Document borQzBNgoY277n29xKGGDX5g

/, / 9 r ^ :*u . -f.* y '-iXtyfy-J.* r- .?>. W" SSS-A ju>nuuTH2 CUTAKROOS ABD TOXICOLOGICAL ;:a i. OF PBCD0CT5 KVOLVTO IB H:E 2 ,h ,$ TIEaiLQItGPHiilCmCKTIC ACID STMTHE213 r,RSiaClTTKD BT KaKSAHTO CHEMICAL CdCPAMT, HITRO, V. 7A. C/.y i' General ObjeotlToa - ,v,-. - A* To dotem lno thei p o te n tia l u c n e /t ^ c iiy Brad a ^ te rtijrr a f f e c ts o f C hoired in A & "*ynth e c ls ' f .2 , $ W ichloropbancrx>aoc t i o Sz aO NN >D C~vll h-- * v> ' cc V.'.' ry;.**SCd^l. ~ ;"!; rirsi :7-y y -. , y -- B*` .To fu rth e r explore the pathocsneelg o f "oecupfet tie r e d acrw*, and tho ' ' 'v !?' ''arymrriidwrMojMi vvhhiicrAhi rr*sna1lt a d frcra narxrr-pLAoiamirr*a. to.n norxp**errKai tio n * oonc^rned if l th > | ^ 3>*v' tho production of 2,h,5-T> doaeribod In throe (3) prerviotia re p o rta v"- frc*i tfai* Laboratory. : >. ;. - - J i n * W l r - y ^ . -i_ .'-' f-i - - 1 Scpi.`ltt8nta.i. Background ^ , arT*y"elf th e l i t e r a t u r e "iranrWLlod p ap er wfclh oohocrned ItsflilT'* ' v* ' *'J', experim ental work performed on rab b i tc Adam o t al dLacueaed r ^ a tic m a , o f ;ra b b iia ta ecepound re p o rte d to her caused acnofom Nr--j:-.';;.'.."''**"* ` i- . i i " > . . ' v_-* 1.-V. 7.'i.'i..fti v';.v.*A->- ``./Ti.iiAvit .< * .s ..LflVr'.^Aii.vv. t i j in. non. -They.ooiaolodod th a t t b a i r a rid m c # ^ohcuii! ;rn `; 4%:V_ acnoforn d e rrm tltlo to be tho r i s l b l o rcw anuj o f the aicin to an ' `3 ? T O ^ i-V " :fe ^ ifritM it a c tin g upon i t fro a tho ex terio r, hnd th a t t h i c rej^^onfio . - -^k^ V ` h V'took tho fo ra of o p ith s lia l hyp^rplaaik, oeoondary in f la m a to r y and -TV ^'vr^ -; .,- x i . .. ;,-:^do24K5arattvo chanjoa, and f in a lly , ro c a n a ra tlv a procoaooa- . ' - .. . The technique dogar i bed by Adaraj and hla oo-uorkaro, urna ojployed in .th in L aboratory in concoction w ith a n o th er v a lu a tio n i n which ta&cam 16146 Pr'>9ar:-5p1 i^JCSr* >: - - -tSrl'T. V '.' 'Papok-y* V' --.v. ivrwproAiaad wi h i f ifttSod waa th e re fo r re^ardad a s a e a le a a f o r :rrrrryryy~'-r~ ---s.-w,,r >; i n . Tar*1n^T?^ ^^ ^r..-vf.. i\v ->-7n^ ^ ^ '> ^ ^ ^ - ' 8 ., c:->..rc_'>>r6;vtv*i,-ni>^.< Ah^jTt.Tm-ImISHtIi>Hlt^-V^- ^rlAi DOW 751740 - 2- a The ch so rru tlo n a of P a rn e ll on the p o s tn a ta l dcvolopartit o f tha i - V ' -- GbD^c plsndB of the r a t a appeared to provj.de a m ans o f e v a lu a tin g ~y~ 'r' r*v " " ! - - .'- r -''' > *I' *' in th is a flfaa l - *P a m r l l daacribed ih c 4rroIopraantal .vk chansira in th e sfcin of r a t e frao b ir th to 31 days. v.?. W.-l.iV*. ;~r *.-a.:>- .A*7?*-;.!.tear 0 to da;; 171 ,^VvWfcittjeoca'yUnAf re added elaBlx and dsrnal f a t xncreaaoa* > . 8 T*y 18 to toy 27i **I*-;.* ' v*v*i..