Document 44xovX65eEBwE9Z1E990RmkNR

*2<i--- L S5SAB ?0&t -> 'V ` Reprinted from American Industrial Hygiene Association Journal Vol. 22, Xo. 5 October, 1961 Copyright 1961 by The Williams & Wilkin* Co. Prnued in tl.S.A. The Toxicity of Vinyl Chloride as Determined by Repeated Exposure of Laboratory Animals T. R. TORKELSON, M.S., 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, 100 or 50 ppm vinyl chloride in air. Detectable changes occurred at all but the lowest concentration. The results are discussed and handling precautions suggested. Introduction ~\l INYL chloride (CH,=CHC1) is a chemical V of great industrial importance. It is used in the preparation of polyvinyl chloride resin, as a copolymer in saran and other plastics, as a chemical intermediate and as a solvent. Be cause of the flammability of vinyl chloride, it has been generally assumed that the greatest hazard 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 Oettingen1 and more recently by Mastromatteo et al,J von Oettingen concluded that the gas was anesthetic in high concentra tions and that considerable interest had been shown in the 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 Schaumann* were discussed by von Oettingen. These repeated exposures indicated little or no chronic effects even from anesthetic concentrations. Mastromatteo et al* also discussed the pub lished data and reported the results of single exposures of mice, rats and guinea pigs which confirmed the low acute toxicity of vinyl chloride, Mastromatteo reported that only two human fatalities due to vinyl chloride had been reported. It can be concluded from the published toxi cological data that anesthesia is the only sig nificant effect of acute exposure. Sufficient re peated exposures have not been reported to draw conclusions about chronic toxicity. The Threshold Limit Value of 500 ppm suggested by the American Conference of Governmental In dustrial Hygienists (ACGIH)* is reported by Smyth* to be hased on single animal exposures and human experience. The following report summarizes the results of repeated exposures of laboratory animals to either 500, 200, 100 or 50 ppm of vinyl chloride. The significance of the results is discussed and recommendations for a threshold limit value are made. Experimental Procedures Materials Tested Vinyl chloride, CH,=CHC1, is a colorless gas. It has a boiling point of --13.35*C (-1-7.93'F) and a freezing point of --154'C (--244.S2F). The material polymerizes readily and hence is sometimes inhibited with phenol or tertiary butylcatechol. Vinyl chloride is very flammable, its flashpoint being --7S'C ( -- lOS'F). The ex plosive limits are from 4% to 22% by volume. It has little odor although high concentrations may smell faintly sweet. A single, uninhibited sample was used in these studies. It was shown by mass spectrographic analysis to be essentially pure CH,=CHC1, air being the only impurity detected in gas phase samples. Source and Feeding of Animals The rats and rabbits used in this study were obtained from the stock colony of this labora tory, the guinea pigs were obtained from a commercial grower and the dogs were purebred beagles obtained from a local kennel. The rats and dogs were fed Purina Laboratory Chow* or Famo Laboratory Ration.