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PROTOCOL 419-001 : EMBRYU-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETUNITRILE IN NEW ZEALAND WHITE RALSBYrs (SrCMENT II EVALUATION ) TABLE 1(PACE 1) : ANTEMORTEM PHYSICAL SICNS OBSERVED IN RABBITS - SUMMARY

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# _ ,_Y t •s ^ K~ _ -~s' ~ c ;~ : w .r~r u, , r • ° S ^ • ~ : • ~ t .Yl►nJJ.s• ~ o yS ' °
. ♦ -IY r/ :V _ - : . : vr i'^ i . +i . ' : s' •r• n -~ ~ if • ~ - (o o u
u1v.t,t ., .• 1 Y4
.Y11 . 21 0 U l 17 0 U 0 0 0 i a 1 1 2 u I l I Yrl• Y~Y - - 24 L Y Y 0 0 Y 0 0 )] )Y 0 1] 1 17 7, 0YrYYII• J) Y Y 2 Y 7 1 Y 0 11 tl Y II 1 1 1 Y U U . 64 Y - do . 2111 lY• f• 7 Y Y Y 0 Y 71 7 4• 7)• 11 U w• I~
. u Y .bYil+ IS 1• 0 0 ll l 7 0 Y 0 0 0 Y ) 1 0 U U Yr,• 644 71 - • JY ! 11 Y Y Y Y 0 1 4 ! kY 1Y• V• Y ui•
w .u 

### b&, . ly ~ 7 = t 1 ► t lt u 1 o u u u.l . s77 17,1 q,7 7r 64 3 7N 7 1 1 l l 7s d• w u v~

U, i l 1


## i[ Code for observed physical sign
. * Significantly different from control value by Fisher's exact test (P< 0 .05) . ** Significantly different from control value by Fisher's exact test (l'<0 .01) . *** Significantly different from control value by Fisher's exact test (P7,O .0U1) . a . Rabbit 7849 was found dead .on day 23 of gestation . Necropsy revealud umbilical hernia und w .1rKt]d hewurrlw be in herniated pora_1on of intestine (strangulation)

. b . Rabbits 7875, 7780 and 7785 were found dead on days 17, 12 and 19, reS(lectivrly . Fur rul,l,J.ts 7 10 5 jn .i 7885, necropay revealed a stom,Jch wall which appeared thin in the cardiac region . For rabbit /HtlU, ., dried light red exudate was ubservcd around the nostrils and a co ;rlu .s llyuld was uLburvuJ art,unll tl
.. O Inuutll at nucrupay . C :) c . Rabbit 7868 aborted on day 23 of gestation . Necrupay revea :ed colurluss liquid, (-15 ml) In 4b110 ❑ l11 .{I CD cavity ; two depualts of red-tan mucoid material (-1 u71 each) in r1611t Ibduulen .uld „Ile (-Z lut ) 11, 1e1 t C:) abJuwun . caudul to kidnuya ; firm tun-bruvn mass (- 2 wa x I cm) on right lip of vulva

. 

# W

,.- ~..f,
. PRUTU(;UL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WIII'11 kAUttl'1'S (SLCMENT 11 EVALUATION) TAllLE 2 (I'ACI; 1) - U'1BRINE (AN'('6:N15 AND LITI'kR DA'1'A IN INDIVIDUAL HAIIUITS) WHICH UIliU, Auol(7•cn Oh W .L! :'L,<' .U NATURAU
.
Y Uosayu Grou p 

## (my/kg/days 6-18 Corpora Lutua Iar,lantationb t:nlUryos ur tr'ccu~l :aJ I~y It,tl /, L of Presumed Certa- tlou & FWUbit No,) Ta[iUlnaClOn N . 1 . T u • ^•

# p . 33

PlWT(X:UL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OP ACETONITRILE IN NEW ZEALAND W)IITE RAHBITS (SEGMENT II EVALUATION) A9LE 2(PAGt 1) - UTERINE CONTENTS AND LITTER DATA IN INDIVIDUAL RABIfIT .°, WHICH DIED, ABORTED OR DELIVEKE D NA'CUNALLY



## Dosage Group (my/kg/days 6-1 8 of Presumed Gesta- Corpora Lutea Implantations Embryos or !'etuses a tion & kalablt No, kesorNtions b 

