12
.. !\ t e P r ocl\1 ::-t><l tJ!> l TO. 4- 1 6 l ?. 8l d Do c IIJ J-'J ,7.:J8TCN WA SH 1 NG' l' C N I NC rJ ,? _ "' 4 / v.J ..:. fl C" ...,) :'$(;.<, Sc-= -:l _,. n .. Attachment Ill F:l.:!W ( ft C:J P ISS: ), l O .; -·,·: ;:s K :;:ETA.RY S TUDY rA: TH 1 , 2 , 1 - T R : 1 .•i !':'E l JE ':"l'C:;{ DA '!'ED Che mic;, 1 Ca

relevant sections of a final report submitted to the U.S ... · FiMir.gs . Repnrtej ~0 ~.\U49'!YCOt/ Stud;r . Clr~ctoY . o/22/S. 8/22!91 . 10/31 /91 . Z/21/92 . 5!11/92 7/23/92 ll/9/92

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~ t e Pr ocl1 -tgtltl

tJgt l TO 4-1 6 l

8ld Do c IIJ

J-J7J8TCN WASH 1 NGlC N I NC

rJ _ 4 vJ fl C )

$(lt

Sc-= -l _ n

Attachment Ill

FlW ~~)T ( ft CJ P ISS ) l O -middotmiddotsK ETARY CFRC t~OGLNC fl S TUDY

rA TH 1 2 1 - T R ~ -i4LPi~D~pound1-ZE-NE ~ ~JS 1bulli E COV~R l JE lC DA ED

Che mic 1 Ca

Juu11 15 1994

VI A liESSStG_ER

Tii SCA Section 4 H~k Gorol TSCA Pu~llc lnfor a Ktion Of f lcn

(ao

Ofico ot ronution nv~ntiou awJ Taxtcs US Rn 1bull-~n~ ~~bulltol P~uluc~lo~ Agency Roobull N F Hu ll i 102

7 )( f 1 bullf T~J tr middot

trJ M Stt oot Sil ilbullshington DC 2~1~0

1pound middot Chori~tultl Bbullaunes ~middot J M Tost 11ule Oncoaencty ToSliux u 12bull-lrlchlc oborcuu ( ~~ CFl 7Y910S3) Fina l Report

Joo r Sir~~du

Thft C lnl bull al ttouuacl u rar~ A ooltion suba i t sLx O~gt ils o f the f iutd r nporl f~ l it J(d

104-lleei jecbullry Cuci nogouid Ly S~udy 111Lh 1 2 4-Triclolorobtuzeno irRlts

The study ropo-t i s uba ttod on beholf of t he tost s pouo- Stx~rd Cl ocine Cheaka Corany lac

14j ~ues L tons -egamprd ~ ne tl t S SUbbull s Ott s-hobullJ ld bo d 1 reeteJ to tH Chloro=gtPn7r-ncs P~ncd 1-~JilAe= 0- Cllrol R Stack o~~ t (20~) lHU- 11 S6

t--~ Lang ampy A Spurlock PhD CApound Yica Praidanc CIIEHSTA~

cc Hit~anl Stahl DirfJto r Offire of Coapiance Honi toring Roeltgtlt N~lson OTCCJCTlB Chlo~Ohftngtogt~lt Panol 12o-TCB Task CrltgtbullJp

bull Standard Cnlorine of Oelagt-are In ~

GoverOO J Lee Road Celaware Ci ty Oelawabullmiddote 19706

FINAL P ~ P()Pl

Stydy Title

10~ rcck 01llary CarcHIliJ~nlclty S1ue1y wh 1 2 4-Irithlorobenzere 1n Rats

llut b r

Hmiddotch~el R Moor~ PhD DliBT

Studt CoTulttino Oae

J middotcrc 10 IS94

Per forolM l aportory

kaz l e~on Jashington Inc (HIA)13ZO-B Picc~rd Dr1 ve

Rockvi lle Maryland 20SS~

HIA 26C3-103

V( )ume I of 4

bull Page l of s ~ s

HIA 26C3-l ~3 ~ HAZLEtON ~ W~ SHIN3 i ON

CC~PlllCE ST A TEHHT IOmiddot - ~ee~ Dletary Carcinogenic Hy S~udy

wl h JZ 4-Trlchl orohenene In Rat~

lhls Sl~dt as conlUbullted In ccrpll ance oltlt- the GccJ _abordtnry Prar t1cc Rcgul dl 1ans ~s set bullorlh In T1tle CO of the LS Co~~ uf Fedcbullal RPg ul at middotons Pot 792 lssu~d November 29 1903 (etfectlve D~cc11tgter 29 l9Bl) a-ll bull i 1h any aicablc arendTents All delallcn~ fro11 tn probullotgt andor i~s are lls cd 1n AppPndlx Ther~ wHlt no dcbullJi ata on fron the af~r~nbullutloncl reuuhtlons hlch affPctec th~ quallt) or integrity vf lhc study or t he 1nter pnHat lon o f t he middotcsul ts 1n the rcpobull

