Document YjdvXG0J6G9k0roaBV7dRqE1V

\ *. . r`*Tr**y**:,**- - C -I-i \ - .X.-, w*.t' . . . ' - *'C* X a6 y lio n v *n O e c '-p t i o n . 1 ' *.-\Ic.*.r.cr, 7 i6 i,IS 6 3 TOXICmr Of 2*WCKlOtOfHNOXrACCTIC ACJO AND 2AS-TtiaaoxorKCNOxrAcnic aq d A ta p e m Ik ir Atrito m i Q <w < T tM ) it O** WCTOt tU U , 1 . MA. n u u t t M u n u , mjl WWT BOT1I 2.4 fcHorophctocxyricn ic aod (2,4*0) w d 2,4>trichkxophnxniyicttjc d i ( U - T ) a y p h t( kotmm u and M ie id ` a ^ u c t e v facfaf widdy wcd lar tito ceetrd s i canda tjrpe* ai eed o b r a bsd*. Tfccj m* fackf tprayad froat Irpbm o -- y acre of tfxoaSttd Uro* and paxkg tetd aari are ym c l tradnsatrk fJTjemkw* toid t t retaS lor boroc cirdenm . Widi * t a id rfw id me al dsete k r tia d a . fnetifcfc toue ffcet m mpertaae, acd dek af lf twiao tmy eccar e r ruidaci ajr le ioadtettesdy cacoaascred d Ik 1 a earfar repon, 2,4*0 as anefaned i t face* OBtsocie to KBab m i m le a lA m tk n d raBjr."'* K a m tr, A t sajeice si large dotes o tA -D la eanla prodaced syaipleaat akoBar te tfaoae seca a tfaical n ro tan a* Mate ArftiW aUc tcaliera n t itp o n ri I? H>Q and Carile fao ttadfed tke cale w d sefaaoric effeeu af 2,4*0 n r s per!es t anmala.* Tbere h m facen M pera em oennf tle teste ptopenks o 2,4,S*T. Tfae procer thadr contera * ao ilt cal tasickjr i mi driw ic tral tesickj o 2,4*0 and 2.4.S-T a doft. r tx m u M tx u i r n c o c iu Adril ee ap tf d tp af I t t K w en i i Km f A t aaaak ate h u r i ia d e fa h n a rr f e p rin t f i n a A ra a w te M m A *adr a v n i Driaf A i w a i I p M A f *rt immmimi ip itri t f r i n p A de tinca nerita. t k d tp m I d a N n M P i d (F ri ) ad H ito a M 2A*D ta i MJ*T re tM w n l a n trid i A a y rity ai M i n tf W f t m i frrah e f M A UZJ ate U ftt C . m ftctiuly. la A erit ria d a d a crirtettte d e f JAD r 2.C-T n lie it im l w a a** and dan it cafad, The d tp en tlif r e l lar a feriad ef t4 d tp ,te U tWw da car* H it ridfa1a ttfftn a i I r a p M M e de Cae C k a ia l Cea^eay. r tn d e Defamare al P lp io ltp tetf H amectlt p aad d e ntprwacal A f i r t p . Wtjra* Utla n if Gaflcp af Mtrida L (a) K a ek e* t i r V ar a WccA. Sckaec tte t W n a O ratoria A ,a a < V rin ;L :U tta t<Diiint rheaaarrrte Arif a a Schatn HnAcirii la d e T n fitt. Sdtaat fteiC W ?* IMA U ) SaM . F. C.; Hm w . C U tari Carita, A F.: Caaeri al b p a i NSea Fradaetea id ADidfenfleaaajractrie A rii Scinet MSi**tf4, O * (I) K a d , F. G , tari VrideK, JL W ,: A*DtriiketfAre>er tetnk Acri aa a D o n tal Bedc. h C Cae. mi A laclar, i L i : XCaet af DK rtle id< e p m i r AeU aa E tp iiaeen l Aa e a k. Fatc la b Cafar. K at A McC iM O S . INfc 1 SOI, t V , aad Cariek. H : Taalckf si V -D kH m fM *pretic A d i aeaul AaiaeH, 1* k ia ri. H|*. TaakaL S>iO<S, 1*0. a 3? Io 7<-.v . k;'^ V sW ,,*,>V ' -*'*v . ' *- txucsTM t.it. m c tr sF . a x u occlt.it to w tL m sm c ix s tfw tt n t t W f ir4 l i tW th w c ia. fcr U H or M timimmttti m*||7 it tif in 4 n t)i a n i * w a U n i htmL Ek cif f l t ma* inAedihd in a 4 t J (, t<m < t n-- t rini canori A U ni nfcM ri i h a n n i reUr. tW u . ti anaa Ki m 4 si Muondi hAt. Durine ffc* i anioni u t ii|M I n i A. C tn t M con m ukm W kti tW awrnue f 0 *. ikt Xkk r. aa a ri Vhh da? ai * t-- i<cto ti ri *4r. H w e W n a* few fjonri ith a *-- hru b nlni^WT Cpmntk nt ri* f Iht 1;. ri m U ctt T iona w m uln fino ri k art. fcm. fcUncr. adrenal, firn, n* n > r IMO, l 4 in >f> far**!, ani mimmi Uh IcaaW ^. mi k TU U ^ / i d f offe M XWt if j-ithJmnfkmtjvrtit Atti m i l/> T ntV n/kn/rir( Utgt Ia~. ft. IL a. r. r. aKr. rsJ MJU- IM L ML a. ar. L nanna M < m em I . Arnfe Omf Tmridij.