# ) Termination k . L . T . R . L . T . R . L . A ./Del . T . R . L . A ./Del . T. 

# I

O(Vehicle)

7803 DELIVERED DAY 28 8 OF CES'rA'fION 4 12 6 4 10 0 0 9` 9` o 0 1 1 2 .0 

# 7821 DELIVERED DAY 28 6 6 12 5 6 11 0 OF CESTATION 0 1 d ld 0 0 10(Lit) 10(Lk 7824 DELIVERED DAY 29 7 5 12 6 5 1 1



# OF Cl:STATION 0 2 2e 0 1 8(LR)e 9e 15.0 7849 FOUND DEAD DAY 23 5 8 13 3 6 9 OF GESTATION 3 f 6f 0 9f 0 0 0 0

R` Right a . Live unless nuted otherwise
. L - Luit b . Early unless noted otherwise
. U - Deud C . All pups appeared normal, including the two that were partially cannibalized A

- Aburced 1lwlts of evaluotion), and as though they had been alive at the time of delivery~l~l~~ the 't'

- TuL :iI d . The pup appeared normal and appeared as though it had been alive at the time o f Du I . - Da llve rud delivery . ~ 

# R

- Late Resorption e . One pup appeared normal and one was partially cannibalized ; both appeared as though 9 c> they 

# had been alive at the time of maternal death . One of the eight delivered late resorptions C :) was also partially cannibalized . w f . Fetuses appeared normal for developmental age and as though they had been alive at the ( n time of maternal death .

~~ .

PkU'(YI( :UL 419-001 : EMli)tYU-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACE'iONITRILE IN NEW ZEALAND WIIITE RABBITS (SEGMENT 11 EVALUATION ) TADLt 2 (PAGE 2)

- U'1'kklNt CONTENTS AND LI'1'I'Itlt DATA IN INDIVIDUAL RADpITS WHICH DIED, ABORTED OR DELIVEkED NA'1'U I W L1. Y 

# 33 Wsdyu Group (lay/kg/days 6-1 8 of Presumed Gesta_ Coi{x,ra Lutud Iay )lentdtions Embryos Or Yecuscsd 1~surl .LL tiou G k.&l,bit No .) Y'utwination K
. L . T . R . L . T . U
. L . A./Del . T . H . L . A ./Ucl .r . 30 .0 

# )866 DELIVERED DAY 28 5 5 10 3 5 8 0 0 1` I ` 0F CES'I'A'1'IUN ~ I ti~,

# p. 34 , ' ...,-.~.

it PxLrrO( :UL 419-001 : EM1iRYU-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SEGMENT 11 EVALUATION ) TABLE 2(YA( ;E 2) - UTERINE CONTENTS AND LITTER DATA IN INDIVIDUAL RABDITS WHICH DIED, ABORTED OR DELIVERED NATURALLY 

# Dosage Groul, (mg/k(j/d4 ys 6-18 a b Corpora Lutua isV lantaciona Embryos or Fetuses luaorytions of Presumed Gestation L k.+i,bi t No .) Termination R . L . T
. R. L . T . It . L . A ./Del . T . R . L . A ./Del . T
. 30 .0 

# 7866 DELIVERED DAY 28 5 5 10 3 5 8 0 0 1e 1~ 3 1 U~ b OF CESTATION 7867 FOUND DEAD DAY 18 6 7 13 5 5 10 5d 4d 0 9d 0 1 U 1 OF CESTATION 7868 ABORTED AND KILLED 6 3 9 5 3 8 3 1 0 4 2 0 1e 4e

DAY 2301 CE51AfI0N 7875 FOUND DEAD DAY 17 8 3 11 5 2 7 1d ld 0 2d 4 1 U 5 OF GESTATION 

# 7877 ABORTED AND KILLED 5 10 15 5 7 12 0 0 Of Of 0 0 l lf 11f

DAY 27 OF GESTATION 788U FOUND DEAD DAY 12 2 6 B 2 4 6 2d 3d 0 5d 0 1 0 1

OF GESTATION
k
- Kil ;lit u . Live unless nutud otherwise . L- Left • b . Early unleas nuted utheruiae . U a Dead c . One partially cannibalized pup and two placentas were found in the cage pan . The pup 

# A - Aborted appeared as though it had been alive at the time of delivery and appeared normal r, 1' - Total within the limits of evaluation . Two additional early resurptions were observed in Lh e Del .- Delivered birth cnnul . One conceptus was presumed cannibalized . ~ d . Embryos appeared normal for developmental age and as though they had been alive at the 

# O time of maternal death . y°o O e . One early resorption and one placenta were found in the cage pan . One early resorption 0 was observed in the birth canal . Fetuses appeared normal and as though they had been CD rJ alive at the time of maternal death . ON f . F:levuu placentas and eleven early re::orptions were found in the u age pan . One concepcua was presumed cannibalized, precluding determination of viability and age .