Stmiddot~y Olcctor

t-c 1jDate

bull - 2 -

bull

bull

HWA 2603-03

qudy 1ih C4 middot1~ Oietut ~ar1nog~ro1~1ly Stuly wih 14shyl rlchloronc~~ee In Ra s

Prnj cc l tbullc 2G03ltC3

Qu~lly rul 3ncc lnsp~c t lon s ano r1bulllew ~ of thfs s~udy er~ ccnductcl bullbullmiddotttgtrdhtg 111 the Handard opermiddotH ing procedures o f ~hu Ou ~ l Ly 1ssurdllCC Vbull t abullbulld lC Corrllrt~ t~ te (~cd dgtgtramplormiddoty Prmiddotacte rbull~u1H1Cns o l the frvlrcnrrocrtnl Pbullmiddotobullct crt A~~ncy (gt - TSClJ bulllto ~Co the LS Cede f lcdcra RP9uiJior~ Put 92 s~uEd Nobull1omter 29 l9eJ (~ff~lt 1 vc llcccnll~r 29 983) ~nd ltitr ~ny appl iLlJe ancndrnen t s Tn~ se l n srbull~c~ ions and revl~ hCrc pcbullfrrmcc ro= middotmiddot i lrs ~oo~re rmiddot~ rled o the Stdy Olr~rtoc dfHI n- bullbulln~qcm~t H follo~

o-t~s of l nspectluRcvtc

Protocol n~-~~wshy)3~)l

l nsp~tllCII ~OdOf 0ta h~v le1

41226 33~4 131Ct91 7fll 23 29-)J 62591 lD7U9 11 41 5lt 191 ltlo n 2071 zn 4l92 4Z3Z~l7 -2992 715-17 2392 lCIl51G l920l2392 lS93 4f5 12shy 14 93

Repobullmiddott anrl ja t l etl e 027-29 111 -35 ) 12 1515 Sl o 1on4

Date FiMirgs Repnrtej ~0 ~U49YCOt

Studr Clr~ctoY

o22S 82291 1031 91 Z2192 51192 72392 ll992 2393 51793

l169l 610 94

e lunch 8 Hunch gt t11nch 8 Hurc 8 iuncn S Ba11 ~nger Ti llotson 0 1-Lcll 1 J r~nrtsun

K 8~t1eshyl CaHel l

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

Juu11 15 1994

VI A liESSStG_ER

Tii SCA Section 4 H~k Gorol TSCA Pu~llc lnfor a Ktion Of f lcn

(ao

Ofico ot ronution nv~ntiou awJ Taxtcs US Rn 1bull-~n~ ~~bulltol P~uluc~lo~ Agency Roobull N F Hu ll i 102

7 )( f 1 bullf T~J tr middot

trJ M Stt oot Sil ilbullshington DC 2~1~0

1pound middot Chori~tultl Bbullaunes ~middot J M Tost 11ule Oncoaencty ToSliux u 12bull-lrlchlc oborcuu ( ~~ CFl 7Y910S3) Fina l Report

Joo r Sir~~du

Thft C lnl bull al ttouuacl u rar~ A ooltion suba i t sLx O~gt ils o f the f iutd r nporl f~ l it J(d

104-lleei jecbullry Cuci nogouid Ly S~udy 111Lh 1 2 4-Triclolorobtuzeno irRlts

The study ropo-t i s uba ttod on beholf of t he tost s pouo- Stx~rd Cl ocine Cheaka Corany lac

14j ~ues L tons -egamprd ~ ne tl t S SUbbull s Ott s-hobullJ ld bo d 1 reeteJ to tH Chloro=gtPn7r-ncs P~ncd 1-~JilAe= 0- Cllrol R Stack o~~ t (20~) lHU- 11 S6

t--~ Lang ampy A Spurlock PhD CApound Yica Praidanc CIIEHSTA~

cc Hit~anl Stahl DirfJto r Offire of Coapiance Honi toring Roeltgtlt N~lson OTCCJCTlB Chlo~Ohftngtogt~lt Panol 12o-TCB Task CrltgtbullJp

