Document 3JkoaaKpRorD67EKZxD5M7Qvn

project no: REPORT ounger Laboratories BiodtettulU ... PUatmactUoqUU ... Analy&U V 123 CLIFF CAVE ROAD Saint Louis, Mo, 63129 PHONKI TlLBEN 6-2540 % , * SDBJBCT - AROCLZR / Taxieologleal Investigation Of: NCI -29$ Monsanto Saaple Kuabor 57 Monsanto Project Nuabar 1-64-49 ' June 13th, 1964 soL FR-o') STTOT COMDCCTH) Id Monsanto Coapaay, St* Louis, Miasoar! GCFRSZXarUL PBOCDBRI - A) Oral U)}a (Rata, Mix*4 Sax) Tha undiluted eoapound aaa fed by atoaaoh taba to Spragne-Davley atraia albino aala and faaala rata* - Aftar tha approxlaata Nlalaua Lathal Dosa aaa dateralaad, groups of aala and faaala rata vara fad la increasing doaaa at laeraaaata of 0*1 fraotloaal log intervals at four levels designed to blanket tha toxicity range thereby supplying data for calculation of tha U>99 ahich aaa dona according to a aodifieatloa of tha nathod of S* J. do Boar* Obsarratioaa vara aade for toxlo aynptoa0 and tha viscera of tha aninala that aueennbad vara exaaiaed naeroaeopieally* Tha data are ahovn in Table Z* B) Skin Abaorption MU) (Rabbits, Mixed Sax) The undiluted eonpouad vaa applied in iaoreaeing doaaa at inereaenta of 0*2 fractional log intarrala to the closely clipped, intact dcin of Neo Zealand white aala and fanal# rabbits* -- The treated arena vara covered with plastic strips and tha aniaals placed in wooden stocks for periods ap to tvanty-four hours, after Mich tine they vara assigned to individual cages* Observations vara aade for toxic ayaptons and tha viscera of tha aniaals that succunbed vara exaaiaed aacrosoopieally* Tha data are shown in Table ZZ* 6BRNQ02919 LEXOLDMON002316 Tot KoBsuto Coapaap - - St* Louis, Missouri Younger Laboratories Certificate of Analysis - Pag* 2 (6/13/64) - 7-64*49 BCPEBIMEBTAL PBOCBOBI - (Coatinao4) O Skim Irritation (Babbits) Tho undiluted eospouad ous sppliod to tbs clipped, intact skis of sibiso rabbit* sad rcaoved after twenty-four hours* Tbs applieatioa * covered with plastio strips to retard evaporation sad avoid eoataaiaatloa* Observations vor* aad* over a period of several daps for irrltatloa* Tho data, scored according to tho aethod of Draise, Voodard aad Cslvor7 (Jouraal of Phara* aad Exp* Therapeutics, Toluao 82, Doecabor, 1944) ars shown ia Table ZZZ* S) Bp* Irrltatloa (Babbits) 0*1 Milliliter of uadllated saaple was placed la tho conjunctival sac of tho right epe of oaeh of three albino rabbits sad observations aad* over a period of several daps for iaflaaaatloa* Tho opes sore rinsed with vara isotoaie saliao solatia* after twentp-four hours* The data, scored accordlag to ths aethod of Dralss, *t al, are shoe* la Table IT. ' , X) Taper Inhalation (Mai* Bats) Sis aaturo aal* rats were placed ia a aetal chaaber ef 35*liters eapacitp aad exposed for six hours to a concentrated ataosphers of vapors produced bp passing a streaa of air through 130*nillilit*rs of tho eospouad eontaiaed ia a 30Osilliliter Srleaaeper flask* Vapors froa the flask passed iato a oae liter bottlo to reaovo droplets and thea into tho chaaber* Air floe through tho ssaplo was six liters per aiaate as seasored bp a calibrated rotaaeter* This was sufficient to violently agitate tho liquid* Vo suppleaeatarp air vas introduced iaaaaueh as the above supplp was aaplo for the aaiaals oxpgea requireaeats* Tho aaiaals eer* observed for behavior aad, sine* there eer* ao deaths, all were held for tea daps obsorvatioa* The data are ahoea ia Table T* sommaby - *.L;.UJ , / : . '* 1) Oral LD,, (Bats, Mixed Sex) `> l i Vi ' The Oral LD.V for aal* aad feaalo rats sas placed at 4200 ailligraas per kilograa with loser aad upper Halts of 3740 to 4700 ailligraas per kilograa* The coapouad sas classed as slightlp toxic bp oral ingestion ia aal* aad fesal* rats* B) Skia Absorptioa HU) (Babbits, Mixed Sex) Tho Miaiaua Lethal Dos* bp Skia Absorption ia aal* aad fsaal* rabbits sas fouad to b* greater than 301 ailligraas per kilograa aad less than 794 ailligraas per kilogrua* The coapouad sas classed as aederatelp toxLc bp skia absorptioa ia aal* sad feaals rabbits* 6BRN002920 LEXOLDMON002317  Tot Moaaaato Coapaay ' 1 St. Loula, Missouri lounger Laboratories Certificate of Aaaljreis - Poe# 3 (6/13/64) - r-64-49 SUMKAXT - (Continued) C) Ski* Irritation (Babbits) The coapooad mo elooood as a moderate akia irritaat whan appllod undiluted to iataot rabbit akia* .. . . Tho average nartawn ocoro sas 4*9 oat of a poaalblo la tmt^fow kstra. ` . 0) Bye Irrltatioa (Babblta) 1 .> < Tho eoapooad aaa elaaaod aa a aodorato 070 Irritaat* Tho iTtnft maxim oeoro aaa 41*6 oat of a poaalblo 110 la taeatyfour hoars* D Taper lahalatloa (Kale Bata) 111 aalaala aorrirod tho alz hoar exposure aa wall aa tho folloulag toa dap obsorvatloa period* It aaa coaeladod that tho vapora wore practically bob-toxic oador eondltloaa of tho toot* ; ,; / ' '\ TOONS2X IA20BAT0SZB Bit TSSD N. T00NQE1 \ I i Aa v / \ 2 Tb# material in this report is to be used in development ot the product and may be given to responsible sales ccnta:'--. but it is not to be ured by tb sm in advertising copy. T'r* source of this imperial is not to be di\v?f-'d vndl !; err^,! 5 in format publications. No exceptions to che p't :i ru.. inay be made without the approve! of the f. *:>./.;>! D.-P" " went in St. Leu 13. Customers' inquiriit rvyaj-di/v; ir ' * toxicity aro to be referred as before to the M.-diral Dip;-:- tnent in St. Louis for reply. -- Monsanto Chemiral Camper/ BBRN002921 LEXOLDMON002318 Tot Monsanto Company ' St. Louis, Missouri Tounyer Laborstorias Cartifieata of Analysis - Pays 4 (6/13/44) - 1-64-49 IABL1 Z THS OBAL LD,g OP 'MCS-295' FOB BASS Sample Pad Undiluted -i , Animal Me.Sex Weight ..a ! 1- Peaale 2- Peaale 3- Male 4- Male 5 Panels 6- Female 7- Male 8- Male 9- Panale 10- Panale v ' - 11- Male 12- Male 13- Peaale 14- Female 13- Male 16- Male 17- Female 18- Female 19- Male 20- Male 210 225 230 215 220 230 245 235 . 225 220 250 240 215 230 _ 245 240 230 245 250 255 Dose ' 3160 3160 3160 3160 3160 3960 3980 3980 3980 3980 5010 5010 5010 5010 5010 6310 6310 6310 6310 6310 ! Pate Survived Survived Survived Survived Survived Died Survived Survived Died Survived Died Sled Sled Sled Sled Bled Died 4 Sled Sled Sled DXSCQSSIOM - Tbs Oral U>9g for aula and faaala rats uas plaead at 4200 milligrams par kilogran with louar and uppar limits of 3740 to 4700 milligrams par kilogram. Thu compound urns classed as slightly toxic by oral iagastiou in mala and female rats. /. y V_ vy . Survival timo aas one to four days with most deaths occurring in three to four days. Toxic spaptons included severe diarrhea( increasing weakness, tremors, and collapse. At autopsy there was renal and liver hyperemia as well as inflammation of the gastric mucosa by macroscopic examination. GBRN002922 LEXOLDMON002319 Tot Monsanto Cospanp St. Louist Missouri . lounger Laboratories Certificate of Aaalpsia - Pago 5 (6/15/64) - 1-64*49 ~ I A > L I IX IBS MINIMUM LETHAL DOSS Off 'MCS- 299' BI SKIN ABSOHPTZOI II IABBIS Sasplo Applied Undiluted .. 1 1 VO Aniaal Mo. - Sa 1 - Halo 2 - resale 3 - Halo \ 4 - resale 5 - Halo 7 - Mala Voight iXL 3.1 2.6 3.2 2.9 3.4 2.S 3.1 Doso 501 794 1260 2000 3lfe 5010 7940 Teight Chsago 5 Daps Later Is. 0.0 - 0.2 - 0.3 mmmmm 0*3 -- ---- * _______ Tata____ ___ Survived Died -- 6 Daps Died -- 7 Daps Died -- 4 Daps Died -- 5 Daps Died -- 4 Daps Died -- 3 Daps * DISCUSSION - The Minima Lsthsl Doss bp Skin Absorption in anlo sad fsaslo rabbits was found to bo greater than 901 ad.Ulgrass par kiiograa and loss than 794 aHligrass par kilogras. The eoapouad was elassad as soderatelp tonic bp skin absorption in aals and fanalo rabbits. Survival tins was throw to savan daps. Aslda fros raduood appatits and aodaruta lathargp thora was littla show of toxieltp until approzinatalp twantp-four hours praoading daath. Zacrasalog vaaknass, tresors, and dpspnea appaarad at this tins. Autopsp findings iacludod livar with pallowish coloration and ranal kpparaaia. r * * . ; BBRN002923 LEXOLDMON002320 Tot Monsanto Coapany ' St. Louis, Missouri Touager laboratories Certificate of Analysis - Pact 6 (6/13/64) - T-64-49 mu xxz SKIM XBBXZATXQM Dt BABBITS AfTEB APPLXCATIOM OP 'KCS-295' Staple Applied Undiluted . .. _ Aniaal.Muaber Jfuaerieal evaluation At The Etad Of 1 gouy 24 Hours ^S. Sours J2Hours 12Q_Hours l6fl Hours 1 14 3 2 1 0 2 14 2 2 0 0 3 25 4 2 1 0 Average 1*3 4*3 3.0 2.0 0.6 0.0 DISCOSSIOi - The coapouad was classed as a Moderate akia lrritaat vhea applied undiluted to iataet rabbit skim. The average aaziaua score eaa 4.3 out of a possible S la twenty- four hours. Barely perceptible to veil-defined redness sas present after one hour. Overnight there as Moderate redness and edeaa for an average score of 4*3* There sas ao blistering. Xnflaaaatioa gradually reduced following reaoval of the compound se that withia five days only a trace of erytheaa renaiaed oa two aaiaala. \ GBRN00292M LEXOLDMON002321 Tot Monsanto Company St* Louis, Missouri lounger Laboratories Certificate of Analysis - Pago 7 (6/12/64) - T-64-49 - imi it . STS IBBITATIOM ZM BABBITS ATTEB AFPLICATIOM OP >MCS- 295* Sasplo (0.1 Milliliter) Applied Undiluted Animal Humber iuserieal Bvaluatioa At The Sad Of ljtour 24 Hours fB Hours 7? Hours 120. Hoars 168 Hours 1 35 47 41 30 19 6 2 2$ 36 29 19 0 3 32 42 33 22 12 0 iX CM Average 31*6 41*6 i 54.3 i 13*0 9 2.0 DISC1JSSX0S - The compound was olassed as a noderate eye irritant* The average aaxisua score eas 41*6 out of a possible 110 in twenty-foar hours* Discomfort ns noderate immediately following application* . Mild redness and edema, noderate lacrimetioa, and slid dullness of the corneal area developed within one hour* Congestion Increased aonewbat in twenty-four hours at which tine the average score was 41*6* Discharge had ceased and edena was still wild but iris details were not as clear cospared to the one hour reading, fithin seven days two animals sere free of inflaanation* Slight redness of the conjunctivas was still present on the third anlnsl* V GBRN002925 LEXOLDMON002322 * To Monsanto Coapaap - St* Louis, Missouri Touagar Laboratories Cartifieata of Analysis - Fag* 8 (6/13/64) - I-64-49 /** 3t *' ij j "1 --3 T3 1 4 TA BL1 T INHALATION Of 'HCS- 295' TAPOBS BT BAT* Araraga Tasparaturs Znaida Chsabar........ ............................. . Araraga Balatire guaiditp Znaida Chsabar .................. *................. .. Aaouat Of Saapla -- To Start Becortred .................... *............ Vaporised or loft la apparatus 150 os 149 00 79* p. 49 % Aaiaal Mo* - Sea . 1- Mala , 2- Mala ' 5- Halo 4- Halo 5- Mala 6- Mala Tata Surrirad Surrlrad Surrirad Surrirad Surrirad Surrirad Obsarratioas During Exposure Moraal braathing rata Mo paslag at tha aosa NO nasal diseharga ... Mo diacoafort Mo vaakaass* ' DISCUSSION All aniaala sunrlTad tha six hour exposure as wall as tha following taa dap obsarratioa pariod* Zt was eonoludad that ths vapors vara practieallp non-toxic undar conditions of tha test* Tha aaiasls appaarad naaffactad bp tha vapors* Thep shovad no diacoafort during azposura* Mo inflnaastios of tha ocular or sasal aucosao ass datactad shea tha aniaala vara raaored froa tha chaabar* 3ha tarn dap observation parlod ass uneventful. . BBRN002926 IIi LEXOLDMON002323 * jiounger Laboratories fifnimmUti . . Pkmima&lfiiU ... AnaLfiU it* CLtrr cAvm ma aimt Lout. Mes. Min raonli TII.D1I MI40 G&itijficcUe oj Analyiid, LEXOI nMDMnn9994 to: Ikatuto Jjapaay dt. loul*, Rlaaourl Inm*r UmtKoiIm ^irtUlati of rag* - / r_ 4pm 7 *' BmuvTiL rncsni. (c*ati*a*d) C) All Irrltatloa (Babbit*) Dm aadllatad aajinad oaa oplied to th* clipped, lotaat aula of ilblao rahblta ud raaovad after te.-ty four hour*. Th# *ppll*atl covered oito ylMtii atrip* to retard evaporation tad avoid eoataaiaatloa, Okoarratlooa **r* ad# over a period of **v*ral daya for lrrlUtioa, Th* date, acorod aecordiag to tte aataod of 3ralao, loo lard aad Calvary (Journal Of Phara. aad Ary. Th* .-apoutlea, Volua* S3, wocaafcar, 1J44) are how* la Table 111* 0; y* Irritation (Babbit*j 0,1 Hill liter of undiluted aaa pi a aaa placed la th* esajaaetlval aae of tha right ** of aaoh of thra* aieiao raboite aad ohaorratioaa aada over a period of aovoral daya for laflaaaatloa, Th* oyaa aort rlaaad vlth an laotoalo aallao aolutloa after teoatyfoar hoar*. Th* data, ooorad cordiag to th* aothod of Orela*, *t al, ar* ahooa la Table IV, . D Ta*cr lahalatioa (Mala Bata) Six aatur* aal* nt* wor* placed ta a aatal ehaabar of 33 liter* eapaolty tad *xp***d for six boar* to a eoaootrat*d ataoopharv of *ap*r* praduead by a *traa of air through 130 al111liter* of th* **fm i eontalaad la a 2V>alllllitor tall fora gao aaahlng bottl* alth fritted dlae* Vapor* fro* tha bottl* paaaad late a oaa liter bottle to raaov* droplet* aad thea late th* ehaabar* Air flaa through th* mapl* aaa 7 liter* per alaata aa *a**urad by a calibrated rotaaetor, lelo oaa aufflolaat to vieloatly agitato the liquid. ho aapploaoatary air a** la troda*ad laaaaueh o* the above aapply *aa **pl* for th* ahlaala oxjgta rmlraiiU. Th* aalaala or* oboorrad for bhavler aad, alnee th*r* oor* a* death*, all oora bold for tea day* haarvmtioa, Th* date ar* ahovn la Table V, UrJJl! A) Oral (Mta, NLa*d *>) Tha Otel U)ts for aala aad foaal* jate aaa placed at S900 aiili*r*a* p*r kllograa alth lo**r aad upper Ua&ta of 'BiO to 1j,H3 ailiigraae par kllograa. At eaapBd *aa elaaaad aa praatieally noa-toxic by oral lagoatioa in aal* aad faaal* rate* BBRN002928 Vt ' - .; LEXOLDMON002325 I FXm DMOMnno^oR roa Ito *t ftiieurl > * rilwfiu* CtfUflMU of Aaalyle - ftao 4 (7/2V*4) - Y-4V77 mu m oaa to,, or ? 1- 15 * fo> mxs I--pie Fad IIUUvM aol ho, - doc Oalftat <2 a. 1- faoal 0 2- Taoal0 V Halo V Nalo V Faflolo 0- faoala 7- Mala Mala 9- Faoala IO Faoala U- Halo 12- Halo IV Faoal0 IV Faoala IV Halo iv bio 17- Faoala IV Faoala 1** Halo 20- Halo 210 215 23C 220 210 205 235 240 220 215 245 .50 225 215 240 2 to 215 220 235 230 Ooao HiJLlh , 310 o,310 6,310 6, 310 6,310 7,940 7,940 7,940 7.940 7,9-JO 10,000 10,wuO 10,000 10,000 lO.Ouu 12,600 12,600 12,000 12,600 12.600 rata iaralaad Aurrirad iarrlved Sarrlrad farrtvad Died darrload Aarrlcad Died darrtced darrlaad Oil Died Oil Ivrlfat Oil 01 a4 01ad 3ied 01od *f : Tha Oral Uaa .'or aalo add f-.-aala rota oao placed at 3, 900 illifraaa par kila*iaa 1th loeer aad uppor llavta of 7, '30 to 10,145 1111 grow par Kilogna, Iho ooap foil* n ooo clmod m practically aos-taxia by oral lagoatloa 10 oola aad woloal tlM ooo oorototl hour* to foor daya ntt ooat death* ocearrlag la too to throo daya, Ttodo laptoaa inlaM ooooro diarrhea, locraaaiag iNkMti, 0011apoo, al ea of foor to Igfet boat* 4tt(o> At autopay toor* ooo iaflatotlta of the gaotrlo aad raoal ayparalo* BBRN002930 LEXOLDMON002327 St. 1>oule, Klnaourl I gill|tr Uiocmnw Oortifleate of Aoaljels - rags - l .w/&4, - -c j- '; Mill II SIX L-7HA1. JCAA .f TM- : j 4' BT SKIN ABSOBPTIOH Ui AUSalTS Saapla Applied Undiluted bo. - iex raaala ttO.0 raoala Halo Fanaia Hale lilgbt Axi. ..3 <:o A.2 2.7 2.5 2.a Joat &/.*<: 631 IjuO 1580 2510 2510 3* delgfct Cbage 5 Da/a Inter ____ >*2 0.2 0.0 ........ rata Survived oarrived Survived Died -- 2 Da/a Died -- 3 Da/a Died - Overnight DISCUSSION - Ike MlaiMB Lethal Jooe by bain Abaorptioa m aala and feaale pabblta aaa round to ba great*.* Uu ljdO aillLgreao par cxlagraa aad laoa Uaa 2jl0 atjlllgraaa . er magma. Ibo ~nT*--^ aaa tlaaaed aa aildly toxin bp tkla abaorptioa la aala aad feaale rabbi bo. Survival tlae aaa aovaral houra to tbraa da/a. Idzle a/ptoaa included laereading nanbanan, traaora, aaliratioa, aaa collapa*. At aatopo/ tkara mo puiaonar/ k/pereala aad liver discoloration. GBRN002931 f LEXOLDMONOQ2328 BBRN002932 Tai Nouni* Zom/msj St* toili lUmrl Timur UMwtwlil Cartlflaata of Analysis - Paga 7 (7/20/64) - 1-04-77 r a 3 l s iv <.1S IBB TATIOH IN BABBITS lUT-J AKf-UlATIvN II T9- 1 ) 9> tepla (0.1 WUiUtar) Applied Sndllutad Affaal Hunter tuaarlcal evaluation At fha fed Of 1 Hour 24 dours 4d Hours 72 Hours |.O_d0ura lbd_dour L lb :i 6 0 0 2 31 21 U 12 4 J 5 < 4 .'1 *4 0 Average 27.3 20.0 14.3 9.0 2.0 0.0 OISCU&SUN - Tha eoapound aaa claaaad aa a aedarata ays irritant. Tha average narliia aeora aaa 17.3 out of a possible HO la oaa Sour. DiaaoH/art aaa aodarata laasdiately following appllsatiaa* Silent sselli^ and laariantloa, aodarata radnaaa of the conjunctivas, and mid ins congestion aara aotad la ina tour. OinoAarge ceased overnight and iris clarity laproaad. A alight degree of radnaaa that raaaiaad ca tan an.sals aftar five 4aya dlsappaarad altitla aaaaa days. 6BRN002933 It. Lodi, Hieooeri Icwafer MantarlM Certificate of Aaaipala - rage a (7/20/64) - r-c>4-?7 raa l v ..F 'Fa- ; 5 < VArrNS dT A Avarua Teeveriture Inalde Ch-.acar ............................................................. Average Balatlve dueldltp :e lf.aae*r............................................... 'o* p. va t Aacwat of JapU -- :'o utert . in:o**r-d Japonted Left la tiouipeeat .. ` c: ( W AnLeal No* - j<tx 1- Male Halt u Hali* Mai* 5- Mai* Mala fata survived jurrii ad loraivad survived survived survived Obaareatioaa Ounaf No aaaal discharge ... No blincina . Ncraai areatoiog ... soee activity .,. ilii?ot iiacoefort after four 0ISCUM1CN-* , All aalaala aiimaed taa i lx aour axpooura ae veil aa the folloelr* tan dap ofcearwtioa period* It eea concluded taet the tapora were practical ip ao^ toxic under cjadiii ca :f taa teat* 'Qie vapore had little ->r ae affect upon *.aa er.iaala insofar aa ..:>ra a;;.-rvicee raveeled* Ocular tad aaaal ausoaae eara a-t inllaaead ahea the -iniaala *re removed free the inaeber aad raapiratiaa eas .loreel. Activity aad appetite retaraed -luiehij. Ike tea dap oheervetloo period ea xneveatf- l* 6BRN00293H Younger Laboratories BiockamUii ... (Wuumaeoiofi&U ... A*talfiU ias cmrr cavi ioao saint Louis, mo, 63X39 PSONSl TlLDSM 6*3340 Ge/itificate of AnaLfUi August Uth, 1964 SUBJECT - Toxicological Investigation Of: I<ydraul 2 80 Monsanto Sample Nuabor 102 Monsanto Project Nusbcr Y-64-91 .. STUDY CONDUCTS) 702 Monsanto Company, St* Louis, Missouri QCPE2IKZNTAL FSOCEOURi - A) Oral LD,0 (Bats, Mixsd lbs undiluted eoi albino sale szid< ube to oprague-Dawley strain After the and female log into; supplying modification ose vas determined, groups of male ____ Z doses at increments of 0.1 fractional Tela designed to blanket the toxicity range thereby tion of the LD90 which was done according to a of E* J* de Beer* Observations were sad# for toxic symptoms and the viscera of the animals that suecumbed vers examined macroscopieally* lbs data are shorn in Table I* B) Skin Absorption KLD (Babbits, Mixed Sex) The undiluted compound eas applied in increasing doses at increments of 0*2 fractional log intervals to the closely clipped, intact skin of New Zealand white sale and female rabbits. The treated areas were covered with plastic stripe and the animals placed in wooden stocks for periods up to twentyfour hours, after which tine they sere assigned to individual cages. Observations were made for toxic symptoss and the viscera of the aniaals that suceembed were examined aseroscopically. The data are shown in Table GBRN002935 LEXOLDMON002332 Ts Monsanto Company . St. Louis, Missouri lounger Laboratories Csrtiflcats of Analysis - Pag* 2 (8/11/64) - If-64-91 BCPZSZKEXTAL PBOCE5UBE - (Continued) C) Skla Irritatioa (Babbits) Tbs undiluted compound sms applisd to th* clipped, Intact akin of albino rabbits and removed after twenty-four houre. The application was covered eitb plastic strips to retard evaporation and avoid contamination. Observations sere aade over a period of several days for irritation. lbs data, scored according to tb* aathod of 2raise, Woodard and Calvary (Journal of Fbara. and Exp. Therapeutics, Volume 