

anomalie s and/o r malformation s 4 6 8.2. 2 Feta l viscera l examinatio n4 7 8.2. 3 . Ossificatio no f feta l skeleton s 4 8 8.2.3. 1 TABLE : Summar yo f feta l skeleta l

anomalie s and/o r malformation s ~ 5 0 8.2.3. 2 TABLE : Summarize ddat a o f delaye d

skeleta l maturatio n5 2 8.2. 4 Summarize dfeta l abnormalitie s 5 6 8.2.4. 1 TABLE : Summar yo f al l feta l anomalie s

and/o r malformation s 5 7 Appendice s 5 8 9. 1 Statistica l analysi s 5 8 9.1. 1 Bod yweight s 5 9 9.1. 2 Bodyweigh t change s 7 0 9.1. 3 "Corrected " bod yweight s 7 4 9.1. 4 Foo dConsumptio n7 6 9.1. 5 Uterin e dat a 8 0 9.1. 6 Feta l skeleta l finding s 8 9 9. 2 Individua l Dat a 14 9 9.2. 1 Individua l Materna l Clinica l Observation s 14 9 9.2. 2 Bodyweigh t (individua l values ) 24 5 9.2. 3 Bod yweigh t change s (individua l values ) 25 7 9.2. 4 "Corrected " bod yweight s (individua l values). . 26 1 9.2. 5 Foo dconsumptio n(individua l values ) 26 9 9.2. 6 Materna l necrops yfinding s (individua l values ) 2 7 3 9.2. 7 Uterin e data : par t 1 (individua l values ) 28 1TERATOLOG YSTUD YI NRAT S Page-Il l G UProjec t No . 84086 2 Tes t Article : T K 1244 3

TABL E O F CONTENT S (cont'd ) 9.2. 8 Uterin e data : par t 2 , continue d(individua l

values ) 29 3 9.2. 9 Feta l dat a 30 5 9 . 3 Randomizatio n36 1 9. 4 Matingtabl e 36 3 9. 5 Concentratio no f Tes t Articl e i nth e Vehicl e 36 7 1 0 Distributio n36 8TERATOLOG YSTUD YINRATS 1 G UProjec t

No
. 84086 2Tes t Article : T

K 1244 3

1
. INTRODUCTIO N A t th ereques t

o f th ePlastic s an dAdditive s Division ,

ateratogenicit ystud yi nrat s wa s con ducte di norde r

t o determin epossibl eadvers eeffect s o nth eembry

oni c and/o r

feta ldevelopmen t o f th etes t

articl efollowin g th e administratio nfro mda y6 unti lda y1 5 o f pregnancy . Th estud ywa s carrie dou t a t th e Th emai nfeature s o f thi s stud yfollowe dth eOEC D guideline s fo r testin g o f

chemicals , "Teratogenicity " no . 414 , adopte dMa y12 , 1981
. Th estud ywa s performe di naccordanc ewit hth ePrinciple s o f Goo d Laborator yPractice , adopte dMa y12 , 198 1 b yth eOEC D Counci lan dwa s subjecte dt o periodi c qualit yassuranc eevaluation
.TERATOLOG YSTUD YI NRAT S 2 GUProjec t No . 84086 2 Tes t Article : T K 1244 3
Thi s repor t present s th e result s o f th e investigatio na s compile db y th e undersigned" : Stud yDirecto r



### date : '^f^r' A2 ^>tf^ ^

Studysuperviso r

date : Q.0[\ , \\l' ^

Reviewe dan dapprove d (Facilit yManagement )

date :TERATOLOG YSTUD YI NRAT S 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3

SUMMAR YAN D CONCLUSIO N
I nthi s studyT K 1244 3 wa s evaluate dfo r possibl e embryotoxi c activ

it yandteratogeni c potenc yi nth e rat . Base do nth e result s o f a previousl yconducte dpreliminar yteratology study , th e dail ydose s wer e selecte da t 0 , 300 , 100 0 an d300 0 mg/k g o f bodyweight . Th e tes t substanc e wa s suspende di nth e 1: 1 mixtur e o f distille dwate r an dpolyethylen e glyco l 40 0 (PEG400 ) an dadminis

tere dorall ybyintubatio nonc e dail yfro mda y6 unti l da y1 5 o f pregnancy , inclusive . Th e female s wer e checke ddail yfo r clinica l signs , symptom s an dmor talitie s a s wel l a s body-weigh t changes,
- foodconsumptio nwa s deter
mine da t five-day s intervals , i . e . a t leas t onc e a week . Th e female s wer e kille dshor t tim e prio r t o expecte ddeliver yandsubmitte dt o macroscopi c pathologica l examination . Th e uter i wer e dissecte dan d content s examined . Liv e fetuse s wer e weighed , sexe dan devaluate dfo r external , viscera l and/o r skeleta l abnormalities . Th e result s o f th e studyca nb e summarize da s follows : Materna l dat a Clinica l sign s an dsymptom s N o clinica l sign s o r symptom s wer e recorde dt o occu r a s a consequenc e o f treatmen t wit hth e tes t substance . Afev. ' animals , suc ha s tw o fro mth e contro l group , five fro mth e low
dos e grou p andon e fro meac hth e intermediat e andhig hdos e group s develope dsom e necroti c area s o nth e ski nwhic hwer e no t considere d t o b e du e t o th e treatment . Mortalit y N o spontaneou s deat hwa s observe dan dn o interi msacrific e b yreason s o f il l healt hwa s t o b e performe dthroughou t th e period s o f treatmen t an dpost-treatment . Body-weigh t gai n O nth e basi s o f th e statistica l evaluatio no f data , bod yweigh t a s wel l a s body-weigh t change s wer e foun dt o b e comparabl e fo r al l groups . Als o th e "correcte dbod yweight " a s determine da t sacrific e nea r ter m an dbase do nfina l bodyweigh t minu s weigh t o f th e uteru s including contents , wa s no t significantl yaltere di nth e experimenta l groups .TERATOLOG YSTUD YI NRAT S 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Foo dconsumptio n N o decreas e i nfoo dconsumptio nwa s note dfo r th e thre e dos e groups . Macroscopi c pathologica l examinatio n a t sacrific e nea r term N o change s wer e recorde dwhic hmigh t b e relate dt o th e treatmen t wit h th e tes t substance . Reproductio ndat a establishe d a t sacrific e nea r term Th e pregnanc yrate s wer e comparabl e fo r al l group s a t 9 2 % t o 10 0 % . Th e examinatio no f th e uter i an duterin e content s di dno t revea l an y alteratio nattributabl e t o th e treatmen t o f dam s wit hth e tes t substance . Embry o andfetolethalit yoccurre da t a certai nincidenc e simila r fo r al l groups . N o experimenta l significanc e wa s attache dt o partia l abortio no f th e " ^ litte r a s observe di non e dameac ho f th e intermediat e andhighdos e groups . A t 300 0 mg/k g a slightl yincrease dmea nnumbe r o f corpor a lute a an d' ^ decrease dmea nnumbe r o f implantatio nsite s resulte di nanelevate d rati o o f thes e parameter s (corpor a lute a / implantatio nsites ) i n compariso nwit hth e contro l group . A s bot hth e aforementione dchange s concernin g number s o f corpor a lute a andimplantatio nsite s di dno t sho wa statisticall ysignifican t differenc e fro mth e correspondin g contro l data , th e latte r resul t wa s no t attribute dt o th e dams ' treatment .

Feta l dat a Examinatio no f fetuse s survivin g t o sacrific e nea r term O nth e compariso no f the grou p mean s o f feta l bod yweights , a signif

ican t reductio nwa s recorde dfo r th e 100 0 mg/k g group . I nthi s inter

mediat e dos e group als o anincrease ddelayo f skeleta l maturatio nwa s found . I nth e absenc e o f comparabl e result s fro mth e high-dos e group , however , n o experimenta l significanc e wa s assume dfo r thi s finding .TERATOLOG YSTUD YI NRAT S 5 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
Occasiona l significan t difference s fromth e contro l wer e als o note d fo r th e ossificatio nrate s o f severa l skeleta l element s i nth e fetuse s o f th e lo wan dhig hdos e groups . I nth e vie wo f grea t variation s withi nth e group s thes e result s wer e no t attribute dt o treatment , too . Th e externa l examinatio no f th e liv e fetuse s reveale dtw o mal
formation s :

- a fetu s o f th e contro l grou p showe dgeneralize doedem a

- a fetu s o f th e high-dos e grou p showe da nomphalocel e Omphalocel e a s indicatin g failur e o f ventra l closur e durin g lat e stage s o f embryoni c developmen t i s a typ e o f malformatio nals o recorde dt o occu r spontaneousl yi nth e stoc k o f rat s use dfo r thi s study . Th e on e instanc e observe damon g th e high-dos e fetuse s o f the presen t stud ywa s als o considere dt o b e o f a spontaneou s origi nan d no t relate dt o th e treatment . Th e skeleta l assessmen t o nabou t tw o third s o f liv e fetuse s pe r litte r reveale danomalie s exclusivel yconsisten t wit hirregula r ossi

ficatio no f sternebra e :

- 4 fetuse s ( 4 litters ) o f th e contro l grou p

- 4 fetuse s fro m3 litter s o f th e 30 0 mg/k g dos e grou p

- 2 fetuse s ( 2 litters ) o f th e 100 0 mg/k g dos e grou p

- 6 fetuse s fro m3 litter s o f th e 300 0 mg/k g dos e grou p wer e affecte di nthi s respect , th e "pe r litter " a s wel l a s "po i fetus " incidence s bein g simila r fo r al l groups . N o viscera l malformation s o r anomalie s wer e detecte db yapplying the slicin g techniqu e o nabou t on e thir do f liv e fetuse s pe r litter . yTERATOLOG YSTUD YI NRAT S 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

CONCLUSIO N
I nthi s teratolog ystud yo nth e ra t T K 1244 3 wa s devoi do f anembry
otoxi c activit yan dteratogeni c potenc yfollowin g th e ora l ad
ministratio no f dail ydose s o f 300 , 100 0 an d300 0 mg/k g t o th e dam s throug hday s 6 unti l 1 5 o f pregnancy . Statisticall ysignifican t de
viation s fro mth e contro l dat a concernin g a slightl yreduce dfeta l bod yweigh t a t 100 0 mg/k g an ddela yo f skeleta l maturatio na s also , i nparticular , note dfo r thi s intermediat e dos e group , wer e no t con sidere dt o b e du e t o th e dams ' treatmen t wit hth e tes t substance . Furthermore , ther e wa s n o materna l toxicit yrecorde dfo r th e thre e dos e groups . I nth e vie wo f th e foregoing result s n o obviou s "maximu m tolerate ddos e level " wa s attaine di nthi s study . Physico-chemica l propertie s o f larg e amount s o f tes t substanc e i nth e water-PE Gmix

tur e use da s a vehicl e di dno t allo wtreatmen t a t dose s highe r than 300 0 mg/k g unde r th e presen t experimenta l conditions , however .TERATOLOG YSTUD YINRAT S 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
3 . PERSONNE L
Stud ydirecto r Teratologis t Experimenta l Superviso r Mr . B . Schmid t Technica l assistant s

Mr . J . Strat z Statistica l analysi s Reportin gTERATOLOG YSTUD YI NRAT S 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
4 . TIM E SCHEDUL E
Arriva l o f female s (commencemen t o f acclimation ) Augus t 05 , 198 5 Startin g dat e o f experiment-'

- Augus t 06 , 198 5 Startin g dat e o f dosin g Augus t 12 , 198 5 Dat e o f Cesarea nsectio nAugus t 2 7 - 30 , 198 5 Terminatio ndat e o f experimen t Novembe r 11 , 198 5 Dat e o f releas e o f Fina l Draf t Repor t Jun e 30 , 198 6

1 . Assignmen t o f th e firs t subgrou p bein g eviden t o f successfu l matin g t o th e correspondin g dos e group sTERATOLOG YSTUD YINRAT S G UProjec t No . 84086 2 Tes t Article : T K 1244 3

5.1 . Tes t materia l 5 . MATERIAL S AN D METHOD S

Cod e No : Trad e name : Batc hNo : Description : Purity : Solubility : Received : Amoun t received : Expir ydate : Stability : Storage : Vehicl e o r solvent :
Safet yPrecautions : T K 1244 3 TINUVI N23 4 E N02885.3 2 (commercia l grade ) soli d 99. 7 % insolubl e i nwate r Augus t 22 , 198 4 1 0 kg t o b e provide db

yth e sponso r ascertaine db

yth e sponso r roo mtemperatur e 1: 1 mixtur e o f distille dwate r and Polyethylen e Glyco l 40 0 (pract. , FLUKAAG , Buchs , Switzerland ) routin e hygieni c procedure s wer e considere dt o b e sufficien t t o assur e healt han dsafet yo f al l personne lTERATOLOG YSTUD YI NRAT S 1 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.2 . Experimenta l animal s
5.2.1 . Species , stock , sourc e Species : Albin o ra t Stock : Tif : RAIf(SPF) , hybrid s o f RII/ 1 x RII/ 2 Source : Anima l Production , an d Initia l mea nbod yweigh t o f females : 18 0 - 20 0 g Initia l ag e o f females : abou t 2 month s Initia l numbe r o f mate d female s pe r group : 2 4 5.2.2 . Husbandr y Th e experimen t wa s carrie dou t unde r conventiona l standar d laborator yconditions . Th e animal s wer e house di ngroup s o f 4 i nMacrolo ncages ' wit ha wir e mes hto p andwit hstandardise d granulate dsof t woo d(Societ e Parisienn e de s Sciure s Pantin ) servin g a s beddin g material . Th e anima l roo mwa s ai r conditioned : Temperature : 21° C + 1° C Relativ e humidity : 55 % + 15 % Ventilation : abou t 1 6 ai r changes/hou r Ligh t cycle : 1 2 hour s ligh t pe r da y( 6 a.m . - 6p.m . ) Neithe r insecticide s no r othe r chemical s wer eapplie di nth e anima lroo mwit hth eexceptio no f th edisinfectan t

BRADOPHE

N F o r treatmen t

o f loca lski nnecrosis , th eantibioti c TYROSOLVIN ^wa s locall yapplied
.TERATOLOG YSTUD YINRAT S 1 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.2.3 . Die t Pelleted , certifie dstandar ddie t (Nafa g No . 89 0 Tox ) wa s provide da dlibitum . Al l batche s o f die t wer e assaye dfo r compositio nan dcontaminan t level s b yth e manufacturer . Analytica l result s ar e lodge da t th e anima l suppl yoffic e
5.2.4 . Wate r Ta p wate r wa s availabl e adlibitumfromplasti c bottles . Th e drinkin g wate r qualit yfulfille dth e specification s o f th e "Schweizerische s Lebensmittelbuch " (Ed . 1972) . Th e result s o f th e routin e chemica l examinatio no f wate r a t sourc e (Grundwasserfassun g Stein ) a s conducte dperiodicall yb yth e wate r authorit y(Baudepartemen t de s Kanton s Aargau , Abteilun g Gewaesserschutz ) ar e availabl e t o a s wel l a s th e result s o f inhous e chemica l analysi s byth e analytica l laboratorie s o f th e . 5.3 . Procedur e
5.3.1
. Matin g an dacclimatio n Nulliparou s femal erat s wer emate dovernigh t wit hmale s o f prove nfertilit ya t arati o o f