bull Standard Cnlorine of Oelagt-are In ~

GoverOO J Lee Road Celaware Ci ty Oelawabullmiddote 19706

FINAL P ~ P()Pl

Stydy Title

10~ rcck 01llary CarcHIliJ~nlclty S1ue1y wh 1 2 4-Irithlorobenzere 1n Rats

llut b r

Hmiddotch~el R Moor~ PhD DliBT

Studt CoTulttino Oae

J middotcrc 10 IS94

Per forolM l aportory

kaz l e~on Jashington Inc (HIA)13ZO-B Picc~rd Dr1 ve

Rockvi lle Maryland 20SS~

HIA 26C3-103

V( )ume I of 4

bull Page l of s ~ s

HIA 26C3-l ~3 ~ HAZLEtON ~ W~ SHIN3 i ON

CC~PlllCE ST A TEHHT IOmiddot - ~ee~ Dletary Carcinogenic Hy S~udy

wl h JZ 4-Trlchl orohenene In Rat~

lhls Sl~dt as conlUbullted In ccrpll ance oltlt- the GccJ _abordtnry Prar t1cc Rcgul dl 1ans ~s set bullorlh In T1tle CO of the LS Co~~ uf Fedcbullal RPg ul at middotons Pot 792 lssu~d November 29 1903 (etfectlve D~cc11tgter 29 l9Bl) a-ll bull i 1h any aicablc arendTents All delallcn~ fro11 tn probullotgt andor i~s are lls cd 1n AppPndlx Ther~ wHlt no dcbullJi ata on fron the af~r~nbullutloncl reuuhtlons hlch affPctec th~ quallt) or integrity vf lhc study or t he 1nter pnHat lon o f t he middotcsul ts 1n the rcpobull

Stmiddot~y Olcctor

t-c 1jDate

bull - 2 -

bull

bull

HWA 2603-03

qudy 1ih C4 middot1~ Oietut ~ar1nog~ro1~1ly Stuly wih 14shyl rlchloronc~~ee In Ra s

Prnj cc l tbullc 2G03ltC3

Qu~lly rul 3ncc lnsp~c t lon s ano r1bulllew ~ of thfs s~udy er~ ccnductcl bullbullmiddotttgtrdhtg 111 the Handard opermiddotH ing procedures o f ~hu Ou ~ l Ly 1ssurdllCC Vbull t abullbulld lC Corrllrt~ t~ te (~cd dgtgtramplormiddoty Prmiddotacte rbull~u1H1Cns o l the frvlrcnrrocrtnl Pbullmiddotobullct crt A~~ncy (gt - TSClJ bulllto ~Co the LS Cede f lcdcra RP9uiJior~ Put 92 s~uEd Nobull1omter 29 l9eJ (~ff~lt 1 vc llcccnll~r 29 983) ~nd ltitr ~ny appl iLlJe ancndrnen t s Tn~ se l n srbull~c~ ions and revl~ hCrc pcbullfrrmcc ro= middotmiddot i lrs ~oo~re rmiddot~ rled o the Stdy Olr~rtoc dfHI n- bullbulln~qcm~t H follo~

o-t~s of l nspectluRcvtc

Protocol n~-~~wshy)3~)l

l nsp~tllCII ~OdOf 0ta h~v le1

41226 33~4 131Ct91 7fll 23 29-)J 62591 lD7U9 11 41 5lt 191 ltlo n 2071 zn 4l92 4Z3Z~l7 -2992 715-17 2392 lCIl51G l920l2392 lS93 4f5 12shy 14 93

Repobullmiddott anrl ja t l etl e 027-29 111 -35 ) 12 1515 Sl o 1on4

Date FiMirgs Repnrtej ~0 ~U49YCOt

Studr Clr~ctoY

o22S 82291 1031 91 Z2192 51192 72392 ll992 2393 51793

l169l 610 94

e lunch 8 Hunch gt t11nch 8 Hurc 8 iuncn S Ba11 ~nger Ti llotson 0 1-Lcll 1 J r~nrtsun

K 8~t1eshyl CaHel l

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull Standard Cnlorine of Oelagt-are In ~

GoverOO J Lee Road Celaware Ci ty Oelawabullmiddote 19706

FINAL P ~ P()Pl

Stydy Title

10~ rcck 01llary CarcHIliJ~nlclty S1ue1y wh 1 2 4-Irithlorobenzere 1n Rats

llut b r

Hmiddotch~el R Moor~ PhD DliBT

Studt CoTulttino Oae

J middotcrc 10 IS94

Per forolM l aportory

kaz l e~on Jashington Inc (HIA)13ZO-B Picc~rd Dr1 ve

Rockvi lle Maryland 20SS~

HIA 26C3-103

V( )ume I of 4

bull Page l of s ~ s

HIA 26C3-l ~3 ~ HAZLEtON ~ W~ SHIN3 i ON

CC~PlllCE ST A TEHHT IOmiddot - ~ee~ Dletary Carcinogenic Hy S~udy

wl h JZ 4-Trlchl orohenene In Rat~

lhls Sl~dt as conlUbullted In ccrpll ance oltlt- the GccJ _abordtnry Prar t1cc Rcgul dl 1ans ~s set bullorlh In T1tle CO of the LS Co~~ uf Fedcbullal RPg ul at middotons Pot 792 lssu~d November 29 1903 (etfectlve D~cc11tgter 29 l9Bl) a-ll bull i 1h any aicablc arendTents All delallcn~ fro11 tn probullotgt andor i~s are lls cd 1n AppPndlx Ther~ wHlt no dcbullJi ata on fron the af~r~nbullutloncl reuuhtlons hlch affPctec th~ quallt) or integrity vf lhc study or t he 1nter pnHat lon o f t he middotcsul ts 1n the rcpobull

