Tes t No. : 84085 8 7 a <= > yti) 3

Protectio n o f Healt h an d Environmen t

G U2. 3 Experimenta l Patholog y

NUCLEU S ANOMAL Y TES T I NSOMATI C INTERPHAS E NUCLE I O F CHINES E HAMSTE R

Tes t material : TK 1 2 44 3 (TINUVI N234 )

Date : February11 , 198 5 This document is directed to USEPA pursuant the Toxic Substances Control Act (TSCA). This document is the property of the sponsor and may be used only for that purpose intended by the sponsor and as authorized under applicable law. Every other or additional use, exploitation, reproduction, publication or submission to other parties requires the written permission of the sponsor, except as otherwise required by applicable law (e.g., TSCA). The use of these studies/documents for regulatory, registration or other commercial purposes [including but not limited to Registration, Evaluation, Authorization and Restriction of Chemical Substances (REACH)], without the express written permission of the sponsor is unauthorized and strictly prohibited.- 2 - INDE X Genera l Summar yan d Assessmen t Procedur e Result s Literatur e Pag e 2 Pag e 4 Pag e 6 Pag e 9 Pag e 9 GENERAL Typ e o f stu(3y : Anima l species : Purpose :

Tes t material : Batc hNO. : Purity : Validity : Stability : Sponsor : Testing facility :

Personnel : Nucleu s anomal ytes t Chines e hamste r (Cricetulu s gri
seus ) randomoutbre d strain , Evaluatio n o f an

ymutageni c effec t o n somati c interphas e cell s b yshor t ter

mtreatmen t a s manifeste d b

ynucleu s anomalies , T K 1 2 44 3 (TINUVI N234 ) E N02885.3 2 Commercia l grad e Informatio n provide d b ysponso r b yreques t Ensure d b

ysponso r

Technica l conduct : Investigation s o f th e slides : Statistics : ,- 3 -

Tes t No. : Rout e o f administration : Dosage : No . o f animal s pe r group : 84085 8 Ora l b ystomac htub e 1250 , 2500 , 500 0 mg/kg I n th e tolerabilit ytest : 2 5 9 an d 2 <S6, i n th e mutagenicit y test : 6 2 5 an

d 6 66 . Starting dat e (firs t administration) : Octobe r 1 , 198 4 Dat e o f stud

ycompletion : Decembe r 17 , 198 4 Reporte d an

d filed : February198 5 Locatio n o f archives :- 4 -

SUMMAR Y AN D ASSESSMEN

T T K 1 2 44 3 (TINUVI N234 ) wa s administere d b ygavage . Treatmen t consiste d o f on e dail ydos e o f 1250 , 250 0 o r 500 0 mg/kg o n eac ho f two consecutiv e days . Th e animal s wer e sacrifice d 2 4 hafte r th e secon d application . Fro mth e bon e marro wsmear s wer e made . Th e experimen t wa s performe d t o evaluat e an ymutageni c effec t on somati c interphas e cell s i n vivo . Mutageni c effect s presen t themselve s i n interphas e cell s i n for mo f nucleu s anomalie s o f bon e marro wcell s (Lit.1,2) . Thes e ano malie s occur i n interphas e cell s a s a consequenc e o f damag e during the mitoti c process . Th e increas e i n anomalie s show s a clea r dos e dependency , comparabl e t o th e occurrenc e o f chromosome aberration s i n metaphas e preparation s (Lit.3) . Th e bon e marro wsmear s fromanimal s treate d wit hth e variou s dose s o f T

K 1 2 44 3 showe d n o significan t differenc e fromth e control . Th e incidenc e o f bon e marro wcell s wit hanomalie s o f nucle i correspond s t o th e frequenc yobserve d i n th e con tro l group . B ycontrast , a "positiv e control " experimen t wit hcyclophos
phamid e (12 8 mg/kg ) yielde d 9.42 % cell s wit hanomalie s o f nuclei . Thi s i s significantl ydifferen t fromth e control s (0.033 ) treate d wit hth e vehicl e (0.5 % CMC ) alone .- 5 -

