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p. 32

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

s n

_ ,_Y t •s ^ K~ _ -~s' ~ c ;~ :

w

t

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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

W

:) abJuwun . caudul to kidnuya ; firm tun-bruvn mass (- 2 wa x I cm) on right lip of vulva .

~ ,.- ..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.

p Y Uosayu Grou

of Presumed Certa- (my/kg/days 6-18 Corpora Lutua Iar,lantationb t:nlUryos ur tr'ccu~l:aJ I~y It,tl /, L

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

(SEGMENT II EVALUATION) W)IITE RAHBITS

A9LE 2(PAGt 1) - UTERINE CONTENTS AND LITTER DATA IN INDIVIDUAL RABIfIT.°, WHICH DIED, ABORTED OR DELIVE KE D

NA'CUNALL Y

Dosage Group

(my/kg/days 6-1 8

of Presumed Gesta- Corpora Lutea Implantations Embryos or !'etuses

tion a & kalablt No, kesorNtionsb I ) Termination k . L . T. R. L . T . R. L . A ./Del . T. R. L . A ./Del . T .

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

OF 0

CESTATION 0 1 d ld 0 0 10(Lit) 10(Lk

7824 DELIVERED DAY 29 7 5 12 6 5 1

OF Cl 1

:STATION 0 2 2e 0 1 8(LR)e 9e

15.0

7849 FOUND DEAD DAY 23 5 8 13 3 6

OF 9 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~~ th e 't' - TuL:iI d

. The pup appeared normal and appeared as though it had been alive at the time o

f

Du I . - Dallve rud delivery .

~R - Late Resorption e . One pup appeared normal and one was partially cannibalized ; both appeared as though 9

c>

the y

had been alive at the time of maternal death

C

w f

:) was also partially cannibalized . . One of the eight delivered late resorptions

. 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 (SEGMENT 11 EVALUATION ) WIIITE RABBITS

TADLt 2 (PAGE 2) -

NA'1'U I W L1

U'1'kklNt

. Y

CONTENTS AND LI'1'I'Itlt DATA IN INDIVIDUAL RADpITS WHICH DIED, ABORTED OR DELIVEkED

33 Wsdyu Grou p (lay/kg/days 6-1 8

of Presumed Gesta_ Coi{x,ra Lutud Iay) lentdtions

tiou G k. & l,bit No Embryos Or Yecuscsd 1~surl.LL

.) Y'utwination K . L . T. R. L. T. U . L . A ./Del . T . H. L. A ./Ucl .r.

30 .0

)866 DELIVERED DAY

0F CES'I'A'1'IUN ~ I ti~,

28 5 5 10 3 5 8 0 0 1` I`
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 CESTATIO N

7867 FOUND DEAD DAY 18 6 7 13 5 5 10 5d 4d 0 9d 0 1 U 1

OF CESTATIO N

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 GESTATIO N

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

DAY 27 OF GESTATIO N

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

. Early unleas nuted utheruiae. L- Left • b .

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

d . Embryos appeared normal for

. One conceptus was

developmental

presumed cannibalized

age and as though they had been

. ~

alive at the

O

O e.

time

One early resorption and one placenta

of maternal death . y°o

were found in the cage pan . One early resorptio n

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

NATURALL Y

Dosage Group

tog/kg/days6-18 a U

of Presumed

Gesta- Curl,or'a Lutua lsr) lantationa t:a di ryos 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, "Iid u l IC Il1JLlal L d W,:« .,,, . ., . I; ,~ .. ., p

:35 W

a

.

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 LL Y

Dosage Grou p

g/kg/days 6-18 a b

Presumed Gesta- Corpora Lu[ua Iml,lantations ta b ryos 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

t Significantly different from control value by Mann-Whitney U test (P_0

test (P<U .01) . r" °

.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 21/25

No . deaths 0 0 1 5

No . aborted 0 0 0 2

No . delivered naturally 1 2 0 1

No

No

.