Stmiddot~y Olcctor

t-c 1jDate

bull - 2 -

bull

bull

HWA 2603-03

qudy 1ih C4 middot1~ Oietut ~ar1nog~ro1~1ly Stuly wih 14shyl rlchloronc~~ee In Ra s

Prnj cc l tbullc 2G03ltC3

Qu~lly rul 3ncc lnsp~c t lon s ano r1bulllew ~ of thfs s~udy er~ ccnductcl bullbullmiddotttgtrdhtg 111 the Handard opermiddotH ing procedures o f ~hu Ou ~ l Ly 1ssurdllCC Vbull t abullbulld lC Corrllrt~ t~ te (~cd dgtgtramplormiddoty Prmiddotacte rbull~u1H1Cns o l the frvlrcnrrocrtnl Pbullmiddotobullct crt A~~ncy (gt - TSClJ bulllto ~Co the LS Cede f lcdcra RP9uiJior~ Put 92 s~uEd Nobull1omter 29 l9eJ (~ff~lt 1 vc llcccnll~r 29 983) ~nd ltitr ~ny appl iLlJe ancndrnen t s Tn~ se l n srbull~c~ ions and revl~ hCrc pcbullfrrmcc ro= middotmiddot i lrs ~oo~re rmiddot~ rled o the Stdy Olr~rtoc dfHI n- bullbulln~qcm~t H follo~

o-t~s of l nspectluRcvtc

Protocol n~-~~wshy)3~)l

l nsp~tllCII ~OdOf 0ta h~v le1

41226 33~4 131Ct91 7fll 23 29-)J 62591 lD7U9 11 41 5lt 191 ltlo n 2071 zn 4l92 4Z3Z~l7 -2992 715-17 2392 lCIl51G l920l2392 lS93 4f5 12shy 14 93

Repobullmiddott anrl ja t l etl e 027-29 111 -35 ) 12 1515 Sl o 1on4

Date FiMirgs Repnrtej ~0 ~U49YCOt

Studr Clr~ctoY

o22S 82291 1031 91 Z2192 51192 72392 ll992 2393 51793

l169l 610 94

e lunch 8 Hunch gt t11nch 8 Hurc 8 iuncn S Ba11 ~nger Ti llotson 0 1-Lcll 1 J r~nrtsun

K 8~t1eshyl CaHel l

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

HIA 26C3-l ~3 ~ HAZLEtON ~ W~ SHIN3 i ON

CC~PlllCE ST A TEHHT IOmiddot - ~ee~ Dletary Carcinogenic Hy S~udy

wl h JZ 4-Trlchl orohenene In Rat~

lhls Sl~dt as conlUbullted In ccrpll ance oltlt- the GccJ _abordtnry Prar t1cc Rcgul dl 1ans ~s set bullorlh In T1tle CO of the LS Co~~ uf Fedcbullal RPg ul at middotons Pot 792 lssu~d November 29 1903 (etfectlve D~cc11tgter 29 l9Bl) a-ll bull i 1h any aicablc arendTents All delallcn~ fro11 tn probullotgt andor i~s are lls cd 1n AppPndlx Ther~ wHlt no dcbullJi ata on fron the af~r~nbullutloncl reuuhtlons hlch affPctec th~ quallt) or integrity vf lhc study or t he 1nter pnHat lon o f t he middotcsul ts 1n the rcpobull

Stmiddot~y Olcctor

t-c 1jDate

bull - 2 -

bull

bull

HWA 2603-03

qudy 1ih C4 middot1~ Oietut ~ar1nog~ro1~1ly Stuly wih 14shyl rlchloronc~~ee In Ra s