3 female s t o 1 mal ei nrack s containin g modifie dmatin g cages . Eac hcag ewa s subdivide dint o tw o part s b yashutter , separatin g th esexe s unti labou t 3 a.m. , whe nth eshutte r opene db ymean s o f a nautomati c device
. A t 7 a.m . t o 9 a.m . , successfu lmatin g wa s determine deithe r b y t h epresenc eo f avagina lplu g o r b yth epresenc eo f spermatozo ai nth evagina lsmear . Thi s da ywa s designate dda y "0 " o f pregnancy . Acclimatio nunde r tes t condition s di dtak eplac edurin g th e perio do f

tim ebetwee nallocatio nt o th ecorrespondin g grou p o n da y0an dth efirs t treatmen t

o nda y6 pos t

coitum
. Matin g table s ar eshow ni nth eAppendi xsection
.TERATOLOG YSTUD YI NRATS 1 2 G UProjec t

No
. 84086 2Tes t Article : T

K 1244 3
5.3.2
. Identification , randomisatio nan dhousin g o f dam s Th emate dfemale s wer eallocate dt o experimenta lan dcontro l group s b y usin g ametho do f randomizatio nb y weigh t stratificatio na s show ni nth eAppendi xsection
. Afte r allocation , th efemale s wer eidentifie dindividuall y b y colou r cod eo nth etai l(i.e
. adash-do t code , painte dwit ha felt-tippe dwaterproo f marker ) an dplace di ngroup s o f 4 i n Macrolo ncages . Th ecage s wer eidentifie db y acoloure dlabe l accordin g t o th egroup , th ecod enumber o f th etes t

materia l, th edos ean dth edate s o f treatmen t

an dautopsy . 5.3.3 . Dose-level s Th e dose-level s wer e selecte do n th e basi s o f a previousl y conducte dpreliminar yteratogenicit ystudy . Group s o f eac h1 2 pregnan t rat s wer e treate dwit h0 , 100 0 mg/kg and300 0 mg/k g bodyweigh t fro mday6 unti l day1 5 o f pregnanc y wit hth e tes t substance . Th e result s fro mthi s studyca n b e summarize da s follows : Th e female s o f bot hth e experimenta l group s remaine dunaffecte d b yth e treatment . Foo dconsumption , body\i7eigh t development, , genera l healt han d al l litte r parameter s wer e comparabl e l o thos e o f th e contro l group . On e femal e o f th e contro l grou p die do n da y2 0 pos t coitum : Necrops yreveale dblood yliqui di n th e uterus ; On e malformatio nwa s foun damongs t th e fetuse s ot th e contro l grou p (clef t palat e i n combinatio nwit h maldevelope dtongue) . Du e t o physicochemica l restraint s o f th e tes t article , th e high dos e wa s limite dt o 300 0 mg/k g bodyweight . Base do n th e foregoin g results , i t wa s decide dtha t th e hig h dos e shoul db e 3 00 0 mg/kg , th e indermediat e dos e 100 0 mg/k g an d th e lo wdos e 30 0 mg/kg , a dos e expecte dt o yiel da no-effec i level . 5.3.4 . Preparatio no f tes t article , administratio n TK 124 4 3 V7a

s suspende di n a 1: 1 mixtur e o f distille dwate r an d polyethylen e glyco l 40 0 (practica l grade , FLUK AAG , Buchs , Switzerland ) an d administere dorall yb ygavag e fro

mday6 unti l da y1 5 o f pregnancy , inclusive .TERATOLOG YSTUD YI NRAT S 1 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
Th e suspension s o f th e tes t materia l wer e freshl yprepare d dail yan dth e homogeneit yo f th e suspension s wa s maintaine db y mean s o f a magneti c stirrer . Th e volum e administere dwa s 1 0 ml/k g an dadjuste dt o actua l dail ybod yweights . Th e conten t analysi s o f th e tes t articl e suspension s showe dvalue s rangin g fro m93. 5 t o 100. 8 % o f th e nomina l values . Th e result s ar e show ni nAppendi x9.5 . .Th e suspension s prepare dcontaine d0 mg/ml , 3 0 mg/ml , 10 0 mg/m l an d30 0 mg/m l o f T K 12443 . 5.3.5 . Conten t analysi s Conten t analysi s o f th e differen t concentration s o f TK 124 4 3 wa s performe db yth e centra l analytica l laborator yo f

fro msample s take nfro mthi s stud yo nAugus t 22 , 1985 . 5.3.6 . Grou p identificatio n Th e experimenta l desig nwa s a s follows :
Grou p

Vehicl e contro l Lo wdos e Intermediat e dos e Hig hdos e Dos e leve l mg/k g 0 30 0 100 0 300 0 Femal e

number s
1-2 4 2 5 - 4 8 4 9 - 7 2 7 3 - 9 6 Colou r

o f cag e label s blu e gree n yello w re d Cag e number s
1 - 6 7-1 2 1 3 - 1 8 1 9 - 2 4

5.3.7 . Observation s o ndam s durin g lif e phas e Th e followin g parameter s wer e recorde do ndam s durin g th e experiment : Mortalit ydail y Sign s o f Abortio ndail y Genera l healtl i conditio ndail y Bod yweigh t dail y Foo dconsumptio nday s 6 , 11 , 1 6 an d2 1 o f pregnanc yTERATOLOG YSTUD YI NRAT S 1 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
Th e mea ndail yfoo dconsumptio nwa s calculate da s follow s :

foo dconsumptio n(g ) pe r perio d day s pe r perio dxno . o f animal s pe r cag e
5.3.8 . Euthanasi a Dam s wer e kille dbycarbo ndioxid e inhalatio n(dr yice ) o nday 2 1 o f pregnanc yan dfetuse s wer e remove dbyCesarea nsectio n andals o kille db ycarbo ndioxid e inhalation .

5.3.9 . Observation s o ndam s a t sacrific e A t necrops yth e followin g parameter s wer e recorded :

- Macroscopi c pathologica l examinatio no f th e mai norgan s o f th e thoraci c an dabdomina l cavities , i nparticula r th e genitals .

- Numbe r o f corpor a lute a i neac hovar y

- Weigh t o f th e uteru s includin g content s

- Uterin e contents :

- - numbe r andlocatio no f liv e anddea dfetuse s i nth e uterin e horn s

- - numbe r an dlocatio no f intrauterin e resorptio nsite s (early/lat e ) [earl yembryona l resorptions : implantatio nsite s withou t placenta ; lat e embryonal/feta l resorptions : implantatio n site s wit hplacenta ; abortions : "empty " implantatio n site s wit hwhit e o r yello wstaine dnodule s i nth e uteru s hor nvisibl e fro mth e outside] . Uterin e horn s showin g n o implantatio nsite s wer e place d int o a naqueou s solutio no f ammoniu msulfid e t o visualiz e possibl e haemorrhagi c alteration s o f suc h site s , accordin g t o th e metho do f Salewsk y< 1 > .TERATOLOG YSTUD YINRAT S 1 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.3.10 . Observatio no nfetuse s Afte r beein g remove dfro mth e uterus , th e fetuse s wer e submitte dto :

- sex-determinatio n(o nth e basi s o f ano-genita l distance )

- carefu l externa l (gross ) inspectio n

- bod yweigh t determinatio n Assignmen t t o eithe r individua l viscera l o r individua l skeleta l evaluatio n(a t a 1 : 2 ratio ) wa s computer-generated . I ncas e o f gros s anomal yand/o r malformation , however , fetuse s wer e allocate dt o on e o f th e tw o technique s dependin g o ntyp e and incidenc e o f th e finding . Th e liv e fetuse s wer e the nkille db ycarbo ndioxid e inhalatio n andprocesse dfo r viscera l o r skeleta l examination . 5.3.10.1.Gros s examinatio n Th e liv e fetuse s wer e subjecte dt o carefu l externa l inspection , specia l attentio nbein g attache dtO :

- extremitie s o r part s thereo f (e.g . absent , shortened , deformed , additional )

- tai l (e.g . absent , shortened , "kinked" )

- trun k (e.g . failur e o f closur e o f spina l cord , atresi a o t bod yorifices , omphalocele )

- hea d(e.g . absent , reduced , deformed ) brai n(e.g . cranioschiosis , encephalocele , exencephal y rhinencephaly )

- eye s (e.g . absent , reduced ; "ope neyes" )

- pinna e (e.g . absent )

- jaw s (e.g . absent , shortened )

- ora l orific e (e.g . absent )TERATOLOG YSTUD YINRAT S 1 6 GUProjec t No . 84086 2 Tes t Article : T K 1244 3

- clef t li p and/o r clef t jaw s and/o r clef t palat e al l bod yregion s (e.g . generalize do r localize doedema , haemorrhage ) 5.3.10.2.Viscera l examinatio n Th e viscer a o f on e thir do f th e fetuse s pe r litte r wer e examine daccordin g t o th e slicin g techniqu e o f Wilso n< 2 > : A solutio ncontainin g ethy l alcohol , formaldehyd e andaceti c aci d serve da s a fixative . Befor e slicing , th e fetuse s wer e place d int o a naqueou s solutio no f ammoniu mhydroge ncarbonate , rinse d i nta p wate r andthe nfroze nfo r severa l hours . Al l specimen s wer e finall ystore dindividually , i.e . pe r fetus , i na mixtur e o f ethano l andglycerol . Inspectio no f th e viscer a o f hea dan dtrun k included , i n particular , th e followin g organ s andorga nsystems : Ski n Centra l nervou s system : brai n(olfactor ybulbs , cerebrum , latera l andmedia l ventricles) , spina l cord , eye s (lenses , vitreous , retina ) Bodycavities : pericardia l cavity , pleura l cavity , diaphrag m Respirator ysystem : nasa l cavity , nasa l septum , choanae , trachea , bronchi , lung s Digestiv e system : ora l cavity , palate , tongue , oesophagus , stomach , intestine , rectum , live r Endocrin e system : thyreoidea , pancreas , adrenals , thymu s Circulator ysystem : spleen , hear t (atria , ventricles , septum) , majo r vessel s Excretor ysystem : kidney s (rena l papillae , rena l pelvis) , ureters , urinar ybladde r Genita l system : testes , epididymides , deferen t ducts , semina l vesicles ; ovaries , oviducts , uteru sTERATOLOG YSTUD YINRAT S 1 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

I ncas e o f eventua l discrepanc yi nse xdeterminatio nbetwee n externa l inspectio nan dslicin g technique , th e se xwa s correcte di naccordanc e wit hth e result s o f th e latter . 5.3.10.3.Skeleta l examinatio n Skeleta l assessmen t i ntw o third s o f th e fetuse s pe r litte r wa s accomplishe dfollowin g stainin g accordin g t o th e techniqu e o f Dawso n< 3 > : Afte r clearin g wit hpotassiu mhydroxid e and stainin g wit halizari nre dS , th e specimen s were , bysevera l steps , finall ypasse dint o glycerol . Thi s typ e o f examinatio ncovered , apar t fro mrevealing possibl e instance s o f skeleta l anomalie s and/o r malformations , als o th e stat e o f skeleta l maturatio no f th e fetuse s shortl ybefor e ter m o nda y2 1 pos t coitum . Routin e investigatio no f th e fetuse s comprehende dskeleta l element s wher e alteration s usuall yoccu r an dar e reliabl y detected ; th e othe r ones , i nbrace s [} , wer e referre dto , i f indicated : Crania l skeleton :

Axia l skeleton : Appendicula r skeleton : nasals , frontals , parietals , interparietals , supraoccipital , exoccipitals , { basioccipital , premaxillae , maxillae , zygomas , squamosals , lacrimals , vomer , palatines , ethmoid , presphenoid , alisphenoids , basisphenoid , pterygoids , tympani c annuli , body o f hyoid , mandible s } vertebra e (bodyan darches ; cervical , thoracic , lumbar , sacral , caudal) , ribs , sternebra e shoulde r girdle : clavicles , scapula e pelvi c girdle : ilia , ischia , [pubes } uppe r extremities : humeri , ulnae , radii , metacarpals , proxima l phalanges , dista l phalange s lowe r extremities : femora , tibiae , fibulae , calcanei , metatarsals , proxima l phalanges , dista l phalange s metacarpals , proxima l phalanges , dista l phalange s lowe r extremities : femora , tibia f fibulae , calcanei , metatarsals , proxima l phalanges , dista l phalange sTERATOLOG YSTUD YI NRAT S 1 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.3.11 . Classificatio no f feta l finding s
Normogenesis : Organ s andorga nsystem s o f a nanima l specie s

develo p withi na rang e o f norm . A s a consequenc e o f individua l geneti c difference s and/o r rando m alteration s o f environmenta l condition s durin g development , organ s andorga nsystem s displa ya certai ndegre e o f variability , particularl ywit h respec t t o th e statu s o f th e ossificatio no f skeleta l elements . Thes e instance s o f variation s ma yals o b e terme dvariant s andare , dependin g e.g . upo nth e exten t o f stil l incomplet e o r stil l absen t ossification , eithe r classifie da s norma l o r eventuall yconsidere dt o b e indicative'o f a dela y o f physiologica l growt ho f th e fetus . Teratogenesis : Developmen t outsid e th e norma l rang e . Wit h

respec t t o th e implication s concernin g postnata l life , maldevelopmen t ma yb e roughl ydifferentiate d a s follows : Malformation s ar e type s o f sever e abnorma l development , irreparabl e andi ngenera l incompatibl e wit hhealthypostpartu mdevelopmen t o f th e youn g animals . Anomalie s ar e mino r difference s fro m"normal " developmen t (e.g . supernumar yossificatio ncente r o f th e sternum , occurrenc e o f a 14t hpai r o f ribs , fusio no f th e basi s o f tw o ribs , dilatatio no f th e rena l pelvis , herniatio no f th e diaphragm , cysts , haemorrhage , haematoma ) whic har e no t considere dt o impai r norma l postpartumdevelopmen t o f th e animal .TERATOLOG YSTUD YI NRAT S 1 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.4 . Statistica l analysi s Genera l Al l value s liste di nth estatistic s sectio no f thi s repor t

wer e analyse db

y th eStudent' s t-tes t < 4 >, except

for th eanalysi s o f feta l anomalies , whichv/er eanalyse db

y th eCHI-squar

etes t < 5 > . Statistica l analysi s i s performe dt o dra

w attentio nt o distinc t values'
. Astatisticall y significan t differenc ebetweentw o value s doe s no t

necessaril y impl y biologica l relevanc eo f tha t deviatio nan

di s no t

conclusiv efor

atreatment

relate deffect
. Hence , th eresponsibl escientis t ma y no t comment

o n statisticall y significan t value s lyin g withi nth ephysiologica l rang ean

do nth eothe r

han dma y commen

t o nstatisticall y no t significan t

values , whic hdiffe r substantiall y fromth e expecte dnorma

l values
. Explanatio nof

sign s an

dremarks * significan t a t p<0.0 5 ( t

test ) -1

- significan t a t p=0.0 5 (CHI-squaretest ) -I--I
-significan t a t p=0.0 1 (CHI-squaretest ) •++ +significan t a t p=0.00 1 (CHI-squar etest ) Nnumbe r

o f sample s o r

numbe r o f animal sTERATOLOG YSTUD YI NRAT S 2 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
5.5 . Deviation s fro mth e protoco l Apar t fro

mamendmen t no . 1 (replacmen t o f th e stud ydirecto r b

y Apri l 01 , 1986 , whic hwa s afte r th e in-lif e phase ) n o furthe r deviation s t o th e protoco l hav e bee nmad e whic hneede da writte namendment .
Amendmen t no . 1
. REASO NFO RAMENIMEN T T h estudydirecto r a s lef t G U2. 1 Toxicolog ya s b yApri l01 , 1986
. 2 . AMENDMEN T Th e in-lif e phas e o f thi s studywa s conducte db y a s stud ydirector . Sinc e lef t GU2. 1 Toxicologya s byApri l 01 , 1986,
- th e fina l repor t wa s generate db y ha s reviewe dth e repor t andsigne da s studydirector .
Ther e wer e n o know ncircumstance s tha t coul dhav e affecte dth e qualit yand/o r integrit yo f th e data .TERATOLOG YSTUD YI NRAT S 2 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
6 . REFERENCE S