~

~•

~' ~~ . ., ` • pRU1'(1(:UL 419-001 : EM11RY0-FETAL TOXICITY AND TERATOCENICITY STUDY Of ACh°PONITRILE IN NEW ZEALAND WHITE lkaui-rs ~ (SEG!!kN'f II EVALUATION) TABLE 2 (PACE 3) - U'i'EkINt ; CONTtNTS ANU LITTER DATA IN INDIVIDUAL RJIUDII'S WHICH DIED, ABORTED OR DFJ.IVk:ki:U NATURALLY

Dosage Group tog/kg/days 6-18 a U of Presumed Gesta- Curl,or'a Lutua lsr)lantationa t:adiryos or Fetuses IWsorl uons tlon G Rabbit No .) '1`urmination k . L . T . R . L . T . k . L . A ./Uel . T . k . L . A ./Uul . T
. 30 .0. . . 

# ill I'll, "I i

# d u

# l IC Il1JLlal

# L d 

# W,:« .,,, ..,. I ; ,~ ..., p:35 Wa . ubserved in 

# the birth canal
. 

# Fetuses appeared nurm:rl and as llwubh they had been 

# alive at the time of maternal death . f . Elevun placentas and eleven early re : :orptlona were found in the uage pan . One conceptua was presumed cannibalized, precluding determination of viability and age .

t'PO( ;UL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW YEALAND WHITE RABBITS (SEGMENT II EVALUATION ) LE 2 (PACE 3) U'1'ERINE CONTENTS AND LITTER DATA IN INDIVIDUAL RABBITS W11ICH DIED, ABORTED OR DELIVERED NA'1'U ItA LLY



## Dosage Group g/kg/days 6-18 a b Presumed Gesta- Corpora Lu[ua Iml,lantations ta bryos or Fetuses Resozy[ions on Rabbit No .) Termination R . L . T . R. L . T . R . L . A ./Del . T . R . L . A ./Del . T . .0 

# 7882 FOUND DEAD DAY 15 3 6 9 3 6 9 3c 6c 0 9 C 0 0 0 U OF GESTATION 7885 FOUND DEAD DAY 19 6 4 10 1 4 5 0 0 0 0 1 4 0 5 OF CES'fATION

a ■ Right a . Live unless noted otherwise . • Left b . Early unless noted otherwise . 

# ■ Dead c . Embryos appeared normal for developmental age and as though they had been alive at the • Aburted time of maternal death . • 1bta 1 

# • Delivered a P
. 0 r t*1 o 

# so cr



# ~r,..__.__. . . _._.. . - . . - __ _ __._.._ _ . , :OTtn.'OL 419-001 : Erlul(YO-FL"1'AL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (Sh:(:MLNT II EVALUATION) .BLE 3(PACE 1) : 

# MATERNAL BODY IJEICIIT DATA - 

# SUMMARY 

# 3-5
Dosage (mg/kg/days 6-18 of Gestation) 0(Vehicle) 2 .0 15 .0 30 .0 Rabbits Treated N 25 25 25 25

# p .36 • Slgulticdntly UittcruuL truw cuntrui valuu by Dunnett's test (P < U .US) . ** Significantly difterent from control value by Dunnett's test (P<U .01) . r" ° t Significantly different from control value by Mann-Whitney U test (P_0 .05) . v.~

~~ . . -t•. *`~-,~"~ .'s~, .,a. , .. :~,p,,,ek` .15~'~j !rtN


## PROTOCOL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SEGMENT II EVALUATION ) TABLE 4(PACE 1) : REPRODUCTION AND FETAL DEVELOPMENT IN RABBITS GIVEN ACL••TONITRILE BY CAVACE FROM DAYS 6-18 OF GESTATION 