82, December, 1944) are shown in Table III. D) Lye Irritation (Babbits) 0.1 Milliliter of undiluted sample was placed in the conjunctival sac of the right eye of each of three albino rabbits and observations cade over a period of several days for inflammation. The eyes sere rinsed with warn isotonic saline solution after twenty-four hours. The data, scored according to the method of 2raize, et el, are shown in Table IV. 5) Vapor Inhalation - 350* 7. (Male Bats) Six mature male rats were placed in a metal chamber of 33 liters capacity and exposed for six hours to a concentrated atmosphere of vapors produced by passing a stream of air through 130-milliliters of the compound contained in a 300-milliliter Lrlenmeyer flask placed in a sand bath on a hot plate and the contents maintained at a temperature of 330* 7. Vapors from the flask passed into a train of two one-liter bottles to remove droplets and then into the chamber. Air flow through the sample was five liters per minute as measured by a calibrated rotameter. This was sufficient to violently agitate the liquid. No supplementary air was introduced inasmuch as the above supply was ample for the animals oxygen requirements. The m1 were observed for behavior and, since there were no deaths, all were held for ten days observation. The data are shown la Table V. SBMKAH - Pydraul 280 A) Oral LDj0 (Bats, Mixed Sex) The Oral LDj0 for male sad female rats was placed at 11,730 milligrams per kilogram with lower and upper limits of 9,370 to 14,390 milligrams per kilogram. The compound was classed as practically non-toxic by oral ingestion in male and female rats. GBRN002936 LEXOLDMON002333 tot Monsanto Conpanyf* St* Louis, Missouri lounger Lsboratorios Certificate of Analysis - Pago 3 (6/11/64) - T-64-91 SOMMABT - (Continued) B) akin Absorption KLD (Babbits, Mixed Sax) Sts Mini*m Lethal Dose bp Skin Absorption in sale and fwale rabbits was found to be greater than 1260 allllgraaa per kilogram and less than 200C milligrams per kilogram. The eonpound eas classed as siIdly toxic bp akin absorption in male and female rabbits* C) Skin Irritation (Babbits) Ow eonpound eas classed as a moderate skin irritant* The average ndan score eas 3*3 out of s possible 8 in twenty-four hours. 0) Sye Irritation (Babbits) The eonpound was classed as a moderate eye irritant* The average aaxlnua score was 31*3 out of a possible 110 in twenty-four hours* 1) Vapor Inhalation 330* P. (Male Sats) All animals survived the six hour exposure as well as the following ten day observation period* It was concluded that the vapors sere nildly toxic under conditions of the test* ycumin i.v.-oa'ircui-c '/^'`L it- - bt: ras m. iororaia __ io 1-rj i mm.sv;.. 1: o -i'.i.; I' J:jv 1 L't'- ssieern.ttt1 a C-i.-Scr^w* i< ltooxsiici :!)" rre to l>j re:>_r_ri_d__;.j .`u lUj * ; .-* 'f il-spjr;* hMt; ias JSeLt. Lboiuuiiae ((nomr reply. ~ Monsanto GtaaicaJ Company GBRN002937 LEXOLDMON002334 Tot Nomaanto Company St. Louie, Missouri Younger Laboratories Certificate of Analysis - Pag* 4 (8/11/64) - T-64-91 UBU Z THE OBAL LDjo 07 'Pydraul 280' FOB BATS Saaple Fad Undiluted Aniaal No* - Sax ieight On. Dose Ng* / Kg* Fate 1- Faaala 2- Faaala > Mala 4> Male 5" Feaale 6- Faaala 7- Male 8- Male 9- Feaale 10- Feaale 11- Male 12- Male . 13- Feaale 14- Female 13- Male 16- Male 17- Female 16- Female 19- Male 20- Male 220 250 . 245 235 225 230 250 245 215 235 250 260 225 210 24C 235 220 225 240 250 7,940 7,940 7,940 7,940 7,940 Survived Survived Survived Died Survived 10,000 10,00c lc.ooc 10,000 10,000 Survived Survived Survived Survived Died I2,6u0 12,60c 12,600 12,60c 12,oGu Survived . Died Died Died Survived 15,800 15.8CC 1560v 15,800 15,800 Died Died Died Survived Died DISCUSSION - The Oral LD90 for oala aad faaala rats aaa placed at 11,750 ailligraaa par kllograa with loaar aad upper liaita of 9,570 to 14,390 ailligraaa par kllograa. Tha eoepouad aaa elaaaad aa practically non-toxic bp oral iagaatlon In sale and faaala rata* Survival tine aaa several hours to six days aith moat deaths occurring in tnroa to four daps* Toxic spaptoaa included loss of appetite, severe diarrhea, increasing aeaknaaa, aad collapaa* At autopsp there aaa renal aad lirer hyperemia as sell as inflaaoatioa of tha gastrie aueosa* 6BRN00293B LEXOLDMON002335 To> Monsanto Ccspanj St. Louis, Missouri lounger Laboratories Cartificat# of Analysis - Pag* 5 (8/11/64) - T-6V91 T A B L ZI IKK MXXXMOM LETHAL 00S 07 'Pydraul 2 8 0* BT SKIN ABiOfiPTIuN IN SAB3ITS Saapla Appliad Dndilatad Aw>--t No. - Sex 1 - Kale 2 - Female 3 - Kale 4 " Female 5 - Kale 6 - Female , eight Kg. 2.7 2.3 3.0 2*4 2.6 2.8 Dose 1,260 2,000 3,160 5,oio 7,940 12,600 1 O VK eight Change 5 Days Later - 0.1 - 0.2 0.4 "0*4 - 0.5 Fate Survived Died -- 8 Days Died -- 7 Days Died -- 8 Days Died -- 5 Days Died -- 7 Days DISCUSSION - Tha Minimum Lethal Doea by Skin Absorption in mala and female rabbita was found to ba greater than 1260 milligrams per kilograa and lesa than 20CC milligrams par kilogram. tha eeapound vaa claaaad aa mildly toxic by akin absorption in aala and feaala rabbits. Survival tiaa aas five to eight days. ' Toxie syaptoas included reduced appetite, weakness in two to three days, and muscular iapainont particularly noticeable in the neek auaelaa causing the head to droop. At autopsy there was liver discoloration and pulaonary hyperaaia aaeroecopically. GBRN002939 LEXOLDMON002336 To: Monsanto Company * St. Louis, Hiaeouri lounger Laboratories Csrtifieate of Analysis - Page 6 (6/11/64) - Y-64-91 TAB Li III SKXX I1SIIATXQN ZH BABBITS ATTEB APPLICATION OF 'Fydraul 280* Saapla Applied Undiluted Animal Number Numerical Evaluation At The nd Of 1 Hour 24 Hours 46 Hours J2 Hours 120 Hours l6S_Hours 1 13 2 0u 2 1 3 3 2 1 Wr 3 24 3 2 1 c Average 1.3 3.3 2.6 2.0 0.6 0.0 DISCUSSION - The coapouad was elaaatd as a moderate akin irritant. Hie average aaxiaum score was 3.3 out of a possible 6 in twenty-four hours. After one hour there was barely perceptible to well-defined redness with no edema. Hell-defined to moderate erythema with very alight edema in twenty-four hours produced an average score of 3>3 following removal of the compound the average score reduced to 0.6 in five days at which time barely perceotibia erythema was still present on two animals. BBRN0029H0 LEXOLDMON002337 Tat Monsanto Coapu - - St. Loula, Missouri lounger Laboratories Certificate of Analysis - Pag* 7 {6/11/Si) - i-64-91 TABLE XV STS IMITATION IN BABBITS AJTB APPLICATION OT 'Pydreul 2 8 0' Sanple (0.1 Milliliter) Applied Undiluted ^ Munber Vuaerical evaluation At The Old Of 1 Hoar 24 Home 48 Hours 72 Hours 120 Hours 168 Hoars 1 2 3 Average 35 53 26 31.3 29 25 19 24.3 21 18 12 17.0 15 11 8 11. 3 9 4 4 5.6 4 2 0 2.0 DISCUSSION - The eoapound asa elasaad aa a aodarata eya Irritant. Tha average aaxLaua aeora van 31*5 out of a poaalbla 110 in twentyfour houra. Considerable dlacoafort developed following adalalstratioa. Slight edaoa and discharge, aodarata erythaaa of tha palpebral conjunctivas, and slid Iris congestion and corneal dullness ware noted within an hour. Edeaa and discharge disappeared overnight. Iaproveaeat continued following irrigation leading to an average score of 2.0 in seven days. BBRN002941 LEXOLDMON002338 Tot Monsanto Companj f St. Louis, Missouri lounger laboratories Certificate of Analysis - Ftgt 8 (8/12/64) - 1-6^91 TA BL V INHALATION 07 'Fydraul 280' VAFG3J BT 3A75 (350* 7.) Average Temperature Inside Chamber ......................................... Arango Balatlra Humidity laaida Chaabar............................... 79* 7. 53 % Amount Of Saapla -- To Start ................................................. 150.0 ee Becovsred ....................................................... 132.0 ee Vaporised or left la appantua....... 7*5 Coadaaaata la lat literbottle......... 10*5 ee Coadaaaata la 2ad literbottle ..... 0.0 ee cc(5.%) Aniaal_No. T-Sax 1 - Mala 2 - Mala 3 - Mala 4 - Mala 5 - Mala 6 - Mala Fata Survived Survived Survived Survived Survived Survived Obaarratioaa Oaring ibcpoaura Moderate discomfort la thirty minutes .. Occasional irregular breathing ..* Modante nasal discharge ... Soma weakness but no danger of collapse. DISCUSSION - AH animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were aildly toxic under conditions of the test. A temperature of 330* 7. was reached in approximately twenty minutes. The blue color changed to pale green and gradually turned to light brown in . four hours. A moderate degree of haze was present in the chamber throughout the test. Discomfort increased with time. Moderately severe inflammation of nasal sad ocular mucosae was noted when the animals were removed. All had a mild degree of bronchial rales. There was no gasping but breathing was somewhat difficult. Inflammation reduced in twenty-four hours and within three to four days breathing was nearly normal. The appeared in good condition at the end of the ten day observation period. GBRN002942 LEXOLDMON002339 Younger Laboratories &iockemiit& ... PkaMiacolotfidii ... Anahf&U 123 CLIFF CAVE ROAD Saint Louis. Mo, 63129 Phone: tilden 6-2510 SUBJECT - tyCSML -3/i Toxicological Investigation 0f MCS 312 Monsanto Saapl# Hashor 14f Monsanto Project gusher 1-64-133 November 12 th, 1964 STUDY CONDUCTED 70B - .. Monsanto Company, St Louis, Kiasoarl EXPEBDCDITAL PBOCEDTOE - - ' A) Oral LD,, (Bata, Mixed Sox) The undiluted coapound oaa fed by stomach take to Spragur-Dawley etraia albino aale and feaalo rata* After the approximate Minimum Lethal Dose warn determined, groups of aale and female rats aere fed in increasing doses at increments of 0*1 fractional log intervals at four levels designed to blanket the toxicity range thereby supplying data for calculation of the LDS, vhleh was done according to a modification of the method of E* J* do Beer* Observations were made for toxic