Document vDop3gaVVo6DY3KkXXLJQ8RY

ELSEVIER MONOGRAPHS ON TOXIC AGENTS jTHE HALOGENATED HYDROCARBONS PF INDUSTRIAL AND TOXICOLOGICAL ! IMPORTANCE Edited by by ETHEL BROWNING, m.d. FORMERLY H.M. MEDICAL INSPECTOR OF FACTORIES, MINISTRY OF LABOUR AND NATIONAL SERVICE, LONDON (GREAT BRITAIN) I i' . lit W.F. VON OETTINGEN, m.d., ph.d. * CONSULTANT IN TOXICOLOGY, FORMERLY MEDICAL OFFICER FOR TOXICOLOGY, NATIONAL INSTITUTE OF ARTHRITIS AND METABOLIC DISEASES, NATIONAL INSTITUTES ON HEALTH, U.S. PUBLIC HEALTH SERVICE, BETHESDA, MD. (U.S.A.) i ! i ELSEVIER PUBLISHING COMPANY AMSTERDAM - LONDON - NEW YORK ELSEVIER PUBLISHING COMPANY AMSTERDAM - LONDON - NEW YORK 1964 to O O ethane derivatives Ethylene dichloride 186 187 Hofmann, A. H., Miincli. med. Wschr., 69 (1922) 159. Hoton, J. Med. Paris, 19 (1907) 7. Kochmann, M. and W. Strecker, Biochem. Z., 43 (1912) 412. KSnio, R., Arch. klin. Chir., 99 (1913) 147. Large, S. A. and E. D. Brown, Laryngoscope, 15 (1905) 883. Lazarew, N. W., Arch. exp. Path. PharmakoL, 141 (1929) 19. Lehmann, K. B. and L. Schmidt-Kehl, Arch. Hyg., 116 (1936) 157. Lotheissen, G., Miinch. med. Wschr., 47 (1900) 601. Maass, Th. A., Ther. Monatsh., 21 (1907) 303. Manufacturing Chemists Association, Safety Data Sheet, SD-50, 1953. Mrat and De Lens (quoted from Th. A. Maass, 1907). MUller, B., Arch. klin. Chir., 75 (1905) 896. Nuckolls, A. H., Underwriters' Lab. Rep., No. 2375, Nov. 1933. Oettingen, W. F. von, C. C. Powell, N. E. Sharpless, W. C. Al ford and L. J. Pecora, Nat. Inst. Hlth. Bull., No, 191 (1949); Arch. int. Pharmacodyn., 81 (1950) 17. Renner, Dtsch. med. Wschr., 44 (1918) 578. Sayers, R. R,, W. P. Yant, C. P. Waite and F. A. Patty, Pub!. Hlth. Rep. (Wash.), 45 (1930) 225. Schott, E., Arch. exp. Path. PharmakoL, 87 (1920) 309. Scoto-Foolieni, L., C. R. Soc. Biol., 105 (1930) 959, 961; 106 (1931) 222. Seiffert, E., Dtsch. med. Wschr., 49 (1923) 55. Seitz, J., Correspondenzbl. Schweiz. Arzte, 31 (1901) 97, 411. Webster, W., Arner. J. Physio!., 27 (1910) 328. Zoepffel, R., Arch. exp. Path. PharmakoL, 49 (1903) 89. 10. ethylene dichloride parts of water to the extent of 0.9 parts at 0 and is freely miscible with alcohol, ether and most organic solvents. When heated with alcoholic solution of potassium hydroxide, chlproethylene (vinyl chloride) is formed. In contrast to its isomer, ethylidene chloride, it is indifferent to cold and concen trated sulfuric acid, it does not react with Fehling solution, and does not give the isonitrile reaction of chloroform. Ethylene dichloride is flammable and is classified as such (inflammable) by the Interstate Commerce Commission. Its flashpoint is 13.33 C (56 F) by the closed cup method and 18.33 C (65 F) by the open cup method. In contact with open flames it is decomposed with the formation of hydrochloric acid and other irritant vapors (Manufacturing Chemists Asso ciation, 1947), Its explosive limits in air are between 6.2 and 15.9% in air. Manufacture Ethylene dichloride is made commercially by treating ethylene with chlorine. In order to restrict the reaction to the formation of ethylene dichloride the temperature and/or the pressure are reduced and to increase the yield catalysts such as ferric chloride, bromine or lead are used. Uses Ethylene dichloride is used as a solvent for oils, fats, paraffin, casein, resins and gums, for the extraction of fats and oils, degreasing of machinery, and as a cleaning agent in soaps and scouring compounds. It is used as a coupling agent in ethyl anti knock fluids and in fumigant mixtures for insect control. Chemistry Ethylene dichloride, sym.