*' ' ' j ^ v ' 7 * C. Cay 27 to day 281 Sebaceous c a ll enlarges and f i l l s v ith aobum a t the pens o f d a rt l fa t* Bobun c o lic disappear in tbo aocrotory phase* D. Day Rfl to day * li Stratua ganednativua i s activated* and - - 1 ' csebtaacceous c o llas a ra yap lacoed ra p id ly - - y - r o t , the daaper lay ers o the c a ll v * IW ' '' Bar# than uaa a Incvn p a tte rn in aebacooua gland devalopoent eherahy tha a p p lic a tio n of a cunpen tod acno&onlo r a te r l a l , in tha prop or t i a a p a rio c /* ig h t a it * ptan* "Ca o f the dyola and perhaps lo ad to ahaagaa * .._ -1.-.-\r - --.' -1 *. ;J .'- > . - *.'*; ,'v. .' ..-. ..% tha cebacaous glands end docta conparabla to thosa obasrvad in acao* '' ' &bT tri' l o ther reasons supported the s e le c tio n o f tlx* r a t as an w tp e ri- v 'i - - .. '*' ''*. . .. t '` ;-r;<'V'- * e n ta l a n in a l. F i r s t , tbo h a ir sycla a^id oooo<dtont a p id a m a l ohan^ea - * j tho r a t vere w all knovsi , Secondly, U>e oabocaoun glanda o f tha r a t * a ra w ell defin ed and e a s ily r c n ita b lo h is to lo g ic a lly T h ird ly f tb e ro woro c v s lla h le data <m the e f f e c t of rely in g v ario u s ohae^Lcal aubstanoos I S 1 4 7 to the opidermifl of the r a t **&.irt*91* * J * 'T '- f r * - (>>.* t ^ r \ . , V 1. - '-t;-;. r r / .^ . :.ViC. * - > ^ ' ' i h i t l i l ' rrouh~ o f" axp^rleaiita 6oe b f thir rripactad''lC iicge(C w /^*'i ^ ^ ^ ^ l l trlo h lo ro an lao la and aavem l control aubatanoaa .w a 'appliad-f^r ***** i<- - ;ilI-.'***} - 3- OO ;'l i f (ln co n sid eratio n o f P arnell* b d e sc rip tio n of ebiLcsous Land \ AOv....';> . t - y e^ws -. - '. . ' -' dsTIopooct) When occrpletely n e ^ tiv re s u lta ver observed in theoo ' cV^' r . x p ariaan ta, i t wuc docicted to apply tho sona sab stan cas in tt loua : 'v . t .... : ; ..... . r. , - -T r fchaaea o f th s h a ir <5ynl*n. I t fus boon re p o rta d by o n t in v e s ti ato r en O fiarciaogens ir* or* ffaotL'roly m ille d to o w ^ tk ia in anacen . r- 'r.X *C.tb* iscond group o f xpariw ooto th e r a t a vero trs a tm i i n v ario u s . * ... - V>*. -i :-ita0 M o f th e h a i r cycl* > .. ' : *~~. r_i. .: , > _ i ,..*& ; : .*- t - V V- / 3V ;'*' ) -- ja itn itta d a s w all as knewr am asu on tbo dyaloping Bsoebaoceoua eland a n d Ju alr f o l l i c i o f votine ra ta * .'Vy; : **. itfyk;. V. i--*_f #i*V.X-5.-..>.^.. ..>.- ' iAc T\. .V.`:L .. *r.\r'\.. -/* --r:A. ~ ~ .' .. ,, .>-.V.*.. atady th pffects o f .tha products subsisted as v a il as kzKvn^. marocca when app lied (taring s p e c ific otabas o f in* h a ir cyola, , talogvru . ; ':^.V:\ Cm '' To study tha affoots of tho repeated application of tha products * *. ' itubaltted and known acno,;ona to tho skin of btaran volunteer with c-.y ;particular rofarfsioo to tha piloebaoeous unit* ' r' ~ vV..J^P* ..7. obtain any infornation rocardin tha parcutanaous toxicity of ' ' * aubstancos aufcmittad, vhon thoy or* applied to rat or Inman 16148 rV* H atoriala and Mntbod8 *.k ; r1 ' , At Experimental Animla ? The r a ta were bred In th is Laboratory f i r * an elhjfln tra in ob- '* . .i - - ' * > ' f-T-i - i . . ta in e d froci Carvorth Parse, Rockland, Bow York Thu r e s u lta n t .