# 0(Vehicle) mg/kg/day 2 .0 mg/kg/day 15 .0 mg/kg/day 30 .0 mg/kg/day No . pregnant/No . inseminated 17/25 18/25 18/25 21/2 5 No . deaths 0 0 1 5 No . aborted 0 0 0 2 No . delivered naturally 1 2 0 1 No . with total resorption 0 0 0 0 No . litteraa 16 16 17 13 Mean No . Corpora Luceaa 12 .3*_1 .7b 12 .422 .7 10 .7s1 .7 11 .6!2 .1 Mean No . Implantsa 8 .923 .0 8 .0t3 .2 7 .6±3 .6 7 .622 .3 Mean Weight Change (kg) a Days 0-6 +0 .03s0 .08 +0 .05±0 .05 +0 .07±0 .10 +0 .06±0 .07 a 

# Days 6-19 +0 .02s0 .18 +0 .0430 .10 +0 .03±0 .18 -0 .07 *-0 .16 Days 19-29 -0 .04±0 .18 +0 .0310 .12 +0 .07 *-0 .14 +0 .16±0 .15** - Lays 6-29 -0 .03s0 .20 +0 .0710 .09t +0 .10±0 .20t +0 .09!0 .17t N Days 0-29 0 .00±0 .21 +0 .1210 .08 +0 .16±0 .26t +0 .15sp .18 z Absolute Maternal Live r Weight (g) ® 103 .6=25 .3 104 .4=20 .1 104 .1±22 .0 103 .4±20 .5 9
a . Excludes rabbits that died, aborted . delivered, or were not pregnant . b . XZS .D a o o * Significantly different form control Value by Dunnett's test (P < 0 .05) . ° , ~' Significantly different from control value by Dunnett'a teat ( P<O . 0 1) . t Significantly different from control value by U test (P<0 .05',
. v, " r~:+,%:=• =- 'k~ . ~~" `, .w'~Af.f~~i-> . -------~--•• - 

# 'r~,
. :OTOCOL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE KABls1TS (SEGMENT 11 EVALUATION ) .BLE :(PACE 2) : REPRODUCTION AND FETAL DEVELOPMENT IN RABBITS CIVLN ACETONITRILE BY CAVACE PKUM UAYS 6-1e OF CESTA'1'IUN

### - - _-- . . .-•„ - v.aiuc U y Uu 11111; lL's tnbL ( k'<u .ul) . p .37 5igic. ._ic'anLly difterc'i_ control value b: . x -'' :.iey U test ( P<U .US '

ffl
. , • 0
. 1 

## ITOCOL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WIIITE RABBITS (SEGMENT IL EVALUATION) 1E 4(1'ACE 2) : REPRODUCTION AND FETAL DEVELOPMENT IN RABBITS CIVEN ACETONITRILE BY GAVACE FROM DAYS 6-18 OF CL•'S7'AT10N 0(Vehicle) mg/kg/day 2 .0 mg/kg/day 15 .0 mg/kg/day 30 .0 mg/kg/day No . pregnaat/No . inseminated 17/25 18/25 18/25 21/2 5 No . deaths 0 0 1 5 No . aborted 0 0 0 2 No . delivered naturally 1 2 0 1 No . with total resorption 0 0 0 0 io. litters a 16 16 17 13 'etai Deat h Pregnant Rabbi C,a 17 18 18 21 Mean No . Resorptiunsa 0 .6s0 .9b 1 .421 .5 0 .731 .0 1 .8±2 .3 Mean Xa 5 .9±7 .7 17 .1 1 18 .4 9 .5*_14 .0 24 .4s28 .9 No . Litters with 'I' q ta1 0 0 0 0 Resorption etuses Total No . Fetuses ( Live + Dead) 133 106 118 75 No . Live 133 106 118 7 4 

# Mean No . Live 8 .3±2 .7 6 .6±3 .1 6 .9 1 3 .5 5 .7s3 .1e y Mean Weight (g) 41 .92s7 .79 45 .04±6 .39 43 .82 :8 .33 46 .2934 .8 5 No . Dead Fetuses 0 0 1 0 1 C_

•v 3xcludes rabbits that died, aborced, delivered, or were not pregnant . 4--- m ttS .U . 