-dichloroethane, 1,2-dichloroethane, ethylene chloride, Dutch liquid, Brocide, C1H2CCH2C1, has the molecular weight 98.97. It is a colorless liquid of pleasant odor and sweetish taste of the specific gravity 1.253 2074, solidifies at --35.3 C and boils at 83.5 C. It is soluble in 100 Determination in air According to Bogatkow (1942) ethylene dichloride may be determined in air by passing the vapor-air mixture through manganese dioxide and determining the chlorine formed nephelometrically as silver chloride. Malnikow and Ssenilow (1940) ZmBLSftZ Bibliography p. 196 188 ETHANE DERIVATIVES Ethylene dichloride 189 heated the air sample for 2 h with sodium alcoholate and deter effects become apparent. According to these authors the intra mined the chloride formed by Volhard's method. venous injection of 0.5 ml/kg causes in dogs deep narcosis, slowing of the respiration, slow and weak heart beat and loss Absorption, fate and excretion of reflexes in 8 min, the animals dying after 6 h without regaining Ethylene dichloride is absorbed through the lungs, from the consciousness. With one half this dose the narcosis lasted only gastro-intestinal tract, and, as shown by Schwander (1936) in 4 min, the animal regained consciousness in 20 min, but never mice, to a moderate extent also through the intact skin. It is theless died within 24 h. Doses of 0.125 ml/kg caused no nar not known whether it is decomposed in the organism, and cosis, but only excitement and incoordination from which the whether it is excreted by other routes than through the lungs. animals recovered. The oral administration of 0.3 ml/kg caused As to its distribution in the organism Ollivier etal. (1954) found temporary respiratory arrest and Cheyne-Stokes respiration. in a case of poisoning on a per kg organ weight basis, 140 mg As to the effect of ethylene dichloride on the circulation Fiih- in the brain, 110 mg in the kidneys, 85 mg in the liver, the same ner (1921) showed that concentrations of 0.031 moles/1 of saline amount in the lungs, only traces in the blood, and none in caused arrest of the isolated frog heart, ethylene dichloride being spleen, stomach, and intestine. in this respect inferior to chloroform and superior to ethyl chloride for which the corresponding concentrations were Determination in biological materials 0.007 and 0.046 moles/1 respectively. Similar findings were Ethylene dichloride may be determined in biological speci reported by Kiessling (1921). Kistler and Luckhardt (1929) mens by the method of Gettler and Siegel (1935) who described noted after oral administration to dogs a fall of the blood pres a special distillation apparatus and micro-rectification flask which sure proportionate to the dose, which, when not marked, re can be used satisfactorily for this purpose. turned to normal within a few minutes. Regarding the toxicity of ethylene dichloride for laboratory Effect on laboratory animals animals Muller (1925) believed it to be less toxic than chloro The effect of ethylene dichloride on laboratory animals is form and carbon tetrachloride and more toxic than methylene characterized by a depression of the central nervous system and chloride, Heppel et al. (1946) considered it as one of the more according to Muller (1925) it ranks in this respect between toxic chlorinated hydrocarbons, and Sayers et al. (1930) thought chloroform and carbon tetrachloride which was confirmed by that it is of the same order of toxicity as chloroform and carbon Lazarew (1929) who determined the narcotic concentration for: tetrachloride with exposure for 1 hour, but less toxic than these mice as 0.00021 moles/1, that for chloroform as 0.00017 and that with shorter exposures. Lazarew (1929) determined the minimal for carbon tetrachloride as 0.00032 moles/1. Similar results were; - fatal concentration with 2 h exposure for mice as 35 mg/1. reported by Lehmann and Schmidt-Kehl (1936) who noted that ;1 Sayers et al. studied its toxicity as illustrated in Table XXVII. concentrations causing light and deep narcosis are very close;: Heppel et al. (1945b) found that single exposure for 7 h to together. Kistler and Luckhardt (1929) reported that in dogs, $3,000 ppm (0.3% or 12.4 mg/1) was fatal to mice, rats, guinea narcosis is preceded by a period of marked excitement and : pigs, and rabbits, the animals showing varying degrees of nar copious salivation, that it takes 30 min for regaining conscious cosis during the exposure, increasing weakness, and dyspnea ness from full narcosis, and that with narcosis for 15 min toxic j before death, racoons and cats being somewhat more resistant. Bibliography p. 196 190 ETHANE DERIVATIVES Ethylene dichloride 191 TABLE XXVII THE TOXICITY OF ETHYLENE DICHLORIDE FOR GUINEA. PIGS (Sayers et al., 1930) Concentration (vot.