< 1 > Salewsky,E . ( 196 4 ).Arch.Ex.Path.Pharmak . 247 , 36 7 -

368 . < 2 > , Wilson,J.G . i n: Teratology,Principle s andTechnique s :

J.G.Wilso nandJ.Warkany,eds.,Th e Universit yo f Chicag o Press , Chicag o andLondo n( 196 5 ) , pp . 26 5 - 27 7 < 3 > Dawson,A.B . ( 192 6 ) . Stai nTech . 1 , 12 3 - 124 . < 4 > Brownlee , K . A . ( 196 5 ) . Statistica l theor yan d'

methodolog yi nScienc e an dengineering.Joh nWile y& Sons , < 5 > Ostle , B . ( 197 2 ) . Statistic s i nResearch . Iow a Stat e

Universit yPress .TERATOLOG YSTUD YI NRAT S 2 2 G UProjec t No . 84086 2 Tes t Article : TK 1244 3

7 . ARCHIVE S Ra w data , protocol , repor t an dspecimen s o f laborator yinvestigation s ar eproperl ystore d a t thi s location
.TERATOLOG YSTUD YINRAT S 2 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
8 . RESULT S

8.1 . Observation s i ndam s
8.1.1 . Materna l clinica l examinatio n Th e administratio no f tes t substanc e di dno t induc e an yobviou s clinica l sign s o r symptom s i nth e dam s o f th e dos e group s i n compariso nwit hth e vehicl e control . Durin g th e perio do f treatmen t necroti c area s o f th e ski no f th e back , aroun dth e righ t ey e an dchee k wer e observe dt o occu r unrelate dt o dosin g o nfemale s nos . 1 7 an d1 9 (contro l group) , nos . 30 , 41 , 43 , 4 4 an d4 5 (lo wdos e group) , no . 5 2 (intermediat e dos e group ) andno . 9 2 (hig hdos e group) . Th e individua l finding s ar e liste di nth e Appendi x9.2.1 . Th e necroti c area s o f th e aforementionen dfemale s wer e locall y treate dwit hTyrosolvi n, a nantibioti c no t considere dt o hav e adversel yaffecte dth e cours e o f th e experiment " i nthes e animals . Fo r femal e no . 9 6 (hig hdos e group ) prematur e birt ho f thre e fetuse s wa s observe do nda y2 1 pos t coitum . Sinc e bod yweigh t an duteru s weigh t coul dno t b e determine do nth e da yo f expecte ddeliver y(day2 1 p.c) , thi s femal e wa s exclude dfrom calculatio no f th e correspondin g means . Th e anima l wa s considered , however , fo r mean s concernin g pregnanc yan dfeta l data .TERATOLOG YSTUD YI NRAT S 2 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.1.1.l.Table : Summarize dmaterna l clinica l observation s
Dose(mg/kg ) Mate ddam s da y: 0- 5 Dam s examine d Dam s w/ o findi n Dam s wit h: Tota l da y: 6-1 6 Dam s examine d Dam s w/ o findi n Dam s wit h: dorsa l necroti c are a necroti c are a o f th e chee k necroti c are a aroun d th e righ t ey e Tota l g

g grou p 1

0 2 4

2 4 2 4 0

2 4 2 2

0 2 0 0

0 0 0 2 grou p 2

30 0 2 4

2 4 2 4 0

2 4 1 9

0 3 0 2

0 0 0 5 grou p 3

100 0 2 4

2 4 2 4 0

2 4 2 3

0 1 0 0

0 0 Q l grou p 4

300 0 2 4

2 4 2 4 0

^2 4 2 3

0 1 0 0

0 1 0 1 da y: 17-2 1 Dam s examine d Dam s w/ o findin g Dam s wit h: Tota l 2 4 2 4 0 2 4

2 4 0 2 4

2 4 0 2 4

2 4 0TERATOLOG YSTUD YI NRAT S 2 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

8.1.2
. Mortalit y I nth ecours eo f thi s teratogenicit ystud yn o femal edie d spontaneousl yno r

ha dt o b ekille di nmoribun dcondition
.TERATOLOGYSTUD YI NRAT S 2 6 G UProjec t

No
. 84086 2Tes t Article : T

K 1244 3

8.1.3
. Materna lbody-weigh t gai n F o r mea nmaterna lbod yweight s durin g gestatio n(Table s an d Figure ) se eth efollowin g pages ; fo r individua lbod yweigh t durin g gestatio na s wel la s statistica levaluatio nse e Appendice s 9.2. 2an d9.1.1 , respectively
. A s show no nth efollowin g Tabl ean dFigur eth emea nbod yweigh t w a s simila r

fo r al lgroups .TERATOLOG YSTUD YI NRAT S 2 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

8.1.3.1.TABLE : Mea nbod yweight s o f dam s (i ng )

Dose(mg/kg ) pregnan t female s day : 0

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 grou p 1 0 2 1 19 4 20 2 20 9
• 21 4 21 8 22 2 22 6 22 9 23 4 24 1 24 8 25 4 26 1 26 5 27 6 28 5 29 9 31 1 32 9 34 5 35 9 36 5 1 5 2 0 1 4 8 0 5 1 1 1 5 8 2 1 1 9 7 1 1 1 grou p 2

30 0 2 4 194. 9 20 4 . 4 211. 3 215. 0 219. 3 223. 5 226. 9 230. 5 236. 2 242. 7 250. 1 256. 3 263. 2 269. 4 276. 2 287. 1 298. 8 313. 9 330. 3 346. 5 362. 2 368. 8 grou p 3

100 0 2 4 197. 2 206. 6 210. 6 215. 7 220. 3 225. 2 228. 2 231. 8 238. 0 243. 8 252. 0 258. 7 264. 8 270. 7 278. 2 288 . 8 300. 5 315. 0 332. 8 348. 6 363. 3 368. 3 grou p 4

300 0 2 3 196. 5 2 0 5. 2 212. 0 216. 8 220. 5 224. 9 229 . 2 232. 8 238. 7 245. 0 252. 4 259. 3 265. 9 271. 1 278. 2 287. 1 299 . 2 314. 6 329. 4 344. 4 357. 6 362 . 5TERATOLOG YSTUD YI NRAT S 2 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.1.3.2.FIGURE : Mea nbod yweight s o f dam s (i ng )



## 39 0 37 0 . 35 0 _ 33 0 31 0 29 0 . 27 0 . 25 0 . 23 0 _ 21 0 19 0 Vehicl e contro l

30 0 mg/kg da

y 100 0 mg/kg da

y 300 0 mg/kg day

0 8 1 0 1 2 1 

# r — I\

# \— 4 1 6 1 8 2 0 Day s pos t coitu

mTERATOLOG YSTUD YINRAT S 2 9 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
8.1.4 . Materna l body-weigh t changes . Fo r mea nmaterna l body-weigh t change s during gestatio nse e th e followin g page ; fo r individua l body-weigh t change s andthei r statistica l analysi s se e Appendice s 9.2. 3 an d9.1.2 , respect
ively . I nth e intermediat e dos e grou p bod yweigh t wa s superio r t o tha t o f th e contro l grou p durin g day s 6 throug h1 1 o f pregnanc y (significan t differenc e confirme db yStudent' s t test , p < 0.05 ) . N o othe r difference s andn o treatment-relate dchange s wer e observed .TERATOLOG YSTUD YINRAT S 3 0 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
8.1.4.1.TABL E : Mea nmaterna l body-weigh t change s durin g

gestatio n

grou p 1 grou p 2 group 3 grou p 4 Dose(mg/kg ) 0 30 0 100 0 300 0 Pregnan t dam s 2 1 2 4 2 4 2 3 0 - 6 32. 9 32. 0 31. 0 32. 8 6-1 1 27. 3 29. 4 30.5 * 30. 1 11-1 6 45. 0 42. 5 41. 8 39. 8 16-2 1 66. 0 70. 0 67. 8 63. 3 0-2 1 171. 0 173. 9 171. 1 166. 0 6-2 1 138. 3 142. 0 140. 1 133. 2 6-1 6 72. 3 71. 9 72. 3 69. 9TERATOLOG YSTUD YINRAT S 3 1 GUProjec t No . 84086 2 Tes t Article : TK 1244 3
8.1.5 . "Corrected " bod yweight s a t necrops ynea r term Th e mea n"corrected " bod yweigh t dat a o f th e dam s ar e summarize do nth e followin g page ; th e individua l "corrected " bod yweight s an dthei r respectiv e statistica l analysi s ar e liste di nth e Appendice s 9.2. 4 and9.1.3 , respectively . N o treatment-relate dchang e o f th e correcte dbod yweigh t wa s observe di nth e experimenta l group s a s compare dwit hth e contro l group .TERATOLOG YSTUD YI NRAT S 3 2 G UProjec t No . 840862 . Tes t Article : TK 1244 3
8.1.5.1.TABLE : Mea n"corrected " bod yweigh t o f dam s

grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
pregnan t dam s 2 1 2 4 2 4 2 3 bod yweigh t (g ) : day6 22 7 22 7 22 8 22 9 da y2 1 36 5 36 9 36 8 36 2 gravi duteru s weigh t (g ) . 11 3 10 8 11 1 10 3 "corrected " bod y weigh t (g ) "corrected " body : weigh t gai ni i "corr. " body
weigh t gai ni n%^1 1 1 5 1 3 1 3 weigh t (g) ^ 25 2 26 1 25 8 26 0 weigh t gai ni ng ^ 2 6 3 4 2 9 3 0

2 . "corrected " bod yweigh t i s th e differenc e o f th e bod yweigh ; (day21 ) minu s th e uteru s weigh t 3 . "corrected " body-weigh t gai ni s equa l t o th e differenc e o f th-.
- "corrected " bod yweigh t (day21 ) minu s bod yweigh t (day6 ) 4 . "corrected " body-weigh t gai ni s equa l t o th e "corr. " body-weiuh t gai ndivide db

yth e bodyweigh t (day6) , time s 10 0TERATOLOG YSTUD YI NRAT S 3 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 8.1.6 . Foo dconsumptio n Mea nfoo dconsumptio ni s presente do nth e followin g Tabl e an d Figure . Th e individua l foodconsumptio nwa s calculate dfro mth e foo dconsumptio npe r cag e an dth e numbe r o f animal s present . Th e value s collecte da s wel l a s thei r statistica l analysi s ar e give ni nth e Appendice s 9.2. 5 and9.1.4 , respectively . Th e foo dconsumptio ndurin g pre-treatment , treatiment an dpost
treatmen t period s wa s comparabl e fo r th e contro l group , th e low andintermediat e dos e groups . Th e sligh t bu t statisticall ysignifican t increas e i nfoo d consumptio nnote dfo r th e high-dos e grou p during day s 6-1 1 an d 6-16 , respectively , v/as considere dt o b e unrelate dt o th e treatmen t ( t test , p < 0.05) .TERATOLOG YSTUD YINRAT S 3 4 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 8.1.6.1.TABL E : Foo dconsumptio ndurin g gestatio n(i ng )

grou p 1 grou p 2 grou p 3 grou p 4 Dose(mg/kg ) 0 30 0 100 0 300 0 No . o f dam s 2 4 2 4 2 4 2 4 day s : 0 - 6 19.0 7 19.4 2 19.5 0 19.7 2 6-1 1 22.1 4 22.8 4 23.0 3 23.87 * 1 1 - 1 6 25.0 7 25.9 6 25.8 9 26.3 0 1 6 - 2 1 23.6 1 25.7 6 24.5 4 25.1 0 0-2 1 22.3 1 23.3 0 23.0 6 23.5 6 6-2 1 23.6 1 24.8 5 24.4 9 25.0 9 6-1 6 23.6 0 24.4 0 24.4 6 25.09 *TERATOLOG YSTUD YINRAT S 3 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.1.6.2.FIGUR E : Grou p mea nfoo dconsumptio ndurin g

gestatio n(i ng )



### 2 7


### . 2 5


### . 2 3


### . 2 1


### . 1 9


### . 1 7


### . 1 5 

### - -'•'Tr.'rrv .



## Vehicl e contro l 30 0 mg/k g da y

—100 0 mg/k g da y

—300 0 mg/k g da y

,



### 1 1 1 6 2 1 Day s pos tC

O i tur nTERATOLOG YSTUD YI NRAT S 3 6 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
8.1.7 . Materna l postmorte mexaminatio n Fo r summarize dgros s postmortemobservation s o nth e animal s se e th e followin g pages ; th e individua l dat a ar e liste di nth e Appendi x9.2.6 . Femal e no . 5 5 (intermediat e dos e group ) wa s foun dt o hav e aborte dpar t o f he r litter . Femal e no . 7 7 (high-dos e group ) aborte dpar t o f he r litter . Femal e no . 7 8 (als o fro mth e high-dos e group ) showe dsom e haemorrhagi c change s o f th e uterin e epithelium . Amon g th e 1 5 implantation s o f thi s dam , includin g 1 3 liv e fetuses , on e dead fetu s wit hdisintegratin g placent a wa s found . Femal e no . 8 6 (.high-dos e group ) showe daplasi a o f th e lef t uterin e horn ; i nth e righ t uterin e hor nimplantation s wer e found . I nth e contro l grou p female s nos . 9 and2 3 wer e no t bearin g implantatio nsite s and , therefore , exclude dfro mcalculatio no f means . Femal e no . 1 5 fro mth e contiro l grou p ha don e dea dfetu s onl y andwa s als o exclude dfro mcalculatio no f means . N o furthe r remarkabl e finding s wer e recorde da t necropsy .TERATOLOG YSTUD YI NRAT S 3 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.1.7.1.TABLE : Summar yo f materna l postmorte mexaminatio n
Dose(mg/kg ) Mate dfemale s grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0 2 4 2 4 2 4 2 4 Female s examine d Female s withou t macroscopi c pathol . finding s o n da y2 1 p.c. : Female s kille d fo r human e reason s : 2 4