I t i s conclude d tha t unde r th e condition s o f thi s experi
ment , n o evidenc e o f mutageni c effect s wa s obtaine d i n Chi
nes e hamster s treate d wit hT K 1 2 443 ,

stud ydirector : Date : February6 , 1 9 8 5

Repor t reviewe d an d approve d by :

Date : February11 , 1 9 8 5- 6 - PROCEDUR E 1 , Dat a o n th e animal s used Chines e hamster s (Cricetulu s griseus ) o f eithe r sex (Q'. 6 = 1:1 ) (weigh t 9 9 21-2 7 g , 6 6 21-2 7 g (tolerabilit y test) , 9 9 22-3 0 g , 6 6 20-3 4 g (mutagenicit ytest) ; ag e 9 9 6-1 0 weeks , 6 6 4- 9 weeks ) wer e used . Standard diet : NAFA G No,924 , Tap wate r a d libitum . Th e animal s wer e kep t i n a n air-conditione d roo ma t a temperatur e o f 23-2 4 C an d a relativ e humidit yo f 56-57% , Th e roo mwa s illumina
ted fo r 1 2 hour s daily . Identificatio n o f th e animal s b y individua l caging . 2 , Tolerabilit ytes t Apreliminarytes t wa s performe d t o determin e th e highes t dosag e o f th e tes t substanc e t o b e applie d i n th e muta genicit yassay . Thre e group s o f four Chines e hamster s ( 2 9 9 an d 2 66 ) ar e treate d wit hthre e differen t doses , on e receiving th e maximu mdos e o f 500 0 mg/kg , o r th e highes t applicabl e dose , an

d th e othe r two dose s o f 1/ 5 an d 1/2 5 o f tha t amoun t respectively . I n th e firs t par t o f th e tolerabili
tytes t th e animal s ar e treate d wit ha singl e dose . Th e observatio n perio d correspond s t o th e interva l betwee n administratio n an

d sacrific e o f th e animal s i n th e muta genicit ytest , plu s on e day . I f al l animal s i n al l dos e group s di e i n th e firs t step , a secon d tes t i s performe d i n whic hth e highes t dos e give n i s 3/ 4 o f th e lowes t use d i n th e preceding test . I f some o f th e animal s i n on e o f th e dos e group s die , th e tes t i s continue d wit ha high dos e corresponding t o a predetermine d fractio n o f tha t dose . Th e highes t dos e survive d b yal l animal s i n th e grou p i s use d i n th e secon d par t o f th e tolerabilit y test .- 7 - I n thi s secon

d part , th e animal s ar e treate d according t o th e scheme use d i n th e mutagenicit ytest , i.e , wit htw o consecutiv e doses . Th e observatio n perio d correspond s t o th e interva l betwee n administratio n an d sacrific e o f th e animals , plu s on e day . Th e highes t dos e i s tha t deter
mine d i n th e firs t par t o f th e test , an d th e furthe r dose s correspon

d t o 2/ 3 an

d 1/ 3 o f tha t amount . Depending o n th e outcome the highes t dos e causing n o death s i s use d a s th e highes t i n th e mutagenicit ytest , o r i f necessary th e tes t i s repeate d wit hlowe r doses . I n thi s experimen t th e dos e o f 500 0 mg/k g wa s determine d a s th e highes t applicabl e i n th e mutagenicit yassay , to gethe r wit hfurthe r two doses , diminishing b ya facto r o f 0,5 , 3 . Treatmen t schedul e i n th e mutagenicit ytes t Th e preparatio n wa s administere d orall yt o group s o f 6 femal e an

d 6 mal e animal s each . Treatmen t consiste d o f dail yon e applicatio n pn 2 consecutiv e days , 2 4 hafte r th e secon

