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rsis ing. iths I STUDIES ON THE TOXICITY/AND SKIN EFFECTS OF COMPOUNDS USED IN THE RUBBER AND PLASTICS INDUSTRIES > II. flMkiim ., ! F. S. MALLETTE, FU>. . t' AXIOM, OHIO AND t VON HAAM. A.O. ' * INDUSTRIAL ASPECTS PLASTICIZERS are frequently added to synthetic resins to increase their flexi bility and extensibility. According to Powe^,*1 2they are not so much desirable as necessary. Plasticizers serve two important functions *: They reduce the vis cosity of resins at processing temperatures, and they soften the resin at normal temperatures, yielding flexible materials. Resins high in vinyl chloride content can be calendered ot molded only with difficulty, and the addition of a plasticizer greatly improves the calendering process. Since plasticized vinyl resins are used in hundreds of articles of commerce, the choice of the plasticizer depends upon the ultimate use of the compound. Most of the plasticizers, especially those used for vinyl resins, are compounds with a high boiling point, usually above 200 C. For this reason industrial exposure to the vapors of these compounds is observed only near the areas of vaporization. In the plants surveyed, the plasticizers are added to the resins in the semidry state and mixed in large or small blenders, together with the coloring agents, stabilizers, and Other ingredients. The mixture is then charged into a Banbury mixer, in which the temperatures may exceed 200 C., resulting in some vaporization of the plasti cizer. However, Banbury mixers are usually enclosed and ventilated, and conse quently normally no undue exposure to the vapors can occur. From the Banbury mixer the hot mass is dropped onto a mill, from which it may either be sheeted off for future use or may be fed directly into the calender. At the mill or the calender, large amounts of vaporized plasticizer may escape. For this reason it is advisable to hood and exhaust these machines. Condensed plasticizers may reduce the efficiency of the exhaust system, so that periodic cleaning of the ducts and fans may become necessary. During the periods of reduced efficiency of the exhaust system, resulting escape of plasticizer vapors, complaints of irritation of the eyes and respir atory tract with occasional reports of headache and nausea, have been received. Prom the Medical Department. The Firestone Tire & Rubber Company (Dr. Mallettc), and the Department of Patbolocy. Ohio State University (Dr. von Haam). 1. Powers, P. ,A.: Synthetic Resins and Rubbers, New York. John Wiley & Sons, Inc., 1943. 2. Reed, M. C.: Survey of Plasticizers for Vinyl Resins, J. Polymer Sc. 1:115, 1947. 231 <$, v-m* - V# ; '* ` n *j * . /a?*-*; s ucc 041218 "" " ' m: I' r -<t- , ** |* - v ' I, l * 232 INDUSTRIAL . HYGIgNE AND OCCUPATIONAL MEDICINE REVIEW OF THE TOXICOLOGICAL LITERATURE . Few data on the toxicity of plasticizers or on their hazard to health ate avail able. The gums, oils, and resinous materials, of which there are literally hundreds in use as softeners, are almost universally considered nontoxic with the exception of certain irritating tars and pitches.' Orthotricresyl phosphate presents a def inite industrial health hazard. In experimental animals it produces toxic hemor rhages in the lungs, liver, kidneys, and spleen and degeneration of the motor nerve cells. The phthalic acid derivatives (dibutyl and diethyl phthalate) are not seriously toxic but may produce skin affections and an anemic condition in animals. Vapors of 2-ethylhexyl phthalate have produced delayed death, in rats with liver and kidney injury.' Diphenylguanidine was reported, as nontoxic to ani mals by Davis,* who concluded that the conjunctivitis, bronchitis, and dermatitis encountered in workers were due to impurities rather than to the compound its3f. 1 Of the solvent plasticizers used in the synthetic rubber industry, acetone, amyl ace tate, benzene, and benzine have been thoroughly investigated, and it has been found that they may exert toxic influences upon the lung, liver, kidney, or blood-forming organs. Benzine also has an injurious effect upon the central nervous system. Carbitol* (diethylene glycol monoethyl ether) is only slightly toxic unless contam inated with diethylene glycol.