Document jBE6keydVQLBKbdd55m4X1Odp

than triohlorabensenaj that the intake of fatal doees (faivljr larga tuatittM perhape * to t tableapaenfula) pill oam m bgrperanla of all internal artua, extensive Atiiamtlfla af the liver, and daaaga of the b o m s neabranes of the etaaaoh. 11th aaaller data* these effeets are laaa severe and there la evidently aoaa tendency toward healing if further absorption af tha to d a material la proventad* Tba contact of Xnsrteea with the akin anuses dryaesa af tha akin* thlokanlng and sealing, and it appaars that sufflolart quantltlaa nay ba abaorbad lo this way to cause daaaga of tha liver* Zt appears that for abort exposure concentrations of 0*5 ag* par liter of air rapreaant tha aaxlaal allowable concentrbtian, and for continued exposure, concentrations below 0*05 ag* pwr liter of air. Dangerous concentrations, or at least potentially dangerous concentrations, aay ba recognised by drawing 10 liters of sir at a rata of about 1 liter per S minutes through a teat tuba contain ing 1 cc* of ethyl alcohol, cooled In dry Ice or in an lea salt mixture, and than pouring the aloohol carefully ou the surface of h few cubic cantlnetera of water In a test tube* If the concentra tion of Xnerteon Is ower 0*03 mg* per liter, a ahlte ring Is pro duced between the two layers* For the sefe handling of Xnerteen it appears necessary that NPCOD008920 200680 r* % I ;) f* e g e r n t n U a B i of Its vapors la d r aro kept bale* 0 * M ig par 11 tar of d r by adequate foread ventilation at the site of the production of such Tutors* Orootast perecnal hygiene is of paramount importance. Coo* taalnation of tha a d a should ba avoided bp prapar protective garments such as gloves, caps and coveralls. Zb case of aceldaata or vlth Short exposure to higher concentretlonsv of and above 0*1 ag par litar of air, rasplrators or opan air masks should be vom. She skin should be kept immaculately clean and ointments such as lanolin or Aquafor should bo applied to tha skin after tha ashing of ths hands* In visa of tha possibility of a toxic action of this material on the liver, parsons suffering from Injuries of tha liver (jaundice) syphilis, and heart diseases should be excluded from operations In vhieh Inerteau is handled* Workers handling Inartaan or with frequent exposuiv to its vapors, should undsrgo psrlodle oxaalnatlons; apsclal attention should ba paid to their nutritional condition, and the condition of tha liver should ba cheeked by dataralnlng the letarle Index In the blood and ths excretion of urobilin and urobilinogen In the urine. Regards tha treatnent of toxic affects of Znarteen, ths local lrrltatlcq of the skin should be treutsd vlth bland ointments after the toxic material has bean removed by Intensive washing and scrub bing. In case there is evidence of Injury of the liver, a diet rich In carbohydrates, administration of glucose end Insulin, and duodenal lavage witch magnesium sulfate may be beneficial. If laarfe ^slPC00008921 200681 +iratoi * * *# b hat been avalload, enetica uoh aa aoap vater or avatard atar ahould be civaa innediataly. Thi* ahould be foliovad bjr trie lavafo ith a auepaaalan oi activated charooal i& atar, and aallae oathartioa auch aa Epaob aalta ahould ba d T u to reaove any toxic notarial fro the intestinal tract* S.fc.M 4 4 t NBG00008922 200682 . i\o3 : \ ! ; ' ;;*vyin " ... . f-' i ;"I ] . i Medical Research Project Ho. MRTHE TOXICITY AND POTENTIAL DAHGERS^IHERTEEN Submitted by W. F. von Oettingen, M.D.', Ph.D. Director Haskell Laboratory of Industrial Toxicology Wilmington, Delaware. ,,emsGKOUsi EtECTtre. uro.co. EAsr.irtssy"-*i*iV* _ <jSCOJ?# ;J-S2 I.1$; - ;,v.# v.