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. -r -^T'rjrminw ifjfnMi ' *'***"' Wfiw-tr.- ijpiii'Acute Iulialation Toxicity of Vinyl Cliloride to Laboratory Animals 'I:. ' E. MASTROMATTEO,- 3I.D.;- A. 31., USHER, Ph.D., II. CHRISTIE, B.Sc^ an^n:: D^2IGER, M,D. ' -Division of Industrial Hygiene, Ontario Di^tartmen^of.-Health, iorbnto. Ontario; Department 0/ PhysiologicalilygiftteiSchpoioj Hygiene; Uidversity of Toronto, Toronto, Ontario; and T?flIatd-iCouniy^Oeneral Hospital, WclUand, Ontario <. . Introduction scribed'oi: very slight; Elimination from the body was very1 rapid. These authors quoted the work T7VLRST prepared in 1333, vinyl chloride, has Jycome into increased use in the last decade in of Schaunaana* with experimental animals. Alice, -the-production oi polyvinyl chloride resins. Thefire nod explosion hazard of the monomer and its' narcotic properties on acute exposure are well, . rats and dogs' were able to endure repeated nar cosis without any pathological evidence of liver or kidney damage. According to Schaunaana. concentrations of- seven to ten per cent in air known. .-Is an industrial material, however, it has been1 regarded as oi moderate toxicity. A Thresh, would be narcotic to humans in a short time and old. limit Value oi 500 ppm was established ,by the American Conference of Governmental'In 12-per cent would be dangerous. -Vinyl chloride has been studied as a possible 1 1 apMthotic ngentl Dstcr and associates* noted that dustrial Hygienists. v No industrial fatalities associated with its. use hitve previously been reported. It was therefore of special interest when two fatalities occurred in a plant handling vinyl chloride. This plant is en gaged in the polymerization of tire gaseous mono mer with the aid of catalysts. One worker died incoordinatcd muscular activity of the extremi ties; and cardiac arrvthmias of a serious naturevvere'observed in all six dogs used in their experi ment. Carr and others1 found that vinyl chloride produced sensitization of the myocardium ia . three of eeven dogs in which it was administered while cleaning out a polymerization vessel and the Other while working in a pit. Details of these two fatalities har e been reported by one thors.1 Published information on the acute oi the au toxicity of . , as an anesthetic agent. Two cases of vinyl chloride gassing occurred fa a factory* in Great Britain where poly-vinyl chior- ide resin was being made. These were reported by the Chief Inspector of Factories.* In one case a vinyl chloride to experimental animals proved scanty. Putty, Yant and Waite5 in H)o0 reported on the acute response of guinea pigs to vinyl chloride. They found that exposure to 20 to 40 process worker was standing outside a polymeri sation vessel and washing it with a water stream. After ten:minutes of this he suddenly collapsed, across the open- manhole. Artificial resuscitation per cent in air killed guinea pigs in a short time; exposure to ten per cent was endured for several hours. Congestion and edema of the lungs with hyperemia of the liver and kidneys were noted. Peoples and Leake1 found the minimal anes thetic range of vinyl chloride in mire exposed for ten minutes was S to 12 per cent in air; 25 to 3U per cent was fatal iu ten minutes. Dogs and rab was successfully .applied. Subsequent symptoms experienced by this worker were tightness of the chest, nausea, abdominal pain unci headache, ibi second case occurred in a maintenance worker who was overcome while repairing a vinyl chlorine leak, Both men were hospitalized. Another worker whose hands were accidentally sprayed with vinyl chloride liquid under pressure developed a bits were anesthetized within one minute when burn. This latter case was reported by Harris.' exposed to n concentration of about 13 per cent i Such burns may occur with other highly volacue in air. Recovery was very rapid with no apparent materials when sprayed onto the hands as a Uqu:u untoward effect even after prolonged um-stliesfa. under pressure. Lehmann and Flury* noted that vinyl cliloride Filatova and Gionsbt-rg11 in 1957 reported on was highly narcotic but had a wide margin be hygienic conditions in a polyvinyl processiiu tween its narcotic and lethal concentrations. Its plant in the U.S.S.R. The plant was engaged ia local irritating effect and its toxicitv wen* de- the polymerization of vinyl chloride by means oi 3H a catalyst. Air sampling was dor| filtration of vinyl chloride wnsfj t'mni about 20 ppm tolabotfl 3l3;i Threshold Limit Value: 1 mg/Ub.- ppm). A spastic type blood vws> .li-scribed in workers from, this pla. Because of the recent'' fatatff above it was decided to isnfarLw 1 iimi studies in laboratory.'aiiiima.'i dally available vinyLhlihifide-Tli for comparison wittC.oa'riiik -War} information on the acufa.rcsfiotii cal changes in more than;oa<? spd animat. ' T'i-k'AVwi-i-'d . * . * /V* <t i i , ' * ,:|,'.v-':v.V"'* *' * Experimental Mdln61i on^i^ Vinyl Chloride: Thel wayhcmof ia a metal cyi.ifitfcr ad>f grade with the-following ypecitfi' rifie *r*vity *t-2fl*C 'oft- .1" WatrrcoDtrat B*:lio< nor* *C ny<troi(vn cUorWid*WotV;. iA';,, ^t xmyitM AostalUtfUyd* ' CSJ-t-;!. J-SWip !;ua Purity (ptr oi) Ii.-puiiiw* teht) 1 Pure vinyl. cIifari^^;ftL<g)fa': tcuvijerntitre; itjTi2iie;piciibi`t a sweetish odor, ifsi'rtjiiuiitiibfat; and Us explosive *)|Liir- wut. It has the mbfcst-pliir farm. I mmols: .\ik-e,tt'|i&ri jtmr in the study..Tq>;t'AJijl-^>ntrrt.-i from- the sgfae.'labdratery etsu *tatida*4 cdmhtwcial ijiirf>.bri;> 1 way. All were of the same was 5Q.8.1Ui6rt';^t%it;tbipi-- window aotj Vin leased in 'Ji^^is 'Iortir.diiriri valve on thjd'-^''fif;"thAriiit;v.i through copnettiag. liijsber -rs hratc-d fisiirV.lIdh:.m^^'J?h-v by motor,at ap ailjhiifablu i>tu a meter. Tlfd st,Eetmwi'S>v air' were combined, sit ,ilfip'Ii'Priat glass -Y-tubf Idaiii'cui;tAiiiru"i> in-* to. the .giiirriul; hHijiiibrr -^SMUfatUisV'Strcaitj7(i*#lie-,-''T ^ I Cali-ufatious utidhli'.;it- *'liue the y4i clibrirle in-liit-tpc,tii:^.ft'f}'.: `nt. All ccineisitr-itaons :i:-* I'-irfas jicr-.'seii-f, by! vVilumi:' r.;V-T.,:-.y-. Vr AP00023576 r Industrial Hygiene Journal 305 I'll. . ntario; into, i from the body uotetl tbo wort 1 animals. Mice, re repeated nar* vidence of liver to Sehaumann, per cent in air . short time and ?d as a possible cites* noted that of the extremia serious nature in their experiX vinyl chloride myocardium in raa administered ssing occurred ia polyvinyl chiorwere reported by In one case a tside a polymeria a water stream. Jdenlv collapsed cbl resuscitation quent symptoms e tightness of the ad headache. The inteaanoe worker ig a vinyl chlorine J. Another worker ly sprayed with ?sure developed a Kirtcd by Harri*-* icr highly volatile e han<U as a liquid . 19.