Prnj cc l tbullc 2G03ltC3

Qu~lly rul 3ncc lnsp~c t lon s ano r1bulllew ~ of thfs s~udy er~ ccnductcl bullbullmiddotttgtrdhtg 111 the Handard opermiddotH ing procedures o f ~hu Ou ~ l Ly 1ssurdllCC Vbull t abullbulld lC Corrllrt~ t~ te (~cd dgtgtramplormiddoty Prmiddotacte rbull~u1H1Cns o l the frvlrcnrrocrtnl Pbullmiddotobullct crt A~~ncy (gt - TSClJ bulllto ~Co the LS Cede f lcdcra RP9uiJior~ Put 92 s~uEd Nobull1omter 29 l9eJ (~ff~lt 1 vc llcccnll~r 29 983) ~nd ltitr ~ny appl iLlJe ancndrnen t s Tn~ se l n srbull~c~ ions and revl~ hCrc pcbullfrrmcc ro= middotmiddot i lrs ~oo~re rmiddot~ rled o the Stdy Olr~rtoc dfHI n- bullbulln~qcm~t H follo~

o-t~s of l nspectluRcvtc

Protocol n~-~~wshy)3~)l

l nsp~tllCII ~OdOf 0ta h~v le1

41226 33~4 131Ct91 7fll 23 29-)J 62591 lD7U9 11 41 5lt 191 ltlo n 2071 zn 4l92 4Z3Z~l7 -2992 715-17 2392 lCIl51G l920l2392 lS93 4f5 12shy 14 93

Repobullmiddott anrl ja t l etl e 027-29 111 -35 ) 12 1515 Sl o 1on4

Date FiMirgs Repnrtej ~0 ~U49YCOt

Studr Clr~ctoY

o22S 82291 1031 91 Z2192 51192 72392 ll992 2393 51793

l169l 610 94

e lunch 8 Hunch gt t11nch 8 Hurc 8 iuncn S Ba11 ~nger Ti llotson 0 1-Lcll 1 J r~nrtsun

K 8~t1eshyl CaHel l

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull

bull

HWA 2603-03

qudy 1ih C4 middot1~ Oietut ~ar1nog~ro1~1ly Stuly wih 14shyl rlchloronc~~ee In Ra s

Prnj cc l tbullc 2G03ltC3

Qu~lly rul 3ncc lnsp~c t lon s ano r1bulllew ~ of thfs s~udy er~ ccnductcl bullbullmiddotttgtrdhtg 111 the Handard opermiddotH ing procedures o f ~hu Ou ~ l Ly 1ssurdllCC Vbull t abullbulld lC Corrllrt~ t~ te (~cd dgtgtramplormiddoty Prmiddotacte rbull~u1H1Cns o l the frvlrcnrrocrtnl Pbullmiddotobullct crt A~~ncy (gt - TSClJ bulllto ~Co the LS Cede f lcdcra RP9uiJior~ Put 92 s~uEd Nobull1omter 29 l9eJ (~ff~lt 1 vc llcccnll~r 29 983) ~nd ltitr ~ny appl iLlJe ancndrnen t s Tn~ se l n srbull~c~ ions and revl~ hCrc pcbullfrrmcc ro= middotmiddot i lrs ~oo~re rmiddot~ rled o the Stdy Olr~rtoc dfHI n- bullbulln~qcm~t H follo~

o-t~s of l nspectluRcvtc

Protocol n~-~~wshy)3~)l

l nsp~tllCII ~OdOf 0ta h~v le1

41226 33~4 131Ct91 7fll 23 29-)J 62591 lD7U9 11 41 5lt 191 ltlo n 2071 zn 4l92 4Z3Z~l7 -2992 715-17 2392 lCIl51G l920l2392 lS93 4f5 12shy 14 93

Repobullmiddott anrl ja t l etl e 027-29 111 -35 ) 12 1515 Sl o 1on4

Date FiMirgs Repnrtej ~0 ~U49YCOt

Studr Clr~ctoY

o22S 82291 1031 91 Z2192 51192 72392 ll992 2393 51793

l169l 610 94

e lunch 8 Hunch gt t11nch 8 Hurc 8 iuncn S Ba11 ~nger Ti llotson 0 1-Lcll 1 J r~nrtsun

K 8~t1eshyl CaHel l

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull

bull

lt~A 2603-103

STJ) iEt-lrtCIbullTIIl ll4- l eek llecry Carctnogenldty Study wit~ 12 -Tri c-- orobanzene In Rats

Sronsor s Rcpres~nlol middot1e

S t ~ody ibulln~ tbl ~ Slc~y ln t at ton lr itbullbull ten a t tos j ng tomplftjobull cf lcbullE1nal Necropsy

Z60l -l )J

1 24-Tn~rorctcnzcnc

CJrol R S o~k Ph D c~en1C dl Han ol~t l~rcrs AssocldLIUII 250 H Street H w ~asnlngtcn OC 2033

Standa rd Cnlor1 nc ot Ochwue r11 Go vernor Lee Ro ad llc1agtare City llel a~o~a r c 19706

Michae l H Moor e Ph D OAR I Ha 71et cn middot~a sh i ng t omiddot nr (HwA) ~20 Leesbur~ Pike VIenna Yirglnl ~ ZlBI- 1699 (703) S53-54GO