* The rabbits and guinea pigs received Famo Rabbit Breeder Ration. The guinea pig diet was supplemented with carrots. Experimental Protocol The experiments were conducted in three phases. In the first phase, groups of 10 male 35. v-'-Tx'-r. Si't&e$s 355 Industrial Hygiene Journal and 10 female rats were exposed seven, hours per day five days per week to 500 ppm for 4.5 months. Exposures were given in a 160-liter chamber previously described." Mortality and growth records were kept. Final organ weights were obtained and tissues were saved for micro scopic examination. Five male and five female rats served as unexposed controls. The second phase consisted of repeated 7hour daily exposures of 20-24 male and 24 fe male rats, ten male and eight female guinea pigs, three male and three female rabbits and one male and one female dog to either 200 ppm or 100 ppm of vinyl chloride. These animals and two groups of controls were carefully selected and matched on the basis of age, condition and weight. The first group of controls received no exposure and served as unexposed controls. The second group received repeated daily 7hour exposures to room air in a chamber similar to the one used for exposures to the chemical. This group is referred to as the air-exposed con trol group. In addition to the animals receiving 7-hour daily exposures, eight separate groups of five male rats each were exposed to either 200 or 100 ppm for 4, 2, 1 or 0.5 hours per day. The procedures and equpiment used were bas ically the same as reported previously,11 Growth and mortality records were kept on all groups. The livers of the dogs were biopsied prior to ex posure and after 3 Vi months of exposure, hence the liver of each dog served as its own control. Pre-exposure and terminal hematological deter minations were made on all 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 killed by exsanguination after anesthesia with thiopental, sodium (Pentothal, Abbott). Samples of blood were taken of representative groups of animals for determination of alkaline phospha tase, serum-urea-nitrogen (SUM), serum-glu- tamic-pyruvic-transaminase (SGPT), and serum-g!utamic-oxalacetic-transaminase (SGOT). The organs were weighed and tissues fixed for histopathological examination. The rats which were not killed the day after exposures were stopped were pastured for eight weeks and then sacrificed in the previously described manner. The third phase of this experiment consisted of repeated daily 7-hour exposures of 24 male and 24 female rats, 12 male and 12 female truinea pigs, 3 male and 3 female rabbits and one male and one female dog to 50 ppm vinyl chloride. Equal matched groups served as unexposed and air-exposed controls. Three additional groups of 10 male rats each were exposed for 4, 2 or 1 hour per day to 50 ppm. The procedures followed were essentially the same as used for exposures to 200 and 100 ppm except that hematological examinations were made on the dogs after three months and liver biopsies were made only prior to exposure. Urine was collected from the rabbits as well as the rats and dogs. The rats which were not sacrificed at the end of the exposures were pastured for six weeks and then sacrificed. Equipment Used The exposure equipment used has been de scribed previously.11 However, in order to gain additional data about the results of repeated short daily exposures, it was necessary to devise a method of introducing additional groups of rats. This was done without opening the doors of the chamber by dropping the rats through chutes made of 3225-inch stainless steel tubing. These chutes were closed with a rubber stopper except during the brief time it took to insert the rats. The chutes, which were sloped at a 45' an gle, ended in covered, screened cages inside the chamber. The additional groups were started 3, 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." Total air flow through the chambers was measured by means of calibrated flow meters. Analysis of the Chamber Atmospheres Analyses of the air were made by direct com bustion of a known volume of air in a heated quartz tube. The resulting chloride was trapped in 1% sodium formate--1% sodium carbonate solution and subsequently titrated by a microVolhard technique. The results of