--() Mortality: The effect o( sagfe m l down cf 2,4-P r 2 ^i> T 0 a n i n l for 14 days b rim e an Table 1. Use deaths neve delayed tn d occurred t n to m day* after the compounds were adawmttrcd. The oral y f t w d 2/i-D van ap | naB tci; 100 mf. per U c y n a ef body weight; for 2 ^ T it m * so the tange of H O n c ^ f <* b%her. ( f ) Body W eight: The large oral dotes of 2,4-D or 2.4A-T produced a f u m e fas body weight (Table 1). Such animats developed various degrees ef y y t !, sad those that fe d refused c m canned dog food toward the end of their trid n l 4 M r i I t A .: A SteUSari a ttllio n w t Caterin a w*V Ughi F*m , JL 832935 i'-f'iiv jC&i tW * 1 P *tlL -W k .{T Z k \i-T fiX IC IT V OF tlLkHIClM.% ftl (f) 5>nf4MiH: Id that died the rrfcct pfi<ductd 1 2,4-1) Aixinl fet*u a vik) ataxia and stifloes* in Ite bmd kg* to a dcfotlr im<4*aib. Initial sign* mete often noted tis hour after the oral admmtoratiua of 2.4-1. At Ihi* tin* the animal* v tn more quid thaa noroaf. and a shght la v a at* ertafafuny ptc<ni. The bind left were always affected fir*; the feerkg b irr vt out al ad. There a usually progressive bercaac in spasm in tto himl legt **ocvMol with feerca-mj ataxia, ad seme-drgi tfnmancumJy extended the hind lunl* in a tfOtic dw tiw u totmg a few v n o d L The knee jerk n titler nrimal or hyperactive. la the early stage* of acute poisoning 4th 2.4-1). the animals mete n*vutly quiet. If the ammil t n E/trd and made to walk. the spasm and ataxia m m ckariy aoticcd, hot after it bad T ied for a wlik, the spa*m and ataxia tended to decrnic. la the later stages of bhrxintion, the animal, when placed on it feet, ma< unable to Maud and m old then sit or lie in an awkward pontine nth pcutic Etnb# narked particularly by spawn of the bind leg*. O tb e rd fi sfaanUcl and rolled on the face be atteapti to right d n b d v b . An occasional dig Iran] n i d m tt of trritaifao or - paia t t a the shut oner the lack of the aeck a (n ^ c d . Son* dog, mhen M l ^ by the shoulder*, mould shorn u e n iw and erm ine of the bind b f e . As the b d e effects of the drug progressed, the dog* eventually rcfa*d the nrioua type* of looid offered. OccaJossiMj. sneering. n U n g of the q n and d u r b a mere riheemd. but eel veetiag . Such signs mere ih o u n one dog that survived a loner dose of 2.4-D fee M f e ji (Tabic 1). la this mstaact the changes mere refatirriy mild and mere Smiled to spasm of the baud kgs and a slight ataxia. U u M effects ere not observed in the dog* receiving 2.4A-T. The changes ere Smiled to a sSgfat or moderate stiffaest in the hind legs, with the devcfepmrm of atoria m the tv dogs receiving the hJfherf f e e t No symptoms were evidem la the owe dog tb i <ficd after a single dn#e of 100 mg./kg. (TaUe 1). (d ) Pathology: Changes olden ed ere Embed to the