# yo° iignlticuntly different from control value by Mann-Whitney U test (P~0 .05) . „~ .



# ~ ~. ~•...,; ; • 1;~ /

# .~°''c~ ~y~ 

# ~~~. Yq~ ~a - ' - ~~ 6
. il~~~~'~^'`~•' :4*_ . 'S: - 'Y' _ l~" ;~"I,M~ti • ~/7 ~ I F vjt~" ~ . " :~•-5' .1 . .. . 'i .ct.~ ... . t : . ~~M1 . . . '•~' . ~ . . .._ .~,, . .'~f'-
. . _. . . , - 4
. . .

. ~~ 

# 3 7 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACE; ONITRIiE IN NEW ZEALAND WNIPE 1<ABBITS

(SEGMENT II EVALUATION ) (PACE 1)

- CONCENITAL MALFORMATIONS OBSERVED 1 : , ' N !

OBSL•'RVL•'D AT DUTC1l1aND LABORATORY ANIlt,I.S,~.NC~FACILITY)CIDENCE AS OF FEBRUARY 15, 198G ;

Rabbits Maintained at 64°F, Approximately 10o Less Than Outside Temperature , 

# Fluorescent Lighting and /uobient Numldity

.

## u . Two fetuses (7815-L2 ; 7837-R1) had each of these variations . p .3 8

v . Two fetuses (7841-RI ; 7843-R2) had each of these variations . 0 t Excludes one fetus (7842-R1) which was lost during processing . ? o 'J t Significantly different from control value by Fisher's exact test (P<0 .05) . C), O


## .A.

PROTOCOL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OP ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SEGMENT II EVALUATIUN ) 

# TABLE 8 (PACE 1 ) : ANTEMORTEM PUYSICAL SICNS OBSERVED IN INDIVIDUAL RABBIT S
Dusabe Croup : O(Vehicle) mg/kg/days 6-18 of Presumed Cestation Observation/Day of Presumed Gestation Cl a ° o o a o r Cr n a o > r > Yn to n,m'O rn W 0.1- w n r > a 7 f'1 O F+ > n^ ^ !7 r' n W n n r•1 0 a 1 ~ r 1^ ~O Cr r 0 M n O n n o ~Y ~~C n r ' n n X~B 0 ^O ^ O

- O 6ir 0 r o^ ow n ov Ow .-rm r0 . ra ;e 90 ^ ~.+e o r.arn ur ! u0 r C os ~o ^ < vn vo 6. un m% v

- < a 014 av ro On ^ B 0 a, v n ~nB v vr ~ P . n fn

- x ~ n ~ r r N ~'O r• a OO Cl p a tu - . Y n .-+ w r :L -- O



### n 1 P . - a ~? r W n G . N M t-' n Y Y-a

- 0 . 7 0 . n a a d ~ a a rn 0 r r r rr
. Rebbit a a 0
. 0 ~ ^ .0 ° c o Cl °° Number a o w a ^ 0 . R 0

. a n 

## 7789 - - - 28 - - - - - - - - - - - - - 7790 - - - 12,13 - - - - - - - 17 - - - - - 14,1 5 16,17 18 .19 7791 - - - - - - - - - - - - - - - - - 7792 - - - - - - - - - - - - - - - - -

a 

# 7793 - - - 14,15 - - - - - - - - - - - - - 16,28 7794 - - - 24,25 - - - - - - - 25,26 - - - 28 - 26 .27 27,28 28 29 -< 7795 - - - - - - - - - - - 5 .6, - - - - - 19,22 25 va7 z7796 

# - - - - - - - - - - - 28 - - - - - n i o r o v r 

## C~) C)( j• Code for observud plrysical sign
. .a ` CD

PROTOCOL 419-001 : EMBRYO-Fb'TAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE kA .MiITS (Sf:CMEN'f II EVALUATION ) TABLE 8 (PACE 2 ) : ANTEMORT}:!! PHYSICAL SICNS OBSERVED IN INDIVIDUAL RABBITS

# p . 39

'ROTOCOL 419-001 ; EMBRYO-FE"fAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SECltEN'P II EVALUATION ) 'ABLE 8(PAGE 2) : ANTk!lORTEM PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBIT S
Dosage Croup : 0(Vellicle) mg/kg/days 6-18 of Presumed Gestation

Observation/Day of Presumed Gestation 0 ~ w° o . . v+ { r > c a :c •e s n a ,wN"BO
. Oi1 y a~ p f`s r > • _ f) O _ r > ~~1 .y v r n I . n n Pf o~ ~t • r c` 