the individual analyses were within 15% of the theoretical con centrations during the exposures to 200, 100 and 50 ppm. The average concentrations recovered were 197, 100.5 and 4S.7 ppm respectively. Results of Repeated Exposures Exposure to 500 ppm Vinyl Chloride The rats exposed repeatedly at 500 ppm for 4.5 months, grew normally and no changes were R&S 041183 October, 1961 355 Table I Summary of Terminal Average Body and Organ Weights of Male Rais Receiving Repeated Exposures to Vinyl Chloride 5 Days per Week Concentration in ppm Months on Exposure Duration of Daily Exposure, hours Ratio of Survival Final Aver* age Body Weight, l Luag Organ Weights, g/100 g Body Weight Heart Liver Sidney Spleen Teste. Uuexposed control.............. 00 Unexposed control,.... Air exposed control,........... 200 200 200 200 200 100 100 100 100 100 Unexposed* control............ jr exposed* control........... ^ 200* too- 0 4.5 0 6 9 9 9 9 0 9 9 9 9 9 0 6 9 9 0 3/5 304 0.54 0.33 2.52 0.71 0.15 0.39 7 7/10 313 0.56 0.33 3.00* 0.73 0.17 0,95 0 11/12 343 0.53 0.32 2.45 0.59 0.14 0.30 7 10/12 358 0.52 0.32 2.52 0.70 0.15 0.76 7 0/12 341 0.52 0.32 2.S5b 0.83 0.17 0.94 4 3/5 339 0.37 0.29 2.66B 0.03 0.16 0.S5 2 3/5 341 0.58 0.30 2.62** 0.64 0.16 0.39 1 3/5 350 0.33 0.23 2.49 0.51 0.13 0.73 0,5 3/5 339 0.51 0.20 2.33 0,67 0.14 0.95 7 7/12 352 0.51 0.20 2.81* 0,63 0-15 0.35 4 3/5 380 0.51 0.23 2-92 0.65 0.15 0.74 2 3/5 331 0.53 0.31 2-94 0.67 0.19 0.93 l 3/5 337 0.49 0.23 2.52 0.64 0.15 0.73 0.5 5/5 353 0.45 0.30 2.42 0.94 0.19 0.73 0 10/12 354 0.49 0.31 2.43 0.64 0.14 0.34 7 8/12 393 0.59 0.30 2.41 0.53 0.15 0.73 7 8/S 3S5 0.47 0.29 2.59* 0.84 0.15 0.71 7 e/7 370 0.37 0.31 2.53f 0.05 0.13 0.75 * Pastured lor 3 weeks after exposures cessed. () P 0.001 (b) P - <0.001 (cl P - 0.07 (d) P - 0.1 (e) P - 0.02 (0 P - 0.13 apparent grossly at autopsy. Microscopically their livers showed increased central lobular granular degeneration and the kidneys showed intersritial and tubular changes. The average weight increase of the livers of the male rats was statistically significant (P = 0.001), Table I. The average weight of the livers of the female rats was above that of the controls but not statis tically significant, Table II. SUN, SGPT, SGOT, and alkaline phosphatase determinations were within normal limits (Table III). Exposure to 500 ppm Vinyl Chloride All groups exposed seven hours per day 13S1*14 times in 204 days were normal in appearance, mortality and growth. Hematological, SUN, SGOT, SGPT and alkaline phosphatase values (Table III) and the results of the urinalysis were within normal limits. Gross pathology ^as normal in all species. Micropathology was Birmal in the rats, guinea pigs and dogs, how ever, adverse effects were noted in the livers of rabbits of both sexes. In the male rabbits this was characterized by central lobular granular de generation and necrosis with some foamy vacuolation. In the female rabbits the changes noted were central lobular granular degeneration and necrosis with periportal cellular infiltration. All organ weights were normal except for the livers of the male and female rats which were in creased significantly after repeated daily 7hour exposures (Tables I, II, IV, V, VI, and VII). In the males this increase was still appar ent eight weeks after exposure ceased, although the liver weights appeared to be decreasing and returning to normal. The male rats exposed to 200 ppm of vinyl chloride for either four or two hours per day for six months had elevated average liver weights (Table I). However, the small size of the ex perimental groups made the finding statistically insignificant (P = 0,07 and 0.1). The groups ex posed for either 1 or 0.5 hours per day were en tirely normal. 