*The latter causes kidney injuries leading to anuria and uremia.' Diethylene dioxide ("dioxane"), is a plasticizer for synthetic rubber. It is a mild pulmonary irritant, and prolonged exposure to it may lead to severe injury of liver and kidney.* The various forms of cellosolve* (methyl cellosolve,* methyl and diethyl, butyl and dibutyl cellosolve*) are all ethers of ethylene glycol and are widely used as solvent plasticizers for acetyl cellulose, nitrocellulose, and soluble resins.. They have slight irritating effects on the mucous membranes and toxic effects on the kidneys. - Glycerin is practically nontoxic and causes symptoms only when administered in high doses. Lactate (ethyl and butyl lactate) in high doses causes death of experimental animals from respiratory paralysis.7 Carbon disulfide and the chlo rinated hydrocarbons are strong narcotics in high concentrations and may act as local lung irritants.* Repeated exposure produces nephritis with albuminuria and bitty degeneration of the liver. The toxicity of the chlorinated hydrocarbons is vari able, and industrial hazard depends on the volatility as well- as on the toxicity of 3. Hamilton, A.: Industrial Poisons in the.United States, New York, The Macmillan Company, 1925. 4. Shaffer, C. B.; Carpenter, C. P., and Smyth, H. F., Jr.: Acute and Subacute Toxicity of Di(2-Ethylhexyl) Phthalate with Notes upon Its Metabolism, J. Indnst. Hyg. & ToxicoL >7:130, 15*5. 5. Davis, P. A.: Toxic Substance* in the Rubber Industry: XVI. Guanidine Compounds, Rubber Age *8:143, 1930. 6. Hamlik, P. J.; Lawrence, W. S.;Fellows, J. K.; Indians, F. P,, and Laqoeur, G. L.: Epidermal Application of Diethylene Glycol Monoethyl Ether (Carbitol) and Some Other Glycols: Absorption, Toxicity and Visceral Damage, J. Indust Hyg. & Toxicol. >9:32$, 1947. 7. Lehmann, K. B, and Flnry, F.: Toxicology and Hygiene of Industrial Solvents. Balti more, William* & Wilkins Company, 1943. 8. Barber, H.: Hemorrhagic Nephritis and Necrosis of the Liver from Dioxane Poisoning, Guy's Hotp. Rep. M:267, 1934. 9. Von Oettingen, W. F.: The Halogenated Hydrocarbons: Their Toxicity and Potential Dangers, J. Indust Hyg. & Toxicol. 19:349, 1937. MAI -Tis as Fw l On. Diet 4. CDart X Nkr - Otn i. Ftet :S the doe . hivtoloi^ pm dfuper ia b their eon ucc 041219 'ICINM eafth are availsrally hundreds i the exception presents a defs ^fe^f&nor- ot^hemotor phthaiate) are c iiiiipdStion in .^jeath. in rats opfbxic to aniMxfc dermatitis nWQpnd itself, xj^itBnyl aeea^beenfound hlopdrfbnning system. irfessMitamto&nnria and grubber. It *we injury .^methyl and rtq'arewidely 3teMe resins. , !W6ftttbn the a*^nistered tf: death of ||the chk>thajt act as nJihuria and ^wis variToxicity of Toxicol. ?<*VG. L: Other 1947. ti*#, Balti- MALLETTE-vow HAAM--TOXICITY-SKIN EFFECTS OF PLASTICIZERS 233 the compounds. The cyclic hydrocarbons occupy a middle position with regard to toxicity. Cyclohexyl acetate is more toxic but less volatile than amyl acetate and produces hemorrhagic edema of the lungs and paralysis of the central nervous sys tem. Unsaturated hydrocarbons are usually more#toxic than the corresponding saturated compounds/ This brief survey presents the laboratory evidence on the chemical groups to which the majority of plasticizers belong. However, the constant introduction of new compounds demands continual investigation, and each new compound should be properly studied .as tb its toxicological properties in order to estimate its indus trial health hazard.