symptoms and the viscera of the animals that saceumbed were examined mmcroseopieally* The data are shown in Table Xe B) Skin Absorption KLD (Babbits, Mixed Sex) . The undiluted compound was applied in increasing doses at increments of 0*2 fractional log intervals to the closely clipped, intact akin of geo Zealand white aale and female rabbits* The treated areas were covered with plastic strips and the animals placed in wooden stocks for periods up to twenty-four hours, after which time they were assigned to individual cagea* Observations were made for toxic symptoms and the viscera of the animals that succuabed were examined mmcroseopieally* _______ _____ The data are shown in Table XX* BBRN002943 |- _ * EXHIBIT LEXOLDMON002340 Tot Monsanto Coapaay St* Louis, Missouri lounger Laborstori*a Certificate of Analysis - Pag* 2 (1V12/64) - 1-64-153 HXPEHDGXTAL PR0CH30P1 - (Continued) C) Skia Zrritatloa (Babbits) ' 2b* undiluted oospouad was applied to th* slipped, intact akin *f albino rabbits and reaoved after tventyfour hoars* Ih* application eas oovered vith plaatie strips to retard evaporation and avoid contadnation* Observations vers sad* over a period of several daps for irritation* The data, scored according to the Method of Praise, Voodard and Calvary (Journal of Pham, and bp* Therapeutic*, Tolua* 82, Pecesber, 1944) are shorn la Table HZ* D) ye Zrritatloa (Babbits) 0*1 Milliliter of undiluted saaple vas placed in th* conjunctival sac of ths right eye of each of three albino rabbits and observations and* over a period of several days for Inflassatioa* 2b* eyes ver* rinsed vith earn isotonic saline solution after tveaty-four hours* The data, scored according to th* nethod of Praise, *t al, are shorn in Table ZT# - . -' S) Tapor Inhalation (Male Bats) your 150-graa sale rats cere placed in a glass desiccator, 250 an in dlaaeter, and exposed for six hours to a concentrated atnospher* of vapors produced by passing a strean of air through 100 aillilitera of th* coapound contained in a 250-aillilltcr Erlenseyer flask* Tapors fron th* flask passed into a one-liter bottle to renov* droplets and then into th* ehaaber* Air flov through the saaple vas five liters per ainute as neasured by a calibrated rotaneter* This vas sufficient to violently agitate the liquid* Mo suppleaentary air vas introduced iaasauch as the above supply vas anple for the aainals oxygen requireaeats* The anlnsls sere observed for behavior and, sine* there ver* no deaths, all ver* held for tea days observation* 2be data are shorn in Table ? SUMMAJK - ,. M CS 311. . ... .i ;. _ ., . A) OrallD,# (Bats, Mixed San) ' The Oral ip** for nal* and feaal* rats vas placed at 6300 ailligraas per kllograa vith lover and upper Halts of 5460 to 7735 ailligraas per kilogrua* The oospouad vas classed as practically non-toxic by oral Ingestion la sale and feaale rats* B) Skin Absorption MU) (Babbits, Mixed Sen) The Mialaua Lethal Pose by Skin Absorption in nale and feaal* rabbits vas found to be greater than 2000 ailligraas per kilograa and less than 3160 ailligraas per kllograa* The coapound van classed as slightly toxic by akin absorption in aal* and feaal*. rabbits* . 6BRN002944 LEXOLDMON002341 Tot Monsanto Coapaay ' St. Louis, Missouri lounger Laborstori Certificate of Analysis - Pt(i 3 (11/12/64) - T-64-133 SDMtUST (Continued) C) 8kla Zrritatioa (Babbits) Tho eoapooad w classed aa a slight skin irritaat ahoa applied ondiluted to Intaot rabbit akla* Tho average sexism score vas 1*3 oat of a possible 8 ia twenty*-four hours. 0) Eye Zrritatioa (Babbits) The eoapooad aas classed as a slight eye irritaat* . The average asriaua score vas 13*0 oat of a possible 110 ia tveaty-four hours. E) Taper Znhalatloa (Male Bats) All aclasis survived the six hoar exposure as veil as the folloviag tea day observatioa period* Zt vas concluded that the vapors vers practically noa-toxic under conditions of the test. . .. - TOGJKJEH LABORATOBZE8 V\ to be used in development of __ :via cnies contacts, GBRN002945 Moasuto LEXOLDMON002342 Tot Hoasaato Coupeay St. Louis, Missouri lounger Laborstories Cortifiests of Analysis - Page 4 (11/12/64) - 1-64-153 TAB LI Z THE OBAL LDJ0 07 'MCS 312' FOB BAS Ssjiplt red Undiluted Aaiaal Mo* * Sex Weight Dos* .S.U. . 9b/.Ki 1* Feaale 2* 7eaalo 3- Mala 4- Male 3- resale 6- Feaale 7- Male - Male 9- resale 10- resale 11- Male 12- Male 13- resale 14- resale 15- Male 16- Male 17- resale 18- resale 19- Kale 20- Male 195 5,010 210 5,010 230 5,010 22$ 5,010 220 5,010 210 6,310 240 6,310 230 6,310 . 20S 6,310 215 6,310 250 7,940 230 7,940 215 7,940 22$ 7,940 245 7,940 230 10,000 210 10,000 223 10,000 240 10,000 250 10,000 _____ .Hi:___ Survived Died Survived Survived Survived Died Survived Survived Died Survived Survived Died - Died Died Survived Died Died Died Died Died DXSCUSSIOB - Tbs Oral LD,0 for sals sad feaale rats vaa plaesd at 6500 ailligrasa per kilograa with lovr and uppor Halts of 460 is 7735 Killlgraaa par kilograa* Tba eoapound was slassod as practically non-toad.0 by oral ingestion is lie and fasals rats* 4 .1 . . Survival tias ssa oas to four days vitk aost deaths oecurriag ia two days* Toxio syaptoaa iaoludsd ssvars diarrhea, treaors, dyspnea, and oollapso* At autopsy tberv vaa iaflaaaatioa of tho gastrio aueosa sad renal hypereaia aaoroscopioally. 6BRN0029M6 LEXOLDMON002343 Tot Moasaato Coapaay * St* Louio, Missouri lounger Laboratories Cortifieato of Analysis - Pago 5 (11/12/64) - T-64-133 mu ix '* TEX KIHIKUN LETHAL DOSS 07 'NCS 312' BI SXIX ABSORPTION ZR RABBIS . Saaple Applied Uadila tod Aalaal go* - Sex eight if* ^ ' Bess /* ;{ Weight Chaago 3 Says later 1 - Male 2 - resale 3 - Male 4 - resale 3 - Male 6 - resale 2.7 794 * 0.1 3*1 1240 - 0.1 2*t . 2000 ' - o*3 v 2.7 3160 0.4 2.4 3010 - 0*4 2.S 7940 -- rate Survived Survived Survived Died -- 6 Days Died -- 4 Days Died -- 4 Days DISCUSSION * -........................ The Minlania Lothal Dost by Skla ibaorptloa la salt aad feaale rabbita vaa found to bo greater thaa 2000 allllgraaa per kilograa aad leaa tbaa 3160 allllgraaa per klltgraa. . The ooapouad vaa elaaaed aa elightly tozie by skla absorptioa la male aad faaale rabbits* Survival tiae vaa four, to sis days* Toxic ayaptoss iaoluded gradual loss of appetite, increasing weakness, aad tresors. Violent convulsions aad squealing were noted approxlaately twenty-four hours before deaths At autopsy there'were hesorrhagie areas la the luags as well as liver discoloration and renal congestion aacroscoplcally* x T GBRN0029U7 LEXOI DMDNnn9^dd Tot Monsanto Coapaap ' ' St* Louis, Missouri lounger Laboratories Csrtifiests of Analpsls - Pt<* 6 (11/12/64) - 1-44-133 T A B L I ZZX orskim imztatiom zm babbits Arm application 'mcs 312* Saapls Applied Undiluted - Anlaal Kuabcr Huaerleal Evaluation At Ths Bad Of 1 Host 24. Hours 43 Hours J^Hours 120^ Hours 1 0X1 0 0 1 02 1 1 0 5 0 10 0 o Attruss 0*0 1*3 0*3 o3 0*0 DXSCUSSXOM - Tbs eoapouad was slasssd as a slight skim irritant Asa applisd undilutsd ts intact rabbit akin* As average aazlaua score vas 1*3 oat of a possible 8 ia tventp-four hoars* lo akin changes war# noted in oat hour* Overnight there vas barelp perceptible redness on two aaiaals and sell-defined redness on the third aniaal for an average score of 1*3* Mo edeaa dereloped* VLthla seventp-tvo hours tvs aniaala tore free ef color and all receifcd a score of cere la five daps* \t A \V Ai \ BBRN0029MB LEXOLDMON002345 * Tot Monsanto Coop*ay / St* Louie, Klaooari Younger Laboratorloa Certificate of Analysis - page 8 (11/12/64) - T-64-133 (ilLl V WHALATiar or a 3ia* tapobs bi un I iTrt|t Teoperatur* Inside Chaober .............. ........... . 78* y. Average Selativ* Huaidity Iaaldo Chaober ......................... 6a % Anoont Of Saople -- To Start Seoovered Taporlsad < Aalnl to. - Sex nt* 1 - Kale 2 - Male 3 " Mol* 4 - Kale -- Survived . Survived Survived Survived -- Observations During Exposure lo nasal discharge Vo dyspnn ... Kild lethargy ... Xo weakness or diseanfert ... Atlils appear uaaffeoted. . j DISCUSSIOI - .... 3 All aaiaala aurrived th* six hoar exposure aa voll as ths following taa day . observation period* .- ^ Ik no ooaeladod that tho vapors ear* praotioally ao>toxie under ooaditiono of j tho toot* l. . Aa oentlonod in tho table, tho anlaols appeared to be uaaffooted by th* ala hoar j exposare. Diseaofort ns nt o olilono and tho only change la behavior was olid * lethargy after approtdaatoly no hear* : The ten day observation period van oaeventful. 0 \ 6BRN002950 LEXOLDMON002346 =rc-'"cti . o; (^P;?.TFiL Younger Laboratories Biockeml&U... PUatmcualoqUU... AnalfiU 133 CLIFF CAVE ROAD SAINT LOUIS, MO, 63139 PBONEI TILDIN 6*3840 SUBJECT - DRkUL. Toxicological Investigation Of: MCS 39 5 Hoasaato Sample Humber 244 Monsanto Project Humber 1-65-213 January 10th, 1966 STUDT C0NDUCT3) FOB Monsanto Company, St* Louis* Missouri EXPERIMENTAL PROCBUBE * .. . A) Oral LD,0 (Bats* Mixsd Sax) Tha aadilutad coapouad as fad by stooaeh tuba to Spragur-Dawley straia albino ala and feaala rats* . After tha approximate Mialsus Lethal Dose was determined, groups of mala sad female rats sera fad la increasing doses at increments of 0*1 fractional log interrala at four larals designed to blanket tha toxicity range thereby supplying data for calculation of the LDj9 which aae done according to a modification of the method of E* J da Beer* Obserrations were aade for toxic syaptoas and the riscern of the animals that succumbed were exanined macroscopieally* . The data are shown in Table I* . i B) Oral MID (Babbits* Mixed Sex) .- * 1 The undiluted compound was fed la increasing doses at iaereaeats of 0*2 . II fractional leg intemla by stomach tube to Hew Zealand white sale and female rabbits* . .