%) Symptoms 10-20 6 .1 0.4- 0.6 0.35 0.12 fatal within a few min after 10 min irritation of eyes and nose, vertigo, static and motor ataxia, retching movements, semi consciousness progressing to unconsciousness, and death after 30 min the same symptoms delayed for 15-20 min dangerous to life In 30-60 min highest concentration which could be tolerated for 60 min no symptoms during 8 h exposure, no death Spencer et al. (1951) determined the toxicity for rats with single exposures as follows: LDt0: 12,000 ppm for 31.8 min; 3,000 ppm for 165 min; 1,000 ppm for 432 min LDo.od 12,000 ppm for 13.8 min; 3,000 ppm for 61.2 min; 1,000 ppm for 222 min No adverse effects: 12,000 ppm for 6 min; 3,000 ppm for 18 min; 1,000 ppm for 90 min. Animals exposed to these concentrations showed depression of the central nervous system, pulmonary irritation and injury of liver, kidneys, and adrenal glands. As to the effects of repeated exposure Heppel et al. (1946) found that 1,000 ppm were fatal to rats, guinea pigs and rabbits after a few 7 hours' exposures, dogs being somewhat more resist ant. Daily exposure for 7 h to 400 ppm was tolerated by dogs for a period of 8 months without apparent symptoms but at autopsy they showed slight fatty degeneration of the liver. With this type of exposure there were some fatalities among rats, guinea pigs, and rabbits. All animals studied tolerated repeated exposures to 100 ppm. According to Spencer et al. (1951) the maximum concentration of ethylene dichloride in air with 7 h exposure on 5 days per week for 6 months causing no adverse effects is for rabbits 400 ppm; for rats 200 ppm; and for mon keys and guinea pigs 100 ppm. Data on the toxicity of ethylene dichloride by other routes of administration are scanty. According to Highman et al. (1951), the subcutaneous injection of 1 ml/kg in young white rats is fatal to 35 % of the animals within 24 h. Wright and Schaffer (1932) found that in dogs oral doses of 3;7 ml/kg cause retching, vomiting, salivation, and marked incoordination followed by rapid recovery. McColIister et al. (1956) gave the oral LDS0 as 680 mg/kg. Barsoum and Saad (1934) gave the minimal lethal dose for dogs with oral administration as 2.5 g (3.13 ml)/kg, and with intravenous injection as 0,175 g (0.22 ml)/kg killing the animals within 30 min. They gave the minimal lethal dose for rabbits with subcutaneous injection as 1.6 g (2.98 ml)/kg, the animals dying in 24 h. One peculiar phenomenon of exposure to ethylene dichloride is cloudiness of the cornea observed in dogs and foxes as report ed by Dubois and Roux (1887), Dubois (1888), Panas (1888), and Steindorff (1922). In the opinion of Heppel et al. (1944) the basic lesion is an injury of the posterior or endothelial sur face of the cornea without evidence of histological lesions, interfering with the deturgescent state of the cornea. Following exposure to ethylene dichloride animals may show the following histo-pathological changes which vary with the intensity of the exposure. As shown by Maloff (1928), Wright and Schaffer (1932), Heppel et al. (1946), and Spencer et al. (1951) the liver may show fatty degeneration, or slight conges tion with slight parenchymatous degeneration. With moderate exposure the kidney may show signs of moderate irritation and Bibliography p. 196 192 ETHANE DERIVATIVES in more severe poisoning varying degrees of tubular damage ranging from slight parenchymatous degeneration to complete necrosis with interstitial edema, congestion