* .huj*-. Tv*/ i' ; v,.V - f.JJJ ;* ' v . . . v* * j*'' ; , N?COQL0O8923 -- ~J 200683 The Toxicity cad Potential Danger* of Znartoan and Mdated Substances, Including Method of Analysis forlalogenatsd BfdMottbflM in Air. V* F. too EDi , FtuD* The toxicological experlaaats on thin probloa voro oarrled out by Dr* J* B* Foulgsr bad Dr* A* J* Flaming of the Department of Toxicology and tho pathological otudioo worm aado by Dr* T* T* fiend, Jr* of tho Department of Fothology of tho Haskell Laboratory The aatorlal was investigated with oral adalaiotratloa to r.ts, application, to tho okla of rate, aad la inhalation experl* ae&ts* She latter voro plaaaod la such a way as to approach as closely as possible the actual conditions encountered in the use of this aatorlal in traasforaoro, in order to evaluate the maximal hasard hioh aay be encountered in its uee for this purpose* For comparison, additional teste ere Bade regards the toxic effects from inhalation of vapors from Pyreaol and Transformer Oil (Vest* Inchouse) Xn addition, a method as worked but for tbs detsr* aiaatioa of Inerteon in air* Effect of Oral Administration. In order to detersine the alnlaal fatal concentration of -Jaertssn for rata, 100 animala ere given by stoaach tube single doses of Zaerteea, as indicated in the table* Dose .Vo* of Ho* Of cc*/kgn* aninals dead treated Tine of death Per cent aortalIt; 1.0*1.49 1*9-1*99 fc.0-fc.49 fc*9-*99 2*0-9*49 a 14 10 00 so 9 4 * within 8 days 19.9 9 6 * m a 37.6 9 8* 9 90.0 10 9 + 8 ` 50.0 19 19 * 9 79.0 w.'ia". NPC00008924 200684 t Xn these, a in subsequent experiments, 11 ruts showed signs of disooafort immediately following th* administration, latsr they became depressed ad refuted, frequently, water ad foodi within fi hour thoj became max nd stuperows, o that they *r* finally uaablo to rise* Khan this tag* reached tby invariably died* On of ths* rats us found to suffer froa albuminuria, one developed treaora of the heau and fore-limbs, and one showed severe hemorrhages froa the intesti nal tract* She table indicates that with oral administration the a Inina1 fatal dose of Zaerteen for rets, which hills 76 per cent of the animals within days, is 9*0 to S*4tt cc. per kilo gram body weight* tfpon pathological examination of 0 of these aulaala, those that hud died spontaneously showed congestion of the i"- which was combined with edema and hemorrhage in several instances* Tan of the animals bed aottltd gray or yellow livers und in three instances there was a diffuse pallor with moderate yellowness* In 5 out of 6 animals studied microscopically the liver showed marked -nd rather extensive hyaline necrosis in the central part of tho lobules; the liver cells in this area revealed futty de generation of the cytoplasm; and in animals that died 5k and 54 hours after the treatment these cells contained increased numbers of dltotie figures* In the majority of the animals tht mucosa of the Intestine as congestsd and the fecal auterlal in the intestines contained old blood; and in m is instance fresh blood was found in the lower third of the ileum, lower colon, * NPe0ff008925 200685 ft and sigmoid. Microscopically the Jjmflfe of two anlnala presented typical hemorrhagic erosions of the mucosa; another showed haoorrbaglc era*a in the mucjs*; and in the regaining animals postmortem chamges did not allow an exact investigation. Zn order to follow up the toxic affect of Xaartaan on the liver, a group of SO white rata was treated in the etna wcgr with tingle oral doaaa of 1*15 to 1*0 cc. par kilogram body weight* Six of theae ware killed ft, 8, and 11 dajri, respectively, after the administration* Upon pathological examination it waa found that t*o of the 6 animals killed after Z days had bloody naterlala in their atonacba i.nd in 80 per cent of theae aniaala the liver vaa slightly yellow in color anu the liver cells were large and con gained nuxeroua nitoaes and occasionally there ^s necrosis of cells immediately about the central veins* Animals killed after 8 days presented a slight cnlargenmt of the liver with a ques tionable yellowish color, the livei cells were large, those urour the centrt.1 veins were dark, aid occasionally there was some fatty degeneration of these cells* Rats killed after 11 days allowed no important, gross pathology* Microscopically, all sec tions showed a slight swelling of the liver cells vith occasion* vacuolization o* the cytoplasm* Ko other organa showed patholo^ changes referable to the exposure* In order to study the effect of repeated of Inerteen, Z groups of 10 rats each were treated in the folio* i log way W:. NPCOO-808926 200686 4 The first group roooiTod from 0*80 to 0*64 oe par kilo for S