Cece) her H 990 April 5 1991 Ar1 9 J993

- 4 -

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull rwl zampogt-lo

SlUrl PfRSOlli It rl tetary c~r~ lrqerql l y St11dy

124-lrlchl or obenzene r Ra t s

~Lucy ClrPcnr Michael R Hoobullc Ph U OA BT

smiddottmy Coo-dnlttor JbullJlle BoTan I S

Ptn~middotCJ ( Rbullcarcc V Cuanoer Ul I bull ~ibullcnate TC1Can (oJ1 y- Ci f gtelcriHY ~ tlmiddotuluggt s

(J i11icbull Pa tho]O(II ~t bull Ren~c C Pearscn M ~ V H Olplo1ae Ancror Ccllc)e of Veterinary Palhol~~~

H~rbull D Walker D VM

Abulll)i(tic l ~~enn t rt ~up~nmiddot 1~u r middot JdCr C Qorchncr u

Dann L bull ThillH liS lfT

fgtrcston L Burl~middot R A Abullq

L~horaorv Grc c eader K Cougla JOlt~~ A I Amiddot

_arctte lllnglcy LAl

- s shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

~~~~ 2603 10~

IIll K~DlK1lDrl

1(1kuOS bull bull Gri_ Pgt~ tnrrent JntJ rJt~~4--~ l e ~ Comp~middota crm~1Jl1on 4rrd ij~l~lllral en Anftly~is or ~~P4~d FormiddotTul~io~s OIJservt I Jn ~ an Qe Mel~

CllnicJI Patnov 1Prr l nJ 1 S ull e~ Sl~ l middotl bullrl l1nil ys~~ ~Jgtecbullmcn Haw Dbull and ll bullnl Repnbullt Slormiddotage

nr SUIIgt ~nl)li~a l lrem LbullJ 111-l ri t Ul erbulllbull~n~ C1 inica l Patbullc Nbull bull lernnl SulilS

JIgt~JSSn gttC CLol~USICII

~1TilOtlG REOi

Rlt~RENCES Sla l l lt ti cal fra1ytestabomiddota tory Pr ocelt4res

FIGURES bull Fl o~ctlar middot ~f ~middotlOVA anc Rc tmiddot eJ Hethods

2 middot 1cju s t eel Perccnmiddot Sumiddot vhmiddotamiddot 3 lein Soct We ights 4 - l~u on Ford = ~ s ~-rp t 1 1HI

5 shy

filli~

e

I I

II

ll

I 13 I ~ lt

17 I 1 J1 I

22 tl 2 32

JS

1J

49 49

20 22

27

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull liiJA 26~3 - C~

~~ HAZ LEtClN ~ W A S _ I ~ G T 0 1

CCtiTEHT~ - C3H l~IJ[G

rn~lyt lal Chelllst-) Result~ c 2 bull Anl11ol 5bullrbulllvalj~1J sled Sur~ val Tdbl~ 52 - uTTarmiddot ICd~nce obull (~ 1rmiddotca rL~l va~tons lZ ~ wed ly ~Pry yhmiddot Hea~s arll 5Lu ol ~ rd Cebullia to middot ~ ~1 ~~ ~ ly bullbull ct~l Uoly let~ middot t (d9e t ~on~ bullnd Stabullbullaltd

Ccbull11 ~ Iobull s R middot u fd Con~uTpt 10 H~a-~ d~ s rbullddfmiddotd oemiddotittlr s 91 5bull lnlal I OgtC (tOIIITIIUIgt Htal amiddotc Stbullnrt~middot d llCIHIgtnl Yb ~ l~okly uc middotldl CuTpJubullbulld Cors n~tic l-Ie~~~ bullnd ~l ~nouc

ll~middotlaion~ go ) ~Uio lndr) ~i cmiddot middot HeIHOlogy lata ~ u~ Gru lnth~ g y lnctdcncc Su1lo1lilry bull Jnschcdul~d Omiddotbullbullths ca PR r o11 IHhgtlgtgy Incidence Su1gt11~ ry middot Tem11 ~ l Scr l t lcc l U IlL tbullmiddoto H Pbull tlw1~~y l nc 1denrc Su-r11a ry - A11 1rt nat s S ~ Ormiddot()bull Weigh OHa lenr na l ltac rl f i e ~~~

101 P bull t h u l o ~y lncmiddotmiddotlcncc Sun ary- Uns~twdullt Dc bull Lhl lOfl tli llopathohiUY lbullc1dennbull Swrrary rc r11 i nll ~acy bull f bulltbullmiddot 17~ lOt bull li t cpdl ho l rgy J roc~ncc Surrrary - All An i rnll l YI JOD [bull Mllltbulld l lls~patr lcqy nCdence Sunry bull tl l Ar1m~ l ~ 211

I 2

rra l y l 10l IndhHJual

C ll e11 i ~l ry Me t hod lltn Ill~1 JHpns ll bull~bull