>T reported oo lyvinyl proiossinic at was engaged in tortile bv means ol j catalyst. Air sampling was done and the con* tions of vinyl chloride concentrations were done nitration bf vinyl chloride was found to vary in the test chamber during the experiments. :om about 20 ppm to about 315 ppm. (U.S.S.Tt. Threshold Limit Value: 1 mg/liter or about TOO ;ipui). A spastic type blood vessel disorder was \ .Inscribed in workers from this plant. Because of the recent fatalities mentioned jbove it was decided to undertake acute inhala Experimental Procedures: Different groups ot" five mice, live rats aud five guinea pigs were placed in the chamber and exposed for thirty minutes to concentrations of 10, 20 and 30 per cent vinyl chloride in air. Similar groups of con trol animals wore maintained but not cxnosed to tion studies in laboratory animals with commer vinyl chloride. At the end of thirty' minutes ex. cially available vinyl chloride. This was done both posure the test animais were immediately re for comparison with earlier work and to provide moved to fresh air. An additional group of five information on the acute response and pathologi guinea pigs was exposed to a concentration of 40 cal changes in more than one species of laboratory per cent vinyl chloride in air. In ail 135 experimen tal animals were involved. Observations were re- rded on the animals during and after exposure. Experimental Materials and Procedures Vinyl Chloride: The vinyl chloride was supplied :n a metal cylinder under pressure. A commercial trade with the following specifications was used: The animals which died either during the exp (sure or after a delay period were autopsieil sooa a ter death. Two weeks'aftcr die exposure surv ving test animals and controls wore sacrificed b a blow to the head with the exception of four ptcifie gravity it 20'C Tattr content Boiling rioje *C Hydrogen eitlorid* ooatent 0.9H-O.9S4 None -II to -9.3 Xoos c( utrol rats which were killed by exsangumation. All animals were examined for gross pathologi es l changes. Tissues were removed from all anim its for microscopic examination. Thu lungs, iceiylenc testaldcbyd# Iron Purity (per ctnt) Impuntics (per eeot) 10 ppm maximum 20 ppm maximum Essentially iron free fi'JJ maximum 0.5 maximum li er, kidney and heart were removed in all c: iea. The brain, adrenal, spieen, trachea, lymph n< des, and the eye were removed from represen tative animals in each group for study. Tim tissues ViliyiThlMIO-L 'u j. uAulLih .l loom temperature; its boiling point is -- 13.'J"C. It has re preserved in formalin and sections made for staining with hematoxylin-cosm. Special stains were made where indicated. i sweetish odor. It3 flash point is given at -7S*C ind its explosive limits in air from 4 to 22 per eat. It has the molecular formula CIIitCHCl. .Iniwmfs: Mice, rats and guinea pigs were used ;a the study. Test and control animais were taken :roin the same laboratory stock. All were fed a tundard commercial diet and housed in the same ray. All wpre of the same stage of development. Observations Control Animals: Xo symptoms were exhibited by the 15 control animals aud no deaths occurred. Ten Per Cent Vinyl Chloride: The response of animals exposed to this concentration is recorded below in summary form: Equipment: The inhalation chamber capacity was 56.G liters. It was equipped with a viewing Exposure Tim* (ffllDUt'*} Rttponu window and an inlet tube. Vinyl chloride was re vised in gaseous form through an adjustable alve ou the top of the containing cylinder, then iirough connecting rubber tubing and a recali'r.itcd Fisher flow-meter. Fresh air was pumped 31 . Slight irritation in mica uod rati. Increased motor activity first in mie*. then rati and guim* pits. Inercsivd motor activity m all atxcirs; twitching of gtrvnu*.is in mica. Pronounced tremor, mittvady gnitmul >y motor at an adjustable controlled rate through i meter. The streams of air aud vinyl chloride 'ere combined at appropriate rates of flow by a :h;s Y-tube leading through lurcher rubber tub- muscular incoordination in oil apn^t. Mies and rat* inside froaition; muscular iocoordirution, tuntiun nod twitching of estrrmities in guinea pics. ilice nntl rat* uncnnanoiu, guinea pigs r'g to the animal chamber inlet, to deliver a "ntinuing stream in the desired proportions. 1 ali'ulations and adjustments were made to proiiiie the following flow concentrations of vinyl very urc*trnriy Hut still standing. Mice nnd nt ia l*p narcosis; tuineo pigs in side position wuU trcmors-oiis unconxuou*. Morale in air for delivery': 10, 20, 00 and 10 per Exposure was stopped and the animals removed '''it. All concentrations are expressed in this re- to fresh air. All recovered within five mimdes. urt as per cent by volume in air. Xo determina- Twenty Per Cent Vinyl Chloride: The response * u. tr*4^ "I t ; i : [ 11 ? .I >' . i .i ` t. - `1 H ivi ! '. .. [yi mjy. i1 ) l m9 v.m ii M '>L AP00023577 396 October, 1060' of animals cxposcil to this concentration, is re Tabor I corded below in summary form: Number of Deaths in Different Groups of Tire Exposure Time (ntinutv*) Response Mice, Hats and Guinea Pigs Exposed for Thirty Minutes to Varying Concentrations of Vinyl 1 Immediate irritation in mire and mu. 2 Muscular iacooMinutioa in mice usd Chloride in Air rata. Vinyl chloride j Laboratory animal i Mire and raU on their side* with marked concentration | tremors sad witcotoi of the extretni* Total tie*; uruteadineii and inuwubr ineo* volum* in ait) | Mice. Rati Guinea puts j ordination in fmo pies. 10 Mice sod raU uncuructous with rapid 10 0/1 0/1 C/J 0/U - irregular brellin*; purne* pics ua* eonacious butshowise marked twiteh* in*. 20 1/5 *0/1 30 5/5 40 | -- V* -- 0/5 uy vy l/ 11/15 S/J -. U All animals in deep narco?U: respirations trrefilar and rapid. Total | 0/15 5/15 3/20 wn N Deep narcoeis; breathlnf slow and slial* low. * A delayed death occurred withia2 4 hours followiog expascir. 25 Brcotbio* ceased in one mmue; frothin* at mouth aod noetnU ia mien aod rate. 30 All aaimuls in deep narcosis. Exposure was stopped and the animals removed to fresh air. Mica ami rats recovered faster than the guinea piers and appeared normal within five minutes except for one mouse which was dead. The guinea pigs continued to .