. litteraa

with total resorption 0 0 0 0

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

Days 6-19 +0 a .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

Weight (g) ®

Maternal Live r

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 Uu11111; 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

I TOCOL 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 21/25

No . deaths 0 0 1 5

No

No

. aborte

. delivered

d

naturally 1 2 0 1

0 0 0 2

No . with total resorption 0 0 0 0

i o . 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

Resorptio n

'I' q ta1 0 0 0 0

etus es

Total No. Fetuses ( Live + Dead) 133 106 118 75

No . Live 133 106 118 74

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

10 1

C_

•v

3xcludes rabbits

ttS .U .

that died, aborced, delivered, or were not pregnant . 4--- m

ii g nlticuntly different from control value by Mann-Whitney yo° 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 . .

.

. ~~

419-001 3 7 : EMBRYO-FETAL TOXICITY AND TERATOCENICITY STUDY OF ACE

(SEGMENT II EVALUATION )

;ONITRIiE IN NEW ZEALAND WNIPE 1<ABBITS

(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

.38

v . Two fetuses (7841-RI ; 7843-R2) had each of these variations .

0

'J t Significantly different

t Excludes one fetus (7842-R1) which was

from control value by

lost during processing

Fisher's exact test

. ? o

(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

> r > Yn to

Cl a

° o o a o r n,m'O rn W Cr 0.1-n a o

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

Rebbit a a

n 1

0. n a a d ~

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

a a rn 0 r r r rr

- 0. 7

.

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

28 29

.27 27,28

-<

7795 - - - - - - - - - - - 5.6, - - - - -

25 va

19,22

7 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

> • _ f) O _ r > ~~1 s n a ,wN"BO .Oi1 y a~ p f`s r

.y v r n I. n n Pf o~ ~t • r c`

•

r+ o or

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 nx~

W

B

1 w 0 m r M rr Y r N 1+ r t O N O M O .~ 0 n o ^•

v w '1 < • V w A. w w co x kA < S. O`C 0%M r O O n'1 9• as

M

0. • x ..~ n

a f/1 LA 8 r ~A r

.- r r• --a -+ a Oo 0. N a N .-. 0 n .-. w r ;.[ -- o

Rabbit 0

0. a Y ~~ 7 M Y n 0. Sw S N t^ n 1- Y C . {L 7

Rabbit o . .°r ~ o -l 0 -

NumbL,=. 0

np w r0

C 0 C• 0 0r

. ~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 O I,w,,, _ _ Y n q q O n M n n m 0 7 O '7 f1 O H > n O ro ►Ow Y a r QQ

O Y .7 O n n w .-. • •~ ~< w r 7 x^ B M •

1 L.

vw ~„1 00 a 010 OY rrY /-0. hrN A •1 .-. O n O ~+ A

~t 0 ur 0 r t w 0 n ~ a n •< v a v• Q. w w co X ~n < N O`C as

r r{ v

a O

.-

x .-- n r n o

- • n r o r M n Lti 7 r

~ a •

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

~~ O r r. v, o Y C G 1•e

> v o e o ~ n ~ w a on

^ O Oy" r O a _ c1 0 _ Y If M n r r .1 O p n n n

'-'Si

o r• o r-3 o 7 ao

O) r O ~+ O M O 00 ° n -14

n r _ O ►~

0

CIO 0 0+ ~+ r a h+ LL P- Y i( 'P .t l .+ 1 0 N 1~+ (k1 v IB+ °I W 00 ~ O ^° .

. ° n vM v~ [1 uA Ooμ t n

t-

° O~ O~ a v h_

-- oo a a a

° O° n M B W aa

.

(A vn H a~ ~nr

Rabbit a p a a~ a `t

y~- ya n Q. ya s ~ u r n e ~-a a c a

.a n r.m :c -- o

if ° a n 0

r ^ Number o a w

0. P- n

►c. ° .cic aa

° '~ a n Da

7804 - - - 16,17

19,20 - ' - 17.18

22 .23

20,21

24 .25

24 .2 5

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 29

22 .23

24,25

26,27 ~

28,2 9

7806 -

- - - - - - - - -

7807 - - - 25 - - - - - - - 27,28 - - - - - v~

7808 -

- - - - - - - - - - - - - m

Y

1 O

ro

-.Code for observed pl qyical 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

W r O P an N r• r

0

`„

&

~ v n O n O 00 N O v O

n 0 n n° A. .-.aC ~f r ' n% .-, N ^ O n O ^ ro g

~ ^ ~ v et v fC a W n m r

p r r• a r G. r In x M 0 .~ r n u r 1 ~.+ 0 r t 0 v~ .< 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

G ~ a0 ~

r A

• w o B

n O Y'O •n

0 r O n a ~i n

s ~ I. P. r 00 n F+

~ O cr r o m n o ,

0 >

w w a

on M 0 r- r .r „ nev 093 .l •r r

m r 0 r O~t 00o w o'o o n rr s r P.