consecutive daps* Sous of them died amd b were killed after the Srd treatment for pathological exmalaatlen* The seeond group a fed doses fro* 0*63 to 0 * M oe* per kilo* two died following tho tad dose and wore killed for antopmy after the Srd administration* 2n the third group the doses ranged frou 13 to 1*TB oc* per kilo* One rat died after the 1st three after the tad and four after the Srd treatment and the remaining aniaals were killed four days after the Srd treat ment* Upon pathological' examination the llrers of the rats of the first group appeared somewhat lighter than usual and one shoved large yellow areas; there was ; diffuse slid swelling of the liver cells r.ith some polychrosusia; occasionally th. cells showe some vacuolar changes ui the cytoplasm but in general these changes were not very severe* In 4 rats of the third group which died after Z treatments the stomachs were dilated with food and in two of these there was also some old blood present* Micro scopically one rat had snail inflammatory ulcers in the fore stomach and another showed hemorrhagic orosions of the pylorus. All shoved some hyperemia of the liver and in- one rut this was of nettled appearance* Microscopically tv.o rate showed swelling of the liver colls with fatty degeneration of those in the centn parts of the liver lobules* Two others presented central necros: of the liver cells with hyperplasia of the endothelial cells in these areas one showing in addition numerous mitotic figures 1 vNPC0'0'08927 200687 1 the liver cells* Of rats vhich re killed 4 days following the 8rd .dalnistration, one hat' snail saount of blood la tho gastric content* The liver of both anInals *p;*-rec moderately enlarged and aicroaco jieally there eaa a generalised evening < tb* liver cell aith no polychronasla* One rut suffered fro a fairly general vacuolar degeneration of the liver eells end another presented vacuolar changes in the central part of the lobules* In order to coapare the toxic effects of Inerteen with trichlorobeascne and ethyl-tetra-penta-cblorobansene, a group of 10 rats was given daily doses of trlchlorobensane ranging fro* 0*26 to 0*58 cc* per kilo body eight* One died after the 1st, four after the Lnd anu four after the 3rd adoinlstratlan, the regaining rat was killed 4 days follovln.,. the trd .rid last treatment. It appears, therefore, that dally doseo of 0*86 to 0.58 cc. oer kilo of trlchlorobensene killed 90 per cent of the animals Kith 3 aoses, whereas it as found that doses of 0*6 to 1*04 cc. per kilo of ethyl-totra-penta-chlorobentene. given in the suae way, killed only 10 per cent, und Inerteen in doses of l*u to -1*78 cc. per kilo, giveu in the sane nay, billed 80 per cent of the rats* Upon pathological examination, aniaals which acre treated _*ith trlchlorobansenc. u.uu which died a onvaneously showed a passive congestion of the lungs and the liver; the %ere distended vlth food; in four sone blood as present in the m m NPC00008928 200688 ft gastric content and la one instance there n i a haaorrhagie erosion of tba aueosa Zn two rats ths jjjjm showwd Irregular nottllng. Liver sections of all aalaals showed aeereals of the liver cells around the central veins and those la the outer parts shoved vacuolar degeneration* Za rets which died b to 4 a*/s after the first treatment there was sene endothelial hyperplasia in the areas of necrotic liver cells* One presented an increase in the nuaber of altotie flguree In the liver celle* Of the 7 rste treated with sthvl-tatra-nanta ehlacohansana. the one which died spontaneously after the 8rd dose showed con gestion and heaorrhnges of the lungs* generalised passive con gestion of the spleen* bone narrow anu other viscera, distended stoauch* and aoderute yellow nottllng of the liver, the liver cells being mildly swollen and showing fine vacuolar degeneration. The animals vliich were killed shoted only a questionable enlarge ment of the liver and kidney ana a slight swelling of the liver cells r.ith occasional vacuolar degeneration, .hich changes were extreaely aild* l.l .v.aafthrai...thmfgre U.ht ZattUta It m i roxlc than trichlorobenzene, the alninal fatal dose *lth oral