-.how muscular in coordination, unsteadiness on their feet until 20 minutes after removal from exposure. Thirty Per Cent Vinyl Chloride: The response of animals exposed to this concentration is recorded below in summary form: Exposure Tim* (minutes) Response -- Mice ahowtd irritation immediately and the rata ibowd irritation quickly thercitUer. Forty Per Cent Vinyl Chloride: Only five guinea pigs were exposed to this concentration. Signs of irritation were immediately apparent. Muscular incoordination appeared within seconds. Aiter five minutes all the guinea pigs were unconscious with slow shallow breathing. At the end of the exposure period onu guinea pig w as dead and the remaining four were in deep narcosis. These sur vivors took 30 minutes to return to their norms'! appearance and activity, but one died within the following 24 hours. The number of deaths occurring in different groups of five laboratory aninvuls exposed for thirty minutes to varying concentrations of vinyl chloride in air is shown in Table I. 1 Muscular incoordination io rate* and rats. Pathological Findings 2 Mice and rats in aid* position with mark*d tremor* uad twitching of th* Gross pathological and histological studies were extremities; muscular incoordination carried out. The findings are summarized below. la guinea pin with developing partly* Control .Inimals: These animals showed co sis of th* extremities. gross or microscopic evidence of damage. 5 All animals unconscious; rapid irregular respirations in mice and mu with Ten Per Cent Vinyl Chloride: All test animals frothing ubout pom and mouth; survived this exposure. They were sacrificed two (witching of extremities still occurred 'weeks later. On gross examination there was evi occasionally in guinea pi**. dence in mice of slight hyperemia of the lungs. 10 Reapimtions stopped in mice; branching slow and shallow in rati: guinea pus This was less marked in rats. Guinea pigs showed still exhibited occasional tn-itehing no difference from control animals. On liistoiog'.c movements ol the extrcmiiie*. examination the mice showed very slight engorge 1$ Breathing stopped in rats; rrpir:iiu>cu ment of the pulmonary vessels. One mouse j slow sad shallow ia guinea pigs; twitching of extremities still pr?tiit showed degenerative changes in the tubular epi in guinea pigs- thelium of tho kidney with hydropic swelling. 30 Mice and mu still; guinea pigs in de*p The rats showed slight congestion of tin: capillar ftnrcosis with slow sluiU>w hrenthint ies in the lung. Lungs in tin- guinea pig were aUo Exposure was stopped and the animals removed slightly more hyperemia than those of the control to fresh air. The mice and rats were death The animals. guinea pigs took 2"i minutes to return to their Twenty Per Cent Vinyl Chloride: One mouse normal appearance and activity. One guinea pig died as a result of .'ifi minutes exposure to this from this group died within 24 hours following concentration. I'ulmouurv congestion was evuicat exposure. Industrial Hygiene Journal engorgement of the blood vo.-cls in patchy areas of atelectasis and m The kidneys showed minimal changes in the epithelium of the > bules. The test animals surviving this sacrificed in two weeks, un tru-- ,-ongcstion of the lungs was nn'r'-.v but it was more marked in the mm in the guinea pigs. Histologically, donee of pulmonary congestion u mala. Some fatty intutration wa* liver of one rat. All other tissues su normal. Thirty PerCent Vinyl Chloride: tion of the animals which ui-d as . exposure revealed congestion of t hemorrhagic areas. The mice and : showed congestion of the liver a:: one guinea pig death was delayed, there was marked congestion o. hemorrhages and the liver was du; friable. The microscopic chain; which died included marked hiu-, pulmonary blood vessel* with co. rhuges in the lungs. Tho trachea of superficial desquamation of the egestion was also evident in the ii of the mice and rats. Tho liver m which hail the delayed death du a (icgcnc-nuioii of tin- over i-osinrn sections stained with Sudan ill. The four surviving guinea pigs two weeks later. Marked pc.irru.r was present with hemorrhagic a: In one case there was evidence of terial infiltration. The iiivr in rgave the appearance os' ic.it y fat was demonstrated on frozen - Forty Per Cent Vinyl Cidnn,guinea pigs exposed to cliis con during the exposure and unutiahours. The two which -ii-i simu gestion of the lungs with hemoi examination. This was also -viseopie examination. The liver of the appearance of fatty inii'.tra: could bp demonstrated on :m..cn The three surviving gum--a two weeks later. Marked v-tv:.'.-. with hemorrhage was evni-a-.f. un,! microscopic examination. the tracheal epithelium was con.; Pathological studio?, winch w. brain, heart, spleen, adrcirais. ,? tin- eyes ,-howcd no dr---. mid animals dying as a n-mt oi .'.i-ji 'twyri" i ? j j...m. --.y. PMIIVW* AP00023578 October, iogq Industrial Hygiene Journal 397 Grouts iif Kir o.ted fur T-iirtv dons of Vinyl n piiet Toeal ' J 0*U * l,U i* 11/13 /$ 3/5 .`20 ll.'M m lollowifif capow. Only five guinea itration. Signs of mrent. Muscular i seconds. After were uncnnsmsi t the end of the vu dead and the rcosi*. These surn to their normal e died within the -ring in different ,als exposed for ntratious of vinyl I. . igical studies were mmarized below. imals showed M : damage... : All test animals ere sacrificed twn ion there was ovimia of the lump, uinea pigs showed . aals. On histologic cry slight engorge* iseis. One mouse n the tubular epb nydropic -swelling, 'on of the capillar* tinea pig wore aho )iose of the control [oridt; Oue mouse a exposure to this lestion was evident fipirally, there wa engorgement of the blood vessels in the lung with ficed two weeks after exposure. Ttiere was a patchy areas of atelectasis and minimal edema, tendency for the blood to remain unclotted in the the kidneys showed minimal degenerative aniniais dying during exposure. This feature ivas .Images in the epithelium of the convoluted tu- noted in the two human fatalities mentioned ear hules. lier but it is not a specific characteristic of vinyl The test animals surviving this exposure were chloride. sacrificed in two weeks. On gross examination. i rongestion of the lungs was present in all species, Discussion but it was more marked in the mice and rats than in the guinea pigs. Histoiogicallv, there was evi-. ilencc of pulmonary congestion in exposed ani mals. Some fatty infiltration was present in the liver of one rat. All other tissues studied appeared , normal. ^ Thirty Per Cent Vinyl Chloride: Gross examina tion of the animals which died as a result of this exposure revealed congestion of the lungs with hemorrhagic areas. The mice and rats in addition ;howed congestion of the liver and kidney. The one guinea pig death was delayed. In this animal there was marked congestion of the lungs with I hemorrhages and the liver was distended and very friable. The microscopic changes in the animals which died included marked engorgement of the pulmonary blood vessels with edema and hemor. tinges in the lungs. The trachea of one rat showed superficial desquamation of the epitheUum. Con gestion was also evident in the liver aud kidney of the mice and rats. The liver of the guinea pig j which had the delayed death showed severe fatty > degeneration of the liver confirmed with frozen j sections stained with Sudan III. j The four surviving guinea pigs were