- . . Observations were aade for toxic syapton and the riseera of the aniaals that succuabed were exaained aacroscopically* The data are shown in Table n* ' < EXHIBIT GBRN002951 TkS* cca&daatUl nport i* sal to fa* e*d is aT faTM f Wtab| witkow* wiitMa fraimim * LEXOLDMON002347 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 2 (1/11/66) - y-6>-213 EXPERIMENTAL PROCEDURE - (Continued) C) Skin Absorption KLD (Rabbits, Mined Sex) The undiluted compound was applied in increasing doses at increments of 0*2 fractional log intervals to the closely clipped, intact skin of Ne* Zealand white sale and female rabbits* The treated areas sere eovered with plastic strips and the animals placed in wooden stocks for periods up to twenty-four hours, after shich time they were assigned to individual cages* . Observations were sad# for toxic symptoms and the viscera #f the animals that succumbed were examined aaeroscopieally* The data are shown in Table HI* D) Skin Irritation (Rabbits, Mixed Sex) The undiluted compound was applied to the clipped, intact skin of male and female albino rabbits and removed after twenty-four hours* The application was covered with plastic strips to retard evaporation and avoid contamination* Observations were made over a period of several days for irritation* The data, scored according to the method of Draize, Voodard and Calvary (Journal of Fharm* and Exp* Therapeutics, Volume 82, Decanter, 1944) are shown in Table IV* E) Rye Irritation (Rabbits, Mixed Sex) 0*1 Milliliter of undiluted sample was placed in the conjunctival sae of the right eye of three albino rabbits and observations made over a period of several days for inflammation* The eyes sere rinsed with warm isotonic saline solution after twenty-four hours* The data, scored according to the method of Draize, et al, are shown in Table V* F) Vapor Inhalation (Hale Bats) Four mature male rats were placed in a metal chamber of 35 liters capacity and exposed for six hours te a concentrated atmosphere of vapors produced by passing a stream of air through 100 milliliters of the compound contained in a 300 milliliter Erlenmeyer flask* Vapors from the flask passed into a one liter bottle to remove droplets and then into the chamber* Air flow through the sample was five liters per minute as measured by a cali brated rotameter* This was sufficient to violently agitate the liquid* Me supplementary air was introduced inasmuch as the above supply was ample for the animals oxygen requirements* The animals were observed for behavior and, since there were no deaths, all were held for ten days observation* The data are ahown in Table VI* 6BRN002952 LEXOLDMON002348 To: Monsanto Company St* Louis, Missouri lounger Laboratories Certificate of Analysis - Page 3 (1/11/6) - Y-65-213 SUMMARY MCS_ 3 95 A) Oral LDjq (fiats. Mixed Sex) The Oral LDJ9 for male and female rats was placed at 4615 milligrams per kilogram with lover and upper limits of 40^0 to 52^0 milligrams per kilogram* Tbe compound was classed as slightly toxic by oral ingestion in sale and female rats* B) Oral MLD (Rabbits, Mixed Sex) The Minimum Lethal Oral Dese for.male and female rabbits was found to be greater than 1530 milligrams per kilogram and less than 2510 milligrams per kilogram* - The compound was classed as slightly toxle by oral ingestion in male and female rabbits* C) Skin Absorption MLD (Rabbits, Mixed Sex) The Minimum Lethal Dose by skin absorption in male and female rabbits was found to be greater than 2510 milligrams per kilogram and less than 3980 milligrams per kilogram* The compound was elassed as slightly toxic by skin absorption in male and female rabbits. D) Skin Irritation (Rabbits, Mixed Sex) The compound was elassed as non-irritating when applied undiluted to the intact skin of male and female rabbits* E) Eye Irritation (Rabbits, Mixed Sex) The compound was classed as a slight eye irritant in male and female rabbits* The average maximum score was 6*5 out of a possible 110 in one hour* T) Vapor Inhalation (Kale Rats) All animals survived the six hour exposure as veil as the following ten day observation period* It vas concluded that the vapors were practically non-toxic under conditions of the test* GBRN002953 LEXOLDMON002349 to: Monsanto Company . St. Louis, Missouri lounger Laboratories Certificate of Analysis - Page 4 (1/10/66) - 1-65-213 TABLE I THE ORAL LD ,0 0? 'MCS 395' FOR RATS Sample fed Undiluted Animal No. - Sez 1- Female 2- Male 3- Female 4- Male 5- Female 6- Male 7- Female 8- Male 9- Female 10- Male 11- Female 12- Male 13- Female 14- Male 15- Female 16- Male 17- Female IB- Male 19- Female 20- Male . Weight Ga . 225 240 220 255 235 26o 230 270 255 255 250 255 225 265 255 200 225 245 240 265 Dose *Sz/.g: 3160 3160 3160 5160 3160 3980 3980 3980 3980 3980 5010 5010 5010 5010 5010 6310 6310 6310 6310 6310 Fate Survived Survived Survived Survived Survived Survived Died Survived Survived Survived Died Survived Died Survived Died Died Died Died Died Died DISCUSSION The Oral LD)0 for Bale and female rats was placed at 4&15 milligrams per kilogram with lower and upper limits of 4060 to 526o milligrams per kilogram. The compound was classed as slightly toxic by oral ingestion in male and female rats. SurwiTal time was several hours to three days with most deaths occurring overnight. Toxic symptoms included severe diarrhea, increasing weakness, tremors, and collapse. At autopsy there was inflammation of the gastric mucosa and renal hyperemia macroseopically. 6BRN002954 LEXOLDMON002350 '' ) To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - page 5 (.1/10/66) - y-65-213 T A B L X ZZ THE MINIMUM LETHAL OHAL DOSE OT *MCS 395' FOB BABBITS Sasple Fed Undiluted * Animal No* - Sex . Weight 1 - resale 2 - Male } - resale 4 - Male . 5 - resale 6 - Male 2.6 3*0 2.7 3*1 2*7 > 2.9 . .. . ' Dess 2&/J& 631 1000 1580 2510 3980 6310 : ; Weight Change 3 Days Later 0.0 0.1 - o.l - 0*4 --' 1 K0N 1 ': rate Survived Survived Survived Died -- 8 Days ,, Died -- 5 Days Died -- 2 Days . DISCUSSION - The Minima Lethal Oral Dose for sale and fesale rabbits was found to be greater than 138o ailligraas per kilogram and less than 2310 ailligrans per kilogras. The compound was classed as slightly toxic by oral ingestion in aale and fenala rabbits. \. v/ ' * Survival tine was two to eight days* Toxic syaptoas in aninals #4 and #3 included poor appetite in twe to three days, weight loss* increasing weakness, treaors, and collapse* At autopsy there was evidence of liver dysfunction and renal hyperenia. GBRN002955 LEXOLDMON002351 To: Monsanto Company St.Louis, Missouri younger Laboratories Certificate of Analysis - page 6 (1/10/66) - Y-65-215 TABLE III THE MINIMUM LETHAL DOSE OF 'MCS 395' BT SKIN ABSORPTION IN RABBITS Sample Applied Undiluted Animal No* ~ Sex 1 - Male 2 - female 3 - Male 4 - Female 5 - Male 6 - Female (eight 3-0 2.5 2.8 2.4 2.5 3*1 Dose 631 1000 15B0 2510 3980 6310 (eight Change 5 Days Later _____ Kfc_____ + 0.2 0.1 o.l - 0.1 * 0*3 - 0.2 Fate Survived Survived Survived Survived Died - 7 Days Died - 9 Days DISCUSSION - The Minimum Lethal Dose by Skin Absorption in sale and female rabbits vas found to be greater than 2510 milligrams per kilogram and less than 3990 milligrams per kilogram. The compound vas classed as slightly toxic by skin absorption in male and female rabbits. Survival time vas Severn to nine days. Toxic symptoms in animals #5 and #6 included reduced appetite and activity in three to four days with increasing veakness, dyspnea, and paralysis. At autopsy the lungs vere hemorrhagic and there vas liver discoloration nacroseepieally. 6BRN002956 * LEXOLDMON002352 To: Monsanto Company ' -- St* Louis, Missouri Younger Laboratories Certificate of Analysis - Page 7 (1/10/66) - 1-65-213 T A B L E IT . SKIN IRRITATION IN RABBITS AFTER APPLICATION OF *MCS 395' Saaple Applied Undiluted Animal_No*_-_Sex Numerical Evaluation At The End Of l_Hour 24_Hours 4S_Eours J2_Hours 12p_Hours 1 - Female 0 0 00 2 - Male 00 00 3 - Female 0 0 O 0 0 0 0 DISCUSSION - The compound eaa classed as non-irritating to intact rabbit skin when applied undiluted* No edema or erythema developed on any of the animals as a result of a twenty-four hour exposure to the undiluted compound* All animals received a score of zero throughout the observation period. GBRN002957 LEXOLDMON002353 To: Monsanto Company St. Louis, Missouri lounger Laboratories Certificate of Analysis - page 8 (1/10/66) - 1-65-213 TABLE T EYE ISHITATION IN RABBITS AFTER APPLICATION OP 'MCS 395' Sample (0*1 Milliliter) Applied Undiluted * . Numerical Evaluation At The End Of Animal No* - Sen 1 Hour 24 Hours 48 Hours 72 Hours 12o Hours 1 - female 7 4 2 0 2 - Hale 74 4 0 3 - Feaale 11 6 4 2 0 0 0 Aierigt ri 8.3 4*6 3.J 0*6 t 0*0 DISCUSSION - The compound *as classed as a slight eye irritant in male and female rabbits. The average naxiaun score was 6.3 out of a possible 110 in one hour. Little discomfort was shown immediately following application. After one hour there was slight discharge and redness, practically no edema, and very slight corneal dullness. Iris and cornea were clear in twenty-four hours and within three days only a trace of redness of the palpebral conjunctivas remained on one animal. GBRN00295B LEXOLDMON002354 To: Monsanto Company ' St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 9 (1/10/66) - 1-65-213 TABLE 71 INHALATION 07 'MCS 395' VAPORS BY RATS Average Temperature Inside Chamber Average Relative Huaidity Inside Chamber Amount of Sample -- To Start................................. 100*0 ec Recovered .................... 99*7 ee Vaporized or left in equipment..................... 0*3 ce (0*3%) 76* 7. 43 St Animal No.