d applicatio n th e animal s wer e sacrifice d b y dislocatio n o f th e cervica l vertebrae , a ) T K 1 2 443 : 1250 , 250 0 an d 500 0 mg/k g i n 20ml/kg vehicle . Vehicle : 0,5 % aqueou s solutio n o f sodium-carboxy
methylcellulos e (CMC) . b ) Cyclophosphamid e (ENDOXAN®) : 12 8 mg/k g i n 2 0 ml/k g 0,5 % CMC (positive control) . Manufactere r o f ENDOXAN® : ASTA-Werke , Germany , c ) 2 0 ml/k g 0,5 % CMC (negative control) . Manufacture r o f CMC : Hercule s Comp, , U,S,A , 4 , Preparatio n o f bon e marro w Bon e marro wwa s harveste d fromth e shaft s o f bot hfemurs . I n a siliconize d pipett e fille d wit happrox , 0, 5 \i l ra t seru mth e bon e marro wwa s draw n up . I n orde r t o receiv e- 8 -
a homogeneou s suspensio n th e conten t o f pipett e wa s aspi
rated gentl yabou t thre e times . Smal l drop s o f th e mix
tur e wer e transferre d o n th e en d o f a slide , spread ou t b ypulling i t behind a polishe d cove r glas s an d th e pre paration s wer e air-dried . Thre e hour s later , th e slide s wer e staine d i n undilute d May-Griinwal d solutio n fo r 2 mi n the n i n May-Griinwal d solution/wate r 1/ 1 fo r 2 mi n an d the n i n Giemsa's , 40 % fo r 2 0 min . Afte r being rinse d i n methano l 55 % fo r 5- 8 se c an d washe d of f twic e i n water , theywer e lef t immerse d i n wate r fo r approx , 2 min . Afte r rinsin g wit hdistille d wate r an d air-drying , th e slide s wer e cleare d i n Xylen e an d mounte d i n Eukitt , 5 , Scoring o f th e slide s Th e slide s o f thre e femal e an d thre e mal e animal s eac ho f th e negativ e contro l group , th e positiv e contro l grou p an d o f th e group s treate d wit hvariou s dose s o f TK 1 2 44 3 wer e examined , 100 0 bon e marro wcell s eac h wer e score d pe r anima l an d th e following anomalie s wer e registered : a ) Singl e Joll ybodies , b ) fragment s o f nucle i i n ery throcytes , c ) micronucle i i n erythroblasts , d ) micronuc
le i i n leucopoieti c cells , e ) polyploi d cells , 6 , Statistic s 2 Th e significanc e o f differenc e wa s assesse d b yX -test .- 9 - RESULT S (Tabl e 1 ) I n al l dosag e group s the percentag e o f cell s displaying ano malie s o f nucle i di d no t diffe r significantl yfro mth e nega tiv e control . B ycontrast , th e positiv e contro l (cyclophosphamide , 12 8 mg/kg ) yielde d a marke d increas e o f th e percentag e o f cell s wit hanomalies . Her e th e mea n percentag e o f anomalie s wa s 9.42 , wherea s the negativ e contro l yielde d a percentag e o f 0.033 . Th e differenc e i s highl ysignifican t (p < 0.05) .

REFERENCE S BOLLER , K . an

d W . Schmi d (1970) , Chemisch e Mutagenes e bei m Sauger . Da s Knochenmar k de s Chinesische n Hamster s al s i n vivo-Testsystem . Hamatologisch e Befund e nac hBehandlung mi t Trenimon , Humangeneti k ii , 35-54 . 2 MATTER , B , an

d W , SCHMI D (1971) , Trenimon-Induce d Chromoso
ma l Damag e i n Bon e Marro wCell s o f Si x Mammalia n Species , Evaluate d b

yth e Micronucleu s Test . Mutatio n Res . 12 , 417-425 , •^MULLER , D, , M , LANGAUER , R , RATHENBERG , F,F , STRASSE R an d R . HES S (1972) , Mikrokerntes t sowi e Chromosomenuntersuch
unge n a n somatische n un

d gonosomale n Zelle n de s Chinesi
sche n Hamster s nac hCyclophosphamidgabe , Verh , Dtsch , Ges , Path , S^ , 381-384 ,Tabl e 1 TH EEFFEC TO FT K 1 2 CHINES EHAMSTER Animal s sacrifice d