sacrificed j two weeks later. Marked puimonary congestion tras present with hemorrhagic areas and edema. ! in one case there was esidenee of secondary bac- j terial infiltration. The liver in these guinea pigs - gave the appearance of fatty infiltration but no fat was demonstrated ca froien section. Forty Per Cent Vinyl Chloride: One of five guinea pigs exposed to this concentration died luring the exposure and another died within 24 hours. Tile two which died showed marked con Tile response of guinea pigs to'inhalation of vinyl chloride was similar to that reported by Patty, Yant and Waite. The guinea pigs in our study, however, tolerated a greater exposure dur ing the experimental period than either the mice or rats. The results ia mice agreed closely with tiiose reported by Peoples and Leake. Rats were similar to mice in their response. The pathological changes in animals which died as a result of exposure were* mainly those of vascular engorgement of the lungs with hemor rhages and edema. The seventy ot these changes varied with the severity of exposure. In the higher concentrations, pulmonary change was marked with severe damage to the tracheal epitheiium. Congestion of the liver and kidneys also occurred in test animals. These changes are similar to those reported by Patty and associates. Evidence of pulmonary congestion was still present in surviving animals sacrificed two weeks after exposure. Patty and associates reported that such changes had disappeared in aUmt eight days Degenerative changes in the tubular epithelium of the kidney were noted in one mouse dying as a resuit of exposure and in one mouse sacrificed two weeks after being exposed. Such changes, however, were minimal and not shown by other animals in the group. One of the guinea pigs with delayed death fol lowing exposure siiowed .'evert: fatty infiltration of the liver. Changes suggestive of fatty infiltra tion were observed in other exposed animals but not confirmed by frozen sections stained with Sudan III. gestion of the lungs with hemorrhages on gross examination. This was also evident on micro Summary scopic examination. The liver of one of these gave Separate groups of laboratory animals com she appearance of fatty infiltration, but no fat prising five mice, five rats and five guinea pigs mild be demonstrated on frozen section. were exposed in an inhalation chamber to concen The three surviving guinea pigs were sacrificed trations of 10, 20 anil 30 per cent vinyl chloride two weeks later. Marked congestion of the lungs in air for oO minutes. An additional five guinea with hemorrhage was evident on both the gro.-s pigs were expose* 1 to a 40 per cent concentration mil microscopic examination. In one guinea pig, for a similar period of time. The response by each 'he tracheal epithelium was completely absent. of the three species to these conmitnitiims is I'atlinlogieal studies which were made of the noted. 'mill, heart, spleen, adrenals, lymph unites and Inhalation of these relatively high nmccntrn- tile ryes showed no difference iictween controls tions produced narcosis and death. Alice were the iri,l animals dying as a result of exposure or bu- most susceptible with guinea pigs considerably t'Ceen, controls aud the surviving animals sacri more resistant. Rats were similar to mice in their ! . .i. , ; . ' : t . ruiyuwt AP00023579 4J . A-'- .SS<9 October, 1060 response. Exposure to ten per cent vinyl chloride in air produced deep narcosis in mice and rats but no deaths; 30 per cent concentrations killed mice ami rats. Exposure of guinea pits to 20 per cent produced deep narcosis; but three of five guinea pigs survived exposure to -JO per cent con centration. Animals dying as a result of exposure were autopsied shortly after death. Survivors and con trol animals were sacrificed two weeks later. Gross pathological and microscopic studies were done and these findings are described. The principal pathological changes in animals dying from exposure were congestion of the lungs with pulmonary edema and hemorrhages in some, and congestion of the liver and kidneys. Failure of the blood to clot was also observed. One of the three guinea pigs which died following exposure showed severe fatty infiltration of the liver. Survivors sacrificed two weeks after exposure showed little difference from the control animals. Pulmonary congestion was still evident but liver and kidney congestion, was not. References 1. Dan^icc*. H.; Accidental Pouomnx by Vinyl Chforidt* port of Two Cui, Canadian Jftd. Aw*. J. ;*. ^5 , v * , 13M). * 2. P.vttt, F, A., W. P. Yant, .1x0 C. P. Wait: Acute of Guiaee Pics to Vipon of Sum* Commercial Crrtme Cotttpnttadj V, Vinyl Chloride, Pub. fU*Uk PeH. y.- j>j (Aucuit U1U). 3. Ptor&u. A. S-. axdC. D. LAKE;Th Aoeetnetie AnientA Vinyl Chloride. J. PAarma^sleyy ;J: 2JJ (li'iift). 4. Lcumaxx, 1C B., 4 F. Flcrti TotU*l*ft *nd Hn-fu tndmtrial Soic/nt$. TraiuUwd by E. Kin* aad H. F. Smite. Jr.. Williams k Wilkin*, Baltimore (1343). 5. SCKMUAX.V, 0-: Ci'-d by Lehmann, K. B. end F, Flury. 6. OettK, H. II., C. J. Cask, J. C. Khaki?. a_nb M. J, Sicxe. wild: Anesthesia XXVII. Xereosts with Vinyl Chloride, S: AS'J t I'M). 7. Cam. J., R. M. Bcrqimjk, J. F. Vrrcite. ajo J. C. K*>n J*.: AnestbesU XXIV. Cbemietl CotuUtutfem of Hruv eerbooe end Cordite Automaurity, /. Pkat-m. and Zsyr. TAemo. 97; l (im. S. Annuai Rtport f tAe CkOf InaptHoi ef fanome* for ui Y>aJ9SI, Loorioa : H.M.S.O. Cmd. S773 OT&reh $. Hahus. D. X.: Iletlih Problems m the Meoufseture tut V* of PLutlcs. Bfit. 7. Ini. .Vrd. 10: a (Jh.tt). 10. Filatova, IT. aso b. S. Groxshkmo: Hycieaie Worns* Condiuone ia Polyvinyl Chloride Tar Plant*. Owtma on, W-42 (January 1337). Abstracted ia ,4/jji. a/ World MrC W (Juljr 1957). . t i ' j J * 1 1 * I j j { 1 Ba.ok Issues or AIHA Quajtterlt or IS YEARS THE AIHA QUARTERLY was the publication of AIHA, then Fin. 1958 it was changed to be the AIHA Journal with six issues per year instead of four. Now limitation of storage space is forcing us to dispose of all back issues of the Quarterly. For individual issues nuantities on hand vary from a low of S upward. All issues except March 19-16 (Vol. 7, No. 1) and June 1956 (Vol. 17, No. 2) are available as we go to press. Some issues are reprinted without cover. The cost is SI.50 per issue (51.00 each when more than three issues are ordered) from Volumes 7 through IS. From 1940 to 1946 AIHA Quarterly appeared as a section in Industrial Medicine and Surgery, however these issues of these sections have been reprinted and are available as a unit. The complete reprint, Vols. 1-7, costs $10.00 to members, and S50.00 to companies or departments of government. Handsomely bound, complete sets of Vols. 1--18 with cumulative index are available for $250.00 per set. Address all orders to; George D. Clayton, Executive Secretary, AIHA, 14125 Prevost, Detroit 27, Michigan. (Back issues of AIHA Journal, 1053 to present, may be obtained directly from our publisher, The IVillinms <fc Wilkins Company, 42S E. Preston, Baltimore 2, Maryland, at SI SO each issue.) Acute i NVILLIA3 Department 3 introduction THE element thallium Crookes in 1S61 by sp* and isolated chemically i Lamy. There arc no lara thallium and its product; The principal u"`s of thu'.'