-Sex 1 - Male 2 - Male 3 - Male 4 " Male Fate Survived Survived Survived Survived 255riSiiSS5-5S^S5_SFPflHri No immediate reaction ... Normal breathing rate ... No discomfort or nasal discharge ... No weakness ... Moderate lethargy after two hours* DISCUSSION All animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were practically non-toxic under conditions of the test. The animals appeared to be unaffected by the exposure* Nasal and ocular mucosae were normal when the animals were removed from the chamber. The ten day observation period was uneventful. BBRN002959 LEXOLDMON002355 Younger laboratories QiockeMti&U... PkcvuMacoloqi&U ... AaaJ^iU las CLIFF CAVE ROAD Saint Lovis. Mo, 60139 PIONII T1I.DIN 6-3 840 SUBJECT - Toxicological Investigation Of: MCS>9-G Monsanto Sample Number 176 .. . Monsanto Project Number Y-66-151 1:- STUDY CONDUCTED FOR Monsanto Company, St. Louis, Missouri October 17th, 1966 % BCPESIKQfTAL P80CHHJSE - A) Oral LD90 (Rats, Mixed Sex) The undiluted compound as fed by stomach tube to Sprague-Dawley strain albino male and female rats. After the approximate Minimum Lethal Dose was determined, groups of male and female rats were fed in increasing doses at increments of 0.1 fractional log intervals at four levels designed to blanket the toxicity range thereby supplying data for calculation of the LDS0 which was dona according to a modification of the method of J. da Beer. Observations were made for toxic symptoms and the viscera of the animals that succumbed were examined macroscopieally. The data are shown in Table I. B) Skin Absorption MID (Babbits, Mixed Sex) The undiluted compound was applied in increasing doses at increments of 0.2 fractional log intervals to the closely clipped, intact skin of New Zealand white male and female rabbits. The treated areas were covered with plastic strips and the animals placed in wooden stocks for periods up to twenty-four hours, after which time they were assigned to individual cages. Observations were made for toxic symptoms and the viscera of the animals that succumbed were examined macroscopieally. The data are shown in Table II. 6BRN002960 LEXOLDMON002356 To: Monsanto Company St. Louis, Missouri founger Laboratories Certificate of Analysis - Page 2 (10/17/6&) Y-00-13I EXPERIMENTAL PROCSDCHE - (Continued) C) Skin Irritation (Rabbits, Mixed Sex) The undiluted compound eras applied to the clipped, intact skin of albino male and female rabbits and removed after twentyfour hours. The application was covered with plastic strips to retard evaporation and avoid contamination. Observations were made over a period of several days for irritation. The data, scored according to the method of Draize, Woodard and Calvary (Journal of Pham, and Exp. Therapeutics, Volume 62, December, 1944) are shown in Table III. D) Eye Irritation (Babbits, Mixed Sex) 0.1 Milliliter of undiluted sample was placed in the conjunctival sac of the right eye of each of three albino male and female rabbits and observations made over a period of several days for inflammation. The eyes were rinsed with warm isotonic saline solution after twentyfour hours. The data, scored according to the method of Draise, et al, are shown in Table IV. ' S) Vapor Inhalation (Male Rats) Four mature male rats were placed in a metal chamber of 35 liters capacity and exposed for six hours to a concentrated atmosphere of vapors produced by passing a stream of air through 100 milliliters of the compound contained in a 250-milliliter Erleameyer flask. Vapors from the flask passed into a one liter bottle to remove droplets and then into the chamber. Air flow through the sample was four liters per minute as measured by a calibrated rotameter. This waa sufficient to violently agitate the liquid. No supplementary air was introduced inasmuch as the above supply was ample for the animals oxygen requirements. The animals were observed for behavior and since there were no deaths, all were held for ten days observation. The data are shown in Table V. SUMHART M CS__9_0 A) Oral LDjg (Bats, Mixed Sex) She Oral LDjq for male and female rats was placed at 5260 milligrams per kilogram with lover and upper limits of 2740 to 3680 milligrams per kilogram. The compound was classed as slightly toxic by oral ingestion in male and female rata. GBRN0Q2961 LEXOLDMON002357 To: Monsanto Company St. Louis, Missouri lounger Laboratories Certificate of Analysis >> Page 3 (10/17/66) - Y-66-151 -7^3 siimmabt - (Continued) B) sic*n Absorption MLD_ (Babbits, Mixed Sex) The Minimus Lethal Dose by Skin Absorption in sale and feaale rabbits eas found to be greater than 2000 ailligraas per kilogran and less than 3160 nilligrass per kilogram. The compound eas classed as slightly toxic by skin absorption in male and feaale rabbits* C) Skin Irritation (Babbits, Mixed Sex) The cospound was classed as a slight irritant when applied undiluted to intact skin of sale and feaale rabbits* The average maximum score eas 1,6 out of a possible 8 in twenty-four hours. D) Eye Irritation (Babbits, Mixed Sex) The compound was classed as a moderate eye irritant in male and feaale rabbits. The average maximum score was 28.0 out of a possible 110 in one hour. - S) Vapor Inhalation (Male Bata) All animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were practically no-toxic under conditions of the teat. - Y0UNGEB LABOBATOBIES f yJ) - ' BY: FBED M.'foUNGEB .. GBRN0029&2 I LEXOLDMON002358 To: Monsanto Company - St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 4 (10/17/66) TABLE I THE OBAL ID 50 OF 'MCS 9 O' FOR RATS Saaplt Fad Undiluted Animal No. - Sex feight 8m . 1- Female 2- Hale 3- Female 4- Male 5- Female 6- Male 7- Female 8" Male 9- Female 10- Male 11- Female 12- Male 1> Female ~ 14- Male 19- Female 16- Male 17- Female 18- Male 19- Female 20- Male 215 245 230 255 210 255 220 245 225 265 215 250 230 245 220 240 235 255 225 260 Dose 2510 2510 2510 2510 2510 3160 3160 3160 3160 3160 3980 3980 3980 3980 3980 5010 5010 5010 5010 5010 _______Fate Survived Survived Died Survived Survived Survived Died Survived Died Survived Survived Died Died Survived Died Died Died Died Died Died DISCUSSION - The Oral LD90 for mala and faaala rata was plaead at 3260 milligrams per kilogram with lower and upper limits of 2740 to 3380 milligrams per kilogram. The compound was classed as slightly toxic by oral ingestion in male and female rats. Survival time was several hours to four days with most deaths occurring in two days. Toxic symptoms included weakness in two to three hours followed by tremors, dyspnea, and coma lasting for several hours. At autopsy there were hemorrhagic areas in the lungs and renal congestion macroscopieally. GBRN002963 LEXOLDMON002359 To: Monsanto Company St. Louis. Missouri Younger Laboratories Certificate of Analysis - Page 5 (10/17/66) - 7-66-151 T A B L II THE MINIMUM LETHAL DOSE OF 'MCS 90* BY SKIN ABSORPTION IN RABBITS Saaple Applied Undiluted Animal No. - Sex 1 - Male 2 - Female 3 - Male 4 - Female 5 - Male 6 - Female Weight .U:. 2.8 2.3 2.9 2.5 2.8 2.6 Dose 501 794 1260 2000 3160 5010 Weight Change 5 Days Later _____ ________ 0.1 0.2 0.0 - 0.2 - 0.4 -- Fate Survived Survived Survived Survived Died -- 6 Days Died -- 2 Days DISCUSSION The Minimus Lethal Dose by Skin Absorption in sale and feoale rabbits was found to be greater than 2000 milligrams per kilogram and less than 3160 milligrams per kilogram. The compound was classed as slightly toxic by skin absorption in male and female rabbits. Surriral time was two to six days. Toxic symptoms included weakness in twenty-four to forty-eight hours, loss of appetite, and tremors. At autopsy there was pulmonary congestion; otherwise no visceral changes of consequence were noted nacroseopieally. 6BRN0029614 i LEXOLDMONOO?3fin To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 6 (10/17/66) - Y-66-151 TABLE III SKIN HABITATION IN BABBITS AFTER APPLICATION OF 'MCS 90* Sample Applied Undiluted Animal_No ._-_Sex Nuaerical Evaluation At The End Of 1 Hour 2^_Hours 48,Hours J2_Hours 120 Hours 1 - Male 2 - Feaale 3 - Male Average 0 110 02 11 02 2 1 0.0 1.6 1.3 0.6 0 0 0 0.0 DISCUSSION The coapound was classed as a slight irritant when applied undiluted to intact akin of male and feaale rabbits. The average aaxiaua score was 1.6 out of a possible 8 in twenty-four hours. No skin changes were noted at the end of one hour. Slight redness on all aniaals and two instances of slight adat were recorded in twnty~four hours. One aninal was given a score of zero in three days and all were free of inflammation within five days. GBRND02965 LEXOLDMON002361 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysts - Page 7 (10/17/66) - *-66-151 TABLE XV EXE IBBITATION IN BABBITS AFTER APPLICATION OF 'HCS 90' Sample (0.1 Milliliter) Applied Undiluted Numerical Evaluation At The End Of Animal No. - Sex 1 Hour 24 Hours 4S_Hours 72 Hours 120_Hours l68_Hours 1 - Male 29 20 13 9 40 2 - Female 24 17 94 0 0 3 - Male 31 24 15 9 40 Average 28.0 20.3 12.3 7.3 2.6 0.0 DISCUSSION - - The eonpouad was classed aa a moderate eye irritant in male and female rabbits. The average maximum score mas 28.0 out of a possible 110 in one hour. There mas blinking but no paming at the eyes following application. Moderate erythema, edema mith mild eversion of the lids, copious laerimatioa, and moderate corneal cloudiness developed mithin one hour. Discharge nearly ceased overnight and iris clarity improved. Edema disappeared within three days and only slight erythema remained on too animals after five days. BBRNQ02966 LEXOLDMON002362 *v To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 3 CIO/17/66) - f-66-ljl TABLE V Average Temperature Inside Chamber ...... ...................... Average Belative Humidity Inside Chamber ......... 77* F. 51 X Amount of Sample -- To start......................... Recovered ........... Vaporized or left in equipment........... 