### • r+ o o

r r on O wr w• Ov o O n n w .-. r 0
. r •-. 1 <N n w M L-j • . r M O ti n x~ W B 0 1 w .~ 0 n o O M O ^• m r M rr Y r N 1+ r t O N v w '1 < • V w A . w w co x kA < S . O `C 0%M r O O n'1 9• as M a f/1 LA 8 r ~A r 0 . • x ..~ n .- r r• --a -+ a Oo 0 . N a N .- . 0 n .- . w r ;.[ -- o 0
. M Y n 0 . S
. {L

a Y ~~ 7 w S N t^ n 1- Y C 7 

## Rabbit 0

. .°r ~ o -l 0 - 

# Rabbit o 0 NumbL,= . 0 C 0 C• 0 

### r np w r0 . ~t 0

. ^ 0

. 7797 

# - - - - - - - - - - - - - - - - - 7798 - - - - - - - - - - - 6 .25 - - - - - 7799 - - - - - - - - - - - - - - - - - 7800 - - - - - - - - - - - - - - - - - 7801 - - - 17 - - - - - - - 14 .21 - - - - - 7802 - - - 26 .27 - - - - - - - 25 .26 - - - - - 2 7 7803 - - 28 26 .27 - - - - - - - - 16 .17 - - - 0 .11 . 28 18,19 12,13 20 .21 14,15 ` n 22 .23 16 .17 24 .25 18 .19 26 .27 20,21 28 22 .23 24,25 X 26 .27 > 28 > 1

1 O r O Or



# - .Code for observed physical sign
.

~.. . .

lROT0C0L 419-001 : EMBRYO-FL"fAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SEC:ML•'N'f II EVALUA'fIUN ) TABLE 8(l'ACE 3) : ANTEHOKTkH PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBIT S Dusabe Croup ; 0(Vellicle) mg/kg/days 6-18 of Presumed CeSLation Observation/Day of Presumed Gestation r n p r" LA cz C= : X O '7 f1 O H > n O ro ► Ow Y a r QQ O I,w,,, _ _ Y n q q O n M n n m 0 7 O O Y .7 O n n w .- . • •~ ~< w r M 7 x^ B • 1 L
. .- . O n O ~+ A vw ~„1 00 a 010 OY rrY /-0

. hrN A •1 w 0 n ~t 0 ur 0 r t O ~ a n •< v a v• Q . w w co X ~n < N O`C as a r r{ v .- x .-- n r n o - • n r o r M n Lti 7 r ~ a • 

### n > N t- n N r av ` np . ~ c ~ Rabbit p a ~ o~ o' < ~ a r c n o r r

# p. 40



# ' 11 _ ill,
. PROTOCOL 419-001 : EMBRYO -Fh"fAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS (SECML••N'f II EVALUATION) TABLE 8 (PACE 3) : ANTEHORTEN PHYSICAL SICNS OBSERVED IN INDIVIDUAL RABBITS Dosage Group : 0(Vehicle) mg/kg/days 6-18 of Presumed Gestation Observation/Day of Presumed Cestation O r r . v, o Y C G 1•e ~~ o n > v o e o ~ n ~ w a _ c1 0 _ Y If M n r r ^ O Oy" r O a .1 O p n n n '-'Si o r• o r-3 o 7 ao O n r _ ►~ n -1 4 

### O) r O ~+ O M O 00 ° CIO 0 0+ ~+ r a h+ LL P- Y i( 'P .t l.+ 1 0 N 1. ~+ (k1 v IB+ °I W 00 ~ O ^° 0 . ° n vM v~ [1 uA Ooμ tn t- ° O~ O~ a v h

_ ° O° n M B W aa (A v n H a~ ~nr -- oo a a a . .a n r.m :c -- o 

## y~- ya n Q
. ya s ~ u r n e ~-a a c a Rabbit a p a a~ a `t if ° a n 0 r ^ 0
. P- n Number o a w

► c . ° .cic a a Da ° '~ a n 7804 - - - 16,1 7 

# 19,20 - ' - 17 .18 22 .23 20,21 24 .25 24 .25 7805 - - - - . - - - - - - 5 .6 .7 - 15,1 6 . - - 8 .9 . 7 .18, 10 .11 19,20, 12,13 21 .22
. 14 .15 23,24, 16,17 25,26, 18 .19 27 .28, 20,21 2 9 22 .23 24,25 26,27 ~ 28,2 9 7806 - 

# - - - - - - - - - 7807 - - - 25 - - - - - - - 27,28 - - - - - v~ 7808 - - - - - - - - - - - - - - m Y 1 O 

### ro



# - .Code for observed plqyical sign .

r . : .