- METHODS AND MATERIAL Twenty-five compounds which are used at present as plasticizers of synthetic resins have been investigated. They are listed according to .their chemical classification in .--Table 1.* The hit group includes compounds whose chemical composition is a proprietary secret and have therefore been listed under thejr trade name with the name of the manufacturer in parenthesis.11 Table 1.--Com-^otmdr Used as Plasticisers L Adipic acid taiadsn .fit _____ Di-Zethylbcsyl adipate ("adipol 2EH") 2. AnMc .aeid ininthts Cyeloheiyl uelate Dibutyl CEUoaolTC* sstliu 2-vtbyIkexyl uelate Metbyl iaobutyl e&rb&nol uelate Fentaeed uelate 2. Capita add derivedm Dietbyfctecsljeel dicanrate 4. Caibwe acid detivaffvaa , Dihiunesithyl dialyail tirtmle . 5. Nitrile defiutieet . Oetedecene nitrile 6. Pbtbalie edd deriyatim Djbntaaytthyl Jihtbalate Cbnelitn Butylwirryl phtbelate ("aaotidscr 160") 7. Rieinoleic add derivatiyea Metbylaeetyl ricinoleate C"Baker's p4") 8. Sebaoe acid deriyatiyea Dioctyl scbacate Dibutyl ecbacate 9. Tiade-name plauieizers "Fleaol 8NS'* (Carbide A Carbon) ' "Pleaticirer 50 F' (Barrett) "Plaatideer Ellieett H" "Plasticizer SC" (Drew) "Feraplea 025" (Robin A Haas) `Taissks 040" (Rebut A Haaa) "Santleiaer 140" (Monsanto) . "Santidier 141" (Monsanto) "Plaatdein X-JS" (Emery) For the determination of toxicity the same methods were used as given in the report on the toxicity of accelerators, activators, and antioxidants.11 Since most of the plasticizers arc insoluble in water, mineral oil or propylene glycol was used as diluent. The criteria for the determination of toxic effects were the minimal lethal doses, the clinical symptoms, and the histological changes as revealed by postmortem examination. For the determination of the L.Djw Smyth's range-finding test was used as a first step and was combined in a second series of experiments with the logarithmic toxicity scale of Deichmann. In the average experiment 16 to 18 animals sufficed for obtaining a clear-cut result. The skin effects of the plasticizers were determined by application to the skin of experimental animals and human volunteers. Two 10. Because of the proprietary nature of many of these compounds exact information as to their composition cannot be obtained. The following information may not be entirely accurate - "Flexol 8NfT =N,N-di-beta-(2-ethylbexyI)ethyl 2-ethylhcxamide "Plasticizer" SOB'' =butylcydohexyl phthaiate "Plasticizer SC" =triethylene glycol dkaprylate "Paraplex C-25" =prohably condensation products of sebacic "Paraplex G-40" =acid with glycols and/or glycerin "Sentkizer 140'* =moootolyldipheny1 phosphate "Santicizer 141" =monooctyldipheny1 phosphate (?) "Plastolein X-55" =diethylene glycol di-pelargonate 1 *% , V.. -fJw"TU * " `>W 1 - 'S:i 'zfm *?*& . tr in i ucc 041220 234 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE to four white rabbits were used for preliminary testing of skin irritability and sensitization, and each compound -was then tested on 15 to JO human subjects. The patch test was used and the reaction classified as slight, moderate, or severe. Sensitization tests were performed two weeks after the primary irritation test.'1 V RESULTS Toxicity Investigations.