100.0 ee 99*9 cc 0.1 ce (0.1%) Animal Ho. - Sex ____ Fate.... .................... Observations During Exposure 1 - Male 2 - Male 3 ~ Male 4 - Male Survived Survived Survived Survived No initial effect ... Normal respiration ... No discomfort ... No nasal or ocular inflammation ... Moderate lethargy. DISCUSSION - All animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were practically non-toxic under conditions of the test. The animals appeared to be relatively unaffected during exposure. The eyes remained open and respiration was normal. Nasal mucosae were free of inflammation when examined upon removal of the from the chamber. No respiratory complications developed during the ten day observation period. GBRN002967 LEXOLDMON002363 Younger Laboratories ftiecAtmV** ... QliMmacolxfiiU ... Artalftii 133 CLIFF CAVE ROAD Saint Louis, Mo, 6SM9 PlONIi TILDEN 6*2840 Ge/dlfjicctie AtuzLfdH November 9th, 1966 SUBJECT - Toxicological Investigation Of: FTORAUL F- 9 Monsanto Sample Number 184 Monsanto Project Number T-66-159 3TUPT CONDUCTED FOR Monsanto Company, St. Louis, Missouri EXPERIMENTAL rRCCEflJKi - A) Oral LDj0 (Bats, Mixed Sex} lie undiluted cospound *ai albino sale and female ra to Sprague-Jawley strain After the approxl female rats wer log intervals supplying data modification o le ess determined, groups of male and fs at increment?, of 0*1 fractional __blanket the tcxiclty range thereby calculation of t*:e LJ,0 which was done acecriing tc a ' i. J. de Beer. Observations wer that succumbed oxic symptoms snd the viscera of the animals macroseopieally. The data are shown in Table I. B) Skin Abaorption MLD (Babbits, Mixed Sex} The undiluted compound was applied in increasing doses at increments of C.2 fractional log Intervals to the closely clipped, intact skin of Nee Lealand white male and female rabbits. Tha treated areas were covered with plastic strips snd the animals placed in wooden stocks for periods up to twenty-four heurs, after which time they were assigned to individual cages. Observations were made for tocic symptoms and the viscera of the animals that succumbed were examined macroseopieally. The data are shown in Table II. LEXOLDMON002364 To: Monsanto Company St. Louis. Missouri Younger Laboratories Certificate of Analysis - Fag* 2 (11/9/66) - Y-66-159 SUMMARY - fydhaoljt- 9 . A) Oral Ujo (Bats, Mixed Sax) lbs Oral LD,0 for salt sad female rats aas placed at 11,200 milligrams par kilogram with lower sad upper limits of 9.855 to 12,770 milligrams per kilogram. Ihe compound was classed as praetieallj bob-toxic by oral iagestioa in sale and female rats. BJ Skin Absorption KLD (Babbits, Mixed Sex) The Minimus Lethal Dose by Skin Absorption in male and female rabbits was found to be greater than 501 milligrams per kilogram and less thaa 794 milligrams per kilogram. Hie compound was classed as moderately toxic by akia absorption ia male and female rabbits. YOUNGS LABOiUTOkl^ ./ 77 <' -./' i - "' c ' '__y'f -- ' BY: FRtD M. YfUNGik S:....... ; i*' T.'. ; ha r.'.f r.t in j;;. v .. , te::;,;:;- tj ; meet in St. Louis !c: i^r i n .'..v'.ij.r '! ~ --' j co: j !I 1 :l. i. Monsanto C;npsny GBRN002969 LEXOLDMON002365 To: Monsanto Company St. Louis, Missouri lounger Laboratories Certificate of Analysis - Page 3 (11/9/66) - -66-159 TABU 1 THfi* OaaXs IsD^q CT 'PYDaAUa F-i' iW kA`fj Sample Fed Undiluted inimal No. - Sex Aeight GD . o *% CM 1- Female 2- Male 3- Female 4- Male 5- Female 6- Kale 7- Female 8- Hale ^ Feaale 10- Male 11- Feaale 12- Male 15- Female 14- Kale 15- Feaale 16- Kale 17- Female 18- Kale 19- Female 20 Kale 215 26o 225 240 245 220 255 215 25o 230 245 220 26C 225 :K 245 225 240 Dose Mg-/ Kg. 7,940 7,940 7,940 7,940 7,940 10,000 10,000 1C.0C0 1C,CCC 12,6cw 12,6ww 12,600 12, 6U 12,600 15, so* lifouC Ij.bCC 15.SC-U 15,'''-. Fate Survived survived Survived Survived Survived Survives Died Survived Died Survived Died oied Survived survived Died *'ii-. Jter. Died Died oled DISCUSSION - The Oral LD90 for nale and female r*ts ms placed at ll,2oC ailligrtir.: :-r Kilogram with lower and upper Units of 9,855 to 12,770 milligrams per kilogram. The compound was classed as practically non-toxic by oral ingestion in male and feaale rata. Survival tine was two to five days, Tozle sywptoas included weakness after several hours, diarrhea, loss of appetite, treaors, and dyspnea. At autopsy tilers was renal and liver hyperenia by naeroscopie examination. GBRN002970 LEXOLDMON002366 To: Moaaaato Company fife. Leate( Missouri Younger Laboratories Certificate of Analysis - Page 4 (11/9/66) - T-66-159 TABLE XX THE MINIMUM LLTHAL DOSE OF 'PYDKAUL F- 9' BT SKIN ABSORPTION IN BABBITS Sample Applied Undiluted Animal No. - Sex height il:. dose *-A*Ei Weight Change 5 Days Later _____________ 1 - Female 2.3 316 2 - Male 2.6 501 3 - Female 2.4 794 4 - Male 2.8 126c 5 - Female 2.4 20CX 6 - Male 2.6 316c 0.0 - 0.2 - 0.3 - 0.3 - 0.2 - 0.4 Fate Survived Survived Died -- 7 Jays Died -- 7 Days Died -- 6 Days Died -- 5 Days DISCUSSION - The Minimum Lethal Ooae by Skin Absorption la male aad female rabbits mb found to be greater than 301 milligrams per kilograa end less feaan 794 milligrams per kilogram. Die compound sae classed as moderately toxic by skin absorption in sale and female rabbits. Survival time was five to sewan days. Toxic symptoms included loss of appetite, lethargy, aad noticeable weakness in two to three days* At amtopmy there earn pulmonary hyperemia; otherwise no visceral changes of consequence were noted maeroecopically. GBRNQ02971 LEXOLDMON002367 Younger Laboratories &iochemiiU ... Plta^maaUatfiiU ... AttaLpUl 123 CLIFF CAVE ROAD Saint Louis. Mo, 63129 . PHONE: TILDES 6-2540 SUBJECT Toxicclogieal Investigation Of: FYDRAUL 2 fi 0 Monsanto Sanpie Number 186 Monsanto Project Humber Y-66-161 STDJY CuKDUCr.^> 5W Monsanto Company, St. Louis, Missouri hevexter ?t:., 19b'- SCFSaIMzJvI/vL laCCIDiikL - A) Oral LD$o (Bta, Mixed Sex The undiluted compound a male and female rats .rogue-Datley strcir. alt.no After the approj MiaAmVm LithaL/jcci was determined, groups of stale and female rats vex Ffed in iscR^aiagasses at increments of 1.1 fractional lor intervale at fi levels desi^fWTTc blanket the toxicity range thereby supplying data\ ealculal an of the LD90 which was done according to a modification ol me the J. de Beer. Observations were toxic symptoms and the viscer? :: the animals that succumbed were examined icroeeopicaily. The data are shown in Table 1. B; akin Absorption KLD (Babbits, Mixed Sex) The undiluted compound was applied in increasing doses at increments of C.2 fractional log intervals to the closely clipped, intact akin of New Zealand white male and female rabbits. ' The treated areas were oovered with plastic strips and the animals plaeeo in wooden stocks for periods up to twentyfour hours, after which time they were assigned to individual cages. Observations wars mads for toxie symptoms and the viscera of tne animals that succumbed sere examined macroacoplcally. The data are shown in Table IZ. 6BRN002980 Thi* cosfidatial report i not to b need in my fora of wfrorown* without written LEXOLDMON002368 Tot Monsanto Cospany it. Louis, Missouri lounger Laborstori os Cartifieata ef Analysis - Fage 2 (11/9/66) - I-66-161 SUMMARY FTLRAPL 2 8 0 A} Oral LOjo (Hats, Mixed Sex) The Oral LSjo for sale and female rats eas placed at 6,440 milligrams per kilogram with lower and upper limits of 6635 to 10, 360 milligrams per kilogram. The compound was classed as practically non-toxic by oral Ingestion in male and female rats. B) Skin Absorption MLS (Babbits, Mixed Sex) The Minisua Lethal Lose by akin Absorption in male and female rabbits was found to be greater than 20Gu milligrams per kilogram aai less than 5l60 milligrams per kilogram. The compound was classed as slightly toxic by akin absorption in male and female rabbits. YOUNGLR LABORATORIES BY: FKoD M.'-tOUNG-R The material in thia report is to be used in development oi the product and may be given to responsible ealee contacts, but it ia not to be used by them in advertising copy. The source of this material ia not to ha divulged until it appears in formal publicotions. No exceptions to the established rule msy be made without the reproval c: the Medical Depart* ment in St, Louis. Customers' inquiries reratding matters of toxicity are to bo referred as before to the .Medical Depart; ment in St. Louis for reply. . -- Monsanto Company GBRNQ02981 LEXOLDMON002369 To: Monsanto Company St. Louis, Missouri lounger Lahoretoriee Certificate of Analysis - Page 3 (11/9/66) - Y-66-161 TABU I TH OEAL U50 Of 'PYOiUui 280` IDE EATS Saapls fed Undiluted Animal No. - Sex teight On . Dose Mg,/Kg. 1- female 2- Kale 3" Fenale 4- Male 5" Female 6- Kale 7* Female 8- Male ^ Female 10- Male 11- Female 12- Kale 13- Female 14- Male 13- Female 16- Kale 17- Female 18- Male 19- Female 20- hale 22o 6,310 255 *,310 23C 6,310 240 6,310 213 6,310 2 So 7.940 225 7.940 250 7,940 220 7.540 270 7,940 225 10,000 265 10,000 230 10, tOC 2yC 10,wvv 225 . 