and hemorrhages as reported by the same investigators. Heppel el at. (1946) saw occasionally necroses and hemorrhages in the adrenal cortex, and Wright and Schaffer (1932) and Kistler and Luckhardt (1929) noted after oral doses and after inhalation irritation of the gastro-intestinal tract and hemorrhages in the mesentery and in the mucosa of the intestine. The lungs may be congested and slightly edematous as reported by these investigators and accord ing to Heppel el at. (1946) after continuous exposure the heart may show degenerative changes in the myocardium. Heppel et at. (1945a) studied the effect of various diets on the toxic action of ethylene dichloride. They found that diets low in choline and protein (casein) increased the susceptibility, which could be corrected by addition of choline, methionine, and increase of the casein content in the diet. Animals kept on a low protein-high fat diet showed the highest incidence of hemor rhagic necroses in the adrenal cortex, premedication with pamino-benzoic acid, methionine, aniline, and sulfonamide giving some protection. Heppel et at. (1947) found that addition of /-cysteine and ^/-methionine to a low-casein-high-fat diet offered some protection which w'as not produced by addition of choline hydrochloride. Of other substances studied, addition of sodium sulfate, sodium thiosulfate, cysteic acid, and aurine, and S-benzyl-/-cystcinc had no protective effect in contrast to that of thiourea, thiouracil, 2-thiobarbituric acid, [}, p'-dithiodipropionic acid and /-cysteine hydrochloride. It appears, there fore, that the protective action is bound to the ability of such compounds to furnish sulfhydrylic groups. As shown by Highman et at. (1951) the mortality and the incidenceof fatty degen eration of heart, liver and kidneys was reduced in rats by the oral administration of methionine, BAL (2,3-dimercapto-lpropanol) and cysteine if given immediately after the subcutane ous injection of ethylene dichloride. The incidence of renal Ethylene dichloride 193 necrosis was increased by addition of methionine and adminis tration of thiourea increased the mortality rate when given immediately after the injection of ethylene dichloride. It appears, therefore, that the protective action of certain chemicals does not extend to the same degree to liver and kidneys. Toxicity for humans Intimate contact of ethylene dichloride with the skin may give rise to dermatitis as reported by Wirtschafter and Schwartz (1939). Most cases of ethylene dichloride poisoning in humans have resulted from its accidental ingestion as reported by Hueper (1935), Hueper and Smith (1935), Ienistea and Mezinesco (1943), Van Meurs (1944), Keyser (1944), Noetzel (1944), Hulst et al. (1946), Roubal (1947), Stuhlert (1949), Lochhead and Close (1951), Hubbs and Prusmack (1955), Weiss (1957), and Morozow (1958). In most instances the amount ingested was not known but the ingestion of 20 and 60 ml have resulted in death. Depending upon the amount of food in the stomach, several hours may elapse before signs and symptoms of poisoning become manifest. Sooner or later the patient becomes nau seated and vomits, this may be very persistent, the vomitus containing blood. Not infrequently this is followed by diarrhea, associated with epigastric pain and cramps. Sooner or later the patient feels dizzy, sometimes inebriated, he suffers from headache, his gait becomes staggering, and he becomes somno lent, unconscious, and later stuporous. As his condition be comes worse, the respiration becomes stridulous, rales appear over the lungs and signs of pulmonary edema may develop. If the patient is in stupor the body temperature may be lowered and the pupils are dilated and nonreactive. In delayed poisoning signs of liver injury such as jaundice and of kidney injury such as albuminuria with casts may develop. Death is due to respi ratory and/or circulatory failure and if delayed for several days to hepatic coma, and