557 Industrial Hygiene Journal Table II Summary of Average Body and Organ Weights of Female Rats Receiving Repeated 7-Hour Ex posures to Vinyl Chloride 5 Days per Week JeS S- cVu ---- _ S'-- U Orffia Weights, V -2 M 14 X/100 Body o = > ru> s Weight .3 - -- "a S4 2* '== u 2 *V to V >4Js C cuti 2 c/T Unexposed coo* trol.. 0 500 1.3 5/5 9/10 194 0.52 0.41 3.06 0.30 0.19 1 1 193 0.6310.33 3.22* 0.31 0.20 Unexposed cootrol...,,....,. 0 10/12 202 0.6510.33 2.92 0.32 0.17 Air exposed control .......... s 9/12! 223 0.6610.39 2.99 0.31 0.13 200 5 10/12 90S 0,63(0.23 3.39b 0.34 0.13 100 6 11/12 231 0.59 0.39 3.35e 0.79 0.20 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 male rats exposed to 100 ppm for either four or two hours per day. The groups exposed for either . 1.0 or 0.5 hour per day were entirely normal. Exposures to SO ppm Vinyl Chloride The increase in weight of the rat livers, the only significant finding in animals exposed to 1G0 ppm, did not occur in rats 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 DO. A statistically significant decrease in kidney weight which was seen in the female rats (Table II) was considered to be an artifact since it was not seen at higher concentrations. Discussion Unexposed* eoatrol,....,,. 0 3/12 223 Q.61j0.37 2.67 0.32 0.13 Air exposed* control...,----- Q too* 0 100* 0 9/12 240 0.53(0.37 2.97 1 12/12 233 0.6110.33 3.06 12/12 235 0.63 0,40 3.17 0.33 0.13 0.31 0.30 0.33 0.31 Uoexposed con0 11/12 211 0.33 0.39 3.02 0.33 0.30 Air exposed control 6 12/12 202 0.59 0,38 2.93 0.S4 0,30 50 a 9/12 200 0.61 0.37 3.02 0.S4 0.20 Unexposed** control..,,.... 0 11/10 195 0.66 0.40 2.33 0.91 0.22 Air exposed control**.,.... 6 9/1= 221 0.03 0.40 3.01 0.37 0.19 50** $ 11/12 233 0.G3 0.33! 2.33 o.str1 0.2Q Pastured for 6 weeks after exposures ceased. ** Pastured for 6 weeks after exposures ceased. (a) P - 0.17 (b) P - 0.03 (c) P - 0.01 (d) P - 0.05 Exposure to 100 ppm Vinyl Chloride All species exposed to 100 ppm of vinyl chlo ride, seven hours per day, 13S-144 times in 204 days, were judged normal on the basis of the fol lowing criteria: appearance, mortality, growth, hematological examination, SUN, SGOT, SGPT, alkaline phosphatase determination, uri nalysis and gross and microscopic examination of tissue. However, slight increases were found in Repeated exposure to vinyl chloride at con centrations considerably below the level that has been considered safe for human exposure has been shown to have an effect on the liver and kidney of laboratory animals. Histopathological 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 rats and micropathological changes in the livers of the male and female rabbits. The only effect noted after repeated daily 7-hour exposures to 100 ppm for six months 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. Hence, 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 at 500 ppm were only slight to moderate; growth, mortality, and gen eral 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 injur}' would escape detection. Secondly, the 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 (5-3 weeks of recovery (Tables I, II and VIII). !> Table III Summary of Average Biochemical Values Determined for Animals Receiving Repeated Exposures to Vinyl Chloride 5 Days per Week Species and Dog No. Sex Concentration in ppm Months oa Exposure Duration of Daily Exoosurc, hours Number ot Animals Alkaline Phos* phatxse KingArm* strong Units Blood #Ura Nitrocen. mg/' 100 ml 5GPT SCOT Slgma-Frinkel Unit Dog *101............................... *113............................... #41............................... #93............................... Dog .# IDS,................ . * 107............................... *103............................... *110............................... Rut...................... ................... it F M Rat,............. .......................... F Unexposed control Air exposed control 200 100 Unexposed control Air exposed control 200 100 Unexposed control 500 200 200 200 100 100 100 Unexposed control 500 200 100 0 6 6 6 0 6 6 6 0 4.5 0 6 S 0 0 0 0 0 6 6 0 7 7 i 0 7 i 7 0 7 7 4 1 7 4 1 0 7 7 7 i 13.2 24 13 43 4.1 19 19 17 8.S 11 13 43 1 4.5 10 21 19 1 j.i 11 10 26 1 7.1 20 14 17 1 7.9 14 16 26 1 5.S 10 10 14 5 32.0- 20.6* 30 4 18.9 13.3 35 5 17.7 16.2 36 4 18.4 16.2 32 3 20.2 17.7 42 4 19.4 15.0 27 3 14,7 10.3 36 3 19.0 15.3 30 4 12.1 20.5 33 3 10-1 22.3 26 5 13.0 22.2 21 G 9.5 22. S 23 bbit...,.,....,,............... M Control 200 100 G 0 5 4.0 25 30 G 7 3 5-3 21 23 G 7 2 5.9 20 26 Babbit............................ F Control 200 100 0 0 6 4.9 33 33 6 7 3 5.0 27 35 0 7 3 4.0 2S 35 * Because of two unusually* high individual values in this group these average values arc elevated aad do not correspond with the values obtained on similar control groups in our laboratory. Normal control values are in the same raoges as those of the experimental groups listed in this table. Table IV Summary of Average Hematological Values for Animals Receiving Repeated 7-Hour Exposures to Vinyl Chloride Specie* or Dog .# Sex Concentration in ppm Months on No, of Expert* Animals ment Hemo globin g/IUU fi Hema WBC X Neutro tocrit 10* phils Lym pho cyte* Mono Eosino cytes phils Rat___ Rat..___ _ Ihil................................. Hut................................. Dog #101.............. ,... Dog # 101..................... Dog #113..................... Dog #113..................... Dog #111..... ............... Dog 111......... .......... . Dog *93...................... Dog #98..................... Dog # IOC.................... Dog # 100.................... Dog *107..................... ^)g #107..................... b *103..................... uog * no.................... Dog #110..................... M M F F M M M M 31 M M M F F F F F F F F Air exposed control 200 Air exposed control 2UQ Unexposed control Unexposed control Air exposed control Air exposed control 200 2iw) 100 100 Unexposed control Unexposed control Air exposed control Air exposed control 200 200 100 100 G4 G5 G 05 01 G 0^ 1 G1 0l G1 01 G1 0 G1 01 G 0 G1 01 G 14.5 51 IS.3 2G,5 71.2 1.5 0.S 14.4 50 10.7 19 77.3 0.2 3 14.0 19.5 13.5 22.5 74.5 0.2 2.3 13.5 47.4 ---- _12.3 -- 24.3 70.2 _ 1.0 4 -- 15 53 14.2 40 51 0 3 14.5 50 13. S G1 23 5 11 14.5 52 13.2 53 34 4 4 n 47 IG.2 CG 23 2 13 16.5 53 13.3 50 41 T 1 15.5 32 19.3 4G 4G 4 4 1G 54 13. G 01 39 0 0 14,5 51 21.3 42 37 3 IS 15,5 54 10.5 54 41 1 4 15 53 U.-t 55 33 4 8 10 57 11,7 GO 23 4 7 14 50 17.5 44 48 3 5 15 54 12.5 44 15.5 54 17.3 40 10.3 hi 14.4 49 51 37 50 0 *9 1 3 0 0 ,iS3 359 Industrial Hygiene Journal Table V Summary of Terminal Average Body and Organ Weights of Guinea Pigs Receiving Repeated Daily 7-Hour Exposures to Vinyl Chloride 5 Days per Week for 6 Months c .2 U1C'J Or;an Weights, s/100 % si<4 (StMli tCCicjl eaZ-. s 6'~ *3 ss ac J) lb Body Weignt ts ati _u> >V, 5 * 2 vT L7u. M Unexposed 8/l0i 927 i 0-64 0.251 3*32 0.70 0.1C 0.43 control | 31 Air exposed 5/101 1030 0.52 0.231 3.36 0,8t!0.10;0.4S control 1 11 M 200 7/10! 1044 0.53 0.27 3.01 0.60:0.0910,44 M 100 7/l0| 10S9 0,52 0.25! 2.79* 0.5Sio.li:o.47 JI Unexposed 8/12 91S 0*60 0.29 3.24 o.6S;o.i: 0.52 control M Air exposed 11/12 936 0.61 0.27 3*31 0.6410.12:0.50 control 11 M 50 10/12 1001 0.53 0.291 3*14 0.6110.12 0.43 F Unexposed G/S 99 0,62 0.27 3.20 0.63:0.12 control F Air exposed 7/3 367 0.GG 0.35 3.23 0.67 0.11 control F 200 7/8 397 0.74b 0.27 3.60* 0.6910.13 F 100 7/8 949 0*53 0.26 3.50 0.64'0.12 F Unexposed 9/12 723 0.73 0.34 3.41 0.69 0.15 control F .Ur exposed 3/12 364 0.65 0*25 3,34 0.65 0.14 control F 50 11/12 906 0.69 a.23 3*44 0.64 0*14 () P - 0.05 (b) P - 0.24 (c) P - 0.23 Table VI Summary of Terminal Average Body and Organ Weights of R.abbits Receiving Repeated Daily 7-Hour Exposures to Vinyl Chloride 5 Days per Week for 6 Months * w r>t c z. OT HU (A e -- .2 5 U Organ Weights. */10O 1 Body Weight *- 1 e ^ 3 -- >1 u2 -Si *5 M Unexpoaed iiii 3/3 3.01 ;o.3u!0.nii2.n7;o.