215 77S

3 l nd 1v1Cual Cli ni cal O~~e rbullaL s 23b middot11 shymiddot1R shy

1 nl l middot rcal lndlvlda l I nd 1vi J~a bull

IIOU) w iyhl1 Bcdt Weight Chan~e~ r ccd Cmgt$UTP~1ln

3~7 4 11 4S9

II bull

lntlividuol ndbullmiddotnduol

~cn~cund ConsuTp ion ~l1bull1cal lcratoloJY al ues - Jcschdul ed

sos D~a lhs

7(1 bull gtoJIIIthtdl ~JI~Ca bull rCCatOlOg j a]ue~ bull T m 1-a 1 So-n f middot cc ~5C

0 - I~C1bulldua1 ~nibull Scrca- llepomiddotmiddot ccz ~

10 bull )ta middotr~n~Or~atlc~ s SLC ~middotoocol zrc Anebullocents

J~ ~~4

I - lr~toccl antior ~l Oe~ middot a t en s 1 ~ 7

bull - 7 bull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

I

bull 12 4middot lthlormiddot(l~iZCnc ~as adrinisler~d dcrl middott bullI bullI

I 3ampC rat fobull Jl ~tbull l Camp bullcnse~utlwe ~ccks t o evaluamiddote Lhbull cncn~cnlt

potcnl~l cl the test Tbullt~r middot bulll

11 rr ~r bullPI ( 3 abulld c arltJtl diear coro=bullmiddottratmiddotrn of 4

lr ~rhlorobcn7cbullc ~ere IJC 350 and 1200 ppm Paa 1n Cbullmiddotcup I wcbullmiddotc

adrrlnl~ttrc~ th~ bbullbullbulll dl~t ai Qbulle and serwec as he ccncurbullcnt cobullLrcl

~roup rr1 antmiddotIPr CI~IU)tCd WCfC TOrtalJy cl1n1ca ol~e~ld t l Ori~ llmiddotbullt~

clqh ooc consultrpLion and 1gtnomd ccr~gtup~ lon Jala hcllatololtn

pHa~ctn orgabull wc 1qh t da~ acd nerrvpsy bullnd hlgtt~~bull L ltqy f lndinrp

rnr forobullmiddot s 7 3 and 4 dun ng Wee ks I th ruu~~ 104 Lhrmiddot IJrbull tr

drllly consumed -~sc (based on taru~middot d i eta ry ccnrrntratlons) ot I ~ middotimiddot

lrchlorobcnc~ne bulla~ S 5 18 9 anod oo ) ngjkgjday r espectively tlw

moltbull 1 67 ng ana 793 ~glcgd ay respectively in tht feflbullalcs

The nc3n C)l lt ccr~u~cd duse [baed an ossayed dlPtary tJncer tr~lmiddotOnl wa1 56 19 4 ltml 55 5 rgikgiJay middotmiddote~pcctwcly In tre To les gtbulltJ 6 9 21 5

Jrd tl 4 1 1 vbullbulllt 1n ltP fettd les r Croups 2 J anrr 1 1 dre lu- bullmiddot

trmiddotcghcu l t rc Sl~C) 1c 11car la1 y doe tun~ hy fenalcs i11 Groutl c 2

3 DnC 4 gt~31 la 21 2 amiddotd 89X yr~er re~~eclvely h1n t middotc ncan

doily l~H c~middots r~cd b1 Tales ibull the sa--e dosr grs

Fur tmiddotbull a~nlr stratlon 124-Tr lcnlor3~ErLenbull to F-l44 rltLS at dctary concenra1 3ns obull Do 3SC and 2CD pp~ he hlqh jose ( ZCC ~m

PUItd o be tc ccrvct-etgtect - level nlfl) icr ca cinoyeniil) olS

Jl middot It~~middot -- middoter- ~e~ ) sc l~TU) lr - i es am fbullmiddotTlps Tbulla rrmiddotdmiddot

dc~e (3C IJII) bulllS lhe nc-otser~-~ ffc t - l evel (tCEll fobull S)Hetrlr

t a gtrmiddot t i n les abulld fltCalcs

bull

The IZlJ n dl eary concentbulla ion pr cuced the 11c-middotny

treatnert-bullelbullted ~rrecs t hat her e indicat1bull1 af a Max l ~uT Tole r atec Dcse

(110) ~ 5ltJniflcan decreose In strr-1-tal o f he JT~Jcs at riHk 104 bull

siqnllc~bullt depression of nean b~dbull ~eigh t ga in fJr ~ecbulls hrl-~h 2C In

- s shy

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

bull ~~lcs and fe~bulllbullbull s hepaocclllar hyp~r t roP) ~ener a middot y qradcd sl 1gh t to