2 4

0 0 2 4

2 4

0 0 2 4

2 3

0 0 2 4

2 1

0 0 Female s w cesarea n sectio n Female s withou t pregnanc y: Dam s V 7 tota l resorption s Dam s wpreter m deliver y: 2 4

0 2 0 0 0 0 2 4

0 0 0 0 0 0 2 4

0 0 0 0 0 0 2 4

0 0 0 0 0 1 Female s w spont . deat h Female s w finding s 0 0
0 0 0 0

0 0 0 0

0 1 0 0

0 3

5
. no . 55 : partia labortio n 6 . no . 77 : partia labortion , n o 78. : uteru s v/it hhaemorrluu ii changes ; no . 86 : lef t uterus-hor nabsen tTERATOLOG YSTUD YI NRAT S 3 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.1.8 . Examinatio no f ovaries , uteru s anduterin e content s Th e summarize ddat a o nCesarea nsectio nar e tabulate do nth e followin g pages . Fo r individua l ovarian , uterin e an d litte r dat a se e Appendice s 9.2. 7 and9.2.8 . Th e statistica l analysi s o f thes e dat a i s presente di nth e Appendi x9.1.5 . Th e mea nnumbe r o f corpor a lute a wa s slightl ybu t no t significantl yincrease da t 100 0 mg/kg an d300 0 mgAg / th e mea n numbe r o f implantatio nsite s slightl yincrease da t 100 0 mg/k g an dslightl yreduce da t 300 0 mg/k g (als o n o statisticall y significan t differenc e fro mth e control) . A s a consequenc e o f slightl yincrease dnumbe r o f corpor a lute a an dreduce dnumbe r o f implantatio nsite s a t 300 0 mg/k g th e pre-implantatio nlos s (rati o corpor a lute a / implantatio nsites ) i nthi s hig hdos e grou p v;a

s superio r t o tha t determine dfo r th e contro l group . Th e pregnanc yrate s o f th e dam s survivin g t o ter mwer e confirme db

yth e presenc e o f implantatio nsite s anddetermine d a t 91. 7 % (contro l group ) and10 0 % (experimenta l groups) . Fo r on e femal e eac ho f th e 100 0 mg/k g grou p (no . 55 ) andth e 300 0 mg/k g grou p (no . 77 ) partia l abortio no f th e litte r wa s recorded . N o tota l abortio no f a litte r wa s observe di nanyo f th e groups . I na furthe r da mo f th e high-dos e grou p (no . 96 ) prematur e birt ho f par t o f th e litte r (3/1 8 fetuses ) occurre da fewhour s prio r t o plannec a sacrifice . Thi s litte r wa s exclude dfro m uterine-dat a (Tabl e 8.1.8. ) bu t considere dfo r externa l examinatio na s wel l a s viscera l andskeleta l assessment . Th e rate s o f embry o andfetolethalit y(resorption s indicating post-implantatio nloss ) wer e foun dt o b e simila r fo r al l groups . On e dea dfetu s wa s foun damongs t a litte r o f th e high-dos e grou p (femal e no . 78) . Th e uterin e content s o f a femal e fro m th e contro l grou p consiste do f on e dea dfetu s only . I nth e high-dos e group th e meanlitte r siz e showe da sligh t bu t statisticall yno t significan t reductio nan dremaine dunchange d i nth e lo wandintermediat e dos e groups . Th e averag e numbe r o f mal e andfemal e fetuse s pe r litte r wa s simila r fo r al l groups . Th e male-to-femal e se xratio s v/er e comparabl e fo r al l group s i n thi s study .TERATOLOGYSTUD YI NRAT S 3 9 G UProjec t

No
. 84086 2Tes t Article : T

K 1244 3

T h eaverag ebod yweigh t o f th eliv efetuse s wa s no t significantl yaltere di nth eexperimenta lgroup s o nth eper - litte r basis
. Comparin g th emea nfeta lbod yweight s per ' group , however , a significan t

reductio no f

th eaverag efemal ebod yweigh t i nth e l o w dos egrou p ( t test , p < 0.05 ) an do f th eaverag emale , averag efemal ean doveral laverag ebod yweigh t o f th e intermediat edos egrou p (p < 0.05 ) wa s observed
. Th elatte r finding s wer eno t assume dt o b eo f a nexperimenta l significance
.TERATOLOG YSTUD YI NRAT S 4 0 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
8.1.8.l.TABLE : Summar yo f cesarea nsection , pregnanc ydat a

dos e (mg/kg ) grou p 1 group 2 grou p 3 grou p 4 0 30 0 100 0 300 0
mate dfemale s female s sacrifice d da y2 1 p.c . female s w deciduomat a pregnan t female s 

## ( % 7 dam s wpartia l abortio n (% ) dam s wpartia l premat . birt ha t da y 2 4 2 4 0 2 2 91. 7 0 0 2 4

2 4 0 2 4 10 0 0 0 2 4

2 4 0 2 4 10 0
1 4. 2 2 4

2 4 0 2 4 10 0
1 4. 2

2 1 (% ) 

### dam s wtota l resorp . (% ) . 

### dam s wpart , resorp . (% ) 

### dam s wliv e fetuse s (% ) 3 7 8 7 0 0 0 0 9

. 5 21
-

. 5 0

0 0 0 1 5 62. 5 2 4 10 0 0

0 0 0 1 3 54. 2 2 4 10 0 1

4. 2 0 0 1 4 58. 3 2 3 10 0

7 . %-value s ar e indicate da s percen t o f mate dfemale s 8 . Femal e no . 9 6 exclude dfro mal l furhte r calculation s du e t o partia l prematur e birt ho f par t o f it s litte rTERATOLOG YSTUD YI NRAT S 4 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 8.1.8.2.TABLE : Summar yo f cesarea nsection , uterin e data(l )

Cesarea nsectio n(mea nvalues) : uterin e dat a 1 dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
mate dfemale s pregnan t female s aliv e a t da y2 1 dam s wliv e fetuse s 2 4 2 2 2 1 2 4

2 4 2 4 2 4

2 4 2 4 2 4

2 4 2 3 Corpor a lute a : tota l n o mea nn o 33 9 38 3 39 5 38 9 16. 1 16. 0 16. 9 16. 9 Implant.site s : tota l n o mea nn o pre-implantatio n los s (%) ^ implantatio n efficienc y(% ) Earl yresorp . tota l n o mea nn o g . 1 1 1 0 32 2 15. 3 6. 6 93. 4 1 0 0.4 8 3. 1 36 5 38 4

15. 2 16. 0 5. 7 94. 3 2 1 o;8 8 5. 8 7. 6

92. 4 2 3 0.9 6 6. 0 33 0

14. 3 15. 0 85. 0 2 0 0.8 7 6. 1 Lat e resorp . : tota l n o mea nn o Tota l resorp . tota l n o mea nn o 1 0.0 5 0. 3 1 1 0.5 2 3. 4 2 1

0.8 8 5. 8 1

0.0 4 0. 3 2 4 1.0 0 6. 3 2

0.0 8 0. 6
2 2 0.9 6 6. 7

9 . %-value s ar e indicate da s pe r cen t o f tota l numbe r o f corpor a lute a 10 . earl yresorption s = embryoni c resorptions , lat e resorption s = feta l resorption s 11 . %-value s ar e indicate da s pe r cen t o f tota l implantation sTERATOLOG YSTUD YI NRAT S 4 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Cesarea nsectio n(mea nvalues) : uterin e dat a 1 grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0 Dea dfetuse s : tota l n o 0 0 0 1 mea nn o 0 0 0 0.0 4 % 0 0 0 0. 3 Al l dea dimplant s tota l n o 1 1 2 1 2 4 2 3 mea nn o 0.5 2 0.8 8 1.0 0 0.9 6 3. 4 '5. 8 6. 3 7. 0 % Post-implantatio n los s (% ) 3. 4 5. 8 6. 3 7. 0

12 . dea dimplant s = resorption s -i

- dea dfetuse sTERATOLOG YSTUD YINRAT S 4 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 8.1.8.3.TABLE : Summar yo f cesarea nsection , uterin e data(2 )

dos e (mg/kg ) grou p 1 group 2 grou p 3 grou p 4 0 30 0 100 0 300 0
mate ddam s 2 4 2 4 2 4 2 4 pregnan t dam s aliv e a t da y2 1 dam s V 7 liv e fetuse s tota l liv e fetuse s litte r siz e 2 2 2 1 31 1 ,14. 8 2 4

2 4 34 4 14. 3 2 4

2 4 35 9 15. 0 2 4

2 3 30 6 13. 3 Feta l viabilit y (%)1 3 lef t uteru s righ t uteru s tota l Mal e fetuse s : tota l pe r litte r Femal e fetuse s : tota l pe r litte r Sex-rati o : pe r litte r pe r grou p dam s wdea dfetuse s (%)1 4 10 0 10 0 10 0 14 2 6. 8 16 9 8. 0 0.4 6 0.4 6 0 0 10 0

10 0 10 0 16 5

. 6. 9 17 9 7. 5 0.4 9 0.4 8 0 0 10 0

10 0 10 0 16 5 6. 9 19 4 8. 1 0.4 6 0.4 6 0 0 99. 3

10 0 99. 7 15 5 6. 7 15 1 6. 6 0.5 0 0.5 1 1 4. 3

13 . % viabl e fetuse s o f tota l (deadandviable ) fetuse s 14 . %-value s a s pe r cen t o f dam s wit hliv e fetuse sTERATOLOG YSTUD YI NRAT S 4 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 8.1.8.4.TABLE : Summar yo f ceasarea nsection , feta l dat a

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
mate dfemale s pregnan t dam s aliv e a t da y2 1 litter s evaluate d no . liv e fetuse s gravi duteru s weigh t (g ) litte r weigh t (g ) mea nbodyweigh t (g ) pe r litter : 2 4 2 4 2 4 2 4 2 1 2 1 31 1 11 3 1. 8 2 4

2 4 34 4 10 8 78. 4 2 4

2 4 35 9 11 1 79. 9 2 3

2 3 30 6 10 3 72. 6

mal e fetuse s femal e fetuse s tota l mea nbodyweigh t (g ) pe r group : mal e fetuse s femal e fetuse s tota l 5

• 5 5

5 5 5 7 4 5

7 4 5 5. 7

5. 3 5. 5

5. 7 5.3 * 5. 5 5. 5

5. 2 5. 4

5.5 * 5.2 * 5.3 * 5

5 5

5 5 5 6 4 5

6 4 5TERATOLOG YSTUD YI NRAT S 4 5 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 8.2 . Observation s i nfetuse s
8.2.1 . Externa l examinatio no f th e fetuse s Fo r summar yo f finding s se e th e following pages . Fo r individua l finding s se e Appendi x9.2.9 , fo r th e respectiv e statistica l analysi s se e Appendi x9.1.6 . Th e followin g tw o malformation s wer e found :

Grou p 1 (Control) : Grou p 4 (300 0 mg/kg) : no . 19/ R0 3 (male) : generalize doedem a no . 84/ L 0 4 (female) : omphalocel e
N o malformation s o r anomalie s wer e recorde dfo r th e lo wand intermediat e dos e groups .TERATOLOG YSTUD YI NRAT S 4 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 8.2.1 . l.TABLE : Summar yo f feta l externa l anomalie s cind/or

malformation s

dos e (mg/kg ) grou p 1 group 2 grou p 3 grou p 4 0 30 0 100 0 300 0 litter s evaluate d fetuse s examine d 2 1 31 1 2 4

34 4 2 4

35 9 2 4

32 4 externall ymalf . fetuse s : tota l (% ) pe r litte r (% ) litter s wextern a malforme dfetuse s tota l (% ) Il y 0 , 0 . 0 ,

4 , 1 .3 2 .0 5 .3 2

1 .7 6 0

0 0 0

0 0 0

0 0 0

0 0 0 . 0 . 0 .

4 . 1 .3 1 .0 4 .3 0

1 .1 7TERATOLOG YSTUD YI NRAT S 4 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

8.2.2 . Feta l viscera l examinatio n Th e individua l feta l dat a ar e liste di nAppendi x9.2.9 . N o malformation s o r anomalie s wer e detecte di nan yo f th e groups , experimenta l an dcontrol , b yapplyin g th e slicin g technique .TERATOLOG YSTUD YINRAT S 4 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.2.3 . Ossificatio no f feta l skeleton s Fo r summar yo f feta l skeleta l finding s se e th e following pages . Fo r individua l feta l skeleta l finding s se e Appendi x9.2.9 , fo r thei r statistica l analysi s se e Appendi x9.1.6 . Abnorma l ossificatio n Th e followin g anomalie s wer e noted : 

### Grou p 1 (control ) no . 13/ R0 2(female) : 6t hsternebr airregularl yossifie d no . 19/ R0 3 (male) : 1s t sternebr a irregularl yossifie d no . 20/ R0 4 (female) : 1s t an d2ndsternebra e fuse d no . 22/ R0 1 (female) : 6t hsternebr a irregularl yossifie d Grou p 2 (30 0 mg/kg ) no . 25/ R0 6 (male) : 1s t an d2ndsternebra e fuse d no . 39/ L 0 1 (male) : 1s t sternebr a irregularl yossifie d no . 39/ L 0 9 (male) : 1s t and2ndsternebra e fuse d no . 45/ R0 2 (female) : 1s t sternebr a irregularl yossifie d Grou p 3 (100 0 mg/kg ) no . 49/ L 0 7 (male) : 1s t and2ndsternebra e fuse d no . 70/ L 0 3 (female) : 1s t and2ndsternebra e fuse d Grou p 4 (300 0 mg/kg ) no . 76/ L 0 5 (female) : 1s t and2ndsternebra e fuse d n o . 76/ L0 6 (male) : 1 s t an d2n dsternebra efuse dTERATOLOG YSTUD YI NRAT S 4 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

no . 76/ L 0 7 (female) : 1s t and2ndsternebra e fuse d Grou p 4 ctd . no . 89/ L 0 4 (female) : 1s t sternebr a irregularl yossifie d (bipartit e int o tw o unequa l centers ) no . 95/ L 0 3 (male) : 1s t and2ndsternebra e fuse d no . 95/ R0 8 (male) : 1s t and2ndsternebra e fuse d
Rrigh t L lef t