# ~, - . - 3TOCOL 419-001 : EMBRYO0 .FETAL TOXICITY AND TERATOCENICITY STUDY OF ACh'1'ONITRILE IN NEW ZEALAND WHITE RABBITS (SEGMENT II EVALUATION ) 9LE 8 (PACE 4 ) : ANTENOH'fEH PHYSICAL S1CNS OBSERVL•' n IN INDIVIDUAL RABBITS
Dosage Group : O(Vehicle) mg/kg/days 6-18 of Presumed Gestation Observation/Day of Presumed Gestation v p ° °

yy n o B O r' Q n 7 ~. C• P

. hr ^ 0 C, O i-• i n .7 ~ C r rr Y n a!1 'n O P an N r• r W r 0 `„ & n 0 n n° A
. .- .aC ~f g r ' n% .-, N ^ O n O ^ ro ~ v n O n O 00 N O v O p r r• a r G . r In x M 0 m r .~ r n u r 1 ~ .+ 0 r t 0 v~ ~ ^ ~ v et v fC a W n .< v< Y1 0`G P C r~ N o n'1 tn t~ N O"1 n v, ,

# p.41

-,,,~' ~7b" - i ~ s~y'4' !~!'g,S.^ .~Y~~~~ k*a ..^s~._ ~5~~ .' •
.:r :'
. . . 

# 'OCOL 419-001 : EMBRYO=FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS

(SECliFNT II EVALUATION) I E g(PACE 4) : ANTE!lONTEM PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBITS
Dosage Croup : O(Vehicle) a&/kg/days 6-18 of Presumed Gestation

Observation/Day of Presumed Gestation
r A G ~ a0 ~ • w o B 0 r O n a ~i n n O Y'O •n I . P
. r 00 n F+ 

### s ~ 0 > on M 0 r- r .r „ nev 093 .l •r r ~ O cr r o m n o , w w a .-. 1< e r tif n x~-+ B w - ; o n o w m r 0 r O ~t 00o w o'o o n rr s r P
. r w 90 .t • 0 ~~~+ ++. n u r I u 0 r It 0 'e ~w r1 < v• va 0 . u0 Go 7i tn< w 0 14 OV rw 0n n B w aa In % n8 m ur --a n • ~x - .n - .r r• -v . ..a w 0 . w N Y .ra n - w r :,C •-• o n n r a~T+ r a ~+ a a w 7' 1~ r n is hr w 0 . C 7 0 . • YOi M `< : ( w w e~ r r r r n 

## bit a 0 a p• p M ;^ °c oa c w o a ° 

## aber °' o w r n 0 . r 0

. w ~ a n 309 - - - 15,1 6 

# 310 - - - - - - - - - - - 5 .11 . - - - - - 20,21 23 11 - - - 15,16 - - - - - - - 16 - - - - - 12 - - - 24 - - - - - - - - - - - - - 13 - - - - - - - - - - - - - - - - -

N H
'C

~

• 

## m 

# a a' nr t+7 r 1 O r 0 

### oor


# ~ Code for observed physical sign .
+~~~+f~i: s ^~is;•%']I~',_. -' ; ::~"yY

.: ._ :. .~, - - - - - - - -- - -----~----~' .,--•___ •. .

_

_ s,r .,_..,., r<.:.. 3r-
.. , > - _ - '"~ ` =r -• '-`°dL` . , . -. _ 

# ~ ~. . ~, _ :~:.~ •r

TOCOL 419-001 : EMBRYO-FL"fAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS

(Sl:(Y4F:N'C II EVALUATION ) LE 8 (PACE 5 ) : ANTE!lOK7'EH PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBIT S
Dosage Group : 2 .0 mg/kg/days 6-18 of Presumed Gestation Observation/Day of Presumed Gestation p rl ~ r ►r tn Y c c :L •<