*v < ' ' ' ' . T ; ' . . : *. V. ,r. a V l i t t e r s averaged 1 0 - 1 2 a n im la . Weaning uaa c a rrie d o u t a t the id or th re e (3) weeks. Rata were n o t re tro d fo r a t le a s t ona ` month follow ing weaning. Only wile r a t a war uosd throughout the J"i V. e x p e ric o n ta l work, \ *. 4 **;;-.'*;-*;.V k; 'f::\: \ 3* - Chaole a Is Employed! f ; 1* TrichloroaniBola ; - * ,: : ._v. .77. " vi'lf 8 Pontaohloroonlsolo ... ' <O1l H- CJ1 y: I f . .. t ;J, <*- V p e e lf ie gravity,OV792* ,ejt ,.V>f... .H*;t V--1 V" . v T -. . ^ i *v *,- : r* - 7# ''lialowax 101b" 7 Xnown act gens.. aaploycd a s c o n tro ls *v v~ - - The to a t so lu tio n s used fo r ft p lic a tio n to the sk in w e p repared .- * ` . * - i as $ i w eight In too tone so lu tio n axeo p t in the case o f 'Vrlngor Cake" which i a i diaoalvod in v ator. C Techniques i IS - 1 Anlssal h ipor i-w nta A a k in t e s t s i t e m easuring E p p ra x im te ly 1 obi i n d i s a s t e r , and 16149 >7?-- 'le c * ia d w ith i t s sn tm -lo r edge a t th s s f a s u l d a r - tb s r^VV.C m it ' * ' ' 4/^4 : ' * t 'r i * '* * of the acdaol vso jiaoti. ; V. - <v bw ? to rW n s of an tie d tr io Clipper, and';tiiU ' `'m & m 'i& r ^ 7 ~ : ttfflci tly o ften to T.:v: the h a ir toove -tbs tAcU scsrfaoe 'Jti&f-Mil rf/ft1*'TO DEROPNT ORfGiNAI s>-  I Y.*v- - 5- DOW 75175 lo s* than 2 can in lanfpth during the oxperlnent* . A nw duLwnau lfo l wera pJ J UaXinI i te d d a lly with a f u l l y w etted c& nelts hedr l' * tru ah (Bo. 1-3536 type c a p i t a h a ir hraah W* Onttobeeher, \T- v *** a d a ily a p p lic a ti * . t o e o U U d * f thro# C3) ;;::.7 V ;' v i ,vv.^P iaW t^painU nc w ith a fu lly w etted bm aU ....Later in tho . i : " J' " . :;.vVj:^ oouroo o f tho xporijaoata, fiv e (5) f u l l y v e tte d a p p lio a tio a o o f the bruah were caado each day. The t o t a l doee per tro at& en t ' : .V-dQ *i-v fo r aoh subatonoa a p p lie d was c a lc u la te d and recorded. D aily * * / \' , painting of the aniaala uaa continued fo r an appropriately plum ed length of tia o . (See Tables fb r to ta l dose applied in oaure. )* ^ f o l la i i a ^ t e t a f / t f c e i'r.i. '.nr*.-*1*1** j* \ >*' Ar v 5 L"V OAinala e re anoethe t i l e d w ith K eabutal^. given in tra c e r! to- * m M y t and necropsied. . / i l . ; . -- . {r,,^ # in the In v e s tig tio n s w ith trio h lo ro o n ijo la and th e Halcmxae .,. v ... ftrfetfattfmcftenntt pruerrdiorwdMs orvff rvrarr*yri`nntgT'dA'rwavtfi.fomnn vw*erren ArmpllonvyAed^ amn-wdl in itia te d in d iff ra n t phases of tho r a t h air cyole. .