pMrnmtwwii! tract and bug*. Four dogs (1 ,2 .4 , and 6) weed ing 2,4-D and two dugs (13 and 17) fed 2&5-T showed sd d to d f f tu revfeeu of the mscosa in the sntafl intestine, lu some dogs pneumonia was present. Histologically, the stove dng homed some oecrmu and hffammatfaa of the b c s tiu l m am a. Ovw dog (13) had a moderate, tffnnm k p s it seem it. Two dogs (U tad* 16) had a odd degree of renal tubular degcrw la meut dog* that <cd the finding* were S nted to nonspecific changes. Such as hepatic congestion. Is way case* death n s apparently due to pneumonia, which fallowed the development of anorexia, w rigk h u , and myotonia. IT. Chrpwic Orwt Tmricitj.--() Mortality: All dngt receiving 2, 5. oe 10 mg. f 2,4-D or 2.4A-T per Idlognm cf tody -eight survived tto 90-day test period. The dogs receiving 20 mg-AC- of the* cwnpovwds dkd during the study. The adwiVifTilirii af 20 mgvkg. in dirided dose* twice a day produced death ia both dogs rtcriring 2,4^-! d ieo o r dog reeriring 2,4-D (Table 2). (1) Body W exgb: Tbe only significant change fa tody weight occurred fa the aasmals that (ailed to survive the study (Table 2 j. Lot* of right b the dogs hegna 7 to 12 days before tbe death of the dog. (r) Gerwra! Synytoras: Dogs that survived the ora) aJauiustTitiion of 2.4-D or 2.4.J-T far 90 days were free of toy ijry to u i. 8326936 M * u ^ w . f m * . f - r f t r / c m * of n u m n 'w tx . 41 (O S jm < w : Ir A f thal cd the rlen frmtuml 1} 2,4>U twicd (4 a avW n a v a aad stflnes* h the isnd leg* lo 1 cTmitr m iR iiui. | retal spi* * n t fim aoted sis Ww< after the oral a<ka>iraiMt af A->. \x ih* tae thr anhmU t n M r gmet tfcaa aorasl, and a afiche ataxb a* teodonally prcrol. Thr find k p v e n ahray affccttd fit*t; the ferrfcs b trr m mA at a l/T h e rr a anoDr a p ttg m m r lacrease vi sfiuin ia lie hitad Wt* a*eebk4 a-kh n rra-in ; xuvi. are! iohk tpna w w aly extended the hnd U U i a \niic w n wtm lu it{ a fctr acconds. The hace Jeii va rie l reinal or hj^eractire- la d e earty n a g a ef actae fotMoi; vitfa 4*1), the animal ere m o Hv f L if >ia aM l * n fifted and nade tu nBc, the aparea in t ataxb m ckark otced. Wt after k la d catkrd (or a hile, the apv**a jd auxsa tended to mease. Ja fhe hace A p i ef totoxcarioa, the animal, wfcea pheed on k< feet. a* ambir to d a d aad n d d the re or fie to aa avi-vard ptMoa rth ifo tiit fin nrVrrf pMteabrfjr hjr t p w of the l d Ices. Othrr i{ * a m lM and roHed w the Acor la an u d es la rigft KXbdm. .Va aecanbnal ihnvtd evidente ef im atioo or : f d i fita the A k # w thr Ucfc d the vede *s cromad. Some dog,. heo hrM ap ly Ihe ih m lm , ueW shc* cxReurw and cnorag ef the faind fimf. As che fiadle cffsrti af the A ve progreased (he dogs ctm onlly icMf the n rise* h o f eCertd. OecaockBj:, saccacg, rd jb irj f dar ejes, and durrhea ere Svefc sgM ere abo seca a ave deg thai sarm ed a fanrrr don of Z4-D (or M p (T tlic 1). la A i toataarc the cha y i w t nbsircty a U and e n W icf to y in tf lle M k p a d a iG tf ta iB a . H artad effads e n aot efcserad a (be dop rectiireg 4 i* T . Thr d a a f v e n fiavted to a sgbt ar a e dente stitfaei* n the hmd fcgs, kh the derelnpawtt af a te to as the tv u d e p m eiring the bighert