10 f 0 JO 26o 12, tx 215 12,600 255 12,60c 210 12,600 240 12,600 fate survived survived Survived Survived ./ied survived ->ied Survived 01 ed Survived Survived 4>ied *>ied Survived Survived Oied Died Jied Oied Oied DISCUSSION - The Oral w50 for sals and fsaale rats sas placed at 8,440 milligraas per kilogra with loser and upper limits of 6.6J5 to 10,380 milligrams per kilograii. Tbs compound eas classed as practically non-toxic by oral ingestion in male and female rats. Survival time eas several hours to four days. Toxic symptoms included tremors after too to three hours, lethargy, loss of appetite, and collapse. At autopsy there eas inflammation of the gastric mucosa as sell as liver hyperes: 6BRN002982 LEXOLDMON002370 To: Monsanto Coapany St. Louis, Missouri lounger Laboratories Csrtifiests of Analysis - Pag* 4 (11/9/66) - Y-66-161 T A S L 2 II TBS MINIMUM LiZHAL DOSi OF 'PYDBAUL 2 8 0' BT SKIN ABSORPTION IN BABBITS Sasple Applied Undilut*d No. - Sax eight Kg . Dose eight Chang* 5 Days Later _ *. Male 2.6 794 resale 2.5 126o Male 2.7 2000 Fesale 2.5 5160 Male 2.7 5C10 Fesale 2.5 7940 C.O - 0.2 - 0.2 - 0.4 - u.3 - 0.3 Fate Survived Survived Survived Died - 10 ways Died -- 7 Days Died -- 7 Days DISCUSSION - Th* Hiniaua Lethal Dos* by Skin Absorption in sal* and fesale rabbits aas found to b* grsatar than 2000 silligrass p*r kilograa and lass than Jl6o ailligraas per kilogras. Tb* compound was classed as slightly toxic by skin absorption in sal* and fesale rabbits. Survival tin* was seven to ten days. Toxic syaptoas included weakness and inactivity after two to three days followed by treaors and collapse. At autopsy there was liver dehydration and discoloration as well as pulsonary congestion. GBRN0029B3 LEXOLDMON002371 Younger Laboratories feiockemUti-... Pha^macoiacfiiti ... Attaly&U 123 CLIFF CAVE ROAD Saint Louis, Mo, 63129 PHONE: TlLDEN 6-2540 SUBJECT Toxicological Investigation Of: FIDRAUL 13 5 Norember 9th, 1966 After the appr female rata ee intervals at i supplying datd modification o me was determined, groups of sale and has at increments of w.l fractional log blanket the toxicity range thereby on of the Ll/90 which was done according to a f E. J. de Beer. Observations wwr^eeda -Sdfr toxic symptoms and the viscera of the animals that succumbed sere examined saeroscopieally. The data are shorn in Table I. B) Skin Absorption MLD (Rabbits, Mixed Sex) The undiluted eonpound ens applied in increasing doses at increments of 0.2 fractional log intervals to the closely clipped, intact akin of New Zealand white male and female rabbits. The treated areas were covered with plastic strips and the animals placed in wooden stocks for periods up to 'twenty-four hours, after which time .they were assigned to individual cages. ' ' . Observations were made for toxic symptoms and the viscera of the s ninela that succumbed were examined saeroscopieally. The data are shown la Table XX. . -. `a . --* . GBRN002984 LEXOLDMON002372 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Pago 2 (.11/9/66) - T-66-160 SUMMARY FYPRAP1 13 5 A) Oral LD,o (Bats, Mixed Sox) The Oral LD,0 for aalo aad feaale rata aaa plaead at 4200 allllgraaa par kilogram with lower aad upper limits of 5025 to 5840 ailligraaa por kilograa. Tho compound waa elaaaod aa slightly toxic by oral ingestion in anle and feaale rata. B} Skin Absorption MLD (Rabbits, Mixed Sex) The Minimum Lethal Dose by Skin Absorption in aale and feaale rabbits ms found to be greater than 126c ailligraaa per kilograa and leas than 2000 milligrams per kilograa. The coapound sas classed as aildly toxic by akin absorption in aale and feaale rabbits. YOUNGR LABORATORIES r sent in St Louis for reply. --r Monsanto Company GBRN002985 A' LEXOLDMON002373 Tot Monsanto Coapanp St. Louis, Missouri louagar Laboratories Certificate of Analysis - Page 3 (11/9/66) - I-66-160 TABLE X THE ORAL LD90 OT 'FYDRAUL 133* JOB BATS Saaple Fad Undiluted Laal No. - Ssx asight 3a . Doss M_./Kg. Fata 1- Faaala 2- Mala 3- Faaala Ar Mala 5- Faaala 6- Mala 7- Fowls 8- Mala 9- Faaala 10- Male 11- Faaala 12- Mala 13- Faaala 14- Mala 13- Faaala 18- Mala 17- Faaala 18- Mala 19- Faaala 20- Mala 210 235 220 245 215 255 225 23c 220 265 215 240 230 265 225 270 230 245 230 265 3160 3160 3160 3160 3160 3980 3980 3930 3980 3980 5010 3010 5010 5010 5010 6310 6310 6310 6310 6310 survived Survived Died Survived Survived Died Died Survived Died Survived Survived Died Died Survived Died Died Died Survived Died Died DISCUSSION - The Oral LD90 for ailt sad faaala rata aaa placed at 4200 ailligraas par kilograa 4th loser aad appar Halts of 3023 to 5840 all11grass par kilogram. The eoopouad aaa elaaaad aa slightly toxic bp oral iagaatioa la aala aad feoale n Survival tlaa aaa savaral hoars to thraa dapa. Toxic syaptoaa included traaora la two to thraa hours, Alarrhaa, less of appatita aad eoas of six to alght hoars duration. At astopap thara ass raaal, liver, sad pulaoaarp hpparaaia ia addition to 1 lift aatlnii of tha gastrointestinal seas*. 6BRN002986 1* LEXOLDMON002374 Tot Monsanto Coatpany St. Louis, Missouri lounger Laboratories Certlfieets of Analysis - Pago 4 (11/9/66) - I-6-l6o TABLE ZZ THE MINIMUM LETHAL DOSA 07 'PTDRAUL 13 3' BT SKIN ABSORPTION IN RABBITS Sssple Applied Undiluted Aniaal No. - Sex eight Dose **/Ag. eight Change 5 Days Later _ Kg- 1 - Male 2.8 501 2 - Female 2.4 794 3 - Male 3.0 126o 4 - Feaale 2.6 2000 3 - Male 2.8 3160 6 - resale 2.5 5010 - 0.1 - 0.1 - 0.2 - 0.2 - 0.4 - c.3 Fate Survived .survived Survived Died - 11 Days Died -- 9 Days Died -- 8 Days DISCUSSION - The Minisua Lethal Dos* by Skin Absorption in male and fecsle rabbits was found to be greater than 1260 ailligrsas per kilogram and less than 2000 milligrams per kilogran. The compound ess classed as mildly toxic bj skin absorption in male and fesale rabbits. Survival tine nas eight to eleven days. Toxic syaptoas included reduced activity, loss of appetite, narked weakness, and collapse. At autopsy there seta liver discoloration and renal hypereaia aaeroqeopically. GBRN0029B7 LEXOLDMON002375 Younger Laboratories 133 CLIFF CAVE ROAD Saint Louis. Mo, 63129 BiockemiiU ... ... Analyiti 1 CentqiccUe. 0^ AnaiuUiPHONES TlLDIN 6*2540 Noveaber 9th, 1966 SUBJECT - Toxicological Investigation Oft HTJaUL A C Monsanto -ns pie Kuaber 183 Monsanto Project Nuaber T-66-156 STOkT CuNJBCT-L fUi Monsanto Coapany, at. Louis, Missouri iaPL2IMi.Wr-U. PkOCiDURi. - A) Oral LJ90 (tats, Mixed Tha undiluted compound albino sals and feasts ral s to opragueOasley strain After tbs appro/ hiaiMaLethaJ/J6se sas dstsrainsd, groups of sals and fsaals ratf ere fsd ia\gWS$dg dosss at inersasnts of C.l fractional log intervals four levels designed to blanket tbs toxidty range thereby supplying data' ir ealculai' an of the Lils0 ahicb eas done according to a codification of' 5f . J. da Beer. Observations were lie Tor toxic syaptoas and the viscera of the aninals that suceuabed ears exaained aaeroacopically. The data are shown in Table I. B) Skin Absorption KLD (Rabbits, Mixed 6ex; llts undiluted cospound saa applied in increasing doses at Inc vests of 0.2 fractional log Intervals to the elosely clipped. Intact skin of Mae Zealand shite sale and faaale rabbits. The treated areas sere covered with plaatle strips and the placed in soodaa stocks for periods up to teenty^four hours, after taiah tise they sere assigned to individual cages. Observations sere aade for toxic syaptoas and the viscera of the entasis that suceuabed sere exaained saeroacopieally. LEXOLDMON002376 Tot Monsanto Cospaap St. Louis, Missouri lounger Laboratories Certificate of Analpsls - Pug* 2 (11/9/66 - T-66-153 SDKMAST prjaAgL a c A) Oral LD,o (tets, Mixed Sax) Tbs Oral Lii50 far sals sad faaale rats aas plseod at 18,920 silligraas par kilograa sith lovar sad uppar lislts of 16,270 to 21,950 silligraas par kilograa* The eospouad sas elaasad as praetieallp nosr toxic bp oral ingestion in aala and faaale rats. B) Skin Absorptioa MLD (Rabbits, Mixsd Sax) The Miaiaua Lathal dose bp okia Absorptioa la aala and faaale rabbits aaa found to bo greater than 794 silligraas par ktlograa sad lass than 1260 silligraas par kilograa. Cta eospouad aas elaasad as aildlp to aodaratslp toxic bp skia absorption in sals and faaala rabbits. . rooNasi laboratories .1 * 1. Bit FRED M.*iT00NQEB cr* Jt The xpaterial in this report is to be used in development cj, the product and may be given to reversible tales contacts. Monsanto Ccmpar BBRN0029B9 LEXOLDMON002377 Tot Monaanto Company St. Louis, Missouri Younger laboratories Cortifiests of Analysis - Pag* 3 (11/9/66) - 7-66-136 TABU I THL QhAL Ui0 Of f-YOtiADL AC fON BATS staple fed Undiluted Animal No. - Sea eight Ga . 1- feoale 2- Kale 3- female 4- hale 3- Feoale 6- Kale 7" feoale 6- Kale feoale 10 - Hale 11- Feaale 12- hale 13- fmsale 14- Male 13- Female 16- Male 17- feoale 18- hale 19- feaale 2o- Male 213 230 2-5 260 220 2'j-i 233 233 215 26w 2'5 245 220 2 6o 21C 235 220 230 230 265 Dose Mg./ Kg. 12,000 12,600 12,60012,6uc 12,600 15,600 13.&OV 13,60c 15,800 15,800 20,000 V 2w,CJC 20,000 20,0oC 25,100 23,100 23,100 25,100 25,10c fate Survived survived -urvived survived Survived Survived -arrived -urvived Died Survived uied Survived sled Survived survived Jied Jied Died jied Jied DISCUSSION - Tbs Oral LD50 for sals and feaals rats *as plaeod at 18,920 milligram per kilogram with lover and upper Units of 16,270 to 21,930 milligrams per kilogrun. The conpouad was classed as practically aon-taocie by oral ingestion in sale and feaals rats. Survival tins sas several hours to nine days with aost deaths occurring in three to five days. Toxie syapteas included severe diarrhea, loss of appetite, trevora, and increasing seaknsss. . At autopsy the gastrointestinal trust eaa gaseous sad iaflaaued. Liver discoloration and renal congestion were also noted. BBRN002990 LEXOLDMON002378 To: Monsanto Coopaay iit. Louis, Missouri Touager Lsborstorios Certificate of Analysis - Fag* 4 (11/9/66) - Y-66-158 T A B L IZ TH MINIMUM LSTriAL DUO- OF 'rYLBAUL A C ' BT SAIN ABS0Z3TIv-N IN BABBITS Saaple Applied Uadilutsd Aaia&l No. - ocx 1 - Male 2 - Feasle 3 - hale 4 - Feaale 9 - Male 6 - Feaale weight 2.8 2.4 3.1 2.6 2.8 2.5 Sose Kg.ZKgj 501 794 X2&v 200) 3l6t> 5olo weight Change 5 ^ays later - is* . 0.1 o.O - C.2 - 0.5 - 0.2 Fate survived survived Died -- 9 Pays Lied - 10 Lays Lied -- 5 ^ays oied -- 6 jays DISCUSSION - The Minibus Lethal Dose by Skin Abserptios la sals and fasalo rabbits ass found to be greater than 794 sllligmas per kilogram and less than 1260 Milligrams per kilogram. The compound eas classed as mildly to aoderately toxic by skin absorption in sale and feoale rabbits. -arrival tise eas fire to tea days. Toxic syaptoas iaeluded reduced activity sad weakness in two to three days followed by paralysis la aaisals 43 through 46 inclusive. At autopsy there wars hesorrhaglc areas in the lungs sad liver hypereoia. ' GBRN002991 LEXOLDMON002379