A l lforegoin g finding s concer nth eossificatio no f sternebrae
. No significan t

difference s wer eobserve dbetv/ee nth ethre edos e group s an dth econtro lgroup .TERATOLOG YSTUD YI NRAT S 5 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
8.2.3.l.TABLE : Summar yo f feta l skeleta l anomalie s and/o r

malformation s

Dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0 Litter s evaluate d Fetuse s examine d Malformations : Fetuse s affected : tota l (% ) pe r litte r (% ) Litter s affected : tota l (% ) Anomalies : Fetuse s affected : tota l {% ) pe r litte r (% ) Litter s affected : tota l (% ) Fetuse s wdelaye d skel . maturatio n: tota l (% ) pe r litte r (% ) Litter s wdelaye d skel . maturatio n: tota l (% ) 2 1 21 0

0

- 0

- 0

-

4 1.9 0 0.1 9 1.3 1 4 19. 0

20 8 99. 0 9.9 0 99. 2

2 1 10 0 2 4

23 0

0

- 0

- 0

-

4 1.7 4 0.1 7 1.1 9 3 12. 5

23 0 100. 0 9.5 8 100. 0

2 4 10 0 2 4

23 9

0

- 0 — 0 —

2 0.8 4 0.0 8 0.5 1 2 8. 3

23 7 99. 2 9.8 8 99. 4

2 4 10 0 2 4

21 6

0

- 0 — 0

-

6 2.7 8 0.2 5 1.6 6 3 12. 5

21 6 100. 0 9.0 0 100. 0

2 4 10 0TERATOLOG YSTUD YI NRAT S 5 1 G UProjec t No . 84086 2 Tes t Article. : T K 1244 3
Skeleta l maturatio n O nth e followin g Tabl e th e skeleta l maturatio ni s shownfo r th e fetuse s o f th e contro l grou p andth e thre e dos e groups . Fo r th e experimenta l group s som e statisticall ysignifican t deviation s fro mth e contro l group wer e note d(CHI-squar e test , p < 0.0 5 - 0.001) . Delaye dossificatio n(a s indicate db ystil l absen t o r poo r o r incomplet e ossification ) wa s observed , i nparticular , i nth e fetuse s fro mth e intermediat e dos e group , concerning :

- centre s o f cervica l vertebra e

- metatarsa l 1

- for e paw : proxima l phalangea l nucle i 2 an d5 (no . 5 als o affecte da t 300 0 mg/kg )

- rea r paw : proxima l phalangea l nucle i 2- 5 (nos . 2- 4 als o affecte da t 30 0 mg/kg ; nos . 3 an d4 a t 300 0 mg/kg )

- 1s t sternebr a

- cente r o f 10t hthoraci c vertebr a I nth e absenc e o f an ydose-relationship , i . e . anaccumulatio n o f finding s i nth e intermediat e dos e group , n o experimenta l significanc e wa s attribute dt o th e foregoin g findings .TERATOLOG YSTUD YI NRAT S 5 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

8.2.3.2.TABLE : Summarize ddat a o f delaye dskeleta l maturatio n

dos e (mg/kg ) litter s evaluate d fetuse s examine d ossification stil l absoi t (no . o f fetuses) : Cente r o f cervic.vertebr . 1 g rou p 1 0
2 1 21 0

16 1 g roup 2

30 0
2 4 23 0

18 7 grou p 3

100 0
2 4 23 9

19 2 g rou p 4

300 0
2 4 21 6

14 5 •

1 5 2 3 4 5 6 7 Sternebr a 2 Sternebr a 5 Ri b1 3 (R ) Ri b1 3 (L ) Ri b1 3 (L+R)
- Ri b1 3 (total ) Metacarpal s 5 (L+R ) Calcaneu s (R ) Calcaneu s (L ) Calcane i (L+R ) Calcane i (total ) Metatarsa l 1 (R ) Metatarsa l 1 (L ) Metatarsa l 1 (L+R ) Metatarsa l 1 (total ) ant.dist.phal . nucleu s 5 (L ) ant.prox.phal . nucleu s 2

2 2 2 3 4 4 4 (R ) (L ) (L+R ) (total ) (L+R ) (L ) (R ) (L+R ) 18 7 6 8 3 7 2 3 1 7 0 1 0 2 0 1 3 0 2 9 17 8 18 9 0 1 6 7 0 20 2

7 5 5 0 3 6 1 9 1 1 1 2 1 1 4 0 6 1 0 19 1 20 7 2 2 1 0 14 0 21 3

9 2 6 7 4 8 2 5 3 0 0 0 1 1 2 0 4 1 0 18 4 19 8 1 2 1 7 2 0 + + + + + + 18 3

5 5 3 5 2 1 1 7 2 2 0 0 0 0 0 1 9 8 15 6 17 3 1 0 1 1 1 2 0 0 1 2 3 0 0 1 0 1

3 5 9 0 0 0 0 0

6 1 2 + 1 8 + + 0 1 0 0 0

1 5 6 1 0 1 1 + +

15 . L+R = lef t an d righ tTERATOLOG Y G UProjec t No . 84086 2

dos e (mg/kg )

4 (total ) 5 (R ) 5 (L ) 5 (L+R ) 5 (total ) post.prox.phal . nucle i 2 (R )

2 (L ) 2 (L+R ) 2 (total ) 3 (R ) 3 (L ) 3 (L+R )

, 3 (total ) 4 (R ) 4 (L ) 4 (L+R ) 4 (total ) 5 (R ) 5 (L ) 5 (L+R ) 5 (total ) poorl yossified : Sternebra e 1 2 3 5 6 Metacarpa l 5 (R ) ant.prox.phal . nucleu s 2 (R )

2 (L ) 2 (L+R ) 2 (total ) 3 (L ) 3 (R ) 3 (total ) 4 (L ) 4 (R ) 4 (L+R ) 4 (total ) 5 (R ) 5 (L ) 5 (L+R ) 5 (total ) Calcaneu s (R ) Calcaneu s (L ) Calcane i (L+R ) grou p 1 0 1 2 4 4 1 0 1 1 6 2 2 3 9 6 3 1 0 1 9 6 2 1 1 1 9 1 8 1 1 5 4 8 3 3 5 0 2 0 0 2 2 0 4 0 1 1 0 1 0 1 6 ' 2 3 1 1 2 2 2 STUD YI N

grou p 2 30 0 0 5 7 6 1 8 1 6 9 3 8 6 3 8 3 3 2 4 3 8 2 3 1 4 1 1 9 1 5 7 6 11 0 8 2 0 5 3 0 2 3 6 1 1 0 0 0 0 0 0 0 6 1 0 8 2 4 2 0 0 RAT S Tes t Artic l
group 3

+

+ + + +

+ + + +

-1
-

+ + 100 0

1 2 1 0 1 8 3 0 1 7 8 5 9 8 4 1 2 3 3 8 5 2 1 4 4 3 6 5 4 1 3 1 2 9 8 12 3 1 2 0 0 2 4 0 2 2 0 4 0 0 0 0 0 0 0 8 8 5 2 1 1 3 1 5 3 e : T K 1244 3
grou p 4

+ + + +

++ + ++ +

++ + ++ +

++ + ++ +

++ + +

+ + 300 0

2 3 1 0 8 2 1 + 1 6 6 3 3 5 5 7 2 2 7 + + 3 6 + 4 2 2 8 + + 3 4 + 1 5 1 1 6 8 9 4 3 1 1 3 1 2 1 4 0 5 1 0 1 1 0 1 2 4 2 4 1 0 5 2 0TERATOLOG YSTUD YI N G UProjec t No . 84086 2 RAT S Tes t Article : T K 5 4 1244 3

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0 Calcane i (total ) Metatarsa l 1 (R ) post. p nucle i

Shor t Shor t Shor t Shor t r dumbbell
Cente r cervi c Cente r thora c rox.phal .

2 (R ) 2 (L ) 2 (L+R ) 2 (total ) 3 (R ) 3 (L ) 3 (L+R) . 3 (total ) 4 (R ) 4 (L ) 4 (L+R ) 4 (total ) 5 (R ) 5 (L ) 5 (L+R ) 5 (total ) ri b1 3 (R ) ri b1 3 (L ) ri b1 3 (L+R ) i b1 3 (total ) shaped : o f .vertebr . 1

2 o f .vertebr . 5

8 9 1 0 1 1 1 2 6

2 2 3 2 7 1 1 1 3 0 1 0 1 9 1 3 1 2 3 8 4 1 1 3

9 0 0 0 0 0 3 1 2

0 2 2 1 5 2 2 2 6 2 2 2 6 8 9 8 + 2 5 7 7 3 1 7

6 1 1 2 0 1 3 2 5

0 3 0 1 4 0 2 0 2 0 1 1 2 4 5 + 1 1 0 + + 5 7 3 1 5

9 0 0 0 0 5 + 3 1 7

0 1 0 0 1 0 1 1 2 0 1 1 2 6 5 1 1 2 5 4 3 1 2

1 6 0 0 0 3 4 4 2 bipartit e : Cente r o f cervic.vertebr . Cente r o f thorac.vertebr . 1

1 0 1 1 1 2 1 3 1 0 1 4 1 0 2 2 +

0 0 1 1 0 1

0 1 1 1 0

2 1 1 0 0

0 0 0 0TERATOLOG YSTUD YI NRAT S 5 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0 

### OSS
. incomplete : Sternebra e 3 4 5 0

0 3 1

1 3 0

2 5 0

0 4TERATOLOG YSTUD YI NRAT S 5 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

8.2.4 . Summarize dfeta l abnormalitie s On e instanc e o f gros s malformatio nwa s recorde dfo r eac hth e contro l grou p (generalize doedema ) andth e high-dos e grou p (omphalocele) . N o gros s malformation s wer e observe di nth e lo wan d intermediat e dos e groups . Ther e wer e n o viscera l o r skeleta l malformation s foun di nan

y o f th e groups . Som e skeleta l anomalie s wer e foun dt o occu r a t simila r incidence s amon g th e fetuse s o f al l groups , experimenta l and control . Mos t o f thes e anomalie s wer e consisten t wit h synostosi s o f sternebra e 1 and2 . Th e occurrenc e o f irregula r ossificatio no f sternebra e 1 o r 6 wa s als o noted . Th e finding s concernin g skeleta l maturatio nwer e no t considere d t o b e consisten t wit hanomalie s o r malformations . Al l finding s o nexternal , viscera l an dskeleta l abnormalitie s ar e liste do nth e followin g Table . Th e individua l dat a ar e represente di nth e Appendi x9.2.9 , thei r statistica l analysi s i nth e Appendi x9.1.6 .TERATOLOG YSTUD YINRATS 5 7 G UProjec t

No
. 84086 2 Tes t Article : T

K 1244 3 8.2.4.l.TABLE : Summar yo f al lfeta lanomalie s and/o r malformation s

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0 litter s evaluate d fetuse s wgros s malf . fetuse s examine d fetuse s wviscera l anomalie s fetuse s wviscera l malf . fetuse s examine d fetuse s wskeleta l malf . fetuse s wskeleta l anomalie s fetuse s examine d Tota l n o malf./anomalou s fetuse s Tota l n o fetuse s examine d % anomalous/malf . fetuse s 2 1 1 31 1 0

10 1 0 1 6
0 4 21 0



### 3i r 1.2 9 2 4

0 34 4

. 0 0 11 4 0 4 23 0

34 4 2 4

0 35 9 0 0 12 0 0 2 23 9

35 9 2 4

1 32 4 0 0 10 8 0
-

21 6

1.1 6 0.5 6 32 4 2.2 i

16 . Exclude d2 fetuse s fro mfemal e no . 1 9 (nos . L 0 5 andR02 ) selecte db ymistak e fo r skeleta l assessmen t (ther e included )TERATOLOG YSTUD YI NRAT S 5 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
APPENDICE S

9.1 . Statistica l analysi s Student', s t-tes t ha s bee napplie dt o al l th e dat a liste di n thi s section , excep t fo r th e analysi s o f anomalies , t o whic h th e CHI-squar e tes t wa s applied . * : value s differen t a t th e 5%-confidenc e leve l (t-Test )
+ : value s differen t a t th e 5%-confidenc e leve l

(CHI-square-test )
+ + : value s differen t a t th e 1%-confidenc e leve l

(CHI-square-test )
++ + : value s differen t a t th e 0.1%-confidenc e leve l

(CHI-square-test ) N: numbe r o f value s evaluate d S.D . : standar ddeviatio nTERATOLOG YSTUD YI NRAT S 5 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 9.1.1 . Bod yweight s Analysi s o f Bod yweigh t dat a (dams ) Da y0 : grou p 1 grou p 2 grou p 3 dos e (mg/kg ) 0 30 0 100 0 grou p 4 300 0
N min . max . mea n +S.D . stat.sig n 2 1 17 6 21 2 19 4 8. 3 2 4

17 6 21 2 19 5 9. 8 2 4

17 9 21 4 19 7 9. 3 2 3

18 0 21 4 19 6 8. 5

Da y1 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign , 2 1 18 7 21 9 20 3 8. 5 2 4

18 1 22 2 20 4 10. 0 2 4

18 7 22 0 20 7 8. 8 2 3

18 0 22 6 20 5 11. 2TERATOLOG YSTUD YI NRAT S 6 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y2 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 19 0 22 5 20 9 8. 2 2 4

18 9 22 9 21 1 10. 6 2 4

19 4 22 3 21 1 8. 7 2 3

18 9 23 4 21 2 11. 0

Da y3 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0

N• min . max . mea n +S.D . stat.sign . 2 1 19 6 2-3 2 21 4 8. 4 2 4

19 5 22 8 21 5 9. 2 2 4

19 5 22 9 21 6 9. 2 2 3

19 3 23 9 21 7 11. 1TERATOLOG YSTUD YI NRAT S 6 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y4 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 19 9 23 2 21 8 8. 6 2 4

19 4 23 6 21 9 10. 8 2 4

20 0 23 1 22 0 9. 8 2 3

20 0 24 5 22 1 11. 5

Da y5 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat . sig n 2 1 20 6 23 8 22 2 7. 7 2 4

19 8 2 4 0 22 4 10. 8 2 4

20 4 24 0 22 5 9. 5 2 3

20 3 25 3 22 5 12. 0TERATOLOG YSTUD YI NRAT S 6 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y6 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 20 8 24 3 22 7 8. 3 2 4

20 1 24 7 22 7 11. 6 2 4

20 8 24 0 22 8 10. 4 2 3

20 7 25 3 22 9 11. 2

Da y7 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sig n 2 1 21 0 24 5 22 9 8. 8 2 4

20 1 25 1 23 1 11. 5 2 4

21 2 25 0 23 2 10. 5 2 3

20 4 25 6 23 3 12. 6TERATOLOG YSTUD YI NRAT S 6 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y8 :
dos e (rag/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 21 2 25 4 23 4 9. 9 2 4