.. to its rodenticidnl property used as a depilating ngm also used in the produecto optical glass and in the mi. tion counters. An examination of the number of published tepor thallium toxicity following rides containing thallium saturable amount of wore the depilating action of tii laboratory animals uu.i : tribution and excretion (T1M1) has been reporteu tigatorsA' *10 Recently, .y ere11 have demonstrap.il containing sulfur act as acute thallium poisoning m The work reported Iviuu acute toxicity of thnllous inoxide (TO) following use compounds to several ,;vv oral routes. The ingestion pounds was also iuvestig-ithree months. Experimental Method! one Tiie two thallium i.-otni- tainud from the Anwni nn Co., Denver, Colorado it!,. i'-al Commerce, Newark. acetate). The purity nf ; relatively high -i-.ia- THU paper i on unrk r**-- 5`** .si/'ifn.c l t.- .-.t \ ^ HoeKcvtcr Atumie flncfiry I'r> i> - i AP00023580 Kenrmtfd trom American Indvitrial Hyoiano Association Journal Vol. 22, No. 6 October, iOu`1 Copyright 1551 by Tlio William* it Wilkins Co. Printed m L'.X.A., The Toxicity of Vinyl Chloride as Determined by Repeated Exposure of Laboratory Animals T. R. TORKELSON, M.5., F. OYEN, and V. K. ROWE, M.S. Biochemical Research Laboratory, The Dow Chemical Company, Midland, Michigan Groups of laboratory animals were exposed repeatedly for up to six months to either 500, 200, 300 or 50 ppm vinyl chloride in air. Delectable changes occurred at all but the lowest concentration. The results arc discussed and handling precautions suggested. 1 Introduction The following report summarizes the results of repeated exposures of laboratory animals to VINYL chloride (CH,=CHC1) is a chemical cither 500, 200, 100 or 50 ppm of vinyl chloride. of great industrial importance. It is used in The significance of the results is discussed and the preparation of polyvinyl chloride resin, asrecommendations for a threshold limit value are a copolymer in saran and other plastics, ns a made. chemical intermediate and as a solvent. Be cause of the flammability of vinyl chloride, it has been generally assumed that the greatest hazard Experimental Procedures associated with vinyl chloride is that due to its flammability rather than its toxicity.1 The toxicity of vinyl chloride has been re viewed by von OeUmgcn1 and more recently by Mastromattco et al.' von Oettingen concluded that the gas was anesthetic in high concentra tions and that considerable interest had been shown in tbe use of vinyl chloride as a surgical anesthetic. However, its effect on the circulatory system has discouraged exploitation of this prop erty. No doubt the hazard from flammability has also hindered this use. Only limited repeated exposures which were reported by Schnuraann1 were discussed by von Oettingen. These repeated exposures indicated little or no chronic effects even from anesthetic concentrations. Mastromattco et al.* also discussed tho pub Materials Tested Vinyl chloride, CU^=CHC1, is a colorless gas. It has a boiling point of -- (+7.93F) and a freezing point of --15I'C (--244.82'F). The material polymerizes readily and hence is sometimes inhibited with phenol or tertiary butylcatechol. Vinyl chloride is very flammable, its flashpoint being --TS'G ( -- lOS'F). Tho ex plosive limits arc from i.% to 22CI by volumo. It has little odor although high concentrations may smell faintly sweet. A single, uninhibited sampie was used in these studies. It was shown by mass spcctrographic analysis to be essentially pure CH,=OHCl, air being the only impurity detected in gas phase samples. lished data and reported the results of single oxposures of mice, rats and guinea pigs which Source and Feeding oj Animals confirmed tho low acute toxicity of vinyl chloride. Mastromattco reported that only two human fatalities due to vinyl chloride had been The rats and rabbits used in this study were obtained from tbe stock colony of this labora tory, the guinea pigs were obtained from a reported. commercial grower' and tho dogs were purebred It can be concluded from the published toxi beagles obtained from a local kennel. The rats cological data that anesthesia is the only sig and dogs were fed Purina Laboratory Chow' nificant effect of acute exposure. Sufficient re or Famo Laboratory Ration.' Tho rabbits and peated exposures have not boon reported to guinea pigs received Famo Rabbit Breeder draw conclusion! about chronic toxicity. The Ration. The guinea pig diet was supplemented Threshold Limit Value of 500 ppm suggested by with carrots. the American Conference of Governmental In dustrial ITygicnists (ACGHI)* is reported by Experimental Protocol Smyth* to be based on single animal exposures The experiments were conducted in three and human experience. phases. In the first phase, groups of 10 male sm 355 Industrial Hygiene Journal and 10 female rats were exposed seven hours per and one female dog to 50 ppm vinyl chloride. day five days per week; to 500 ppm for 4.5 Equal matched groups served as unexposed and months. Exposures were given in a IGO-liter air-exposed controls. Three additional groups of chamber previously described." Mortality and 10 male rats each were exposed for 4,2 or 1 hour growth records were kept. Final organ weights per day to 50 ppm. were obtained and tissues were saved for micro The procedures followed were essentially the scopic examination. Five male and (ivo female same as used for exposures to 200 and 100 ppm rats served as unexposed controls. except that hematological examinations were The second phase consisted of repeated 7- made on the dogs after three months and liver hour daily exposures of 20-24 male and 24 fe biopsies were mado only prior to exposure. Urine male rats, ten male and eight female guinea pigs, was collected from the rabbits as well as the rats three male and three female rabbits and one and dogs. The rats which were not sacrificed at male and one female dog to cither 200 ppm the end of the exposures were pastured for six oi 100 ppm of vinyl chloride. Those animals and weeks and then sacrificed. two groups of controls were carefully selected and matched on the basis of age, condition and Equipment Used weight. Tb.c first group of controls received no exposure and served as unexposed controls. The second group received repeated daily 7- The exposure equipment used has been de scribed previously.11 Ilowever, in order to gain additional