. . Contro l (0.5 % CMC )

C: y c l oph o spham i d e (12 8 mg/kg )
/'
T K 1 2 44 3 (125 0 mg/kg )

T K 1 2 44 3 (250 0 mg/kg )

T K 1 2 44 3 (500 0 mg/kg ) 4 4 3
2 4 h Perc e

M r H ! S g

- H C t a m o u Q ) j Q ^ 3 2 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 AND C

^
afte r
n t o f

tf l r A t a E 1- 1 c t a M- l o X ( U C O ? 9 9 6 6 6 9 9 9 d 6 6 9 9 9 6 6 6

. 9 9 9 6 < J d 9 9 9 d d d rcLOPH(
t h e s « cell s

U ) Q ) • H

- d o X I > i i H .- H 0 to 0 ) r H O l c •r H W
0 . 1 0 . 1

5 . 9 5 . 4 3 . 7 8 . 0 7 . 2 9 . 1 0 . 1 0 . 1 0 . 1
0 . 3 0 . 1 0 . 1 0 . 2

0 . 2 0 . 2 DSPHAM

scon d wit h

• H 0 ) f- l o 3 t n C Q ) + j m> , 0 u 0 C O u + J x : C + J Q ) > i s ff O l < u ( 0 nc E n- H

2 . 1 1 . 2 0 . 3 1 . 3 1 . 0 1 . 3 No . [ID EO NB O applicat i anomalie s 1 o u X i 4- 1 > i U 0 ) c • H
•H t u r- { o D C C O 0 + J H 1 0 C J t o •r l r- l S XI

1 . 2 I . O 0 . 5 2 . 4 1 . 5 1 . 8 D f

exp e OT; MAR5

o n
o f nu c

1 o u 3 0 ) r H C •r l U l n H • H . H 0 ) ( U r H O C J 3 c ; C - H 0 + J M ( U O - H • H O s a .

0 . 1 0 . 3 0 . 2 0 . 2 0 . 1 riment : OW_CELL §

l e i

C O r H r H ( U U T i
• H o r H a > 1 r H o C n

0 . 2 0 . 4
0 . 1 8 4 0 ;_g F

. H I d +J O H 0 . 0 . 0 . 0 . 0 . 0 . 9 . 8 . 5 . 1 1 . 9 . 1 2 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 8 5 8

0 1 1 0 o 0 3 1 1 9 8 3 1 0 1 0 1 0 3 1 1 2 0 0 2 2 0 0 0 0

### Verteiler ;

HH ,QUALIT Y ASSURANCE STATEHEN T Fom . 30 1 C STUD Y TITL E : T K 1 2 44 3 (TINUVI N234 )

NUCLEU S ANOMALY TES T I NSOMATI C INTERPHAS E NUCLE I OF CHINES E HAMSTE R Sponsor : Stud y Ref. /

Dispo.Nr. : 84085 8 Stud y Director : Q AInspector N«wi

TH E QUALIT

Y A55WANC E INSPECTION(S ) WA S (WERE ) PERFORME D O NTH E FOLLOWIN

G DATE(S ) t 01.10.8 4 04.02.8 5 (Fina l repor t audit ) 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 l e
TH E FINDINGS WER

E REPORTE D T

O TH E STUD Y DIRECTO

R AN D T D TH E MANAGEMEN

T O NTW E FOLLOWIN

G DATE(S ) 01.10.8 4 04.02.8 5 1 2 3 4 5 6 7 e s QSE/OA UKeneger : 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 IB Dete : 04,02,8 5 Signeture :