21 0 25 8 23 6 12. 1 2 4

21 5 25 5 23 8 11. 1 2 3

21 5 27 5 23 9 14. 5

Da y9 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 3000 '
N min . max . mea n + S.D . stat.sign . 2 1 22 1 26 0 24 1 9. 8 2 4

21 6 26 9 24 3 12. 0 2 4

22 3 25 9 24 4 10. 4 2 3

21 9 27 1 24 5 1 4 . 0TERATOLOG YSTUD YI NRAT S 6 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y10 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat . sig n 2 1 22 8 26 6 24 8 0. 1 2 4

22 1 27 4 25 0 12. 2 2 4

22 8 27 4 25 2 11. 2 2 3

22 8 29 2 25 2 15. 4

Da y11 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 22 7 27 4 25 4 11. 4 2 4

22 7 28 6 25 6 13. 6 2 4

23 4 27 9 25 9 11. 4 2 3

23 3 29 4 25 9 15. 8TERATOLOG YSTUD YI NRAT S 6 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y12 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat . s i gn . 2 1 23 6 28 1 26 1 11. 7 2 4

23 3 293
- 26 3 13. 8 2 4

23 6 28 7 26 5 12. 1 2 3

24 0 31 2 26 6 17. 2

Da y13 :
dos e (mg/k g grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 23 9 28 9 26 6 12. 9 2 4

23 5 30 3 26 9 5. 1 2 4

24 2 29 6 27 1 12. 2 2 3

24 1 31 3 27 1 17. 2TERATOLOG YSTUD YI NRAT S 6 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y14 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat . s i gn . 2 1 24 5 29 8 27 6 13. 6 2 4

24 3 31 7 27 6 15. 4 2 4

24 9 30 9 27 8 13. 6 2 3

24 5 32 8 27 8 19. 4

Da y15 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 25 3 31 0 28 5 15. 2 2 4

24 9 33 0 28 7 17. 1 2 4

25 8 32 6 28 9 14. 5 2 3

25 7 34 2 28 7 20. 3TERATOLOG YSTUD YI NRAT S 6 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y16 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sig n 2 1 27 1 32 4 29 9 15. 0 2 4

26 1 34 7 29 9 17. 9 • • 2 4

27 2 35 8 30 1 15. 5 2 3

26 5 36 4 29 9 22. 6

Da y17 :
dos e (mg/kg ; grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 27 9 34 0 31 2 6. 4 2 4

27 7 36 7 31 4 19. 3 2 4

28 4 35 8 31 5 17. 0 2 3

27 2 38 7 31 5 24. 7TERATOLOG YSTUD YI NRAT S 6 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y18 : grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n +S . D . stat.s i gn . 2 1 29 6 36 3 33 0 17. 0 2 4

28 6 39 3 33 0 22. 1 2 4

30 3 38 0 33 3 18. 2 2 3

27 5 41 2 32 9 29. 2

Da y19 : grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n
+ S. D sta t s i gn . 2 1 30 8 37 9 34 5 19. 9 2 4

29 8 41 4 34 7 23. 5 2 4

31 7 40 6 34 9 20. 9 2 3

28 0 43 5 34 4 32. 3TERATOLOG YSTUD YI NRAT S 6 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y20 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 31 7 39 9 35 9 21. 4 2 4

32 1 42 4 36 2 24. 0 2 4

32 9 42 1 36 3 22. 0 2 3

28 2 45 8 35 8 36. 5

Da y21 :
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 .30 0 100 0 300 0
N min . max . mea n + S.D . stat . s i gn . 2 1 32 6 41 5 36 5 25. 0 2 4

32 9 43 3

' 36 9 25. 1 2 4

31 8 43 0 36 8 27. 2 2 3

28 8 46 0 36 2 35. 8TERATOLOG YSTUD YI NRAT S 7 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

9.1.2 . Bod yweigh t change s

Da y0- 6
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 25. 7 43. 1 32. 9 4. 3 2 4

20. 7 48. 3 32. 0 6. 9 2 4

24. 1 50. 4 31. 0 5. 7 2 3

15. 6 48. 4 32. 8 6. 8

Da y6-1 1
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 . 300 0
N min . max . mea n + S.D . stat.sign . 2 1 19. 0 37. 3 27. 3 4 . 9 2 4

2 0
. 9 42. 9 29. 4 5 . 3 2 4

21. 5 40. 3 30. 5 4 . 3 2 3

19. 7 45. 1 30. 1 6 . 1TERATOLOG YSTUD YI NRAT S 7 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y11-1 6
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0

m m . max . mea n +S.D
. stat.sig n 2 1 28. 5 58. 7 45. 0 6 . 2 2 4

32. 7 61. 6 42. 5 6 . 4 2 4

2 9
. 8 58. 4 4 1
. 8 6 . 8 2 3

17. 8 70. 0 39. 8 10. 2

Da y16-2 1

dos e(mg/kg ; grou p 1 grou p 2grou p 3 grou p 4 030 0100 0300 0
N min . max . mea n + S.D . stat.sign . 2 1 52. 1 91. 6 66. 0 11 . 9 2 4

56. 1 98. 2 70. 0 10. 3 2 4

35. 7 100. 9 67. 8 14. 2 2 3

23. 4 95. 6 63. 3 16. 5TERATOLOG YSTUD YI NRAT S 7 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y0-2 1
dos e (mg/kg ;

Da y6-2 1

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.s i gn . 2 1 133. 3 227. 4 171. 0 23. 0 2 4

144. 5 234. 0 173. 9 22. 5 2 4

134. 8 242. 0 171. 1 24. 7 2 3

95. 0 255. 6 166. 0 32. 2

grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign . 2 1 103. 5 184. 3 138. 3 20. 3 2 4

115. 4 185. 8 142. 0 18. 8 2 4

106. 0 191. 6 140. 1 20. 9 2 3

67. 8 207. 3 133. 2 27. 7TERATOLOG YSTUD YI NRAT S 7 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y6-1 6 grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 49. 9 92. 9 72. 3 10. 1 2 4

57. 1 100. 0 71. 9 10. 0 2 4

60. 1 98. 6 72. 3 9. 5 2 3

44. 4 111. 7 69. 9 14. 1TERATOLOG YSTUD YI NRAT S 7 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

9.1.3 . "Corrected " bod yweight s Analysi s o f "corrected " Bod yweigh t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N mi n. max . mea n + S.D . stat . sign . 2 1 22 0 28 9 25 2 19. 6 2 4

22 1 30 4 26 1 20. 4 2 4

22 4 31 5 25 8 21. 2 2 3

22 2 30 4 26 0 21. 9

Analysi s o f "corrected " bod yweigh t gai n grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
2 1 2 4 2 4 2 3 -7. 0 1. 0 6. 0 9. 8 58. 1 68. 4 75. 3 86. 0 25. 6 33. 7 29. 4 30. 4 16. 7 17. 1 15. 1 18. 1 N min . max . mea n +S.D . stat . sig nTERATOLOG YSTUD YI NRAT S 7 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Analysi s o f "corrected " bod yweigh t diff . % grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat . s i gn . 2 1 -3. 0 25. 2 11. 3 7. 3 2 4

0. 4 32. 2 14. 9 7. 7 2 4

2. 5 31. 4 12. 8 6. 3 2 3

4. 1 39. 7 13. 3 8. 0

Analysi s o f gravi duteru s weigh t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 8 1 13 5 11 3 12. 2 2 4

6 5 12 9 10 8 14. 8 2 4

8 0 13 9 11 1 14 . 9 2 3

1 2 15 5 10 3 ~ 33. 1TERATOLOG YSTUD YI NRAT S 7 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

9.1.4 . Foo dConsumptio n Analysi s o f Foo dconsumptio n Da y0- 6 grou p 1 grou p 2 grou p 3 dos e (mg/kg ) 0 30 0 100 0 grou p 4 300 0

m m . max . mea n +S.D . stat.sign . 2 4 18 . 2 20. 3 19. 1 1. 0 . 2 4

18. 8 21. 1 19. 4 0 . 8 2 4

18. 7 20. 8 19. 5 0. 8 2 4

18. 2 20. 4 19. 7 0. 8

Da y6-1 1

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min
. max . mea n + S.D
. stat . s i g n . 2 4 20. 6 24. 0 22. 1 1 . 5 2 4

21. 6 24. 7 22. 8 1 . 0 2 4

21. 4 24. 2 23. 0 1 . 1 2 4

22. 5 25. 1 23. 9 1 . 0 *TERATOLOG YSTUD YI NRAT S 7 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y11-1 6
dos e(mg/kg ) grou p 1 grou p 2grou p 3 grou p 4 030 0100 0300 0 N min . max . mea n + S.D . stat.sig n 2 4 23 . 2 27. 0 25. 1 1. 2 2 4

2 4
. 0 27. 3 26. 0 1 . 2 2 4

24. 8 27. 1 26. 0 0 . 8 2 4

24. 3 27. 9 26. 3 1. 2

Da y16-2 1
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sig n 2 4 20. 8 27. 2 23 . 1 2. 1 2 4

23. 6 27. 1 25. 8 1. 4 2 4

22. 0 26. 7 24. 5 1. 6 2 4

24. 4 25. 7 25. 1 0. 6TERATOLOG YSTUD YI NRAT S 7 ! G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y0-2 1
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4

. 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 4 20. 6 24. 4 22. 3 1 . 3 2 4

21. 8 2 4
. 9 23. 3 1. 0 2 4

22. 1 24. 5 23. 1 1 . 0 2 4

22. 6 24. 3 23. 6 0 . 7

Da y6-2 1
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 4 21 . 5 26. 1 23. 6 1. 5 2 4

23. 0 26. 4 24. 9 l.l ' 2 4

23. 5 26. 0 24 . 5 1. 0 2 4

24. 3 26. 0 25. 1 0. 7TERATOLOG YSTUD YI NRAT S 7 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Da y6-1 6 grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n
+ S . D . stat . sign . 2 4 21. 9 25. 5 23. 6 1. 3 2 4

22. 8 26. 0 24. 4 1. 0 2 4

23. 1 25. 6 24. 5 0. 9 2 4

23.7 . 26. 5 25. 1 1. 0 *TERATOLOG YSTUD YI NRAT S 8 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

9.1.5 . Uterin e dat a
Corpor a lute a tota l
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat : s i gn . 2 1 1 2 2 2 16. 1 2.1 5 2 4

1 1 2 0 16. 0 2.3 3 2 4

1 3 2 0 16. 9 1.5 7 2 3

8 2 3 16. 9 2.8 1

Implantation s tota l

dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . s i gn . 2 1 1 1 1 8 15. 3 1.8 3 2 4

1 0 1 9 15. 2 2.1 9 2 4

1 3 1 9 16. 0 1.5 6 2 3

1 1 9 14. 3 3.9 0TERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Resorption s earl ytota l grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . s i gn . 2 1 0 2 0.4 8 0.6 0 2 4

0 3 0 . 8 8 0.9 0 2 4

0 5 0.9 6 1.3 7 2 3

0 7 0.8 7 1.4 6

Resorption s lat e tota l
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 0 1 0.0 5 0.2 2 2 4 2 4 • 0 1 0.0 4 0.2 0 2 3

0 1 0.0 9 0.2 9TERATOLOG YSTUD YINRAT S 8 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Resorption s tota l
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 0 2 0.5 2 0.6 8 2 4

0 3 0.8 8 0.9 0 2 4

0 5 1.0 0 1.3 5 2 3

0 7 0.9 6 1.4 6

Dea dfetuse s tota l
dos e (mg/kg ; grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . s i gn . 2 1 0 2 0.1 1 0.1 9 2 4 2 4 0 1 0.0 5 0.2 0 2 3

0 1 0.0 4 0.2 1TERATOLOG YSTUD YI NRAT S 8 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Liv e Fetuse s tota l
dos e (mg/kg ; grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S.D . stat.sign , 2 1 1 0 1 7 14.8 1 1.8 1 1 4

2 2 4 7 1 8 3 3 6 3 1 4 2 2 4 1 1 1 9 9 6 .1 0 2 3

1 0 1 9 13.3 0 4.4 4

Liv e Fetuse s mal e
dos e (mg/kg ; grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 4 1 0 6. 8 .7 3 2 4

4 1 1 6. 9 2.0 9 2 4

3 1 3 6. 9 2.3 1 2 3

0 1 2 6. 7 2.9 9TERATOLOG YSTUD YI NRAT S 8 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Liv e Fetuse s femal e
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n +S . D . stat.sign . 2 1 5 1 2 8. 0 2.1 6 2 4

2 1 2 4. 5 2.8 6 2 4

4 1 2 8. 1 2.0 4 2 3

0 1 1 6. 6 2.7 1

Sex-rati o pe r litte r
dos e(mg/kg ) grou p 1 grou p 2grou p 3 grou p 4 030 0100 0300 0
N min . max . mea n +S.D . stat.sign . 2 1 0.2 5 0.6 7 0.4 6 0.1 1 2 4

0.2 9 0.7 5 0.4 9 0.1 5 2 4

0 . 2 1 0.7 6 0.4 6 0.1 2 2 3

0.0 0 1.0 0 0.5 0 0.2 0TERATOLOG YSTUD YI NRAT S 8 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Litte r weigh t
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . s i gn . 2 1 58. 6 96. 6 81. 8 9. 0 2 4

43. 9 95. 3 78. 4 11. 8 2 4

48. 1 103. 7 79. 9 12. 3 2 3

5. 7 111. 1 72. 6 2 4 . 8

Bod yweigh t mal e (pe r litter ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat.sign . 2 1 5. 1 6. 2 5. 7 0.3 2 2 4

5. 0 6. 5 5. 7 0.3 6 2 4

2. 9 6. 1 5. 5 0.6 1 2 2

2. 8 7. 0 5. 6 0.7 8TERATOLOG YSTUD YI NRAT S 8 6 G UProjec t No . 84086 2 Tes t Article : TK 1244 3

Da yBod yweigh t femal e (pe r litter ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N2 1 2 4 2 4 2 2 min . 4. 9 4. 7 3. 1 4. 3 max . 5. 9 5. 9 5. 7 6. 8 mea n5. 4 5. 3 5. 2 5. 4 +S.D . 0.2 7 0.3 0 0.5 1 0.5 6 " stat.sign .

Bod yweigh t tota l (pe r litter ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min
. max . mea n + S.D
. 