data about the results of repeated hour exposures to room air in a chamber similar short daily exposures, it was necessary to devise to the one used for exposures to the chemical. a method of introducing additional groups of This group is referred to as the air-cxposcd con rats. Tliis was done without opening the doors trol group. In addition to the animals receiving of the chamber by dropping the rats through 7-hour daily exposures, eight separate groups of chutes made of 3-25-inch stainless steel tubing. five male rats each were exposed to cither 200 These chutes were closed with a rubber stopper or 100 ppm for 4, 2, 1 or 0.5 hours per day. except during the brief time it took to insert the The procedures and equpiment used were bas rats. The chutes, which were sloped at a 45' an ically the same as reported previously.11 Growth gle, ended in covered, screened cages inside the and mortality records were kept on all groups. chamber. The additional groups were started 3, The livers of the dogs were biopsied prior to ex posure and after 3'/r months of exposure, hence the liver of each dog served as its own control. Pre-exposure and terminal hematological deter minations were made on nil dogs and terminal determinations on representative groups of rats. Urine samples were collected from the dogs and representative groups of rats. At the termination of the experiment, part of the rats were starved overnight and then these and all the guinea pigs and rabbits were killed by decapitation on the day after their last exposure. The dogs were 5, 6 and 6.5 hours after the 7-hour exposures started. Since all animals were removed after the 7-hour exposure was completed, this routine re sulted in exposures lasting 4, 2, 1 or 0.5 hours. The vinyl chloride was metered from a saran plastic bag which served as a reservoir for the gas. Metering of the gas was done by Dual Syringe Pumps.11 Total air flow through the chambers was measured by means of calibrated flow meters. Analysis of the Chamber Atmospheres killed by exsanguinntion after anesthesia with thiopental, sodium (Pcntothal, Abbott). Samples of blood were taken of representative groups of animals for determination of alkaline phospha tase, serum-urea-nitrogen (SUN), serum-glu- Analyses of the air were made by direct com bustion of a known volume of air in a heated quart* tube. The resulting chloride was trapped in 1% sodium formate--1% sodium carbonate solution and subsequently titrated by a micro- tamic-pyruvie-transaminase (SGPT), and se- Volhard technique. The results of the individual rum-glutamic-oxalacetic-transaminasc (SCOT). analyses were within 152 of the theoretical con The organs were weighed and tissues fixed for histopathological examination. The rats which were not killed the day after exposures were stopped wore pastured for eight weeks and then centrations during the exposures to 200, 100 and 50 ppm. The average concentrations recovered were 107, 100.5 and 4S.7 ppm respectively. sacrificed in the previously described manner. Results of Repeated Exposures The third phase of this experiment consisted of repeated daily 7-hour exposures of 24 male Exposure to 500 ppm Vinyl Chloride nnd 24 female rats, 12 male and 12 female guinea The rats exposed repeatedly at D00 ppm for pigs, 3 male and 3 female rabbits nnd one male 4.5 months, grew normally and no changes were S57 Industrial Hygiene Journal Tabi.e IX Summary of Avernsfrs Body anil Organ Weights of Feimde Itiits Rcmving Repeated "-Hour IApo.-urL'-- to Vinyl Chloride o Days per Week Orcan Weight*, o C/100 c Body S3 > Wtifbt II si 1" C.1 ll ji* K l, & I.iv c 2 Id *tA3. JUIKJ | Unexpustideouirel................ 0 5/S m 0.82 0.41 3.09 0.80 0.19 300 4.5 vio 155 Q.I1SQ.M 3.22* 0.81 0.20 Uooxposed cod* trol................ 0 10/12 202 0.65 0.3$ 2.62 0.82 0.17 Air exposed control........... 5 9m 223 0.6ft 0.39 2.09 0.81 0.18 100 6 10/12 208 0.63 0.3S 1.39k 0.84 0.18 100 6 11/12 221 0.59 0.39 3.35* 0. 79 0.20 Uactposcd* control........... 0 8/12 223 O.fil 0.37 3.67 0.32 0.18 Air exposed* oontrol........... 6 200* 9 10C* 0 Unexpcscd con trol................ o o/u 2-10 0.43 0.37 8.AT 0.83 0.19 12/12 233 0.61 0.38 3.06 0.21 0.20 i2/ia 235 0.63 0.40 3.17 Q.es 0.21 11/12 211 0.5$ 0.39 3.02 0.33 0.20 AU exposed oontrol........... 6 EO Q 12/12 202 0.59 o.n 2.93 O.fii 0.20 S/12 90 0.01 0.37 3.03 0.84 0.20 Uecxpoaed** control........... 0 Air exposed control**........ 5 50** 8 11/12 125 o.cc 0.40 2. IS 0.91 0.32 C/18 221 0.63 0.40 3.01 0.87 0.19 11/13 233 0.83 0.33 2.53 O.Ba4|o.80 `Twturcd for 8 vccka aftar exposure* ceftsed. '* Pastured for 6 ircelu after exposure* ceased. (a) i 0.17 (b) l> - 0.03 (c) P - C.01 (d) P 0.05 Exposure to 100 ppm Vinyl Chloride All species exposed to 100 ppm of vinyl chlo ride, seven hours per tiny, 13S-1-U timc3 in 204 days, were judged normal on the basis of the fol lowing criteria: appearance, mortality, growth, hematological examination, SUN, SGQT, SGPT, alkaline phosphatase determination, uri nalysis and gross and microscopic examination of tissue. However, slight increases were found in the average weights of the livers of male and fe male rats (Tables I and II). Although not sig nificant statistically, an increase was also seen in the average weight of the livers of the mole rats exposed to 100 ppm for either four or two hours per day. The groups exposed for either 1.0 or 0.5 hour pur day were entirely normal. Exposures to oO ppm Vinyl Chloride The increase in weight of (.he rat livers, the only signilicant finding in animals exposed to 100 ppm, did not occur in ruts exposed repeatedly to 50 ppm of vinyl chloride, 130 times in 1S9 days. All groups of animals were judged normal in all other respects. See Tables II, V, VI, VII, VIII and IX. A statistically significant decrease in kidney weight which was seen in the fcrnalo rats (Table II) was considered to be an artifact since it was not teen at higher concentrations. Discussion Repeated exposure to vinyl chloride at con centrations considerably below the level tint has been considered safe for human exposure has been shown to have an effect on the liver and kidney of laboratory animals. Histopathalogical changes and increased liver weights in male and female rats were noted after repeated exposure at 500 ppm. Repeated exposure at 200 ppm for six months resulted in an increase in the average weight of the livers of male and female ruts and micropathoiogicul ciianges in the livers of the male and female rabbits. The only effect noted after repeated daily 7-hour exposures to 100 ppm for six mouths was a slight increase in the aver age weight of the rat livers. Repeated 7-hour exposures to 50 ppm for six months had no effect on any species studied. Henco, the highest con centration without detectable effect on any spe cies was 50 ppm. It is interesting to