may ensue after hours, mostly after one Bibliography p. 196 194 ETHANE DERIVATIVES day and occasionally after several days. The pathological changes seen in oral poisonings consist in irritation of the gastro-intestinal tract characterized by hemor rhagic gastritis, inflammation of esophagus and duodenum and the latter may exhibit hemorrhages and contain blood exudation. The liver is hyperemic and may show fatty degeneration and diffuse necrosis and offer the picture of toxic hepatitis. The kidneys are hyperemic and may show the picture of toxic nephrosis with degeneration of the epithelium of the contorted tubules. The spleen may be hyperemic. The lungs are usually congested with small hemorrhages and may show emphyse matous, edematous, pneumonic, and atelectatic changes. The heart may be dilated to the right, show infarcts, pericardial hemorrhages, and fatty degenerative changes of the myocardium. The brain is frequently, hyperemic and edematous, it may exhibit perivascular hemorrhages and may offer the picture of meningi tis. Poisonings from inhalation of ethylene chloride, mostly of occupational character, were reported by Korelova (1937), Wirtschafter and Schwartz (1939), McNally and Fostvedt (1941), Holtzmann (1943), Baader (1950), Ollivier et ah (1954), and Menschick (1957). With the exception of the cases of Holtz mann and Menschick these were of comparatively light nature; the former's patient died after one day and the two of the latter developed liver injury, of several months' duration. Victims of ethylene dichloride poisoning from inhalation experience fatigue, become drowsy, suffer from headache, nervousness, sometimes from sleeplessness and not infrequently from tremors. They may be nauseated, suffer from anorexia and vomiting, and may lose weight. With more severe exposure the liver may be en larged and tender and this may be associated with epigastric pain. There may be a moderate leukocytosis, the heart beat may be slowed, and the blood pressure low. Some patients may exhibit nystagmus and in severe poisoning clonic-tonic convul sions have been reported. In the opinion of McCollister et ah Ethylene dichloride 195 (1956) concentrations of 200 ppm can be tolerated for 7 h, 1,000 ppm for 1 h and 3,000 ppm for 6 min without untoward effects. Treatment In case of ingestion of ethylene dichloride and if seen early the stomach should be washed and saline cathartics should be given if the condition of the patient permits. In poisoning from inhalation the victim should be transferred to fresh air, kept comfortably warm and at rest. If the respiration is impaired oxygen should be given, if necessary with artificial respiration. If the blood pressure is low, no attempts should be made to improve it by vasopressor agents such as epinephrine. In case liver injury should develop a high-protein-high-carbohydrate diet should be given. Otherwise the treatment is symptomatic and supportive. Prevention ofpoisoning Operations in which ethylene dichloride is handled should be supplied with adequate exhaust ventilation to keep its concen tration below the threshold limit value of 50 ppm (200 mg/ms) as proposed by the American Conference of Governmental Industrial Hygienists (1962). As pointed out in the Safety Data Sheet SD-18 published by the Manufacturing Chemists Asso ciation (1947), processes in which it is handled should not be located near open flames. If it is necessary to enter small en closures such as tanks, these should be washed and ventilated first and such premises should only be entered with protection by an open air or self-contained oxygen mask, together with rescue harness and lifeline and under supervision of a person familiar with first aid work. It should also be remembered that ethylene dichloride is a flammable material and may form explosive mixtures with air so that open flames or electric tools which may spark should not be used under these conditions. Bibliography p. 196