### stat . s i gn . 2 1 5 . 0 6 . 0 5 . 5 0.2 8 2 4

4 . 9 6 . 3 5 . 5 0.3 4 2 4

3 . 0 5 . 8 5 . 4 0.5 5 2 3

2 . 8 6 . 8 5 . 5 0.7 7TERATOLOG YSTUD YI NRAT S 5 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Bod yweigh t mal e (pe r group ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . sign . 14 2 3. 6 6. 5 5. 7 0.4 2 16 5

4. 2 6. 7 5. 7 0.4 7 16 5

2. 1 6. 5 5. 5 0.7 2 * 15 5

2. 6 7. 1 5. 6 0.6 0

Bod yweigh t femal e (pe r group ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S.D . stat . sig n 16 9 3. 6 6. 3 5. 4 0.3 7 17 9

2. 6 6. 4 5. 3 0.4 4 19 4

2. 8 6. 0 5. 2 0.5 4 15 1

3. 9 6. 8 5. 4 0.5 1TERATOLOG YSTUD YI NRAT S 8 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Bod yweigh t tota l (pe r group ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
N min . max . mea n + S . D . stat.sign . 3 1 1 3 . 6 6 . 5 5 . 5 0.4 3 34 4

2 . 6 6 . 7 5 . 5 0.5 0 35 9

2 . 1 6 . 5 5 . 3 0.6 4 30 6

2 . 6 7 . 1 5 . 5 0.5 7TERATOLOG YSTUD YI NRAT S 8 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
9.1.6 . Feta l skeleta l finding s

Externa l feta l malformation s grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 31 1 34 4 35 9 32 4 Numbe r o f affecte dfetuse s 1 0 0 1 o stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 0 0 1 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 9 0 G UProjec t No . 84086 2 Tes t Article : TK 1244 3
Feta l skeleta l anomalie s
dos e (mg/kg ) grou p 1 grou p 2 grou p 3 grou p 4 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 4 o stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 4 o stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f Cerv.Vert.(1 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 Numbe r o f affecte dfetuse s 16 1 18 7 19 2 o stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 Numbe r o f affecte dlitter s 2 1 2 4 2 4 Stat.sign.(ch i ) 21 6 14 5
+ 2 4
2 3TERATOLOG YSTUD YI NRAT S 9 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Cerv.Vert.(2 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 18 7 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2 1 stat.sign.(ch i ) 23 0 20 2

2 4 2 4 23 9

21 3

2 4 2 4 21 6

18 3

2 4 2 4

Skeleta l maturation : oss . o f Cerv.Vert.(3 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 Stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s 21 0 6 8

2 1 1 9 23 0

7 5

2 4 1 9 23 9

9 2

+ +
2 4 2 0 21 6

5 5

2 4
stat.sign.(ch i

^2 ,TERATOLOG YSTUD YI NRAT S 9 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Cerv.Vert.(4 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 Numbe r o f affecte dfetuse s 3 7 5 0 6 7 stat . sign , (chi'^ ) + + Tota l numbe r o f litter s 2 1 2 4 2 4 Numbe r o f affecte dlitter s 1 7 1 7 1 8

9 Stat.sign.(ch i ) 21 6 3 5

2 4 1 4

Skeleta l maturation : oss . o f Cerv.Vert.(5 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s 21 0 2 3

2 1 1 3 23 0

3 6

2 4 1 4 23 9

4 8

2 4 1 4 21 6

2 1

2 4 1 2 stat.sign.(ch i

. 2 ,TERATOLOG YSTUD YI NRAT S 9 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : oss . o f Cerv.Vert.(6 ) absen t grou p 1 grou p 2 grou p 3 grou p ' dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s Stat . sign , (chi'^ ) 21 0 1 7

2 1 1 1 23 0

1 9

2 4 23 9

2 5

2 4 21 6

1 7

2 4 1 0

Skeleta l maturation : oss . o f Cerv.Vert.(7 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4.,iJSj^:
. TERATOLOG YSTUD YI NRAT S 9 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Sternebr a (2 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f Sternebr a (5 ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 9 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
Skeleta l maturation : oss . o f Calcanei(L+R ) absen t grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 Numbe r o f affecte dfetuse s 17 8 19 1 18 4

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 24 2 4 Numbe r o f affecte dlitter s 2 1 2 4 2 4

9 stat.Sign.(ch i ) 21 6
15 6

+ +
2 4
2 3

Skeleta l maturation : oss . o f Calcane i (R ) absen t grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s , 2 1 Numbe r o f affecte dlitter s 2

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 9 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Calcane i (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 9 1 01 08

9 Stat.sign.(ch i) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 8 6 9 7

9 stat.sign.(ch i )
Skeleta l maturation : oss . o f Calcane i (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s • 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 18 9 20 7 19 8 17 3

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 2 1 2 4 2 4 2 3

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 9 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Metatarsa l 1 (L+R ) absen t group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

1 0

2 4 23 9

1 7 + 2 4 21 6

1 1

2 4

Skeleta l maturation : oss . o f Metatarsa l 1 (R ) absen t group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YINRAT S 9 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Metatarsa l 1 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f Metatarsa l 1 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 Numbe r o f affecte dfetuse s 7 1 4 2 0

9 stat.Sign.(ch i ) + Tota l numbe r o f litter s 2 1 2 4 2 4 Numbe r o f affecte dlitter s 6 7 9 stat.sign.(chi^ ) 21 6 1 2

2 4TERATOLOG YSTUD YI NRAT S 9 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Ri b1 3 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f Ri b1 3 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2 stat.sign.(chi^ ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Ri b1 3 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f Ri b1 3 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 3 stat.sign.(chi^ ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.dist.phal.nucle i 5 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 2 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f •

" affecte dfetuse s 2

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

9 stat.sign.(ch i ) 23 0

2 4 23 9

1 2

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucle i 2 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9

2 1 2 4 2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucle i 2 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucle i 2 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3

9 Stat.sign.(chi^ ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 3

9 stat.sign.(ch i ) 23 0

2 4 23 9

+ + 2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 3 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 4 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9

2 1 2 4 2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 4 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 Stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 4 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.Sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 4 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 10 6 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 5 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 4

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 4

9 stat.sign.(ch i ) 23 0

2 4 23 9

+ + 2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 5 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 4

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 4

9 stat.sign.(ch i ) 23 0

2 4 23 9

1 0

2 4 21 6

1 0

2 4TERATOLOG YSTUD YI NRAT S 10 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 5 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s stat.sign.(ch i

.2 , 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f ant.prox.phal.nucleu s 5 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 9 stat.sign.(ch i) 23 0

2 4 23 9

3 0
+ + 2 4 1 1 21 6

2 1
+ 2 4 1 0TERATOLOG YSTUD YI NRAT S 10 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Metacarpa l 5 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 0001 9 stat.sign.(ch i) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 0 0 0 1

9 stat.sign.(ch i )
Skeleta l maturation : oss . o f post.prox.phal.nucle i 2 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4

• dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 ' 21 6 Numbe r o f affecte dfetuse s 2 23 8 5 9 3 3 stat.sign.(chi^ ) ++ + Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 5 1 1 1 4 1 2

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 10 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 2 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s stat.sign.(ch i

. 2 . 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f post.prox.phal.nucle i 2 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 1 1 1 6 1 7 1 6

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 1 1 1 1 1 1 0

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 11 0 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 2 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3 9

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1 5

9 stat.sign.(ch i ) 23 0 6 3

2 4 1 6 23 9

8 4 + + + 2 4 21 6

5 5

2 4 1 5

Skeleta l maturation : oss . o f post.prox.phal.nucle i 3 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 0

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 23 0 3 2
+ + 2 4 1 1 23 9

3 8

++ + 2 4 1 1 21 6

2 7

+ + 2 4 1 1TERATOLOG YSTUD YI NRAT S 11 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 3 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3

9 Stat.Sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

• 2 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f post.prox.phal.nucle i 3 (R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 6

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 6

9 stat.sign.(ch i ) 23 0

2 4 23 9

1 2

2 4 1 0 21 6

2 4TERATOLOG YSTUD YI NRAT S 11 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 3 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 1 9 4 3 5 2 3 6 stat.sign.(chi^ ) + + ++ + + Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 2 1 4 1 4 1 2

9 stat.sign.(ch i )
Skeleta l maturation : oss . o f post.prox.phal.nucle i 4 (L+R ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 1 1 3 1 3 6 2 8 stat.sign.(chi^ ) + + ++ + + + Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 5 1 1 1 0 1 1

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 11 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 4 (L ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : oss . o f post.prox.phal.nucle i 4 (R ) absen t grou p 1 grou p 2 group - 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 . 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 6

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 6

9 stat.sign.(ch i ) 23 0

2 4 23 9

1 4

2 4 1 0 21 6

2 4TERATOLOG YSTUD YI NRAT S 11 4 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 4 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 9

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1 1

9 stat.sign.(ch i ) 23 0 23 9
4 1

+ +
24
1 3 5 4

'++ +
24
1 4 21 6

3 4 +
2 4
1 2

Skeleta l maturation : oss . o f post.prox.phal.nucle i 5 (L+R ) absen t grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Number " o f affecte dfetuse s 54

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1 6

9 stat.sign.(ch i ) 23 0
7 6

2 4 1 9 23 9

9 8
+ + + 2 4 1 9 21 6

6 8

2 4 1 7TERATOLOG YSTUD YI NRAT S 11 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
Skeleta l maturation : oss . o f post.prox.phal.nucle i 5 (L ) absen t grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 9

9 Stat.sign.(ch i ) 23 0 1 5

2 4 1 0 23 9

1 2

2 4 21 6

1 1

2 4

Skeleta l maturation : oss . o f post.prox.phal.nucle i 5 (R ) absen t grou p 1 grou p 2 group 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 1 1 2 3 0

1 9

2 4 1 1 23 9

1 3

2 4 1 0 21 6

1 5

2 4 1 0TERATOLOG YSTUD YI NRAT S 11 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f post.prox.phal.nucle i 5 (total ) absen t grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 8 3

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2 0

9 Stat.sign.(ch i ) 23 0 11 0

2 4 2 0 23 9

12 3

2 4 2 2 21 6

9 4

2 4 1 9

Skeleta l maturation : Sternebr a 1 poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

1 2

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 11 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Sternebr a 2 poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 5

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r of . affecte dlitter s 5

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 0 + 21 6

2 4

Skeleta l maturation : Sternebr a 3 poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 11 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Sternebr a 5 poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Sternebr a 6 poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 Stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 11 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Calcaneu s (L+R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 2 0 1 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 2 0 1 0

9 stat.sign.(ch i )
Skeleta l maturation : Calcaneu s (R ) poorl yossifie d grou p 1 grou p 2 . grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 2 2 1 5

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 2 2 1 5

9 stat.sign.(ch i )TERATOLOG YSTUD YIN
- RAT S 12 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Calcaneu s (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s ^ 2

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Calcane i (total ) poorl yossifie d grou p 1 grou p 2 grou p 3 group . 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 6

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 6

9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Metacarpa l 5 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9

2 1 2 4 2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 2 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 Numbe r o f affecte dfetuse s 0 6

9 Stat.sign.(ch i ) + Tota l numbe r o f litter s 2 1 2 4 Numbe r o f affecte dlitter s 0 4

9 stat.sign.(ch i ) 23 9

2 4 0 + 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 2 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

. 9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 2 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 2 (total ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 4 1 1 4 ' 5

• 2 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 3 8 4 4

9 stat.sign.(ch i )
Skeleta l maturation : Ant.prox.phal . nucle i 3 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 0 0 0 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 0 0 0 1

9 Stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 124 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 3 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant , prox . phal . nucle i 3 (total ) pcx^rl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s stat.sign.(chi^ ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 4 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 4 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Nuraber o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 4 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

. 9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 4 (total ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

. 9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4 UTERATOLOG YSTUD YI NRAT S 12 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 5 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3

• 2 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 3

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 5 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affec-tedfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

1 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 12 8 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : Ant.prox.phal . nucle i 5 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 6

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 6

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Ant.prox.phal . nucle i 5 (total ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 1

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 9 stat . sig n. (clii" ) 23 0 2 4

2 4 1 2 23 9

2 1

2 4 1 1 21 6

1 0

2 4TERATOLOG YSTUD YI NRAT S 12 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : oss . o f Metatarsa l 1 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f 

### affecte dfetuse s 2000 9 

### stat.Sign.(chi ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 2 0 0 0

9 stat.sign.(ch i )
Skeleta l maturation : pos t .prox: . phal . nucle i 2 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 2 11 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 2 11 0

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 13 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucleu s 2 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 3

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : post.prox.phal.nucle i 2 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 2

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 2 (total ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 7 5 4 1

9 Stat.sign.(ch i ) + Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 6 5 4 1

9 Stat . sig n. (ch i • ) +
Skeleta l maturation : post.prox.phal.nucle i 3 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 21 6 Numbe r o f affecte dfetuse s 1 2 0 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s '2 1 .2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 2- 0 1

9 Stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 13 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 3 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : post.prox.phal.nucle i 3 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 3 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 3 (total ) poorl y ossifie d group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) , 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : post.prox.phal.nucle i 4 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0 stat.sign.(chi^ ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0 stat.sign.(chi" ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 4 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : post.prox.phal.nucle i 4 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 4 (total ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9 21 6

2 1 2 4 2 4 2 4

Skeleta l maturation : post.prox.phal.nucle i 5 (L+R ) poorl y ossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0 23 0 23 9 21 6

2 1 2 4 2 4 2 4TERATOLOG YSTUD YI NRAT S 13 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nucle i 5 (L ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 3 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1 1

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 3
+ + 21 6

5

+
2 4
5 +
Skeleta l maturation : post.prox.phal.nuecle i 5 (R ) poorl yossifie d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 9

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 5

9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 7 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : post.prox.phal.nuecle i 5 (total ) poorl y ossifie d group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0 2 3

2 1 1 2 23 0

2 5

2 4 1 4 23 9

1 0 + + 2 4 4 + 21 6

1 2

2 4

Skeleta l maturation : Shor t ri b1 3 (L+R ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 Stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Shor t ri b1 3 (L ) group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0

2 1 2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Shor t ri b1 3 (R ) grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s - 21 0 Numbe r o f affecte dfetuse s 8

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 6

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 13 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Shor t ri b1 3 (total ) group 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

. 9 Stat.sign.(ch i ) 21 0 1 3

2 1 23 0

1 7

2 4 1 3 23 9

1 5

2 4 21 6

1 2

2 4

Skeleta l maturation : Cervica l vertebr . 1 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

1 6

2 4 1 0TERATOLOG YSTUD YI NRAT S 14 0 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Cervica l vertebr . 2 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

• 2 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Thorac.vertebr . 5 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 1 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Thorac.vertebr . 8 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat . sig n. (chi"^ ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Thorac.vertebr . 9 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Thorac.vertebr . 1 0 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

5 + 2 4 21 6

2 4

Skeleta l maturation : Thorac.vertebr . 1 1 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s stat.sign.(ch i

, 2
. 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 3 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : Thorac.vertebr . 1 2 dumbbell-shape d grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1

o stat . sign , (chi'^ ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 1

9 stat.sign.(chi^ ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Cerv.vertebr . 1 bipartit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 1 0

9 Stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 9

9 stat.sign.(ch i ) 23 0 1 4

2 4 1 0 23 9

1 0

2 4 21 6

2 2 + 2 4TERATOLOG YSTUD YI NRAT S 14 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Thorac.vertebr . 1 bipcirtit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.Sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9

