Document Eq8aO9nv3zzYd679yoeNZZo2g

SUMtS*;;- REPORT TO MONSANTO CHEMICAL COMPANY SUBACUTT DERMAL TOXICITY OF - AROCLOR 1249 . I* btyodctl> wd Qytllw of FrocMur* A sample identified n Aroclor 1249 received from Monitnw Chemical Company for evaluation of 20-day luhicutr dermal in Albino rAbbitt. Skin application* Of tb* llkt material, la th* form of a corn Oil solution, *tr- mode dolly to throo toot groups consisting of two rb< bit a each (one mote And on* fsmaW) for a period of 20 day a. Th*** teat group* corresponded to doily dermol doeee of 10, 40 and 100 mt/fcg/day respectively. In addition to the three tael group** a treated control group of two rabbit* wa* alao employed. The Animate in thla group received d*:lv drrmol application* of corn oil comparablr to the volume administered to th* higheat te*t do** group. Th* rabbit* In all group* were hou*ed individually over the period of Investigation and observation* ware made with respect to body weight effect** iocidenc* of mortality* reaction* displayed *nd statu* ol tb* HONS 050l75 hematopoietic end urinary systems. Special emphasis was placed on ohaervatloot tor akin Irritation produced hy the test maim. I, fallowing the tO-day application parted, the rehktta wvra kept Mar eheervetten watil u additional 14 days had elapsed. Ai the end f thia parlad, (teal mortality tabulations vara madr aad all surviving rakkita (ram aack taat and caatrol group arara sacrificed tor patkalogie studies. Croat autopsiss vara performed and a complete sat of reprceentatiee tissue# aad organs vaa takaa (root aack rakkii and preserv'd in tormolin. Microscopic enamteatleae of oalactad tissues and organa ara made to ascertain tka praaoaca or akaaoca of histopathologic change at a result of dermal applications of (hr irat material at the dtif levels employed. The doeage schedule aad other pertinent data are presented in Ta ble I. Tka BS'erltt la iMa report viteto--d the pmjort t"J > to *w to "*** t hi. not f to ve-d to f-n. o advarintan r*r ",, ,, , r- f - d-'t+ tH.1.1 -l aPto*"* J,,,*W. IW-tlMOS. kor. .*S tea.te`4le*.el p,y|. mUHhoot.h.a-t m.l aflto M-'-i lh^ VM in Si Lomii <w nth- \ HONS m [yT Opowp T-C T-l r-n T-m TAau | WD*)t hhtaM Denial Taatclty . Mklw> laMln Mrnktr oi Amimmlt DMt|i kWili ssn-- */Wayl NamWr ef $t k*4*J**l l-- l 10 i *0 i IM <0 10 . 10 10 * AJmkUhrii ft* a 4.4 ytr tfftl ftalatlae la can oil. ** TV* ttftata* caaftnt rakktlft TftC.Wn **.. a| c.rft ail camfiraklc i *"> la Ikal ft|*lle4 ta Iha rakklla < Ik* kl|ft 4a.. |roup. HONS 050177 ' V' :. V- , '.' fti&W- D- iMrMlAWioubl Procedure A. Bwertmootal Animate TW animate employed la the tt4oy Hktnt. 4*r*ul toairtiy '*dv r i4till, Neo Ki!t4 attain atliM nMli. TW My *fl|M. or I hr tea! animal* orfe in thr toe-to-tbrae kilogram range. A total ot nM adult rabbit* oere aelectad frbm 0 larger population after Mmi- of rich animat for general pkyalcal oett-Wtng. Coek animal elected for tW anparimeni oaa Wuaed Individually in a oire.bottomed lumltii e*l rabbit cage for tW AintW ( |W teat. Alt rMii oere fed a etaadard laboratory rabbit ration* plue oater >4 UMlaw. B. Method of Application U pr|Mr<tiM for tW teat* the kick it uek rabbit war akeved utini rlrctric clipper*. TW aupoaur* alt* tho* prepared on rach an;* mat conetiluird approximately ita per cent of tW total body aurface arra. TW aoimala cr tWo returned to tWir alack cage** and 24 hour# oar* alloovd to rlagit Wforr tW llrat ptrcuar*i application* wrrt made. TW# period permitted tW akin to recover from tW alight diaturbance of tW etratom coroaum ca##d by tW clipping procedure aod alto permitted the Waling of bay microacoplc abraaion* poaa ibly produced during tW charing procedure. At tW cod of tW 24-Wur recovery period* the calculated doer a of tW teat malarial In tW form of a 4.0 per cent <o/v) com oil eolation Rockland Rabbit Ration* Rockland farm#* Mao City* Noo York. HONS 050178 w*fe gently (vIiImm rvbWni) ever the entire appt.i i,i>n #* on th<> (rat rabbits. Th* animals In (hr treated rairl group rr ir*ir4 if th. nmr manner dinar in th.- tret grown iih thr McrfHun that *f o;l alone *m applid to thr ill.. Following thr dermal application*, tho animal# wee return. 