administration, killing 70 aer cent of the anlaala. being around : 8*0 cc. aer kilo rat: vrhereas ethyl-tatra-panta-chlorobgnzene does not uoocar to be nearly as toxic with oral administration. . The patholqiflft1,1 chances observed after oral administration of Inerteen none: r to be fairly consistent and obvious. .Large dopes i'wmm Vi. NPCO0608929 200689 I T m t t i n fitol to m ar ,i p flui. t i n t i i m f 1 i ii i Iti llTr 1th necrosis around the veins. and lneatly. flf ttt ilttrtt M i l * uhl So m u .. mit.M n thr d a y tmtiUs Irritation and hoaatle a im of joeaaaratlan. the latter 1 decidedly if airkd a f t T Hht dare. and after ltrt d a y aa doft.ilto llw. natholorr ay be a n u n t . It f t W M l l M fct Mtttfti gilt ttftt single larse doaas anuaar to b >* in<uM... ^ such doa g l T n in fraction. Effact of application tn the Bkln Ion *hlte rati tr# treated daily with an application of at out 05 cc. of Inerteau to the shaved skin of the back, pre cautions being taken to prevent absorption through the gastro intestinal tract by licking and by inhalation All rats lost eight during thi experiment but thay shoved njo toxic si(pis aside fron a alight restlessness at the beginning of the ex periment. fit the site of the administration the akin became dry, thickened and scaled without any fissures being formed. Similar reactions ere observed on the human skin especially on the hands, cheeks and forehead One a; the rats dleu after U , and three after 15 treatments, the regaining being killed ' L4 hours after the lbth application Upon pathological examination the liver of all animals i-iiB found to be dark gray brown in color with mottling on the ''S'T'j NPC00008930 200690 t surface. In those rat which died spontaneously there a fatty degeneration of the liver oells with necrosis of those around the eentral veins and in animals killed at the end of the experiment there was a mild veiling of the liver cells with occasional vacuolar degeneruti >n in acne. Kioroecoplc&ULy the akin at the site of application of 4 rats thawed hyperkerstlnisation with occasional blieter formation, one animal showed perifolliculitis, one hyperplasia of the eolthellua rather than hyperkeratlnisation, and in 5 rats there was a nild fibroblastic prolifarstloo with sons round cell infiltration in the underlying connective tissue It appears, therefore^ that the contact of Inerteen with thm akin does not only cause local reactions such as dryneea. thlekonln uni scaling of the skin, but also systemic effects as indicated by the Injurious effect on tho liver. ?f f i c t i o n of Vapors. In evaluating the toxic effects of inhalation of vapors liberated froa Inertcen ut elevated temperatures, uttempts were made to reproduce conditions more severe tbau would be .net in the overheating of a transformer. In these experiments ratswere exposed in a limited space of about 1 cubic foot capacity to'the vapors of the boiling material which entered ^directly into the chamber through a hole in the bottom. In each experiment a ruts were exposed on 0 to 66 occasions for . fcO minutes, twice daily, to vapors from Inerteen, Pyranol, or pe&oooagu 200691 transformer Oil (1eetinghouea). Darla: this time they ho irritation of ttaa akin, which appeared to be most narked on s3> those parta of tha body not protected by hair, anu uieh peralatad for some tiaa aftar tha exposure. Pyranol appeared to produoa tha aoat affaet la thla respect, folioad by Xaartaaa and Transformer Oil, in the ordar given. la opposition to tha L rata exposed to Pyranol and transformer Oil, <S out of 6 rata axpoaad to Znartaan loot weight, but no othar toxic i l p a vara observed* Xt la quite peaalbla that rata axpoaad in thla ay abaortoad aona toxic natarial through tha gaatro-lateetlnnl tract by licking the fur during or after tha exposure since tha mate rial had a tendency to condense on the valla of the chamber and on the aurfacc of the* animala* She aaxiuun concentration of Inertcen to which those rats ere exposed was determined as about 0*5 m&* par liter of air Upon pathological examination of ruts exposed in this way on 14, S5 and 06 occasions to Xnerteen, no definite pathological signs could bo