-3:o.oc'o. is M Air exposed 2/3 3.00 0.3l!U.lSi2.4llo.40i0.02:Q.l6 control M 200 M 100 >111! 3/3 3.48 jQ.32!0.1912.3410.5410.02.0,15 3/3 3.65 jo.:c;0.13:2*0410.4010.02`0.15 M Unexposed 2/3 J.SO 0.3210.17 2.3310,45(0.02:0*15 control I M Air exposed 1/3 3.S7 0.37!0.13 3,t8l0.53l0.03!0.14 control M 50 3/3 3.70 0.30:0.:o!3.to;o.47j0.03:0.1: F Unexpoaed 3/3 4.13 0.31:0.17:2.22:0.40:0.0:1 F Air exposed 3/3 3.01 0.30:0. Isit'.lSiO,4110.01 control F 200 II I I 2/3 4.10 0.32:0.1012.30:0.4310.05 F 100 3/3 4.12 |o,2'jio.i3ii.3;;o.3sio.o5 F Unexpoaed 3/3 4.31 ,0.30.0.17 1.04:0.4010.04 control I1 |1 F Air exposed 2/3 3.05 10.300.171,solo.3o;o.011 control F 50 3/3 4.J1 ,I 0.32 1 0.171> 3.40I 0.23:I0.011, Table VII Summary of Final Body and Organ Weights of Dogs Receiving Repeated Daily 7-Hour Ex posures to Vinyl Chloride 5 Days per Week for 6 Months 1S tI I JO 1C 0rgan Weigh te. S/IOQ ; <3 Body Wei? it d 2 1G4 --cu EaZ-. cz > O *2 - E "riS* CSB l J ^ --H *V1 m 3" a U* 1 1 ' M 101 Unexposed 1/1 13.0 0.66 0,62:2,46 0,:s:0.32:0.15 control 11 1 1 31 113 Air exposed 1/1 8.5 O.fiS.'Q.7712.63.0.47 0.19:0.14 control 111 ji 111 200 1/1 10.2 l.OsiQ.96:2*50 0.32 0.25:0.13 JI 93 100 1/1 12.0 0.S6,0.50i2.30 0.42'O,28 0.15 M 152 Unexposed 1/1 13.3 O.SO'0.73:2.63.0.5310.23.0,11 control 1 1 11 1 JI 153 Air exposed 1/1 10.6 0.77 0.37:3.03,0.45:0.26:0.14 control 1111 JI 162 50 I/i 9.8 0.89:0.7312.40,0.43:0.2310.12 F 106 Unexposed 1/1 9.6 0.71i0.6312.8710.43:0.211 control 11111 F 107 Air exposed 1/1 a.? 0.77;0.80I3.15:0.43;0.33I control 1111| F 103 200 1/1 10.5 0.73:0.71! 1.33'0.45l0.251 F 110 100 1/1 11.9 0.99I0.7S12.14:0.43:0.3ll F 151 Unexposed 1/1 8.6 0.09:0.3214.10.0.4510.43i control 11111 F 155 Air exposed 1/1 11.3 0.70(0.3413,3i:0.40;0.25f control 1111| F 161 50 1/1 -.4 0,5710.7612.4S:0.47:0.331 11 I`1 Table VIII Summary of Terminal Average Body and Organ Weights of Male Rats Receiving Repeated Ex posures to Vinyl Chloride 5 Days per Week z > x** rt rta0 m u5 COEJ = --"- ,1 j- 0e a3 ti - ss i !Si 1 UUJ>ZJ >u iz- Jia 1*3 ,=0; u X tZ Orsin Weishts, j/lOog Body Weignt Unexposed 0 0 3/S 319 0.5010,3312.07,0.:5.0*1$:0,93 control Air exposed 6 7 12/12 347 ` 0.51 0.32 2.4i:0.:010.1610.31 control 50 50 50 50 I I6 7 12/12 339 0.50 0.31 2.4310.6S!o. 1710.37 6 4 8/1U 348 0.51 o.ooio.soio.Goio.ldio.31 6 it 6/10 322 0,4'J 0.32j2.5710.7010.10:0.30 6 1 9/10 345 0.4710.3212.5110.7310.17:0.54 Unexposed* 0 0 8/3 33G 0.solo.3212.3710.72:0.10:0.S3 control III I Air exposed* 6 7 12/12 370 0.5310.2012.42!o.ll4lo. 14,0.75 control 50` IIIII 6 i 12/12 360 0.40:I0,33:2I.511I0.GS 0'.151 0.S2 * Puaiured for G weeks tifter exposures ccued. Thirdly, it is doubtful whether it would be possi ble for humans to be exposed continuously at 500 ppm in production plants since this high a gen eral concentration would indicate severe leaks in the equipment and extremely high concentrations tfflk n-SZ:?n>*--a*--*!'*? t-t October, 1361 360 Table IX Summary of Average Hematological Values for Dogs Receiving Repeated 7-Hour Exposures to Vinyl Chloride Dos * Sex Concentration in ppm Months on Experi ment No. of Animals Hemo globin 2/100 i Hema \VBX X Neutro tocrit 10* phils Lympnocyces Mono- Eosinocytes pnils Da* * 152..................... Doc *152...................... Dog *152..................... Dog *158..................... Dog *155,..,.,....... Dog *159.................. . Dog * 162...................... Do *16Z..................... Dog *162..,.......... . Dos *151..................... Dog *151..................... Dog *151..................... Dog *155..................... Dog *155..................... Dog * 155..................... Dog * 161..................... Dog *161.,................ Dog *181................. M J1 It Jt M il Jt Jt M F F F F F F F F F Unexpoaed control Unexposed control Unexpoaed control Air exposed control Air exposed control Air excostd control 50 50 50 Unexposed control Unexposed control Unexposed control Air exposed control Air exposed control Air exposed control 50 50 50 0 3 6 0 3 < 0 3 8 0 3 ft 0 3 6 0 3 6 1 11 43 12.9 54 41 4 1 15 52 19.4 42 50 4 4 1 15.5 54 15.4 52 40 5 3 ---- ---------- 1 14.5 50 13.4 45 50 2 3 1u 50 11.1 55 23 5 12 1 10.5 39 13.6 48 88 2 2 1 14.5 54 I2-T 83 88 3 I 1 15.5 53 11.2 43 50 4 3 1 11 48 13.3 59 30 3 9 1 14.5 52 23.8 67 25 0 8 1 15.5 53 15.5 46 42 3 9 l 13 1 lfi 46 14 61 59 13.2 60 37 33 0 5 2 4 1 15.5 38 17.0 53 31 5 11 1 10.5 35 15.3 55 .40 5 0 1 15.5 58 13.4 56 42 2 0 1 15.5 38 12,3 43 43 3 u djacent to the leaks. The flammability of vinyl aloride precludes such severe leaks if this hazrd 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-hour exposures are limited to 100 ppm or less. Although the level of 100 ppm may not ap pear to oner any margin of safety since rats ex posed repeatedly to this 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 all exposure should probably not exceed 50 ppm. Summary Vinyl chloride (CH,=CHC1) 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 to have a slight capacity to cause ver .ind kidney injury on repeated exposures, )dale and female rats showed micropathologicnl changes after repeated daily 7-hour exposures at 500 ppm for 4.5 months. Repeated 7-hour ex posures at 200 ppm for six months resulted in micropathologicnl 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 the average weight of rat livers, the 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 were without effect, longer exposures caused a slight increase in liver weight. The standard for evaluating regular daily 7to S-hour exposures may be denned 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 1. Manufacturing Chemist* Assoc. Chemical Safety- Data Sheet SD-56 (1054). 2. von Oettinoen, W, F.: The Ifntnnennted Jludrocarbont, Toxicity nn/{ Potential Don/jern, (tT. S. Public Health Service. Publication No, 411,) Government Printing Office, Washington, D. C. (1955), 3. MASTnoxfATTEO, E., A. M. Fisher, H. CnnrsTtc, and D. Dinzicer: Acute Inhalation Todcitv of Vinyl Chlo ride to Laboratory Animals. Am. Ind, Hya. Assoc, J. it: 301 (1900). 4. Scttacmann, O., cited by Iv, B. Lehman and F. Flurt, t'. A- p-y iSg Industrial Hygiene Journal Toxicol, u. Hyg. dcr teehnischen Losungsmittel, J, Springer. Beriin, 1933 p. 130. (From the translation, TaxieoloQ y and Hygiene of Industrial Solvents by E. King and H. F. Smyth, Jr., 11341). 3. A.C.C.I.U. Threshold Limit Values for 1060. A.UA Arch, of Envir, Health 1: 62 (1060). 6. Smyth, H. F.t Jn.; Improved Communication--Hygiene Standards for Duly Inhalation. .4m. Ind. Uytj. Assoc. J. IT: 139 (1953). 7. Cherry Hill Farms, Camden, New Jersey. 8. Ralston Purina Company. St. Louis. Missouri. 9. Harris Milling Company, Mount Pleasant, Michigan. 10. Sps^ces, H. C., V. K. Rowe, E. M. Adams. D, D. McCollistsr. AND D. D. Irish: Vapor Toxicity of Ethylene Diehtoride as Determined by Experiments on Laboratory Animals. AMA Arch. Ind. Hyg, and Occvp. J/ed. 4: 4S2 (1051). 11. Toukelson, T. R., M. A. Wolf. F. Oten. and V. K. Rowe: Vapor Toxicity of Allyl Chloride as Determined on Laboratory Animals. Am, Ind. Hyg. Aisoe. J, !0: 217 (10391. 12. Dual Syringe Feeder Pumps, Modem Metalcraft. Mid* land, Michigan. &> co o b 00 (O IH i isKv ls8 #