speculate on the apparent discrepancy between the effects observed at 100 ppm in this experiment and the lack of reported injury in humans using a threshold limit of 500 ppm. Several factors may be contributory. First, the effects noted in animals nt 500 ppm were only slight to moderate; growth, mortality, and gen era! appearance were unaffected. Hence, it is possible that if humans were exposed repeatedly at 500 ppm slight injury might occur but due to the lack of subjective symptoms the injury would escii])C detection. Secondly, (he injury was apparently reversible. The liver weights of both male and female rats which had shown definite increases after exposures at 200 and 100 ppm were normal or approaching normal after 0-S weeks of recovery (Tables I, II and VIII). Table III Summary of Average Biochemical Values Determined for Animals Receiving Repealed Exposures to Vinyl Chloride 5 Days per Weelc Species and Dog N'o. Sex Concentration in ppm Months on Exposure Duration of Daily Exposure, hours Number of AuimaU Alkaline Vhoi- pkatAie KlnrArmstrong Units Blood Urea Nltruircn. mj{/10<> ml SGPT SOOT Sigma-Frankel Unit Dog *10!.............................. S 113.............................. *41.............................. *98.............................. Dug * 108.............................. *107............................ 103.............................. *110.............................. Rat.............. . M F U Rat........................................ F Rabbit............. ............... M Rabbit................................... F Unexposed control Air expwed control 200 100 Unexpoacd control Air exposed control 200 100 Unexposcd control 500 200 200 200 100 100 100 Unaxpoaed control 500 200 100 Control 200 100 Control 200 100 0 0 6 6 0 0 6 0 0 4.5 6 6 0 6 0 0 0 0 6 0 6 6 0 6 6 0 0 7 7 7 0 7 7 7 0 7 7 4 l 7 4 0 7 7 7 0 7 7 0 7 7 l 12.3 24 18 43 1 4.1 19 19 17 1 3.5 11 IS 43 1 4.5 16 21 19 l 5.1 1! 10 26 1 7.1 20 14 17 1 7.9 14 16 26 1 5.4 10 10 24 5 32.9* 20.6* 30 4 13.9 13.3 35 6 17.7 16.2 36 4 18.4 16.3 32 3 20.2 17.7 42 4 19.4 15.0 27 3 14.7 16.3 36 3 19.0 15.3 30 4 12.1 2Q.5 38 3 U.l 22.3 26 5 13.4 22.2 21 6 9.1 22.3 23 5 4.0 25 36 3 5.3 21 23 2 5.0 26 26 G 4.9 33 33 2 6.6 27 35 3 4.0 26 35 Boeause of two unusually lugh individual value* in thi* group the** average vuluca are elevated and do not correspond tvitfa. tUe values obtained on sirnilur control groups in our laboratory. Normal control valuta are in tbesaiae ranges as those of tbs experimental groups listed in this table. Table IV Summary of Average Hematological Values for Animals Receiving Repeated 7-IIour Exposures to Vinyl Chloride Species or Dog* Sex Concentration in ppm Months on Experi ment Xo. of Animals Hemo globin c/ioo g Hema V.'BC X Neutro tocrit lu> phils Lym pho cytes Mono Eosino cytes phils Rat............................... Rat.............................. Hat.......... .................... Rat............................... Do* *101.................... Doc *101.................... Du* *113.................... Doc * 113.................... Do* *111.................... Do* *111..................... Do* *38..................... Do* *98............... Do* % 100.................... Do* * 100.................... Do* * 107.................... Do* *107.................... Do* *103.................... Do* *103.................... Do* *110..................... Du* *110.................... M M F F M M M M M M M M F V F V F F F F Air exposed control 200 Air exposed control 200 Unexposcd control Unexposed control Air exposed control Air exposed control 200 200 100 100 Unexposed control Unexposcd control Air exposed control Air exposed control 200 200 100 100 0 6 C 6 0 6 0 6 0 0 0 6 0 0 0 G 0 6 0 0 4 14.5 61 15.8 20.5 71.2 1.5 0.8 5 14.4 50 16.7 19 77.8 0.2 3 4 14.0 49.5 . 13.5 22.5 74.5 0.2 2.3 _5 13.6 47.4 12.S 24.8 70.2 1.0 4 1 -- _ __ _ __ __ 1 15 53 U.l 40 51 0 3 l 11.5 50 13.5 01 23 5 11 1 14.5 52 13.2 5* 34 4 4 1 13 47 1G.2 5G 28 3 13 1 10.5 58 15.8 50 41 2 1 1 15.5 52 16.8 40 46 4 4 1 1G 54 18.6 61 39 0 P 1 14.5 51 21.3 42 37 3 18 1 15.6 54 1 15 53 1 16 57 16.5 54 14.4 55 11.7 66 41 33 23 1 4 4 4 8 7 1H 50 17.5 44 48 3 6 l 16 54 1 12.5 44 1 15.5 54 17.3 40 1C.3 01 14.4 40 61 37 50 0 2 1 3 0 0 SSS AP00023584 359 Industrial Hygiene Journal Table V Summary of Toiminol Average Body and Organ Weights of Guwrsv Rifts Receiving Repented Daily 7-Uottr Erasures to Vinyl Chloride 5 Days per Week for 0 Months | VU.-Cit Organ Wright*, r/100 c _ 1Vt> Ok S5 at > -* < >. sl K r- | |JS S' Body Weight y a 1 t C 14 5 ? M Unexposed control 8/10 W7 0.64 0.2S 3.32 o.to'o.ig 0.48 M Air exposed 5/10 1030 0.52 0.25 J.3G 0.St 0.10 0.48 control M 200 7/10 1044 0.53 0.2? 3.01 0.60 0.09 0.44 M 100 7/10 Hi? 0.53 0.23 2.7S*,0.5S!0.11 0.47 M Unexposed S/12 918 0.60 0.2) 3.24 10.6310.12 0.62 control 1 U Air exposed 11/12 9J6 0.61 0.27 3.31 0.04j0.12 0.50 control M 50 10/12 1001 0.63 0.26 3.14 o.ei'o.u 0.43 F Unexposed S/8 S99 0.62 0.27 1.20 lO.HjO.U control F Air exposed 7/8 SS7 0.66 0.25 3.26 0.67 0.11 control F 200 7/a Si/7 0.7A** 0.271 3.fiQ;0.M'l0.K F 100 7/8 949 0.58 0.20! 3.60 0.64 0.12 F Ucexposed 0/12 723 0.78 0.34 3.41 O.GO 0.15 control F Air exposed 8/12 RS4 0.65 0.2C 3.84 0.C3 0.14 control F 50 11/12 90S 0.60 0.23 3.44 0.C4 0.14 {&) P - 0,05 (b) P - 0.24 (c; P - 0.23 Table VI Summary of Terminal Average Body and Organ Weights of Rabbit.* Receiving Repeated Daily 7-Hour Exposures to Vinyl Chloride 5 Days per Week for 6 Months a .r2i si S? uVJwS *3 I'i <Uj. i <r S' OrgxnW'eishts, f/!00 I Body Weight M Uncxposcd 3/S 3.Cl M Air exposed 2/3 3.90 0.2112.27t0 .*4>0.03'o. lfi `o. is;2.4i|o. 4aiQ.02;o.tt control M 200 MM 100 UccxdomI 3/3 3.48 IG.32J0. I9 2.34 0.6lj0.02 0.15 3/3 3.65 |0.33:0.1S 2.C4!0,|0.02,0.15 8/8 3.60 M control Air exposed lo.37 0.lsL.!s!o.53 tt.03|O.H 1/3 3.87 control M 50 F Ucexposed 3/3 3/3 3.70 4.13 '00..3361.00..2107i2j..3je2.OlH.IOr '00..0033| 0.17 F Air exposed 3/3 3.91 O.SO O.lSjJ.li o.djo.tn control F 200 1/3 4.10 i0.32j0.10i2.30 0.c|o.D5 F 100 F Ucexposed 3/3 4.12 O.Mp-Ish.H'.O.K'O.OJ 3/3 4.31 p.30,O.17il.i;o.(j'0.01 control F Ale exposed 2/3 3.05 F control 0 3/3 4.31 0.17 l.SSO.SOO.aij | II |o,I7j9.40j0.5SO.#l Table VII Summary u( Tina! Holly nml Organ Weights of Hogs Hoccivin" Kopeatoii Daily 7-Honr Ex posures to Vinyl Chloride 5 Days per Week for 0 Months 6 5r< w u &Q *i0a gn Weitrl.l*. {?/100 % 3e aa *f. , B Ay Weight a o. as a i 11 millrt eta * 5 |rt6'" g!? ] " P a E ]3 | ! 1! 