observed In the liver or other organs vlilch could be referred to the exposure* Two rata treated with 41 exposure* to the vapors of PyrunoJ .shoved no definite cellular changes in the ,,liver although in one there us an increased number of mitotic figures in the liver cells* Two rats exposed on 44 occasions to the vapors of Trans former Oil (baatinghouae) showed no definite pathological changes of the internal organa* NBC06008932 200692 xo lo ordtr to study tha offsets of ASttlttlflJHBttnCI* 10 rota vere axpoaad a hours dolly on a days o ok for 80 days to eoueantretlons of 0.00 a|, to 0*08 a, of Inertean par lltor of air* They ahoved bo toxic aor pathologies! signs rafaroblo to tba exposure} tbar art b o dafinlto ohanges of tha rod blood aorpuaelaa or tba hemoglobin* Xha aninale era killad 8 doya oftar 80 exposures* It oeara. therefore. that neither frequently repeated abort exposures for 80 mitmtmm n Cb to concentrations of 0.B me. of Inertean uer liter el*. no continued to concentre- tlono of 0.0B to 0.08 g. oar liter olr cause a definite toxic offaet on tba liver. Determlnatl of eencentratlons of Inertean In tha olr. In ordar to dataralae tba coacantrotlon of Inertean vtpors in the olr tha following nephtloaetrlc method oa eorked out, after several other proeadureo hod bean conaldored, 1 definite volume of olr to be tested is d r a m at a rota of about 1 liter every 4 minutes through a teat tuba containing S cc. of ethyl alcohol, Immersed In dry Ice-acetone Mixture In order to prerent the evaporation of the alcohol* At the end of the aompllng 1 cc* of the alcohol was mixed vlth 10 cc* of dis tilled voter and the resulting turbidity voo measured with e photo electric cell, usint, a sodium vapor lamp as the source of light. .* The turbidity of unknown samples vaa compared to the vNPC'dT0008933 200693 11 tubldltgr produead by knovn lUadardi itd* up af trlahlara bansana and ethyl alcahal* Skis nathad i t Mtlifaettrj raadlngs avar * r u | i fron 0*80 to 8*0 ng Iltar of air and vhon tba original dilutlana vara tukan lato iceoaat, lt vaa sufficlantlj aansltlva to dataat guontltlaa aa lov aa 0*08 ng* of Zaartaaa par litar of air* Tba mathod la aot paelflc for the Tarions maobars of tba huloganatad hjrdro- earbons but alaeo tho vapora llbaratad froa Xaortaoa ooaalat oalnly of trichlorobansana, aa vlll ba shown balow, lt a<qr ba uaad far tho dataralaatloa of Zaartaon vapora la air Xn ordar to obtala Information ragarda ebaagas of tho conoantrutlon of vapora la air slth tha dlataaea froa tba aouroa of production aaaplaa of air vara tukan la a cloaad apaca &t varylng dlataacaa froa bolllng Inartean uid tba folioing concentrations vara datarainads Distana (lnchea) Concentration ng. per litar 14 4*80 80 1.88 88 1.14 86 1*14 khan aaaplaa ara taken at various distanas over an open baaker of boiling Zaartean the results were us followst Distana ; (Inches) Concentration Bg. per litar 8 0.86 10 0.48 18 0*84 80 0*84 NPC000089 3 4 200694 XI I b n i xparlJM&ts abo that ti e a o o n t n t t o u f Xaertem In ir dcras npittj Ith th dlitoe f m th u o t m f thlr preduetiau la ordr to studjr of tb eoaceatretloae ortr priod of t l M and aith difforeat temperatura, a eurzeat o 10 litara par minute of air t u pasad orr tb arfa of Znr- ten of about 10 squar lachas, contalnad la a flaab aad tba lato a bll jar 8aapla ere tafeen tram. tb jar at rarlous lnterrals aftar tb fio a a atartd and wlth arioua temperaturas Ib folltvlBi conoentrations r determinad Tiae of saapliag in hours Concentration of trioblorobensene in ag* par liter Temperatur of triehlerobensen in flash *6 * oso s 0.81 060 1 l.M 4 170 1 i.to 88 88 88 0 80 00 4 0.58 88 This tabulation ahova that th dtralnationa aad at 88C* aad with tb 6 hour aaapl war* almost th aam for trlchlorobensene (060 i|. par liter) and Xnerteea <0ft8 ag pr liter)- this suggests tb possibility that the bulfe of the vapors liberated froa Znrten at this toaporatur may be trlchlorobensene; so that the hazards froa inhalation of Xaer - t m Vapors are identioal lth those froa the inhalation of *< N*C00008935 200695 IS t r U U m b i u u M * Xb order to ooBfln M S sc* of l u r t M i were -- knitted to fractional distillation and the following rosolts voro obtained! Fraction Tanpereture of Velune Specific Boiling distillation oelleeted Oravity feint H e. of fraction 1 8 8 4 Residue 840 840-884 -- * 880 -- 0-800 above 800 88 48 48 80 180 1.468 1.478 1.488 1.877 1*888 808-818 EM 840 8-- Since the opoeiflc gravity of trlchlorobensene is 1.486 anl tha bailing point 808*0-19"B., it is ovidont that up to 40*0 the vapors consist exclusively of trlchlorobenseae and . that for this reason the above stat.