--Tabic 2 lists the compounds which have been found nontoxic or practically nontoxic. The animals supported intraperitoneal injection of 6 gm. or more per kilogram of body weight without showing any immediate or delayed effects. All animals were subjected to autopsy after one month of observa tion. Careful histological examination of all organs failed to show any evidence of pathologic change. The injected material could often be found remaining in the peritoneal cavity, surrounded by necrotic formed adhesions aind fibrous tissue. Micfbscopically, foreign body granulomas could be observed and some of the mate rial could be followed in the endothelial cells of the liver and spleen. Five of the plasticizers examined showed a moderately toxic effect in laboratory animals. They were dioctyl phthalate, butylbenzyl phthalate, "santidzer 140," % Table 2,--Nontoxic Plasticisers % ui-i-Mttyniexyl ftdipttr CyeUhnjl zzeltte Dtbtttyl celkwolve azelate 2-etbylheieyI Methyl frobutyl carhtaol azelate Peataaol azelate Diethylene glycol ditunte Dibntoxycthyl diglycol carbonate OctftdcoM Me DitetHijiltyl phthalate Dicapnrt phthalate MethyUcctyl ricinaicate EHoctyl tebacatc Dibutyl sebacate 4*PUztieizer SO B** (Barrett) "Fbatfcter EOfeett H" "Plafltidser SC^ (Drew) "Fantplu 0-25" (Rohm A *** ) "Pamplex G*40" (Rchm k Haas) "Plaztoleio X-55" (Emery) "santidzer 141," and "flexol 8N8." Intraperitoneal injection of dioctyl phthalate proved fatal in doses higher than 2 gm. per kilogram of body weight. Lower doses produced weight loss, leucocytOsis, severe anemia, and hematuria, from which the animals recovered after one to two months. No delayed effect or permanent injury was noted in the surviving animals. Butylbenzyl phthalate killed rats after intraperitoneal administration of doses higher than 1.8 gm. per kilogram of body weight. Oral administration of more than 4 gm. per kilogram of body weight proved equally fatal. The animals died after four to eight days, showing weight loss, apathy, and leucocytosis. The histological examination of the organs revealed toxic splenitis and degenerative lesions of the central nervous system with congestive encephalopathy, myelin degeneration, and glial proliferation. "Santidzer 140" proved fatal in intraperitoneal doses of higher than 1 gm. per kilogram of body weight. Oral doses up to 4 gm. were supported. Toxic animals became lethargic on the second or third day, and a profuse diarrhea developed. They died with symptoms of paralysis. Autopsy showed a generalized capillary paralysis with severe edema and numerous small hemorrhages in the brain. 11. Mallette, F. S., and Von Haam, .: Studies on the Toxicity and Skin Effects of Com pounds Used in.the Rubber and Plastics Industries: I. Accelerators, Activators, and Anti oxidants, A. M. A. Arch. Indust Hyg. 5:311, 1952: *' : Ac !1 A* < . t -1 i 0* 1 c t wit c ru t r r z 'E S Tn 44* is \ rr ucc 041221 1i , `e' i, and', the fedf/two- found jection MALLETTE-wh HAAtt--TOXICITY-SKIN EFFECTS-OF PLASTICIZERS 235 "Santicizer 141" killed animals after intraperitoneal administration , of doses higher than 2.4 gm., but oral administration.of 4 gm. per kilogram of body weight was tolerated. With the intraperitoneal administration, the animals became para lyzed and lethargic. Recovery from nonfatal lesions was delayed.1 The histopathological examination demonstrated a severe acute hemorrhagic encephalopathy with cerebral edema, ganglion cell degeneration, and small hemorrhages. As delayed effects, focal gliosis and persistent foci of myelin degeneration could be observed. Taslk 3.--Determination of Skin Effect* hSfate m Nun of Compound Utfk Mid derlretlm * AnimellWte (Cone. 100%) i-- -- ---- ---i Inlte- Soul- tin tubs Met Bffeet Dt-tethtlbexyl edlpete..................... 0 0 Ud*fe mM derteetlm . Otddbexpl aeeMte ............................ 0 Maty] mUomIt** uelete........... + MkrlUQl uelete .......................... V + Httkjrl taobutji tubMt Mdtti Puteeol Melmte ...................................9 0 + Clndc (dd dMiTNUVM DttthyWoe ftycol dfnpnN........... -H- 0 tirtraak Mid detiretlne Dtntmrtbji diclj'ooi tuMnl* o o Mifli derieettm Oetedeeene nitrile .............................. 