n n . No tjv f ta n t e n rndent fa d v ove dog ot (Sed after a single dnsc ef 100 wg./kg. (TaUe l j . ( f ) Tiflolcp : Ch a t ohwm f en fsnhrd to the pstnntestm al tn c t and h a p . Fovr dogs (1 ,2 ,4 . and 6) racefiBg 2.4-0 and M d u p l U and 17) fed 2/O -T sfaovtd refld to fiS v e itto e a ef the recen ai the saall inK <e. la m e dogs yveatoonb x a presea*. H iioiogbB r, d a afaon dnp.hoved *omr bkto aad toarenvtiua of d v ineittoil.acosa. (X e dog (U ) faad a dente. Sdc hejatie H c n . Tre doga (U asid ) had a ato degree of m a l taU dv degen- tn e h a. la n a dogs da* fied the toafitip en finrd to voos^cciSc clumgr. aaeh as hcpatic congestin. la a a a j cases deith u tpfarm tly doc to pnrtanoma. vfisch feBoa td the dwefapmta t of a m ia , R g k loo, and stjv o n u . 17. CV sxif Orwl T u iritj.--(s) 3 1 ertt% : AH dng rcccivin f % 5. or 10 tg. of 2,4-0 or Z43*T per llognca o hndj eigta eanrxd the 90-dav M t peod. The dogs rect i iiog 20 rg -A l- ^ o xryounds dkd doring the stody. The d am tn d M of 20 ngvV t- to dkided dotct ticr a xy produced drxth to Woih dogs n crietog 2A3*T d to ooe dog tren ring 2.4-D (Tahk 2). ( i) Bodr IVeicto: The oalj aiga ifa ia cfcxagt la hadr veght oceuned to the aaw vh Chat toed to sorve che atadr (Tahle 2). Loas ef e ^ ta to tfaen dogs tegaa 7 to 12 dajs hefon the desth af the deg. (r) General Sjrmptocnt: Dogs that sarm ed the oral administrattoe of 2.4-0 ae K - T lar 90 6 j i v e n free of tay 8326936 n io * U iXDUSTXt.U. m V IC X E A X tl OCCVtAUOXAL UCUtltXF. Th* Ita #5 *1* d*d Wl* ircm ing the IwjhrM et 2.4*1) iM til Men Pifferine Kwnrwhat frow t W obetvol m (hr arolr Miidir. The dng* ere <|uk'l, , Did Irti m fM u ttt than nermil. M iw k i>mh i higher io the bind ice, fefticebrh- k piM e n k M u n . The bind Iq* were hrld ire stiffly lia r tn a l *** ^ ** I* * . Having Hie bt two lo Ihrrt day of their arih ai h o vd the doc# rimar! dJficwhr ia cterming or swallowing sod etteteally ere* related small boiui o( canned dog food (Mutly readily con* MMed). T hen m s alio seme ooring of Uood (ruin che gum sod bueeal mucosa. T*U l P A(*l --ri j m d #f Xh+t F t i ) i'D r iW /U * r |a r / c A tti --i ^ T d tU m firu t) .y fk A t'd far Pf 4}t WM* *a u HI as ffMt mterrmn--*mmat--Umm^ma4wmmw4<i I!*m-->*r<I,raXn.*tmr a--meoW--i.m. . --a1 k#n I t d a p that died e U t rccehing 2,<3*T, the prominent effects t m weakness, lig h t stiffness m the h*od k p , dfficvhy in wallowing food, end, in enc dog. lieedfef (m a the giaas. (d ) Blood C ourt: The administration ct 2,4-D or W .5-T did not have any epdfieaat effect ee (hr V m ocU n, red cefl cooat, or total white cefl count of --mm3* that w r vired or thtd during the study. The differential Moodcoart remained to n a l m the arm ing snianls. In three animals that died a terminal b n m the f t t t r B a p ef lymphocyte m s d n e n td (Table 2). ( r ) Organ Weights: T hen m s an sigrafcart chaegt is the tg lc ot the thyroid (b o d , adrenal gland, heart, liver, ot kidney ia animals that arrived the fO-dar period of tfarij. la two ot the three docs that died daring the trfawai itration 8326337 r /y'i It <* Vv/^-'vucii p a L L - u ik A r iK A - r o x ic n r o f UHkmcmtL% a af 2,4-D, Chert v u