-- ait ii toaetrtad. M j.w. fan nit erxu Sltieam tha haaa^da tram n a a w o f Inert-- *r* identical with those froa trichlorObanxane. The experiments discussed in this report show that with oral adalnistratlon Zaerteen is considerably less toxic than trlchlorobensene, the alnlual fatal dose hilling froa 70 to 78 per oent of the rets being around 80 cc. por kilogram body weight and 1*4 to 1*6 per ldlograa body weighty respectively, fatal doses will cause passive congestion of all viscera, ex tensive degeneration of the liver, and ulceration of the gastric ' aucosa. With sublethal doses these effects ere less severe and there is evidence tlu.t they will heal when no further exposure occurs 1?PG000089 36 200696 14 Continued Application of Inerteen to the akin of t o and banana eausca dryness of tha akin, thickening end scaling! and the observations node la rats Indicate that sufficient quantities nay be absorbed through the akin to produce lajurloua effects oh the liver* Repeated Inhalation for short psrlods of concentrations of 0*8 mg* of Inerteen vapors per liter of air* or repatted inhalation for 6 hours of concentrations of 0*05 to 0*08 ng* par liter of air causes no definite injurious effects In rata* Vapors llbaratad fron boiling Pyranol Znerteen, and Iranaforaer Oil (Westlnghouse) are irritant and the irritant action decreases fron Pyrenol to Tranafomer Oil (Westlnghouse), Inertaan baing intermediate in this respect* Zt has been shown that vapors llbaratad fron Inertesn under conditions approaching those as night be sneouatered in traasforusra consist mainly of trichlorobenscne* a slaple netbod for tha datarninatlon of Inerteen (trichlorobcnacnt) vapors in air is given* If 10 liters of air are drawn at a rata of about 1 liter every S ninutes through a test tube containing 1 cc* of ethyl alcohol cooled In dry ice or in an let salt mixture ad the alcohol is then poured care fully on the surface of a few cubic centimeters of water in a test tuba' a ring of turbidity is produced if the concentra tion of Inerteen (trlchlorobeasene) is over 0*03 mg* par liter of air* Zf under these conditions a white ring la produced NPC8U008937 200697 1 the air tested should be regarded with eusplelm end should be improved by nor effeotlve ventilation. It waa fouact that the caneentratlam of Inert#a (trlchlorobenaene) in a closed gpace 14 laohaa abort the ourfaoa of boiling Imerteea la 4t mg. par 11tar end la an open apaea B lachos abort the aurfaca of bailing Znartaon la 0.6B ug. par liter and ban the taaparatura in a transformer standing la a closed roan (vault) rlaaa to 90^6. the air nay contain 1*9 ng. par liter of air* Proa the animal experiments reported, It appeara that concentrations below 0.06 ac> per liter of air will cause no toxic signs or symptoms even tilth continued exposure. Regards 8rnfflU.nJttftBtf.Mt the folioslag nay be suggestedi It appearr; to be of paramount Importance thi.t the contami nation of the air be reduced to concentrations below 0.06 ag. per liter of air by sdequata forced ventilation at the site of the production of such vapors. Oreateat personal hygiene la not laaa important. Contami nation of the skin should be avoided by wearing proper protective garments such as gloves caps and coveralls. In caae of accldan-pr v.ith exposure to higher concentrations of and above O.E ag pe liter respirators or open air aasks should be worn. The skin should be kept immaculately d e a n and ointments such as lanolin Xkr iquafor should be applied to the skin after washing the hands. in Tier, of the hepatotoxic aetion of this compound indi viduals suffering from injuries of the liver syphilis and heart NPC0in)08938 200698 f