11 101 Ucexposed l/l 15.0 'o 66 0.62 2.46jD.28j0.32 0.15 control 1 i 1 1M 113 Air exposed i/i 8.5 .0.68 0.77 2.03:0.47:0. wuu control M 111 200 1/1 10.2 :i.03 0.96 2.500.52`0.25.0.13 M 33 100 VI 12.0 0.6G!0.80 2.600.42 0.20:0.15 1 i 1 1M 152 Uncxposed l/l 13.3 o.so;o.7$ 2.63.0.53,0.23,0.11 eontrol i 1 1 1 iM I5G Air exposed l/l 10.6 ,0.7T0.87 3.05,0.45,0.36 0,14 control M 182 50 i/i 9.6 0.63,0.78 2.40'0.45'0.23'0.12 F 1IC Unexposed i/i 9.6 .0.710.63 2.67 0.410.21 control F 107 Air exposed l/l S.7 0.77 0.80 3.15 0.43 0.23 eontrol i F 103 200 1/1 10.5 0.78 0.71 I.8S;0.4V0.2S,' F no 100 1/1 11.9 0.99,0.78,2.14 0.43 0.31 F 151 Unetposed i/i 8.6 jO.99 0.82 4.10 0.750.U control F 15$ Air exposed i/i 11.3 jO.70 0.84 3.31 0.40.0,25 control F 161 SO i/i 7.4 jO.87 0.76 2.48,0.47 0.33 1i Table VIII Summary of Terminal Average Body and Organ Weights of Male lints Receiving Repented Ex posures to Vinyl Chloride 5 Days per Week a -a fi Org*nAVIfj)ts. k/1u0( '> Body Weight s3* rt ia1 ilh eg -si <iS*s- {e! V32 <K EiS ,S :ssi % Me . 2a 'lZ * 3 1 *e % j OT l Unexpoxed 0 0 8/8 319 0.50I0.33 2.67 0.75.0.1S 0.08 oontrol I Air exposed 6 7 t2/12 347 0.51 0.39 2.11 o.Toio.io 0.S1 oontrol 1 50 7 12/12 339 0.50 0.31 2.40 0.6s 0.1" Q.S7 50 6/10 346 0.5i;0.33 2.59 0.00 0.10,0.81 50 9 2 6/10 372 OA'J 0.32 2.5? 0.70.0.16.0.80 50 6 1 9/10 31S 0.47 0.32 2.J1 0.73 0.17 0.61 Unexposcd* 0 0 8/8 320 0.53 0.32 2.37 0.72 0.16.0.83 coutrol Air exposed* 6 13/12 370 O.M 0.20 2.42 0.C4 0.14.0.75 control 1 50* 6 7 12/12 300 ,0.49 0.33 2.51 1 10.6S.0.150.S2 * Postured for 6 ,rooks after exposure* cessed. Thirdly, it is doubtful whether it would be possi ble for humans to be exposed continuously at 600 ppm in production plants since this high a gen eral concentration would indicate severe leaks in the equipment and extremely high concentrations AP00023585 October, 1961 360 Tabi.k IX Summary of Average Hematological Values for Doga Receiving Repeated 7-Hour _____________ Exposure* to Vinyl Chloride Doc * Sex Concentration in ppm Months on Ei peri' meat Mo. of Animals llema* s'.nbsn E/lQO fi Hema WAV X Neutro tocrit 16* phils Lym pho cyte* Mono Eosino cytes phils Do< f 112................... Doc *U2.................... Do* *152................... Dot *156................... Do* *156................... Do* *156................... Do* * 162................... Dot *163................... Dos *163................... Dc *161................... Dot *151................... Do* *151................ , Do* *155.................. Do* *155................... Doc *145................... Dos *161................. Do *161................... Do* v\n.............. M M M M 51 li M M M F F Y F F P F F F Uoexpoaci control Unexpoaetl control Unerpefod control Air exposed control Air exposed control Air exposed control 50 80 50 UncxooMd control U&expond control Unopposed control Air exposed control Air exposed control Air exposed control 50 60 50 0 3 0 0 3 6 0 0 3 6 O 6 11 43 13.9 54 41 4 15 53 19.4 42 59 -- _l 15.5 54 15.4 53 1 40 s' 3 14.5 50 (3.4 <5 50 2 3 11 50 11.1 55 28 5 12 16.5 38 13.6 49 43 2 14.5 54 12.7 43 48 8 1 15.5 53 11.2 43 SO 3 n 48 13.3 59 20 3 14.5 83 23.6 07 25 0 6 l 28.5 58 15.5 4ft 42 3 9 l 15 48 14 61 37 0 2 16 59 18.3 60 33 5 2 15.5 56 17.0 53 31 6 11 10.5 35 15.S 53 40 5 0 l 15.5 58 13.4 56 42 2 0 15.6 56 12.3 43 43 3 11 adjacent to the leaks. The flammability of vinyl chloride precludes such severe leaks if this haz ard of vinyl chloride is to be controlled. Industrial Hygiene Standard The data presented indicate that little like lihood of injury would be expected if repeated daily 7- to 8-liour exposures are limited to 100 ppm or less. Although tho level of 100 ppm may not ap pear to offer any margin of safety since rats ex posed repeatedly to thi3 level were very slightly affected, the vast amount of human experience that is available while operating under an MAC of 500 ppm indicates that injury is not likely. Likewise the effects of even rather severe over exposure are not serious, hence this level seems reasonable. A time-weighted average for nil exposure should probably not exceed 0 ppm. Summary Vinyl chloride (CBh=CHCl) is a monomer used in very large quantities in the production of plastics. Repeated exposures of laboratory ani mals to several concentrations of vinyl chloride in air were conducted to determine the chronic toxicity of this material towards animals in or der to assess the hazard to humans. Vinyl chlo ride was found 1o have a slight capacity to cause liver and kidney injury on repeated exposures. Male and female rats showed micropatliological changes after repeated daily 7-hour exposures at 500 ppm for 4.5 months. Repeated 7-liour ex posures at 200 ppm for six months resulted in micropathaiogical changes in the livers of rab bits and statistically significant increases in the average weight of the livers of male and female rats but no detectable changes in dogs and guinea pigs. Repeated 7-hour exposures at 100 ppm resulted in slight increases in tho average weight of rat livers, tho other species were not affected. All species studied tolerated repeated daily 7-hour exposures to 50 ppm for six months with no detectable injury. Repeated daily 1-hour exposures at 200 and 100 ppm of vinyl chloride wore without effect, longer exposures caused a slight increase in liver weight. The standard for evaluating regular daily 7to 8-hour exposures may be defined as the con centration below which practically all analytical results must fall. The value of 100 ppm is sug gested as this standard for vinyl chloride, with a time-weighted average for all exposures not to exceed 50 ppm. References I. Manufacturina ClicmiM, Asbm. Chemical 8af.lv Data Sl.wt SD-S8 (1951), 1. Vcv Oirm-.-cay, W, r : 77,c [ralooenaud Hydrocarbons, Toxieitv anH Potential Danijcr*. (U. S. Publlfl Ks&lth Secviee. Publication Nro. 4H.) Government Printing OHieo, Washington. D. C. (165S), 3. MA*TowATTEf*. E., A. M, Finnrn. H. CnmsTr*, and D. Da.vx!:i:rj Arute IwhMatioo Toxicity of Vinyl Chicrid* to l-rthATHtory Anim.il*. Am. Ind. flvo* A*soc. J. SI: 394 4. SCTUUMANH, O., tiled by K, B. LtHMAM AMD F, FtrilT, S61 Industrial Hygiene Journal Toxicol, u. Hyg. rier tedmisohen Losunc'rnittel, J. Springer, Berlin, 133$ p. ISO. (From the tiawUtion, Toxieoioov ond Hygiene of Industrial Solvents by E. King and 1L F. Smyth, Jr., 1911). 5. A.C.Q.I.H. Threshold Limit Values (or 1D60. A.WA Arth. of Emit. Health l: 62 (1300). 0. Smytb, II. F., Ja.: Improved Communication--Hygiene Standard* for Daily Inhalation, dm. Ind. Hyg. Assoc. J. 17: 120 (1350). 7. Cherry Hill Farms, Camden, New Jersey. 8. Ralston Purina Company, St. Louis, Missouri. 9. Harris Milling Company, Mount Pleasant, Michigan. 10. Spfncer, U. C., V. K. Rowe, E. M. Aoams, D. D. MtCoT.URTtn, and D. D. Inteu: Vapor Toxicity of Ethylene Dichloride u Determined by Experiment* on Laboratory Animals. AMA Arch, Ind. Uyg. and Occup. Med. 4: (92 (1951). 11. Toukelsdn, T. R., M. A. Volt, F. Oven, and V. IC. Rowe: Vapor Toxieity of Allyl Chloride as Determined on Laboratory Animals, Am. Ind. Uyg. Assoc. /. 10: 217 (19591. 12. Dual Syringe Feeder Pumps, Modem Metalcraft, Mid land, Michigan. AP00023587