*! * The a n in a l experim entstlon was c o n tro lle d by tre a tin g a l i t t e r - - -- aate w ith tho T ahicle uord an a aolvant for the ch odoal being : : i ' . A r ----- . . . - < ; * ' . ..................- . . . . - .. S " . . . ' -\V ap p ralaed . Other o cn tro la war uood in d lffarein t pbaaoo of i the t o t a l experim ental p ro cess, and were aa follcw ai -16150 (V. - r I ,,.J . ^ . V . * ' T r a . Untroatod. ';' c'T'*.p-"-r.;v-- # .r.' ?/* - =y "w 1* a ' i ! tho.jJcin o f tb a xLlaal was ytrolaVt irt 'tk > AM r./A #- v > u /v v . - ^ w . ^ r v r " f . f V 1 ^ ^ 7.U>r^.:;7^V:y-- r m u m pad fb r t i a a j . ' ' :V*. - --- ^ *r.bfw,i:*-': " **/*-**- %" > . " * i, , \T n^* \* L'.` Vv->- '> 1 - 6- C7 o o* Hrush*dt tho ak in o r th a a n tm l was stro k e d or brushed w ith C l a d ry carnal* h a ir brash fo r 15 tin e a * cn cc d* P e tro la tu m tbo kin o f th e a n ln a l wu> rubbed w ith w hit' ,; p e tro ls tea* ' ' " '"" ' ; ;' *\ :' ; ir >: A ddA ttiH tie fteftaorlng appraxinataly- ttte\(<0i Inches in .' d ia a o te r and lo c a te d error th e c an to r o f th e scapula, was used* : The akin, a re a was p a in te d d a lly w ith one o f th e s e v e ra l n a te ria ls under study fo r varying periods of tia e as Indi es tod I n Tables 17 and V* Tbo t e s t a lt s a s observed a t . frequent Intervals and a t tbo cessatio n of treato o n tj a tisanes vara fixed D* Susnsry o f Paqperiaental Procedures i ; The d e ta ils o f each axpcrloent aro recorded In Tables I --VI and * " \+fj^ aay ba taanarlsed as follows i .-prrrv^i-a^"T7-- < w-.'j'..,,-w-V. ..J&porinflaita fXV.'.A$.i6\ . (T _ able -:s ... i 1 Sections A and B)* -. . TVJ - . , -- ^ . 8t h,5> tr lc h lo r a n la o le and the c o n tro l substances wore a p p lie d re p e a te d ly to the s k in o f yoimf: ra ts * These a p p lic a tio n s 16X51 v-`/~ * \ - 1 ' **" > rV~Ti OO - 7- Esperlnanta jTT r 8 (Table IX ). T ' -j.'T-vl >^5 trichloranaolo and tho control subatancafl were applied repeatedly to the akin o f young ra t during apoctfio ptasea o f ths h air ey d n . Tho t i n t .group of animals 'vas trea te d during ' 3)'emaeMifi*fe''i^gai?phasoa o ld :|rbop''during D ) mceaaivo ietogenpbaacs o f 'the r a t b aircy n la ' r-T* V. ' . >V 'ut. EEaxrprwerMimiuemntt, #M9 i(1Table m ) . ' .- i,$ trlohlorophenosyacotlo a d d , psentaoliloroaniaolo and r'-V &*'>*: *!'`y ringer Cako waro applied repeatedly to r a t akin fo r 60 " v Vy , .. .d a ily application in an attem pt to determine tho a ffe c t of ki Cl h* <F CJl aandECCi, **a applied Wpeated l^ 'to*'-' -;' the akin 6 t four (1*) huoan subjects w ith apparently normal V-rli- -akin fo r a period o f 2? days. y..-.y~;y '*^Vr . - Experiment #11 (Table 7 ). e * J,, * * * . '# p; ^V.VC,'. -Pfntaoliloroardoolo and 2,k,-T wore ap p lied repeatedly to the. *. - ^ **. ' ' * > ' , * ' r; \* ' ' "** ** ^ Skin of two (ft) groups of bnaon subjects (two in each group) . - v ;;. *-. w ith apparently normal kin, fo r a period of $9 day 16152 DOW 751755 tf.; -V. ' & . r ..