.-

r w 90

. 1< e r tif n x~-+ B w -

.t • 0 ~~~+++. n u r

I

u

; o n o w

0 r It 0

'

~w r1 < v• va 0 e

--a n • ~x -

. u0

.n -

Go 7i tn< w 0 14 OV rw 0n n B w aa In % n8 m ur

.r r• -v . ..a w 0. w N Y .ra n

-

n n r a~T+ w r :,C •-• o

bit a

0. • YOi M `<

r a ~+ a a w 7' 1~ r n

:( w w e~ r r r r 0

is hr w 0. C 7

n

a

p• p M

;^ °c oa c w o a °

aber °' o w r n 0

w ~ a n

. r 0.

309 - - - 15,16

310 - - - - - - - - - - - 5.11 . - - - - -

20,21

2 3

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 0 Y >n o .+.~v .~w oi ar w n r ~

►- o d n or Y n n

-n rt w ~ .r ty n y rv n~1 0 7 n o r r '-+ o o' . a ._ ~C n r ~f • n x

0 r on 0000 ov oa rra B w ^ o rt 0

v• •1 < v n v• 0. u• O~ x lA < u Gra rM ponu•on,

`< P C

~+ n urJ w0 rt o~

-r 0. rt • r w O n n 6 1n O. 7 tn tn 7 y t.n

-

x ..

w ~ ~" "'d ~ r

. n .... r r•

M n P

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

. a • ? Y C" n Y r W CL C 7

bbit•

vber ~

a p w ] MQ ~ Y r n

'< w r rt0 r r r r n

.0 0 wl 7 C) 7 O

0 w r~+, a n u. °m o.
p. 42

.Y} _ ,~~ . . .,~: :~ . . . "~►'~ ~. +nt•a+ j

OFpil

...

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 Pres umed Gestation

ri o i o a o r on

c

Y • 7 n

v y ►+ Y s n to n. Y•O A a A. ~+ oo nw n► ~

0 r y n n " 0 n a n n M 0A 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 l C 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 -+

M Y R S R • S Y l'~ !~ Y F' Y O. C O W t M ^0 a

Rabbit

P. W Y Y

a 0

as ~C W Y n 0 r r r r n

Nuabnr ,a

br Y a` °c 0 c n o r°-

. o aA a ►~ o. a a

7814 - - - - - - - - - - - - - - - - -

781 5

7816 - - - - - - - - - - - - - - - - -

7817 - - - 14,16 - - - - - - - 17 - - - - -

1 9

7818 - - - 17 - - - - - - - - - - - - -

7819 - - - 25 - - - - - - - 25.26 - - - - -

7820 - - - 21 - - r - - - - - - - - - -

In

7821 - - 28 25

27 26

.26 27 - .- - - - - 24.25 - - - - -

7822 - - - - - - - - - - - - - - - - -

7823 - - - - - - - - - - - - - - - - - ^~ a~

C1 r

M

• 1 O

Y t

r O %O

- .Code for observed physical sign .

-•~

n

~ Y~7s :~,, •i1~ .~a~'• .si~li~t: ,.~~=

IT !•` r

OCOL 4 19-001 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 w° o e o r c

l =

v y r

~ d~

Y w _ O n

0 P. f. n pl Y'C ~ a 0. r 0~ ~ n

v r

_ r Y ?f n .y v n a n n M 0 a n F, r

0 a ti 'O n n w .-. a ~ K r ^f n x^+ B W ~

0

Co r ~T, r O1 O Oo W O

n o ~ n

.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

w r

a P a Vf ~ B W V.

w ~ r 7 r a n G

. RJ .

.- O pp Cl W Y In -+ a n w • t - r,

. o w ~ Y r n Y ~- W a ~ c-

)it a a a~ a `< ^r na a ~• n o n