DISTRIBUTION : ^ Stud yDirector ®G U6. 3 FU e

SA V 10 3 C / Sep . 198 3

# ..o

^Tes t No. : 84085 8

Protectio n o f Healt h an d Environmen t

G U2. 3 Experimenta l Patholog y

NUCLEU S ANOMAL Y TES T I NSOMATI C INTERPHAS E NUCLE I O F CHINES E HAMSTE R

Tes t material : T K 1 2 44 3 (TINUVI N234 )

Supplemen t t o th e repor t (date d Februar y11 , 1985 )

Date : May26 , 198 7Additiona l data : Tes t No. : 84085 8

Copie s o f ra wdat a availabl e fro mindividua l analysi s record s ar e attache d t o thi s supplement .

\ Stud y Director :K E RNANOMALIE-TES T Q NA T 2 0 CH

A D NA T 12W CH

A Versuchs-Nr. : "^ ^ CiS i .S V KERNANOMALIE-TES T

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Substanz : >

k VVM,\- S Anomalie nType n Einzeln e Jolly-K6rperche n Kerntrtliinie r

i nErythrozyte n Kikiokern e i n Erythroblastc n Hikirokern e i nleukopoetl
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n KerntrOiMoe

r i nErythroryte n Hikrokern e i n Erythroblatte n Hikrokem e i nleukopoeti
oche nZelle n Polyplold e Zelle n Einzeln e Jolly-Urperche n KemtrOnme r

i nErythroiyte n Milurokem e i n Erythroblaste n Hikrokem e i nleukopoetl
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-XArperche n KerntrOnme r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-Mrperche n KemtrOnoie r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoetl
sche nZelle n Polyplold e Zelle n Einxeln e Jolly-KSxperche n KemtrOaae r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Dosis : j'J . Versuchs-Datum : 1 v.v« V . "^o- K

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i nErythrozyte n 1 Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-Karperche n KemtrOiune r

i nErythrozyte n Hikrokem e i n Erythroblaste n• Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n KemtrOmae r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n

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i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KSzperche n Kemtrthane r

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sche nZelle n| Polyplold e Zelle n Dosis : f . . Versuchs-Datum: \ .•fjoi . .U.oJv > . Zah l de r

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i nErythrozyte n Hikrokem e i n 1 Erythroblaste n Hikrokem e i nleuXopoeti
EchenZelle n Polyplold e Zelle n Einzeln e Jolly-Kfirperche n Kerntramoie r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n KemtriJnane r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoetl
sche nZelle n Polyploid s Zelle n Einzeln e Jolly-KSrperche n KemtrCmne r

i nErythrozyte n Hikrokem e I n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Z«lle n Einzeln e Jolly-KOrperche n KemtrOame r

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sche nZelle n Polyplold e Zelle n Dosis : C Versuchs-Datum : 1 xT-'s. o ^•Ay., , Zah l de r aellf nmi t

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1 sche nZelle n Polyplold e Zelle n j Einzeln e Jolly-KOrperche n IKerntrOmmer

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoetl
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n Kemtramme r

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyploid s Zelle n Einzeln e Jolly-KOrperche n Kemtr<imiiie

r i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e I nleukopoeti
BchenZelle n Polyploid s Zelle n Einzeln e Jolly-KOrperche n Kemtrflnmier

i nErythrozyte n Hikrokem e i n1 Erythroblaste n Hikrokem e i nleukopoeti
- 1 sche nZelle n{ Polyplold e Zelle n Einzeln e Jolly-KOrperche n KemtriJniDe r

i nErythrozyte n| Hikrokem e i n1 Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n| Polyplold e Zelle n Dosis : ^ . Versuchs-Datum : 1 "V-^o O --V^ v Zah l de r

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sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n Kemtr<tonier

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
sche nZelle n Polyplold e Zelle n Einzeln e Jolly-KOrperche n KemtrflBmer

i nErythrozyte n Hikrokem e i n Erythroblaste n Hikrokem e i nleukopoeti
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