* )w f ft:-.-*.'*-ji^w *.' - 8..-* .. ppi *'' :J*I ' ` '***. * . . V .'k/."y* ~Busnary of gladimsa -- ,,.y* ap p licatio n to the afctn o f y u u n g /m la ra ts tricfcloronniaolo to r varying periods up to n ~r,\ ; .V,ifiiuw:,vt.\- -jj *.-.* ' %.c;;-\.t%.-*.' .."T-.ynr r s < \ . c \ -i.. : $X s o lu tio n s o f ."Solim lG l*'.id *H*lo*x ^ >: la jr a ts fo r p e rio i up- to ) \ days fa ile d f e . -, V^.} ,.v., * .. .* ; -, - .--.. - .:." "V .or&m oyete c a . pathological ebangss in tho skin or other o f a .J f Solution of 2,1^$.trfohlorQanlooJo to. f . r . -to a s n okln, rtondod over a three^-aonth p erio d , produced no ^ 1 m / `V * y k# . A * , Ji*::^ o i l n in n i o r p a th o lo g ic a l Qhanea In tho akin* --- *+ ^ --J .________ 'a ...*....... 16153 ^ N y irl .f^ fethaliHfiaMl.:ahmaea in th* kla, c- 7 '^ ''.'`/ r . . " P * * ^ * i- * .' ;.. *` **l'*-`*. : .*-: - -rr.- ..'*'. - -- ''i**' *- V . . ` r " :: ... - 9- : c* Ihe application of a 5.1 so lu tio n of Halouax 1011;" to bomn afctn i .Vj.A-r" \ `. , V / ' over ft fournftok "period produced no c lin ic a l or pathological :. changes In the akin v, In terp ratfttlcn a and Oanaidratl-na fo r Future InvsatlR ation -- ... ^ ; *l5" . - - ff - T v . -- . oeares have bean reproduced u ith four (Ji) o f .the suspected s a te rla ls * * . *** knoira acnegoes such as *Haloajc 3001* ad " U m a x lolli" nndsr th e p e ria c n ta l conditions CRfuloyed* In r a ts , as mochas 372 of trich lo ro an lso le and the Holcuanos vuro applied over a period . 7\ . .: . -*v - . r ' * ' ' . -- j _ i-. , * _. ; .. t; o f "Wrin^* C*krtyro applied daring ii- 1 '" 'pfi chans** ^In hna*ra> itxpoahro. to. 0#h6,55 o f .V '* - T' -r ' , ****- -<- -.**r,:v;-1 *; , : .:v^'4 v w -Svkvr- i U '- i.li^3*vvhiC ?-V:p\y in ^3 -dally a p p licatio n s. ,1*06 am of pentaohloroanitola la :.;u^vv-*/ ;*v' ' *;; 53 d a lly ap p licatio n s, 1.06 graa o f In 53 daily applications, :.. ,, - v" ^ a s 133 90 o f Z, 5 trio liloroanU cle in O sario# of 96 tk ily :c--VV ' .'a p p lic a tio n s, produced no c lin ic a l or pathological offoot *V**'V' I t la apparent th a t the cirounstances w^iich brought about the c lin ic a l >' - prohlao in tho p lan t exposure were n o t approached in eith er the animal r - --'r-'- 'v ..... . .... , *_. : 16154 t r* 1 osporiam to* Borao p e rtin en t questions to bo raised In 00a - "/ rV* i r v . . T ' . ' "p'^-'-oj^V?; ' *v*<">-'*/ y * - ...... ..... DOW 751757 i 10 - . - , -. ' ` - v ' : > i . ' , ' . 