llnlerate in SC~n ly) bulln 304 ~ 1rales and 3750 f e11h tl t rruse f all)

c h ange i n l he lver 1n 4 49 n4le~ bullncf 3050 fcm ~ le s loepa t q luca l ry~ lt t

dcqcncra t1 on 1n i94~ 11a lcs I HJR1 f 1can l ly inlt r eased ncar lblol ule l iV e rmiddot

~IJio and nean l tver- lomiddot l ~rRi n a l -body- ~c l gn l r a l o bulln mhs Ancl ren~a l cs

~middotlndiranmiddotly 1nreH~d nbullbullarbull l iver o-bra ~rmiddotw~bullyht r~io in Mirs wi l ~ an

nrmiddotp)Scd rcn bullmiddotaL~ (net gtlgnlt~ant) 1r fltnd~ PnllvgN1 liVCIS ~J t c

bulln 1J rrtles 4t nbullbull(OPS cnll cmiddot~hmiddot1S rr1n~r-t1 izamiddot io1n tn 491JJ aulc and -1Pl~O fCTIC1 fG ~h1 tlw mPbull e~i y s~re kdS 10 (n ( ale in

n-t 1 vmiddot 1~ 4_rlnlTdl l o l t~tampt ~n fcnJ =S ~rdn1 umal ccll

bulltcr~lHbull Hf middoth~ nral ~cldc u~othelltuT ahPrlC~ llll) 1ro namiddot~5 lh

a iltltmiddotuCI cf 350 11 Tebulln S~ llj ~co rmiddote of t gt chrun iL ~tragri~~1vc

tlllifumiddot~r-a 1 y fo r lfh 1r thl ~cvr-rity (Te Jo n 5C Or l of) C) w iurreastd V~i

l oo rn l c5 middot~ r a~umiddotarpnl edlrouy l o uppca tmiddotancc o f thbull middotmiddot olu tf Jl nltcrop~) 1n

J1SO Otl lr-~ bJl Ci y li~O f~Td l~- ~~ rtnd ~ean ~ ~~ o middotmiddot l c and -el-tt bull rbull Jidncy

lt11)~~ ~hat li l tmiddot (H~a~cd i no ~a J St l t-all stsr f clrt ma l es ul

f cnmiddotJh~

The 353 ppn cmiddotctJry concntbullaiM P ~J bull -1 bullc lredlmobullnt-rPId

~f((tS lr contr~~t o the 2CO ~-n 9rctt middot-~ bullncnhmc- anclilll Selen y

gti his middot ~3rr ~ middotc tbullcbullmiddotcs th~ l~gtu anJ ludnbulls tf tbull- 35gt ppr

ud11a i ol2 C CTp r~Ole tl -~rtrr valus fo r- heal)C~ 11 uL

hJIbullrtnop t middot nc-dcnce -a 51 50 bullnd SSO i n bullnamp 3SO ~~~~ naes and

bull

fclttltohbull respeltt el1 cnl red middoto 2EC ond 6SO i n the ct~ntro rra l es end

f ~nal c s respectivel y rcr ~iff s c fa t t y chnf in l hc er Lmiddote

nltbullrJ cnc~ ~ 5i 50 and 2150 In the 350 ~~n male s Mlcl females

r~ bull pc t ivPl y comp~ r cd l o SjSO and 5 0 In t ne c~ n tral m ~ l t~ ona fen~ales

rrmiddotsp~ t iv e 1 1 ro r Mlal1C foul tj s tic degeneral iltH1 (o~sermiddotmiddotcd only i n

~3 lt sj ~he i nc i dbull nc c as ~SO bulln lee 35l ocr1 nacs ~nared l gt 9 50 in

~he ccnt-o i roamiddot _ Formiddot bull cna l pe lvi s rneol i zat br h~ tn~tdence (on J

nean sever ity score bullas t4S ( 1 0) c 4 50 (lC In the 3~gt ppn nl ~~

3d f~~bullle s bullc s ~ecLively CCTpar~~ lo 3~ 5) (Oi) bullmiddotc 394~ (0 8) 1 he

- 9 shy

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull

HY ~603 I 03 bull rontrol n~ l c s and fewa l cs far trans i tional c~ ll

hvpebullmiddotpl a ~i a of the tmiddotenal pelbullmiddot ur othelium (observ2d on l y iltl ma l es) t he

ore ) as 250 (0 0 ) ltn the JSO ppor ma les

cgtm~ared Lc zso (U I i ~ LJe con trol ralcs f er chron i c pr11gre~~v bull

n~Jn ropalhy the mean severi~ sco r e as 26 10 the 3SD Jm m~lcs (Ortpred

t o 7 1 In the contr~l nalcs

Tht 100 ~pn u bullelHy ~oncen r a t 1 on al gto Jroduced no trelt t m~r t shy

rc l alcd cttc~is

- 10 shybull