2 1 2 4 2 4 21 6

2 4

Skeleta l maturation ; Thorac.vertebr . 1 0 bipartit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 Stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0

2 1 >3 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Thorac.vertebr . 1 1 bipartit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 stat.sign.(ch i ) 21 0 23 0 23 9

2 1 2 4 2 4 21 6

2 4

Skeleta l maturation : Thorac.vertebr . 1 2 bipartit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s Numbe r o f affecte dfetuse s

9 stat.Sign.(ch i ) Tota l numbe r o f litter s Numbe r o f affecte dlitter s

9 Stat.sign.(ch i ) 21 0

2 1 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 6 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Thorac.vertebr . 1 3 bipeirtit e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.Sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Sternebr a 3 oss . incomplet e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 14 7 G UProjec t No . 84086 2 Tes t Article : TK 1244 3 Skeleta l maturation : Sternebr a 4 oss . inccmplet e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 0

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 0

- 9 Stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4

Skeleta l maturation : Sternebr a 5 oss . incomplet e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 Numbe r o f affecte dfetuse s 3

9 Stat.sign.(chi^ ) Tota l numbe r o f litter s 2 1 Numbe r o f affecte dlitter s 3

9 stat.sign.(ch i ) 23 0

2 4 23 9

2 4 21 6

2 4TERATOLOG YSTUD YI NRAT S 1 4 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3 Skeleta l maturation : Sternebr a 6 oss . inccmplet e grou p 1 grou p 2 grou p 3 grou p 4 dos e (mg/kg ) 0 30 0 100 0 300 0
Tota l numbe r o f fetuse s 21 0 23 0 23 9 216 ' Numbe r o f affecte dfetuse s 1 3 2 2

9 stat.sign.(ch i ) Tota l numbe r o f litter s 2 1 2 4 2 4 2 4 Numbe r o f affecte dlitter s 1 2 2 2

9 stat.sign.(ch i )TERATOLOG YSTUD YI NRAT S 14 9 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

9.2 . Individua l Dat a

9.2.1 . Individua l Materna l Clinica l Observation s

Individua l Materna l Clinica l Symptcmi s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .G UProjec t No . TERATOLOG YSTUD YI NRAT S 15 0 84086 2 Tes t Article : T K 1244 3

Individua l Materna l Clinica l Symptom s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .TERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 Tes t Article : 15 1 TK 1244 3

Individua l Materna l Clinica l Symptom s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .TERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 Tes t Article : 15 2 T K 1244 3

Individua l Materna l Clinica l Symptom s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .G UProjec t No . TERATOLOG YSTUD YI NRAT S 15 3 84086 2 Tes t Article : T K 1244 3

Individua l Materna l Clinica l Symptom s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .TERATOLOG YSTUD YI NRAT S 15 4 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Individua l Materna l Clinica l Symptcxn s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .TERATOLOG YSTUD YI NRAT S 15 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

Individua l Materna l Clinica l Symptcan s : dam s grou p 1 : 0 mg/k g Da mn o Observatio nFindin g

da yp.c .

### TERATOLOGYSTUDYINRAT S 30 5 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
9.2.9 . Feta l dat a EXPLANATION S The following abbreviationsar e use di nthi s section ;

,Uundetermine dsex o.a , ossificatio nstil l absen t o.p . ossificatio npoo r o.i . ossificatio nincomplet e d-shap e o.irr . bip . short , fus . : O.B . (vertebral ) cente r stil l dumb
bell-shape d irregula r ossificatio n bipartit e (two apparen t ossificatio ncenters ) shortend fusedossificatio ncenter s n o finding s

MET () MEC () CAL(L , CVC () THVC () LVC ()
PHAL AP ( R )

1 '

)


### AD ( ) Metatarsal s (positio nnumber ) Metacarpal s (positio nnumber ) Calcaneu s (lef t an dright ) Cervica l vertebra l center s (positio nnumber ) Thoraci c vertebra l center s (positio nnumber ) Lumba r vertebral , center s (positio n number ) Phalange s anterior , proxima l (position number ) anterior , dista l (positio nnumber )TERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 30 6 Tes t Article : T K 1244 3

PP ( )
PD ( )
STER ( ) W S

RIB ( ) posterior , proxima l (positio n number ) posterior , dista l (positio n number ) Sternebra e (position ) Wid e sutur e (frontal s an d parietal s concerne di nthi s respect ) ri b(positio nnumber ) (L ) (R ) (L,R ) lef t righ t lef t andrigh t
E R F R F P
V S M embryoni c resorptio n feta l resorptio n prematur e birth , rando massignmen t o f fetu s t o uterin e positio n viscera l examinatio n skeleta l examinatio n genera l malformation , observe da t externa l examinatio n (M ) (A ) Malformatio n Anomal yTERATOLOG YSTUD YI NRATS 36 1 G UProjec t

No
. 84086 2 Tes t Article : T

K 1244 3
9.3
. Randomizatio n
Randomizatio nwa s achieve db yth efollowin g metho d: O nsevera lconsecutiv eday s betwee n1 2an d2 8 mate dfemale s ar eweighe d an dnumbere daccordin g t o thei r bod yweigh t

(th eanima lvri.thth esmalles t weigh t i s numbe r

on e).Th eranke danimal s ar edistribute damong th edos e group s accordin g t o th estratificatio nschem epresente do n-th efollcwin g pag e. Thi s mixtur eo f randcmLzatio nan dstirati f icatio nallcsw s a necgualweigh t distributio namon g th edifferen t dos egroups . Th eanimal s receiv ethei r fina lnumbe r

a t th etim ethe yar eallocate dt o th erespectiv edos egroups .

Randomizatio nTabl e
Weekda yIDistributio namon g 4 group s

Igrou p 1 grou p 2grou p 3 grou p 4 Tu e We d Th u F r i 0

1 2 3 1

2 3 0 2

3 0 1 3

0 1 2



### Numbe r o f mate d dam s eac hda

y Allocation s o f weight-ranke ddam s

grou p 1 grou

p 2 grou

p 3 grou p 4

——— 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 3,4,9,1 0

3,4,9,1 0 13 * 4,7,8,1 1 1*,14 * 5,8,9,1 2 1*,2*,15 * 2,6,11,1 5 2,6,11,1 5 17 * 2,7,12,1 7 1*,18 * 2,7,12,1 7 1*,18*,19 * 1,7,14,2 0 5,9,11,1 7 1,7,14,2 0 5,9,11,1 7 21 * 2,5,7,1 2

2,5,7,1 2 3,5,10,1 2 4,6,11,1 3 4,7,10,1 3 4,7,10,1 3 3,8,11,1 6 3,8,11,1 6 2,6,15,1 9 2,6,15,1 9 1,3,14,1 6

1,3,14,16 . 4,9,10,1 5 4,9,10,1 5 3,8,13,1 8 3,8,13,1 8 1,6,8,1 1

1,6,8,1 1 2,6,9,1 3 3,7,10 , 1 4 5,8,9,1 2 5,8,9,1 2 5,6,13,1 4 5,6,13,1 4 4,10,12,1 6 4,10,12,1 6TERATOLOG YSTUD YI NRAT S 36 2 G UProjec t No . 84086 2 Tes t Article : T K 1244 3

2 2 2 3 2 4 2 5 2 6 2 7 2 8 2, 7

5, 9 1* , 2, 7 5, 9 1* , 1, 9 5, 1 1, 9 5, 1 25 * 2, 1 6, 1 1* , 2, 1 6, 1 1* , 1, 1 5, 6 ,16,2 1 ,14,1 8 22 * ,16,2 1 ,14,1 8 22*,23 * ,16,2 4 1.14.2 0 ,16,2 4 1,14,2 0 0,17,2 5 2.15.2 1 26 * 0,17,2 5 2,17,2 1 26*,27 * 0,19,2 8 ,23,2 4 3,8,15,2 0 4,10,13,1 9 6,11,12,1 7

3,8,15,2 0 4,10,13,1 9 6,11,12,1 7 2,8,17,2 3 3,7,18,2 2 4,6,19,2 1 10,12,13,1 5 2.8.17.2 3 3,7,18,2 2 4,6,19,2 1 10,12,13,1 5 3.9.18.2 4 4,8,19,2 3 5,7,20,2 2 11,13,14,1 6 3,9,18,2 4 4,8,19,2 3 5,7,20,2 2 11,13,14,1 6 2,9,20,2 7 3,8,21,2 6 4,7,22,2 5 11,13,16,1 8 12,14,15,1 7

* = Thes e animal s wer e no t allocate dt o an ydos e grou pTERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 Tes t Article ; 36 3 T K 1244 3

9.4 . Matingtabl e

Males : Numbers : Initia l Bod yWeight : Initia l Age : Females : Numbers : Tif : RAI f (SPF ) albin o rat s 0 1 - 5 5 ; Deliver yfro m09.04.198 5

(Batch-No . 38427 ) 30 0 - 35 0 g 7 - 8 week s Tif:RAI f (SPF ) albin o rat s 0 1 - 24 , 2 5 - 48 , 4 9 - 72 , 7 3 - 9 6 Deliver yfro m05.08.198 5 (11579D )

Group 1 Femal e numbe r 00 1 00 2 00 3 00 4 00 5 00 6 00 7 00 8 00 9 01 0 Oi l 01 2 01 3 01 4 01 5 01 6 01 7 01 8 01 9 02 0 02 1 02 2 02 3 02 4 da y0 pc .

06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 Male s

numbe r 0 1 0 1 2 5 1 6 2 7 3 6 3 5 2 4 5 0 0 8 1 4 0 6 3 4 2 1 3 5 2 4 0 5 1 5 0 2 2 5 1 1 0 7 3 3 4 0 Batc h

• 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 cxxitrol Ag e (weeks ) Remark s 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 . 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5G UProjec t No . TERATOLOG YSTUD YI NRAT S ' 36 4 84086 2 , Tes t Article : TK 1244 3

Males : Numbers : Tif : RAI f (SPF ) albin o rat s 0 1 - 5 5 ; Deliveryfro m09.04.198 5

. (Batch-No . 38427 ) Initia l Bod yWeight : Initia l Age : 30 0 - 35 0 g 7 - 8 week s Females : Numbers : Tif:RAI f (SPF ) albin o rat s 0 1 - 24 , 2 5 - 48 , 4 9 - 72 , 7 3 - 9 6 Deliver yfro

m05.08.198 5 (11579D )

Grou p 2 Femal e numbe r 02 5 02 6 02 7 02 8 02 9 03 0 0 3 1 03 2 03 3 03 4 03 5 03 6 03 7 03 8 03 9 04 0 04 1 04 2 04 3 04 4 04 5 04 6 04 7 04 8 da y0pc .

06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5

, 06.08.8 5 06.08.8 5 06.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 Male s

numbe r 1 2 0 3 2 8 2 8 0 2 2 0 2 9 2 7 0 8 3 9 1 4 2 1 2 9 3 8 1 3 3 8 3 0 1 4 0 7 3 4 0 3 4 0 1 7 4 1 Batc h

3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 •3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 30 0rrgA g

Ag e (weeks ) Remark s 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5TERATOLOG YSTUD YI NRAT S 36 5 G UProjec t No . 84086 2 Tes t Article : TK 1244 3

Males : Numbers : Tif : RAI f (SPF ) albin o rat s 0 1 - 5 5 ; Deliveryfrom09.04.198 5

(Batch-No . 38427 ) Initia l Bod yWeight ; Initia l Age : 30 0 - 35 0 g 7 - 8 week s Females : Numbers : Tif:RAI f (SPF ) albin o rat s 0 1 - 24 , 2 5 - 48 , 4 9 - 72 , 7 3 - 9 6 Deliver yfrom05.08.198 5 (11579D )

Grou p 3 Femal e numbe r 04 9 05 0 05 1 05 2 05 3 05 4 05 5 05 6 05 7 05 8 05 9 06 0 06 1 06 2 06 3 06 4 06 5 06 6 06 7 06 8 06 9 07 0 07 1 07 2 da y 0pc .

06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.85

- 08.08.8 5 08.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 Male s

numbe r 1 9 2 2 3 2 3 3 ,1 9 2 6 4 7 2 5 3 1 1 1 1 8 2 3 0 4 1 8 1 7 4 3 1 2 0 7 3 1 4 2 0 8 1 3 2 1 1 6 Batc h

3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3 8 4 2 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 100 0ngA g

Ag e (weeks ) Remark s 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5TERATOLOG YSTUD YI NRAT S G UProjec t No . 84086 2 Tes t Article : 36 6 TK 1244 3

Males : Numbers : Initia l BodyWeight ; Initia l Age : Females : Numbers : Tif : RAI f (SPF ) albin o rat s 0 1 - 5 5 ; Deliveryfrom09.04.198 5

(Batch-No . 38427 ) 30 0 - 35 0 g 7 - 8 week s Tif:RAI f

(SPF ) albin o rat s 0 1 - 24 , 2 5 - 48 , 4 9 - 72 , 7 3 - 9 6 Deliver yfro m05.08.198 5 (11579D )
Grou p 4 Femal e numbe r 07 3 07 4 07 5 07 6 07 7 07 8 07 9 08 0 08 1 08 2 08 3 08 4 08 5 08 6 08 7 08 8 08 9 09 0 09 1 09 2 09 3 09 4 09 5 09 6 da y0pc .

06.08.8 5 06.08.8 5 06.08.8 5 06.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 07.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 08.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 09.08.8 5 Male s

numbe r 1 8 0 4 ' 0 9 1 3 1 0 2 7 1 7 2 8 3 0 0 9 0 2 2 2 0 1 2 6 3 7 3 7 3 1 3 8 4 1 2 0 4 2 1 2 0 5 4 2 Batc h

3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 3842 7 Ag e

(weeks ) 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5

. 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 24-2 5 3000ngA g

Remark sTERATOLOG YSTUD YINRAT S G UProjec t No . 84086 2 Tes t Article ; 36 7 TK 1244 3

9.5 . Concentratio no f Tes t Articl e i nth e Vehicl e Th e conten t o f T K 1244 3 i nth e vehicl e wa s determine dwit h sample s o f al l thre e concentration s prepare do nAugus t 22 , 1985 . Th e analysi s wa s performe dbyth e centra l analytica l laborator yo f . Th e analytica l repor t i s file dwit hth e ra wdata .

VOLUM E m l 2. 0 2. 0 2. 0 NOMINA L

VALUE S mg/m l •3 0 10 0 30 0 VALUE S

DETERMINE D mg/m l 29. 5 93. 5 302. 3 300. 2 RELATIO N % 98. 3 93. 5 100. 8 100. 1

Thes e value s ar e al l withi nacceptabl e limits .

### TERATOLOGYSTUDYINRAT S 36 8 G UProjec t No . 84086 2 Tes t Article : T K 1244 3
10 . DISTRIBUTION Thi s repor t wa s distribute dto :

- Plastic s an

d Additive s Divisio n

-

- Qualit yassuranc edepartmen t