4 ^ A- ;' . i ' , -i ' ' ^ V y A :;:. f e i ''; - ' .. A. A i I# tha r u t an appropriate experim ental nial fox* euoh a atadty? * - v- * \ - ' * A * i : '* ' %-\ ^ * : - v . " fT -' r - ^ 1 ; * ' ' ^ (_ -* # A y t i ' * c. jW thogw atw i t f ^ 1'' to*r to them qtM fftAonflver&ybe pLdftd in to t moreral :^ `\ ' j " -V a p p r o a c h a f l to th ie profclaa which should W uonsidared fo r '. v; ' '. the continuation o f th is A nveatigatiye program ->*i l* JLltfcough the. r a t sid a appears to have raaained o m lte ra d with composure employed -iatoa- x^fir<f?; j ,*.-.;^.--iri^/"-*'^-,'-^'*'t.V w-V^" *'-*<-?>.'-t*".->-- i--ry*\,'j**....'*>-*; _Vr_^,t; a n l a a l a which spontaneously develop, or In Wdch there nay >*''-<-<:V.-. . / i r:. '..-,---t - j v O - ' . - ' . - . ; . `" v ' < -? '. '- . . -j ^ .'. - ** \7. j j 1 v'* _,jr V i : ^ . 't * * - -- ;. ho induced, fo llic u la r in fla m a tio n ouch ao in tito dog or oat* I t wwld bo v o ll to oonnider a lso apectfic a lte a In ex p arlsen tal an sala in which thare la on abundanca o f .larg e aebaoeoua lando* Such a s i t s la the external au d ito ry canal o f the r ib h lt (not :r':V :iB 1 55tho akin o f the auricle \hioh w b ecployed hy Aden* and b is :" .-7 "*:X- - '-. --*~ '..<V - oo-worfcars) Tho usafulnoee o f th is area for larreetig rtio n .*.xtmt '^t*izr< jj j'(Wcrfhod o can tly * y DihriCTJ W'ffilfv.STTr^q:-V;t?wTj;.^ U - k u t - t o t v (+yM*V2}'c>#<%. .. ^ ;* ^ ^^ ^ ^ ' y{|. --''"**~C^T*r'^'* _ . S v V J i^ * g "'* > DOW 751758 t -H N* lik e ly th a t cutaneous absorption of aone^ena under experi -.1 mental conditions nay be H alted * To enhance euoh absorption \ : r:': the adiiiL on of W lb c ta n ta to the appliedocO ntlona m y bo - t. , . - .. , -i''s * - , __ ................... . trie d ...., 'V >- ^ *. - Oq -a . ci - >-> '-a ai _ ' 5- T t poarnibio th atb a n e <* i l l <jf tb o -few (li) obrfcanaM ^:V^Tj . `l-X.>^ ;.;J;^ ^trim lh4 fc ^ h j'^ -a a te rin la obosen f o r ' tW i n i t i a l study are ' ~not aonaconic* Severtholsos' elnce tha wrtboda o f .ap p raisal * V;Vf. produced negative re s u lts v lth known acoegeqs, those four (h) as v e il as the ran&indar o f the se to rio Is su h aitted , should be in v estig ated la future studied* *, should be recorded a s explore- ... /; /; fp tlre a c tiv ity should be carried out sinultAnooualy in. a e ra ra l directions i f progress is to be mdo. That new oases a ris e cu rrently in the 2,h#5-T synthesla^ dosp ite tthrefol reorganisation of the process and r ig id hygionlo precautions, Indicates th a t aenm^eno oro s t i l l belnr* evolved and th at t)w> p o ten tial basard is s t i l l present 16157 svsr/T x^1, ',-rt ' ^ TMr--***.':. . < " T!)afrcEt"p o i'C b i>r ' DOW 7517li0 I' .i' ; L- i t seems im perative, therefo re, th a t a fundamental investigation or vr j. .`.7,, v tho pathogenesis of *chlaracrioq and d dota ile d ap p raisal of tbo na- - te r ia la which gave ris e to th e liitro Syndroms, bo carried out* Hot)da of study oust be developed before the najor objectives can ' 'lx* approachod* I t w ill req u ire tb o Oeohlju>d s k ill and riin c of ' e c ia n tlflc d iscip lin e to naite tnoh watboda o f Study and tbs 'ap p raisal of the suspected acnegena, p o ssib le, -the study w ill require ' ri*' ` ' ` -*a long tar proras sy a tcn a tle ally organised, in idtich the problems Vi: * * j$>\;.