Y >n o .+.~v .~ ~ 

### w oi ar w n r Y • n 0 r Y n n .r ty n y rv n~1 0 7 n o r r '-+ o o'

►- o d n o - n rt w ~. a ._ ~C n r ~f • n x B w ^ o rt 0 0 r on 0000 ov oa rra ra rM ponu•on, ~+ n urJ w0 rt o~ v• •1 < v n v• 0 . u• O~ x lA < u G `< P C r w O n n 6 1n O . 7 tn tn 7 y t.n -r 0 . rt •

- x ... n ... . r r• .-. C . .-. 7 W C
. n Y Y r- pn .~ R o

w ~ ~" "'d ~ r M n P . a • ? Y C" n Y r W CL C 7 

### bbit• a p w ] M '< w r rt 0 r r r r n Q ~ Y r n .0 0 wl 7 C) 7 O vber ~ 0 w r~+, a n u. °m o.

# p. 42

.Y} _ ,~~

. ..,~::~ . . . "~► '~ ~ . +nt•a+ j 

# OF pil ... PROTOCOL 419-001 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OP ACETONITRILE IN NEW ZY.ALAND WHITE RABBITS (SEGMENT 11 EVALUATION ) 

# TABLE 8 (PACE 5 ) : ANTklVJR1•EN PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBIT S
Dosage Group : 2 .0 mg/kg/days 6-18 of Presumed Gestation

Observation/Day of Presumed Gestation

r i o i o a o r on c w n v y ► + Y s n to n . Y•O A a A. ~+ oo n ►~ Y • 7 n 0 r y n n " 0 n a n n M 0 A h a r r ~ o Q r ~ o Y " -+ o ~ n n W ~ a - `< W I M n X - B• -+ O A O ^- w P . 0 P
. On Ooo a 0V oY r1+•Y r0. o- (a San w o n u ► - t w 0 r t O Y v W ~1 < V• v• O . w • m% %A < Y G lC 0110 M W O n n 9• O7 tn N 8 as ~n r K ~ n r- r r+ • - V .-. ? Oo 0 . W 0~ Y ~ a n r+ W 1- :t -+ O W t M ^0 M Y R S R • S Y l'~ !~ Y F' Y O . C a 

### P . W Y Y as ~C W Y n 0 r r r r n Rabbit a 0 

## br Y a` °c 0 c n o r°- Nuabnr ,a. o aA a ►~ o. a a 7814 - - - - - - - - - - - - - - - - - 7815 

# 7816 - - - - - - - - - - - - - - - - - 7817 - - - 14,16 - - - - - - - 17 - - - - - 19 7818 - - - 17 - - - - - - - - - - - - - 7819 - - - 25 - - - - - - - 25 .26 - - - - - 7820 - - - 21 - - r - - - - - - - - - - In 

# 7821 - - 28 25 .26 27
- . - - - - - 24 .25 - - - - - 27 26 7822 - - - - - - - - - - - - - - - - - 7823 - - - - - - - - - - - - - - - - - ^~ a~ C1 r M 

### Y t • 1 O r O 

# %O



# - .Code for observed physical sign.

-•~ n ~ Y~7s :

~,, •i1~ .~a~'• .si~li~t: , .~~=

IT !•` r OCOL 419-001 1 EMSRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACETONITRILE IN NEW ZEALAND WHITE RABBITS

( SEClIkN•f II EVALUATION) y ~ C 8(PACE 6) : ANTP!lORTkM PHYSICAL SIGNS OBSERVED IN INDIVIDUAL RABBITS
Dusage Croup : 2 .0 mg/kg/days 6-18 of Presumed Gestation Observation/Day of Presumed Gestatio n 

# ; o 

# I l w° o e o r c 

# = ~ d~ v y r 

# P
. f. n pl Y'C ~ a 0 . r 0~ ~ n Y w _ O n 0 _ r Y ?f n .y v n a n n M 0 a n F, r v r 0 a ti ' O n n w .- . a ~ K r ^f n x^+ B W ~ 0 n o ~ n Co r ~T, r O1 O Oo W O .O O y r 1~ a ►• O. P. -w }Y M u W ; o N ~~++ fl u 1+ 1 v O r t O a ~I W '1 < v w V a O. ld w OD k ln < Y O`C O~'C r w• n 1y p a P a Vf ~ B W V

. w r. RJ . .- O pp Cl W Y In -+ a n w • t - r, w ~ r 7 r a n G . o w ~ Y r n Y ~- W a ~ c- 

### )it a a a~ a `< ^ r na a ~• n o n