0 + ftthdfc Mid dertratiToe ttbatoxyetSpi pbthelete.............. o * wprri pntbsUu........................... ++ WMtyl pbthelete .......................... ++ MSMuil pbtbelete .................... -H- . + double Mid derivetfree Sethyleeetrl tidnolHU.................. ++ **ede Mid derivetlvM 0 BfcKtyl MbMStN ............................... 9 0 Mwtjl eebecete ................................ ttdMumt pleetieiiera 0 0 "Knol N8" ...................................... 9 + TUetldMr bo B".......................... -H- + "FUitideer KOIeott H".................... o 0 "Meetieleer 8C" ............................... 0 0 'Pireplex G-" .............................. ++ 9 `Tereplex 0-40'* ............................... 0 0 m "ntMeer 140" ................................. + "nUdwr 141" ............................... +++ 0 0 "Heetoieln X-M"................................ 0 0 OpD- Hagftttv* Wont caot* Baa*- iMfr ttOO.% *04*% tlon, % 100 m 0 100 n ' m 47 68 100 m U 100 m %> 100 . ' 40 100 or t, 100 0 9 100 M 19 n uo 10 m 10 m 10 m 0 a 11 HO 90 10 100 mo 100 100 0 0 10 100 100. as SB 10 & loo 66 m 74 00 n 48 90 00 ss 40 M 18 40 68 48 10 10 7 I BmuiTMi ----- ` Siren Bcn^ Brae- tiaodL^ IrrittOn tton % Kffart 0 0 * 0 8 Moderate 0 0 Moderate 0 0 sau*t 07 .0 0 ' fXbdmtt 0 lo night 00 9 0 0 mu*t ,o 0 - 0 0 Moderate 0 8 Moderate 0 0 Moderate 0 IS BUht 00 00 0 0 & 9 Sente 0 0 Moderate 0 0 Moderate 0 0 Moderate 10 10 Seme 0 18 Seme 0 0 Moderate 0 10 Moderate 0 0 gllfbt SenejtMne Kffaet & -Might 0 0 Moderate 0, 0 9 0 Slight 0 Modemt * 0 might 0 0 0 Moderate Moderate 0 Moderate 0 Large fatal doses also proved a powerful hemolytic agent with marked vascular hemolysis, hemoglobinuria, and hemosiderosis of the spleen. 1 "Flexol 8N8" proved fatal in doses higher than 4.0 gm. per kilogram of body weight. The animals developed convulsions followed by paralysis. The histological examination of the brain gave the picture of toxic hemorrhagic encephalopathy with edema, swelling of ganglion cells, and small hemorrhages. Skin Effects.--The results of the studies on the effects of the plasticizers on the skin are shown in Table 3. Preliminary experiments on animals always preceded the application of the compound to human subjects. Sensitizing `effects were studied after a two-week 236 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE ._ interval had elapsed. From the table it can be seen that only five compounds proved neither irritating nor sensitizing. Six compounds had some sensitizing effect on animals but were innocuous in the human investigations. AU compounds which produced primary irritation on the animal skin also proved irritating to the human skin. Twenty compounds produced a definite reaction on the human skin. Five produced a reaction in approximately 10% of the persons tested, and six produced a reaction in more than 30% of those tested. "Paraplex G-25" and "flexol 8N8" pro duced reactions which must be regarded as uncommonly severe. Nine compounds produced some sensitizing effect on the human skin, with "paraplex G-25'' and "paraplex G-40" the severest sensitizers. The following plasticizers proved entirely innocuous in the concentrations tested: di-2-ethylhexy! adipate, dibutoxyethyl diglycol carbonate, dibutoxyethyl phthalate, dioctyl sebacate, and dibutyl sebacate. summaky The toxicity and skin effects of 25 plasticizers were tested by standardized meth ods. Five of the plasticizers proved moderately toxic in doses from 0.6 to 2.4 gin. per kilogram of body weight. The toxic reaction was displayed by the erythrocytes, the blood capillaries, and the central nervous system: Seventeen plasticizers proved to be slight or moderate skin irritants, threesproved to be severe skin irritants, and five proved to be moderate sensitizers. Five plasticizers showed no irritating or sensitizing effect, and the lack of toxic properties recommends them as the most innocuous compounds tested in this series. 7 ucc 041223