-.-C' *" " any be assailed froa several direotloca drajltaneously. This atuefy Should be ccmddorwd in terms of not la ss than a throe to firo -y ear ';T,*VTfae prograa' fo r the next two ( Z) years should include th e following `i-T ''I,- la-V->" Vi- - cutaneous i ^ j ^ t a p t o )i(j t f w p fJcW _*^(5ena 1 - r t f . . *- . . . * . - |^y1^-'ther<jhaB doal n a W iils frota tho *^ h ,^ ~ 'j a iooa|f .sfiin a l l i e d . in high concentrations and over larr^o cutaneous areas bo a v ariety of experimental aninalo including dags, o a ts, r a ts , etc B# Detoraln too cutaneous and systemic effeota o f known aonegons '.'.'"TV" t ch ad ob1 m tc rla le frem the fc, preaeae when adeinlatared repeatedly over *n oxtandad period by 3jU3almtion"ftndr'h3r"rQral fesdlng* A v&riaty of experimental animals should bo used. '~?X-hr ' ' ' t - _* _ it> ** C U tilise the eobecoouo-rloh skin of the ex tern al auditory canal pftsf iitp-r&crt, v *'^ `. ' a ,.,.T -J . J id snd.jtotarnina; the e ffe c t .o f.wooffiBUI m -7. -.v-''<-----n*;v- -.------------ *.*--- 1-- ~~ J, * ' '. "" ~ . v;: r ;"-. 161SS WX-.- DoVV 7517b'l .'j L - ' 1 - ' * --li; ^ r' '* i ... : 5fifr*t'.:;:*-*:vVV-A- . .Da Ccntiitua tho humn eaqiarinonts in which known acnoons and . cbertical aa te r in la froa the procaoe aro to be applied , .repeatedly in high concentrations to areas oaon3y affected , . -ash *a Bftlar eninenceo, proauricular areas, ala nasi and to - ' '."* -i i ' .. ': - CV1'-/!` .'V ,`-i Surihco d ctiT o 'agitata noy'be tioad io absorption o f -'the acobseni and enhance ethod o f inducing plloeofcaoous changes in an in als oocparable developed, the cytologic and cytochoedcal a p p raisal a t ouch .A~-- mm yr;\^ -';cb an ee which nay b* induced fay in d iv id u al acnoGtma should bo c arried ^ .. rv-P. ' ........... j^ .in s lu d e ' th e .penaidaratina Of;lipddfl, 7ph*ph*t**ej* ''<" - ' .V;'' ^T'/d th e r e a ta r a n e f l,'^ and k eratin mm detearedned hlfftodw rically#" .'-v`.-'-ft: /^'rj7.\-'`iii:; ".*-/; . .... r- ; * -*.s *-*>' J \- -_ i; - i ', `f - ' ' : ' * _ - -\ ...." - i '-------------m-- . .* - ' > t .. i - k ""v : - T*- . w ,* > j,, . , ; ' - v , ' . ie tU rla g 'la b o ra to ry , in the Eeportaent of Proventlvo s Kodlaine, :College o f Kodldne, Dnivcroity of ' 11" - -V;-; - j - t . l ^ i - report byj , # > * * * ^ ^ ' V in ia n R. Buckloyi K*E. x tK ^rr'p -* ' ; - k arg o ro t W alker, * ' " 'Baywmd T+* BusCdnd, H.D. J. i v i v V - r - ` C 'l ' S f t s p ^ r c f ". |MfeSaV-.'ffc ' "' Appro,/nd ...: ... . ^ . ....................................i../..'.-.i..v.i *- ' ^,,r v..- ' i ,;* >fr . * , * . ' / ' * ' *' . . ' . v . 