stfehl feercuc io hctft end kidney ttif h t. A u n ib r ch in p m weed io two of the lour dop that fe d u a m o h of 2,4,6-T. ( /) C rcu Fuhofagj: Two d o p n e o w j 2,4*D (26 and 64) showed a rm of tdnese ia the duodenum. With the sdadmantSoQ of 2,4,6-T there d n tlo ftd fa def 42 a diffusely reddened duodenum asd jtjn n n , while in dog 4S, aniopeied on t b 99th day, a p aen listd k lcna n s demonstrated. Taaes 1 - fftrl *f tj-P *W i/J-T n M fbW , W O y w iih f C*m (i i I A S. mw |lMi a t . am mt m -- - as----------- n w OK__________- a__________ . o a -- . . ,, - Bt BT ae - .. B m m -------- - B M 0 BJt MB BK w- a us ' MB . %m taa os B Jt BB BB B BB AS BB BB 0 BB MB MB 0 BB 0 KB KB 0 BB SB aa BB m KB BB KB BB BB B e, MS. BOO M lv SB SB M SB BBS B mm SB Mjm OB xm M mm a a feat OB mm a s BJB a s SUB SB tm urn SB w OB IM* OB BJB aa a a SB SJK -a BBS SB SUB SB BJB OB OJB u>r IB as AMMi aa an t a BJB oa BBS OB mm OB BBS SB SUB SB US r. *. ik L I-N ti * T-t MS V ***: B B aa B Baa B m aa Bm aa B mt aa Ba t a mai 0a m m B B s a a a _ mBt a4 m m B a 4 s t a aa m B B a s a 0 a 4 a m 9a 4 a a mB 1 a mB 4 aa m m B B t 4 # B t B r- mB B Sa- m V ** B a a a 4i aB t a B Ba ai B B 4at B a a a a a Ba B 4 i a a a a as ( f ) Microscopic Chacges: T V heart, hasp, thyroid, adrenal, e w ) , w twtea M net d ti u ttc any aapaficaat tla n ( ti Three of the d o p rectivfag 2,4,5-T ad two racth iag 2A-D bowed a* occarional area of fecal necrosis fa the fiver. This lading. however, was not related to either the dbae 1 the compounds or the f e d et an j animal (Tafafe 4) and was judged to he of no wpificaose. The duod e n at dop 26,24,42, and 48 showed varyinf degree of hyperemia and m e rip hfihntfe of ctfis fa the n to a . The a f e n e r a and across were normal. 8326938 .v 'l.f >^ v.-rkK- *1; p J t i * IXDVSTMUL^ UYCtEXE A S ti OCCVtATWSAL UEPIC1XE A lliffrt m rM tt in lhc mrml<r of U tl in L k try K tliuni w it nolo! in some dog. CU * 4 ), hut again thi u nnrtlatrd to dosage and as of doutxful significance. coM Ksrr J1 * * * * * * Audies, single Urge oral do* of 2,4-D administered to dvjs may product sip characteristic of cKoics! myotonia. This effect of 2.4-D t a t similar to th e t observed tfurr various experimental specks had received injection*.*-* Jn * * dogs showed tip is of irritation and pain when the shin of U hack of * tw d c was grasped. winch may indicate meningeal irritation. The extension and cro*ug of tin hied limbs, when Rftcd by the shoulders, may point to a spinal or Taaia <Hirf*fwW Cfe*f n h Lkrr mU K**j t{ D f t Ft* 2S-D m 2.4^-T to D*jt w .vt. a* tmai r- W St H* O a *1+1 mM IK tH .H .H .M S S fv cewtral lesion. Other effects occasionally ohaenred were sneering, rubbing of the yet, and dmnfcca. The effects of 2,4,5-T, preriously studied, were aot as severe. Vriag Bunted to stiffness in the hind legs and ataxia. The higher doses of either compound pcoducH anorexia and right loss. Although initial effects nay be mcq fat howrs after the compounds are given, the syndrome developed slowly in the dogs, and death was ddayed, ocesrring seven] days after the administration of the la the r ir onic studies, the dogs sun-fred doses of 2, S. or 10 mg. of 2.4-D or t/l& T per LQograa