4 to their tdividnal cage* to await (rating on the following day. The above schedule waa followed every da, ioclosing week . rode, for a tola) of 20 ccnecutivt days. C. Body Wright Effects On thr mrrntng of thr firat teat day, thr body wnght o< eut. rabbit in avery group waa 4<rrmlnrd and recorded. Thereafter, indi vidual weighing# wrr made weakly and thr data recorded an index lb bdy weight affocta. Date calculation# wtr* made weekly to coin cide with chaogaa in body weight. 0. Mortality and lit adieus Chock a fur mortality and abnormal behavior*! reatnona w<n- mod* daily during thr 20-day taal period aa well aa during th. 14-dai obaarvation period. Special emphasis waa placed on ohoervatton* lor local akin reactions in vtdsr lo determine the degree of akin irritation produced by the last material. 1. Hematologic Simile# and Urine Analyte# Blood etudlra includ.ng dolarmlnatlona of hemoglobin concent ration# erythrocyte count, and both total and differentia! leukocyte HONS 050179 lOuata, #ri< mad* i iKf beginning of ihf etudy #nd at ihr end < h* td*day teat period. Ufliw iMlyiti for fiibtMiKM ind miirw ecop(< flrmrnii war** alno 4mm m th*ae lima InlvrviU. The blwod atudiea and urine analyse* wef* don* on the k*dJvdu*l rabbit in (h roup. F * Off iN MlcrntfU >tblaii jtudle* Amairmrali *ir nuf ( mbpci any (imI which might 4i* 4in| the ini to a iron *ulop*y. Aloo, In thote laatance* when poet-mortem change* were not advanced, faction* of representative tieaur* an4 organa war* ach*4ul*4 to b* taken for histopathologic ivd> . At the conchifioa of the investigational period, all surviving rabbit* in ach group w*r* aacrlfico4 an4 groat an4 mtcroacopic atudir* wrr* performed. The following titaure and organa mere included In th* microscopic atudiea: heart, aorta, lung, traebaa, Uv*r, gall bladder, panerrat, esophagus, ttomach, amall Intestine, caecum, colon, spleen, lymph n -de, kidney, urinary bladder, tvatia, every, proatate, uterua, pituitary, adrenal gland, cnbmaaillary salivary gl.md, thyroid, parathyroid, akaletal mutcle, bone marrow, peripheral n*rv>-f aptnal cord, brain, and akin. *ONS 001f Weekly Individual body weight* for each tail group and llv control group are aaarmblrd hi Tabtr D. 1ABUC a dy Weight Data Croup Animal Individual Body Weight* (Kilogram*} Number Teal Day Number: and See 0 7 id 10 Ob." ation Day Number M T-C 1-1 l-M i-r 1-M 2-F 2.31 2. SC 2.1b 2.61 2.31 2.63 3.00 2.64 2.41 2.60 3.12 2.04 2.17 2.00 3.24 3.11 2.74 2.46 J. 34 3. 37 T-n 1-M 2-F 2.10 2.2* 2.12 2.76 (2.17) 2.7S 2.66 2.7* 1 -U1 1-M 2-r (2.01J 2.10 (1.73) - ee NN Note: Figure* in parentheaia reprearnt autopay weight*. 4 ATtttl d?LL W B. MoIiIUy The morullty (Ul irr lummirlir^ In Tikl< III. TU d*i in- 4ic*l (M MwWr 4U the iota I number ( Bane* rfcdvrl prior to death. The mortality data were atatiatically enalyted employing th. technique of litchfitM M Wilcoaon*, iM the mean lubacute pmu> tanrouc lethal doer <LD$q) calculate* together with tw Li>0| 0, ar.d the LD^(f< For the puipo#e of theae calculation# the teat period *.m aitumrd to be 14 dayi, l.e. a JO-day application period plu# a two* week obaervatton period. All animal# that died during the interval, at each dote level, were used in c#tabli thing the per cent mortality for the do#e level. Tbe data are presented ir. Table IV and are graphi cally tlluatrated in Figure I. * J. T. Litchfield, Jr. and F. Wilcoaon, "A Simplified Method of evaluating Doan-effect experiment#", J. Fharm. h Exp. Ther., Vot. Pi, No. tj pp. 44-111 (1444). tOHS 050162 Group 1-C T *1 T*n T-in TAHLE 10 Summary Mortality Data NumWr Ttllftf Ntamtor D*U NumWr of (oo(iiv( Doifi Rf.fivfd i - i 0- i 1M i 1M 1r M 5 12 HONS 050163 10 TABLE tV SlKIllUil Anilyili of Mortality Oau Dotr mc/kg/dav Number Dead Number Totted 6beerved Per Cent Dead Eiprcti'd Per Cem Dead 10 0 2 0 0.0 SO 1 2 SO SO.O 100 22 100 99.0 Mean Subacute Drrmal Lethal Dose (LD^o) SO mi/ki/diy* 99 Per Cent Confidence Limit# of LD$o * 21 to 09 mg/kg/dav Subacute Dermal LDq.oi * If1** mg/kg/day Subacuir Dermal LDq^,^ * ISO mg/kg/day * The LD)o apoeiflcally refora to the dote which, administered each day over a 20*day period, would be eapected to kill SO per cent of the animal* dosed within the 20-day doting period plue an additional 14 daye during which the tat material < not applied. HONS 050184 MONS