1 IW '^ * 1 TM W ifj r - r e r f / r t i c y j ^ ' ^ i . ,-w - x i.. * 16158 . Jtobort A. Keho#, iUU, Cdrcotor V7`.'She ^K rtterlaa la b o re to ry . ^ ^ - . . . - * * - - . j , . . :?* * ' ' " .* > . ' ;* w m m . V *w l * * *. M og A' ; v 9 t s *pJ00eU c r lT T BTX3 xprtJ i *o*2- DOW. 7 5 1 7 6 3 '..V "fr': xAoix X j*.:;.{: f ''lj*r 'I*-rTl. '! ,. - ,i .` Tba F ffoota o f Repeated A pplication o f 2,li5 Trt.chlorci.*ola, Btto** 10G1% and Control ____________ ________ :_____ :______________________ t e - t Ion A) - kperlnnnto :;ri?T* i-, f - -R * ** -* \k . -.fV' ; A .. An Co* Mo* o f /- `& . S ta r t p le tlo n : U irailon to ta l ))0f f .** o f : fiaao- ;i at- t T o rti. / v / '.V : : . . AnInalo, l t : _ o f . (m l* A *. Toot*'- . Tort AO; Ot ; AfVllO^i Applica r tlt* c a l i v i o cro p ^ f tlooo T?. tion ' Appll*4 na> f i h p i H atarlai* '* '* ,fc * Controlo : Chtroatod rota) Mrt&- '1 1 (Hoyo) ^* Ct*) i. l/x "A- (roy*)v .. p*a* . >* *V * f i ' H' U ntrm ta^ llntrofttoti 1 *. . 1 .1: A " -- -- 1 f' otl - ; 7. * ' -- t r __ _i 1 *.. . w A : -- Jj h- h - nfcroatod 1 . ` -- - ii - V V K ... f o i 'Ja . Aceton 1 .J 11. -i ' fl cjr lioiovsx 1 0 d K ", .. (5t by a t. In aaotonol .a w . 2Ii, 5 TrictUoro-- ntoola (5 t b7 \rtV- .. . * i ; / * i <"1*3: '* / i;** :r> 111 Hl A 'nirm tad Aotori "lUlcnmx lOi* % 1 i '- 1' . I 1 X 1 /r wf li . , "3 1:3 ` 1 lo io . ^ >s r.y , ,;i _ _ u v ! . T r ' '> *1: ?*' 'V :1 ' -' ; * - i t V t " ! 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(nw #*loj :p m i ; . ' *'+*'' M jg g : * v -.'y PravLort, iV N o . o f f f i B );, '> Applioa-. SJdn .: .vj Troublp jt,| Twt Mrttyil' Pwitachloro- tlooa V a r i m oajaolst (5 9** ia^ loo [53 - ; $ - " U aotono] ' F i* I ' : n S | p :*Vl->v.> t s S m J a u ia o Ia " (S ' * a . ,-O.C.. ( ? <' B c rn a l.}' *7 lo o ^ i l a a o o r i & " t M ontor 1 ! ' ' ! : i : - r T i . k - u. | . ! ; !,7 j u _ ( r m l o ) ;. r , :.`ii'ir , piornal I:, ^Hopa1 <: ?"`t ;-jp l ^ T trl* -..* .: o h lo r o^jrrnoncjM1 o o f t l o I d d '. (5:(P*iln 100, fe - f :; s : m 1 l y : ' C.a*! ( F q o ilo ) ;{ .!J610'i&i.\ , , .*;CI*ij* I fcrmX'rff. - 5 ' <! `.a ; .f-., '%.. r -.M f{ ; > g S ?r . yi'-fij c-tilio-ro^Swnoxjwj O r t l o ^ c i d Wi' (Spvom'ln IjOQ '( ** Voob) { S*- lili vj irlr.n ljo l) | | i*>i- s -v . * rm i. r . . A l ' kcn a ) V;|p' ^lf!rla M ff Si f f i s f f i i p af i t e t f f Toploal^P p*i.*i. yTTrTT- AScmy r s|>g<g;j 7ol|]Krll *7 iVf iu M- ' j y o d . f y*>^ H l 13 s i -V lg tjfl V ' j M * yj ^ t e 67 f f e t ': i i 8 :& . > ^ i t . T'^pio'U' ,-!) JSlar.Kr. " ^" ;AppU*dtjlj; ^ControX PlnUPflJ C jj . 0.06 iT < '-koatacm , _ - -K ;rr ? `gil?:* . ^Vr- * - i." A\: < ; // - *'*' DOW 7 5 1 7 al'> * ...............i. V.M \ v it - \\ 'y - \'.v 'm r:'-. \\\\& W S'C 'v ->s"fVd''s^Hs s? 1 T IL |v&. \ * ; >v y, \ % ss V. T . 1 Vr-.^V ' VS V \V V/*'