of Wady weight without apparent eB effects. However, the M y oral *dnm i*tntioa of 20 mg-Ag: 2.4-D produced d n th in three of la dogs wfcfcen U to 49 days. This delayed death may Indicate a mmnhh`n effect ef 2,4-D. The rip eU cm d in arimali dying (font the 20 mgAg- deee of 2,4-D 8326939 miUM KATZKA-TOXtClTV Of HSKMCWtS V dWcted somewhat from d w c seen Sr the acute tfadin. Wnh the chronic adminitraiiow, the M i exhibited rhidly a stiffness eCthe hind kg* and ataxia, weak M l, dttficahy io chtwfag or twafiowfag. and occasionally bleeding (rota the gums. A l leer lo p which m ired 30 tng.As- o( 2,44-T succumlad between the llih and the 3Slb day of the tady. Toxic effects in (hex amsiaU consistently included sfigfet wuueW pawn and difficulty in swallow-fag food. Thus, the chronic oral toxic dbae far O T fa d a p acts to be fa the o n e n n p as that obtained with 2,4-D. With loth drags, th en was a tenofaal feat fa body weight H op snrm fag the chronic doses ad 2,4-D or 2.4,5-T did not show any significant t f a y * hewegfabhi, total blood cotmU, or differential blood count. In three aTAc d o p (64, 57, and 105) which died while Httiii n 20 mg-Af. of 2,4*D or 2.4V5T, Acte was a definite decrease fa the percentage of lymphocyte* fa the peripheral blood. fUB and CaHHk* bare nUeried a faB fa the polymorphonuclear ta w e p t coant in ooe dog and a decrease fa the per cect of lymphocytes f a two 'f a p to which 50 atg^ftf.af 2,4-D waa adwnnfatmd intravenously each day far six dipt. In sacs which rsu ivtd A n tic fajectfaae then was oo attention fa the pcnpMTv PDOQp e w * Large doses of 2.4-D adnfaifterad H n r t to tdy tr , to the present study, orally acawonoSy produced sene necrosis fa the fiver. However, the adnotstm tioa d thnnic oral doses produced only a fight and incansifleat local m o m s of doobtlul afrtltra c e (Tabic 4 ). Dcatha during the chronic oral adnfaittntfan of 2,4-D or arm not correhied with ^ sifar t U f a t in the fiver, kidney, e r other The acne oral L D cf 2,4-Achlorophenoxyacetic add (2.4-D) fa d o p was appraxtouady 100 atg. per kffopaa of body weight. Done fa this n n p er higher pndbeert a definite myoOaok sccnanpenied by m re x a and weight lots. The Kate oral L D far 2,4^-triehioroptwwaxyicctic add (2.4,5-T) was fa the n n p of 100 a g per H e p i n or higher. Soeh tex if dotes produced only sign* of a 3d AM d o p aurv n td the oral fetdmg i f `2, S, ar 10 mg. pee Idlogna of 2,4-D or 2A5-T 5 dsys a weth lor a period tf 90 days. These dotes did not p ro d any symptom a r changes a bo^f weight, o^gaa w rit es, or blood enuat. Three of the fowr d o p recdifag tepeated dons of 20 n g . per IcDognn cf 2,4-D dad, and aO fear d o p n a i w f 20 n g . per kfiognxi of 2,4,5-T died during the tody. Toxicity to 2;4-D at the dasap Iced was accacnpsBird by bleeding (to n the p n , necrotic danger fa the tweed maeon, and some tfJfiaifcy fa chewing and wiBowfag, lo t then waa only fittle cridc of cGnical myotoma. A te m a a l td l fa Mot p em o tap of lyinglw t n was observed to th m of the animals. D oth daring the repeated admfabtratioa cf 2,4-D or 2,4,5-T waa not related to pathological changes fa the fiver, kidney, er ether organs examined. 8326340